Inhibitors of SARM1

Abstract

To provide compounds and methods useful for inhibiting SARM1 and / or treating and / or preventing axonal degeneration.SOLUTION: The present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, where ring A is a 5-6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 958,178, filed January 7, 2020, and U.S. Provisional Patent Application No. 63 / 065,736, filed August 14, 2020, which are incorporated by reference in their entireties.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated by reference in its entirety. The ASCII copy created on December 22, 2020 is named 2012800-0069_SL.txt and is 8,857 bytes in size. [Background technology]

[0003] Axonal degeneration is a hallmark of several neurological disorders, including peripheral neuropathy, traumatic brain injury, and neurodegenerative diseases (Gerdts et al., SARM1 activation triggers axon degeneration locally via NAD(+) destruction. Science 348 2016, pp. 453-457, incorporated herein by reference in its entirety). Neurodegenerative diseases and injuries are devastating to both patients and caregivers. The costs associated with these diseases currently exceed hundreds of billions of dollars annually in the United States alone. The incidence of many of these diseases and disorders increases with age, so their incidence is rapidly increasing as demographics change. Summary of the Invention

[0004] The present disclosure provides, inter alia, techniques useful for treating and / or preventing neurodegeneration (e.g., reducing axonal degeneration). In some embodiments, the techniques provided inhibit SARM1.

[0005] In some embodiments, the present disclosure provides certain compounds and / or compositions that are useful in medicine, and in particular for treating neurodegeneration (e.g., for reducing axonal degeneration).

[0006] In some embodiments, the present disclosure provides a compound having a structure as set forth in formula I: [ka] or a pharma- ceutically acceptable salt thereof, wherein: Ring A is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 1 is an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Each R x are independently halogen, cyano, OR, SR, N(R)2, or C 1-4 an optionally substituted group selected from aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; L is an optionally substituted C 1-4 an aliphatic chain in which 1 or 2 carbon atoms are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)N(R)-, -N(R)S(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring; Each R is independently hydrogen or C 1-6an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from phenyl, and oxygen, nitrogen, and sulfur; or two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 3-7 membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 2 is hydrogen, halogen, N(R)2, OR, or C 1-6 an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; n is 0, 1, or 2.

[0007] In some embodiments, the present disclosure provides a compound having a structure as set forth in formula I': [ka] or a pharma- ceutically acceptable salt thereof, wherein: Ring A is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 1is an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Each R x are independently halogen, cyano, OR, SR, N(R)2, S(O)2N(R)2, C(O)OR, C(O)N(R)2, or C 1-4 an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; L is an optionally substituted C 1-4 an aliphatic chain in which 1 or 2 carbon atoms are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -S(O)2-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from phenyl, and oxygen, nitrogen, and sulfur; or two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 3-7 membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 2 is hydrogen, halogen, N(R)2, OR, or C 1-6an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; n is 0, 1, or 2.

[0008] In some embodiments, provided compounds have the structure of formula Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, Ihi, Ii, Iii, Ij, Iji, Ik, Iki, Il, Ili, Im, Imi, In, Ini, Io, Ioi, Ip, Ipi, Ip-ii, Iq, Iqi, Ir, Is, It, Iu, and Iv, as described below.

[0009] In some embodiments, one or more compounds of formula I are provided and / or utilized in a solid form (eg, a crystalline or amorphous form).

[0010] In some embodiments, the disclosure provides compositions that include and / or deliver a compound of formula I (eg, in the form described herein), a prodrug, or an active metabolite thereof.

[0011] In some embodiments, the disclosure provides compositions that contain and / or deliver a compound of formula I. In some embodiments, such compositions are pharmaceutical compositions that include at least one pharma- ceutically acceptable carrier, diluent, or excipient.

[0012] In some embodiments, provided SARM1 inhibitors reduce or inhibit the binding of NAD+ by SARM1. In some embodiments, provided SARM1 inhibitors bind to SARM1 in a pocket that includes one or more catalytic residues (e.g., the catalytic cleft of SARM1).

[0013] In some embodiments, provided compounds and / or compositions inhibit the activity of SARM1.Alternatively or additionally, in some embodiments, provided compounds alleviate one or more attributes of neurodegeneration.In some embodiments, the present disclosure provides a method for treating a neurodegenerative disease or disorder associated with axonal degeneration.

[0014] In some embodiments, one or more compounds and / or compositions described herein are useful, for example, in the practice of medicine.In some embodiments, one or more compounds and / or compositions described herein are useful, for example, for treating, preventing, or improving axon degeneration (e.g., one or more characteristics or features thereof).In some embodiments, one or more compounds and / or compositions described herein are useful, for example, for inhibiting axon degeneration, including axon degeneration resulting from reduction or depletion of NAD+.In some embodiments, one or more compounds and / or compositions described herein are useful, for example, for preventing axons distal to axonal injury from degenerating.

[0015] In some embodiments, one or more compounds and / or compositions described herein are useful for treating one or more neurodegenerative diseases, disorders, or conditions, for example, selected from the group consisting of neuropathy or axonopathy. In some embodiments, one or more compounds and / or compositions described herein are useful for treating, for example, neuropathy or axonopathy associated with axon degeneration. In some embodiments, the neuropathy associated with axon degeneration is a genetic or congenital neuropathy or axonopathy. In some embodiments, the neuropathy associated with axon degeneration results from a neo- or somatic mutation. In some embodiments, the neuropathy associated with axon degeneration is selected from the list contained herein. In some embodiments, the neuropathy or axonopathy is associated with axonal degeneration, including, but not limited to, Parkinson's disease, Parkinsonian syndromes, or Parkinson-plus syndromes, such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis (ALS), demyelinating diseases, such as multiple sclerosis, ischemia or stroke, chemical injury, thermal injury, and AIDS.

[0016] In some embodiments, the subject to which the compound or composition described herein is administered may be or include a subject suffering from or susceptible to a neurodegenerative disease, disorder, or condition.In some embodiments, the neurodegenerative disease, disorder, or condition may be or include traumatic nerve injury.In some embodiments, the traumatic nerve injury is blunt trauma, closed head injury, open head injury, exposure to impact and / or explosive force, or penetrating injury in or to the brain cavity or innervation area of ​​the body.In some embodiments, the traumatic nerve injury is a force that causes axons to deform, stretch, crush, or rotate.

[0017] In some embodiments, the methods provided include administering a compound as described herein to a patient in need thereof. In some such embodiments, the patient is at risk of developing a condition characterized by axonal degeneration. In some embodiments, the patient has a condition characterized by axonal degeneration. In some embodiments, the patient has been diagnosed with a condition characterized by axonal degeneration.

[0018] In some embodiments, the methods provided include administering a composition as described herein to a patient population in need thereof. In some embodiments, the population is taken from individuals who engage in activities that have a high probability of traumatic nerve injury. In some embodiments, the population is taken from athletes who engage in contact sports or other high-risk activities.

[0019] In some embodiments, the patient is at risk for developing a neurodegenerative disorder, in some embodiments, the patient is elderly, in some embodiments, the patient is known to have genetic risk factors for neurodegeneration.

[0020] In certain embodiments, the present disclosure provides compounds that are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present disclosure.The compounds provided by the present disclosure are also useful for testing SARM1 function in biological and pathological phenomena, and for comparative evaluation of novel SARM1 activity inhibitors in vitro or in vivo.

[0021] In some embodiments, one or more compounds and / or compositions described herein are useful as a method for inhibiting the degeneration of neurons derived from a subject, for example.In some embodiments, one or more compounds and / or compositions described herein are useful for inhibiting the degeneration of in vitro cultured neurons or parts thereof.In some embodiments, one or more compounds and / or compositions described herein are useful as a stabilizer for promoting the survival of in vitro neurons. [Brief description of the drawings]

[0022] [Figure 1] 1 shows the structure of the SARM1 protein.

[0023] definition Aliphatic: The term "aliphatic" refers to a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain, or a monocyclic or bicyclic hydrocarbon, that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "hydrocarbon" or "alicyclic"), and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, an "alicyclic" (or "carbocyclic") refers to a monocyclic C3-C8 hydrocarbon or a bicyclic C7-C8 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic. 10Refers to a hydrocarbon. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene groups, and hybrids thereof.

[0024] Alkyl: The term "alkyl," used alone or as part of a larger moiety, refers to a saturated, optionally substituted, straight or branched chain, or cyclic hydrocarbon group having 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The term "cycloalkyl" refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0025] Alkyl: The term "alkylene" refers to a divalent alkyl group. In some embodiments, an "alkylene" is a divalent straight or branched alkyl group. In some embodiments, an "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, for example, 1-6, 1-4, 1-3, 1-2, or 2-3. An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are optionally replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups, and also those described herein. It will be understood that two substituents of an alkylene group may be joined together to form a ring system. In certain embodiments, two substituents may be joined together to form a 3-7 membered ring. The substituents may be on the same atom or different atoms.

[0026] Alkenyl: The term "alkenyl", used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain, or cyclic hydrocarbon group having at least one double bond and having 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentyl, cyclohexenyl, and cycloheptenyl.

[0027] Alkynyl: The term "alkynyl" used alone or as part of a larger moiety refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0028] Aryl: The term "aryl" refers to monocyclic and bicyclic ring systems having a total of 5-14 ring members, where at least one ring of the system is aromatic and each ring of the system contains 3-7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the invention, "aryl" refers to aromatic ring systems including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic carbocyclic or heterocyclic rings, such as indanyl, phthalimidyl, naphthaimidyl, phenanthridinyl, tetrahydronaphthyl, imidazolidinyl, imidazolidin-2-one, and the like.

[0029] Binding: As used herein, the term "binding" is typically understood to refer to a non-covalent association between or among two or more entities. "Direct" binding includes physical contact between the entities or moieties, and indirect binding includes physical interaction through physical contact with one or more intermediate entities. Binding between two or more entities can usually be assessed in any of a variety of contexts, including when the interacting entities or moieties are studied in isolation or in the context of a more complex system (e.g., in covalent or other context with a carrier entity and / or in a biological system or cell).

[0030] Biological sample: As used herein, the term "biological sample" typically refers to a sample obtained or derived from a biological source of interest (e.g., tissue or organism or cell culture) as described herein. In some embodiments, the source of interest includes organisms such as animals or humans. In some embodiments, the biological sample is or includes biological tissue or fluid. In some embodiments, the biological sample can be or include bone marrow, blood, blood cells, ascites, tissue or fine needle biopsy samples, bodily fluids containing cells, suspended nucleic acid, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural fluid, feces, lymph, gynecological fluid, skin swabs, vaginal swabs, oral swabs, nasal swabs, lavages or irrigations such as ductal irrigation or bronchoalveolar irrigation, aspirates, scrapings, bone marrow specimens, tissue biopsy specimens, surgical specimens, feces, other bodily fluids, secretions, and / or excretions, and / or cells derived therefrom, and the like. In some embodiments, the biological sample is or comprises cells obtained from an individual. In some embodiments, the obtained cells are or comprise cells from the individual from whom the sample is obtained. In some embodiments, the sample is a "primary sample" obtained directly from the source of interest by any suitable means. For example, in some embodiments, the primary biological sample is obtained by a method selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of bodily fluids (e.g., blood, lymph, feces, etc.), and the like. In some embodiments, as the context will allow, the term "sample" refers to a preparation obtained by processing the primary sample (e.g., by removing one or more components and / or adding one or more agents). For example, filtering using a semi-permeable membrane. Such a "processed sample" may include, for example, nucleic acids or proteins extracted from the sample or obtained by subjecting the primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and / or purification of specific components.

[0031] Biomarker: The term "biomarker" is used herein to refer to an entity, event, or characteristic whose presence, level, extent, type, and / or form correlates with a particular biological event or condition of interest, and is therefore considered a "marker" for that event or condition. To name just a few, in some embodiments, a biomarker can be or include a marker for a particular disease state, or for the likelihood of a particular disease, disorder, or condition developing, occurring, or recurring. In some embodiments, a biomarker can be or include a marker for a particular disease or treatment outcome, or the likelihood thereof. Thus, in some embodiments, a biomarker is predictive, in some embodiments, a biomarker is prognostic, and in some embodiments, a biomarker is diagnostic for the relevant biological event or condition of interest. A biomarker can be or include any chemical class of entity, and can be or include a combination of entities. For example, in some embodiments, a biomarker can be or include a nucleic acid, a polypeptide, a lipid, a carbohydrate, a small molecule, an inorganic substance (e.g., a metal or ion), or a combination thereof. In some embodiments, the biomarker is a cell surface marker. In some embodiments, the biomarker is intracellular. In some embodiments, the biomarker is detected outside the cell (e.g., secreted or otherwise produced or present outside the cell in bodily fluids such as, for example, blood, urine, tears, saliva, cerebrospinal fluid, etc.). In some embodiments, the biomarker may be or include a genetic or epigenetic signature. In some embodiments, the biomarker may be or include a gene expression signature.

[0032] In some embodiments, the biomarker may be or include a marker for neurodegeneration or for the likelihood of onset, development, or recurrence of a neurodegenerative disease, disorder, or condition. In some embodiments, the biomarker may be or include a marker for neurodegenerative treatment outcome or likelihood. Thus, in some embodiments, the biomarker is predictive, in some embodiments, the biomarker is prognostic, and in some embodiments, the biomarker is diagnostic for a neurodegenerative disease, disorder, or condition. In some embodiments, changes in biomarker levels can be detected via cerebrospinal fluid (CSF), plasma, and / or serum.

[0033] In some embodiments, neurodegeneration can be assessed, for example, by detecting an increase and / or decrease in the concentration of neurofilament protein light chain (NF-L) and / or neurofilament protein heavy chain (NF-H) (or its phosphorylated form (pNF-H)) contained in the cerebrospinal fluid of a subject. In some embodiments, the incidence and / or progression of neurodegeneration can be assessed via positron emission tomography (PET) using synaptic vesicle glycoprotein 2a (SV2A) ligand. In some embodiments, detectable changes in constitutive NAD and / or cADPR levels in neurons can be used to assess neurodegeneration.

[0034] In some embodiments, detectable changes in one or more neurodegeneration-associated proteins in a subject compared to a healthy reference population can be used as a biomarker of neurodegeneration. Such proteins include, but are not limited to, albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acidic protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractant protein (MCP)-1, neurogranin, neuron-specific enolase (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM)2, phospho-tau, and / or total tau. In some embodiments, increases in cytokines and / or chemokines, including, but not limited to, Ccl2, Ccl7, Ccl12, Csf1, and / or Il6, can be used as a biomarker of neurodegeneration.

[0035] Carrier: As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the composition is administered. In some exemplary embodiments, the carrier can include sterile liquids, such as, for example, water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. In some embodiments, the carrier is or includes one or more solid ingredients.

[0036] Combination therapy: As used herein, the term "combination therapy" refers to a situation in which a subject is exposed to two or more treatment regimens (e.g., two or more therapeutic agents) simultaneously. In some embodiments, the two or more regimens may be administered simultaneously, in some embodiments, such regimens may be administered sequentially (e.g., all "doses" of a first regimen are administered prior to administration of any dose of a second regimen), and in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, "administration" of a combination therapy may include administration of one or more agents or modalities to a subject receiving the other agent or modality in combination. For clarity, combination therapy does not require that the individual agents be administered together in a single composition (or even necessarily simultaneously), although in some embodiments, two or more agents or active portions thereof may be administered together in a combination composition or even in a combination compound (e.g., as part of a single chemical complex or covalent conjugate).

[0037] Composition: One of ordinary skill in the art will understand that the term "composition" may be used to refer to a separate physical entity that includes one or more specific components. In general, unless otherwise specified, a composition may be in any form - e.g., gas, gel, liquid, solid, etc.

[0038] Domain: As used herein, the term "domain" refers to a section or portion of an entity. In some embodiments, a "domain" is associated with a particular structural and / or functional property of an entity, such that when the domain is physically separated from the remainder of its parent entity, it retains the particular structural and / or functional property intact. Alternatively or additionally, a domain may be or may comprise a part of an entity that, when separated from its (parent) entity and combined with a different (recipient) entity, substantially maintains and / or confers to the recipient entity one or more structural and / or functional properties that characterize it in the parent entity. In some embodiments, a domain is a section or portion of a molecule (e.g., a small molecule, carbohydrate, lipid, nucleic acid, or polypeptide). In some embodiments, a domain is a section of a polypeptide, and in some such embodiments, a domain is characterized by particular structural elements (e.g., particular amino acid sequences or sequence motifs, alpha-helical nature, beta-sheet nature, coiled-coil nature, random coil nature, etc.), and / or particular functional properties (e.g., binding activity, enzymatic activity, folding activity, signaling activity, etc.).

[0039] Dosage form or unit dosage form: Those skilled in the art will understand that the term "dosage form" can be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, such an amount is a unit dosage (or a whole fraction thereof) appropriate for administration according to a dosing regimen (i.e., a therapeutic dosing regimen) that has been determined to correlate with a desirable or beneficial outcome when administered to a relevant population. Those skilled in the art will understand that the total amount of a therapeutic composition or agent to be administered to a particular subject is determined by one or more attending physicians and may include administration of multiple dosage forms.

[0040] Dosing regimen or treatment regimen: Those skilled in the art will understand that the terms "dosing regimen" and "treatment regimen" can be used to refer to a series of unit doses (typically more than one) administered individually to a subject, typically separated by a period of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which can include one or more doses. In some embodiments, a dosing regimen includes multiple doses, each separated in time from the other doses. In some embodiments, the individual doses are separated from each other by periods of the same length, and in some embodiments, a dosing regimen includes multiple doses and at least two different periods that separate the individual doses. In some embodiments, all doses within a dosing regimen are in the same unit dose amount. In some embodiments, different doses within a dosing regimen are in different amounts. In some embodiments, a dosing regimen includes a first dose in the amount of the first dose, followed by one or more additional doses in the amount of the second dose that is different from the amount of the first dose. In some embodiments, the dosing regimen includes a first dose in a first dose amount, followed by one or more additional doses in a second dose amount that is the same as the amount of the first dose. In some embodiments, the dosing regimen correlates with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0041] Excipient: as used herein refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, etc.

[0042] Heteroaryl: The terms "heteroaryl" and "heteroar-" are used alone or as part of a larger moiety, for example, "heteroaralkyl" or "heteroaralkoxy" refers to a group having 5 to 10 ring atoms, preferably 5, 6, 9, or 10 ring atoms, with 6, 10, or 14 pi electrons shared in a cyclic array, and having 1 to 5 heteroatoms in addition to the carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes the oxidized forms of nitrogen or sulfur, and the quaternized forms of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-" as used herein also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings.Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one.Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0043] Heterocyclic ring: As used herein, the terms "heterocycle", "heterocyclyl ring", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 3-8 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more heteroatoms, such as 1-4, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, and nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (such as N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group can be monocyclic, bicyclic, tricyclic, or polycyclic, preferably monocyclic, bicyclic, or tricyclic, more preferably monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl moieties are independently optionally substituted. Additionally, heterocyclic rings include groups in which the heterocyclic ring is fused to one or more aryl rings (eg, 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[b][1,4]dioxin, etc.).

[0044] Inhibitor: As used herein, the term "inhibitor" refers to an entity, condition, or event whose presence, level, or extent correlates with a decrease in the level or activity of a target. In some embodiments, an inhibitor can act directly (where it exerts its effect directly on the target, e.g., by binding to the target), and in some embodiments, an inhibitor can act indirectly (where it exerts its effect by interacting with and / or otherwise altering the target's regulator, resulting in a decrease in the target's level and / or activity). In some embodiments, an inhibitor is one whose presence or level correlates with a target level or activity that is decreased compared to a particular reference level or activity (e.g., observed under appropriate reference conditions, such as the presence of a known inhibitor or the absence of the inhibitor in question).

[0045] Neurodegeneration: As used herein, the term "neurodegeneration" refers to a reduction in one or more properties, structures, functions, or characteristics of neurons or nervous tissue. In some embodiments, neurodegeneration is observed as a pathological reduction in an organism. Those skilled in the art will understand that neurodegeneration is associated with certain diseases, disorders, and conditions, including those that affect humans. In some embodiments, neurodegeneration can be transient (e.g., sometimes occurring in association with certain infections and / or chemical or mechanical disruption), and in some embodiments, neurodegeneration can be chronic and / or progressive (e.g., often associated with certain diseases, disorders, or conditions, such as, but not limited to, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, or Alzheimer's disease). In some embodiments, neurodegeneration can be assessed, for example, in a subject, by detecting an increase in a biomarker associated with neurodegeneration. In some embodiments, neurodegeneration can be assessed, for example, in a subject, by detecting a decrease in a biomarker associated with neurodegeneration. Alternatively or additionally, in some embodiments, neurodegeneration can be assessed by magnetic resonance imaging (MRI), cerebrospinal fluid-containing biomarkers, or other biomarkers observed in patients. In some embodiments, neurodegeneration is defined as a score of less than 24 on the Mini-Mental State Examination. In some embodiments, neurodegeneration refers to loss of synapses. In some embodiments, neurodegeneration refers to reduction in nerve tissue associated with traumatic injury (e.g., exposure to external forces that disrupt the integrity of nerve tissue). In some embodiments, neurodegeneration refers to reduction in peripheral nerve tissue. In some embodiments, neurodegeneration refers to reduction in central nerve tissue.

[0046] Oral: As used herein, the phrases "oral administration" and "administered orally" have their art-understood meaning to refer to administration of a compound or composition by mouth.

[0047] Parenteral: As used herein, the phrases "parenteral administration" and "administered parenterally" have their art-understood meaning to refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0048] Partially unsaturated: As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties as defined herein.

[0049] Patient: As used herein, the term "patient" refers to any organism to which a provided composition is or can be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is human. In some embodiments, the patient is suffering from or susceptible to one or more disorders or conditions. In some embodiments, the patient exhibits one or more symptoms of a disorder or condition. In some embodiments, the patient has been diagnosed with one or more disorders or conditions. In some embodiments, the patient is undergoing or has undergone a particular treatment to diagnose and / or treat a disease, disorder, or condition.

[0050] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active agent formulated together with one or more pharma- ceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose amount suitable for administration in a treatment or dosing regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical compositions may be specifically formulated in solid or liquid form for administration, including those adapted for oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and those targeted for systemic absorption, boluses, powders, granules, pastes for application to the tongue, etc.; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., sterile solutions or suspensions, or sustained release formulations; topical application, e.g., creams, ointments, or sustained release patches or sprays applied to the skin, lungs, or oral cavity, vaginally or rectally, e.g., pessaries, creams, or foams, sublingually, ophthalmically, transdermally, or to the nose, lungs, and other mucosal surfaces.

[0051] Pharmaceutically acceptable: The term "pharmacologically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0052] Pharmaceutically acceptable carrier: As used herein, the term "pharmacologically acceptable carrier" means a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, that is involved in carrying or transporting a compound of interest from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials which can serve as pharma- ceutically acceptable carriers include sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, and the like; excipients such as powdered tragacanth, malt, gelatin, talc, cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, 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, pH buffered solutions, polyesters, polycarbonates, and / or polyanhydrides, as well as other non-toxic, compatible substances used in pharmaceutical formulations.

[0053] Pharmaceutically acceptable salts: The term "pharmaceutical acceptable salts" as used herein refers to salts of compounds that are suitable for use in pharmaceutical contexts, i.e., salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, or other problems or complications, within the scope of sound medical judgment, and that are commensurate with a reasonable risk-benefit ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. J. Pharmaceutical Sciences, 66:1-19 (1977) provides a detailed description of pharmaceutical acceptable salts. In some embodiments, pharmaceutical acceptable salts include, but are not limited to, non-toxic acid addition salts that are salts of amino groups, such as those formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids, such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. In some embodiments, pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lanthanide ... Representative salts include, but are not limited to, carbohydrate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.In some embodiments, pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates, and aryl sulfonates, as appropriate.

[0054] Prevent or Prevention: As used herein, the term "prevent" or "prevention," when used in relation to the occurrence of a disease, disorder, and / or condition, refers to reducing the risk of developing the disease, disorder, and / or condition and / or delaying the onset of one or more characteristics or symptoms of the disease, disorder, or condition. Prevention may be considered complete if the onset of the disease, disorder, or condition has been delayed for a predetermined period of time.

[0055] Specific: The term "specific," as used herein with respect to an active agent, is understood by those of skill in the art to mean that the agent distinguishes between potential target entities or conditions. For example, in some embodiments, an agent is said to "specifically" bind to a target if it preferentially binds to that target in the presence of one or more competing surrogate targets. In many embodiments, the specific interaction depends on the presence of a particular structural feature (e.g., epitope, cleft, binding site) of the target entity. It is understood that specificity need not be absolute. In some embodiments, specificity may be assessed relative to that of the binding agent to one or more other potential target entities (e.g., competitors). In some embodiments, specificity is assessed relative to that of a reference specific binding agent. In some embodiments, specificity is assessed relative to that of a reference non-specific binding agent. In some embodiments, the agent or entity does not detectably bind to a competing surrogate target under conditions that bind to the target entity. In some embodiments, the binding agent binds to the target entity with a higher binding rate, a lower dissociation rate, an increased affinity, a decreased dissociation, and / or an increased stability to the target entity compared to the competing surrogate target.

[0056] Subject: As used herein, the term "subject" refers to an organism, typically a mammal (e.g., a human, including in some embodiments prenatal human forms). In some embodiments, the subject is afflicted with the relevant disease, disorder, or condition. In some embodiments, the subject is susceptible to the disease, disorder, or condition. In some embodiments, the subject exhibits one or more symptoms or characteristics of the disease, disorder, or condition. In some embodiments, the subject does not exhibit any symptoms or characteristics of the disease, disorder, or condition. In some embodiments, the subject is one that has one or more characteristics characteristic of susceptibility or risk for a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual for whom diagnosis and / or treatment is and / or has been administered.

[0057] Substituted or Optionally Substituted: As described herein, the compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. "Substituted" applies to one or more hydrogens that are explicitly or implicitly present from the structure (e.g., [ka] At least [ka] Refers to, [ka] At least [ka] (refers to "optionally substituted" groups). Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and if 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 the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that are substantially unchanged when exposed to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0058] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen, -(CH) 0-4 R°, -(CH2) 0-4 OR°, -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°, -(CH2) 0-4 CH(OR°)2, -(CH2) 0-4 SR°, R° may be substituted -(CH2) 0-4 Ph, R° may be substituted -(CH2) 0-4 O(CH2) 0-1 Ph, may be substituted with R° -CH=CHPh, may be substituted with R° -(CH2) 0-4 O(CH2) 0-1 -Pyridyl, -NO2, -CN, -N3, -(CH2) 0-4 N(R°)2, -(CH2) 0-4 N(R°)C(O)R°, -N(R°)C(S)R°, -(CH2) 0-4 N(R°)C(O)NR°2, -N(R°)C(S)NR°2, -(CH2) 0-4 N(R°)C(O)OR°, -N(R°)N(R°)C(O)R°, -N(R°)N(R°)C(O)NR°2, -N(R°)N(R°)C(O)OR°, -(CH2) 0-4 C(O)R°, -C(S)R°, -(CH2) 0-4 C(O)OR°, -(CH2)0-4 C(O)SR°, -(CH2) 0-4 C(O)OSiR°3, -(CH2) 0-4 OC(O)R°, -OC(O)(CH2) 0-4 SR°, -(CH2) 0-4 SC(O)R°, -(CH2) 0-4 C(O)NR°2, -C(S)NR°2, -C(S)SR°, -SC(S)SR°, -(CH2) 0-4 OC(O)NR°2, -C(O)N(OR°)R°, -C(O)C(O)R°, -C(O)CH2C(O)R°, -C(NOR°)R°, -(CH2) 0-4 SSR°, -(CH2) 0-4 S(O)2R°, -(CH2) 0-4 S(O)(NH)R°, -(CH2) 0-4 S(O)2OR°, -(CH2) 0-4 OS(O)2R°, -S(O)2NR°2, -(CH2) 0-4 S(O)R°, -N(R°)S(O)2NR°2, -N(R°)S(O)2R°, -N(OR°)R°, -C(NH)NR°2, -P(O)2R°, -P(O)R°2, -OP(O)R°2, -OP(O)(OR°)2, SiR°3, -(C 1-4 Linear or branched alkylene)ON(R°)2, or -(C 1-4 linear or branched alkylene)C(O)ON(R°), where each R° is optionally substituted as defined below and is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5-6 membered heteroaryl ring), a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-10 membered bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or notwithstanding the above definitions, two independent occurrences of R° may be taken together with their intervening atoms to form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0059] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° taken together with their intervening atoms) are independently halogen, -(CH2), 0-2 R ● , -(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 S.R. ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● And each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently represents C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0060] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: ═O ("oxo"), ═S, ═NNR* 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S- is mentioned, R * Each independent occurrence of 1-6 Aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to adjacent substitutable carbons of an "optionally substituted" group include -O(CR * 2) 2-3 O- and R * Each independent occurrence of 1-6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0061] R * Suitable substituents on the aliphatic group include halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0062] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † Each R † are independently hydrogen, C which may be substituted as defined below 1-6 aliphatic, unsubstituted -OPh, unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definition, two independent R † occurrences of, taken together with their intervening atoms, form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0063] R † Preferred substituents on the aliphatic groups are halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is unsubstituted or, if preceded by "halo", substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0064] Therapeutic Agent: As used herein, the phrase "therapeutic agent" generally refers to any agent that induces a desired pharmacological effect when administered to an organism. In some embodiments, an agent is considered to be a therapeutic agent if it exhibits a statistically significant effect across an appropriate population. In some embodiments, the appropriate population may be a population of model organisms. In some embodiments, the appropriate population may be defined by various criteria, such as a particular age group, sex, genetic background, pre-existing clinical conditions, and the like. In some embodiments, a therapeutic agent is a substance that can be used to alleviate, ameliorate, reduce, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition. In some embodiments, a "therapeutic agent" is an agent that has been approved, or needs to be approved, by a government agency before it can be sold for administration to humans. In some embodiments, a "therapeutic agent" is an agent that requires a prescription for administration to humans.

[0065] Treat: As used herein, the terms "treat", "treatment", or "treating" refer to any method used to partially or completely alleviate, ameliorate, reduce, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not show signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who shows only early signs of a disease, disorder, and / or condition, for example, for the purpose of reducing the risk of developing a pathology associated with the disease, disorder, and / or condition.

[0066] Additionally, unless otherwise stated, in some embodiments, structures depicted herein include compounds which differ only in the presence of one or more isotopically enriched or isotopically labeled atoms. Isotopically labeled compounds may have one or more atoms replaced by an atom having an atomic mass or mass number normally found in nature. Examples of isotopes present in compounds of Formula I or Formula I', and subgenera described herein, include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, and 18 Isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, including, but not limited to, F, are included. In addition to being useful as therapeutic agents, certain isotopically labeled compounds of Formula I or Formula I', and subgenera described herein, are also useful as analytical tools in drug and / or substrate tissue distribution assays, or as probes in other biological assays. In one aspect of the invention, tritiated (e.g., 3 H) and carbon 14 (e.g. 14 C) isotopes are useful given their ease of detection. In another embodiment of the invention, one or more hydrogen atoms are replaced with deuterium (e.g., 2 Substitution with heavier isotopes such as 3H can provide certain therapeutic advantages.

[0067] Detailed Description of Specific Embodiments Programmed axonal degeneration and SARM1 Axonal degeneration is a major pathological characteristic of neurological diseases, including, but not limited to, Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis, diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, hereditary neuropathies, traumatic brain injury, and / or glaucoma. Damaged or unhealthy axons are eliminated by an intrinsic self-destruction program that is distinct from conventional cell death pathways such as apoptosis, known as Wallerian degeneration. (Gerdts, J., et al., Neuron, 2016, 89, 449-460; Whitmore, AV et al., Cell Death Differ., 2003, 10, 260-261). During Wallerian degeneration, peripheral nerves undergo selective degradation of axonal segments distal to the injury, while proximal axonal segments and cell bodies remain intact. This degeneration is characterized initially by depletion of nicotinamide mononucleotide adenyltransferase (NMNAT), followed by loss of nicotinamide adenine dinucleotide (NAD+), loss of adenosine triphosphate (ATP), neurofilament protein degradation, and axonal degradation approximately 8-24 hours after injury. (Gerdts, J., et al., Neuron, 2016, 89, 449-460).

[0068] NAD+ is a ubiquitous metabolite that plays a key role in energy metabolism and cell signaling (Belenkey et al., Trends Biochem., 2007, 32, 12-19; ​​Chiarugi et al., Nat. Rev. Cancer, 2012, 12, 741-752). Homeostatic regulation of NAD+ levels is also involved in maintaining axonal stability and integrity. Thus, manipulations that increase the axonal localization of NMNAT1 confer axonal protection (Babetto et al., Cell Rep., 2010, 3, 1422-1429; Sasaki et al., J. Neurosci., 2009).

[0069] A genome-wide RNAi screen in primary mouse neurons identified sterile alpha and TIR motif-containing 1 (SARM1), and knockdown of SARM1 led to long-term protection of sensory neurons against injury-induced axonal degeneration (Gerdts et al., J Neurosci, 2013, 33, 13569-13580). SARM1 belongs to the family of cytosolic adaptor proteins, but is unique among them because it is the most evolved ancient adaptor, paradoxically inhibiting TLR signaling and identified as a central executor of injury-induced axonal death pathways (O'Neill, LA & Bowie, AG, Nat. Rev. Immunol., 2007, 7, 353-364; Osterloh, JM, et al., Science, 2012, 337, 481-484; Gerdts, J., et al., J. Neurosci. 33, 2013, 13569-13580). Activation of SARM1 via axonal injury or forced dimerization of the SARM1-TIR domain promotes rapid and catastrophic depletion of nicotinamide adenine dinucleotide (NAD+), followed quickly by axonal degradation, thus highlighting the central role of NAD+ homeostasis in axonal integrity. (Gerdts, J., et al., Science, 2015, 348, 453-457). SARM1 is required for this injury-induced NAD+ depletion both in vitro and in vivo, and SARM1 activation locally causes axonal degeneration through NAD(+) destruction (Gerdts et al., et al., Science, 2015 348, 452-457; Sasaki et al., J. Biol. Chem. 2015, 290, 17228-17238, both of which are incorporated herein by reference in their entirety).

[0070] Genetic loss-of-function studies have revealed that SARM1 functions as a central executor of the axonal degeneration pathway following injury. Genetic knockout of SARM1 allows axonal preservation for more than 14 days after nerve transection (Osterloh, JM, et al., Science, 2012, 337, 481-484; Gerdts, J., et al., J. Neurosci., 2013, 33, 13569-13580) and improves functional outcome in mice after traumatic brain injury (Henninger, N. et al., Brain 139, 2016, 1094-1105). In addition to the role that SARM1 has in direct axonal injury, SARM1 is also required for the axonal degeneration observed in chemotherapy-induced peripheral neuropathy. Loss of SARM1 blocks chemotherapy-induced peripheral neuropathy and inhibits both the axonal degeneration and increased pain sensitivity that develop after chemotherapy vincristine treatment (Geisler et al, Brain, 2016, 139, 3092-3108).

[0071] SARM1 contains multiple conserved motifs, including a SAM domain, an ARM / HEAT motif, and a TIR domain (Figure 1) that mediates oligomerization and protein-protein interactions (O'Neill,LA& Bowie,AG,Nat.Rev.Immunol.,2007,7,353-364; Tewari,R.,et al.,Trends Cell Biol.,2010,20,470-481; Qiao,F.& Bowie,JU,Sci.STKE 2005,re7,2005). TIR domains are commonly found in signaling proteins that function in innate immune pathways, where they function as scaffolds for protein complexes (O'Neill,LA& Bowie,AG,Nat.Rev.Immunol.,2007,7,353-364). Interestingly, dimerization of the SARM1-TIR domain is sufficient to induce axonal degeneration and to rapidly cause the degradation of NAD+ by acting as an NAD+ cleaving enzyme (Milbrandt et al., WO2018 / 057989; Gerdts, J., et al., Science, 2015, 348, 453-457). Given the central role of SARM1 in axonal degeneration pathways, and its identified NADase activity, attempts have been made to identify agents that can modulate SARM1 and potentially function as useful therapeutic agents to protect against, for example, peripheral neuropathy, traumatic brain injury, and / or neurodegenerative diseases, including neurodegenerative diseases.

[0072] Among other things, the present disclosure provides certain compounds and / or compositions that act as SARM1 inhibitors (eg, as SARM1 inhibitors), and technology relating thereto.

[0073] compound In some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, wherein: Ring A is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 1 is an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Each R x are independently halogen, cyano, OR, SR, N(R)2, or C 1-4 an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; L is an optionally substituted C 1-4 an aliphatic chain in which one or two carbon atoms are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)N(R)-, -N(R)S(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from phenyl, and oxygen, nitrogen, and sulfur; or two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 3-7 membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 2is hydrogen, halogen, N(R)2, OR, or C 1-6 an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; n is 0, 1, or 2.

[0074] In some embodiments, the present disclosure provides a compound of formula I': [ka] or a pharma- ceutically acceptable salt thereof, wherein: Ring A is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 1 is an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Each R x are independently halogen, cyano, OR, SR, N(R)2, S(O)2N(R)2, C(O)OR, C(O)N(R)2, or C 1-4an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; L is an optionally substituted C 1-4 an aliphatic chain in which one or two carbon atoms are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -S(O)2-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from phenyl, and oxygen, nitrogen, and sulfur; or two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 3-7 membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 2 is hydrogen, halogen, N(R)2, OR, or C 1-6an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; n is 0, 1, or 2.

[0075] As generally defined above, ring A is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, ring A is a 5 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, ring A is pyrrolyl, furanyl, or thiophenyl. In some embodiments, ring A is a 5 membered heteroaryl ring having 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, ring A is a group selected from pyrazolyl, imidazolyl, isothiazolyl, and thiazolyl.

[0076] In some embodiments, ring A is a 5-membered heteroaryl ring having three heteroatoms independently selected from oxygen, nitrogen, and sulfur, hi some such embodiments, ring A is a group selected from triazolyl and thiadiazolyl.

[0077] In some embodiments, ring A is a 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is pyridin-2(1H)-onyl.

[0078] In some embodiments, ring A is selected from: [Table 1-1] [Table 1-2]

[0079] In some embodiments, ring A is selected from: [Table 2] In the formula, R x But, C 1-4 an optionally substituted group selected from aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0080] In some embodiments, ring A is selected from: [Table 3]

[0081] In some embodiments, ring A is selected from: [Table 4] During the ceremony, R on nitrogen atom x But, C 1-4 an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; R on carbon atom x is halogen, cyano, OR, SR, N(R)2, or C 1-4 an optionally substituted group selected from aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0082] In some embodiments, ring A is [ka] It is.

[0083] In some embodiments, ring A is [ka] It is.

[0084] In certain particularly preferred embodiments, Ring A is [ka] is selected from.

[0085] In some embodiments, ring A is [ka] is selected from.

[0086] As generally defined above, R 1 is an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0087] In some embodiments, R 1 is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 1 is an optionally substituted 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 1 is an optionally substituted group selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.

[0088] In some embodiments, R 1 is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0089] In some embodiments, R 1 is an optionally substituted 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 1 is an optionally substituted 5-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 1 is an optionally substituted group selected from pyrazolyl, thiazolyl, and thiophenyl rings. In some embodiments, R 1 is an optionally substituted group selected from imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, and thiophenyl rings.

[0090] In some embodiments, R 1 is an optionally substituted 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In some embodiments, R 1 is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R 1is an optionally substituted group selected from pyridinyl, pyrimidinyl, and pyridazinyl.

[0091] In some embodiments, R 1 is selected from the following: [Table 5]

[0092] In some embodiments, R 1 is selected from the following: [Table 6]

[0093] In certain particularly preferred embodiments, R 1 teeth, [ka] is selected from.

[0094] As generally defined above for formula I, each R x are independently halogen, cyano, OR, SR, N(R)2, or C 1-4 an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. x are independently halogen, cyano, OR, SR, N(R)2, S(O)2N(R)2, C(O)OR, C(O)N(R)2, or C 1-4an optionally substituted group selected from aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0095] In some embodiments of Formula I or Formula I′, R x is halogen. In some such embodiments, R x is chloro or bromo. In some embodiments of Formula I or Formula I', R x is fluoro.

[0096] In some embodiments of Formula I or Formula I′, R x is cyano.

[0097] In some embodiments of Formula I or Formula I′, R x In some embodiments of Formula I or Formula I', R x is OR, R is hydrogen and optionally substituted C 1-6 In some embodiments of Formula I or Formula I', R x is OR, R is hydrogen and optionally substituted C 1-4 In some embodiments of Formula I or Formula I', R x is selected from OH, OCH3, and OCH2CH3.

[0098] In some embodiments of Formula I or Formula I′, R x In some embodiments of Formula I or Formula I', R x is SR, R is hydrogen and optionally substituted C 1-6 In some embodiments of Formula I or Formula I', R x is SR, R is hydrogen and optionally substituted C1-4 In some embodiments of Formula I or Formula I', R x is selected from SH, SCH3, and SCH2CH3.

[0099] In some embodiments of Formula I or Formula I′, R x is N(R). In some embodiments of Formula I or Formula I', R x is N(R)2, where R is hydrogen and optionally substituted C 1-6 In some embodiments of Formula I or Formula I', R x is N(R)2, where R is hydrogen and optionally substituted C 1-4 In some embodiments of Formula I or Formula I', R x is selected from NH2, NHCH3, NHCH2CH3, N(CH3)2, and N(CH2CH3)2.

[0100] In some embodiments of Formula I or Formula I′, R x is an arbitrarily substituted C 1-4 In some embodiments of Formula I or Formula I', R x is CH, CD, or CHCH. In some embodiments of Formula I or Formula I', R x is an arbitrarily substituted C 3-4 In some such embodiments, R x is tert-butyl, [ka] In some embodiments of Formula I or Formula I', R x teeth, [ka] It is.

[0101] In some embodiments of Formula I or Formula I′, R x is a halogen, -(CH2)0-4 R°, -(CH2) 0-4 OR°, -(CH2) 0-4 N(R°)2, -(CH2) 0-4 C(O)OR°, and -(CH2) 0-4 C(O)NR°2 optionally substituted with a group selected from 1-4 In some such embodiments, R° is hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5-6 membered heteroaryl ring), a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two independent occurrences of R° together with their intervening atoms form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0102] In some embodiments of Formula I or Formula I′, R x is C optionally substituted with a group selected from halogen, -R°, -OR°, -N(R°)2, -C(O)OR°, and -C(O)NR°2; 1-4 In some embodiments of Formula I or Formula I', R x is C optionally substituted with halogen 1-4 In some such embodiments, R x is selected from -CH3, -CF3, -CHF2, and CH2F. In some embodiments of Formula I or Formula I', R x is selected from -CH3, -CD3, -CF3, -CHF2, and CH2F.

[0103] In some embodiments of Formula I or Formula I′, R xis selected from -CHR°, -CHOR°, -CHN(R°), -CHC(O)OR°, and -CHC(O)N(R°). In some such embodiments, R x is selected from -CHOH, -CHOCH, -CHC(O)NH, -CHC(O)NHCH, and -CHC(O)N(CH). In some embodiments of Formula I or Formula I', R x is CHC(O)OR°. In some such embodiments, R x is CO2CH3 or CO2CH2CH3.

[0104] In some embodiments of Formula I or Formula I′, R x is C optionally substituted with a group selected from halogen, -R°, -OR°, -N(R°)2, -C(O)OR°, and -C(O)NR°2; 1-4 It is aliphatic.

[0105] In some embodiments of Formula I', R x is selected from S(O)N(R), C(O)OR, and C(O)N(R). In some embodiments of Formula I', R x is S(O)2N(R)2. In some such embodiments, R is hydrogen. In some embodiments of formula I', R x In some embodiments of Formula I', R x is C(O)OR. In some such embodiments, R is selected from halogen, CH3, and CH2CH3. In some embodiments of formula I', R x is C(O)OCH2CH3. In some embodiments of Formula I', R x is C(O)N(R). In some such embodiments, R is hydrogen or CH. In some embodiments of I', R x is C(O)NH2 or R x is C(O)N(CH). In some embodiments of Formula I or Formula I', Rx is an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments of Formula I or Formula I', R x is an optionally substituted 5-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments of Formula I or Formula I', R x is an optionally substituted 5- to 7-membered saturated carbocyclic ring. In some such embodiments, R x is selected from optionally substituted cyclopentyl or cyclohexyl.

[0106] In some embodiments of Formula I or Formula I′, R x is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments of Formula I or Formula I', R x is an optionally substituted 3-4 membered saturated heterocyclic ring having one heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments of Formula I or Formula I', R x is an optionally substituted 5-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments of Formula I or Formula I', R x is an optionally substituted 5-7 membered saturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some such embodiments, R x is selected from optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.

[0107] In some embodiments of Formula I or Formula I′, R x is optionally substituted phenyl.

[0108] In some embodiments of Formula I or Formula I′, R xis an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments of Formula I or Formula I', R x is an optionally substituted 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments of Formula I or Formula I', R x is an optionally substituted 5-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some such embodiments, R x is selected from optionally substituted pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, and thiazolyl.

[0109] In some embodiments of Formula I or Formula I′, R x is an optionally substituted 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In some embodiments of Formula I or Formula I', R x is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some such embodiments, R x is selected from optionally substituted pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0110] As generally defined above for formula I, L is an optionally substituted C 1-4 an aliphatic chain in which one or two carbon atoms are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)N(R)-, -N(R)S(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0111] As generally defined above for formula I′, L is an optionally substituted C 1-4an aliphatic chain in which one or two carbon atoms are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -S(O)2-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0112] In some embodiments of formula I or formula I′, L is optionally substituted C 1-2 an aliphatic chain in which one or two carbon atoms are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring. In some embodiments of Formula I or Formula I', L is an optionally substituted C 1-2 In some embodiments of Formula I or Formula I', L is an optionally substituted C(O)-, C(R ... 1-2 an aliphatic chain in which one or two carbon atoms are optionally replaced by a group independently selected from -O-, -N(H)-, -S-, -C(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0113] In some embodiments of formula I or formula I′, L is optionally substituted C 3-4an aliphatic chain in which one or two carbon atoms are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring. In some embodiments of Formula I or Formula I', L is an optionally substituted C 3-4 In some embodiments of Formula I or Formula I', L is an optionally substituted C(O)-, C(R ... 3-4 an aliphatic chain in which one or two carbon atoms are optionally replaced by a group independently selected from -O-, -N(H)-, -S-, -C(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0114] In some embodiments of formula I or formula I′, L is optionally substituted C 1-4 an aliphatic chain in which one carbon atom is replaced by -C(O)- and one additional carbon atom is optionally replaced by a group selected from -O-, -N(R)-, -S-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)N(R)-, -N(R)S(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0115] In some embodiments of formula I or formula I′, L is optionally substituted C 1-4In some embodiments of Formula I or Formula I', L is an optionally substituted C(O)-, C(O)-, or C(O)-. In some embodiments of Formula I or Formula I', L is an optionally substituted C(O)-, C(O)-, or C(O)-. 1-4 an aliphatic chain in which one carbon atom is replaced by -C(O)- and one additional carbon atom is optionally replaced by a group selected from -O-, -N(H)-, -S-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0116] In some embodiments of formula I or formula I′, L is optionally substituted C 3-4 In some embodiments of Formula I or Formula I', L is an optionally substituted C(O)-, C(O)-, or C(O)-. In some embodiments of Formula I or Formula I', L is an optionally substituted C(O)-, C(O)-, or C(O)-. 3-4 an aliphatic chain in which one carbon atom is replaced by -C(O)- and one additional carbon atom is optionally replaced by a group selected from -O-, -N(H)-, -S-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0117] In some embodiments of Formula I or Formula I', L is selected from the following: [Table 7]

[0118] In some embodiments of Formula I', L is selected from the following: [Table 8]

[0119] In certain particularly preferred embodiments of formula I or formula I', L is [ka] In certain particularly preferred embodiments of formula I or formula I', L is selected from: [ka] is selected from.

[0120] As generally defined above, each R is independently hydrogen or C 1-6 In some embodiments, R is an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from phenyl, and oxygen, nitrogen, and sulfur, or two R groups taken together with the nitrogen atom to which they are attached form an optionally substituted 3-7 membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is hydrogen. In some embodiments, R is C 1-6 an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from phenyl, oxygen, nitrogen, and sulfur, or two R groups together with the nitrogen atom to which they are attached form an optionally substituted 3-7 membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0121] In some embodiments, R is optionally substituted C 1-6 In some embodiments, R is C optionally substituted with oxo and OR°. 1-6 Aliphatic, R° is C1-6 In some such embodiments, R is -C(O)OtBu.

[0122] In some embodiments, R is C 1-6 In some such embodiments, R is methyl or ethyl.

[0123] In some such embodiments, R is selected from hydrogen and optionally substituted C 1-6 In some such embodiments, R is selected from hydrogen, methyl, or ethyl.

[0124] As generally defined above, R 2 is hydrogen, halogen, N(R)2, OR, or C 1-6 an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0125] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is halogen, N(R)2, OR, or C 1-6an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0126] In some embodiments, R 2 is halogen. In some embodiments, R 2 is N(R). In some such embodiments, R 2 is NH2. In some embodiments, R 2 In some such embodiments, R 2 is OH.

[0127] In some embodiments, R 2 is an arbitrarily substituted C 1-6 In some embodiments, R 2 is an optionally substituted group selected from cyclopentyl and cyclohexyl. In some embodiments, R 2 is C 1-6 In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is tert-butyl. In some embodiments, R 2 is neopentyl (i.e., 2,2-dimethylpropyl). In some embodiments, R 2 is cyclohexyl.

[0128] In some embodiments, R 2 is optionally substituted phenyl.

[0129] In some embodiments, R 2 is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 2 is an optionally substituted 3-membered saturated heterocyclic ring having one heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments, R 2 is an optionally substituted 4-membered saturated heterocyclic ring having one heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments, R 2 is an optionally substituted 5-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 2 is an optionally substituted 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 2 is an optionally substituted group selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.

[0130] In some embodiments, R 2 is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 2 is an optionally substituted 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 2 is an optionally substituted 5-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some such embodiments, R 2is an optionally substituted group selected from thiophenyl, pyrazolyl, and imidazolyl.

[0131] In some embodiments, R 2 is an optionally substituted 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In some embodiments, R 2 is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R 2 is an optionally substituted group selected from pyridinyl or pyrimidinyl.

[0132] In some embodiments, R 2 is an optionally substituted 8-10 membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring. In some embodiments, R 2 is an optionally substituted 9-membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring. In some such embodiments, R 2 is optionally substituted 2,3-dihydro-1H-indenyl. In some embodiments, R 2 is an optionally substituted 10-membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring. In some such embodiments, R 2 is an optionally substituted group selected from 1,2,3,4-tetrahydronaphthalenyl and naphthalenyl.

[0133] In some embodiments, R 2 is an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 2 is an optionally substituted 9-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 2is an optionally substituted 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some such embodiments, R 2 is an optionally substituted group selected from chromanyl, isochromanyl, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, and 2H-benzo[b][1,4]oxazin-3(4H)-onyl.

[0134] In some embodiments, R 2 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 2 is an optionally substituted 9-membered bicyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some such embodiments, R 2 is an optionally substituted group selected from indolyl, benzopyrazolyl, benzimidazolyl, and imidazo[1,2-a]pyridinyl.

[0135] In some embodiments, R 2 is selected from the group consisting of: [Table 9-1] [Table 9-2]

[0136] In some embodiments, R 2 is selected from the group consisting of: [Table 10]

[0137] In certain particularly preferred embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] Be selected.

[0138] In some embodiments of formula I or formula I', L is [ka] Thus, in some embodiments, the present disclosure provides a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, wherein rings A, R x , R 1 , R 2 Each of , R, and n is as defined above and described herein.

[0139] In some embodiments of formula I or formula I', L is [ka] Thus, in some embodiments, the present disclosure provides a compound of formula Ib: [ka] or a pharma- ceutically acceptable salt thereof, wherein rings A, R x , R 1 , R 2 Each of , R, and n is as defined above and described herein.

[0140] In some embodiments of Formula I or Formula I′, R 1 teeth, [ka] Thus, in some embodiments, the present disclosure provides a compound of formula Ic: [ka] or a pharma- ceutically acceptable salt thereof, wherein rings A, R x , L, R 2 Each of , R, and n is as defined above and described herein.

[0141] In some embodiments of Formula I or Formula I′, R 1 teeth, [ka] Thus, in some embodiments, the present disclosure provides a compound of formula Id: [ka] or a pharma- ceutically acceptable salt thereof, wherein rings A, R x , L, R 2 Each of , R, and n is as defined above and described herein.

[0142] In some embodiments of Formula I or Formula I', Ring A is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. Thus, in some embodiments, the present disclosure provides compounds of Formula Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, In, or Io: [Table 11] or a pharma- ceutically acceptable salt thereof, wherein L, R 1 , R 2 Each of R is as defined above and described herein.

[0143] In some embodiments of formula I or formula I', L is [ka] Thus, in some embodiments, the present disclosure provides a compound of formula Ip: [ka] or a pharma- ceutically acceptable salt thereof, wherein rings A, R x , R 1 , R 2 Each of , R, and n is as defined above and described herein.

[0144] In some embodiments, the present disclosure provides a compound of the formula: [Table 12] or a pharma- ceutically acceptable salt thereof, wherein R x , R 1 , R 2 Each of R is as defined above and described herein.

[0145] In some embodiments, the disclosure provides a compound of formula Iai, Ibi, Ici, Idi, Iei, Ifi, Igi, Ihi, Iii, Iji, Iki, Ili, Imi, Ini, Ioi, Ipi, or Ip-ii: [Table 13-1] [Table 13-2] or a pharma- ceutically acceptable salt thereof, wherein ring A, R x , L, R 1 , R 2 Each of n is as defined above and described herein.

[0146] In some embodiments, the present disclosure provides a compound of formula Iq or Iqi: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 Each of R is as defined above and described herein.

[0147] In some embodiments of any of formulas I, Ib, Ibi, Ic, or Ici, ring A is [ka] isn't it.

[0148] In some embodiments of any of formulas I, Ib, or Ibi, ring A is [ka] But no.

[0149] In some embodiments of formula Ie or formula Iei, L is [ka] isn't it.

[0150] In some embodiments of formula Ih or formula Ihi, L is [ka] isn't it.

[0151] In some embodiments of any of Formulas I, Ib, Ie, Iei, Ih, or Ihi, R 1 teeth, [ka] isn't it.

[0152] In some embodiments, the present disclosure provides a compound selected from: [Table 14-1] TIFF0007659110000053.tif233166 TIFF0007659110000054.tif219167 TIFF0007659110000055.tif224167 TIFF0007659110000056.tif233168 TIFF0007659110000057.tif226168 TIFF0007659110000058.tif221168 TIFF0007659110000059.tif239167 TIFF0007659110000060.tif224169 TIFF0007659110000061.tif229167 TIFF0007659110000062.tif232168 TIFF0007659110000063.tif210168 TIFF0007659110000064.tif218167 TIFF0007659110000065.tif223169 TIFF0007659110000066.tif227169 TIFF0007659110000067.tif227168 TIFF0007659110000068.tif213166 TIFF0007659110000069.tif211168 TIFF0007659110000070.tif197166 TIFF0007659110000071.tif224169 TIFF0007659110000072.tif228168 TIFF0007659110000073.tif229167 TIFF0007659110000074.tif228168 TIFF0007659110000075.tif228169 TIFF0007659110000076.tif227166 TIFF0007659110000077.tif224167 TIFF0007659110000078.tif228167 TIFF0007659110000079.tif224168 TIFF0007659110000080.tif223167 TIFF0007659110000081.tif227167 TIFF0007659110000082.tif224167 TIFF0007659110000083.tif218166 TIFF0007659110000084.tif222168 TIFF0007659110000085.tif221168 TIFF0007659110000086.tif221168 TIFF0007659110000087.tif222169 TIFF0007659110000088.tif216165 TIFF0007659110000089.tif229169 TIFF0007659110000090.tif218169 TIFF0007659110000091.tif224169 TIFF0007659110000092.tif164169 or a pharma- ceutically acceptable salt thereof.

[0153] In some embodiments, the present disclosure provides a compound selected from: [Table 15-1] TIFF0007659110000094.tif213167 TIFF0007659110000095.tif221166 TIFF0007659110000096.tif223168 TIFF0007659110000097.tif224166 TIFF0007659110000098.tif216166 TIFF0007659110000099.tif220168 TIFF0007659110000100.tif218166 TIFF0007659110000101.tif209169 TIFF0007659110000102.tif166168 or a pharma- ceutically acceptable salt thereof.

[0154] In certain particularly preferred embodiments, the present disclosure provides a compound selected from: [Table 16-1] TIFF0007659110000104.tif222166 TIFF0007659110000105.tif226168 TIFF0007659110000106.tif223169 TIFF0007659110000107.tif222169 TIFF0007659110000108.tif112169 or a pharma- ceutically acceptable salt thereof.

[0155] In some embodiments, the present disclosure provides a compound selected from: [Table 17-1] or a pharma- ceutically acceptable salt thereof.

[0156] In some embodiments, the present disclosure provides a compound selected from: [Table 18-1] TIFF0007659110000111.tif217166 TIFF0007659110000112.tif218169 TIFF0007659110000113.tif218167 TIFF0007659110000114.tif222166 TIFF0007659110000115.tif222167 TIFF0007659110000116.tif223169 TIFF0007659110000117.tif223167 TIFF0007659110000118.tif212166 TIFF0007659110000119.tif165169 or a pharma- ceutically acceptable salt thereof.

[0157] In some aspects, the disclosure provides compounds according to the following embodiments:

[0158] Embodiment 1. A compound of formula I, [ka] or a pharma- ceutically acceptable salt thereof, Ring A is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 1 is an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Each Rx are independently halogen, cyano, OR, SR, N(R)2, or C 1-4 an optionally substituted group selected from aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; L is an optionally substituted C 1-4 an aliphatic chain in which 1 or 2 carbon atoms are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)N(R)-, -N(R)S(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; or two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 3-7 membered monocyclic heterocycle having 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 2 is hydrogen, halogen, N(R)2, OR, or C 1-6an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring, an 8-10 membered bicyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; A compound wherein n is 0, 1, or 2.

[0159] Embodiment 2. The compound of embodiment 1, wherein ring A is a 6-membered heteroaryl ring having 1-2 nitrogen atoms.

[0160] Embodiment 3. A compound according to embodiment 1, wherein ring A is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0161] Embodiment 4. A compound according to embodiment 3, wherein ring A is a 5-membered heteroaryl ring having two heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0162] Embodiment 5. A compound according to embodiment 3, wherein ring A is a 5-membered heteroaryl ring having 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0163] Embodiment 6. The compound of embodiment 1, wherein Ring A is selected from: [Table 19]

[0164] Embodiment 7. Ring A is [ka] The compound of embodiment 6, selected from:

[0165] Embodiment 7a. Ring A is [ka] The compound of embodiment 6, selected from:

[0166] Embodiment 8. The compound of embodiment 1, wherein Ring A is selected from the following: [Table 20-1] [Table 20-2]

[0167] Embodiment 9. Ring A is selected from: [Table 21] In the formula, R x But, C 1-4 The compound of embodiment 1, wherein the optionally substituted group is selected from aliphatic, a 3-7 membered saturated or partially unsaturated carbocycle, a 3-7 membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0168] Embodiment 10. The compound of embodiment 1, wherein Ring A is selected from the following: [Table 22]

[0169] Embodiment 11. Ring A is selected from: [Table 23] During the ceremony, R on nitrogen atomx But, C 1-4 an optionally substituted group selected from aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; R on carbon atom x is halogen, cyano, OR, SR, N(R)2, or C 1-4 The compound of embodiment 1, wherein the optionally substituted group is selected from aliphatic, 3-7 membered saturated or partially unsaturated carbocycle, 3-7 membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0170] Embodiment 12.R x The compound of any one of embodiments 1-11, wherein is halogen.

[0171] Embodiment 13.R x The compound of any one of embodiments 1-11, wherein is cyano.

[0172] Embodiment 14.R x The compound of any one of embodiments 1-11, wherein is OR.

[0173] Embodiment 15.R x The compound of any one of embodiments 1-11, wherein is SR.

[0174] Embodiment 16.R x The compound of any one of embodiments 1-11, wherein is N(R)2.

[0175] Embodiment 17. R is selected from hydrogen and optionally substituted C 1-6The compound according to any one of embodiments 14 to 16, which is selected from aliphatic.

[0176] Embodiment 18. R is selected from hydrogen and optionally substituted C 1-4 The compound of embodiment 17, wherein the compound is selected from aliphatic.

[0177] Embodiment 19.R x The compound according to any one of embodiments 14, 17, and 18, wherein is OH, OCH3, and OCH2CH3.

[0178] Embodiment 20.R x The compound according to any one of embodiments 15, 17, and 18, wherein is SH, SCH3, and SCH2CH3.

[0179] Embodiment 21.R x The compound of any one of embodiments 16-18, wherein is selected from NH2, NHCH3, NHCH2CH3, N(CH3)2, and N(CH2CH3)2.

[0180] Embodiment 22.R x But, with any substitution C 1-4 The compound of any one of embodiments 1-11, which is aliphatic.

[0181] Embodiment 23.R x But, with arbitrary substitutions C 3-4 The compound of embodiment 22, which is aliphatic.

[0182] Embodiment 24.R x But tert-butyl, [ka] 24. The compound of embodiment 23, selected from:

[0183] Embodiment 25.R x But halogen, -(CH2) 0-4 R°, -(CH2) 0-4 OR°, -(CH2)0-4 N(R°)2, -(CH2) 0-4 C(O)OR°, and -(CH2) 0-4 C(O)NR°2 optionally substituted with a group selected from 1-4 The compound of embodiment 22, which is aliphatic.

[0184] 26. R° is hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Compounds according to embodiment 25, wherein Ph is selected from -CH2- (a 5-6 membered heteroaryl ring), a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two independent occurrences of R°, taken together with their intervening atoms, form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0185] Embodiment 27.R x is optionally substituted with a group selected from halogen, -R°, -OR°, -N(R°)2, -C(O)OR°, and -C(O)NR°2; 1-4 The compound of embodiment 22, which is aliphatic.

[0186] Embodiment 28.R x C optionally substituted with halogen 1-4 The compound of embodiment 22, which is aliphatic.

[0187] Embodiment 29.R x is selected from -CH3, -CF3, -CHF2, and CH2F.

[0188] Embodiment 29a.R x is selected from -CH3, -CD3, -CF3, -CHF2, and CH2F.

[0189] Embodiment 30.R x The compound of embodiment 22, wherein is selected from -CH2R°, -CH2OR°, -CH2N(R°)2, -CH2C(O)OR°, and -CH2C(O)N(R°)2.

[0190] Embodiment 31.R x is selected from -CH2OH, -CH2OCH3, -CH2C(O)NH2, -CH2C(O)NHCH3, and -CH2C(O)N(CH3)2.

[0191] Embodiment 32.R 1 The compound of any one of embodiments 1-31, wherein is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0192] Embodiment 33.R 1 is an optionally substituted 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0193] Embodiment 34.R 1 is an optionally substituted 5-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0194] Embodiment 35.R 1 The compound of embodiment 32, wherein is an optionally substituted 6-membered heteroaryl ring having 1 to 3 nitrogen atoms.

[0195] Embodiment 36.R 1 The compound of embodiment 35, wherein is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms.

[0196] Embodiment 37.R 1 is selected from the following: [Table 24]

[0197] Embodiment 38.R 1 but, [ka] The compound according to embodiment 37, selected from:

[0198] Embodiment 39. L is an optionally substituted C 1-2 The compound of any one of embodiments 1-38, which is an aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)N(R)-, -N(R)S(O)-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0199] Embodiment 40. L is an optionally substituted C 1-2 The compound of embodiment 39, which is an aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -C(O)-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0200] Embodiment 41. L is an optionally substituted C 1-2 The compound of embodiment 38 or 39, which is an aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from -O-, -N(H)-, -S-, -C(O)-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0201] Embodiment 42. L is an optionally substituted C 3-4The compound of any one of embodiments 1-38, which is an aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)N(R)-, -N(R)S(O)-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0202] Embodiment 43. L is an optionally substituted C 3-4 The compound of embodiment 42, which is an aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -C(O)-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0203] Embodiment 44. L is an optionally substituted C 3-4 The compound of embodiment 42 or 43, which is an aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from -O-, -N(H)-, -S-, -C(O)-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0204] Embodiment 45. L is an optionally substituted C 1-4 The compound of any one of embodiments 1-38, which is an aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)- and one additional carbon atom is optionally replaced by a group selected from -O-, -N(R)-, -S-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)N(R)-, -N(R)S(O)-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0205] Embodiment 46. L is an optionally substituted C 1-4The compound of embodiment 45, which is an aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)- and one additional carbon atom is optionally replaced by a group selected from -O-, -N(R)-, -S-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0206] Embodiment 47. L is an optionally substituted C 1-4 The compound of embodiment 45 or 46, which is an aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)- and one additional carbon atom is optionally replaced by a group selected from -O-, -N(H)-, -S-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0207] Embodiment 48. L is an optionally substituted C 3-4 The compound of embodiment 45 or 46, which is an aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)- and one additional carbon atom is optionally replaced by a group selected from -O-, -N(R)-, -S-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0208] Embodiment 49. L is an optionally substituted C 3-4 The compound of embodiment 48, which is an aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)- and one additional carbon atom is optionally replaced by a group selected from -O-, -N(H)-, -S-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0209] Embodiment 50. A compound according to any one of embodiments 1 to 38, wherein L is selected from: [Table 25]

[0210] The compound of any one of embodiments 1 to 38, wherein L is selected from the following: [Table 26]

[0211] In the embodiment 51.L, [ka] The compound of embodiment 50, selected from:

[0212] In the embodiment 51a.L, [ka] The compound of embodiment 50, selected from:

[0213] Embodiment 52. A compound according to any one of embodiments 1 to 51a, wherein R is hydrogen.

[0214] Embodiment 53. A compound according to any one of embodiments 1 to 51a, wherein R is -CH3.

[0215] Embodiment 54. R is an optionally substituted C 1-6 The compound according to any one of embodiments 1 to 51a, which is aliphatic.

[0216] Embodiment 55. A compound according to embodiment 54, wherein R is an aliphatic optionally substituted with oxo and OR°.

[0217] 56. R° is C 1-6 The compound of embodiment 55, which is aliphatic.

[0218] Embodiment 57. A compound according to embodiment 54, wherein R is methyl or ethyl.

[0219] Embodiment 58.R 2 The compound of any one of embodiments 1-57, wherein is hydrogen.

[0220] Embodiment 59.R 2 is halogen, N(R)2, OR, or C 1-6 The compound of any one of embodiments 1-57, which is an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0221] Embodiment 60.R 2 is N(R)2.

[0222] Embodiment 61. A compound according to embodiment 60, wherein R is NH2.

[0223] Embodiment 62.R 2 But, with arbitrary substitutions C 1-6 The compound of embodiment 59, which is aliphatic.

[0224] Embodiment 63.R 2 is methyl or ethyl.

[0225] Embodiment 64.R 2 is optionally substituted cyclohexyl.

[0226] Embodiment 65.R 2 is optionally substituted phenyl.

[0227] Embodiment 66.R 2is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0228] Embodiment 67.R 2 is an optionally substituted 5-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0229] Embodiment 68.R 2 68. The compound of embodiment 66 or 67, wherein is an optionally substituted group selected from thiophenyl, pyrazolyl, and imidazolyl.

[0230] Embodiment 69.R 2 is an optionally substituted 6-membered heteroaryl ring having 1 to 3 nitrogen atoms.

[0231] Embodiment 70.R 2 is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms.

[0232] Embodiment 71.R 2 is an optionally substituted group selected from pyridinyl or pyrimidinyl.

[0233] Embodiment 72.R 2 is an optionally substituted 8-10 membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring.

[0234] Embodiment 73.R 2 The compound of embodiment 72, wherein is an optionally substituted 9-membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring.

[0235] Embodiment 74.R 2is optionally substituted 2,3-dihydro-1H-indenyl.

[0236] Embodiment 75.R 2 The compound of embodiment 72, wherein is an optionally substituted 10-membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring.

[0237] Embodiment 76.R 2 is an optionally substituted group selected from 1,2,3,4-tetrahydronaphthalenyl or naphthalenyl.

[0238] Embodiment 77.R 2 is an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0239] Embodiment 78.R 2 is an optionally substituted 9-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0240] Embodiment 79.R 2 is an optionally substituted 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0241] Embodiment 80.R 2 is an optionally substituted group selected from chromanyl, isochromanyl, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, and 2H-benzo[b][1,4]oxazin-3(4H)-onyl.

[0242] Embodiment 81.R 2is an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0243] Embodiment 82.R 2 is an optionally substituted 9-membered bicyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0244] Embodiment 83.R 2 83. The compound of embodiment 81 or 82, wherein is an optionally substituted group selected from indolyl, benzopyrazolyl, benzimidazolyl, and imidazo[1,2-a]pyridinyl.

[0245] Embodiment 84.R 2 is selected from the group consisting of: [Table 27-1] [Table 27-2]

[0246] Embodiment 84a.R 2 is selected from the group consisting of: [Table 28-1] [Table 28-2]

[0247] Embodiment 85.R 2 but, [ka] The compound according to embodiment 84, selected from:

[0248] Embodiment 85a.R2 but, [ka] The compound according to embodiment 84a, selected from:

[0249] Embodiment 86. The compound of embodiment 1, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0250] Embodiment 87. The compound of embodiment 1, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0251] Embodiment 88. The compound of embodiment 1, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0252] Embodiment 89. The compound of embodiment 1, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0253] Embodiment 90. The compound of embodiment 1, wherein the compound is selected from the following: [Table 29] or a pharma- ceutically acceptable salt thereof.

[0254] Embodiment 90a. The compound of embodiment 1, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0255] Embodiment 91. The compound of embodiment 1, wherein the compound is selected from the following: [Table 30] or a pharma- ceutically acceptable salt thereof.

[0256] Embodiment 91a. The compound of embodiment 1, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0257] Embodiment 92. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 91a and a pharma- ceutically acceptable carrier.

[0258] EMBODIMENT 93. A method comprising the step of administering to a subject (i) having a condition characterized by axonal degeneration, or (ii) at risk of developing a condition characterized by axonal degeneration, a compound of any one of embodiments 1-91a.

[0259] Embodiment 94. A method for treating or preventing axonal degeneration, comprising administering to a subject in need thereof a compound according to any one of embodiments 1 to 91a.

[0260] Embodiment 95. A method of inhibiting SARM1, comprising contacting a biological sample with a compound according to any one of embodiments 1 to 91a.

[0261] Embodiment 96. A compound of formula I', [ka] or a pharma- ceutically acceptable salt thereof, Ring A is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 1 is an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; Each R x are independently halogen, cyano, OR, SR, N(R)2, S(O)2N(R)2, C(O)OR, C(O)N(R)2, or C 1-4 an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; L is an optionally substituted C 1-4 an aliphatic chain in which one or two carbon atoms are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -S(O)2-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from phenyl, and oxygen, nitrogen, and sulfur; or two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 3-7 membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 2 is hydrogen, halogen, N(R)2, OR, or C 1-6 an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; A compound wherein n is 0, 1, or 2.

[0262] Embodiment 97. A compound according to embodiment 96, wherein ring A is a 6-membered heteroaryl ring having 1-2 nitrogen atoms.

[0263] Embodiment 98. A compound according to embodiment 96, wherein ring A is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0264] Embodiment 99. A compound according to embodiment 98, wherein ring A is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0265] Embodiment 100. A compound according to embodiment 98, wherein ring A is a 5-membered heteroaryl ring having 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0266] Embodiment 101. A compound according to embodiment 96, wherein Ring A is selected from: [Table 31]

[0267] Embodiment 102. Ring A is [ka] The compound according to embodiment 101, selected from:

[0268] Embodiment 103. Ring A is [ka] The compound according to embodiment 101, selected from:

[0269] Embodiment 104. A compound according to embodiment 96, wherein Ring A is selected from the following: [Table 32-1] [Table 32-2]

[0270] Embodiment 105. Ring A is selected from: [Table 33] In the formula, R x But, C 1-4 Compounds according to embodiment 96, which are optionally substituted groups selected from aliphatic, 3-7 membered saturated or partially unsaturated carbocyclic rings, 3-7 membered saturated or partially unsaturated heterocyclic rings having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and 5-6 membered heteroaryl rings having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0271] Embodiment 106. A compound according to embodiment 96, wherein Ring A is selected from the following: [Table 34]

[0272] Embodiment 107. Ring A is selected from: [Table 35] During the ceremony, R on nitrogen atom x But, C 1-4 an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; R on carbon atom x is halogen, cyano, OR, SR, N(R)2, or C 1-4 The compound of embodiment 96, wherein the optionally substituted group is selected from aliphatic, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0273] Embodiment 108.R x The compound of any one of embodiments 96-107, wherein is halogen.

[0274] Embodiment 109.R x The compound according to any one of embodiments 96-107, wherein is cyano.

[0275] Embodiment 110.R x The compound of any one of embodiments 96-107, wherein is OR.

[0276] Embodiment 111.R xThe compound according to any one of embodiments 96-107, wherein is SR.

[0277] Embodiment 112.R x The compound according to any one of embodiments 96-107, wherein is N(R)2.

[0278] Embodiment 113. R is selected from hydrogen and optionally substituted C 1-6 The compound according to any one of embodiments 110-112, which is selected from aliphatic.

[0279] Embodiment 114. R is selected from hydrogen and optionally substituted C 1-4 The compound according to embodiment 113, wherein the compound is selected from aliphatic.

[0280] Embodiment 115.R x The compound according to any one of embodiments 110, 113, and 114, wherein is OH, OCH3, and OCH2CH3.

[0281] Embodiment 116.R x The compound according to any one of embodiments 111, 113, and 114, wherein is SH, SCH3, and SCH2CH3.

[0282] Embodiment 117.R x The compound according to any one of embodiments 112-114, wherein is NH2, NHCH3, NHCH2CH3, N(CH3)2, and N(CH2CH3)2.

[0283] Embodiment 118.R x But, with arbitrary substitutions C 1-4 The compound according to any one of embodiments 96-107, which is aliphatic.

[0284] Embodiment 119.R x But, with arbitrary substitutions C 3-4 The compound of embodiment 118, which is aliphatic.

[0285] Embodiment 120.R xBut tert-butyl, [ka] The compound according to embodiment 119, selected from:

[0286] Embodiment 121.R x But halogen, -(CH2) 0-4 R°, -(CH2) 0-4 OR°, -(CH2) 0-4 N(R°)2, -(CH2) 0-4 C(O)OR°, and -(CH2) 0-4 C(O)NR°2 optionally substituted with a group selected from 1-4 The compound of embodiment 118, which is aliphatic.

[0287] Embodiment 122. R° is hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Compounds according to embodiment 121, wherein the heteroatoms are selected from Ph, -CH2- (a 5-6 membered heteroaryl ring), a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two independent occurrences of R°, taken together with their intervening atoms, form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0288] Embodiment 123.R x is optionally substituted with a group selected from halogen, -R°, -OR°, -N(R°)2, -C(O)OR°, and -C(O)NR°2; 1-4 The compound of embodiment 118, which is aliphatic.

[0289] Embodiment 124.R x C optionally substituted with halogen 1-4 The compound of embodiment 118, which is aliphatic.

[0290] Embodiment 125.R x is selected from -CH3, -CF3, -CHF2, and CH2F.

[0291] Embodiment 126.R x is selected from -CH3, -CD3, -CF3, -CHF2, CH2F, CH2CH3.

[0292] Embodiment 127.R x The compound of embodiment 118, wherein is selected from -CH2R°, -CH2OR°, -CH2N(R°)2, -CH2C(O)OR°, and -CH2C(O)N(R°)2.

[0293] Embodiment 128.R x The compound of embodiment 127, wherein is selected from -CH2OH, -CH2OCH3, -CH2CO2CH3, CH2CO2CH2CH3, -CH2C(O)NH2, -CH2C(O)NHCH3, and -CH2C(O)N(CH3)2.

[0294] Embodiment 129.R x The compound of any one of embodiments 96-107, wherein is selected from S(O)2N(R)2, C(O)OR, and C(O)N(R)2.

[0295] Embodiment 130.R x is S(O)2N(R)2.

[0296] Embodiment 131.R x is SO2NH2.

[0297] Embodiment 132.R x is C(O)OR.

[0298] Embodiment 133.R xThe compound of embodiment 132, wherein is selected from CO2CH3 and CO2CH2CH3.

[0299] Embodiment 134.R x is C(O)N(R)2.

[0300] Embodiment 135.R x is selected from C(O)NH2 and C(O)N(CH3)2.

[0301] Embodiment 136.R 1 The compound of any one of embodiments 96-135, wherein is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0302] Embodiment 137.R 1 is an optionally substituted 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0303] Embodiment 138.R 1 Compounds according to embodiment 137, wherein is an optionally substituted 5-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0304] Embodiment 139.R 1 The compound according to embodiment 136, wherein is an optionally substituted 6-membered heteroaryl ring having 1 to 3 nitrogen atoms.

[0305] Embodiment 140.R 1 The compound of embodiment 139, wherein is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms.

[0306] Embodiment 141.R 1 is selected from the following: [Table 36]

[0307] Embodiment 142.R 1 but, [ka] The compound according to embodiment 141, selected from:

[0308] Embodiment 143. L is an optionally substituted C 1-2 The compound of any one of embodiments 96-142, which is an aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -S(O)2-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0309] Embodiment 144. L is an optionally substituted C 1-2 The compound of embodiment 143, which is an aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -S(O)2-, -C(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0310] Embodiment 145. L is an optionally substituted C 1-2 The compound of embodiment 143 or 144, which is an aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from -O-, -N(H)-, -S-, -S(O)2-, -C(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0311] Embodiment 146. L is an optionally substituted C 3-4The compound of any one of embodiments 96-142, which is an aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -S(O)2-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0312] Embodiment 147. L is an optionally substituted C 3-4 The compound of embodiment 146, which is an aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from -O-, -N(R)-, -S-, -S(O)2-, -C(O)-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0313] Embodiment 148. L is an optionally substituted C 3-4 The compound of embodiment 146 or 147, which is an aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from -O-, -N(H)-, -S-, -S(O)2-, -C(O)-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0314] Embodiment 149. L is an optionally substituted C 1-4 The compound of any one of embodiments 96-142, which is an aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)- and one additional carbon atom is optionally replaced by a group selected from -O-, -N(R)-, -S-, -S(O)2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0315] Embodiment 150. L is an optionally substituted C 1-4The compound of embodiment 149, which is an aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)- and one additional carbon atom is optionally replaced by a group selected from -O-, -N(R)-, -S-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0316] Embodiment 151. L is an optionally substituted C 1-4 The compound according to embodiment 149 or 150, which is an aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)- and one additional carbon atom is optionally replaced by a group selected from -O-, -N(H)-, -S-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0317] Embodiment 152. L is an optionally substituted C 3-4 The compound of embodiment 149 or 150, which is an aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)- and one additional carbon atom is optionally replaced by a group selected from -O-, -N(R)-, -S-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0318] Embodiment 153. L is an optionally substituted C 3-4 The compound according to embodiment 152, which is an aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)- and one additional carbon atom is optionally replaced by a group selected from -O-, -N(H)-, -S-, and a divalent 3-5 membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0319] Embodiment 154. A compound according to any one of embodiments 96 to 142, wherein L is selected from the following: [Table 37]

[0320] Embodiment 155. A compound according to any one of embodiments 96 to 142, wherein L is selected from: [Table 38]

[0321] In the embodiment 156.L, [ka] The compound according to embodiment 155, selected from:

[0322] In the embodiment 157.L, [ka] The compound according to embodiment 155, selected from:

[0323] Embodiment 158. A compound according to any one of embodiments 96 to 157, wherein R is hydrogen.

[0324] Embodiment 159. A compound according to any one of embodiments 96 to 157, wherein R is -CH3.

[0325] Embodiment 160. R is an optionally substituted C 1-6 The compound according to any one of embodiments 96-157, which is aliphatic.

[0326] Embodiment 161. A compound according to embodiment 160, wherein R is an aliphatic optionally substituted with oxo and OR°.

[0327] In the embodiment 162.R° is C 1-6 The compound according to embodiment 161, which is aliphatic.

[0328] Embodiment 163. A compound according to embodiment 160, wherein R is methyl or ethyl.

[0329] Embodiment 164.R 2The compound of any one of embodiments 96-163, wherein is hydrogen.

[0330] Embodiment 165.R 2 is halogen, N(R)2, OR, or C 1-6 The compound of any one of embodiments 96-163, which is an optionally substituted group selected from aliphatic, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0331] Embodiment 166.R 2 is N(R)2.

[0332] Embodiment 167. A compound according to embodiment 166, wherein R is NH2.

[0333] Embodiment 168.R 2 But, with arbitrary substitutions C 1-6 The compound according to embodiment 165, which is aliphatic.

[0334] Embodiment 169.R 2 The compound according to embodiment 168, wherein is selected from methyl, ethyl, t-butyl, and neopentyl.

[0335] Embodiment 170.R 2 The compound according to embodiment 165, wherein is optionally substituted cyclohexyl.

[0336] Embodiment 171.R 2is optionally substituted phenyl.

[0337] Embodiment 172.R 2 Compounds according to embodiment 165, wherein is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0338] Embodiment 173.R 2 Compounds according to embodiment 172, wherein is an optionally substituted 5-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0339] Embodiment 174.R 2 174. Compounds according to embodiment 172 or 173, wherein is an optionally substituted group selected from thiophenyl, pyrazolyl, and imidazolyl.

[0340] Embodiment 175.R 2 Compounds according to embodiment 172, wherein is an optionally substituted 6-membered heteroaryl ring having 1 to 3 nitrogen atoms.

[0341] Embodiment 176.R 2 Compounds according to embodiment 175, wherein is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms.

[0342] Embodiment 177.R 2 is an optionally substituted group selected from pyridinyl or pyrimidinyl.

[0343] Embodiment 178.R 2 The compound according to embodiment 165, wherein is an optionally substituted 8-10 membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring.

[0344] Embodiment 179.R 2The compound according to embodiment 178, wherein is an optionally substituted 9-membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring.

[0345] Embodiment 180.R 2 is optionally substituted 2,3-dihydro-1H-indenyl.

[0346] Embodiment 181.R 2 The compound according to embodiment 178, wherein is an optionally substituted 10-membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring.

[0347] Embodiment 182.R 2 The compound of embodiment 181, wherein is an optionally substituted group selected from 1,2,3,4-tetrahydronaphthalenyl or naphthalenyl.

[0348] Embodiment 183.R 2 is an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0349] Embodiment 184.R 2 is an optionally substituted 9-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0350] Embodiment 185.R 2 is an optionally substituted 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0351] Embodiment 186.R 2Compounds according to embodiment 185, wherein is an optionally substituted group selected from chromanyl, isochromanyl, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, and 2H-benzo[b][1,4]oxazin-3(4H)-onyl.

[0352] Embodiment 187.R 2 is a 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0353] Embodiment 188.R 2 is an optionally substituted 9-membered bicyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0354] Embodiment 189.R 2 189. The compound according to embodiment 187 or 188, wherein is an optionally substituted group selected from indolyl, benzopyrazolyl, benzimidazolyl, and imidazo[1,2-a]pyridinyl.

[0355] Embodiment 190.R 2 is selected from the group consisting of: [Table 39-1] [Table 39-2] [Table 39-3]

[0356] Embodiment 191.R 2 is selected from the group consisting of: [Table 40-1] [Table 40-2]

[0357] Embodiment 192.R 2 but, [ka] The compound according to embodiment 190, selected from:

[0358] Embodiment 193.R 2 but, [ka] The compound according to embodiment 191, selected from:

[0359] Embodiment 194. The compound of embodiment 96, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0360] Embodiment 195. The compound of embodiment 96, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0361] Embodiment 196. The compound of embodiment 96, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0362] Embodiment 197. The compound of embodiment 96, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0363] Embodiment 198. The compound according to embodiment 96, wherein the compound is selected from the following: [Table 41] or a pharma- ceutically acceptable salt thereof.

[0364] Embodiment 199. The compound of embodiment 96, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0365] Embodiment 200. The compound of embodiment 96, wherein the compound is selected from the following: [Table 42] or a pharma- ceutically acceptable salt thereof.

[0366] Embodiment 201. The compound of embodiment 96, wherein the compound is selected from the following: [Table 43] or a pharma- ceutically acceptable salt thereof.

[0367] Embodiment 202. Ring A is [ka] The compound of any one of embodiments 1, 3, 4, 8, 12-89, 90a, 91, 96, 98, 99, 101, 104, 108-197, 199, and 201, wherein

[0368] Embodiment 203. The compound of embodiment 202, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0369] Embodiment 204. The compound of embodiment 202, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0370] Embodiment 205. The compound of embodiment 202, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0371] Embodiment 206. The compound of embodiment 202, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0372] Embodiment 207. The compound of embodiment 202, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0373] Embodiment 208. The compound of embodiment 202, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0374] Embodiment 209. The compound of embodiment 202, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0375] Embodiment 210. The compound of embodiment 202, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0376] Embodiment 211. The compound of embodiment 202, wherein the compound is: [ka] or a pharma- ceutically acceptable salt thereof.

[0377] Embodiment 212. A pharmaceutical composition comprising a compound according to any one of embodiments 96 to 211 and a pharma- ceutically acceptable carrier.

[0378] EMBODIMENT 213. A method comprising the step of administering to a subject (i) having a condition characterized by axonal degeneration, or (ii) at risk of developing a condition characterized by axonal degeneration, a compound described in any one of embodiments 96-211.

[0379] Embodiment 214. A method for treating or preventing axonal degeneration, comprising administering to a subject in need thereof a compound according to any one of embodiments 96 to 211.

[0380] Embodiment 215. The method of embodiment 94 or embodiment 214, wherein the axonal degeneration is associated with a neurodegenerative disease or disorder.

[0381] Embodiment 216. The method of embodiment 215, wherein the neurodegenerative disease or disorder is selected from an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.

[0382] Embodiment 217. The method of embodiment 215 or embodiment 216, wherein the neurodegenerative disease or disorder is selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy, and chemotherapy-induced peripheral neuropathy.

[0383] Embodiment 218. The method of embodiment 217, wherein the neurodegenerative disease or disorder is amyotrophic lateral sclerosis (ALS).

[0384] Embodiment 219. The method of embodiment 217, wherein the neurodegenerative disease or disorder is multiple sclerosis (MS).

[0385] Embodiment 220. The method of embodiment 217, wherein the neurodegenerative disease or disorder is diabetic neuropathy.

[0386] Embodiment 221. The method of embodiment 217, wherein the neurodegenerative disease or disorder is chemotherapy-induced peripheral neuropathy.

[0387] Embodiment 222. A method for inhibiting SARM1, comprising contacting a biological sample with a compound according to any one of embodiments 96 to 211.

[0388] composition In some embodiments, a compound of formula I or formula I' may be provided in a composition, for example in combination (eg, a mixture) with one or more other components.

[0389] In some embodiments, the disclosure provides compositions that contain and / or deliver a compound of Formula I or Formula I', or an active metabolite thereof, when contacted with or otherwise administered to, e.g., a system or environment that may contain SARM1 NADase activity, and in some embodiments, administration of such a composition to a system or environment achieves inhibition of SARM1 activity, as described herein.

[0390] In some embodiments, a provided composition described herein may be a pharmaceutical composition in that it comprises an active agent and one or more pharma- ceutically acceptable excipients, and in some such embodiments, a provided pharmaceutical composition comprises and / or delivers to a relevant system or environment (e.g., a subject in need thereof) a compound of Formula I or Formula I', or an active metabolite thereof, as described herein.

[0391] In some embodiments, one or more compounds of Formula I or Formula I' are provided and / or utilized in the form of a pharma- ceutically acceptable salt.

[0392] In particular, the present disclosure provides a composition comprising a compound of formula I or formula I', or a pharma- ceutically acceptable salt or derivative thereof, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the provided composition is such that it is effective to measurably inhibit axonal degeneration in a biological sample or a patient. In certain embodiments, the provided compound or composition is formulated for administration to a patient in need of such a composition. The compounds and compositions according to the methods of the present disclosure may be administered using any amount and any route of administration effective to treat or reduce the severity of any disease or disorder described herein. The provided compounds are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The phrase "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. However, it will be understood that the total daily usage of the provided compounds and compositions will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level in any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the activity of the specific compound used, the specific composition used and its route of administration, the patient's species, age, weight, sex, and diet, the general condition of the subject, the timing of administration, the excretion rate of the specific compound used, the duration of treatment, drugs used in combination or concomitantly with the specific compound used, and the like.

[0393] The provided compositions may be administered orally, parenterally, by inhalation or nasal spray, topically (e.g., by powder, ointment, or infusion), rectally, bucally, intravaginally, intraperitoneally, intracisternally, or via an implanted reservoir, depending on the severity of the condition being treated. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. In certain embodiments, the provided compounds are administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg of subject body weight per day, one or more times per day, to obtain the desired therapeutic effect.

[0394] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Sterile injectable forms of the compositions provided may be aqueous or oily suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media.

[0395] For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as tween, span and other emulsifiers or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms, can also be used for formulation purposes.

[0396] The injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0397] In some cases, it is desirable to slow down the absorption of the compound from subcutaneous or intramuscular injection in order to prolong the effect of the compound provided. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot preparations are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the nature of the particular polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot preparations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0398] The pharmaceutically acceptable compositions described herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.In such solid dosage forms, active compound can be mixed with at least one inert diluent, such as sucrose, lactose, or starch.Such dosage forms can also contain additional substances other than inert diluents, such as lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as is customary.When aqueous suspension is required for oral use, active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners, flavors, or colorants can be added.

[0399] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) hygroscopic agents, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents, such as kaolin and bentonite clay; and / or i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.The active compounds can also be in microencapsulated form with one or more excipients as noted above.

[0400] Solid compositions of a similar type can also be used as fillers for soft and hard filled gelatin capsules, using such excipients as lactose or milk sugar, and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings (i.e., buffers) and other coatings well known in the pharmaceutical formulation art. These compositions can also optionally contain opacifying agents, and can be of a composition that releases the active ingredient only, or preferentially, in a certain part of the digestive tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0401] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to active ingredients, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide oil (specifically cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and aromatics.

[0402] Alternatively, the pharma- ceutically acceptable compositions described herein can be administered in the form of suppositories for rectal or vaginal administration.These can be prepared by mixing the compounds of the present disclosure with suitable non-irritating excipients or carriers that are solid at room temperature but liquid at body temperature (rectum or vagina), and therefore melt in the rectum or vaginal cavity to release active compounds.Such materials include cocoa butter, suppository wax (e.g., beeswax) and polyethylene glycol.

[0403] The pharma- ceutically acceptable compositions described herein may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract.Topical application to the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.

[0404] Dosage forms for topical or transdermal administration of the provided compounds include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier and, if necessary, with necessary preservatives or buffers. Ophthalmic preparations, ear drops, and eye drops are also considered to be within the scope of the present disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. This rate can be controlled by either providing a flow-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0405] For topical application, the provided pharma- ceutically acceptable composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, the provided pharma-ceutically acceptable composition can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharma-ceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0406] For ophthalmic use, the pharma- ceutically acceptable composition may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or, preferably, as a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharma-ceutically acceptable composition may be formulated in an ointment, such as petrolatum.

[0407] The pharma- ceutically acceptable compositions of the present disclosure may also be administered by nasal aerosol or inhalation.Such compositions are prepared according to techniques well known in the art of formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0408] Most preferably, the pharma- ceutically acceptable compositions of the present disclosure are formulated for oral administration.

[0409] Identification and / or characterization of compounds and / or compositions In particular, the present disclosure provides various techniques for identifying and / or characterizing the compounds and / or compositions described herein.For example, the present disclosure provides various assays for evaluating SARM1 inhibitory activity, in particular for evaluating SARM1 inhibitory activity.

[0410] In some embodiments, the performance of one or more compounds or compositions of interest in an assay as described herein is compared to the performance of a suitable reference. For example, in some embodiments, the reference can be the absence of a relevant compound or composition. Alternatively or additionally, in some embodiments, the reference can be the presence of an alternative compound or composition, for example, the alternative compound or composition has a known performance in a relevant assay (e.g., as a positive or negative control, as understood in the art). In some embodiments, the reference can be an alternative but equivalent set of conditions (e.g., temperature, pH, salt concentration, etc.). In some embodiments, the reference can be the performance of the compound or composition with respect to a SARM1 variant.

[0411] Further alternatively or additionally, in some embodiments, the performance of one or more compounds or compositions of interest in the assays described herein can be evaluated, for example, in the presence of a suitable reference compound or composition, such that the ability of the compound or composition to compete with the reference is determined.

[0412] In some embodiments, a plurality of compounds or compositions of interest may be subjected to analysis in a particular assay and / or compared to the same reference. In some embodiments, such a plurality of compounds or compositions may be or may include a set of compounds or compositions that are considered to be a "library" because multiple members share one or more characteristics (e.g., structural elements, source identity, synthetic similarity, etc.).

[0413] Certain exemplary assays that may be useful in practicing the present disclosure are illustrated in the Examples below. Those of skill in the art reading this disclosure will recognize that useful or relevant systems for identifying and / or characterizing compounds and / or compositions according to the present disclosure are not limited to those included in the Examples or discussed below.

[0414] In some embodiments, the compounds and / or compositions can be identified and / or characterized based on one or more activities or characteristics, such as promoting axonal integrity, cytoskeleton stability, and / or neuronal survival. In some embodiments, the provided SARM1 inhibitors inhibit the catabolism of NAD+ by SARM1. In some embodiments, the provided SARM1 inhibitors slow down the rate of NAD+ catabolism.

[0415] In some embodiments, the provided SARM1 inhibitor reduces or inhibits the binding of NAD+ by SARM1. In some embodiments, the provided SARM1 inhibitor binds to SARM1 in a pocket that includes one or more catalytic residues (e.g., catalytic cleft of SARM1). An example of such a catalytic residue includes glutamic acid at position 642 (E642).

[0416] In some embodiments, the provided SARM1 inhibitors disrupt and / or prevent the multimerization of the TIR1 domain of SARM1. In some embodiments, the provided SARM1 inhibitors disrupt the multimerization of the SAM domain. In some embodiments, the provided SARM1 inhibitors disrupt the axonal signaling cascade that leads to NAD+ depletion.

[0417] In some embodiments, the present disclosure provides assays useful for identifying and / or characterizing one or more activities and / or characteristics of compounds and / or compositions of interest. For example, in some embodiments, the present disclosure provides in vitro, cellular, and / or in vivo systems for assessing one or more such activities and / or characteristics.

[0418] SARM1 activity assay In some embodiments, a method for identifying a SARM1 inhibitor includes: a) providing a mixture comprising i) a mutant or fragment of SARM1, ii) NAD+, and iii) a candidate inhibitor, wherein the mutant or fragment has constitutive activity; b) incubating the mixture; c) quantifying the NAD+ in the mixture after incubation; and d) identifying the candidate inhibitor compound as an inhibitor if the amount of NAD+ is greater than the amount of a control mixture not containing the candidate inhibitor.

[0419] In some embodiments, a method is provided for identifying a SARM1 inhibitor comprising: a) providing a mixture comprising i) full-length SARM1, ii) NAD+, and iii) a candidate inhibitor, wherein the full-length SARM1 has constitutive activity; b) incubating the mixture; c) quantifying NAD+ and ADPR (or cADPR) in the mixture after incubation; d) determining the molar ratio of NAD+:ADPR (or cADPR); and e) identifying the candidate inhibitor compound as an inhibitor if the molar ratio is greater than that of a control mixture not containing the candidate inhibitor.

[0420] In some embodiments, a method is provided for identifying a SARM1 inhibitor, comprising: a) providing a mixture comprising i) full-length SARM1 and at least one tag, ii) NAD+, and iii) a solid support bound to a candidate inhibitor; b) incubating the mixture; c) quantifying the NAD+ after incubation; and d) identifying the candidate inhibitor compound as a SARM1 inhibitor if the concentration of NAD+ is higher than that of a control.

[0421] SARM1 binding assay In some embodiments, the efficacy of the provided SARM1 inhibitors can be determined, for example, according to the assays described in WO2018 / 057989 published March 29, 2018, which is incorporated herein by reference in its entirety. In some embodiments, the provided SARM1 inhibitors can be applied to a solution containing SARM1 or a fragment thereof. In some embodiments, the provided SARM1 inhibitors can be applied to an in vitro system. In some embodiments, the provided SARM1 inhibitors can be applied in vivo. In some embodiments, the provided SARM1 inhibitors can be applied to a patient. In some embodiments, the SARM1 inhibitors can be mixed with SARM1 or a fragment thereof labeled with an epitope tag. In some embodiments, the amount of bound SARM1 inhibitor can be compared to the amount of unbound SARM1 inhibitor, resulting in affinity for the SARM1 inhibitor.

[0422] In some embodiments, the mutant or fragment of SARM1 is a SAM-TIR fragment with constitutive activity. The fragment of SARM1 with constitutive activity includes, but is not limited to, for example, SARM1 with deleted autoinhibitory domain, at least one point mutation of SARM1 that makes the autoinhibitory domain inactive, a fragment of SARM1 containing the TIR domain, or a fragment of SARM1 consisting of the SAM domain and the TIR domain. In some embodiments, the SARM1 polypeptide can include one or more additional amino acid sequences that can act as a tag, such as a His tag, a streptavidin tag, or a combination thereof. In some embodiments, the SARM1 polypeptide can include a tag at the amino terminus, the carboxy terminus, or a combination thereof. In some embodiments, the SARM1 or a fragment thereof labeled with an epitope tag can be used to measure the binding efficiency of the provided SARM1 inhibitor.

[0423] Purification of the SARM1-TIR domain In some embodiments, the SARM1-TIR domain can be engineered with various proteins or epitopes, tags, which may be useful, for example, in purification. In some embodiments, the present disclosure also provides an NRK1-HEK293T cell line, which comprises HEK293T cells transformed with nicotinamide riboside kinase 1 (NRK1). In some embodiments, the HEK293T cells are transformed or transfected with a DNA sequence encoding nicotinamide riboside kinase 1 (NRK1). In some embodiments, the DNA encoding NRK1 can be genomic or cDNA. In some embodiments, the HEK293T cells are stably or transiently transfected with DNA encoding NRK1 from a source exogenous to the host cell. In some embodiments, the HEK293T cells are stably or transiently transfected with DNA encoding NRK1 such that the cells express NRK1 at a higher level compared to control cells. In some embodiments, the DNA encoding NRK1 is under the control of one or more exogenous regulatory DNA sequences, such as a promoter, an enhancer, or a combination thereof. In some embodiments, the combination of the DNA sequence encoding NRK1 and the regulatory sequence is a combination that does not occur in nature.In some embodiments, the DNA encoding NRK1 is either genomic or cDNA, and includes an expression vector, such as FCIV expression vector.In some embodiments, the DNA encoding NRK1 is derived from genomic or cDNA from vertebrate or invertebrate species, such as, but not limited to, human, mouse, zebrafish, or Drosophila.In some configurations, the NRK1 DNA is human NRK1 DNA.

[0424] Intended Use and Use The present disclosure provides various uses and applications of the compounds and / or compositions described herein, for example, in view of their activities and / or characteristics described herein. In some embodiments, such uses may include therapeutic and / or diagnostic uses. Alternatively, in some embodiments, such uses may include research, production, and / or other technical uses.

[0425] In one aspect, the disclosure provides methods that include administering to a subject one or more compounds of Formula I or Formula I', for example, to treat, prevent, or reduce the risk of developing one or more conditions characterized by axonal degeneration. In some such embodiments, the compound of Formula I or Formula I' is a SARM1 inhibitor.

[0426] Another embodiment of the present disclosure relates to a method of inhibiting SARM1 activity in a patient, comprising administering to the patient a provided compound, or a composition comprising said compound.

[0427] Inhibition of enzymes in biological samples is useful for a variety of purposes known to those of skill in the art, including, but not limited to, biological assays, gene expression studies, and identification of biological targets.

[0428] In certain embodiments, the present disclosure relates to a method for treating axonal degeneration in a biological sample, comprising contacting the biological sample with a compound or composition of formula I or formula I'. In some embodiments, one or more compounds and / or compositions described herein are useful, for example, as a method for inhibiting the degeneration of neurons derived from a subject. In some embodiments, one or more compounds and / or compositions described herein are useful for inhibiting the degeneration of in vitro cultured neurons or portions thereof. In some embodiments, one or more compounds and / or compositions described herein are useful as stabilizers for promoting the survival of in vitro neurons.

[0429] In some embodiments, provided compounds and / or compositions inhibit the NADase activity of SARM1.Alternatively or additionally, in some embodiments, provided compounds alleviate one or more attributes of neurodegeneration.In some embodiments, the present disclosure provides a method for treating a neurodegenerative disease or disorder associated with axonal degeneration.

[0430] In some embodiments, one or more compounds and / or compositions described herein are useful, for example, in the practice of medicine.In some embodiments, one or more compounds and / or compositions described herein are useful, for example, for treating, preventing, or improving axon degeneration (e.g., one or more characteristics or features thereof).In some embodiments, one or more compounds and / or compositions described herein are useful, for example, for inhibiting axon degeneration, including axon degeneration resulting from reduction or depletion of NAD+.In some embodiments, one or more compounds and / or compositions described herein are useful, for example, for preventing axons distal to axonal injury from degenerating.

[0431] In some embodiments, one or more compounds and / or compositions described herein are useful, for example, as a method for inhibiting the degradation of peripheral nervous system neurons or a portion thereof. In some embodiments, one or more compounds and / or compositions described herein are useful, for example, as a method for inhibiting or preventing the degeneration of the central nervous system (neurons) or a portion thereof. In some embodiments, one or more compounds or compositions described herein are characterized in that, when administered to a population of subjects, they reduce one or more symptoms or characteristics of neurodegeneration. For example, in some embodiments, the relevant symptoms or characteristics may be selected from the group consisting of the extent, speed, and / or timing of neuronal destruction.

[0432] In certain embodiments, the present disclosure provides compounds that are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present disclosure. Compounds provided by the present disclosure are also useful for testing SARM1 activity in biological and pathological phenomena, and for comparative evaluation of novel SARM1 activity inhibitors in vitro or in vivo. In certain embodiments, the present disclosure provides assays for identifying and / or characterizing the compounds and / or compositions provided herein. In some embodiments, the provided assays utilize specific reagents and / or systems (e.g., specific vector constructs and / or polypeptides) that are useful for assaying SARM1 activity. For example, in some embodiments, the provided assays may utilize, for example, SAM-TIR with the SARM1 N-terminal autoinhibitory domain deleted, and / or one or more tagged versions of the TIR domain.

[0433] In some embodiments, one or more compounds and / or compositions described herein are useful as a method for inhibiting the degeneration of neurons derived from a subject, for example.In some embodiments, one or more compounds and / or compositions described herein are useful for inhibiting the degeneration of in vitro cultured neurons or parts thereof.In some embodiments, one or more compounds and / or compositions described herein are useful as a stabilizer for promoting the survival of in vitro neurons.

[0434] In some embodiments, one or more compounds and / or compositions described herein are useful, for example, for affecting biomarkers associated with neurodegeneration. In some embodiments, changes in biomarkers can be detected systemically or using cerebrospinal fluid (CSF), plasma, serum, and / or tissue samples from a subject. In some embodiments, one or more compounds and / or compositions can be used to affect changes in the concentration of neurofilament protein light chain (NF-L) and / or neurofilament protein heavy chain (NF-H) contained in the cerebrospinal fluid of a subject. In some embodiments, one or more compounds and / or compositions described herein can affect constitutive NAD and / or cADPR levels in neurons and / or axons.

[0435] In some embodiments, the one or more biomarkers of neurodegeneration include a concentration of neurofilament light chain protein (NF-L) in one or more of a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject; a concentration of neurofilament heavy chain protein (NF-H) in one or more of a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject; a concentration of ubiquitin C-terminal hydrolase L1 (UCH-L1) in one or more of a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject; a concentration of alpha synuclein in one or more of a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject; constitutive NAD+ levels in neurons and / or axons of the subject; constitutive cADPR levels in the subject; levels of albumin, amyloid-β (Aβ) 38, Aβ 40, Aβ 42, glial fibrillary acidic protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractant protein (MCP)-1, neurogranin, neuron-specific enolase (NSE), soluble amyloid precursor protein (sAPP) α, sAPP β, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, or total tau in one or more of a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, a skin biopsy sample, a neuronal biopsy sample, and a brain biopsy sample from the subject; and CC in one or more of a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, a skin biopsy sample, a neuronal biopsy sample, and a brain biopsy sample from the subject. including levels of Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colony-stimulating factor (CSF) 1, or interleukin (IL) 6.

[0436] In some embodiments, one or more compounds and / or compositions described herein can affect detectable changes in the levels of one or more neurodegeneration-associated proteins in a subject. Such proteins include, but are not limited to, albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractant protein (MCP)-1, neurogranin, neuron-specific enolase (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM)2, phospho-tau, and / or total tau. In some embodiments, one or more compounds and / or compositions described herein can affect changes in cytokines and / or chemokines, including, but not limited to, Ccl2, Ccl7, Ccl12, Csf1, and / or Il6.

[0437] Diseases, Disorders, and Conditions In some embodiments, the compounds and / or compositions described herein can be administered to a subject suffering from one or more diseases, disorders, or conditions. In some embodiments, the one or more diseases, disorders, or conditions are mediated by SARM1.

[0438] In some embodiments, the neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.

[0439] In some embodiments, the neurodegenerative disease or disorder comprises an acute disease or disorder of the PNS. In some embodiments, the acute disease or disorder of the PNS is the result of mechanical injury, thermal injury, or injury from a chemical or chemotherapy agent. In some embodiments, the mechanical injury comprises a compressive or constriction injury or a pressure injury. In some embodiments, the compressive or constriction injury comprises carpal tunnel syndrome, direct trauma, penetrating injury, contusion, fracture, or dislocation of a bone. In some embodiments, the pressure injury comprises pressure involving the superficial peroneal nerve, pressure from a tumor, or elevated intraocular pressure. In some embodiments, the chemical or chemotherapy agent comprises a cytotoxic anticancer drug, thalidomide, an epothilone, a taxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drug, or an auristatin. In some embodiments, the epothilone is ixabepilone. In some embodiments, the taxane is paclitaxel or docetaxel. In some embodiments, the vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine. In some embodiments, the proteasome inhibitor is bortezomib. In some embodiments, the platinum-based drug is cisplatin, oxaliplatin, or carboplatin. In some embodiments, the auristatin is conjugated monomethyl auristatin E.

[0440] In some embodiments, the neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS. In some embodiments, the chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder.

[0441] In some embodiments, the chronic disease or disorder of the PNS includes hereditary neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathies (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies or other peripheral neuropathies.

[0442] In some embodiments, the systemic disorder comprises diabetes, uremia, AIDS, leprosy, nutritional deficiencies, atherosclerosis, enteric neuropathy, axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.

[0443] In some embodiments, the pain disorder comprises chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, cancer pain, arthritis, sciatica, headache, surgical pain, muscle spasm, back pain, visceral pain, injury pain, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve injury, shingles, herniated disc, torn ligament, or diabetes.

[0444] In some embodiments, the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, erythrocytosis, amyloidosis, acromegaly, porphyria, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lipid / glycolipid metabolism disorders, nutritional deficiencies, vitamin deficiencies, or mitochondrial disorders.

[0445] In some embodiments, the neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS, hi some embodiments, the acute disease or disorder of the CNS comprises ischemia, traumatic CNS injury, chemical injury, thermal injury, or viral encephalitis.

[0446] In some embodiments, ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.

[0447] In some embodiments, traumatic CNS injury includes spinal cord injury, TBI, mechanical injury to the head and / or spine, traumatic injury to the head and / or spine, blunt trauma, closed head injury, open head injury, exposure to percussive and / or explosive forces, penetrating injury to the CNS, increased intraocular pressure, or injury due to forces that deform, stretch, crush or thin axons.

[0448] In some embodiments, viral encephalitis comprises enteroviral encephalitis, arboviral encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyaviral encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).

[0449] In some embodiments, the neurodegenerative disease or disorder comprises a chronic disease or disorder of the CNS.

[0450] In some embodiments, the chronic disease or disorder of the CNS is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler's syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital cerebral hypomyelopathy, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus-Merzbach disease, periventricular leukoencephalopathy, cerebrovascular disease, cerebrovascular accident ... The chronic disease or disorder of the CNS includes neurotoxic hearing loss, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, dementia with Lewy bodies, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, spinocerebellar ataxia, preeclampsia, hereditary spastic paraplegia, spastic paraplegia, familial spastic paraplegia, French colonial disease, Strampel-Loraine disease, nonalcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supranuclear palsy (PSP), Friedreich's ataxia, or spinal cord injury. In some embodiments, the chronic disease or disorder of the CNS is neurotoxic hearing loss. In some such embodiments, the neurotoxic hearing loss is caused by chemotherapy or antibiotics.

[0451] In some embodiments, the chronic disease or disorder of the CNS comprises optic neuropathy, traumatic CNS injury, or a metabolic disease or disorder.

[0452] In some embodiments, optic neuropathy comprises acute optic neuropathy (AON), hereditary or idiopathic retinal conditions, Leber's congenital amaurosis (LCA), Leber's hereditary optic neuropathy (LHON), primary open angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, outer retinal neuropathy, optic neuritis, optic nerve degeneration associated with multiple sclerosis, Kedzier's optic neuropathy, ischemic optic neuropathy, vitamin B12 deficiency, folate (vitamin B9) deficiency, isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, or exposure to cyanide.

[0453] In some embodiments, the CNS disease or disorder is a tauopathy. In some such embodiments, the tauopathy occurs as a result of progressive supranuclear palsy or corticobasal degeneration.

[0454] In some embodiments, the neurodegenerative disease or disorder is caused or results from protein misfolding.

[0455] In some embodiments, the neurodegenerative disease or disorder is a synucleinopathy, such as, for example, the abnormal accumulation of aggregates of α-synuclein protein in neurons.

[0456] In some embodiments, the neurodegenerative disease or disorder is multiple system atrophy.

[0457] In some embodiments, the traumatic CNS injury comprises traumatic brain injury (TBI), spinal cord injury, traumatic axonal injury, or chronic traumatic encephalopathy (CTE).

[0458] In some embodiments, the metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, lipid / glycolipid metabolism disorders, nutritional / vitamin deficiencies, and mitochondrial disorders.

[0459] In some embodiments, the neurodegenerative disease or disorder comprises a disease associated with neurodegeneration, hi some embodiments, the neurodegenerative disease or disorder results from blood clotting problems, inflammation, obesity, aging, stress, cancer, or diabetes.

[0460] In some embodiments, the condition is acute peripheral neuropathy. Chemotherapy-induced peripheral neuropathy (CIPN) is an example of acute peripheral neuropathy. CIPN can be associated with various drugs, including but not limited to thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin), and the like.

[0461] In some embodiments, one or more compounds and / or compositions described herein are useful for treating one or more neurodegenerative diseases, disorders, or conditions, for example, selected from the group consisting of neuropathy or axonopathy. In some embodiments, one or more compounds and / or compositions described herein are useful for treating, for example, neuropathy or axonopathy associated with axon degeneration. In some embodiments, the neuropathy associated with axon degeneration is a genetic or congenital neuropathy or axonopathy. In some embodiments, the neuropathy associated with axon degeneration results from a de novo or somatic mutation. In some embodiments, the neuropathy associated with axon degeneration is selected from the list contained herein. In some embodiments, the neuropathy or axonopathy is associated with axon degeneration, including, but not limited to, Parkinson's disease, non-Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating disease, ischemia or stroke, chemical injury, thermal injury, and AIDS.

[0462] In some embodiments, one or more compounds or compositions described herein are characterized by reducing one or more symptoms or characteristics of neurodegeneration when administered to a population of subjects. For example, in some embodiments, the relevant symptoms or characteristics may be selected from the group consisting of the extent, rate, and / or timing of neuronal destruction. In some embodiments, neuronal destruction may be or may include axonal degradation, loss of synapses, loss of dendrites, loss of synapse density, loss of dendritic branching, loss of axonal branching, loss of neuronal density, loss of myelination, loss of neuronal cell body, loss of synaptic potentiation, loss of action potential potentiation, loss of cytoskeletal stability, loss of axonal transport, loss of ion channel synthesis and turnover, loss of neurotransmitter synthesis, loss of neurotransmitter release and reuptake capacity, loss of axonal potential propagation, neuronal hyperexcitability, and / or neuronal hypoexcitability. In some embodiments, neuronal destruction is characterized by an inability to maintain an appropriate resting neuronal membrane potential. In some embodiments, neuronal destruction is characterized by the appearance of inclusions, plaques, and / or neurofibrillary tangles. In some embodiments, neuronal destruction is characterized by the appearance of stress granules. In some embodiments, neuronal destruction is characterized by the intracellular activation of one or more members of the cysteine-aspartic acid protease (caspase) family. In some embodiments, neuronal destruction is characterized by neurons undergoing programmed cell death (e.g., apoptosis, pyroptosis, ferroapoptosis, and / or necrosis) and / or inflammation.

[0463] In some embodiments, the neurodegenerative or neurological disease or disorder is associated with axonal damage resulting from axonal degeneration, axonal injury, axonopathy, demyelinating diseases, central pontine myelinopathy, neuronal injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, leukoencephalopathy, or leukodystrophy.In some embodiments, the neurodegenerative or neurological disease or disorder is spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital dysmyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus-Merzbacher disease, periventricular leukomalacia, spherical cell leukodystrophy (Krabbe disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis, ALS, Lou Gehrig's disease, Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sachs disease, Gaucher disease, Hurler syndrome, traumatic brain injury, post-radiation injury, neurological complications of chemotherapy (chemotherapy-induced neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, glaucoma, Leber's hereditary optic atrophy (neuropathy), Leber's congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, Acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraplegia, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy, West Nile virus encephalitis, La Crosse virus encephalitis, Bunyaviral encephalitis, childhood viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal myeloneuropathy, progressive supranuclear palsy (PSP), Friedrich's ataxia, hereditary In some embodiments, the disease is selected from the group consisting of: chronic ataxia, noise-induced hearing loss, congenital hearing loss, dementia with Lewy bodies, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegia, spastic paraplegia, familial spastic paraplegia, French Settlement, Strampel-Loraine disease, and non-alcoholic steatohepatitis (NASH).

[0464] In some embodiments, the present disclosure provides the inhibitor of SARM1 activity for treating neurodegenerative or neurological disease or disorder associated with axon degeneration or axonopathy.The present disclosure also provides the method of using the inhibitor of SARM1 activity to treat, prevent or ameliorate axon degeneration, axonopathy, and neurodegenerative or neurological disease or disorder associated with axon degeneration.

[0465] In some embodiments, the present disclosure provides methods of treating neurodegenerative or neurological diseases or disorders associated with axonal damage due to axonal degeneration, axonal injury, axonopathy, demyelinating diseases, central pontine myelinolysis, neuronal injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, leukoencephalopathy, or leukodystrophy.

[0466] In some embodiments, neuropathy and axonopathy include any disease or condition involving neurons and / or supporting cells, such as glia, myocytes, or fibroblasts, particularly those diseases or conditions involving axonal damage. Axonal damage can be caused by traumatic injury or by non-mechanical damage resulting from disease, condition, or exposure to toxic molecules or drugs. The result of such damage can be axonal degeneration or dysfunction, and loss of functional neural activity. Diseases and conditions that cause or are associated with such axonal damage are in the majority of neuropathic diseases and conditions. Such neuropathy can include peripheral neuropathy, central neuropathy, and combinations thereof. Furthermore, peripheral neuropathy symptoms can be caused by diseases that are primarily centered in the central nervous system, and central nervous system symptoms can be caused by diseases that are peripheral or systemic in nature.

[0467] In some embodiments, peripheral neuropathy may include injury to peripheral nerves and / or may be caused by nerve disease or as a result of systemic disease.Some such diseases include diabetes, uremia, infectious diseases such as AIDS or leprosy, nutritional deficiency, vascular or collagen disorders such as atherosclerosis, and autoimmune diseases such as systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, and polyarteritis nodosa.In some embodiments, peripheral nerve degeneration results from traumatic (mechanical) injury to nerves, as well as chemical or thermal injury to nerves. Such conditions that damage peripheral nerves include glaucoma, carpal tunnel syndrome, direct trauma, penetrating injury, crush injury, compression or constriction injury such as fracture or bone dislocation, compression involving the superficial peroneal nerve (ulnar, radial, or fibular) that may result from long-term use of crutches or staying in one position for a long time, or tumor, intraneural bleeding, ischemia, exposure to cold or radiation or certain medicines, or toxic substances such as herbicides or pesticides. In particular, nerve damage may be caused by chemical damage caused by cytotoxic anticancer drugs, such as taxol, cisplatin, proteasome inhibitors, or vinca alkaloids such as vincristine. Typical symptoms of such peripheral neuropathy include weakness, numbness, paresthesia (abnormal sensations such as burning, tickling, tingling, or tingling), and pain in the arms, hands, legs, and / or feet. In some embodiments, neuropathy is associated with mitochondrial dysfunction. Such neurological disorders may manifest as decreased energy levels, i.e., decreased levels of NAD and ATP.

[0468] In some embodiments, the peripheral neuropathy is metabolic and endocrine neuropathy, including a wide range of peripheral neuropathy associated with systemic diseases of metabolic origin.These diseases include, inter alia, diabetes mellitus, hypoglycemia, uremia, hypothyroidism, liver failure, polycythemia, amyloidosis, acromegaly, porphyria, lipid / glycolipid metabolism disorder, nutritional / vitamin deficiency, and mitochondrial disorder.The common characteristic of these diseases is the involvement of peripheral nerves by changes in myelin and axon structure or function caused by dysregulation of metabolic pathways.

[0469] In some embodiments, neuropathy includes optic neuropathy such as glaucoma, retinal ganglion degeneration such as that associated with retinitis pigmentosa and outer retinal neuropathy, optic nerve neuritis and / or degeneration including that associated with multiple sclerosis, trauma to the optic nerve, which may include, for example, damage during tumor removal, hereditary optic neuropathy such as Kell's disease and Leber's hereditary optic neuropathy, ischemic optic neuropathy such as that secondary to giant cell arteritis, metabolic optic neuropathy such as neurodegenerative diseases including the previously mentioned Leber's neuropathy, neuropathy caused by nutritional deficiency such as vitamin B12 or folic acid deficiency, toxicity, adverse drug reaction such as that caused by ethambutol or cyanide, and neuropathy caused by vitamin deficiency.Ischemic optic neuropathy also includes non-arteritic anterior ischemic optic neuropathy.In some embodiments, the optic neuropathy is age-related macular degeneration.

[0470] In some embodiments, the neurodegenerative disease associated with neuropathy or axonopathy in the central nervous system includes various diseases.Such diseases include progressive dementia such as Alzheimer's disease, senile dementia, Pick's disease, and Huntington's disease, central nervous system diseases that affect muscle function such as Parkinson's disease, motor neuron disease, progressive ataxia such as amyotrophic lateral sclerosis, demyelinating diseases such as multiple sclerosis, viral encephalitis group such as those caused by enteric viruses, arboviruses, and herpes simplex viruses, and prion diseases.Mechanical damage or trauma such as glaucoma to the head or spine can also cause nerve damage or degeneration in the brain and spinal cord.In addition, conditions such as ischemia and stroke, and nutritional deficiency and chemical toxicity such as chemotherapy can cause central nervous system neuropathy.

[0471] In some embodiments, the present disclosure provides a method for treating neuropathy or axonopathy associated with axon degeneration.In some such embodiments, the neuropathy or axonopathy associated with axon degeneration can be, for example, hereditary or congenital, or any of several neuropathy or axonopathy, such as Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating disease, ischemia or stroke, chemical injury, thermal injury, and AIDS-related.In addition, the neurodegenerative diseases not listed above, as well as a subset of the above diseases, can also be treated with the method of the present disclosure.Such a subset of diseases can include Parkinson's disease or non-Parkinson's disease, or Alzheimer's disease.

[0472] subject In some embodiments, the compounds and / or compositions described herein are administered to a subject suffering from or susceptible to a disease, disorder, or condition described herein. In some embodiments, such disease, disorder, or condition is characterized by axonal degeneration, such as one of the conditions mentioned herein.

[0473] In some embodiments, the subject to whom a compound or composition as described herein is administered exhibits one or more signs or symptoms associated with axonal degeneration. In some embodiments, the subject does not exhibit signs or symptoms of neurodegeneration.

[0474] In some embodiments, the methods provided include administering a compound of Formula I or Formula I' to a patient in need thereof. In some such embodiments, the patient is at risk of developing a condition characterized by axonal degeneration. In some embodiments, the patient has a condition characterized by axonal degeneration. In some embodiments, the patient has been diagnosed with a condition characterized by axonal degeneration.

[0475] In some embodiments, the methods provided include administering a composition described herein to a patient population in need thereof. In some embodiments, the population is taken from individuals who engage in activities that have a high probability of traumatic nerve injury. In some embodiments, the population is taken from athletes who engage in contact sports or other high-risk activities.

[0476] In some embodiments, the subject is at risk of developing a condition characterized by axonal degeneration. In some embodiments, the subject is identified as at risk of axonal degeneration based on, for example, the subject's genotype, a diagnosis of a condition associated with axonal degeneration, and / or exposure to agents and / or conditions that induce axonal degeneration.

[0477] In some embodiments, the patient is at risk of developing a neurodegenerative disorder. In some embodiments, the patient is elderly. In some embodiments, the patient is known to have a genetic risk factor for neurodegeneration. In some embodiments, the patient has a family history of a neurodegenerative disease. In some embodiments, the patient expresses one or more copies of a known genetic risk factor for neurodegeneration. In some embodiments, the patient is taken from a population with a high incidence of neurodegeneration. In some embodiments, the patient has a hexanucleotide repeat expansion in open reading frame 72 of chromosome 9. In some embodiments, the patient has one or more copies of the ApoE4 allele.

[0478] In some embodiments, the subject to which the compound or composition described herein is administered may be or include a subject suffering from or susceptible to neurodegenerative disease, disorder, or condition.In some embodiments, the neurodegenerative disease, disorder, or condition may be or include traumatic nerve injury.In some embodiments, the traumatic nerve injury is blunt trauma, closed head injury, open head injury, exposure to impact and / or explosive force, or penetrating injury in or to the brain cavity or innervation area of ​​the body.In some embodiments, the traumatic nerve injury is a force that causes axons to deform, stretch, crush, or rotate.

[0479] In some embodiments, the subject engages in an activity identified as a risk factor for neurodegeneration, for example, a subject who engages in a contact sport or occupation that has a high chance of traumatic neurological injury.

[0480] For example, the subject may be a patient who is undergoing or is prescribed chemotherapy related to peripheral neuropathy.Examples of chemotherapeutic agents include, but are not limited to, thalidomide, epothilone (e.g., ixabepilone), taxane (e.g., paclitaxel and docetaxel), vinca alkaloid (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitor (e.g., bortezomib), platinum-based drug (e.g., cisplatin, oxaliplatin, and carboplatin), etc.

[0481] In some embodiments, the methods provided include administering a composition as described herein to a patient or patient population based on the presence or absence of one or more biomarkers. In some embodiments, the methods provided further include monitoring the levels of the biomarkers in the patient or patient population and adjusting the dosing regimen accordingly.

[0482] Administration Those skilled in the art will appreciate that in some embodiments, the exact amount of a particular compound included in and / or delivered by administration of a pharmaceutical composition or regimen as described herein may be selected by a physician and may vary for different subjects, taking into account, for example, one or more of the subject's species, age, and general condition, and / or the identity of the particular compound or composition, its method of administration, etc. Alternatively, in some embodiments, the amount of a particular compound included in and / or administered by administration of a pharmaceutical composition or regimen as described herein may be standardized across a relevant patient population (e.g., all patients, all patients of a particular age or disease, or all patients expressing a particular biomarker, etc.).

[0483] The provided compounds or compositions of the present disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of drug that is appropriate for the patient to be treated. However, it will be understood that the total daily usage of the provided compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level in any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the clinical condition of the individual patient, the cause of the disorder, the activity of the specific compound used, the specific composition used, the age, weight, general health, sex, and diet of the patient, the timing of administration of the specific compound used, the delivery site, route of administration, and excretion rate of the drug, the duration of treatment, drugs used in combination with or simultaneously with the specific compound used, and similar factors well known in the medical arts. The effective amount of the compound to be administered will be governed by such considerations, and is, for example, the minimum amount required to inhibit SARM1 activity required to prevent or treat an undesirable disease or disorder, such as neurodegeneration or traumatic nerve damage.

[0484] The pharma- ceutically acceptable compositions of the present disclosure can be administered to humans and other animals orally, rectally, intravenously, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment, or infusion), buccal, oral or nasal spray, etc., depending on the severity of the disease, disorder, or infection being treated. The daily dose is, in certain embodiments, given as a single daily dose, or as divided doses two to six times daily, or in sustained release form. This dosing regimen can be adjusted to provide the optimal therapeutic response. The compounds can be administered on a regimen of one to four times daily, preferably once or twice daily.

[0485] In some embodiments, the compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, intravaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intradermal, intraocular, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0486] In some embodiments, the pharma- ceutically acceptable compositions of the present disclosure may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract, for each of which suitable topical formulations are readily prepared.

[0487] Most preferably, the pharma- ceutically acceptable composition of the present disclosure is formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharma- ceutically acceptable composition of the present disclosure is administered without food. In other embodiments, the pharma- ceutically acceptable composition of the present disclosure is administered with food.

[0488] These additional agents may be administered separately from the provided compound or compositions thereof as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form and mixed together with the provided compound in a single composition. When administered as part of a multiple dose regimen, the two active agents may be presented simultaneously, sequentially, or within a period of each other, usually within 5 hours of each other.

[0489] It should also be understood that the specific administration and treatment regimen for a particular patient may depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, and the severity of the particular disease being treated. In some embodiments, the amount of a compound of the present disclosure in the composition will also depend on the particular compound in the composition.

[0490] In some embodiments, the SARM1 inhibitors described herein may be used in combination with one or more other therapies to treat associated diseases, disorders, or conditions. In some embodiments, the administration of the SARM1 inhibitor is altered when used in combination therapy compared to when administered as monotherapy. Alternatively or additionally, in some embodiments, the therapy administered in combination with the SARM1 inhibitors described herein is administered according to a different regimen or protocol than the regimen or protocol when administered alone or in combination with one or more therapies other than SARM1 inhibition. In some embodiments, the additional therapeutic agent, the composition comprising the additional therapeutic agent and the provided compound, may act synergistically. In some embodiments, one or both therapies utilized in combination regimen are administered at a lower level or less frequently than when it is utilized as monotherapy.

[0491] In some embodiments, the compounds and / or compositions described herein are administered with chemotherapeutic agents, including but not limited to alkylating agents, anthracyclines, taxanes, epothilones, histone deacetylase inhibitors, topoisomerase inhibitors, kinase inhibitors, nucleotide analogs, peptide antibiotics, platinum-based agents, retinoids, vinca alkaloids and derivatives. In some embodiments, the compounds and / or compositions described herein are administered in combination with a PARP inhibitor. EXAMPLES

[0492] The present teachings, including the description, are provided by examples that are not intended to limit the scope of the claims. Unless specifically presented in the past tense, the inclusion of examples does not mean that the experiment has actually been carried out. The following non-limiting examples are provided to further illustrate the present teachings. In light of the present disclosure, those skilled in the art will understand that many changes can be made in the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the present teachings.

[0493] method Some of the methods and compositions described herein utilize laboratory techniques well known to those of skill in the art and can be found in laboratory manuals, such as Sambrook, J., et al., Molecular Cloning: A Laboratory Manual, 3rd ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2001; Methods In Molecular Biology, ed. Richard, Humana Press, NJ, 1995; Spector, DL et al., Cells: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1998; and Harlow, E., Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999. Methods of administration and dosing regimes for pharmaceutical agents can be determined according to standard principles of pharmacology using methods provided by standard reference texts, such as Remington: the Science and Practice of Pharmacy (Alfonso R. Gennaro ed. 19th ed. 1995), Hardman, JG, et al., Goodman & Gilman's The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill, 1996, and Rowe, RC, et al., Handbook of Pharmaceutical Excipients, Fourth Edition, Pharmaceutical Press, 2003.

[0494] Example 1: Synthesis of Compounds General synthesis method The compounds according to the invention and their intermediates can be obtained using synthetic methods known to those skilled in the art and described in the literature of organic synthesis.Preferably, the compounds are obtained in a manner similar to the preparation methods described more fully below, especially as described in the experimental section.In some cases, the order of carrying out reaction steps can be changed.Variants of reaction methods known to those skilled in the art but not described in detail here can also be used.

[0495] The general process for preparing the compounds according to the invention will be apparent to one skilled in the art upon studying the following schemes. The starting materials can be prepared by methods described in the literature or herein, or by analogous or similar methods. Any functional groups in the starting materials or intermediates can be protected using conventional protecting groups. These protecting groups can be cleaved again at a suitable stage in the reaction sequence, using methods well known to those skilled in the art.

[0496] Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions can be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Intermediates and products can be purified by chromatography on silica gel, recrystallization, and / or reverse phase HPLC (RHPLC). Discrete enantiomers can be obtained by separation of racemic products using chiral HPLC. RHPLC purification methods used 0-100% acetonitrile in water containing 0.1% formic acid, 0.1-0.01% TFA, 10 mM aqueous ammonium bicarbonate, or 0.2% aqueous ammonium hydroxide, and one of the following columns: a) Waters Xbridge C18 10μm 30×100mm column b) Waters Sunfire C18 10μm 30×100mm column c) Waters Xbridge C18 3.5μm 50×4.6mm column d) HALO C18 2.7μm 30×4.6mm column e) Waters Sunfire C18 3.5μm 50×4.6mm column

[0497] Synthesis Examples The carboxylic acids used to prepare the compounds disclosed herein are either commercially available, can be readily prepared by one of ordinary skill in the art, or can be prepared using one of the following methods: The acid chlorides used to prepare the compounds disclosed herein can be readily prepared by one of ordinary skill in the art from the carboxylic acid with reagents such as oxalyl chloride and sulfonyl chloride.

[0498] Method A [ka] To a solution of R-1 (0.97 g, 5.39 mmol) and malonic acid (0.81 mL, 8.08 mmol) in pyridine (3.15 mL) was added piperidine (53 μL, 0.539 mmol). The reaction mixture was stirred at 115° C. for 19 h. After this time, the reaction mixture was concentrated under vacuum. The residue was acidified to pH=4 with 1 M aqueous HCl, the resulting solid was filtered under vacuum, and then triturated from acetonitrile / water to give a solid (1.2 g), which was dissolved in methanol (19.7 mL) and dichloronickel hexahydrate (291 mg, 1.21 mmol) was added. The reaction mixture was cooled to 0° C. and sodium borohydride (307 mg, 8.10 mmol) was added slowly. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. The reaction mixture was acidified with 2M aqueous HCl (10 mL) and extracted with CHCl3:IPA (3:1) (3 x 20 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo to give R-2 (0.59 g, 44%).

[0499] Method B [ka] To a solution of ethyl acetate(diethoxyphosphoryl) (0.60 mL, 3.01 mmol) in THF (13 mL) cooled to 0 °C was added sodium hydride (60% in oil, 115 mg, 2.88 mmol) in one portion. The mixture was stirred at 0 °C for 20 min. A solution of R-3 (500 mg, 2.74 mmol) in THF (3 mL) was added over 2 min and the mixture was stirred at 0 °C for 1 h and then at room temperature for 24 h. The reaction was poured into saturated aqueous sodium bicarbonate (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 7% to 40% EtOAc in heptane) to give R-4 as a 2:1 mixture of regioisomers (120 mg, 15%).

[0500] To a solution of R-4 (85 mg, 0.334 mmol) in methanol (3 mL) at room temperature was added dichloronickel hexahydrate (24 mg, 0.01 mmol) followed by sodium borohydride (25 mg, 0.66 mmol). The mixture was stirred at room temperature for 3 h, then treated with water (5 mL) and poured into saturated aqueous sodium bicarbonate (10 mL). The aqueous phase was extracted with EtOAc (3×20 mL), washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (SiO2, 2% to 30% EtOAc in heptane) to give ethyl 2-(7-chloro-3,4-dihydro-2H-1-benzopyran-4-yl)acetate (60 mg, 47%).

[0501] To a solution of ethyl 2-(7-chloro-3,4-dihydro-2H-1-benzopyran-4-yl)acetate (60 mg, 0.22 mmol) in THF (2 mL) and water (0.2 mL) was added lithium hydroxide hydrate (19 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 20 h and then quenched by adding 1 M aqueous HCl (10 mL). The aqueous layer was extracted with EtOAc (3×8 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give R-5 (50 mg, 94%).

[0502] Method C [ka] To a solution of 3-ethoxy-3-oxopropanoic acid (0.63 mL, 5.30 mmol) in pyridine (2 mL) was added piperidine (35 μL, 0.35 mmol) and R-6 (500 mg, 3.53 mmol). The reaction mixture was stirred at 115° C. for 2 h. After this time, the reaction mixture was cooled and then neutralized with 2 M aqueous HCl. The aqueous mixture was extracted with EtOAc (3×20 mL) and the organic phase was dried (Na2SO4) and concentrated under vacuum. The crude was purified by flash column chromatography using a gradient from (SiO2, 0% to 50% EtOAc in heptane) to give the ethyl ester (448 mg, 50%).

[0503] To a solution of the ethyl ester (400 mg, 1.89 mmol) in methanol (3.3 mL) was added dichloronickel hexahydrate (227 mg, 0.95 mmol). The reaction mixture was cooled to 0° C. and sodium borohydride (143 mg, 3.78 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with EtOAc (20 mL) and filtered through glass fiber filter paper. The filtrate was washed with saturated aqueous sodium bicarbonate (2×10 mL), brine (10 mL), dried (Na2SO4), and concentrated in vacuo to give the saturated ethyl ester (212 mg, 52%).

[0504] To a solution of the saturated ethyl ester (212 mg, 0.84 mmol) in THF (1 mL) and methanol (1 mL) was added 2M aqueous LiOH (0.42 mL, 0.84 mmol). The reaction mixture was stirred at room temperature for 3 h, then the volatiles were concentrated in vacuo. The remaining aqueous mixture was acidified to pH 3 with 2M aqueous HCl, then extracted with DCM:MeOH (3:1) (3×10 mL), dried (Na2SO4), and concentrated in vacuo to give R-7 (93 mg, 56%).

[0505] Synthesis of amines The amines used to prepare the final compounds of the invention are either commercially available, can be readily prepared by one skilled in the art, or can be prepared using one of the following methods.

[0506] Method D [ka] A mixture of R-8 (500 mg, 3.88 mmol) and aminoguanidine hydrochloride (853 mg, 7.76 mmol) was stirred at 190° C. for 2 h. The reaction mixture was cooled to room temperature, then water (5 mL) was added and neutralized with aqueous NaOH (6 mol / L). The mixture was filtered and the filtrate was purified by preparative HPLC to give R-9 (60 mg, 10%).

[0507] Method E [ka] A solution of methyl isonicotinate (4 g, 29 mmol) in anhydrous THF (40 mL) was cooled to -60°C in a dry ice / ethanol bath with N2 protection. LHMDS (1.0 M, 43.6 ml) was added dropwise while keeping the temperature below -55°C. After stirring at -60°C for 1.5 h, propionitrile (3 mL, 43.6 mmol) was added slowly. The reaction mixture was stirred at -60°C for an additional 1.5 h and then warmed to room temperature. THF was removed under reduced pressure, the residue was treated with CHCl (50 mL), and the resulting solid was filtered, washed with cold CHCl (50 mL), and dried to give the lithium salt intermediate (5 g).

[0508] The lithium salt (1 g, 6.25 mmol) in ethanol (100 ml) was slowly treated with AcOH (375 mg, 6.25 mmol) followed by hydrazine hydrate (98 wt%, 1.17 g, 18.75 mmol). The reaction mixture was stirred at reflux overnight. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (SiO2, 8% MeOH in CH2Cl2) to give R-11 (672 mg).

[0509] Synthesis of exemplary compounds Method F: Synthesis of Example 17 [ka] R-13 (0.30 g, 1.87 mmol) and R-12 (22 uL, 1.87 mmol) were dissolved in DMF (2.0 mL) and N-ethyl-N-isopropyl-propan-2-amine (654 uL, 3.75 mmol) and propanephosphonic anhydride (50% in ethyl acetate, 1.67 mL, 2.81 mmol) were added. The reaction mixture was stirred at 100° C. for 24 h. After this time, the reaction mixture was diluted with ethyl acetate and the organics were washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and concentrated under vacuum. The crude product was recrystallized from methanol to give the title compound (323 mg, 52%).

[0510] The following compounds were prepared in a similar manner from the appropriate carboxylic acids and amines: Examples 1, 12-13, 15-17, 20-23, 29, 37-39, 44-46, 48-50, 52-55, 57-58, 61, 64-66, 70, 76-81, 83-87, 97, 101-108, 116-120, 158, 159, 161, 162, 167-173, 177-182, 186-197, 202-215, 220-222, 224, 227-237, 263-266, 270-273, 278-280, 282-285, 295, 297, 301-306, 309-312, 316, 319, and 321-323.

[0511] Method G: Synthesis of Example 146 [ka] To a mixture of R-14 (150 mg, 0.93 mmol) and DIPEA (488 μL, 2.79 mmol) in CHCl (2.5 mL) was added R-13 (138 μL, 0.93 mmol) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with CHCl, filtered, and the solid was washed with CHCl. ​​The solid residue was then heated to 250° C. for 30 min. The crude product was purified by preparative HPLC to give the title compound (72 mg, 26%).

[0512] The following compounds were prepared in a similar manner from the appropriate carboxylic acids and amines: Examples 113, 121-123, 127-128, 133, and 143-145.

[0513] Method H: Synthesis of Example 27 [ka] To a solution of R-15 (160 mg, 0.86 mmol), R-11 (150 mg, 0.86 mmol), DIPEA (0.30 mL, 1.72 mmol) in anhydrous DMF (3 mL) was added propanephosphonic anhydride (50% in ethyl acetate, 0.77 mL, 1.29 mmol). The mixture was purged with nitrogen and stirred at room temperature in a sealed vial for 1 h. After this time, saturated aqueous sodium bicarbonate (10 mL) and water (10 mL) were added. The mixture was extracted with DCM (3×10 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO, 0-10% MeOH in CHCl) to give a solid which was triturated with CHCl (5 mL), collected under vacuum filtration, washed with CHCl (3×10 mL), and dried in a vacuum oven at 40° C. for 7 days to give the title compound (115 mg, 38%).

[0514] The following compounds were prepared in a similar manner from the appropriate carboxylic acids and amines: Examples 2, 5, 8-11, 14, 18, 34-36, 51, 59-60, 148, 150-155, 199, 200, 219, 250, 261, 262, 267, 268, 269, 274, and 291-293.

[0515] Method I: Synthesis of Example 75 [ka] To a mixture of R-16 (402 mg, 1.86 mmol) and N-ethyl-N-isopropyl-propan-2-amine (683 μL, 3.91 mmol) in DCM (2 mL) was added oxalyl chloride (182 μL, 2.05 mmol) at 0° C., followed by R-17 (300 mg, 1.86 mmol). The reaction mixture was stirred at room temperature for 1 h and then allowed to stand at room temperature for 48 h. The reaction mixture was diluted with DCM and water, filtered, and the solid was washed with further DCM to give a solid (324 mg), which was then heated to 250° C. for 5 min in a sealed vial. The crude residue was purified by flash column chromatography (SiO2, 0% to 100% ethyl acetate in heptane, then 0% to 20% MeOH in DCM) to give the crude product, which was further purified by trituration with methanol and then DCM to give the title compound (9 mg, 2%).

[0516] The following compounds were prepared in a similar manner from the appropriate carboxylic acids and amines: Examples 73-75, 93-96, 109, 124-126, 129-132, and 134-142.

[0517] Method J: Synthesis of Example 114 [ka] To a mixture of R-17 (29 μL, 0.54 mmol), R-13 (100 mg, 0.542 mmol), and N-ethyl-N-isopropyl-propan-2-amine (279 μL, 1.60 mmol) in anhydrous DMF (1 mL) was added HATU (304 mg, 0.80 mmol) and the reaction mixture was stirred at room temperature for 3 h in a sealed vial. The reaction mixture was washed with DCM and brine, separated through a hydrophobic frit, and the retained aqueous layer was washed with DCM and separated. The combined organics were concentrated under vacuum and purified by preparative HPLC to give a solid. The resulting solid was heated at 250° C. for 15 min in a sealed tube. The reaction mixture was cooled to room temperature and the solid was triturated with acetonitrile and filtered under vacuum to give the title compound (25 mg, 14%).

[0518] Method K: Synthesis of Example 62 [ka] To a solution of R-17 (73 mg, 0.46 mmol) and R-18 (100 mg, 0.46 mmol) in pyridine (3.2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (71 mg, 0.46 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with DCM, washed with brine, separated through a hydrophobic frit and the retained aqueous solution was washed with DCM and separated. The combined organics were concentrated in vacuo and purified by preparative HPLC to give the title compound (3 mg, 2%).

[0519] The following compounds were prepared in a similar manner from the appropriate carboxylic acids and amines: Example 47.

[0520] Method L: Synthesis of Example 30 [ka] R-18 (22 μL, 3.71 mmol), R-19 (601 mg, 3.71 mmol), and N-ethyl-N-isopropyl-propan-2-amine (1.3 mL, 7.43 mmol) were dissolved in DMF (6.0 mL) and propanephosphonic anhydride (50%, 3.32 mL, 5.57 mmol) was added. The reaction mixture was stirred at 100 °C for 18 h in a sealed vial. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated aqueous sodium bicarbonate (3 × 100 mL), brine (50 mL), dried (Na2SO4), and concentrated under vacuum. The crude product was purified by flash column chromatography using a gradient of 0% to 100% EtOAc in heptane to give R-20 (580 mg, 38%) [LCMS Method G, retention time = 0.84 min, mol ion = 362.1, 364.1].

[0521] To a suspension of R-20 (930 mg, 2.57 mmol) in chloroform (10 mL) was added 4-methylbenzenesulfonic acid hydrate (1:1) (49 mg, 0.26 mmol) and 3,4-dihydro-2H-pyran (0.23 mL, 2.57 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum and the crude residue was purified by flash column chromatography (SiO2, 0-100% EtOAc in heptane) to give a mixture of R-21 and R-22 (3:1) (750 mg, 63%) [LCMS Method G, retention time = 1.00, mol ion = 446.1, 448.1].

[0522] To a mixture of R-21 and R-22 (750 mg, 1.68 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneboron-2-yl)pyridazine (364 mg, 1.76 mmol) in 1,4-dioxane (5.2 mL) and 2 M aqueous potassium carbonate (2.6 mL, 5.20 mmol) was added cyclopentyl(diphenyl)phosphane, dichloropalladium, iron (146 mg, 0.20 mmol). The reaction mixture was degassed for 5 min and then stirred at 100 °C for 2 h in a sealed vial. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (30 mL) and the layers were separated. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, 0% to 100% EtOAc in heptane, then 0% to 20% methanol in EtOAc) to give a mixture of isomers (510 mg, 68%). The isomers were dissolved in MeOH (5 mL), treated with 4 M HCl in dioxane (5.0 mL, 20.0 mmol) and allowed to stand at room temperature for 20 min. The reaction mixture was concentrated in vacuo, then triturated with water, filtered in vacuo, washed with acetonitrile, and dried in a vacuum oven for 18 h to give the title compound (320 mg, 77%).

[0523] The following compounds were prepared in a similar manner from the appropriate carboxylic acids and boronic esters or acids: Examples 19, 24-26, 31, 40, 163, 198, 225, 238, 239, 260, 281, 286, 294, 298, 299, 300, 307, 308, 313, 314, 315, 318, 320, 324, and 325.

[0524] Method M: Synthesis of Example 32 [ka] To a suspension of R-23 (20.0 g, 88.2 mmol) in THF (200 mL) at 0 °C, sodium hydride (60% in oil, 3.53 g, 88.2 mmol) was added portionwise and the reaction mixture was stirred at room temperature under nitrogen for 30 min. The reaction mixture was cooled to 0 °C, [2-(chloromethoxy)ethyl](trimethyl)silane (17 mL, 97.0 mmol) was added and the reaction mixture was stirred under nitrogen for 18 h. The reaction was quenched with water, diluted with EtOAc, the layers were separated, the organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, 0% to 50% EtOAc in heptane) to give the protected triazole (30.0 g, 95%) [LCMS Method G, retention time = 1.07 min, mol ion = 355.9, 357.9].

[0525] To a solution of the protected triazole (9.00 g, 25.2 mmol) in NMP (4 mL) was added potassium carbonate (8.71 g, 63 mmol) and 1-(4-methoxyphenyl)methanamine (3.44 mL, 26.3 mmol). The reaction mixture was stirred in a sealed vial at 140 °C for 2 h. The reaction mixture was diluted with ethyl acetate, washed with brine, and the organic layer was dried (MgSO4) and concentrated under vacuum. The crude residue was purified by flash column chromatography in heptane (SiO2, 0% to 100% EtOAc) to give R-24 (9.6 g, 78%) [LCMS Method G, retention time = 1.35 min, mol ion = 414.8].

[0526] To a solution of R-24 (7.31 g, 16.1 mmol) in DMF (80 mL) was added sodium hydride (60% in oil, 650 mg, 16.2 mmol) in portions and the reaction mixture was stirred at room temperature under nitrogen for 15 min. R-13 (2.91 mL, 16.2 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with water, separated through a hydrophobic frit and the retained aqueous was washed with DCM and separated. The combined organics were concentrated under vacuum. The crude residue was purified by flash column chromatography (SiO2, 0% to 100% EtOAc in heptane) to give the intermediate amide (5.4 g, 52%) [LCMS Method G, retention time = 1.26 min, mol ions = 579.1, 581.1].

[0527] A solution of the intermediate amide (500 mg, 0.862 mmol) and (2-methoxy-4-pyridyl)boronic acid (132 mg, 0.862 mmol) in 2 M potassium carbonate (1.3 mL, 2.60 mmol) and 1,4-dioxane (2.6 mL) was degassed with nitrogen for 5 min before adding cyclopentyl(diphenyl)phosphane, dichloropalladium, iron (75 mg, 0.102 mmol). The reaction mixture was stirred at 100 °C in a sealed tube for 10 h. The reaction mixture was washed with brine, separated through a hydrophobic frit and the retained aqueous was washed with further DCM and further separated. The combined organics were concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, 0% to 100% EtOAc in heptane) to give the intermediate pyridine (140 mg, 26%) [LCMS Method G, retention time = 1.14 min, mol ion = 608.3].

[0528] To a solution of the intermediate pyridine (141 mg, 0.23 mmol) in DCM / TFA (1:1) (1 mL) was added trifluoromethanesulfonic acid (72 μL, 0.46 mmol) and the reaction mixture was stirred at room temperature for 1 h. The crude residue was purified by Biotage ISOLUTE® SCX-2 chromatography, eluting with MeOH and then 7M NH3 in MeOH. The ammonia-containing fractions were combined and concentrated in vacuo, then triturated from acetonitrile / water to give the title compound (43 mg, 52%).

[0529] The following compounds were prepared in a similar manner from the appropriate carboxylic acid and boronic ester or acid: Examples 33, and 42-43, 156, 157, and 217.

[0530] Method N: Synthesis of Example 41 [ka] To a suspension of R-23 (20.0 g, 88.2 mmol) in THF (200 mL) at 0 °C, sodium hydride (60% in oil, 3.53 g, 88.2 mmol) was added portionwise and the reaction mixture was stirred at room temperature under nitrogen for 30 min. The reaction mixture was cooled to 0 °C, [2-(chloromethoxy)ethyl](trimethyl)silane (17 mL, 97.0 mmol) was added and the reaction mixture was stirred under nitrogen for 18 h. The reaction was quenched with water, diluted with EtOAc, the layers were separated, the organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, 0% to 50% EtOAc in heptane) to give the protected triazole (30.0 g, 95%) [LCMS Method G, retention time = 1.07 min, mol ion = 355.9, 357.9].

[0531] A solution of the protected triazole (5.00 g, 14.0 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.87 g, 14.0 mmol) in 2 M aqueous potassium carbonate (21 mL, 42.0 mmol) and 1,4-dioxane (30 mL) was degassed with nitrogen for 5 min before adding cyclopentyl(diphenyl)phosphane, dichloropalladium, iron (1.03 g, 1.40 mmol). The reaction mixture was stirred at 100° C. in a sealed tube for 2 h. The reaction mixture was diluted with EtOAc (25 mL) and the organics were washed with 1×20 mL of saturated aqueous brine. The organics were separated, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, 0% to 10% EtOAc in heptane, then 0% to 20% MeOH in EtOAc) to give R-25 (2.80 g, 56%) [LCMS Method G, retention time = 0.99 min, mol ion = 355.1, 357.1].

[0532] A mixture of R-25 (200 mg, 0.563 mmol) and 3-(4-chlorophenyl)propan-1-amine (0.10 mL, 0.62 mmol) was dissolved in anhydrous NMP (1 mL) and potassium carbonate (0.47 g, 3.38 mmol) was added. The reaction mixture was stirred in a sealed tube at 140 °C for 3 h. The reaction mixture was diluted with EtOAc (10 mL) and washed successively with water (2 × 5 mL) and brine (5 mL). The organic phase was dried (Na2SO4) and concentrated under vacuum. The crude residue was purified by flash column chromatography (SiO2, 0%-10% EtOAc in heptane, then 0%-20% MeOH in EtOAc) to give the protected triazole (60 mg, 22%) [LCMS Method G, retention time = 1.29 min, mol ion = 445], which was dissolved in DCM (1 mL) and trifluoroacetic acid (45 μL, 0.61 mmol) was added. The reaction mixture was stirred at room temperature for 20 h and then concentrated in vacuo The crude residue was purified by preparative HPLC and lyophilized to give the title compound (8 mg, 20%).

[0533] The following compounds were prepared in a similar manner from the appropriate amines: Examples 28 and 317.

[0534] Method O: Synthesis of Example 92 [ka] To a mixture of R-14 (300 mg, 1.86 mmol) and N-ethyl-N-isopropyl-propan-2-amine (683 uL, 3.91 mmol) in DCM (2 mL) was added R-14 (312 mg, 1.86 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and then allowed to stand at room temperature for 16 h. The reaction mixture was diluted with DCM and water, filtered, and the solid washed with DCM. The solid residue was subsequently heated to 250° C. in a sealed vial for 15 min and then purified by preparative HPLC to give the title compound (31 mg, 5%).

[0535] The following compounds were prepared in a similar manner from the appropriate amines: Examples 7, 160, 164, 165, 166, 183-185, 226, 276, 277, and 296.

[0536] Method P: Synthesis of Example 6 [ka] R-17 (250 mg, 1.56 mmol) was suspended in anhydrous DMF (1 mL) and 4-nitrophenyl carbonochloridate (76 uL, 1.56 mmol) and N-ethyl-N-isopropyl-propan-2-amine (572 uL, 3.28 mmol) were added. The reaction mixture was stirred at room temperature for 30 min, after which 1-(4-chlorophenyl)-N-methylmethanamine (243 mg, 1.56 mmol) was added and the reaction mixture was stirred at room temperature for an additional 30 min. The reaction mixture was then stirred at 90° C. for 4 h. The reaction mixture was diluted with DCM, washed with water, separated through a hydrophobic frit, and the retained aqueous layer was washed with DCM and separated. The organics were concentrated under vacuum and the crude residue was heated to 250° C. for 20 min in a sealed vial. The crude product was purified by preparative HPLC to give the title compound (11 mg, 2%).

[0537] The following compounds were prepared in a similar manner from the appropriate amines: Examples 174, 216, and 218.

[0538] Method Q: Synthesis of Example 99 [ka] To a mixture of R-27 (29 uL, 0.54 mmol), R-13 (100 mg, 0.54 mmol), and N-ethyl-N-isopropyl-propan-2-amine (279 uL, 1.60 mmol) in anhydrous DMF (1 mL) was added HATU (304 mg, 0.80 mmol) and the reaction mixture was stirred at room temperature in a sealed vial for 17 h. After this time, the reaction mixture was diluted with DCM, washed with brine, separated with a hydrophobic frit, and the retained aqueous was washed with DCM and separated. The combined organics were concentrated under vacuum then purified by preparative HPLC to give the title compound (13 mg, 7%).

[0539] The following compounds were prepared in a similar manner from the appropriate amines: Examples 100 and 115.

[0540] Method R: Synthesis of Examples 98, 110, and 111 [ka] To a solution of Example 136 (50%, 295 mg, 0.503 mmol) in anhydrous DMF (1 mL), sodium hydride (60% in mineral oil, 60 mg, 1.51 mmol) was added and the reaction mixture was stirred at room temperature for 15 minutes. Iodomethane (94 μL, 1.51 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by preparative HPLC purification to give the title compounds Example 98 (12 mg, 8%), Example 110 (13 mg, 8%), and Example 111 (9 mg, 6%).

[0541] The following compounds were prepared in a similar manner from the appropriate amines: Examples 287 and 288.

[0542] Method S: Synthesis of Example 82 [ka] To a solution of R-14 (269 mg, 1.67 mmol) and R-28 (22 uL, 1.67 mmol) in DMF (4.35 mL) was added N-ethyl-N-isopropyl-propan-2-amine (0.58 mL, 3.34 mmol) and propanephosphonic anhydride (50%, 1.5 mL, 2.50 mmol). The reaction mixture was stirred at 100 °C for 20 h. The reaction mixture was diluted with EtOAc (20 mL) and washed successively with saturated aqueous sodium bicarbonate (2 × 10 mL), brine (10 mL), dried (Na2SO4) and concentrated under vacuum. The crude product was purified by flash column chromatography (SiO2, 0% to 100% EtOAc in heptane) to give the Boc-amine (327 mg, 39%), which was dissolved in DCM (3 mL) and TFA (0.45 mL, 6.1 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The crude residue was purified by preparative HPLC and then lyophilized to give the title compound (42 mg, 20%).

[0543] The following compounds were prepared in a similar manner from the appropriate amines: Examples 3, 4, 56, 63, 69, 175, 176, 201, 223, 275, 289, and 290.

[0544] Method T: Decomposition of Examples 67 and 68 Example 117 (95 mg, 0.30 mmol) was dissolved in a mixture of methanol / acetonitrile and purified by supercritical fluid chromatography on a Chiralpak OD-H, 10×250 mm, 5 μm column eluted with a gradient of 0% to 15% methanol in CO2 at a flow rate of 15 mL / min to give the title compound.

[0545] Method U: Decomposition of Examples 71 and 72 Example 109 (226 mg, 0.67 mmol) was dissolved in a mixture of methanol, acetonitrile, IPA, and formic acid and purified by flash column chromatography on a Chiralpak OD-H, 20 x 250 mm, 5 μm column eluted with methanol at a flow rate of 9 mL / min to give the title compound.

[0546] Method V: Decomposition of Examples 88 and 89 Example 131 (82 mg, 0.257 mmol) was dissolved in a mixture of methanol, IPA, and formic acid and purified by flash column chromatography on a Chiralpak AD-H, 20 x 250 mm, 5 μm column eluted with methanol at a flow rate of 9 mL / min to give the title compound.

[0547] Method W: Decomposition of Examples 90 and 91 Example 132 (21 mg, 0.063 mmol) was dissolved in a mixture of methanol and IPA and purified by flash column chromatography on a Chiralpak AD-H, 20×250 mm, 5 μm column eluted with methanol at a flow rate of 9 mL / min to give the title compound.

[0548] Example 2. Compound characterization. LCMS method: Analytical LC / MS analysis method A: ESI+ / -ion mode 150-850Da Column: Phenomenex Kinetix-XB C18, part number 00D-4498-AN, 2.1 x 100 mm, 1.7 μm Temperature: 40℃ gradient: [Table 44]

[0549] Analytical LC / MS analysis method B: ESI+ / -ion mode 150-850Da Column: Phenomenex Gemini-NX C18, part number 00D-4453-B0, 2.0 x 100 mm, 3.0 μm Temperature: 40℃ gradient: [Table 45]

[0550] Analytical LC / MS analysis method C: ESI+ / -ion mode 100-1000Da Column: Waters UPLC® BEH™ C18, part number 186002352, 2.1×100 mm, 1.7 μm Temperature: 40℃ gradient: [Table 46]

[0551] Analytical LC / MS analysis method D: ESI+ / -ion mode 100-1000Da Column: XBridge C18, 3.5μm 4.6×50mm column Temperature: 40℃ gradient: [Table 47]

[0552] Analytical LC / MS Analysis Method E: ESI+ / -ion mode 100-1000Da Column: XBridge SB-C18, 3.5μm 4.6×50mm column Temperature: 40℃ gradient: [Table 48]

[0553] Analytical LC / MS analysis method F: ESI+ / -ion mode 100-1000Da Column: Sunfire C18, 3.5μm 4.6×50mm column Temperature: 50℃ gradient: [Table 49]

[0554] Analytical LC / MS analysis method G: ESI+ / -ion mode 100-1000Da Column: Waters UPLC® BEH™ C18, part number 186005297, 1.7 μm 2.1 x 50 mm column Temperature: 40℃ gradient: [Table 50]

[0555] The results are presented in Table 1. [Table 51-1] TIFF0007659110000218.tif248163 TIFF0007659110000219.tif250166 TIFF0007659110000220.tif243168 TIFF0007659110000221.tif134169

[0556] Example 3: ARM-SAM-TIR SARM1 IC50 Assay This example describes the assay of ARM-SAM-TIR NADase activity and its use to measure the effectiveness of compounds of formula I or formula I' to block SARM1-mediated NAD+ cleavage. This assay is optimized to characterize the effectiveness of compounds of formula I or formula I' to inhibit SARM1 activity and calculate the IC50 value of each compound. This assay uses full-length SARM1, including ARM, SAM, and TIR domains. As shown herein, expression of this fragment without the autoinhibitory N-terminal domain produces a constitutively active enzyme that cleaves NAD+.

[0557] Preparation of ARM-SAM-TIR lysate (STL) NRK1-HEK293T cells were cultured at 150 cm 2 The following day, the cells were transfected with 15 μg of ARM-SAM-TIR expression plasmid, SEQ ID NO:1.

[0558] To minimize toxicity due to overexpression of ARM-SAM-TIR, cultures were supplemented with 1 mM NR at the time of transfection. 48 h after transfection, cells were harvested, pelleted by centrifugation at 1,000 rpm (Sorvall ST 16R centrifuge, Thermo Fisher) and washed once with cold PBS (0.01 M phosphate-buffered saline NaCl 0.138 M, KCl 0.0027 M, pH 7.4). Cells were resuspended in PBS containing protease inhibitors (cOmplete™ protease inhibitor cocktail, Roche product number 11873580001) and cell lysates were prepared by sonication (Branson Sonifer450, power = 3, 20 episodes of strokes). Lysates were centrifuged (12,000 × g for 10 min at 4°C) to remove cellular debris, and the supernatants (containing ARM-SAM-TIR proteins) were stored at -80°C for later use in the in vitro ARM-SAM-TIR NADase assay (see below). Protein concentrations were determined by the bicinchoninic acid (BCA) method and used to normalize lysate concentrations. ARM-SAM-TIR IC50 Assay for Compounds of Formula I or Formula I'.

[0559] Enzyme assays were performed in 384-well polypropylene plates in Dulbecco's PBS buffer with a final assay volume of 20 μL. ARM-SAM-TIR lysates at a final concentration of 5 μg / mL were pre-incubated with the respective compounds at a final assay concentration of 1% DMSO for 2 h at room temperature. The reaction was initiated by adding NAD+ at a final assay concentration of 5 μM as substrate. After 2 h of room temperature incubation, the reaction was stopped with 40 μL of a stop solution of 7.5% trichloroacetic acid in acetonitrile. NAD+ and ADPR concentrations were analyzed by a RapidFire high-throughput mass spectrometry system (Agilent Technologies, Santa Clara, CA) using an API4000 triple quadrupole mass spectrometer (AB Sciex Framingham, MA).

[0560] The results are presented in Table 2. Compounds with activities designated as "A" have IC 50 Compounds with activities designated as "B" provided IC 50 Compounds with activities designated as "C" provided IC 50 Compounds with activities designated as "D" provided IC 50 >30 μM was provided. nd: Undetermined. [Table 52-1] TIFF0007659110000223.tif249167 TIFF0007659110000224.tif248163 TIFF0007659110000225.tif44169

[0561] Example 4: Axonal Degeneration Index This example illustrates an in vitro axon degeneration assay used to characterize compounds of Formula I or Formula I'. This assay was used to test the effectiveness of compounds of Formula I or Formula I' to prevent axon degeneration in mouse dorsal root ganglion (DRG) drop cultures.

[0562] Mouse DRG drop culture: Mouse dorsal root ganglion neurons (DRG) are dissected from E12.5 CD1 mice (50 ganglia per embryo) and incubated with 0.5% trypsin solution containing 0.02% EDTA (Gibco) for 15 min at 37 °C. Cells are then triturated by gentle pipetting and washed three times with DRG growth medium (Neurobasal medium (Gibco) containing 2% B27 (Invitrogen), 100 ng / ml 2.5S NGF (Harland Bioproducts), 1 mM 5-fluoro-2'deoxyuridine (Sigma), penicillin, and streptomycin). Cells are suspended in DRG growth medium. DRG drop cultures are made by spotting 5000 cells / well into the center of each well of a 96-well tissue culture plate coated with poly-D-lysine (0.1 mg / ml, Sigma) and laminin (3 mg / ml, Invitrogen). After cells were allowed to attach to the plates for 15 min in a humidified tissue culture incubator (5% CO2), DRG growth medium was gently added (100 ml wells).

[0563] Axon degeneration assay: Axon degeneration is stimulated by either manual axonal transection using a scalpel blade or by chemotoxic stimulation. After an appropriate experimental period, DRG cultures are fixed in 1% PFA + sucrose and stored in a refrigerator before imaging. Brightfield images of DRG axons and somata are collected using a 20x water immersion lens on a Phenix automated confocal microscope (PerkinElmer) and quantification of axons is performed using an in-house developed script (Acapella, PerkinElmer).

Claims

1. The formula: 【Chemistry 1】 A compound represented by the formula: R 1 is 【Chemistry 2】 and L, 【Chemistry 3】 wherein C(O) of L is bonded to NH and CH 2 of L is bonded to R 2 ; A compound or a pharma- ceutically acceptable salt thereof, wherein R2 is an optionally substituted phenyl or an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein R2 is optionally substituted phenyl.

3. The compound of claim 1 or a pharma- ceutically acceptable salt thereof, wherein R2 is an optionally substituted group selected from pyridinyl or pyrimidinyl.

4. R 2 is 【Chemistry 4】 2. The compound of claim 1, selected from: 【Request 5】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof, for administration to a subject (i) having a condition characterized by axonal degeneration or (ii) at risk of developing a condition characterized by axonal degeneration.

8. A pharmaceutical composition for treating or preventing axonal degeneration, comprising a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof.

9. A pharmaceutical composition for inhibiting SARM1, comprising a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof.

10. A pharmaceutical composition for treating or preventing a disease or disorder selected from amyotrophic lateral sclerosis, multiple sclerosis, diabetic peripheral neuropathy, and chemotherapy-induced neuropathy, comprising a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof.

11. Use of a compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of axonal degeneration.

12. Use of a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a disease or disorder selected from amyotrophic lateral sclerosis, multiple sclerosis, diabetic peripheral neuropathy, and chemotherapy-induced neuropathy.

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