SARM1 Modulators, Their Preparation, and Uses

Abstract

Provided herein are compounds of formula (I), compositions containing same, and methods of using same, including use in the treatment of various diseases and conditions, e.g., diseases and conditions caused by axonal degeneration. JPEG2024539222000204.jpg43128

Description

[Technical field]

[0001] The present disclosure relates to compounds that modulate SARM1, compositions comprising the compounds, methods for preparing the compounds, and methods of using the compounds to treat various diseases or conditions, for example diseases or conditions caused by axonal degeneration. [Background technology]

[0002] Axonal degeneration drives disease progression and accumulating disability in many degenerative diseases of the peripheral nervous system (PNS) and central nervous system (CNS), such as multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), or in acute conditions such as traumatic brain injury. (Hughes RO, Bosanac T, Mao Rep., January 5, 2021; 34th Sense (Issue 1): Volume 108588, doi:10.1016 / j.celrep.2020.108588.PMID:33406435;PMCID:PMC8179325 )(Todd Bosanac, Robert O Hughes, Thomas Engber, Rajesh Devraj, Andrew Brearley, Kerstin. Danker, Kenneth Young, Jens Kopatz, Melanie Hermann, Antoine Berthemy, Susan Boyce, Jonathan Bentley, Raul Krauss, "Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy," Brain, 2021;awab184, https: / / doi.org / 10.1093 / brain / awab184). Axonal protection is therefore an important neuroprotective approach for the treatment of chronic and acute CNS and PNS neurodegenerative disorders.(Hughes RO、Bosanac T、Mao X、Engber TM、DiAntonio A、Milbrandt J、Devraj R、Krauss R、Small Molecule SARM1 Inhibitors Recapitulate the SARM1- / -Phenotype and Allow Recovery of a Metastable Pool of Axons Fated to Degenerate.Cell Rep. 2021, January 15, 2021; Framework 34 (figure 1):frame108588 doi:10.1016 / j.celrep.2020.108588.PMID:33406435;PMCID:PMC8179325)(Todd Bosanac, Robert O Hughes, Thomas Engber, Rajesh Devraj, Andrew Brearley, Kerstin Danker, Kenneth Young, Jens Kopatz, Melanie Hermann, Anthony Berthemy, Susan Boyce, Jonathan Bentley, Raul Krauss, Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy.

[0003] SARM1 (Sterile Alpha and TIR Motif-containing 1) is a unique member of the Myd88 family of adaptor proteins and is thought to be a key driver of an evolutionarily conserved program of axonal degeneration downstream of chemical, inflammatory, mechanical, or metabolic insults to axons. (Hughes RO, Bosanac T, Mao Rep., January 5, 2021; Volume 34 (Issue 1): Volume 108588.doi:10.1016 / j.celrep.2020.108588.PMID:33406435;PMCID:PMC8179325. )(Bosanac T, Hughes RO, Engber T, Devraj R, Brearley A, Danker. K, Young K, Kopatz J, Hermann M, Berthemy A, Boyce S, Bentley. J, Krauss R, "Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy." Brain., 8 May 2021: awab184, doi:10.1093 / brain / awab184. Online early edition (Epub ahead of print.) PMID: 33964142.SARM1 is recognized as a central mediator of axonal degeneration in numerous diseases or conditions, including ALS, Parkinson's disease, multiple sclerosis, traumatic brain injury, and diabetic neuropathy, as well as chemotherapy induced peripheral neuropathy (CIPN), which is a major cause of morbidity and a major cause of dose reductions and interruptions in cancer treatment. (Hughes RO, Bosanac T, Mao Rep., January 5, 2021; 34(1): Volume 108588.doi:10.1016 / j.celrep.2020.108588.PMID:33406435;PMCID:PMC8179325. )(Bosanac T, Hughes RO, Engber T, Devraj R, Brearley A, Danker K, Young. K, Kopatz J, Hermann M, Berthemy A, Boyce S, Bentley J, Krauss. R, "Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy." Brain., May 8, 2021: awab184, doi:10.1093 / brain / awab184. Epub ahead of print. PMID: 33964142. SARM1 is a promising target for treating neurodegeneration characterized by axonal damage in the peripheral and central nervous systems.

[0004] SARM1 contains a mitochondrial targeting sequence, an N-terminal domain with armadillo repeats (ARM), two sterile α-motif (SAM) domains, and a Toll / interleukin-1 receptor (TIR) ​​domain (Gerdts J, Summers DW, Sasaki Y, DiAntonio A, Milbrandt J, "Sarm1-mediated axon degeneration requires both SAM and TIR interactions." J Neurosci. 2014, 113:131–132. Neurosci., 2013 Aug 14; vol. 33(no. 33):13569-80, doi:10.1523 / JNEUROSCI.1197-13.2013. PMID:23946415; PMCID:PMC3742939.) The TIR domain of SARM1 is an NAD+ hydrolase (NADase) that converts NAD+ to ADPR or cADPR and NAM. (Sporny M, Guez-Haddad J, Lebendiker M, Ulisse V, Volf A, Mim C, Isupov MN, Opatowsky Y. "Structural Evidence for an Octameric Ring Arrangement of SARM1." J Mol Biol., 2019 Sep 6;431(19):3591-3605, doi:10.1016 / j.jmb.2019.06.030. Epub, 2019 Jun 3, PMID:31278906.) This NADase activity is essential for its axon degeneration function.(Bosanac T, Hughes RO, Engber T, Devraj R, Brearley A, Danker K, Young K, Kopatz J, Hermann M, Berthemy A, Boyce S, Bentley J, Krauss R, "Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy." Brain., 8 May 2021: awab184, doi:10.1093 / brain / awab184. Online early edition (Epub ahead of print.) PMID: 33964142.). SARM1 activity also depends on oligomerization formed through the SAM domain (Sporny M, Guez-Haddad J, Lebendiker M, Ulisse V, Volf A, Mim C, Isupov MN, Opatowsky Y. Structural Evidence for an Octameric Ring Arrangement of SARM1. J Mol Biol. 2019 Sep 6; 431(19):3591-3605, doi:10.1016 / j.jmb.2019.06.030. Epub 2019 Jun 3, PMID:31278906.) and is autoinhibited by the ARM domain (Shen C, Vohra M, Zhang P, Mao X, Figley MD, Zhu J, Sasaki Y, Wu H, DiAntonio A, Milbrandt J., "Multiple domain interfaces mediate SARM1 autoinhibition.", Proc Natl Acad Sci USA., January 26, 2021; Volume 118 (Issue 4): No. e2023151118, doi:10.1073 / pnas.2023151118.PMID:33468661;PMCID:PMC7848697. ).

[0005] Specific SARM1 inhibitors have been described by Bosanac et al. Brain., May 8, 2021:awab184, doi:10.1093 / brain / awab184.Epub ahead of print.PMID:33964142.), Hughes et al. (Hughes RO, Bosanac T, Mao X, Engber TM, DiAntonio A, Milbrandt J, Devraj R, Krauss R, “Small Molecule SARM1 Inhibitors Recapitulate the "SARM1- / -Phenotype and Allow Recovery of a Metastable Pool of Axons Fated to Degenerate.", Cell Rep., January 5, 2021; 34(1): Volume 108588, doi:10.1016 / j.celrep.2020.108588.PMID:33406435;PMCID:PMC8179325.), Sporny et al. (Sporny M, Guez-Haddad J, Khazma T, Yaron A, Dessau M, Shkolnisky Y, Mim C, Isupov MN, Zalk R, Hons M, Opatowsky Y., “Structural basis for SARM1 inhibition and activation under energetic stress.”, Elife., November 13, 2020; Volume 9: No. e62021, doi:10.7554 / eLife.62021.PMID:33185189;PMCID:PMC7688312.), WO 2018 / 057989(Al), WO 2020 / 081923, and WO 2021 / 142006Al. Certain dipeptidyl peptidase inhibitors (e.g., biphenyl or phenyl benzimidazole derivatives) are disclosed in U.S. Patent Application Publication No. 2005 / 0272765(A1). Certain benzylbenzoxazole derivatives as Met kinase inhibitors are disclosed in WO 2008 / 148449(A1). The present disclosure describes SARM1 inhibitors that can be used to prevent axonal degeneration in peripheral and central axonopathies and to provide transforming disease modifying treatments for these diseases or conditions. Summary of the Invention

[0006] One aspect of the present disclosure provides a compound selected from the compounds of the formula disclosed herein, its tautomers, solvates or stereoisomers of the compound or the tautomers, or pharma- ceutically acceptable salts of the foregoing, which can be employed in the treatment of various diseases or conditions, such as diseases or conditions caused by axonal degeneration. For example, disclosed herein are compounds of the following structural formula I: [ka] [In the formula, In ring A, one or two of X1, X2, X3, and X4 are N, and the remaining of X1, X2, X3, and X4 are C; Ring B is phenyl, or one or two of Y1, Y2, Y3, and Y4 in Ring B are N, and the rest of Y1, Y2, Y3, and Y4 are C; R a H, -OR s , halogen, -NR p R q , C3-C6 cycloalkyl, CN, and C1-C6 alkyl; R a C3-C6 cycloalkyl and C1-C6 alkyl are halogen, -OR s , and -NRp R q and optionally substituted with 1 to 3 groups selected from R c are H, CN, -S(=O) w NR p1 R q1 , -OR s , halogen, -NR p1 R q1 , and halogens, -OR s , and -NR p1 R q1 C1-C6 alkyl optionally substituted with 1 to 3 groups selected from c is not CH2OH; R b is absent or is H, halogen, -C(=O)(C1-C6 alkyl), -NR p1 R q1 , -OR s , and halogens, -OR s , and -NR p1 R q1 C1-C6 alkyl optionally substituted with 1-3 groups selected from; R d is absent or H, CN, -S(=O) w NR p1 R q1 , -OR s , halogen, -NR p1 R q1 , C3-C6 cycloalkyl, halogen, -OR s , and -NR p1 R q1 C1-C6 alkyl optionally substituted with 1 to 3 groups selected from d is not CH2OH; R b and R c may be taken together to form an optionally substituted 5- to 7-membered heterocyclic or aromatic heterocyclic ring; R b and R d may be taken together to form an optionally substituted 5- to 7-membered heterocyclic or aromatic heterocyclic ring; Re H, halogen, -CN, halogen, -OR s , and -NR p1 R q1 C1-C6 alkyl optionally substituted with 1-3 groups selected from; R s is independently selected at each occurrence from H, phenyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, and C1-C6 alkyl; s wherein the phenyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, and C1-C6 alkyl are each optionally substituted with 1-3 groups selected from halogen, -OH, and -O(C1-C3 alkyl); R p and R q is independently selected at each occurrence from hydrogen, phenyl, 9-10 membered aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, and C1-C4 alkyl; p and R q wherein the phenyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, and C1-C4 alkyl are each optionally substituted with 1-3 groups selected from -COO(C1-C4 alkyl), halogen, -OH, -CN, -COOH, -CONH2, -CONH(C1-C3 alkyl), -NH(C1-C3 alkyl), -O(C1-C3 alkyl), and C1-C4 alkyl; R p1 and R q1 is independently selected at each occurrence from hydrogen, -CO(C1-C6 alkyl), -SO2CH3, C3-C6 cycloalkyl, and C1-C6 alkyl; p1 and R q1 C3-C6 cycloalkyl and C1-C6 alkyl are each optionally substituted with 1 to 3 halogens; m is an integer independently selected from 0, 1, 2, and 3; n is an integer independently selected from 0, 1, and 2; and w is an integer selected from 1 and 2, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0007] In one aspect of the disclosure, the compound of the formula disclosed herein is selected from compounds 1-120 shown below, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0008] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the formula disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical composition may comprise a compound selected from compounds 1-120 shown below, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, and a pharma- ceutically acceptable carrier. These compositions may further comprise an additional active pharmaceutical agent.

[0009] Another aspect of the present disclosure provides a method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formulae disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing, wherein the disease or condition is selected from amyotrophic lateral sclerosis (ALS), Parkinson's disease, parkinsonism, ischemia, stroke, herpes infection, demyelinating diseases such as multiple sclerosis, traumatic brain injury, sepsis, and chronic diseases of the PNS include inherited neuropathies, but are not limited to, Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy (CIDP), optic neuropathies such as glaucoma and retinal ganglion degeneration, colitis, metabolic diseases or disorders such as diabetic neuropathy, nonalcoholic fatty liver disease, and the like. These include, but are not limited to, peripheral neuropathy such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), as well as CIPN induced by various drugs.

[0010] A further aspect of the present disclosure provides a method for treating a disease or condition caused by axonal degeneration or neuronal damage mediated by SARM1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formulae disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0011] In some embodiments, the method of treatment comprises administering to a subject in need thereof a compound selected from compounds 1-120 shown below, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0012] In some embodiments, the method of treatment comprises administering to a subject in need thereof an additional active pharmaceutical agent, either in the same pharmaceutical composition as a compound of the formula disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, or in a separate composition. In some embodiments, the method of treatment comprises administering a compound selected from compounds 1-120 shown below, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, together with the additional active pharmaceutical agent, either in the same pharmaceutical composition or in a separate composition. When administered as a separate composition, the additional therapeutic agent may be administered prior to, simultaneously with, or after administration of a compound, tautomer, solvate, stereoisomer, or pharma- ceutically acceptable salt of the presently disclosed compound.

[0013] Also disclosed herein is a method of modulating, e.g., inhibiting, SARM1 in a subject in need thereof, comprising contacting the subject with a compound of the formula disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of modulating, e.g., inhibiting, SARM1 in a subject in need thereof comprises contacting the subject with a compound selected from compounds 1-120 shown below, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0014] Also disclosed herein is a method of inhibiting or preventing axonal degeneration in a subject in need thereof, comprising contacting the subject with a compound of the formulas disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of inhibiting or preventing axonal degeneration or SARM1-mediated neuronal injury in a subject in need thereof comprises contacting the subject with a compound selected from compounds 1-120 shown below, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] I. Definition The terms "a" or "an" when used herein to refer to a noun include the phrase "at least one," and thus include both the singular and plural units of the noun. For example, "an additional pharmaceutical agent" means a single or two or more additional pharmaceutical agents.

[0016] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched-chain saturated hydrocarbon groups containing 1 to 20, e.g., 1 to 18, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkyl groups include methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), and 1,1-dimethylethyl or t-butyl ("t-Bu"). Other examples of alkyl groups include 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl. Lower alkyl groups contain 1 to 8, preferably 1 to 6, more preferably 1 to 4, and more preferably 1 to 3 carbon atoms.

[0017] The term "alkenyl" refers to a hydrocarbon group selected from linear and branched chain hydrocarbon groups containing at least one C=C double bond and 2 to 20, e.g., 2 to 18, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl groups may be selected from ethenyl or vinyl groups, prop-1-enyl groups, prop-2-enyl groups, 2-methylprop-1-enyl groups, but-1-enyl groups, but-2-enyl groups, but-3-enyl groups, buta-1,3-dienyl groups, 2-methylbuta-1,3-diene groups, hex-1-enyl groups, hex-2-enyl groups, hex-3-enyl groups, hex-4-enyl groups, and hex-1,3-dienyl groups. A lower alkenyl contains 2 to 8, preferably 2 to 6, and more preferably 2 to 4 carbon atoms.

[0018] The term "alkynyl" refers to at least one [ka] It refers to a hydrocarbon group selected from linear and branched chain hydrocarbon groups containing a triple bond and 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, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl. Lower alkynyl contains 2 to 8, preferably 2 to 6, and more preferably 2 to 4 carbon atoms.

[0019] The term "heteroalkyl" refers to an alkyl group, as defined herein, in which one or more of the member carbon atoms has been replaced with a heteroatom, e.g., nitrogen, oxygen, or sulfur, e.g., CH3CH2OH, CH3CH2OC2H5, CH3CH2SH, CH3CH2SC2H5, CH3CH2NH2, CH3CH2NHC2H5. In some embodiments, in addition to replacement of one or more of the member carbon atoms with nitrogen, oxygen, or sulfur, a heteroalkyl group is optionally further substituted as defined herein.

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

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

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

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

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

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

[0026] As used herein, the term "unsaturated" means that a moiety has one or more units or degrees of unsaturation. Unsaturation is a situation in which not all of the available valence bonds in a compound are satisfied by substituents, thus causing the compound to contain one or more double or triple bonds.

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

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

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

[0030] 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. A "non-aromatic" ring refers to a carbocyclic or heterocyclic ring that does not meet the requirements set forth above for an aromatic ring, and may be either fully or partially saturated. Non-limiting examples of aromatic rings include aryl and heteroaryl rings, which are further defined as follows. An "aromatic ring" refers to a carbocyclic or heterocyclic ring that is: [ka] It may also be depicted as a ring with conjugated double bonds, such as [ka] It is sometimes depicted as a ring with a circle inside, such as:

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

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

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

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

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

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

[0037] The term "acyl" refers to a substituent where the point of attachment 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'' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, any of which may be further substituted with one or more substituents.

[0038] Some compounds exist that have different points of attachment of hydrogen, called "tautomers." For example, a compound that contains a carbonyl -CH2C(O)- group (keto form) may tautomerize to form a hydroxyl -CH=C(OH)- group (enol form). Both the keto and enol forms, either alone or in mixtures, are intended to be included where applicable.

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

[0040] Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction 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.

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

[0042] The term "substantially pure" in the context of stereoisomers means that the stereoisomer of interest contains 35% by weight or less, such as 30% by weight or less, further such as 25% by weight or less, and even further such as 20% by weight or less of any other stereoisomer. In some embodiments, the term "substantially pure" means that the stereoisomer of interest contains 10% by weight or less, such as 5% by weight or less, such as 1% by weight or less of any other stereoisomer.

[0043] Unless otherwise indicated, the structures depicted herein are meant to include all isomeric forms of the structures, such as racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the compounds disclosed herein are within the scope of the disclosure. Unless otherwise indicated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

[0044] The disclosure provides pharma- ceutically acceptable salts of the disclosed compounds, tautomers, solvates, and stereoisomers. A salt of a compound is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0045] As used herein, the term "pharmaceutical acceptable" refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. A "pharmaceutical acceptable salt" means any non-toxic salt that is capable of providing, either directly or indirectly, a compound of the present disclosure upon administration to a recipient.

[0046] "Pharmaceutically acceptable salts" include, for example, salts with inorganic acids selected from hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, and nitrates; as well as alkanoates, such as, for example, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, acetates, and HOOC-(CH2) n-COOH, n is selected from 0 to 4. Similarly, examples of pharma- ceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, magnesium, aluminum, lithium, and ammonium. Suitable pharma-ceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, pp. 1-19.

[0047] Acids commonly used to form pharma- ceutically acceptable salts include inorganic acids (e.g., hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid), as well as organic acids (e.g., para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid). Accordingly, such pharma- ceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate (i.e., caprate), caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4, butyrate-2,5, butyrate-3,5, butyrate-4,5, butyrate-5,5, butyrate-6,5, butyrate-7,5, butyrate-8,5, butyrate-9,5, butyrate-10,5, butyrate-11,5, -diacid, hexyne-1,6-dioic acid, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In some embodiments, pharma- ceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0048] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N +(C1-C4 alkyl)4 salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Further non-limiting examples of pharmaceutically acceptable salts include salts of ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0049] If a compound is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is a free base, an addition salt, such as a pharma- ceutically 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 a variety of synthetic methodologies that can be used without undue experimentation to prepare non-toxic pharma-ceutically acceptable addition salts.

[0050] The compounds, tautomers, solvates, stereoisomers, and pharma- ceutically acceptable salts of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, -CD3, -CD2H, or -CDH2 contain one or more deuterium atoms in place of hydrogen. For example, the compounds may contain radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 C) can be radioactively labeled. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0051] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted" refers to the replacement of a hydrogen radical in a given structure with a group of a specified substituent. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at all positions. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.

[0052] In some embodiments, the substituents are optionally substituted heteroatoms and optionally substituted, optionally hetero-, optionally cyclic C-C 18 Independently selected from hydrocarbyls, in particular optionally substituted, optionally hetero-, optionally cyclic C-C 18 The hydrocarbyl is an optionally substituted, optionally hetero-, optionally cyclic alkyl, alkenyl or alkynyl, or an optionally substituted, optionally hetero-, optionally aryl; and / or the optionally substituted heteroatom is halogen, optionally substituted hydroxyl (alkoxy, aryloxy, etc.), optionally substituted acyl (formyl, alkanoyl, carbamoyl, carboxyl, amido, etc.), optionally substituted amino (amino, alkylamino, dialkylamino, amido, sulfamidyl, etc.), optionally substituted thiol (mercapto, alkylthiol, arylthiol, etc.), optionally substituted sulfinyl or sulfonyl (alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, etc.), nitro, or cyano.

[0053] In some embodiments, the substituents are selected from the group consisting of halogen, -R', -OR', =O, =NR', =N-OR', -NR'R'', -SR', -SiR'R''R''', -OC(=O)R', -C(=O)R', -COR', -C(=O)NR'R'', -OC(=O)NR'R'', -NR''C(=O)R', -NR'-C(=O)NR''R''', -NR'-SONR''R''', -N Particularly preferred are groups having 0, 1 or 2 substituents independently selected from R″CO2R′, —NH—C(NH2)═NH, —NR′C(NH2)═NH, —NH—C(NH2)═NR′, —S(O)R′, —S2R′, —SO2NR′R″, —NR″S2R, —CN, —NO2, —N3, —CH(Ph)2, perfluoro(C1-C4 alkoxy, and perfluoro(C1-C4)alkyl. R' and R''' each independently represent hydrogen, unsubstituted C1-C8 alkyl and heteroalkyl, C1-C8 alkyl and heteroalkyl substituted with 1-3 halogens, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C1-C4)alkyl groups. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. Thus, -NR'R'' includes 1-pyrrolidinyl and 4-morpholinyl. When the aryl group is 1,2,3,4-tetrahydronaphthalenyl, it may be substituted with a substituted or unsubstituted C3-C7 spirocycloalkyl group. The C3-C7 spirocycloalkyl group may be substituted in the same manner as defined herein for "cycloalkyl". In some embodiments, the substituents are selected from halogen, -R', -OR', =O, -NR'R'', -SR', -SiR'R''R''', -OC(=O)R', -C(=O)R', -COR', -C(=O)NR'R'', -OC(=O)NR'R'', -NR''C(=O)R', -NR''COR', -NR'-SONR''R'''', -S(=O)R', -SOR', -SONR'R'', -NR''SOR, -CN, -NO, perfluoroC1-C4 alkoxy, and perfluoroC1-C4 alkyl, where R' and R'' are as defined above.

[0054] In some embodiments, the substituents are a substituted or unsubstituted heteroatom, a substituted or unsubstituted C1-C6 alkyl containing 0-3 heteroatoms (e.g., C1-C3 alkyl or C1-C2 alkyl), a substituted or unsubstituted C2-C6 alkenyl containing 0-3 heteroatoms (e.g., C2-C4 alkenyl), a substituted or unsubstituted C2-C6 alkynyl containing 0-3 heteroatoms (e.g., C2-C4 alkynyl), or a substituted or unsubstituted C6-C7 alkyl group containing 0-3 heteroatoms (e.g., C6-C7 alkyl). 14 aryl (eg, C5-C6 aryl), and each heteroatom is independently oxygen, phosphorus, sulfur, or nitrogen.

[0055] In some embodiments, the substituents are independently selected from aldehyde groups, aldimine groups, alkanoyloxy groups, alkoxy groups, alkoxycarbonyl groups, alkyloxy groups, alkyl groups, alkenyl groups, alkynyl groups, amine groups, azo groups, halogen groups, carbamoyl groups, carbonyl groups, carboxamide groups, carboxyl groups, cyanyl groups, ester groups, haloformyl groups, hydroperoxyl groups, hydroxyl groups, imine groups, isocyanide groups, isocyanate groups, N-tert-butoxycarbonyl groups, nitrate groups, nitrile groups, nitrite groups, nitro groups, nitroso groups, phosphate groups, phosphono groups, sulfide groups, sulfonyl groups, sulfo groups, sulfhydryl groups, thiol groups, thiocyanyl groups, trifluoromethyl groups, and trifluoromethyl ether groups (OCF3).

[0056] Preferred substituents are disclosed herein and illustrated in the tables, structures, examples, and claims, and may be applicable across different compounds of the disclosure, for example, the substituents of a given compound may be used in combination with other compounds.

[0057] It may be advantageous to separate reaction products from each other and / or from starting materials. The desired products of each step or sequence of steps are separated and / or purified (hereinafter, separated) to the desired degree of homogeneity by techniques common in the art. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may involve any of a number of methods, such as, for example, reverse and normal phase; size exclusion; ion exchange; high-, medium-, and low-pressure liquid chromatography methods and equipment; small-scale analysis; simulated moving bed ("SMB") and preparative thin-layer or thick-layer chromatography, as well as small-scale thin-layer and flash chromatography techniques. Those skilled in the art can apply such techniques to achieve the desired separation.

[0058] Non-limiting examples of suitable solvents that may be used in the present disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or methylene chloride (CHCl), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethylsulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl-tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0059] 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).

[0060] The term "subject" refers to animals, including humans.

[0061] The term "therapeutically effective amount" refers to the amount of a compound for which it is administered that produces the desired effect (e.g., amelioration of 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). The disease or condition may be caused by axonal degeneration. The exact amount of a therapeutically effective amount will depend on the purpose of the treatment and may be ascertained by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0062] As used herein, the term "treatment" and its synonyms refer to slowing or stopping disease progression. As used herein, "treatment" and its synonyms include, but are not limited to, the following: complete or partial remission, cure, or reduction of the risk of disease or condition, of a disease or condition or its symptoms, such as ALS, Parkinson's disease, multiple sclerosis, traumatic brain injury, diabetic neuropathy, and CIPN. The disease or condition may be caused by axonal degeneration. The improvement or reduction of the severity of any of these symptoms can be evaluated according to methods and techniques known in the art.

[0063] The terms "about" and "approximately," when used in connection with numbers, such as percentages, include the specified number and a range of numbers recognized by one of ordinary skill in the art (e.g., a percentage range, e.g., a range of ±10% for a particular point value).

[0064] II. Compounds and Compositions In a first embodiment, the compounds of the present disclosure have the following structural formula I: [ka] [In the formula, In ring A, one or two of X1, X2, X3, and X4 are N, and the remaining of X1, X2, X3, and X4 are C; Ring B is phenyl, or one or two of Y1, Y2, Y3, and Y4 in Ring B are N, and the rest of Y1, Y2, Y3, and Y4 are C; R a H, -OR s , halogen, -NR p R q , C3-C6 cycloalkyl, CN, and C1-C6 alkyl; R a C3-C6 cycloalkyl and C1-C6 alkyl are halogen, -OR s , and -NR p R q and optionally substituted with 1 to 3 groups selected from R c are H, CN, -S(=O) w NR p1 R q1 , -OR s , halogen, -NR p1 R q1 , and halogens, -OR s , and -NR p1 R q1 C1-C6 alkyl optionally substituted with 1 to 3 groups selected from c is not CH2OH; R b is absent or is H, halogen, -C(=O)(C1-C6 alkyl), -NRp1 R q1 , -OR s , and halogens, -OR s , and -NR p1 R q1 C1-C6 alkyl optionally substituted with 1-3 groups selected from; R d is absent or H, CN, -S(=O) w NR p1 R q1 , -OR s , halogen, -NR p1 R q1 , C3-C6 cycloalkyl, halogen, -OR s , and -NR p1 R q1 C1-C6 alkyl optionally substituted with 1 to 3 groups selected from d is not CH2OH; R b and R c may be taken together to form an optionally substituted 5- to 7-membered heterocyclic or aromatic heterocyclic ring; R b and R d may be taken together to form an optionally substituted 5- to 7-membered heterocyclic or aromatic heterocyclic ring; R e H, halogen, -CN, halogen, -OR s , and -NR p1 R q1 C1-C6 alkyl optionally substituted with 1-3 groups selected from; R s is independently selected at each occurrence from H, phenyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, and C1-C6 alkyl; s wherein the phenyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, and C1-C6 alkyl are each optionally substituted with 1-3 groups selected from halogen, -OH, and -O(C1-C3 alkyl); R p and R qis independently selected from hydrogen, phenyl, 9-10 membered aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, and C1-C4, each occurrence of R p and R q wherein the phenyl, 9-10 membered aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, and C1-C4 alkyl are each optionally substituted with 1-3 groups selected from -COO(C1-C4 alkyl), halogen, -OH, -CN, -COOH, -CONH2, -CONH(C1-C3 alkyl), -NH(C1-C3 alkyl), -O(C1-C3 alkyl), and C1-C4 alkyl; R p1 and R q1 is independently selected at each occurrence from hydrogen, -CO(C1-C6 alkyl), -SO2CH3, C3-C6 cycloalkyl, and C1-C6 alkyl; p1 and R q1 C3-C6 cycloalkyl and C1-C6 alkyl are each optionally substituted with 1 to 3 halogens; m is an integer independently selected from 0, 1, 2, and 3; n is an integer independently selected from 0, 1, and 2; and w is an integer selected from 1 and 2, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0065] Combinations of substituents disclosed herein are those that result in the formation of stable or chemically feasible compounds. In the case of abbreviations or by convention, specific hydrogen atoms bonded to specific atoms (e.g., carbon atom C or nitrogen atom N) are not specifically shown in the chemical structures, formulas, or symbols; the hydrogen atoms are considered to be present to the extent that the valence of the specific atom (e.g., C or N) is satisfied.

[0066] In a second embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer of the present disclosure, or a pharma- ceutically acceptable salt of the present disclosure, Ring A is a pyridinyl group, a pyrimidinyl group, or a pyridazinyl group; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0067] In a third embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or a pharma- ceutically acceptable salt of the present disclosure, ring B is a phenyl group or a pyridinyl group (one of Y1, Y2, Y3, and Y4 is N, and the rest of Y1, Y2, Y3, and Y4 are C). All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0068] In a fourth embodiment, the compound of the present disclosure has the following structural formula IIa: [ka] or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0069] In a fifth embodiment, the compound of the present disclosure has the following structural formula IIb: [ka] or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0070] In a sixth embodiment, the compound of the present disclosure has the following structural formula IIc: [ka] or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0071] In a seventh embodiment, the compound of the present disclosure has the following structural formula IId: [ka] or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0072] In an eighth embodiment, the compound of the present disclosure has the following structural formula IIIa: [ka] or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0073] In a ninth embodiment, the compound of the present disclosure has the following structural formula IIIb: [ka] or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0074] In a tenth embodiment, the compound of the present disclosure has the following structural formula IIIc: [ka] or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0075] In an eleventh embodiment, the compound of the present disclosure has the following structural formula IIId: [ka] or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0076] In a twelfth embodiment, the compound of the present disclosure has the following structural formula IIIe: [ka] or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0077] In a thirteenth embodiment, the compound of the present disclosure has the following structural formula IIIf: [ka] wherein W1 and W2 are each independently selected from NH and O; If W1 is O, then R c’ is selected from H, C3-C6 cycloalkyl, and C1-C6 alkyl, c’ wherein the C3-C6 cycloalkyl and the C1-C6 alkyl are each optionally substituted with 1-3 groups selected from halogen, -OH, and -O(C1-C3 alkyl); When W1 is NH, R c’ is selected from hydrogen, -CO(C1-C6 alkyl), -SO2CH3, C3-C6 cycloalkyl, and C1-C6 alkyl; R c’ C3-C6 cycloalkyl and C1-C6 alkyl are each optionally substituted with 1 to 3 halogens; If W2 is O, then R b’ is selected from H, C3-C6 cycloalkyl, and C1-C6 alkyl, s wherein the C3-C6 cycloalkyl and the C1-C6 alkyl are each optionally substituted with 1-3 groups selected from halogen, -OH, and -O(C1-C3 alkyl); When W2 is NH, R b’ is selected from hydrogen, -CO(C1-C6 alkyl), -SO2CH3, C3-C6 cycloalkyl, and C1-C6 alkyl; R b’ wherein C3-C6 cycloalkyl and C1-C6 alkyl are each optionally substituted with 1-3 halogens, or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of any of the foregoing; All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0078] In a fourteenth embodiment, the compound of the present disclosure has the following structural formula IVa: [ka] [In the formula, R b and R c are taken together to form an optionally substituted 5- to 7-membered heterocyclic or aromatic heterocyclic ring, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0079] In a fifteenth embodiment, the compound of the present disclosure has the following structural formula IVb: [ka] [In the formula, R b and R c are taken together to form an optionally substituted 5- to 7-membered heterocyclic or aromatic heterocyclic ring, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0080] In a sixteenth embodiment, the compound of the present disclosure has the following structural formula IVc: [ka] [In the formula, R b and R c are taken together to form an optionally substituted 5- to 7-membered heterocyclic or aromatic heterocyclic ring, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0081] In a seventeenth embodiment, the compound of the present disclosure has the following structural formula IVd: [ka] [In the formula, R b and R c are taken together to form an optionally substituted 5- to 7-membered heterocyclic or aromatic heterocyclic ring, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0082] In an eighteenth embodiment, the compound of the present disclosure has the following structural formula Va: [ka] [In the formula, R a is C1-C3 alkyl, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0083] In a nineteenth embodiment, the compound of the present disclosure has the following structural formula VIa: [ka] [In the formula, R c -OR s or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0084] In a twentieth embodiment, the compound of the present disclosure has the following structural formula VIb: [ka] [In the formula, R b -OR s or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0085] In a twenty-first embodiment, the compound of the present disclosure has the following structural formula VIc: [ka] [In the formula, R b -OR s ;R c is halogen, -OR s and C1-C3 alkyl, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0086] In a twenty-second embodiment, the compound of the present disclosure has the following structural formula VId: [ka] [In the formula, R c -OR s ;R e is selected from halogen, a tautomer thereof, a solvate or stereoisomer of the compound or of the tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0087] In a twenty-third embodiment, the compound of the present disclosure has the following structural formula VIe: [ka] [In the formula, R c and R d are respectively -OR s and halogen], a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0088] In a twenty-fourth embodiment, the compound of the present disclosure has the following structural formula VIf: [ka] [In the formula, R c -OR s and halogen], a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0089] In a twenty-fifth embodiment, the compound of the present disclosure has the following structural formula VIIa: [ka] [In the formula, R a H, -OR s , halogen, -NR p R q , C3-C6 cycloalkyl, CN, halogen, -OR s , and -NR p R q R is selected from C1-C6 alkyl optionally substituted with 1 to 3 groups selected from p and R qis independently selected from hydrogen, C1-C3 alkyl, phenyl, 9-10 membered aryl, and 5-10 membered heteroaryl, each occurrence of R p and R q The phenyl, 9-10 membered aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 groups selected from -COO(C1-C4 alkyl), halogen, OH, -CN, -COOH, -CONH2, -CONH(C1-C3 alkyl), -NH(C1-C3 alkyl), -O(C1-C3 alkyl), and C1-C4 alkyl; R f is selected from halogen, C1-C4 alkyl, C2-C4 alkynyl, and CN, and p is an integer selected from 0, 1, and 2; one, two, or three of Z1, Z2, and Z3 are N, and if one or two of Z1, Z2, and Z3 are N, then the remainder of Z1, Z2, and Z3 are C, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharma- ceutically acceptable salt of the foregoing; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0090] In a twenty-sixth embodiment, the compound of the present disclosure has the following structural formula VIIb: [ka] [In the formula, R a H, -OR s , halogen, -NR p R q , C3-C6 cycloalkyl, CN, halogen, -OR s , and -NR p R q R is selected from C1-C6 alkyl optionally substituted with 1 to 3 groups selected from p and R q is independently selected from hydrogen, C1-C3 alkyl, phenyl, 9-10 membered aryl, and 5-10 membered heteroaryl, each occurrence of R p and R qThe phenyl, 9-10 membered aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 groups selected from -COO(C1-C4 alkyl), halogen, OH, -CN, -COOH, -CONH2, -CONH(C1-C3 alkyl), -NH(C1-C3 alkyl), -O(C1-C3 alkyl), and C1-C4 alkyl; R f is selected from halogen, C1-C4 alkyl, C2-C4 alkynyl, and =O, and p is an integer selected from 0, 1, and 2; Z2 and Z3 are each independently selected from O, N, S, and C, and at least one of Z2 and Z3 is a heteroatom; D is selected from O, S, and NH; and one or two of X1 and X2 are N], a tautomer thereof, a solvate or stereoisomer of the compound or of the tautomer, or a pharma- ceutically acceptable salt of the foregoing; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0091] In a twenty-seventh embodiment, the compound of the present disclosure has the following structural formula VIIc: [ka] [In the formula, R a H, -OR s , halogen, -NR p R q , C3-C6 cycloalkyl, CN, halogen, -OR s , and -NR p R q R is selected from C1-C6 alkyl optionally substituted with 1 to 3 groups selected from p and R q is independently selected from hydrogen, C1-C3 alkyl, phenyl, 9-10 membered aryl, and 5-10 membered heteroaryl, each occurrence of R p and R qThe phenyl, 9-10 membered aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 groups selected from -COO(C1-C4 alkyl), halogen, OH, -CN, -COOH, -CONH2, -CONH(C1-C3 alkyl), -NH(C1-C3 alkyl), -O(C1-C3 alkyl), and C1-C4 alkyl; R f is selected from halogen, C1-C4 alkyl, C2-C4 alkynyl, and =O, and p is an integer selected from 0, 1, and 2; Z2 and Z3 are each independently selected from O, N, S, and C, and at least one of Z2 and Z3 is a heteroatom; D is selected from O, S, and NH; and one or two of X1 and X2 are N], a tautomer thereof, a solvate or stereoisomer of the compound or of the tautomer, or a pharma- ceutically acceptable salt of the foregoing; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0092] In a twenty-eighth embodiment, the compound of the present disclosure has the following structural formula VIIc: [ka] [In the formula, R a H, -OR s , halogen, -NR p R q , C3-C6 cycloalkyl, CN, halogen, -OR s , and -NR p R q R is selected from C1-C6 alkyl optionally substituted with 1 to 3 groups selected from p and R q is independently selected from hydrogen, C1-C3 alkyl, phenyl, 9-10 membered aryl, and 5-10 membered heteroaryl, each occurrence of R p and R qThe phenyl, 9-10 membered aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 groups selected from -COO(C1-C4 alkyl), halogen, OH, -CN, -COOH, -CONH2, -CONH(C1-C3 alkyl), -NH(C1-C3 alkyl), -O(C1-C3 alkyl), and C1-C4 alkyl; R f is selected from halogen, C1-C4 alkyl, C2-C4 alkynyl, and =O, and p is an integer selected from 0, 1, and 2; Z1 and Z2 are each independently selected from O, N, S, and C, and at least one of Z1 and Z2 is a heteroatom; D is selected from O, NH, and S; and one or two of X1 and X2 are N, a tautomer thereof, a solvate or stereoisomer of the compound or of the tautomer, or a pharma- ceutically acceptable salt of the foregoing; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0093] In a twenty-ninth embodiment, the compound of the present disclosure has the following structural formula VIIe: [ka] [Wherein, halogen, -OR s , and -NR p R q H, -OR s , halogen, -NR p R q , C3-C6 cycloalkyl, CN, and C1-C6 alkyl, R p and R q each occurrence is independently selected from hydrogen, C1-C3 alkyl, phenyl, 9-10 membered aryl, 5-10 membered heteroaryl; R p and R qThe phenyl, 9-10 membered aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 groups selected from -COO(C1-C4 alkyl), halogen, OH, -CN, -COOH, -CONH2, -CONH(C1-C3 alkyl), -NH(C1-C3 alkyl), -O(C1-C3 alkyl), and C1-C4 alkyl; R f is selected from halogen, C1-C4 alkyl, C2-C4 alkynyl, and =O, and p is an integer selected from 0, 1, and 2; Z1 and Z2 are each independently selected from O, N, S, and C, and at least one of Z1 and Z2 is a heteroatom; D is selected from O, NH, and S; and one or two of X1 and X2 are N, a tautomer thereof, a solvate or stereoisomer of the compound or of the tautomer, or a pharma- ceutically acceptable salt of the foregoing; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0094] In a thirtieth embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharma- ceutical acceptable salt of the disclosure, R a H, -OR s , halogen, -NR p R q , C3-C6 cycloalkyl, CN, halogen, -OR s , and -NR p R q R is selected from C1-C6 alkyl optionally substituted with 1 to 3 groups selected from s is independently selected at each occurrence from H, phenyl, -CFH2, -CF2H, -CF3, and C1-C3 alkyl; R p and R q is independently selected from hydrogen, C1-C3 alkyl, phenyl, 9-10 membered aryl, and 5-10 membered heteroaryl, each occurrence of R p and R qthe phenyl, 9-10 membered aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 groups selected from -COO(C1-C4 alkyl), halogen, OH, -CN, -COOH, -CONH2, -CONH(C1-C3 alkyl), -NH(C1-C3 alkyl), -O(C1-C3 alkyl), and C1-C4 alkyl; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0095] In a thirty-first embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharma- ceutical acceptable salt of the disclosure, R a are H, -CH3, -CH2CH3, -OCFH2, -OCF2H, -OCF3, -OCH3, CN, Cl, OH, NH2, -NHCH3, and [ka] all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0096] In a thirty-second embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharma- ceutical acceptable salt of the disclosure, R b is absent or is H, halogen, -C(=O)(C1-C3 alkyl), -NR p1 R q1 , -OR s and halogen and -NR p1 R q1 R is selected from optionally substituted C1-C3 alkyl substituted with 1 to 2 groups selected from s is independently selected at each occurrence from H, -CF, -CFH, and C-C alkyl; R p1 and R q1is independently selected at each occurrence from hydrogen and optionally substituted C1-C3 alkyl; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0097] In a thirty-third embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharma- ceutical acceptable salt of the disclosure, R b is H, methyl, CH2NH2, -C(=O)CH3, NH2, F, Br, OH, and [ka] all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0098] In a thirty-fourth embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharma- ceutical acceptable salt of the disclosure, R c are H, CN, -S(=O) w NR p R q , -OR s , halogen, -NR p1 R q1 and halogen and -NR p1 R q1 R is selected from C1-C3 alkyl optionally substituted with 1 to 3 groups selected from s is independently selected at each occurrence from H and C1-C3 alkyl; R p1 and R q1 is, at each occurrence, independently selected from hydrogen and C1-C3 alkyl; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0099] In a thirty-fifth embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharma- ceutical acceptable salt of the disclosure, Rc is selected from H, methyl, ethyl, CHF2, CF3, F, Cl, Br, NH2, OH, OCH3, CN, and -S(=O)2NH2; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0100] In a thirty-sixth embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharma- ceutical acceptable salt of the disclosure, R d are H, CN, -S(=O) w NR p R q , -OR s , halogen, -NR p1 R q1 and halogen and -NR p1 R q1 R is selected from C1-C3 alkyl optionally substituted with 1 to 3 groups selected from s is independently selected at each occurrence from H and C1-C3 alkyl; R p1 and R q1 is, at each occurrence, independently selected from hydrogen and C1-C3 alkyl; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0101] In a thirty-seventh embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharma- ceutical acceptable salt of the disclosure, R d is selected from H, methyl, ethyl, CHF2, CF3, F, Cl, Br, NH2, OH, OCH3, CN, and -S(=O)2NH2; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0102] In a thirty-eighth embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharma- ceutical acceptable salt of the disclosure, R eis selected from H, halogen, and C1-C3 alkyl optionally substituted with 1-3 groups selected from halogen and -NH2; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0103] In a thirty-ninth embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharma- ceutical acceptable salt of the disclosure, R e is selected from H, methyl, F, and Cl; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0104] In a fortieth embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharma- ceutical acceptable salt of the disclosure, R b and R c , or R b and R d taken together, represent CN, halogen, =O, =S, =NH, halogen and -NR p R q and R p and R q is independently selected at each occurrence from hydrogen, C1-C3 alkyl, and -C(=O)C1-C3 alkyl; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0105] In a forty-first embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharma- ceutical acceptable salt of the disclosure, R b and R c , or R b and R d Put together, the following: [ka] all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0106] In a forty-second embodiment, the compound of the present disclosure has the following structural formula VIIa: [ka] [In the formula, R g is selected from C1-C3 alkyl, CN, OH, -O(C1-C3 alkyl), -NH(C1-C3 alkyl), halogen, and q is an integer selected from 0, 1, and 2; Z1 and Z2 are each independently selected from O, NH, S, and CH2, and at least one of Z2 and Z3 is a heteroatom; D is selected from O and S; one or two of X1 and X2 are N; U is C or N; and W3 is O or NH, or a tautomer thereof, a solvate or stereoisomer of the compound or of the tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0107] In certain embodiments, at least one compound of the present disclosure is selected from compounds 1-120 depicted in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0108] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0109] Another aspect of the present disclosure provides pharmaceutical compositions comprising at least one compound selected from the compounds of the formulae disclosed herein, compounds 1-120, tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, and at least one pharma- ceutically acceptable carrier.

[0110] In some embodiments, the pharma- ceutically acceptable carrier is selected from a pharma- ceutically acceptable vehicle and a pharma- ceutically acceptable adjuvant, hi some embodiments, the pharma- ceutically acceptable carrier is selected from a pharma- ceutically acceptable filler, disintegrant, surfactant, binder, and lubricant.

[0111] It will also be understood that the pharmaceutical compositions of the present disclosure can be used in combination therapy: that is, the pharmaceutical compositions described herein can further comprise an additional active pharmaceutical agent. Alternatively, a pharmaceutical composition comprising a compound selected from the compounds of the formulas disclosed herein, compounds 1-120, tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, can be administered as a separate composition, simultaneously with, prior to, or after a composition comprising the additional active pharmaceutical agent.

[0112] In some embodiments, pharma- ceutically acceptable carriers can be selected from adjuvants and vehicles. Pharmaceutically acceptable carriers used herein can be selected from, for example, any and all solvents, diluents, other liquid vehicles, dispersants, suspending agents, surfactants, isotonicity agents, thickening agents, emulsifiers, preservatives, solid binders, and lubricants suitable for the specific dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York disclose various carriers used in formulating pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, for example, by producing any undesirable biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharma- ceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer 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, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, wool fat, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as carboxymethylcellulose, cellulose acetate, cellulose esters ... Ingredients that can be used include, for example, sodium 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, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, releasing agents, coating agents, sweeteners, flavors, fragrances, preservatives, and antioxidants.

[0113] Compounds selected from the compounds of the formulas disclosed herein, compounds 1-120, tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions disclosed herein, can be administered orally in solid dosage forms such as capsules, tablets, lozenges, dragees, granules, and powders, or in liquid dosage forms such as elixirs, syrups, emulsions, dispersions, and suspensions. Compounds, tautomers, solvates, stereoisomers, or pharma-ceutically acceptable salts described herein can also be administered parenterally in sterile liquid dosage forms such as dispersions, suspensions, or solutions. Other dosage forms may also be used to administer the compounds, tautomers, solvates, stereoisomers, or pharma- ceutically acceptable salts described herein; as ointments, creams, drops, transdermal patches, or powders for topical administration; as ophthalmic solution or suspension formulations, e.g., eye drops, for ophthalmic administration; as aerosol sprays or powder compositions for inhalation or intranasal administration; or as creams, ointments, sprays, or suppositories for rectal or vaginal administration.

[0114] Gelatin capsules containing the compounds disclosed herein, their tautomers, solvates or stereoisomers of the compounds or the tautomers, and / or pharma- ceutically acceptable salts of the foregoing and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. may also be used. Compressed tablets may be prepared using similar diluents. Both tablets and capsules may be prepared as sustained release products, allowing the sustained release of pharmaceutical agents over a period of time. Compressed tablets may 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.

[0115] Liquid dosage forms for oral administration may further comprise at least one agent selected from coloring and flavoring agents to enhance patient acceptance.

[0116] Generally, water, suitable oil, saline, aqueous dextrose (glucose) solution and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol may be examples of suitable carriers for parenteral solutions. Solutions for parenteral administration may contain a water-soluble salt of at least one compound described herein, at least one suitable stabilizer, and at least one buffer substance, if necessary. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, alone or in combination, may be examples of suitable stabilizers. Citric acid and its salts and sodium EDTA may also be used as examples of suitable stabilizers. In addition, parenteral solutions may further contain at least one preservative, for example, selected from benzalkonium chloride, methylparaben and propylparaben, and chlorobutanol.

[0117] Pharmaceutically acceptable carriers are selected from carriers that are compatible with the active ingredients of the composition (in some embodiments, can stabilize the active ingredients) and are not harmful to the subject being treated. For example, solubilizers such as cyclodextrins (which can form specific and more soluble complexes with at least one compound and / or at least one pharma-ceutically acceptable salt disclosed herein) can be utilized as pharmaceutical excipients for delivery of active ingredients. Other examples of carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow#10. Suitable pharma-ceutically acceptable carriers are described in Remington's Pharmaceutical Sciences, A. Osol.

[0118] For administration by inhalation, the compounds, tautomers, solvates, stereoisomers, or pharma- ceutically acceptable salts described herein can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer.The compounds, tautomers, solvates, stereoisomers, or pharma- ceutically acceptable salts described herein can also be delivered as powders that can be formulated, and the powder compositions can be inhaled using an insufflation powder inhaler.One exemplary delivery system for inhalation can be a metered dose inhalation (MDI) aerosol, which can be formulated as a suspension or solution of the compounds, tautomers, solvates, stereoisomers, or pharma- ceutically acceptable salts described herein in at least one suitable propellant selected from, for example, fluorocarbons and hydrocarbons.

[0119] For ocular administration, ophthalmic preparations can be formulated with a solution or suspension of an appropriate weight percentage of a compound, tautomer, solvate, stereoisomer, or pharma- ceutically acceptable salt described herein in a suitable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a period of time sufficient to allow the compound to penetrate the corneal and internal regions of the eye.

[0120] Pharmaceutical dosage forms useful for administration of the compounds, tautomers, solvates, stereoisomers, or pharma- ceutically acceptable salts described herein include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injectables, 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.

[0121] The term "unit dosage form" refers to physically discrete units suitable as unitary dosage forms for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes in the case of liquid compositions, or pills, tablets, capsules, drops, and the like in the case of solid compositions. In such compositions, the active material is usually in the range of about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight, with the remainder being various vehicles or carriers and processing aids that serve to form the desired dosage form. The 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 forms are packaged in multipacks adapted for sequential use, such as blister packs containing at least 6, 9, or 12 sheets of unit dosage forms.

[0122] In some embodiments, unit capsules can be prepared by filling each standard two-piece hard gelatin capsule with, for example, 100 milligrams of powder of a compound described herein, tautomer, solvate, stereoisomer, or pharma- ceutically acceptable salt, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams of magnesium stearate.

[0123] In some embodiments, a mixture of a compound, tautomer, solvate, stereoisomer, or pharma- ceutically acceptable salt described herein and a digestible oil, such as soybean oil, cottonseed oil, or olive oil, can be prepared and injected by a positive displacement pump into gelatin to form a soft gelatin capsule containing 100 milligrams of the active ingredient. The capsule is washed and dried.

[0124] In some embodiments, tablets can be prepared by conventional procedures so that a dosage unit contains, for example, 100 milligrams of the compound, its stereoisomer, or its pharma- ceutically acceptable salt, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch, and 98.8 milligrams of lactose. Appropriate coatings can be applied to enhance palatability or delay absorption.

[0125] In some embodiments, a parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of a compound disclosed herein and / or at least one enantiomer, diastereoisomer, or pharma- ceutically acceptable salt thereof in 10% by volume propylene glycol. The solution is made up to volume with water for injection and sterilized.

[0126] In some embodiments, an aqueous suspension can be prepared for oral administration. For example, 5 milliliters of each aqueous suspension can be used, containing 100 milligrams of micronized compound, its stereoisomer, or its pharma- ceutically acceptable salt, 100 milligrams of sodium carboxymethylcellulose, 5 milligrams of sodium benzoate, 1.0 gram of sorbitol solution (USP), and 0.025 milliliters of vanillin.

[0127] When the compounds, tautomers, solvates, stereoisomers or pharmaceutically acceptable salts described herein are administered stepwise or in combination with at least one other therapeutic agent, the same dosage form can generally be used.When drugs are administered in physical combination, the dosage form and administration route should be selected according to the compatibility of the drugs to be combined.Therefore, the term co-administration is understood to include administration of at least two drugs simultaneously or sequentially, or administration as a fixed dose combination of at least two active ingredients.

[0128] The compounds, tautomers, solvates, stereoisomers, or pharma- ceutically acceptable salts disclosed herein can be administered as the sole active ingredient or in combination with at least one second active ingredient.

[0129] The compounds, tautomers, solvates, or stereoisomers described herein can be used as such or in the form of their pharma- ceutically acceptable salts, such as hydrochloride, hydrobromide, acetate, sulfate, citrate, carbonate, trifluoroacetate, etc. When the compounds, tautomers, solvates, stereoisomers, or pharma-ceutically acceptable salts described herein contain relatively acidic functional groups, the salts can be obtained by adding the desired base, either neat or in a suitable inert solvent. Examples of pharma-ceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, etc. When the compounds, tautomers, solvates, or stereoisomers described herein contain relatively basic functional groups, the salts can be obtained by adding the desired acid, either neat or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include those derived from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and the like) and relatively non-toxic organic acids (e.g., acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like).Also included are salts of amino acids such as arginates, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0130] The neutral forms of the pharma- ceutically acceptable salts described herein can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.

[0131] The present disclosure provides prodrugs. Prodrugs of the compounds, tautomers, solvates, stereoisomers, or pharma- ceutically acceptable salts described herein undergo easy chemical changes under physiological conditions to provide the compounds, tautomers, solvates, stereoisomers, or pharma- ceutically acceptable salts of the present disclosure. In addition, prodrugs can be converted to the compounds, tautomers, solvates, stereoisomers, or pharma- ceutically acceptable salts of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds, tautomers, solvates, stereoisomers, or pharma- ceutically acceptable salts of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because they are easier to administer than the parent drug in some situations. For example, oral administration can result in higher bioavailability than the parent drug. Prodrugs can also have improved solubility in pharmacological compositions than 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. An example of a prodrug includes, but is not limited to, a compound of the present disclosure that is administered as an ester (the "prodrug") but then metabolically hydrolyzed to the carboxylic acid, ie, the active form.

[0132] Certain compounds, tautomers, stereoisomers, or pharma- ceutically 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 pharma- ceutically acceptable salts of the present disclosure may exist in multiple crystalline or amorphous forms.

[0133] Certain compounds, tautomers, solvates, or pharma- ceutically acceptable salts in this disclosure possess asymmetric carbon atoms (optical centers) or double bonds. The racemates, enantiomers, diastereoisomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of this disclosure.

[0134] III. Treatment Methods and Uses Another aspect of the present disclosure provides a method of treating a disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formulae disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutical composition comprising any of the foregoing, wherein the disease or condition is amyotrophic lateral sclerosis (ALS), Parkinson's disease, parkinsonism, ischemia, stroke, herpes infection, demyelinating diseases such as multiple sclerosis, traumatic brain injury, sepsis, PNS In some embodiments, the disease or condition is caused by axonal degeneration or neuronal damage, including, but not limited to, inherited neuropathies, including, but not limited to, Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy (CIDP), optic neuropathies, such as glaucoma and retinal ganglion degeneration, colitis, metabolic diseases or disorders, such as diabetic neuropathy, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and peripheral neuropathies, such as CIPN induced by various drugs, including, 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.

[0135] In another aspect, disclosed herein are compounds, tautomers, solvates, stereoisomers, or pharma- ceutically acceptable salts described herein, including compounds of the formulas disclosed herein, compounds 1-120, tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, for use as a medicament.

[0136] In another aspect, disclosed herein is the use of a compound, tautomer, solvate, stereoisomer, or pharma- ceutically acceptable salt described herein, including a compound of the formula disclosed herein, compounds 1-120, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a disease or condition, such as amyotrophic lateral sclerosis (ALS), Parkinson's disease, parkinsonism, ischemia, stroke, herpes infection, demyelinating diseases, such as multiple sclerosis, epidermal growth factor syndrome, cerebral infarction, cerebrovascular disease, cerebrovascular accident ... In some embodiments, the disease or condition is caused by axonal degeneration or neuronal damage, including, but not limited to, traumatic brain injury, sepsis, chronic diseases of the PNS, including inherited neuropathies, such as Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy (CIDP), optic neuropathies, such as glaucoma and retinal ganglion degeneration, colitis, metabolic diseases or disorders, such as diabetic neuropathy, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and peripheral neuropathies, such as CIPN induced by various drugs, such as taxanes, vinca alkaloids, and proteasome inhibitors. In some embodiments, the disease or condition is caused by axonal degeneration or neuronal damage.

[0137] In a further aspect of the disclosure, the compounds, tautomers, solvates, stereoisomers, or pharma- ceutically acceptable salts described herein, including compounds of the formulas disclosed herein, compounds 1-120, tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in the treatment of a disease or condition, such as amyotrophic lateral sclerosis (ALS), Parkinson's disease, parkinsonism, ischemia, stroke, herpes infection, demyelinating diseases, such as multiple sclerosis, traumatic brain injury, pulmonary circulation, and the like. In some embodiments, the disease or condition is caused by axonal degeneration or neuronal damage, including, but not limited to, chronic diseases of the PNS, including inherited neuropathies, such as, for example, Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy (CIDP), optic neuropathies, such as, for example, glaucoma and retinal ganglion degeneration, colitis, metabolic diseases or disorders, such as, for example, diabetic neuropathy, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and peripheral neuropathies, such as CIPN induced by various drugs, such as taxanes, vinca alkaloids, and proteasome inhibitors. In some embodiments, the disease or condition is caused by axonal degeneration or neuronal damage.

[0138] Another aspect of the present disclosure provides a method of inhibiting or preventing axonal degeneration comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formulae disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0139] In another aspect, disclosed herein is the use of a compound, tautomer, solvate, stereoisomer, or pharma- ceutically acceptable salt described herein, including a compound of the formula disclosed herein, compounds 1-120, a tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for inhibiting or preventing axonal degeneration or neuronal injury.

[0140] In a further aspect of the disclosure, the compounds, tautomers, solvates, stereoisomers, or pharma- ceutically acceptable salts described herein, including compounds of the formulas disclosed herein, compounds 1-120, tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in inhibiting or preventing axonal degeneration or neuronal injury.

[0141] Another aspect of the present disclosure provides a method of regulating, e.g., inhibiting, SARM1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of a formula disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0142] In another aspect, disclosed herein is the use of a compound described herein, a tautomer, solvate, stereoisomer, or pharma- ceutically acceptable salt, including a compound of the formula disclosed herein, compounds 1-120, a tautomer, a solvate, or stereoisomer of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, to modulate, e.g., inhibit, SARM1 in a subject in need thereof.

[0143] In another aspect of the disclosure, the compounds, tautomers, solvates or stereoisomers of the compounds or tautomers, or pharma- ceutically acceptable salts thereof described herein, including compounds of the formulas disclosed herein, compounds 1-120, tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in modulating, e.g., inhibiting, SARM1 in a subject in need thereof by contacting the subject with the compound, tautomer, solvate or stereoisomer of the compound or tautomer, pharma- ceutically acceptable salt, or pharmaceutical composition.

[0144] The compounds of the formulae disclosed herein, compounds 1-120, tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, may be administered, for example, once daily, twice daily, or three times daily, for the treatment of diseases or conditions including, but not limited to, amyotrophic lateral sclerosis (ALS), Parkinson's disease, parkinsonism, ischemia, stroke, herpes infection, demyelinating diseases such as multiple sclerosis, traumatic brain injury, sepsis, chronic diseases of the PNS. The neuropathies include, but are not limited to, hereditary neuropathies, such as Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy (CIDP), optic neuropathies, such as glaucoma and retinal ganglion degeneration, colitis, metabolic diseases or disorders, such as diabetic neuropathy, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and peripheral neuropathies, such as CIPN induced by various drugs, such as taxanes, vinca alkaloids, and proteasome inhibitors. In some embodiments, the disease or condition is caused by axonal degeneration or neuronal damage.

[0145] The compounds of the formulas disclosed herein, compounds 1-120, tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, can be administered in a variety of ways, for example, orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir, although the most suitable route in any given case will vary depending on the particular host and the nature and severity of the condition for which the active ingredient is being administered. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The compositions disclosed herein are conveniently provided in unit dosage form and may be prepared by any of the methods well known in the art. Parenteral administration may be by continuous infusion over a selected period of time. Other dosage forms contemplated in the present disclosure are as described in WO 2013 / 075083, WO 2013 / 075084, WO 2013 / 078320, WO 2013 / 120104, WO 2014 / 124418, WO 2014 / 151142, and WO 2015 / 023915.

[0146] Contacting is generally accomplished by administering to the subject an effective amount of one or more of the compounds, tautomers, solvates, stereoisomers, and pharma- ceutically acceptable salts disclosed herein. Generally, administration is adjusted to achieve a therapeutic dose of about 0.1-50, preferably 0.5-10, and more preferably 1-10 mg / kg, although optimal doses vary from compound to compound and are generally determined empirically for each compound.

[0147] The dosage will vary depending on factors such as the recipient's age, health and weight, the extent of the disease, the type of concurrent treatment, if any, the frequency of treatment, and the nature of the effect desired. In general, the daily dose of the active ingredient may vary, for example, from 0.1 to 2000 milligrams per day. For example, 10 to 500 milligrams, one or more times a day, may be effective to obtain the desired results.

[0148] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of a compound of the formulae disclosed herein, compounds 1-120, tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, is administered once daily, twice daily, or three times daily. The compounds, tautomers, solvates, stereoisomers, or pharma- ceutically acceptable salts described herein are administered in the morning / midday with an off day in the evening. EXAMPLES

[0149] In order that the disclosure set forth herein may be more fully understood, the following examples are disclosed herein. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any way.

[0150] Example 1. Synthesis of exemplary compounds Compounds of the present disclosure selected from the compounds of the formulae set forth herein, tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, can be made according to standard chemical methods or as illustrated herein, including the following synthetic schemes for compounds 1-120 as representative of formula I. [ka]

[0151] 4-Bromopyridin-2(1H)-one 1-01 (174 mg, 1.0 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 1-02 (246 mg, 1.2 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), X-phos (95 mg, 0.2 mmol), and aqueous K3PO4 (5 M, 1 mL, 5.0 mmol) were placed in 1,4-dioxane (2 mL) under N2. The mixture was then stirred at 105 °C for 12 h. The reaction mixture was cooled to room temperature, extracted with EA, washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give compound 1 as a white solid (24 mg, yield: 13.9%). Mass (m / z):173.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.70(s,1H),8.91(d,J=2.4Hz,1H),8.65(dd,J=4.7,1.6Hz,1H),8.12 (dt,J=8.0,2.1Hz,1H),7.54-7.46(m,2H),6.69(d,J=1.8Hz,1H),6.57(dd,J=6.8,1.9Hz,1H). [ka]

[0152] Following the procedure outlined for compound 1, the title compound 2 was prepared in 4.3% yield. Mass (m / z): 187.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.62(dd,J=5.4,1.6Hz,1H),8.57(d,J=2.0Hz,1H),7.65(d,J=5.4Hz ,1H),7.50(d,J=6.7Hz,1H),6.37(d,J=1.8Hz,1H),6.26(dd,J=6.7,1.8Hz,1H),2.40(s,3H). [ka]

[0153] A mixture of 4-bromopyridin-2(1H)-one 1-01 (150 mg, 0.86 mmol), Pd(PPh3)4 149 mg, 0.13 mmol), K2CO3 357 mg, 2.58 mmol), and 4-methoxy-3-(4,4,5,5-tetramethyl-132-dioxaborolan-2-yl)pyridine 3-01 (243 mg, 1.03 mmol) in dioxane (12 mL) and H2O (3 mL) was stirred at 100° C. for 2 h under N2. The reaction mixture was cooled to room temperature and diluted with water. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed under vacuum and purified by preparative TLC to give compound 3 as a white solid (20 mg, yield: 11%). Mass (m / z):203.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.61(s,1H),8.49(d,J=5.8Hz,1H),8.38(s,1H),7.39(dd,J=6.7,0.7Hz, 1H),7.18(d,J=5.8Hz,1H),6.43(dd,J=1.8,0.7Hz,1H),6.33(dd,J=6.8,1.8Hz,1H),3.88(s,3H). [ka]

[0154] Following the procedure outlined for compound 3, the title compound 4 was prepared in 35.1% yield. Mass (m / z): 186.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.41(d,J=5.0Hz,1H),8.33(s,1H),7.32(d,J=5.0Hz,1H),7.27(t,J=7.8Hz,1H),6.84-6.68(m,3H),2.25(s,3H). [ka]

[0155] A mixture of 3-bromo-5-hydroxybenzonitrile 5-01 (150 mg, 0.76 mmol), Pd(dppf)Cl2 (83 mg, 0.11 mmol), K2CO3 (314 mg, 2.27 mmol), and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 2-01 (191 mg, 0.83 mmol) in dioxane (10 mL) and H2O (2 mL) was stirred at 100° C. for 2 h under N2. The reaction mixture was cooled to room temperature and diluted with water. The aqueous phase was extracted with EA. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed under vacuum and purified by flash to give 3-hydroxy-5-(4-methylpyridin-3-yl)benzonitrile compound 5 (63 mg, yield: 40%) as a white solid. Mass (m / z):211.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.46(s,1H),8.45(d,J=5.0Hz,1H),8.37(s,1H),7.35(d,J=4. 9Hz, 1H), 7.32 (t, J = 1.5Hz, 1H), 7.22-7.17 (m, 1H), 7.08 (t, J = 2.0Hz, 1H), 2.25 (s, 3H). [ka]

[0156] Following the procedure outlined for compound 5, the title compound 6 was prepared in 24.9% yield. Mass (m / z): 211.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.57(s,1H),8.86-8.39(m,2H),7.79(t,J=3.6Hz,2H),7.62(dd,J=8.6,2.3Hz,1H),7.16(d,J=8.6Hz,1H),2.43(s,3H). [ka]

[0157] Following the procedure outlined for compound 5, the title compound 7 was prepared in 43% yield. Mass (m / z): 249.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.42(s,1H),7.88(dt,J=7.2,1.9Hz,1H),7.83( t,J=1.7Hz,1H),7.73-7.65(m,2H),7.44(s,2H),7.40(d,J=5.0Hz,1H),2.28(s,3H). [ka]

[0158] Following the procedure outlined for compound 5, the title compound 8 was prepared in 44.4% yield. Mass (m / z): 198.9 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ8.44(d,J=5.0Hz,1H),8.38(s,1H),7.43(d,J=8.0Hz ,2H),7.30(d,J=8.0Hz,2H),7.19(d,J=5.0Hz,1H),3.97(s,2H),2.29(s,3H). [ka]

[0159] Following the procedure outlined for compound 5, the title compound 9 was prepared in 45.8% yield. Mass (m / z): 185.9 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.42 (s, 2H), 7.26-7.23 (m, 1H), 7.19 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 2.34 (s, 3H). [ka]

[0160] Following the procedure outlined for compound 5, the title compound 10 was prepared in 54.3% yield. Mass (m / z): 171.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.85-8.79(m,1H),8.55(d,J=3.6Hz,1H),7.99(d,J=7.9Hz,1H) ,7.46(dd,J=7.7,4.8Hz,1H),7.29(t,J=7.8Hz,1H),7.13-7.04(m,2H),6.83(dd,J=7.9,1.6Hz,1H). [ka]

[0161] Following the procedure outlined for compound 5, the title compound 11 was prepared in 18.2% yield. Mass (m / z): 204.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.43(d,J=5.0Hz,1H),8.31(s,1H),8.12(s,1H),7.39-7.28(m,1H),7.20-6.90(m,2H),6.69(m,1H),2.13(s,3H). [ka]

[0162] Following the procedure outlined for compound 5, the title compound 12 was prepared in 19.9% ​​yield. Mass (m / z): 204.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.39 (d, J = 5.1 Hz, 1H), 8.29 (s, 1H), 7.38 (d, J = 5.2 Hz, 1H), 7.12 (t, J = 8.6 Hz, 1H), 6.80-6.74 (m, 1H), 6.74-6.64 (m, 1H), 2.27 (s, 3H). [ka]

[0163] Following the procedure outlined for compound 5, the title compound 13 was prepared in 24.8% yield. Mass (m / z): 204.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.02 (s, 1H), 8.41-8.21 (m, 2H), 7.39-7.12 (m, 2H), 7.12-6.89 (m, 2H), 2.23 (s, 3H). [ka]

[0164] Following the procedure outlined for compound 5, the title compound 14 was prepared in 11.5% yield. Mass (m / z): 203.9 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.42 (d, J = 5.2 Hz, 1H), 8.31 (s, 1H), 7.40 (d, J = 5.2 Hz, 1H), 7.07 (t, J = 9.2 Hz, 1H), 6.87 (m, 1H), 6.69 (dd, J = 6.0, 3.0 Hz, 1H), 2.28 (s, 3H). [ka]

[0165] Following the procedure outlined for compound 5, the title compound 15 was prepared in 12.3% yield. Mass (m / z): 263.7 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.46(s,1H),8.39(d,J=5.0Hz,1H),8.33(s,1H),7.51(d,J=2.2Hz, 1H),7.30(d,J=4.9Hz,1H),7.22(dd,J=8.3,2.2Hz,1H),7.04(d,J=8.3Hz,1H),2.25(s,3H). [ka]

[0166] Following the procedure outlined for compound 5, the title compound 16 was prepared in 6.7% yield. Mass (m / z): 263.7 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.43(d,J=5.0Hz,1H),8.33(s,1H),7.32(d,J=5. 0Hz,1H), 7.00(t,J=2.0Hz,1H),6.99(t,J=1.6Hz,1H),6.75-6.73(m,1H),2.25(s,3H). [ka]

[0167] Following the procedure outlined for compound 5, the title compound 17 was prepared in 14.2% yield. Mass (m / z): 263.7 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.42(d,J=5.0Hz,1H),8.33(s,1H),7.55(d,J=8.1Hz, 1H), 7.32(d,J=5.0Hz,1H),6.90(d,J=2.0Hz,1H),6.73(dd,J=8.1,1.8Hz,1H),2.24(s,3H). [ka]

[0168] Following the procedure outlined for compound 5, the title compound 18 was prepared in 33.3% yield. Mass (m / z): 239.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.45(d,J=4.9Hz,1H),8.37(s,1H),8.05(s,1H),7.80(d,J=1.9Hz,1H),7.52(dd,J=7.7,2.0H z,1H),7.43(d,J=7.8Hz,1H),7.36(d,J=5.0Hz,1H),3.43(dd,J=6.6,3.8Hz,2H),2.97(t,J=6.6Hz,2H),2.26(s,3H). [ka]

[0169] Following the procedure outlined for compound 5, the title compound 19 was prepared in 32.7% yield. Mass (m / z): 204.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.65 (s, 2H), 7.95 (s, 1H), 7.26 (dd, J = 11.0, 8.3 Hz, 1H), 7.03 (dd, J = 8.2, 2.1 Hz, 1H), 6.89 (m, 1H), 2.57 (s, 3H). [ka]

[0170] Following the procedure outlined for compound 5, the title compound 20 was prepared in 20.1% yield. Mass (m / z): 203.9 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ8.35(d,J=5.1Hz,1H),8.31(d,J=25.8Hz,1H),7.34(d,J=5.1Hz,1H),6.54(qt,J=2.3,1.9Hz,3H),2.30(s,3H). [ka]

[0171] Following the procedure outlined for compound 3, the title compound 21 was prepared in 6.4% yield. Mass (m / z): 209.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.23(s,1H),8.42(s,2H),7.58-7.44(m,2H),7.43-7.28(m,2H),7.09(d,J=8.3Hz,1H),6.48(s,1H),2.30(s,3H). [ka]

[0172] Following the procedure outlined for compound 5, the title compound 22 was prepared in 10.4% yield. Mass (m / z): 215.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.42(d,J=5.0Hz,1H),8.32(s,3H),7.34(t,J=6.8Hz,2H ),6.88(d,J=1.6Hz,1H),6.82(dd,J=7.7,1.6Hz,1H),3.98(s,2H),2.26(s,3H). [ka]

[0173] Following the procedure outlined for compound 3, the title compound 23 was prepared in 6.4% yield. Mass (m / z): 209.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.20(s,1H),8.40(d,J=4.8Hz,2H),7.62(dd,J=8.2,3.1Hz,1 H),7.46-7.24(m,3H),7.00(t,J=5.5Hz,1H),6.53-6.39(m,1H),2.29(d,J=3.3Hz,3H). [ka]

[0174] Following the procedure outlined for compound 5, the title compound 24 was prepared in 27% yield. Mass (m / z): 210.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.19(s,1H),8.46-8.39(m,2H),8.12(s,1H),7.76(s,1H),7.63(d,J=8.6Hz,1H),7.40-7.30(m,2H),2.27(s,3H). [ka]

[0175] Following the procedure outlined for compound 5, the title compound 25 was prepared in 43% yield. Mass (m / z): 210.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.56(s,1H),8.46-8.38(m,2H),8.28(s,1H),7.8 2-7.46(m,2H),7.37-7.29m,1H),7.25-7.15(m,1H),2.28(d,J=2.4Hz,3H). [ka]

[0176] Following the procedure outlined for compound 5, the title compound 26 was prepared in 22.5% yield. Mass (m / z): 200.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.50(s,1H),8.42(d,J=5.0Hz,1H),8.21(s,1H),7.32(d,J=5.0Hz,1H),7. 07(t,J=7.8Hz,1H),6.86(d,J=7.2Hz,1H),6.55(dd,J=7.6,1.0Hz,1H),2.03(s,3H),1.80(s,3H). [ka]

[0177] Following the procedure outlined for compound 5, the title compound 27 was prepared in 22.4% yield. Mass (m / z): 219.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.45(d,J=5.0Hz,1H),8.25(s,1H),7.34(d,J=5.0Hz,1H),7.1 9(t,J=7.8Hz,1H),7.01(d,J=8.0Hz,1H),6.67(d,J=7.2Hz,1H),2.08(d,J=3.4Hz,3H). [ka]

[0178] Following the procedure outlined for compound 5, the title compound 28 was prepared in 15% yield. Mass (m / z): 200.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.48(d,J=2.6Hz,1H),8.38-8.27(m,2H),7.27(d,J=4.9Hz,1H),7. 08(s,1H),7.01(d,J=8.2Hz,1H),6.86(d,J=8.2Hz,1H),2.25(d,J=2.5Hz,3H),2.16(s,3H). [ka]

[0179] Following the procedure outlined for compound 5, the title compound 29 was prepared in 5.2% yield. Mass (m / z): 214.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.46(d,J=2.6Hz,1H),8.37-8.27(m,2H),7.27(d,J=4.8Hz,1H),7.08(s,1H),7 .02(d,J=8.1Hz,1H),6.86(d,J=8.3Hz,1H),2.58(d,J=7.6Hz,2H),2.26(s,3H),1.15(t,J=7.8Hz,3H). [ka]

[0180] Following the procedure outlined for compound 5, the title compound 30 was prepared in 7.7% yield. Mass (m / z): 216.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.15(d,J=2.7Hz,1H),8.37(d,J=7.0Hz,2H),7.28(d,J=4.9Hz,1H) ,6.92(s,1H),6.89-6.83(m,1H),6.77(d,J=8.2Hz,1H),3.79(d,J=2.4Hz,3H),2.28(s,3H). [ka]

[0181] Following the procedure outlined for compound 5, the title compound 31 was prepared in 19.7% yield. Mass (m / z): 220.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.46-8.27(m,2H),7.37(s,1H),7.30(t,J=3. 7Hz,1H), 7.17(d,J=8.2Hz,1H),7.06(dd,J=8.3,2.4Hz,1H),2.25(d,J=2.7Hz,3H). [ka]

[0182] Following the procedure outlined for compound 5, the title compound 32 was prepared in 8.3% yield. Mass (m / z): 200.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.43-8.35(m,1H),8.31(s,1H),7.30(d,J= 4.8Hz, 1H), 7.15 (d, J=7.6Hz, 1H), 6.79-6.66 (m, 2H), 2.25 (s, 3H), 2.17 (s, 3H). [ka]

[0183] Following the procedure outlined for compound 5, the title compound 33 was prepared in 41% yield. Mass (m / z): 211.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.36-8.26(m,2H),7.29-7.22(m,1H),7.04(s,1H),6.97-6.87(m,1H) ),6.62-6.53(m,1H),5.72(s,1H),3.52-3.42(m,2H),3.00-2.90(m,2H),2.31-2.23(s,3H). [ka]

[0184] Following the procedure outlined for compound 5, the title compound 34 was prepared in 47% yield. Mass (m / z): 227.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.28(s,1H),8.47-8.42(m,1H),8.40-8.36(m,1H),7.46(dd,J =7.5,2.5Hz,1H),7.43-7.38(m,1H),7.37-7.26(m,2H),6.50-6.46(m,1H),2.17(s,3H). [ka]

[0185] Following the procedure outlined for compound 5, the title compound 35 was prepared in 33.9% yield. Mass (m / z): 221.9 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.43 (d, J = 5.2 Hz, 1H), 8.32 (s, 1H), 7.41 (d, J = 5.2 Hz, 1H), 7.05 (m, 1H), 6.74 (m, 1H), 2.27 (s, 3H). [ka]

[0186] Following the procedure outlined for compound 5, the title compound 36 was prepared in 41% yield. Mass (m / z): 211.0 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.58 (s, 1H), 8.56-8.50 (m, 1H), 7.89-7.79 (m, 3H), 7.35 (dd, J = 8.5, 2.8 Hz, 1H), 2.38 (d, J = 3.0 Hz, 3H). [ka]

[0187] Following the procedure outlined for compound 5, the title compound 37 was prepared in 14% yield. Mass (m / z): 275.0 [M+H+H2O] + . 1 H NMR (400 MHz, methanol-d4) δ 8.73 (s, 2H), 7.96 (s, 1H), 7.88-7.40 (m, 1H), 7.16-7.05 (m, 0.62H), 6.65-6.57 (m, 0.44H), 2.50 (d, J=5.2 Hz, 3H). [ka]

[0188] Following the procedure outlined for compound 5, the title compound 38 was prepared in 47% yield. Mass (m / z): 228.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.06(d,J=3.0Hz,1H),8.55-8.31(m,2H),7.97(dd,J=8.5,2.9Hz ,1H),7.42-7.27(m,1H),6.99(t,J=4.7Hz,2H),2.80-2.62(m,3H),2.28(d,J=2.9Hz,3H). [ka]

[0189] Step 1: Compound 39-02 was prepared following the procedure outlined for compound 5. Purification by silica gel chromatography (MeOH = 0% to 10% in DCM) affords 2-fluoro-6-methoxy-3-(4-methylpyridin-3-yl)phenol 39-02 (120 mg, 45%) as a white solid. Mass (m / z): 234.2 [M+H] + .

[0190] Step 2: To a solution of 2-fluoro-6-methoxy-3-(4-methylpyridin-3-yl)phenol 39-02 (120 mg, 0.51 mmol) in DCE (6 mL) was added BBr3 (1.29 g, 5.14 mmol) dropwise under nitrogen protection. After addition, the mixture was heated to 80° C. and stirred for 12 h. The reaction mixture was quenched with water (8 mL) and then extracted with ethyl acetate (25 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a residue. The crude product was purified by silica gel chromatography (MeOH=0%-10% in DCM) and purified by preparative HPLC to give the title compound 39 (17.3 mg, yield: 15.3%) as a black oil. Mass (m / z): 220.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.84(s,1H),9.28(s,1H),8.74-8.50(m,2H),7.73(d,J=5.6Hz,1H),6.78-6.56(m,2H),2.29(s,3H). [ka]

[0191] Following the procedure outlined for compound 5, the title compound 40 was prepared in 14.2% yield. Mass (m / z): 227.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.76(s,1H),8.42(d,J=5.0Hz,1H),8.36(s,1H),7 .39(d,J=1.4Hz,1H),7.33(d,J=5.0Hz,1H),7.22-7.13(m,2H),2.27(s,3H). [ka]

[0192] Following the procedure outlined for compound 5, the title compound 41 was prepared in 11.3% yield. Mass (m / z): 224.9 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 8.36 (d, J = 5.1 Hz, 1H), 8.32 (s, 1H), 7.38 (d, J = 5.1 Hz, 1H), 7.29 (s, 1H), 7.23 (dd, J = 8.0, 1.2 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 3.63 (s, 1H), 3.61 (s, 1H), 2.35 (s, 3H). [ka]

[0193] Following the procedure outlined for compound 5, the title compound 42 was prepared in 26.8% yield. Mass (m / z): 200.9 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ8.27-8.21(m,2H),7.28(dd,J=4.4,0.6Hz,1H),6.80(d ,J=8.0Hz,1H),6.66(d,J=2.0Hz,1H),6.61(dd,J=8.0,2.0Hz,1H),2.31(s,3H). [ka]

[0194] Following the procedure outlined for compound 5, the title compound 43 was prepared in 20.1% yield. Mass (m / z): 201.2 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ8.33-8.14(m,2H),7.28(d,J=5.2Hz,1H),6.73(dd,J=24.4,5.2Hz,2H),6.52(dd,J=8.0,2.2Hz,1H),2.30(s,3H). [ka]

[0195] Following the procedure outlined for compound 5, the title compound 44 was prepared in 20.2% yield. Mass (m / z): 225.9 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 8.39-8.23 (m, 2H), 7.34 (d, J=5.2 Hz, 1H), 7.15-7.09 (m, 1H), 7.01-6.96 (m, 2H), 2.31 (s, 3H). [ka]

[0196] Following the procedure outlined for compound 5, the title compound 45 was prepared in 18.8% yield. Mass (m / z): 240.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),8.41(s,1H),8.34(s,1H),7.32(s,1H),7.01(s,1H),6.98(s,2H),4.63(s,2H),2.27(s,3H). [ka]

[0197] Following the procedure outlined for compound 5, the title compound 46 was prepared in 18.8% yield. Mass (m / z): 239.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.38(d,J=5.0Hz,1H),8.33(s,1H),7.30( d,J=5.0Hz,1H),7.14(s,2H),6.86(d,J=7.9Hz,2H),4.36(s,2H),2.27(s,3H). [ka]

[0198] A mixture of compound 47-01 (108 mg, 0.5 mmol) in HBr (48%, 4 mL) was stirred at 90° C. for 3 h. The mixture was concentrated in vacuo. Purification by silica gel chromatography afforded the title compound 47 (50 mg, yield: 49.7%) as a white solid. Mass (m / z): 202.1 [M+H] + .1 H NMR(400MHz,DMSO-d6)δ9.35(s,2H),8.62(d,J=9.2Hz,2H),7.80(d,J=5.5Hz,1H),6.91-6.80(m,2H),6.72(d,J=8.2Hz,1H),2.45(s,3H). [ka]

[0199] Following the procedure outlined for compound 5, the title compound 48 was prepared in 28% yield. Mass (m / z): 211.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.79(s,1H),8.55(s,1H),8.51-8.43(m,2H),8.30(s,1H),8.20(s,1H),7.42-7.36(m,1H),2.29(d,J=3.1Hz,3H). [ka]

[0200] Following the procedure outlined for compound 5, the title compound 49 was prepared in 3% yield. Mass (m / z): 211.0 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ9.13(s,1H),8.79(s,1H),8.62(d,J=5.9Hz,1H),8.25(d, J=3.0Hz,1H), 8.05(d,J=2.8Hz,1H),7.89(d,J=5.9Hz,1H),2.60(d,J=2.9Hz,3H). [ka]

[0201] Following the procedure outlined for compound 5, the title compound 50 was prepared in 40% yield. Mass (m / z): 211.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ13.43(s,1H),8.59(s,1H),8.51-8.45(m,1H),8.36(s,1H),8 .13(d,J=8.6Hz,1H),7.59(d,J=8.7Hz,1H),7.40-7.34(m,1H),2.38(d,J=3.2Hz,3H). [ka]

[0202] Following the procedure outlined for compound 5, the title compound 51 was prepared in 13.8% yield. Mass (m / z): 241.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.35 (s, 1H), 8.30 (s, 1H), 7.36 (s, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.88 (s, 1H), 4.63 (s, 2H), 2.33 (s, 3H). [ka]

[0203] Following the procedure outlined for compound 5, the title compound 52 was prepared in 8.9% yield. Mass (m / z): 227.0 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.38 (s, 1H), 8.33 (s, 1H), 7.43-7.21 (m, 2H), 7.08 (d, J = 12.0 Hz, 2H), 2.32 (s, 3H). [ka]

[0204] Following the procedure outlined for compound 5, the title compound 53 was prepared in 25.3% yield. Mass (m / z): 226.9 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.34(t,J=18.4Hz,1H),7.26(s,1H),6.66(d,J=11.0Hz,1H ),5.97(s,1H),4.13(d,J=25.9Hz,2H),3.31(dd,J=13.4,9.3Hz,2H),2.27(s,3H). [ka]

[0205] Following the procedure outlined for compound 5, the title compound 54 was prepared in 27.8% yield. Mass (m / z): 226.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.35(d,J=5.0Hz,1H),8.28(s,1H),7.27(d,J=5.0Hz,1H),6.72(d,J=8.1Hz,1H) ,6.54(d,J=2.1Hz,1H),6.45(d,J=6.0Hz,1H),5.87(s,1H),4.16(s,2H),3.31-3.30(m,2H),2.25(s,3H). [ka]

[0206] Following the procedure outlined for compound 5, the title compound 55 was prepared in 28.0% yield. Mass (m / z): 225.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.60 (s, 2H), 7.89 (s, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 7.3 Hz, 1H), 6.92 (s, 1H), 3.59 (s, 2H), 2.52 (s, 3H). [ka]

[0207] Following the procedure outlined for compound 5, the title compound 56 was prepared in 21.7% yield. Mass (m / z): 187.1 [M+H] + .1 H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.46(d,J=5.0Hz,1H),8.38(s,1H),8.19(d,J=2.7 Hz,1H), 8.06(d,J=1.8Hz,1H),7.36(d,J=5.0Hz,1H),7.18(t,J=2.3Hz,1H),2.27(s,3H). [ka]

[0208] Following the procedure outlined for compound 5, the title compound 57 was prepared in 46.3% yield. Mass (m / z): 240.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.95(s,1H),8.41(d,J=5.0Hz,1H),8.39(s,1H),7.32(d,J=5.0Hz,1H),7 .15(d,J=1.5Hz,1H),7.06(d,J=8.0Hz,1H),6.99(dd,J=8.0,1.6Hz,1H),3.31(s,3H),2.29(s,3H). [ka]

[0209] Following the procedure outlined for compound 5, the title compound 58 was prepared in 51.2% yield. Mass (m / z): 244.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ13.73(s,1H),8.49-8.39(m,2H),8.25(d,J=1.4Hz,1H), 7.77(d,J=1.2Hz,1H),7.52(d,J=1.3Hz,1H),7.36(d,J=5.0Hz,1H),2.28(s,3H). [ka]

[0210] Following the procedure outlined for compound 5, the title compound 59 was prepared in 51.2% yield. Mass (m / z): 241.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.47(d,J=5.0Hz,1H),8.41(s,1H),7.76(d,J=7.8Hz,1H), 7.67-7.59(m,1H),7.50(dd,J=7.8,1.5Hz,1H),7.37(d,J=5.0Hz,1H),4.44(s,2H),2.28(s,3H). [ka]

[0211] A mixture of 3-bromo-4-methylpyridine 60-01 (100 mg, 0.58 mmol), (3-chloro-5-hydroxyphenyl)boronic acid 60-02 (101 mg, 0.58 mmol), Pd(dppf)Cl2 (45 mg, 0.05 mmol), and K2CO3 (243 mg, 1.74 mmol) in dioxane (5 mL) / H2O (1 mL) was stirred at 95 °C for 2 h under N2. The reaction mixture was cooled to room temperature and diluted with water. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. The mixture was concentrated and further purified by silica gel column chromatography to give 60 as a white solid (17.8 mg, yield: 13.8%). Mass (m / z): 220.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.43(d,J=4.8Hz,1H),8.34(s,1H),7.33(d,J=4.8Hz,1H),6.87-6.86(m,2H),6.71(s,1H),2.25(s,3H). [ka]

[0212] Following the procedure outlined for compound 60, the title compound 61 was prepared in 16.4% yield. Mass (m / z): 238.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.42(d,J=4.8Hz,1H),8.36(s,1H),7.33-7.26(m,3H),2.28(s,3H) [ka]

[0213] Following the procedure outlined for compound 60, the title compound 62 was prepared in 25.5% yield. Mass (m / z): 220.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.47(d,J=5.0Hz,1H),8.40(s,1H),7.68-7.57(m,4H),7.37(d,J=5.0Hz,1H),7.10(t,J=55.8Hz,1H),2.27(s,3H). [ka]

[0214] Following the procedure outlined for compound 60, the title compound 63 was prepared in 25.5% yield. Mass (m / z): 254.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.46(d,J=5.0Hz,1H),8.38(s,1H),7.35(d,J=5.0Hz,1H),7.16-7.08(m,2H),7.04(m,1H),2.26(s,3H). [ka]

[0215] Following the procedure outlined for compound 5, the title compound 64 was prepared in 12.6% yield. Mass (m / z): 225.0 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 8.49 (d, J = 4.6 Hz, 1H), 7.51 (d, J = 5.1 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 1.3 Hz, 1H), 7.11 (dd, J = 8.0, 1.5 Hz, 1H), 2.51 (s, 3H). [ka]

[0216] Following the procedure outlined for compound 5, the title compound 65 was prepared in 46.8% yield. Mass (m / z): 225.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.50(s,1H),8.41-8.39(m,2H),7.71(s,1H),7.33-7.30(m,2H),7.25(dd,J=8.5,1.5Hz,1H),5.42(s,2H),2.29(s,3H). [ka]

[0217] Following the procedure outlined for compound 5, the title compound 66 was prepared in 1.1% yield. Mass (m / z): 261.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.79(s,1H),8.21(s,1H),7.52(s,1H),7.42(s,1H),7.19(t,J=6.4Hz,2H),2.28(s,3H). [ka]

[0218] Following the procedure outlined for compound 60, the title compound 67 was prepared in 15.6% yield. Mass (m / z): 241.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.90(s,1H),8.55(s,1H),7.70(s,1H),7.47(s,1H),7.23(d,J=2.1Hz,2H),2.63(s,3H),2.41(s,3H). [ka]

[0219] To a solution of 5-(4-methylpyridin-3-yl)-1H-indazole 24 (40 mg, 0.19 mmol) in CH3CN (10 mL) and acetic acid (4 mL) was added Selectfluor (135 mg, 0.382 mmol) at rt. The reaction mixture was stirred at 80 °C for 12 h. The reaction was cooled to room temperature and quenched with H2O (20 mL). The pH of the resulting solution was adjusted to 7-8 and the aqueous was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by preparative HPLC to give compound 68 (6.5 mg, yield: 14.96%) as a white solid. Mass (m / z): 228.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.41-8.28(m,2H),7.57(d,J=1.7Hz,1H),7.38(dd,J=8.0,1.7Hz,1H),7.22(d,J=8.0Hz,1H),7.04-6.93(m,2H). [ka]

[0220] Step 1: 4-(4-Methylpyridin-3-yl)aniline 69-02 was prepared in 78% yield (250 mg, 1.36 mmol) from 4-bromoaniline 69-01 (300 mg, 1.74 mmol) following the procedure outlined for compound 5. Mass (m / z): 185.1 [M+H] + .

[0221] Step 2: To a solution of 4-(4-methylpyridin-3-yl)aniline 69-02 (100 mg, 0.54 mmol) and Sc(SOCF) (40 mg, 0.08 mmol) in water (4 mL) was added cyanamide (27 mg, 0.65 mmol) at room temperature. The reaction was stirred at 100° C. for 12 h. The reaction mixture was cooled to room temperature and extracted with EA. The combined organic layers were washed with brine, dried over MgSO and concentrated in vacuo. The crude product was purified by preparative HPLC to give compound 69 (4.5 mg, yield: 3.66%) as a white solid. Mass (m / z): 227.1 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ8.70-8.61(m,2H),7.92(d,J=5.8Hz,1H),7.60-7.52(m,2H),7.50-7.43(m,2H),2.56(s,3H). [ka]

[0222] Following the procedure outlined for compound 5, the title compound 70 was prepared in 16.5% yield. Mass (m / z): 276.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.63-8.54(m,2H),7.68(d,J=5.5Hz,1H),7.08(s,1H),6.99(s,2H),3.21(s,3H),2.42(s,3H). [ka]

[0223] Following the procedure outlined for compound 5, the title compound 71 was prepared in 15.5% yield. Mass (m / z): 237.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.45(t,J=4.0Hz,2H),7.84(d,J=2.0Hz,1H),7.74(dd ,J=8.7,2.0Hz,1H),7.50(d,J=8.0Hz,1H),7.36(d,J=4.0Hz,1H),6.96(s,2H),2.31(s,3H). [ka]

[0224] Following the procedure outlined for compound 5, the title compound 72 was prepared in 12.6% yield. Mass (m / z): 240.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.42(d,J=5.0Hz,1H),8.32(s,1H),7.33(d,J=5.0Hz,1H),7. 18(d,J=7.7Hz,1H),6.87(dd,J=7.6,1.6Hz,2H),6.74(d,J=1.5Hz,1H),4.37(s,2H),2.25(s,3H). [ka]

[0225] Following the procedure outlined for compound 5, the title compound 73 was prepared in 20.0% yield. Mass (m / z): 267.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.09(d,J=10.0Hz,1H),11.56(s,1H),8.39(dd,J=9. 6,4.0Hz,2H),7.64-7.28(m,3H),7.20-6.94(m,1H),2.28(s,3H),2.18(s,3H). [ka]

[0226] Following the procedure outlined for compound 5, the title compound 74 was prepared in 17.6% yield. Mass (m / z): 228.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ13.60(s,1H),8.68(td,J=5.7,2.7Hz,2H),8.30(d,J=1.0Hz,1H),7 .76(q,J=5.2Hz,1H),7.54(dd,J=8.5,1.0Hz,1H),7.36(dd,J=8.5,6.8Hz,1H),2.32(s,3H). [ka]

[0227] A mixture of compound 2-amino-5-(4-methylpyridin-3-yl)phenol 42 (60 mg, 0.3 mmol) and compound di(1H-imidazol-1-yl)methanethione 75-01 (53.4 mg, 0.3 mmol) in THF (2 mL) was stirred at 80° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with water. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed under vacuum and purified by preparative TLC to give compound 75 (30 mg, yield: 41.1%). Mass (m / z): 243.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ14.00(s,1H),8.45(d,J=5.0Hz,1H),8.40(s,1H),7.64(t,J=1.0Hz,1H),7.39-7.31(m,3H),2.28(s,3H). [ka]

[0228] Following the procedure outlined for compound 5, the title compound 76 was prepared in 38.1% yield. Mass (m / z): 239.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),8.43(d,J=5.0Hz,1H),8.36(s,1H),7.63(dd,J=8.1,1 .9Hz,1H),7.54(d,J=1.8Hz,1H),7.34(d,J=5.0Hz,1H),7.02(d,J=8.1Hz,1H),2.27(s,3H). [ka]

[0229] Following the procedure outlined for compound 5, the title compound 77 was prepared in 2.6% yield. Mass (m / z): 228.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.26(d,J=1.8Hz,1H),7.95(d,J=2.4Hz,1H),7.69(d, J=1.7Hz,1H),7.65(s,1H),7.48(dd,J=8.1,1.8Hz,1H),7.24(d,J=8.1Hz,1H),6.24(s,2H). [ka]

[0230] Following the procedure outlined for compound 5, the title compound 78 was prepared in 89% yield. Mass (m / z): 228.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.03 (s, 1H), 8.59 (s, 1H), 7.49 (d, J = 1.4Hz, 1H), 7.31-7.16 (m, 2H), 2.47 (s, 3H). [ka]

[0231] Step 1: Following the procedure outlined for compound 5, 2-amino-5-(4-methylpyridin-3-yl)benzonitrile 79-02 was prepared in 48.0% yield. Mass (m / z): 210.3 [M+H] + .

[0232] Step 2: To a solution of 2-amino-5-(4-methylpyridin-3-yl)benzonitrile 79-02 (300 mg, 1.43 mmol) in THF (3 mL) was added BH3 (6 mL, 6 mmol, 1M in THF) slowly. After addition, the reaction mixture was stirred at 65° C. for 3 h under nitrogen protection. The reaction mixture was then quenched by dropwise addition of MeOH (3 mL) at 0° C. and then stirred at 50° C. for 5 h. The solvent was removed under vacuum to give a residue. The residue was dissolved in DCM (10 mL) and water (10 mL), the organic layer was separated, and the aqueous layer was extracted with DCM (20 mL×3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product. This was purified by silica gel chromatography (MeOH in DCM = 0% to 20%) to give 2-(aminomethyl)-4-(4-methylpyridin-3-yl)aniline 79-03 (100 mg, 32.7%) as a light brown slurry. Mass (m / z): 214.3 [M+H] + .

[0233] Step 3: A mixture of 2-(aminomethyl)-4-(4-methylpyridin-3-yl)aniline 79-03 (200 mg, 0.94 mmol) and BrCN (149 mg, 1.41 mmol) in EtOH (15 mL) was heated to 60° C. and stirred under nitrogen protection for 3 h. The reaction mixture was quenched with water (6 mL) and extracted with DCM (20 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a residue. This was purified by silica gel chromatography (MeOH=0% to 10% in DCM) and re-purified by preparative HPLC to give the title compound 79 (18 mg, yield: 8.9%) as a pale orange solid. Mass (m / z): 239.1 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 8.35 (d, J = 5.1 Hz, 1H), 8.30 (s, 1H), 7.36 (d, J = 5.1 Hz, 1H), 7.23 (dd, J = 8.2, 2.0 Hz, 1H), 7.13 (s, 1H), 7.02 (d, J = 8.2 Hz, 1H), 4.58 (s, 2H), 2.33 (s, 3H). [ka]

[0234] Following the procedure outlined for compound 5, the title compound 80 was prepared in 29.1% yield. Mass (m / z): 255.1 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ8.47-8.10(m,2H),7.36(d,J=5.1Hz,1H),7.28(dd, J=8.3,2.0Hz,1H),7.23-7.12(m,2H),4.81(s,2H),4.55(s,2H),2.33(s,3H). [ka]

[0235] Step 1: To a solution of 5-bromoindoline-2,3-dione 81-01 (1.00 equiv., 500 mg, 2.21 mmol) in DCM (10 mL) was added DAST (1.0 equiv., 357 mg, 2.21 mmol). The mixture was stirred at room temperature for 2 h. The reaction was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by flash column chromatography to give compound 81-02 (450 mg, yield: 75.5%). Step 2: The title compound 81 was prepared following the procedure outlined for compound 5 in 36.2% yield. Mass (m / z): 243.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),8.44(d,J=5.0Hz,1H),8.38(s,1H),7.76(d,J=2.0Hz,1H ),7.55(dd,J=8.2,1.8Hz,1H),7.34(d,J=5.0Hz,1H),7.10(dd,J=8.1,1.8Hz,1H),2.28(s,3H). [ka]

[0236] Following the procedure outlined for compound 82, the title compound 60 was prepared in 6.6% yield. Mass (m / z): 243.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.77(s,1H),11.49(s,1H),7.34(d,J=1.4Hz,1H),7.27(s,1H),7.16-7.08(m,2H),6.16(s,1H),1.90(s,3H). [ka]

[0237] Following the procedure outlined for compound 60, the title compound 83 was prepared in 11.1% yield. Mass (m / z): 241.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.68(dd,J=5.8,2.3Hz,1H),8.58(d,J=2.5Hz,1H),7.76(d,J =5.5Hz,1H),7.43(d,J=1.5Hz,1H),7.27-7.15(m,2H),2.72(q,J=7.5Hz,2H),1.10(t,J=7.5Hz,3H). [ka]

[0238] Following the procedure outlined for compound 5, the title compound 84 was prepared in 23.6% yield. Mass (m / z): 213.2 [M+H]+ . 1 H NMR(400MHz,DMSO-d6)δ11.84(s,1H),9.00(d,J=2.3Hz,1H),8.65(dd,J=5.0,1.5Hz,1H),8.34(dt,J=8.2,1.9 Hz,1H),7.78(d,J=1.7Hz,1H),7.68(dd,J=8.1,5.1Hz,1H),7.57(dd,J=8.1,1.7Hz,1H),7.23(d,J=8.1Hz,1H). [ka]

[0239] Step 1: 5-(4-Methoxybenzyl)-8-(4-methylpyridin-3-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 85-02 was prepared in 77.9% yield following the procedure outlined for compound 3.

[0240] Step 2: A mixture of 5-(4-methoxybenzyl)-8-(4-methylpyridin-3-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 85-02 (85 mg, 0.23 mmol) and TfOH (2 mL) was stirred at 70° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with water. The aqueous phase was extracted with EA. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuum and purified by preparative HPLC to give compound 85 (45 mg, yield: 77.6%) as a white solid. Mass (m / z): 255.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.92(s,1H),8.59-8.50(m,2H),7.62(d,J=5.4Hz,1H),7.19(d,J=8. 9Hz, 1H), 7.08-6.93 (m, 2H), 4.39 (dd, J=6.1, 5.1Hz, 2H), 2.78 (t, J=5.6Hz, 2H), 2.40 (s, 3H). [ka]

[0241] Following the procedure outlined for compound 5, the title compound 86 was prepared in 49.8% yield. Mass (m / z): 243.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.11(s,1H), 8.63(d,J=1.6Hz,2H),7.73(d,J=1.7Hz,2H),7.37(d,J=1.8Hz,1H),7.26(s,1H),2.43(s,3H). [ka]

[0242] Step 1: A mixture of 3-bromo-5-iodopyridine 87-01 (5 g, 17.6 mmol), aniline 87-02 (1.64 g, 17.6 mmol), Pd2(dba)3 (732 mg, 0.8 mmol), Cs2CO3 (17.2 g, 53 mmol), and Xantphos (462 mg, 0.8 mmol) was stirred at 70 °C for 12 h under N2. The reaction mixture was cooled to room temperature and diluted with water. The aqueous phase was extracted with EA. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed under vacuum to give crude 5-bromo-N-phenylpyridin-3-amine 87-03, which was used directly in the next step.

[0243] Step 2: Following the procedure outlined for compound 5, compound 87 was prepared in 38.2% yield. Mass (m / z): 304.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.82(s,1H),8.41(d,J=1.9Hz,1H),8.33(d,J=2.5Hz,1H),7.84(t,J=2.2Hz,1H) ,7.72(d,J=1.7Hz,1H),7.50(dd,J=8.1,1.7Hz,1H),7.35(dd,J=8.5,7.3Hz,2H),7.26-7.19(m,3H),7.03-6.96(m,1H). [ka]

[0244] Following the procedure outlined for compound 5, the title compound 88 was prepared in 5.52% yield. Mass (m / z): 234.1 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ8.36(d,J=5.6Hz,2H),7.63(d,J=0.7Hz,1H),7.54(d,J=8.6Hz,1H),7.43-7.27(m,2H),7.26(s,1H),2.33(s,3H). [ka]

[0245] Step 1: Following the procedure outlined for compound 5, the title compound 89-02 was prepared in 56.2% yield. Mass (m / z): 200.1 [M+H] + .

[0246] Step 2: A solution of 4-(4-methylpyridin-3-yl)benzene-1,2-diamine 89-02 (150 mg, 0.75 mmol) and 4,5-chloro-1,2,3-dithiazol-1-ium 89-03 (256.9 mg, 0.75 mmol) in pyridine (3 mL) was stirred at 25° C. for 12 h under nitrogen protection. The solvent was removed under vacuum to give the crude product, which was purified by preparative HPLC to give compound 89 (23 mg, yield: 12.9%) as a white solid. Mass (m / z): 235.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ14.30(s,1H),8.47-8.43(m,2H),7.83(d,J=8.5Hz,1H) ,7.75(s,1H),7.44(dd,J=8.5,1.3Hz,1H),7.37(d,J=5.0Hz,1H),2.28(s,3H). [ka]

[0247] Following the procedure outlined for compound 5, the title compound 90 was prepared in 2.9% yield. Mass (m / z): 243.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.71(d,J=30.4Hz,2H),7.67-7.52(m,2H),7.36(dd,J=8.1,1.6Hz,1H),7.22(d,J=8.1Hz,1H),4.05(s,3H). [ka]

[0248] Step 1: To a solution of 7-fluorobenzo[d]oxazol-2(3H)-one 91-01 (306 mg, 2.0 mmol) in DMF (5 mL) was added NBS (356 mg, 2.0 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography to give 6-bromo-7-fluorobenzo[d]oxazol-2(3H)-one 91-02 (463 mg, yield: 99%) as a yellow solid. Mass (m / z): 231.9 [M+H] + .

[0249] Step 2: Following the procedure outlined for compound 5, the title compound 91 was prepared in 5.1% yield. Mass (m / z): 245.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.70-8.55(m,2H),7.71(d,J=5.5Hz,1H),7.19(dd,J=8.1,6.6Hz,1H),7.11(d,J=8.1Hz,1H),2.31(s,3H). [ka]

[0250] Following the procedure outlined for compound 5, the title compound 92 was prepared in 22% yield. Mass (m / z): 235.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ14.50(s,1H),8.53-8.35(m,2H),7.92-7.80(m,2H),7.58(dd,J=8.6,1.6Hz,1H),7.37(d,J=5.1Hz,1H),2.28(s,3H). [ka]

[0251] Following the procedure outlined for compound 5, the title compound 93 was prepared in 26% yield. Mass (m / z): 278.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ14.14(s,1H),8.48-8.38(m,2H),7.81(dd,J=8.7,0.9Hz,1H) ,7.77-7.73(m,1H),7.55(dd,J=8.7,1.6Hz,1H),7.36(d,J=5.0Hz,1H),2.26(s,3H). [ka]

[0252] Following the procedure outlined for compound 5, the title compound 94 was prepared in 10.7% yield. Mass (m / z): 228.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),9.08(d,J=5.1Hz,1H),7.66(d,J=5.2Hz,1H),7 .59(d,J=1.5Hz,1H),7.42(dd,J=8.0,1.6Hz,1H),7.23(d,J=8.1Hz,1H),2.36(s,3H). [ka]

[0253] Following the procedure outlined for compound 87, the title compound 95 was prepared in 11.6% yield. Mass (m / z): 320.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.77(s,1H),9.32(s,1H),8.38(s,1H),8.29(d,J=2.4Hz,2H),7.68-7.58(m,2H),7.44(d d,J=8.2,1.7Hz,1H),7.19(d,J=8.0Hz,1H),7.06(t,J=7.9Hz,1H),6.63-6.53(m,2H),6.31(dd,J=8.1,2.2Hz,1H). [ka]

[0254] Following the procedure outlined for compound 87, the title compound 96 was prepared in 9.2% yield. Mass (m / z): 338.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.39(d,J=2.0Hz,1H),8.34(d,J=2.5Hz,1H),7.70-7.63(m,2H),7.45(dd, J=8.1,1.7Hz,1H),7.29(t,J=8.0Hz,1H),7.18(d,J=8.1Hz,1H),7.15-7.07(m,2H),6.91(dd,J=8.0,2.0Hz,1H). [ka]

[0255] Following the procedure outlined for compound 87, the title compound 97 was prepared in 11.6% yield. Mass (m / z): 334.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.81(s,1H),8.48(s,1H),8.37-8.22(m,2H),7.70-7.58(m,2H),7.42(dd,J=8.1,1.8Hz ,1H),7.19(t,J=8.3Hz,2H),6.79-6.72(m,1H),6.67(t,J=2.2Hz,1H),6.49(dd,J=8.2,2.4Hz,1H),3.73(s,3H). [ka]

[0256] The title compound 98 was prepared following the procedure outlined for compound 87. Mass (m / z): 318.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.74(s,1H),8.37(d,J=1.8Hz,1H),8.26(d,J=2.5Hz,1H),7.79(s,1H) ),7.71(d,J=1.7Hz,1H),7.48(dd,J=8.1,1.7Hz,1H),7.22(d,J=8.1Hz,1H),7.19-7.11(m,4H),2.28(s,3H). [ka]

[0257] Following the procedure outlined for compound 87, the title compound 99 was prepared in 58% yield. Mass (m / z): 359.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.20(dd,J=13.9,2.2Hz,2H),8.06(s,1H),7. 59(d,J=1.6Hz,1H),7.50(t,J=2.3Hz,1H),7.39(dd,J=8.1,1.7Hz,1H),7.17(d,J=8 .0Hz,1H),6.73(d,J=8.0Hz,1H),6.30(d,J=2.2Hz,1H),6.22(dd,J=8.0,2.2Hz,1H) ,5.68(d,J=2.5Hz,1H),3.16-3.10(m,2H),2.58(t,J=6.3Hz,2H),1.82-1.71(m,2H). [ka]

[0258] Step 1: A mixture of 4-fluoroaniline 100-01 (111 mg, 1.00 mmol), 3-bromo-5-iodopyridine 87-01 (284 mg, 1.00 mmol), Pd2(dba)3 (46 mg, 0.0500 mmol), X-phos (24 mg, 0.05 mmol), and tBuONa (115 mg, 1.20 mmol) in toluene (5 mL) was stirred at 90° C. overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated to give the crude product, which was purified by silica gel chromatography to give 5-bromo-N-(4-fluorophenyl)pyridin-3-amine 100-02 (70 mg, yield: 25.67%).

[0259] Step 2: Following the procedure outlined for compound 5, the title compound 100 was prepared in 28.1% yield. Mass (m / z): 322.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.76(s,1H),8.43(s,1H),8.27(dd,J=8.8,2.3Hz,2H),7.63( d,J=1.7Hz,1H),7.54(t,J=2.3Hz,1H),7.43(dd,J=8.1,1.7Hz,1H),7.24-7.06(m,5H). [ka]

[0260] Step 1: Following the procedure outlined for compound 5, the title compound 101-02 was prepared in 51.3% yield. Mass (m / z): 228.1 [M+H] + .

[0261] Step 2: Following the procedure outlined for compound 100-02, the title compound 101 was prepared in 14.1% yield. Mass (m / z): 322.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.82(s,1H),8.91(s,1H),8.46(d,J=1.9Hz,1H),8.38(d,J=2.4Hz,1H),7.85(t,J=2.2Hz,1H),7.73(d,J=1 .7Hz,1H),7.51(dd,J=8.1,1.7Hz,1H),7.32(dd,J=8.2,6.9Hz,1H),7.22(d,J=8.1Hz,1H),7.06-6.94(m,2H),6.74(d,J=2.4Hz,1H). [ka]

[0262] Following the procedure outlined for compound 100, the title compound 102 was prepared in 2.6% yield. Mass (m / z): 322.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.83(d,J=4.1Hz,1H),8.63(d,J=20.4Hz,1H),8.42(s,1H),8.27(d,J=2.4Hz,1H),7.7 6-7.66(m,2H),7.52-7.39(m,2H),7.31(ddd,J=11.6,8.1,1.7Hz,1H),7.25-7.15(m,2H),7.09(d,J=6.4Hz,1H). [ka]

[0263] The title compound 103 was prepared following the procedure outlined for compound 100. Mass (m / z): 346.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.92(s,1H),9.11(s,1H),8.47(d,J=1.8Hz,1H),8.32(d,J=2.5Hz,1H),8.00(t,J=2.2Hz,1H),7.75(d,J=1.7Hz,1 H),7.52(dd,J=8.1,1.8Hz,1H),7.33-7.21(m,2H),7.15-7.07(m,2H),6.95(d,J=7.6Hz,1H),2.89(p,J=6.9Hz,1H),1.22(d,J=6.9Hz,6H). [ka]

[0264] The title compound 104 was prepared following the procedure outlined for compound 87. Mass (m / z): 338.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.83(s,1H),8.88(s,1H),8.44(d,J=1.9Hz,1H),8.33(d,J=2.5Hz,1H),7. 83(s,1H),7.73(d,J=1.7Hz,1H),7.50(dd,J=8.1,1.7Hz,1H),7.40-7.31(m,2H),7.26-7.16(m,3H). [ka]

[0265] The title compound 105 was prepared following the procedure outlined for compound 100. Mass (m / z): 305.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),8.66(s,1H),8.42(d,J=2.8Hz,1H),8. 37(d,J=2.0Hz,1H),8.34(d,J=2.6Hz,1H),8.11(dd,J=4.7,1.4Hz,1H),7.68( d,J=1.7Hz,1H),7.65(t,J=2.3Hz,1H),7.61(ddd,J=8.4,2.9,1.4Hz,1H),7. 47(dd,J=8.1,1.7Hz,1H),7.29(dd,J=8.3,4.6Hz,1H),7.19(d,J=8.1Hz,1H). [ka]

[0266] Following the procedure outlined for compound 100, the title compound 106 was prepared in 29% yield. Mass (m / z): 459.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.40(s,1H),8.25(dd,J=8.6,2.2Hz,2H),7.77-7.67(m,2H),7.61(d,J=2.3Hz,1H),7.54(dd,J=8.1,1.7Hz,1H) ,7.14(d,J=8.1Hz,1H),7.02(d,J=8.2Hz,1H),6.75(dd,J=8.1,2.3Hz,1H) ,3.68-3.59(m,2H),2.67(t,J=6.5Hz,2H),1.88-1.76(m,2H),1.47(s,9H). [ka]

[0267] Following the procedure outlined for compound 87, the title compound 107 was prepared in 11.6% yield. Mass (m / z): 329.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),9.00(s,1H),8.49(d,J=1.9Hz,1H),8.41(d,J=2.5Hz,1H),7.86(t,J =2.2Hz,1H),7.74(d,J=1.6Hz,1H),7.56-7.47(m,4H),7.34(td,J=4.5,4.0,1.5Hz,1H),7.24-7.20(m,1H). [ka]

[0268] The title compound 108 was prepared following the procedure outlined for compound 87. Mass (m / z): 308.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.22 (s, 1H), 7.95 (s, 1H), 7.80 (t, J = 1.8 Hz, 1H), 7.70 (s, 1H), 7.56-7.52 (m, 1H), 7.50-7.41 (m, 2H), 7.16 (d, J = 8.1 Hz, 1H), 6.98 (s, 1H), 3.85 (s, 3H). [ka]

[0269] Following the procedure outlined for compound 87, the title compound 109 was prepared in 17% yield. Mass (m / z): 318.3 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ8.32(d,J=1.7Hz,1H),7.98(d,J=2.7Hz,1H),7.84(dd,J=2.7,1.7Hz,1H),7.60(d,J=1. 8Hz,1H),7.58-7.52(m,2H),7.49(dd,J=8.1,1.8Hz,1H),7.42-7.34(m,3H),7.23(d,J=8.1Hz,1H),3.49(s,3H). [ka]

[0270] The title compound 110 was prepared following the procedure outlined for compound 87. Mass (m / z): 242.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.90(s,1H),8.29(s,1H),7.98(d,J=2.2Hz,1H),7. 79(s,1H),7.69-7.47(m,2H),7.24(d,J=8.1Hz,1H),6.86(s,1H),2.85(s,3H) [ka]

[0271] Following the procedure outlined for compound 87, the title compound 111 was prepared in 12.1% yield. Mass (m / z): 305.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.85(s,1H),10.63(s,1H),8.84(d,J=2.1Hz,1H),8.55(d,J=2.3Hz,1H),8.34(d, J=7.1Hz,2H), 8.09(t,J=2.3Hz,1H),7.80(d,J=1.7Hz,1H),7.59(dd,J=8.1,1.7Hz,1H),7.27-7.19(m,3H). [ka]

[0272] The title compound 112 was prepared following the procedure outlined for compound 100. Mass (m / z): 305.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.79(d,J=2.6Hz,1H),8.36(s,1H),7.88(s,1 H),7.76(d,J=8.2Hz,1H),7.45-7.38(m,3H),7.35-7.29(m,2H),7.18-7.09(m,2H). [ka]

[0273] The title compound 113 was prepared following the procedure outlined for compound 87. Mass (m / z): 305.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.89(s,1H),9.80(s,1H),9.11(s,1H),8.57(d,J=2.5Hz,2H),8.27(dd,J=5.1 ,1.9Hz,1H),7.77-7.67(m,2H),7.53(dd,J=8.1,1.8Hz,1H),7.27(d,J=8.1Hz,1H),7.01-6.89(m,2H). [ka]

[0274] Following the procedure outlined for compound 87, the title compound 114 was prepared in 16.2% yield. Mass (m / z): 306.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),9.08(d,J=5.5Hz,1H),8.80(s,1H),8.74(s,2H),8.53(s,1H),8.44 (s,1H),7.96(d,J=3.0Hz,1H),7.78(d,J=1.7Hz,1H),7.55(dd,J=8.1,1.8Hz,1H),7.23(d,J=8.1Hz,1H). [ka]

[0275] The title compound 115 was prepared following the procedure outlined for compound 87. Mass (m / z): 311.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.79(s,1H),10.53(s,1H),8.69(d,J=2.4Hz,1H),8.47(t,J=2.3Hz,1H),8.44-8.42(m,1H),7 .64(d,J=1.7Hz,1H),7.45(dd,J=8.1,1.8Hz,1H),7.33(d,J=3.7Hz,1H),7.23(d,J=8.1Hz,1H),7.01(d,J=3.7Hz,1H). [ka]

[0276] Following the procedure outlined for compound 87, the title compound 116 was prepared in 18.1% yield. Mass (m / z): 306.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.92(d,J=3.0Hz,1H),8.73(d,J=6.1Hz,1H),8.61(d,J=2.0Hz,1H),8.46(d,J=2.5Hz,1H) ,7.91(t,J=2.3Hz,1H),7.76(d,J=1.7Hz,1H),7.55(dd,J=8.1,1.8Hz,1H),7.25(dd,J=6.1,3.1Hz,1H),7.21(d,J=8.1Hz,1H). [ka]

[0277] Following the procedure outlined for compound 87, the title compound 117 was prepared in 16.2% yield. Mass (m / z): 322.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.73(s,1H),8.43(d,J=1.8Hz,1H),8.18(d,J=2.5Hz,1H),7.71(d,J=1.7Hz,1 H),7.64(t,J=2.3Hz,1H),7.48(dd,J=8.1,1.8Hz,1H),7.23(d,J=8.1Hz,1H),6.02(s,1H),3.63(s,3H),2.14(s,3H). [ka]

[0278] Following the procedure outlined for compound 87, the title compound 118 was prepared in 38% yield. Mass (m / z): 306.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),9.90(s,1H),9.02(s,1H),8.81(dd,J=4.6,1.3Hz,1H),8.61(dd,J=5.2, 3.1Hz,2H),7.72(d,J=1.7Hz,1H),7.60(dd,J=9.0,4.6Hz,1H),7.52(dd,J=8.1,1.7Hz,1H),7.33-7.22(m,2H). [ka]

[0279] Following the procedure outlined for compound 5, the title compound 119 was prepared in 10.6% yield. Mass (m / z): 305.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.81(s,1H),8.72(d,J=2.0Hz,1H),8.32(d,J=2.6Hz,1H),7.75(d,J=2.4H z,2H),7.52(dd,J=8.2,1.8Hz,1H),7.44(t,J=7.8Hz,2H),7.25-7.17(m,2H),7.13(d,J=8.0Hz,2H). [ka]

[0280] Following the procedure outlined for compound 3, the title compound 120 was prepared in 0.5% yield. Mass (m / z): 254.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.43(d,J=5.0Hz,1H),8.38(s,1H),7.83(d,J=2.1Hz,1H),7 .70(dd,J=8.4,2.1Hz,1H),7.34(d,J=5.0Hz,1H),7.27(d,J=8.4Hz,1H),2.26(s,3H)

[0281] Example 2. SAMR1(50-724) Enzyme Assay The enzyme assay was carried out in 384-well plates using Dulbecco's PBS buffer as the reaction buffer. Purified SARM1(50-724) at a final concentration of 2 nM was pre-incubated with test compounds at a final assay concentration of 1% DMSO for 15 min at room temperature. 200 μM NMN as activator and 100 μM NAD as substrate. + The reaction was started by adding a mixture of 100 mM NaCl and 100 mM MgCl. After incubation at room temperature for 1 h, the reaction was stopped with 10 volumes of 70% acetonitrile and then centrifuged at 3800 rpm for 10 min. Samples were diluted to appropriate concentrations with 10 mM ammonium acetate (pH 9.75) and then analyzed using LC-MS / MS.

[0282] The SARM1 inhibitory activities of compounds 1-120 are summarized in Table 2. In Table 2, the activities are provided as follows: A=IC50<5 μM; B=5 μM≦IC50<15 μM; C=15 μM≦IC50≦30 μM; D=IC50>30 μM.

[0283] [Table 2]

[0284] All publications, including but not limited to disclosures and disclosed applications, cited herein are incorporated by reference as if fully set forth. In the event that the specific content of a publication cited herein contradicts or is inconsistent with the present disclosure, the present disclosure shall control.

[0285] 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 disclosure, as defined in the following claims.

Claims

1. Structural formula I: 【Chemistry 1】 [In the formula, X in ring A １ , X ２ , X ３ , and X ４ One or two of X is N; １ , X ２ , X ３ , and X ４ the remainder are C; Ring B is phenyl, or Y in Ring B is １ , Y ２ , Y ３ , and Y ４ One or two of Y is N; １ , Y ２ , Y ３ , and Y ４ the remainder are C; R ａ is H, -OR ｓ , halogen, —NR ｐ R ｑ , C ３ ~C ６ Cycloalkyl, CN, and C １ ~C ６ alkyl, and said R ａ C ３ ~C ６ Cycloalkyl and C １ ~C ６ Alkyl is halogen, —OR ｓ , and -NR ｐ R ｑ and optionally substituted with 1 to 3 groups selected from R ｃ is H, CN, -S(=O) ｗ NR ｐ１ R ｑ１ , -OR ｓ , halogen, —NR ｐ１ R ｑ１ , and halogen, -OR ｓ , and -NR ｐ１ R ｑ１ C optionally substituted with 1 to 3 groups selected from １ ~C ６ alkyl, with the proviso that R ｃ is CH ２ Not OH; R ｂ is absent or is H, halogen, -C(=O)(C １ ~C ６ alkyl), -NR ｐ１ R ｑ１ , -OR ｓ , and halogen, -OR ｓ , and -NR ｐ１ R ｑ１ C optionally substituted with 1 to 3 groups selected from １ ~C ６ alkyl; R ｄ is absent or is H, CN, -S(=O) ｗ NR ｐ１ R ｑ１ , -OR ｓ , halogen, —NR ｐ１ R ｑ１ , C ３ ~C ６ Cycloalkyl and halogen, —OR ｓ , and -NR ｐ１ R ｑ１ C optionally substituted with 1 to 3 groups selected from １ ~C ６ alkyl, with the proviso that R ｄ is CH ２ Not OH; R ｂ and R ｃ may be taken together to form an optionally substituted 5- to 7-membered heterocyclic or heteroaromatic ring; R ｂ and R ｄ may be taken together to form an optionally substituted 5- to 7-membered heterocyclic or heteroaromatic ring; R ｅ is H, halogen, -CN, halogen, -OR ｓ , and -NR ｐ１ R ｑ１ C optionally substituted with 1 to 3 groups selected from １ ~C ６ alkyl; R ｓ Each occurrence of represents H, phenyl, 5- to 10-membered heteroaryl, C ３ ~C ６ Cycloalkyl, and C １ ~C ６ alkyl, wherein R ｓ phenyl, 5- to 10-membered heteroaryl, C ３ ~C ６ Cycloalkyl, and C １ ~C ６ Alkyl is a halogen, —OH, and —O(C １ ~C ３ alkyl); R ｐ and R ｑ Each occurrence of represents hydrogen, phenyl, 9- to 10-membered aryl, 5- to 10-membered heteroaryl, C ３ ~C ６ Cycloalkyl, and C １ ~C ４ alkyl, wherein R ｐ and R ｑ phenyl, 9- to 10-membered aryl, 5- to 10-membered heteroaryl, C ３ ~C ６ Cycloalkyl, and C １ ~C ４ Each alkyl is —COO(C １ ~C ４ alkyl), halogen, —OH, —CN, —COOH, —CONH ２ , -CONH(C １ ~C ３ alkyl), -NH(C １ ~C ３ alkyl), —O(C １ ~C ３ alkyl), and C １ ~C ４ optionally substituted with 1 to 3 groups selected from alkyl; R ｐ１ and R ｑ１ represents, for each occurrence, hydrogen, -CO(C １ ~C ６ alkyl), -SO ２ CH ３ , C ３ ~C ６ Cycloalkyl, and C １ ~C ６ alkyl, wherein R ｐ１ and R ｑ１ C ３ ~C ６ Cycloalkyl and C １ ~C ６ each alkyl is optionally substituted with 1 to 3 halogens; m is an integer independently selected from 0, 1, 2, and 3; n is an integer independently selected from 0, 1, and 2; and w is an integer selected from 1 and 2, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

2. 2. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of claim 1, wherein Ring A is a pyridinyl group, a pyrimidinyl group, or a pyridazinyl group.

3. Ring B is a phenyl group or a pyridinyl group, and Y １ , Y ２ , Y ３ , and Y ４ One of the groups is N and one of the groups is Y １ , Y ２ , Y ３ , and Y ４ and the remainder is C.

4. The compound has the following structural formula IIa: 【Chemistry 2】 2. The compound of claim 1, having the formula:

5. The compound has the following structural formula IIb: 【Transformation 3】 2. The compound of claim 1, having the formula:

6. The compound has the following structural formula IIc: 【Chemistry 4】 2. The compound of claim 1, having the formula:

7. The compound has the following structural formula IId: 【Transformation 5】 2. The compound of claim 1, having the formula:

8. The compound has the following structural formula IIIa: 【Transformation 6】 2. The compound of claim 1, having the formula:

9. The compound has the following structural formula IIIb: 【Transformation 7】 2. The compound of claim 1, having the formula:

10. The compound has the following structural formula IIIc: 【Transformation 8】 2. The compound of claim 1, having the formula:

11. The compound has the following structural formula IIId: 【Chemistry 9】 2. The compound of claim 1, having the formula:

12. The compound has the following structural formula IIIe: 【Chemistry 10】 2. The compound of claim 1, having the formula:

13. The compound has the following structural formula IIIf: 【Chemistry 11】 [In the formula, W １ and W ２ are each independently selected from NH and O; W １ is O, then R ｃ’ is H, C ３ ~C ６ Cycloalkyl, and C １ ~C ６ alkyl, and said R ｃ’ C ３ ~C ６ Cycloalkyl and C １ ~C ６ Alkyl is a halogen, —OH, and —O(C １ ~C ３ alkyl); W １ When is NH, R ｃ’ is hydrogen, -CO(C １ ~C ６ alkyl), -SO ２ CH ３ , C ３ ~C ６ Cycloalkyl, and C １ ~C ６ alkyl, and said R ｃ’ C ３ ~C ６ Cycloalkyl and C １ ~C ６ each alkyl is optionally substituted with 1 to 3 halogens; W ２ is O, then R ｂ’ is H, C ３ ~C ６ Cycloalkyl, and C １ ~C ６ alkyl, and said R ｂ’ C ３ ~C ６ Cycloalkyl and C １ ~C ６ Alkyl is a halogen, —OH, and —O(C １ ~C ３ alkyl); W ２ When is NH, R ｂ’ is hydrogen, -CO(C １ ~C ６ alkyl), -SO ２ CH ３ , C ３ ~C ６ Cycloalkyl, and C １ ~C ６ alkyl, and said R ｂ’ C ３ ~C ６ Cycloalkyl and C １ ~C ６ wherein each alkyl is optionally substituted with 1 to 3 halogens, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

14. The compound has the following structural formula IVa: 【Chemistry 12】 [In the formula, R ｂ and R ｃ and R 1 and R 2 together form an optionally substituted 5- to 7-membered heterocyclic or aromatic heterocyclic ring, or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

15. The compound has the following structural formula IVb: 【Chemistry 13】 [In the formula, R ｂ and R ｃ and R 1 and R 2 together form an optionally substituted 5- to 7-membered heterocyclic or aromatic heterocyclic ring, or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt thereof.

16. The compound has the following structural formula IVc: 【Chemistry 14】 [In the formula, R ｂ and R ｃ and R 1 and R 2 together form an optionally substituted 5- to 7-membered heterocyclic or aromatic heterocyclic ring, or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt thereof.

17. The compound has the following structural formula IVd: 【Chemistry 15】 [In the formula, R ｂ and R ｃ and R 1 and R 2 together form an optionally substituted 5- to 7-membered heterocyclic or aromatic heterocyclic ring, or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt thereof.

18. The compound has the following structural formula Va: 【Chemistry 16】 [In the formula, R ａ is C １ ~C ３ Alkyl, halogen, —O(C １ ~C ３ ) alkyl, —OCFH ２ , -OCF ２ H, -OCF ３ 10. The compound of claim 1, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein

19. The compound has the following structural formula VIa: 【Chemistry 17】 [In the formula, R ｃ is -OR ｓ 10. The compound of claim 1, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein

20. The compound has the following structural formula VIb: [Chemistry 18] [In the formula, R ｂ is -OR ｓ 10. The compound of claim 1, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein

21. The compound has the following structural formula VIc: 【Chemistry 19】 [In the formula, R ｂ is -OR ｓ and R ｃ is a halogen, -OR ｓ , and C １ ~C ３ 2. The compound of claim 1, wherein the aryl group is selected from the group consisting of aryl, arylalkyl, arylsulfonyl ...

22. The compound has the following structural formula VId: 【Chemistry 20】 [In the formula, R ｃ is -OR ｓ and R ｅ is selected from halogen; a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing.

23. The compound has the following structural formula VIe: 【Chemistry 21】 [In the formula, R ｃ and R ｄ are respectively -OR ｓ and halogen], a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

24. The compound has the following structural formula VIf: 【Chemistry 22】 [In the formula, R ｃ is -OR ｓ and halogen], a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing.

25. The compound has the following structural formula VIIa: 【Chemistry 23】 [In the formula, R ａ is H, -OR ｓ , halogen, —NR ｐ R ｑ , C ３ ~C ６ Cycloalkyl, CN, and halogen, —OR ｓ , and -NR ｐ R ｑ C optionally substituted with 1 to 3 groups selected from １ ~C ６ alkyl, and R ｐ and R ｑ is hydrogen, C １ ~C ３ independently selected from alkyl, phenyl, 9- to 10-membered aryl, and 5- to 10-membered heteroaryl, ｐ and R ｑ Phenyl, 9- to 10-membered aryl, and 5- to 10-membered heteroaryl are —COO(C １ ~C ４ alkyl), halogen, OH, —CN, —COOH, —CONH ２ , -CONH(C １ ~C ３ alkyl), -NH(C １ ~C ３ alkyl), —O(C １ ~C ３ alkyl), and C １ ~C ４ optionally substituted with 1 to 3 groups selected from alkyl; R ｆ is a halogen, C １ ~C ４ Alkyl, C ２ ~C ４ alkynyl, and CN, where p is an integer selected from 0, 1, and 2; Z １ , Z ２ , and Z ３ One, two, or three of Z １ , Z ２ , and Z ３ If one or two of １ , Z ２ , and Z ３ and the remainder is C, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing.

26. The compound has the following structural formula VIIb: 【Chemistry 24】 [In the formula, R ａ is H, -OR ｓ , halogen, —NR ｐ R ｑ , C ３ ~C ６ Cycloalkyl, CN, and halogen, —OR ｓ , and -NR ｐ R ｑ C optionally substituted with 1 to 3 groups selected from １ ~C ６ alkyl, and R ｐ and R ｑ is hydrogen, C １ ~C ３ independently selected from alkyl, phenyl, 9- to 10-membered aryl, and 5- to 10-membered heteroaryl, ｐ and R ｑ Phenyl, 9- to 10-membered aryl, and 5- to 10-membered heteroaryl are —COO(C １ ~C ４ alkyl), halogen, OH, —CN, —COOH, —CONH ２ , -CONH(C １ ~C ３ alkyl), -NH(C １ ~C ３ alkyl), —O(C １ ~C ３ alkyl), and C １ ~C ４ optionally substituted with 1 to 3 groups selected from alkyl; R ｆ is a halogen, C １ ~C ４ Alkyl, C ２ ~C ４ alkynyl, and ═O, where p is an integer selected from 0, 1, and 2; Z ２ and Z ３ are each independently selected from O, N, S, and C; Z ２ and Z ３ at least one of is a heteroatom; D is selected from O, S, and NH; X １ and X ２ wherein one or two of is N, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing.

27. The compound has the following structural formula VIIc: 【Chemistry 25】 [In the formula, R ａ is H, -OR ｓ , halogen, —NR ｐ R ｑ , C ３ ~C ６ Cycloalkyl, CN, and —COO(C １ ~C ４ alkyl), halogen, -OR ｓ , and -NR ｐ R ｑ C optionally substituted with 1 to 3 groups selected from １ ~C ６ alkyl, and R ｐ and R ｑ is hydrogen, C １ ~C ３ independently selected from alkyl, phenyl, 9- to 10-membered aryl, and 5- to 10-membered heteroaryl, ｐ and R ｑ Phenyl, 9- to 10-membered aryl, and 5- to 10-membered heteroaryl are halogen, OH, —CN, —COOH, —CONH ２ , -CONH(C １ ~C ３ alkyl), -NH(C １ ~C ３ alkyl), —O(C １ ~C ３ alkyl), and C １ ~C ４ optionally substituted with 1 to 3 groups selected from alkyl; R ｆ is a halogen, C １ ~C ４ Alkyl, C ２ ~C ４ alkynyl, and ═O, where p is an integer selected from 0, 1, and 2; Z ２ and Z ３ are each independently selected from O, N, S, and C; Z ２ and Z ３ at least one of is a heteroatom; D is selected from O, S, and NH; X １ and X ２ wherein one or two of is N, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing.

28. The compound has the following structural formula VIId: 【Chemistry 26】 [In the formula, R ａ is H, -OR ｓ , halogen, —NR ｐ R ｑ , C ３ ~C ６ Cycloalkyl, CN, and halogen, —OR ｓ , and -NR ｐ R ｑ C optionally substituted with 1 to 3 groups selected from １ ~C ６ alkyl, and R ｐ and R ｑ For each occurrence, -COO(C １ ~C ４ alkyl), hydrogen, C １ ~C ３ independently selected from alkyl, phenyl, 9- to 10-membered aryl, and 5- to 10-membered heteroaryl, ｐ and R ｑ Phenyl, 9- to 10-membered aryl, and 5- to 10-membered heteroaryl are halogen, OH, —CN, —COOH, —CONH ２ , -CONH(C １ ~C ３ alkyl), -NH(C １ ~C ３ alkyl), —O(C １ ~C ３ alkyl), and C １ ~C ４ optionally substituted with 1 to 3 groups selected from alkyl; R ｆ is a halogen, C １ ~C ４ Alkyl, C ２ ~C ４ alkynyl, and ═O, where p is an integer selected from 0, 1, and 2; Z １ and Z ２ are each independently selected from O, N, S, and C; Z １ and Z ２ at least one of is a heteroatom; D is selected from O, NH, and S; X １ and X ２ wherein one or two of is N, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing.

29. The compound has the following structural formula VIIe: 【Chemistry 27】 [In the formula, R ａ is H, -OR ｓ , halogen, —NR ｐ R ｑ , C ３ ~C ６ Cycloalkyl, CN, and halogen, —OR ｓ , and -NR ｐ R ｑ C optionally substituted with 1 to 3 groups selected from １ ~C ６ alkyl, and R ｐ and R ｑ is hydrogen, C １ ~C ３ independently selected from alkyl, phenyl, 9- to 10-membered aryl, and 5- to 10-membered heteroaryl, ｐ and R ｑ Phenyl, 9- to 10-membered aryl, and 5- to 10-membered heteroaryl are —COO(C １ ~C ４ alkyl), halogen, OH, —CN, —COOH, —CONH ２ , -CONH(C １ ~C ３ alkyl), -NH(C １ ~C ３ alkyl), —O(C １ ~C ３ alkyl), and C １ ~C ４ optionally substituted with 1 to 3 groups selected from alkyl; R ｆ is a halogen, C １ ~C ４ Alkyl, C ２ ~C ４ alkynyl, and ═O, where p is an integer selected from 0, 1, and 2; Z １ and Z ２ are each independently selected from O, N, S, and C; Z １ and Z ２ at least one of is a heteroatom; D is selected from O, NH, and S; X １ and X ２ wherein one or two of is N, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing.

30. R ａ But H, -OR ｓ , halogen, —NR ｐ R ｑ , C ３ ~C ６ Cycloalkyl, CN, and halogen, —OR ｓ , and -NR ｐ R ｑ C optionally substituted with 1 to 3 groups selected from １ ~C ６ alkyl, and R ｓ Each occurrence of H, phenyl, -CFH ２ , -CF ２ H, -CF ３ , and C １ ~C ３ alkyl; R ｐ and R ｑ But for each occurrence, hydrogen, C １ ~C ３ independently selected from alkyl, phenyl, 9- to 10-membered aryl, and 5- to 10-membered heteroaryl, ｐ and R ｑ Phenyl, 9- to 10-membered aryl, and 5- to 10-membered heteroaryl are —COO(C １ ~C ４ alkyl), halogen, OH, —CN, —COOH, —CONH ２ , -CONH(C １ ~C ３ alkyl), -NH(C １ ~C ３ alkyl), —O(C １ ~C ３ alkyl), and C １ ~C ４ 18. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 17, optionally substituted with 1 to 3 groups selected from alkyl.

31. R ａ is H, -CH ３ , -CH ２ CH ３ , -OCFH ２ , -OCF ２ H, -OCF ３ , -OCH ３ , CN, Cl, OH, NH ２ , -NHCH ３ ,and 【Chemistry 28】 18. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 17, selected from:

32. R ｂ is absent or is H, halogen, -C(=O)(C １ ~C ３ alkyl), -NR ｐ１ R ｑ１ , -OR ｓ and halogen and —NR ｐ１ R ｑ１ optionally substituted with 1 to 2 groups selected from １ ~C ３ alkyl; R ｓ For each occurrence, H,-CF ３ , -CF ２ H and C １ ~C ３ alkyl; R ｐ１ and R ｑ１ each occurrence is hydrogen and optionally substituted C １ ~C ３ 13. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 12, wherein: R is independently selected from alkyl;

33. R ｂ H, methyl, CH ２ NH ２ , —C(═O)CH ３ , N.H. ２ , F, Br, OH, and 【Chemistry 29】 13. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 12, selected from:

34. R ｃ is H, CN, -S(=O) ｗ NR ｐ R ｑ , -OR ｓ , halogen, —NR ｐ１ R ｑ１ and halogen and —NR ｐ１ R ｑ１ C optionally substituted with 1 to 3 groups selected from １ ~C ３ alkyl, and R ｓ For each occurrence, H and C １ ~C ３ alkyl; R ｐ１ and R ｑ１ For each occurrence, hydrogen and C １ ~C ３ 13. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 12, wherein: R is independently selected from alkyl;

35. R ｃ H, methyl, ethyl, CHF ２ , C.F. ３ , F, Cl, Br, NH ２ , OH, OCH ３ , CN, and -S(=O) ２ NH ２ 13. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 12, selected from:

36. R ｄ is H, CN, -S(=O) ｗ NR ｐ R ｑ , -OR ｓ , halogen, —NR ｐ１ R ｑ１ and halogen and —NR ｐ１ R ｑ１ C optionally substituted with 1 to 3 groups selected from １ ~C ３ alkyl, and R ｓ For each occurrence, H and C １ ~C ３ alkyl; R ｐ１ and R ｑ１ For each occurrence, hydrogen and C １ ~C ３ 13. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 12, wherein: R is independently selected from alkyl;

37. R ｄ H, methyl, ethyl, CHF ２ , C.F. ３ , F, Cl, Br, NH ２ , OH, OCH ３ , CN, and -S(=O) ２ NH ２ 13. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 12, selected from:

38. R ｅ is H, halogen, and halogen and —NH ２ C optionally substituted with 1 to 3 groups selected from １ ~C ３ 19. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 18, wherein:

39. R ｅ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 18, wherein is selected from H, methyl, F, and Cl.

40. R ｂ and R ｃ , or R ｂ and R ｄ together form C optionally substituted with 1 to 3 groups selected from CN, halogen, ═O, ═S, ═NH, halogen １ ~C ３ Alkyl, and —NR ｐ R ｑ and R ｐ and R ｑ But for each occurrence, hydrogen, C １ ~C ３ Alkyl, and —C(═O)C １ ~C ３ 8. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 7, wherein: R is independently selected from alkyl;

41. R ｂ and R ｃ , or R ｂ and R ｄ But together, 【Transformation 30】 8. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 7, which forms a structure selected from:

42. The compound has the following structural formula VIIIa: 【Chemistry 31】 [In the formula, R ｇ For each occurrence, C １ ~C ３ Alkyl, CN, OH, —O(C １ ~C ３ alkyl), -NH(C １ ~C ３ alkyl), halogen, and q is an integer selected from 0, 1, and 2; Z １ and Z ２ are O, NH, S, and CH, respectively. ２ and Z ２ and Z ３ at least one of is a heteroatom; D is selected from O and S; X １ and X ２ one or two of are N; U is C or N; W ３ is O or NH, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing.

43. The compound is selected from the group consisting of: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 2. The compound of claim 1 selected from: a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

44. 44. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29, 42 and 43, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing, and at least one pharmaceutically acceptable carrier.

45. A compound according to any one of claims 1 to 29, 42 and 43, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of said compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt, for use in the treatment of a disease or condition selected from ALS, Parkinson's disease, multiple sclerosis, traumatic brain injury, diabetic neuropathy, and CIPN.

46. 44. A compound according to any one of claims 1 to 29, 42 and 43, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition of said compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt, for use in the treatment of a disease or condition caused by axonal degeneration.

47. 44. A method of modulating SARM1, comprising contacting a subject in need thereof with a compound according to any one of claims 1 to 29, 42 and 43, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of said compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt.

48. 44. A compound according to any one of claims 1 to 29, 42 and 43, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of said compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt for use in inhibiting or preventing axonal degeneration.

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