Benzopyrazole inhibitors of SARM1

Abstract

The present disclosure provides compounds and methods useful for inhibiting SARM1 and / or treating and / or preventing axonal degeneration.

Description

[0001] Background

[0002] 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 patients and caregivers. In the United States alone, the costs associated with these diseases currently exceed hundreds of billions of dollars annually. Since the incidence of many of these diseases and conditions increases with age, their incidence is rapidly increasing with demographic changes.

[0003] Overview

[0004] The present disclosure provides techniques that can be used, inter alia, for treating and / or preventing neurodegeneration (e.g., for 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 can be used in medicine, particularly for treating neurodegeneration (e.g., for reducing axonal degeneration).

[0006] In some embodiments, the present disclosure provides compounds having the structure shown in Formula I:

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein:

[0009] Ring A together with the fused carbon atoms is a 6 - membered aryl ring or a 6 - membered heteroaryl ring having 1 - 3 nitrogen atoms;

[0010] L is an optionally substituted C 1-4 aliphatic chain, wherein one carbon atom on the aliphatic chain is optionally replaced by a group 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 an optionally substituted divalent 3 - to 6 - membered monocyclic ring having 0 - 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0011] R 1is an optionally substituted group selected from 3- to 7-membered saturated or partially unsaturated heterocycles having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0012] R 2 is an optionally substituted group selected from C 1-6 aliphatic groups, 3- to 7-membered saturated or partially unsaturated heterocycles having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 5- to 6-membered heteroaryls having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocycles, 8- to 10-membered bicyclic saturated or partially unsaturated heterocycles having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and 8- to 10-membered bicyclic heteroaryl rings having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0013] R y are each independently selected from halogen, cyano, OR, SR, N(R)2, and optionally substituted C 1-4 aliphatic groups;

[0014] Each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic groups, 3- to 7-membered saturated or partially unsaturated heterocycles having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; or:

[0015] Two R groups together with the nitrogen atom to which they are attached form an optionally substituted 3- to 7-membered monocyclic heterocycle having 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; and

[0016] n is 0, 1, or 2.

[0017] In some embodiments, the provided compounds have the structures of I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-e, I-e-i, I-f, I-f-i, I-g, I-h, I-h-i, I-i, I-j, I-j-i, I-k, I-l, I-m, and I-n as shown below.

[0018] In some embodiments, one or more compounds of formula I are provided and / or used in solid form (e.g., crystalline or amorphous form).

[0019] In some embodiments, the present disclosure provides a composition comprising and / or delivering a compound of formula I (e.g., in the form described herein), a prodrug thereof, or an active metabolite.

[0020] In some embodiments, the present disclosure provides compositions comprising and / or delivering a formula I compound. In some embodiments, such compositions are pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0021] In some embodiments, the provided SARM1 inhibitor reduces or inhibits the binding of SARM1 to NAD+. In some embodiments, the provided SARM1 inhibitor binds to SARM1 within a pocket (e.g., the catalytic cleft of SARM1) comprising one or more catalytic residues.

[0022] In some embodiments, the provided compound and / or composition inhibits the activity of SARM1. Alternatively or additionally, in some embodiments, the provided compound alleviates one or more attributes of neurodegeneration. In some embodiments, the present disclosure provides methods of treating neurodegenerative diseases or disorders associated with axonal degeneration.

[0023] In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, in pharmaceutical practice. In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat, prevent, or improve axonal degeneration (e.g., one or more of its characteristics or properties). In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to inhibit axonal degeneration, including axonal degeneration caused by a reduction or depletion of NAD+. In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to prevent axonal degeneration distal to axonal injury.

[0024] In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat one or more neurodegenerative diseases, disorders or conditions selected from neuropathy or axonopathy. In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat neuropathies and axonopathies associated with axonal degeneration. In some embodiments, the neuropathy associated with axonal degeneration is a hereditary or congenital neuropathy or axonopathy. In some embodiments, the neuropathy associated with axonal degeneration is caused by de novo or somatic mutations. In some embodiments, the neuropathy associated with axonal degeneration is selected from the list included herein. In some embodiments, the neuropathy or axonopathy associated with axonal degeneration includes, but is not limited to, Parkinson's disease, Parkinsonism or Parkinson's 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.

[0025] In some embodiments, the subject to whom the compound or composition described herein is administered can be or comprise a subject having or at risk of having a neurodegenerative disease, disorder or condition. In some embodiments, the neurodegenerative disease, disorder or condition can be or comprise traumatic neuronal injury. In some embodiments, the traumatic neuronal injury is blunt force trauma, closed head injury, open head injury, exposure to shock and / or blast forces, or penetrating injury in or to the body's cranial cavity or innervated areas. In some embodiments, the traumatic neuronal injury is a force that causes axonal deformation, stretching, crushing or shearing.

[0026] In some embodiments, the provided method comprises 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.

[0027] In some embodiments, the provided method comprises administering a composition as described herein to a group of patients in need thereof. In some embodiments, the group consists of individuals who participate in activities with a high likelihood of traumatic neuronal injury. In some embodiments, the group consists of athletes who participate in contact sports or other high-risk activities.

[0028] In some embodiments, the patient is at risk of developing a neurodegenerative disease. In some embodiments, the patient is an elderly individual. In some embodiments, the patient is known to have a genetic risk factor for neurodegeneration.

[0029] In certain embodiments, the present disclosure provides compounds that can be used as, for example, analytical tools, probes in bioassays, or therapeutic agents of the present disclosure. The compounds provided by the present disclosure can also be used to study SARM1 function in biological and pathological phenomena and to comparatively evaluate new SARM1 activity inhibitors in vitro or in vivo.

[0030] In some embodiments, one or more compounds and / or compositions as described herein can be used as, for example, a method for inhibiting neuronal degeneration derived from a subject. In some embodiments, one or more compounds and / or compositions as described herein can be used to inhibit the degeneration of neurons or parts thereof cultured in vitro. In some embodiments, one or more compounds and / or compositions as described herein can be used as a stabilizer to promote neuronal survival in vitro. Brief Description of the Drawings

[0032] Figure 1 Example structure of the SARM1 protein.

[0033] Definitions

[0034] Aliphatic group: The term "aliphatic group" refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or contains one or more unsaturated units but is not aromatic (also referred to herein as "carbocyclic" or "cycloaliphatic"), unless otherwise specified, the aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms, and in other embodiments, the aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocyclic") refers to a monocyclic C3-C8 hydrocarbon or bicyclic C7-C 10 hydrocarbon that is completely saturated or contains one or more unsaturated units but is not aromatic. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, and their hybrids.

[0035] Alkyl: The term "alkyl", used alone or as part of a larger moiety, refers to a saturated, optionally substituted, straight-chain, branched-chain, or cyclic hydrocarbon group having 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms. The term "cycloalkyl" refers to an optionally substituted saturated ring system having from about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0036] Alkylene: The term "alkylene" refers to a divalent alkyl group. In some embodiments, "alkylene" is a divalent straight-chain or branched-chain alkyl group. In some embodiments, an "alkylene chain" is a polymethylene group, i.e., -(CH2) n- -, where n is a positive integer, such as 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 of the methylene hydrogen atoms are optionally replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups and also those described in the present specification. It should be understood that two substituents of an alkylene group can together form a ring system. In certain embodiments, the two substituents can together form a 3- to 7-membered ring. The substituents can be on the same or different atoms.

[0037] Alkenyl: The term "alkenyl", used alone or as part of a larger moiety, refers to an optionally substituted straight-chain, branched-chain, or cyclic hydrocarbon group having at least one double bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or polycyclic ring system that contains at least one carbon-carbon double bond and has from about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentyl, cyclohexenyl, and cycloheptenyl.

[0038] Alkynyl: The term "alkynyl", used alone or as part of a larger moiety, refers to an optionally substituted straight-chain or branched-chain hydrocarbon group having at least one triple bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms.

[0039] Aryl: The term "aryl" refers to monocyclic and bicyclic systems having a total of 5-14 ring members, where at least one ring in the system is aromatic and where each ring in the system contains 3-7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system that includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracenyl, etc., which may be substituted with one or more substituents. As used herein, the scope of the term "aryl" also includes groups in which an aromatic ring is fused to one or more non-aromatic carbocyclic or heterocyclic rings, such as indanyl, phthalimido, naphthalimido, phenanthridinyl, tetrahydronaphthyl, imidazolidinyl, imidazolidin-2-one, etc.

[0040] Binding: It should be understood that the term "binding" as used herein generally refers to non-covalent binding between two or more entities. "Direct" binding involves physical contact between entities or portions; indirect binding involves physical interactions through physical contact with one or more intermediate entities. Binding between two or more entities can generally be evaluated in any of a variety of contexts - including when studying interacting entities or portions in isolation or in the context of a more complex system (e.g., when covalently or otherwise associated with a carrier entity and / or in a biological system or cell).

[0041] 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 comprises an organism, such as an animal or a human. In some embodiments, the biological sample is or comprises biological tissue or fluid. In some embodiments, the biological sample can be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; body fluids containing cells; free floating nucleic acid; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washes or lavages, such as catheter lavages or bronchoalveolar lavages; aspirates; scrapings; bone marrow samples; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions and / or excretions; and / or cells therefrom. In some embodiments, the biological sample is or comprises cells obtained from an individual. In some embodiments, the cells obtained are cells from or include cells from the individual from whom the sample was 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: biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluids (e.g., blood, lymph, feces, etc.), etc. In some embodiments, as is clear from the context, the term "sample" refers to an article obtained by processing (e.g., by removing one or more components and / or by adding one or more reagents) the primary sample. For example, filtration using a semi-permeable membrane. Such a "processed sample" can contain, 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, separation and / or purification of certain components, etc.

[0042] Biomarker: The term "biomarker" is used herein to refer to an entity, event, or characteristic whose presence, level, degree, type, and / or form is associated with a particular biological event or state of interest such that it is considered a "marker" of that event or state. By way of just a few examples, in some embodiments, a biomarker can be or include a marker of a particular disease state, or a marker of the likelihood that a particular disease, disorder, or condition may develop, occur, or recur. In some embodiments, a biomarker can be or include a marker of a particular disease or treatment outcome or the likelihood thereof. Thus, in some embodiments, a biomarker is predictive of a relevant biological event or state of interest, in some embodiments, a biomarker is prognostic of a relevant biological event or state of interest, and in some embodiments, a biomarker is diagnostic of a relevant biological event or state of interest. A biomarker can be or include an entity of any chemical class and can be or include a combination of entities. For example, in some embodiments, a biomarker can be or include a nucleic acid, polypeptide, lipid, carbohydrate, small molecule, inorganic reagent (such as a metal or ion), or a combination thereof. In some embodiments, a biomarker is a cell surface marker. In some embodiments, a biomarker is intracellular. In some embodiments, a biomarker is detected extracellularly (e.g., secreted or otherwise produced or present extracellularly, such as in a body fluid such as blood, urine, tears, saliva, cerebrospinal fluid, etc.). In some embodiments, a biomarker can be or include a genetic or epigenetic signature. In some embodiments, a biomarker can be or include a gene expression signature.

[0043] In some embodiments, a biomarker can be or include a marker of neurodegeneration, or a marker of the likelihood that a neurodegenerative disease, disorder, or condition may develop, occur, or recur. In some embodiments, a biomarker can be or include a marker of neurodegeneration, treatment outcome, or the likelihood thereof. Thus, in some embodiments, a biomarker is predictive of a neurodegenerative disease, disorder, or condition, in some embodiments, a biomarker is prognostic of a neurodegenerative disease, disorder, or condition, and in some embodiments, a biomarker is diagnostic of a neurodegenerative disease, disorder, or condition. In some embodiments, changes in biomarker levels can be detected in cerebrospinal fluid (CSF), plasma, and / or serum.

[0044] In some embodiments, neurodegeneration can be evaluated, for example, by detecting an increase and / or decrease in the concentration of neurofilament light chain (NF-L) and / or neurofilament 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 evaluated by positron emission tomography (PET), using a synaptic vesicle glycoprotein 2A (SV2A) ligand. In some embodiments, detectable changes in the constitutive NAD and / or cADPR levels in neurons can be used to evaluate neurodegeneration.

[0045] In some embodiments, detectable changes in one or more neurodegeneration-related proteins in a subject relative to a healthy reference population can be used as biomarkers 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, an increase in cytokines and / or chemokines (including, but not limited to, Ccl2, Ccl7, Ccl12, Csf1, and / or Il66) can be used as a biomarker of neurodegeneration.

[0046] Vehicle: As used herein, the term "vehicle" refers to a diluent, adjuvant, excipient, or medium administered with a composition. In some exemplary embodiments, the vehicle can include sterile liquids, such as water and oils, including oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. In some embodiments, the vehicle is or includes one or more solid components.

[0047] Combination Therapy: As used herein, the term "combination therapy" refers to those situations in which a subject is simultaneously exposed to two or more treatment regimens (e.g., two or more therapeutic agents). In some embodiments, two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all "doses" of the first regimen are administered before any dose of the second regimen); in some embodiments, such agents are administered in an overlapping dosing regimen. In some embodiments, "administration" of a combination therapy may involve administering one or more agents or modalities to a subject who is receiving one or more other agents or modalities in the 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 their active moieties may be administered together in a combined composition, or even in a combined compound (e.g., as part of a single chemical complex or covalent entity).

[0048] Composition: Those skilled in the art will understand that the term "composition" can be used to refer to a discrete physical entity that contains one or more specified components. Generally, unless otherwise stated, a composition can be in any form, such as a gas, gel, liquid, solid, etc.

[0049] Domain: As used herein, the term "domain" refers to a segment or portion of an entity. In some embodiments, a "domain" is associated with specific structural and / or functional characteristics of the entity such that when the domain is physically separated from the remainder of its parent entity, it substantially or completely retains the specific structural and / or functional characteristics. Alternatively or additionally, a domain can be or include a part of an entity that, when separated from the (parental) entity and linked to a different (recipient) entity, substantially retains and / or confers on the recipient entity one or more of its structural and / or functional characteristics that were characteristic in the parent entity. In some embodiments, a domain is a segment or portion of a molecule (e.g., a small molecule, carbohydrate, lipid, nucleic acid, or polypeptide). In some embodiments, a domain is part of a polypeptide; in some such embodiments, a domain is characterized by specific structural elements (e.g., a specific amino acid sequence or sequence motif, α-helical character, β-sheet character, coiled-coil character, random coil character, etc.) and / or specific functional characteristics (e.g., binding activity, enzymatic activity, folding activity, signaling activity, etc.).

[0050] 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 (such as a therapeutic agent or a diagnostic agent) for administration to a subject. Generally, each such unit contains a predetermined amount of the active agent. In some embodiments, such an amount is a unit dose (or a whole part thereof) suitable for administration according to a dosing regimen that has been determined to be associated with a desired or beneficial outcome (i.e., a therapeutic dosing regimen) when administered to a relevant population. Those of ordinary skill in the art understand that the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0051] 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 set of unit doses (usually more than one) that are typically administered to a subject separately over a period of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, the dosing regimen includes multiple doses, each dose being separated from the other doses in time. In some embodiments, the individual doses are separated by the same length of time period; in some embodiments, the dosing regimen includes multiple doses and at least two different time periods separating the individual doses. In some embodiments, all the doses within a dosing regimen have the same unit dose. In some embodiments, the different doses within a dosing regimen have different amounts. In some embodiments, the dosing regimen includes a first dose of a first dosing amount, followed by one or more additional doses of a second dosing amount different from the first dosing amount. In some embodiments, the dosing regimen includes a first dose of a first dosing amount, followed by one or more additional doses of a second dosing amount that is the same as the first dosing amount. In some embodiments, when administered to a relevant population, the dosing regimen is associated with a desired or beneficial outcome (i.e., a therapeutic dosing regimen).

[0052] Excipient: As used herein, refers to a non-therapeutic agent that can be included in a pharmaceutical composition, for example to provide or contribute to the desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, diols, water, ethanol, etc.

[0053] Heteroaryl: The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety such as "heteroalkyl" or "heteroalkoxy" refer to groups having 5 - 10 ring atoms, preferably 5, 6, 9 or 10 ring atoms; having 6, 10 or 14 π - electrons shared in a cyclic array; and having one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of basic nitrogen. Heteroaryl includes, but is not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which the heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclic rings. Non - limiting examples include indolyl, isoindolyl, benzothienyl, benzofuryl, dibenzofuryl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H - quinazolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3 - b]-1,4 - oxazin - 3(4H)-one. Heteroaryl can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic group", any of which includes an optionally substituted ring. The term "heteroalkyl" refers to an alkyl group substituted by a heteroaryl group, wherein the alkyl and heteroaryl moieties are independently and optionally substituted.

[0054] Heterocycle: As used herein, the terms "heterocycle", "heterocyclic group", "heterocyclic residue" and "heterocyclo" may be used interchangeably and refer to a specified 3 - to 8 - membered monocyclic or 7 - to 10 - membered bicyclic heterocyclic moiety which is saturated or partially unsaturated and has one or more, e.g., one to four, heteroatoms as defined above in addition to carbon atoms. When used with respect to the ring atoms 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, nitrogen can be N (as in 3,4 - dihydro - 2H - pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in an N - substituted pyrrolidinyl). The heterocycle can be attached to its side groups at any heteroatom or carbon atom that results in a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxolanyl, dioxolyl, diazanyl, oxazanyl, thiazanyl group, oxazolinyl group, thiazolinyl Base, morpholinyl and thiomorpholinyl. The heterocyclic group can be monocyclic, bicyclic, tricyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic, more preferably monocyclic or bicyclic. The term "heterocyclic group alkyl" refers to an alkyl group substituted by a heterocyclic group, wherein the alkyl and heterocyclic moieties are each independently optionally substituted. Additionally, the heterocycle also includes groups in which the heterocycle is fused to one or more aryl rings (such as 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[b][1,4]dioxin, etc.).

[0055] Inhibitor: As used herein, the term "inhibitor" refers to an entity, condition or event whose presence, level or degree is associated with a decrease in the level or activity of a target. In some embodiments, the inhibitor can act directly (in which case it directly exerts its effect on its target, e.g., by binding to the target); in some embodiments, the inhibitor can act indirectly (in which case it exerts its effect by interacting with a modulator of the target and / or otherwise altering the modulator of the target such that the level and / or activity of the target is decreased). In some embodiments, the inhibitor is an inhibitor whose presence or level is associated with a decreased target level or activity, said decreased target level or activity being relative to a specific reference level or activity (e.g., observed under appropriate reference conditions, such as in the presence of a known inhibitor, or in the absence of the inhibitor being discussed, etc.).

[0056] Neurodegeneration: As used herein, the term "neurodegeneration" refers to a decrease in one or more characteristics, structures, functions, or properties of neurons or neuronal tissue. In some embodiments, neurodegeneration is observed as a pathological decrease 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 disruptions); in some embodiments, neurodegeneration can be chronic and / or progressive (e.g., typically 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 evaluated, for example, by detecting an increase in a biomarker associated with neurodegeneration in a subject. In some embodiments, neurodegeneration can be evaluated, for example, by detecting a decrease in a biomarker associated with neurodegeneration in a subject. Optionally or additionally, in some embodiments, neurodegeneration can be evaluated by magnetic resonance imaging (MRI), a biomarker contained in cerebrospinal fluid, or other biomarkers observed in a patient. In some embodiments, neurodegeneration is defined as a score below 24 on the mini-mental state examination. In some embodiments, neurodegeneration refers to the loss of synapses. In some embodiments, neurodegeneration refers to a decrease in neural tissue associated with a traumatic injury (e.g., exposure to an external force that disrupts the integrity of neural tissue). In some embodiments, neurodegeneration refers to a decrease in peripheral neural tissue. In some embodiments, neurodegeneration refers to a decrease in central neural tissue.

[0057] Oral: As used herein, the phrases "administered orally" and "administered by oral administration" have the meaning understood in the art and refer to the administration of a compound or composition through the oral cavity.

[0058] Parenteral: As used herein, the phrases "administered parenterally" and "administered by parenteral administration" have the meaning understood in the art and refer to a mode of administration other than enteral and topical administration, typically by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0059] 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 include rings having multiple sites of unsaturation, but is not intended to include aromatic moieties (e.g., aryl or heteroaryl) as defined herein.

[0060] Patient: As used herein, the term "patient" refers to any organism to which the provided composition is administered or can be administered, for example, 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 a human. In some embodiments, the patient has or is 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 receiving or has received certain treatments for the diagnosis and / or treatment of a disease, disorder, or condition.

[0061] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit dosage forms suitable for administration in a therapeutic or dosing regimen that, when administered to the relevant population, shows a statistically significant probability of achieving a predetermined therapeutic effect. In some embodiments, the pharmaceutical composition can be formulated specifically for administration in solid or liquid form, including those suitable for: oral administration, such as infusions (aqueous or non-aqueous solutions or suspensions), tablets, such as those for oral, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, as, for example, a sterile solution or suspension or a sustained release formulation; topical administration, such as as a cream, ointment, or controlled release patch or spray applied to the skin, lung, or oral cavity; intravaginal or rectal, such as as a vaginal suppository, cream, or foam; sublingual; ocular; transdermal; or nasal, pulmonary, and other mucosal surfaces.

[0062] Pharmaceutically acceptable: As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0063] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, which participates in carrying or transporting the subject compound from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; diols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; pH buffering solutions; polyesters, polycarbonates, and / or polyanhydrides; and other non-toxic compatible substances used in pharmaceutical formulations.

[0064] Pharmaceutically acceptable salts: As used herein, the term "pharmaceutically acceptable salts" refers to salts of such compounds that are suitable for use in a pharmaceutical context, i.e., salts that are suitable, within the scope of sound medical judgment, for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by S.M. Berge et al. in J. Pharmaceutical Sciences, 66:1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, which are salts formed by the reaction of an amino group with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with an organic acid (e.g., acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods employed in the art (e.g., ion exchange). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactates, lactobionates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, tosylates, undecanoates, valerates, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. In some embodiments, pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide ions, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having 1 to 6 carbon atoms, sulfonate, and arylsulfonate.

[0065] Prevent or prevent from: As used herein, the terms "prevent" or "prevent from" when used in connection with the occurrence of a disease, disorder, or condition refer to reducing the risk of the occurrence of the disease, disorder, or condition and / or delaying the onset of one or more characteristics or symptoms of the disease, disorder, or condition. Prevention can be considered complete when the onset of the disease, disorder, or condition has been delayed for a predefined time period.

[0066] Specificity: As used herein, when referring to an agent having activity, those skilled in the art will understand the term "specificity" to mean that the agent discriminates between potential target entities or states. For example, in some embodiments, an agent is said to "specifically" bind its target if it preferentially binds to the target in the presence of one or more competing alternative targets. In many embodiments, specific interactions depend on the presence of specific structural features (e.g., epitopes, clefts, binding sites) of the target entity. It should be understood that specificity need not be absolute. In some embodiments, specificity can be evaluated relative to the specificity of the binder for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is evaluated relative to the specificity of a reference specific binder. In some embodiments, specificity is evaluated relative to the specificity of a reference non-specific binder. In some embodiments, the agent or entity binds the competing alternative target undetectably under conditions where it binds to its target entity. In some embodiments, the binder binds to its target entity with a higher binding rate, lower dissociation rate, increased affinity, decreased dissociation, and / or increased stability compared to the competing alternative target.

[0067] Subject: As used herein, the term "subject" refers to an organism, typically a mammal (e.g., a human, including in some embodiments a pre-birth human form). In some embodiments, the subject has a relevant disease, disorder, or condition. In some embodiments, the subject is susceptible to a disease, disorder, or condition. In some embodiments, the subject exhibits one or more symptoms or characteristics of a disease, disorder, or condition. In some embodiments, the subject does not exhibit any symptoms or characteristics of a disease, disorder, or condition. In some embodiments, the subject is a human having one or more characteristics 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 to whom a diagnosis and / or therapy has been administered and / or has been administered.

[0068] Substituted or optionally substituted: As described herein, the compounds of the present invention may contain "optionally substituted" moieties. Generally, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. "Substituted" applies to one or more hydrogens that are explicitly or implicitly present in the structure (e.g., means at least and means at least Unless otherwise indicated, an "optionally substituted" group can have stabilizing substituents at each position at which the group is individually capable of substitution, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituents can be the same or different at each position. Preferred combinations of substituents contemplated by the present invention are those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that permit its production, detection, and in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0069] Suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group are independently halogen; –(CH2) 0–4 R o ; –(CH2) 0–4 OR o ; -O(CH2) 0-4 R o , –O–(CH2) 0–4 C(O)OR o ; –(CH2) 0–4 CH(OR o )2; –(CH2) 0– 4SR o ; –(CH2) 0–4 Ph, which may be substituted with R o ; –(CH2) 0–4 O(CH2) 0–1 Ph, which may be substituted with R o ; –CH=CHPh, which may be substituted with R o ; –(CH2) 0–4 O(CH2) 0–1 -pyridyl, which may be substituted with R o ; –NO2; –CN; –N3; -(CH2) 0–4 N(R o )2; –(CH2) 0–4 N(R o )C(O)R o ; –N(R o )C(S)R o ; –(CH2) 0–4 N(R o )C(O)NR o 2; -N(R o )C(S)NR o 2; –(CH2) 0–4 N(R o )C(O)OR o ; –N(R o)N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ;–(CH2) 0–4 C(O)R o ;–C(S)R o ;–(CH2) 0–4 C(O)OR o ;–(CH2) 0–4 C(O)SR o ;-(CH2) 0–4 C(O)OSiR o 3;–(CH2) 0–4 OC(O)R o ;–OC(O)(CH2) 0–4 SR o ;–(CH2) 0–4 SC(O)R o ;–(CH2) 0–4 C(O)NR o 2;–C(S)NR o 2;–C(S)SR o ;–SC(S)SR o 、-(CH2) 0– 4OC(O)NR o 2;-C(O)N(OR o )R o ;–C(O)C(O)R o ;–C(O)CH2C(O)R o ;–C(NOR o )R o ;-(CH2) 0–4 SSR o ;–(CH2) 0–4 S(O)2R o ;–(CH2) 0–4 S(O)(NH)R o ;–(CH2) 0–4 S(O)2OR o ;–(CH2) 0–4 OS(O)2R o ;–S(O)2NR o 2;-(CH2) 0–4 S(O)R o ;-N(R o )S(O)2NRo 2; –N(R o )S(O)2R o ; –N(OR o )R o ; –C(NH)NR o 2; –P(O)2R o ; -P(O)R o 2; -OP(O)R o 2; –OP(O)(OR o )2; SiR o 3; –(C 1–4 linear or branched alkylene)O–N(R o )2; or –(C 1–4 linear or branched alkylene)C(O)O–N(R o )2, where R o each may be substituted as defined below and is independently hydrogen, C 1–6 aliphatic group, –CH2Ph, –O(CH2) 0–1 Ph, -CH2-(5- to 6-membered heteroaryl ring), 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8- to 10-membered bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or, although defined as above, but two independently occurring R o together with their intervening atoms form a 3- to 12-membered saturated, partially unsaturated or aryl mono- or bicyclic having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be substituted as defined below.

[0070] R o (or the ring formed by two independently occurring R o and their intervening atoms) suitable monovalent substituents on are independently halogen, –(CH2) 0–2 R · , –(haloalkyl R · ), –(CH2) 0–2 OH, –(CH2) 0–2 OR · , –(CH2) 0–2 CH(OR · )2; -O(haloalkyl R · ), –CN, –N3, –(CH2) 0–2 C(O)R · , –(CH2) 0–2 C(O)OH, –(CH2) 0–2 C(O)OR · , –(CH2) 0–2 SR ·, –(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 a straight-chain or branched alkylene)C(O)OR · or –SSR · , where R · is each unsubstituted or, if preceded by "halo-", is substituted by only one or more halogens and is independently selected from C 1–4 aliphatic groups, –CH2Ph, –O(CH2) 0–1 Ph or a 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Suitable divalent substituents on the saturated carbon atoms of R o include =O and =S.

[0071] Suitable divalent substituents on the saturated carbon atoms 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–, where each independently occurring R * is selected from hydrogen, a C 1–6 aliphatic group which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Suitable divalent substituents on the ortho-substitutable carbon of an "optionally substituted" group include: –O(CR * 2) 2–3 O–, where each independently occurring R * is selected from hydrogen, a C 1–6 aliphatic group which may be substituted as defined below, or an unsubstituted 5–6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0072] R * Suitable substituents on the aliphatic group of · include halogen, –R · , -(halo-R · ), –OH, –OR · , –O(halo-R · ), –CN, –C(O)OH, –C(O)OR · , –NH2, –NHR · , –NR · 2 or –NO2, where R 1–4 is each unsubstituted or, if preceded by "halo", is substituted only by one or more halogens, and is independently a C 0–1 aliphatic group, –CH2Ph, –O(CH2)

[0073] Suitable substituents on the nitrogen of the "optionally substituted" group include where is each independently hydrogen, a C 1–6 aliphatic group which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or, notwithstanding the above definition, but two independently occurring together with their intervening atoms form an unsubstituted 3- to 12-membered saturated, partially unsaturated or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0074] Suitable substituents on the aliphatic group of · are independently halogen, –R · , -(halo-R · ), –OH, –OR · , –O(halo-R · ), –CN, –C(O)OH, –C(O)OR · , –NH2, –NHR · , –NR · 2 or -NO2, where R 1–4 is each unsubstituted or, if preceded by "halo", is substituted only by one or more halogens, and is independently a C 0–1 aliphatic group, –CH2Ph, –O(CH2)

[0075] Therapeutic agent: As used herein, the term "therapeutic agent" generally refers to any agent that elicits a desired pharmacological effect when administered to a living organism. In some embodiments, an agent is considered a therapeutic agent if it shows a statistically significant effect in an appropriate population. In some embodiments, the appropriate population can be a population of model organisms. In some embodiments, the appropriate population can be defined by various criteria, such as a certain age group, gender, genetic background, pre-existing clinical condition, etc. In some embodiments, a therapeutic agent is a substance that can be used to alleviate, improve, relieve, inhibit, prevent, delay the onset of, reduce the severity and / or reduce the incidence of one or more symptoms or characteristics of a disease, disorder or condition. In some embodiments, a "therapeutic agent" is an agent that has been or needs to be approved by a government agency before it can be marketed for administration to humans. In some embodiments, a "therapeutic agent" is an agent that requires a medical prescription for administration to humans.

[0076] Treatment: As used herein, the terms "treat", "treatment" or "treating" refer to any method for partially or completely alleviating, improving, relieving, inhibiting, preventing one or more symptoms or characteristics of a disease, disorder or condition, delaying its onset, reducing its severity and / or reducing its incidence. Treatment can be administered to a subject who does not exhibit signs of a disease, disorder or condition. In some embodiments, treatment can be administered to a subject who exhibits only early signs of a disease, disorder or condition, e.g., for the purpose of reducing the risk of developing a pathological condition associated with the disease, disorder or condition.

[0077] In addition, unless otherwise indicated, in some embodiments, the structures described herein also include compounds that differ only in the presence of one or more isotopically enriched or isotopically labeled atoms. Isotopically labeled compounds can have one or more atoms replaced by atoms having an atomic weight or mass number that is normally found in nature. Examples of isotopes that can be present in the compounds of Formula I include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as but not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S and 18 F. Certain isotopically labeled compounds of Formula I can be used, in addition to being used as therapeutic agents, for drug and / or substrate tissue distribution assays, as analytical tools or as probes in other biological assays. In one aspect of the invention, tritiated (e.g., 3 H) and carbon-14 (e.g., 14C) Isotopes are useful because they are readily detectable. In another aspect of the invention, replacing one or more hydrogen atoms with a heavier isotope such as deuterium (e.g., 2 H) can provide certain therapeutic advantages.

[0078] Detailed description of certain embodiments

[0079] Programmed axonal degeneration and SARM1

[0080] Axonal degeneration is a major pathological feature of neurological diseases such as, but not limited to, Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis, diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, hereditary neuropathy, traumatic brain injury, and / or glaucoma. Damaged or unhealthy axons are eliminated through an inherent self-destruction program that is distinct from traditional cell death pathways such as apoptosis, called Wallerian degeneration. (Gerdts, J. et al., Neuron, 2016, 89, 449-460; Whitmore, A. V. et al., Cell Death Differ., 2003, 10, 260-261). In Wallerian degeneration, the peripheral nerve undergoes selective destruction of the axonal segment distal to the injury, while the proximal axonal segment and cell body remain intact. This degeneration is characterized by, first, depletion of nicotinamide mononucleotide adenylyltransferase (NMNAT), followed by loss of nicotinamide adenine dinucleotide (NAD+), loss of adenosine triphosphate (ATP), proteolysis of neurofilaments, and ultimately axonal degradation approximately 8 to 24 hours after injury. (Gerdts, J., et al., Neuron, 2016, 89, 449-460).

[0081] 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 responsible for 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).

[0082] In a genome-wide RNAi screen of primary mouse neurons, sterile alpha and TIR motif-containing 1 (SARM1) was identified, and knockout of SARM1 resulted in durable protection of sensory neurons against injury-induced axonal degeneration (Gerdts et al., J Neurosci, 2013, 33, 13569-13580). SARM1 belongs to the family of cytoplasmic adaptor proteins but is unique among its members as it is the most evolutionarily ancient adaptor, anomalously inhibits TLR signaling, and has been identified as a central executor of the injury-induced axon death pathway (O'Neill, L.A. & Bowie, A.G., Nat. Rev. Immunol., 2007, 7, 353-364; Osterloh, J.M. et al., Science, 2012, 337, 481-484; Gerdts, J. et al., J. Neurosci. 33, 2013, 13569-13580). Activation of SARM1 by axonal injury or forced dimerization of the SARM1-TIR domain promotes rapid and catastrophic depletion of nicotinamide adenine dinucleotide (NAD+), followed shortly 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 in vitro and in vivo, and SARM1 activation locally triggers axonal degeneration through NAD(+) breakdown (Gerdts et al., Science, 2015 348, 452-457; Sasaki et al., J. Biol. Chem. 2015, 290, 17228-17238; both papers are incorporated herein by reference in their entirety).

[0083] From loss-of-function studies, it is clear that SARML acts as a central executor of the axonal degeneration pathway after injury. Gene knockout of SARM1 permits axons to be retained for 14 days or longer after nerve transection (Osterloh, J.M. et al., Science, 2012, 337, 481-484; Gerdts, J. et al., J. Neurosci., 2013, 33, 13569-13580) and also improves functional outcomes in mice after traumatic brain injury (Henninger, N. et al., Brain 139, 2016, 1094-1105). In addition to the role of SARM1 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, inhibiting axonal degeneration and the increased pain sensitivity that develops after treatment with the chemotherapeutic vincristine (Geisler et al., Brain, 2016, 139, 3092-3108).

[0084] SARM1 contains multiple conserved motifs that mediate oligomerization and protein-protein interactions, including the SAM domain, ARM / HEAT motifs, and the TIR domain( Figure 1 )(O'Neill, L.A. & Bowie, A.G., Nat. Rev. Immunol., 2007, 7, 353-364; Tewari, R. et al., Trends Cell Biol., 2010, 20, 470-481; Qiao, F. & Bowie, J.U., Sci. STKE 2005, Re7, 2005). The TIR domain is typically found in signaling proteins that function in innate immune pathways, where they serve as scaffolds for protein complexes (O'Neill, L.A. & Bowie, A.G., Nat. Rev. Immunol., 2007, 7, 353-364). Significantly, dimerization of the SARM1-TIR domain is sufficient to induce axonal degeneration and rapidly trigger the degradation of NAD+ by acting as a NAD+-cleaving enzyme (Milbrandt et al., WO 2018 / 057989; Gerdts, J. et al., Science, 2015, 348, 453-457). Given the central role of SARM1 in the axonal degeneration pathway and its identified NADase activity, attempts have been made to identify agents that can modulate SARM1 and potentially act as useful therapeutic agents, such as to protect against neurodegenerative diseases, including peripheral neuropathy, traumatic brain injury, and / or neurodegenerative diseases.

[0085] Among them, the present disclosure provides certain compounds and / or compositions as SARM1 inhibitors (such as as SARM1 inhibitors), and related technologies.

[0086] Compound

[0087] In some embodiments, the present disclosure provides compounds having the structure shown in Formula I:

[0088]

[0089] or a pharmaceutically acceptable salt thereof, wherein:

[0090] Ring A together with the fused carbon atoms is a 6-membered aryl ring or a 6-membered heteroaryl ring having 1-3 nitrogen atoms;

[0091] L is an optionally substituted C 1-4 aliphatic chain, wherein one carbon atom on the aliphatic chain is optionally replaced by a group 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 an optionally substituted divalent 3- to 6-membered monocyclic ring having 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0092] R 1 is an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0093] R 2 is an optionally substituted group selected from a C 1-6 aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl group, a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0094] R y each independently selected from halogen, cyano, OR, SR, N(R)2, and an optionally substituted C 1-4 aliphatic group;

[0095] Each R is independently hydrogen or an optionally substituted group selected from C1-6 An aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl group, a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; or:

[0096] Two R groups together with the nitrogen atom to which they are attached form an optionally substituted 3- to 7-membered monocyclic heterocycle having 0 to 2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; and

[0097] n is 0, 1, or 2.

[0098] As generally defined above, ring A together with the fused carbon atoms is a 6-membered aryl ring or 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In some embodiments, ring A is a 6-membered aryl ring. In some embodiments, ring A is a 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In some embodiments, ring A is a 6-membered heteroaryl ring having 1 to 2 nitrogen atoms. In some embodiments, ring A is a 6-membered heteroaryl ring having 1 nitrogen atom. In some embodiments, ring A is a 6-membered heteroaryl ring having 2 nitrogen atoms. In some such embodiments, ring A is selected from pyrimidinyl and pyridazinyl.

[0099] In some embodiments, the present disclosure provides compounds of formulae I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, I-l, I-m, and I-n:

[0100]

[0101] or a pharmaceutically acceptable salt thereof, wherein L, R 1 , R 2 , R y and n are each as defined above and as described herein.

[0102] As generally defined above, L is an optionally substituted C 1-4 aliphatic chain, wherein one carbon atom on the aliphatic chain is optionally replaced by a group 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 an optionally substituted divalent 3- to 6-membered monocyclic ring having 0 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, L is an optionally substituted C 1-4 aliphatic chain, wherein one carbon atom on the aliphatic chain is optionally replaced by a group selected from: –O- and -N(R)-. In some embodiments, L is an optionally substituted C 1-4An aliphatic chain, wherein a carbon atom on the aliphatic chain is optionally replaced by an optionally substituted divalent 3- to 6-membered monocyclic ring having 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, L is an optionally substituted C2 aliphatic chain, wherein a carbon atom on the aliphatic chain is optionally replaced by a group selected from: –O- and -N(R)-. In some embodiments, L is an optionally substituted C2 aliphatic chain, wherein a carbon atom on the aliphatic chain is optionally replaced by an optionally substituted divalent 3- to 6-membered monocyclic ring having 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0103] In some embodiments, L is selected from

[0104]

[0105] In some embodiments, L is

[0106] As generally defined above, R 1 is an optionally substituted group selected from 3- to 7-membered saturated or partially unsaturated heterocycles having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0107] In some embodiments, R 1 is an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 1 is an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocycle 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.

[0108] In some embodiments, R 1 is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0109] In some embodiments, R 1 is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 1 is an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 1 is an optionally substituted group selected from pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, oxazolyl, and thiophenyl rings.

[0110] In some embodiments, R1 is an optionally substituted 6 - membered heteroaryl ring having 1 - 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 1 is an optionally substituted group selected from pyridyl, pyrimidinyl, and pyridazinyl.

[0111] In some embodiments, R 1 is selected from

[0112]

[0113] In certain particularly preferred embodiments, R 1 is selected from

[0114] As generally defined above, R 2 is an optionally substituted group selected from C 1-6 aliphatic groups, 3 - to 7 - membered saturated or partially unsaturated heterocycles having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 5 - to 6 - membered heteroaryl groups having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, 8 - to 10 - membered bicyclic saturated, partially unsaturated, or aryl carbocycles, 8 - to 10 - membered bicyclic saturated or partially unsaturated heterocycles having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and 8 - to 10 - membered bicyclic heteroaryl rings having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0115] In some embodiments, R 2 is an optionally substituted C 1-6 aliphatic group. In some such embodiments, R 2 is an optionally substituted group selected from cyclopentyl or cyclohexyl. In some embodiments, R 2 is a C 1-6 aliphatic group. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is cyclohexyl.

[0116] In some embodiments, R 2 is an optionally substituted phenyl

[0117] In some embodiments, R 2 is an optionally substituted 3 - to 7 - membered saturated or partially unsaturated heterocycle having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 2 is an optionally substituted 3 - membered saturated heterocycle having 1 heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments, R2 is an optionally substituted 4-membered saturated heterocycle having 1 heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments, R 2 is an optionally substituted 5-membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 2 is an optionally substituted 6-membered saturated or partially unsaturated heterocycle having 1-3 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.

[0118] In some embodiments, R 2 is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 2 is a 5-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 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some such embodiments, R 2 is an optionally substituted group selected from thienyl, pyrazolyl, and imidazolyl.

[0119] In some embodiments, R 2 is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, R 2 is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some such embodiments, R 2 is an optionally substituted group selected from pyridinyl and pyrimidinyl.

[0120] In some embodiments, R 2 is an optionally substituted 8- to 10-membered bicyclic saturated, partially unsaturated, or aryl carbocycle. In some embodiments, R 2 is an optionally substituted 9-membered bicyclic saturated, partially unsaturated, or aryl carbocycle. In some such embodiments, R 2 is an optionally substituted 2,3-dihydro-1H-indenyl. In some embodiments, R 2 is an optionally substituted 10-membered bicyclic saturated, partially unsaturated, or aryl carbocycle. In some such embodiments, R 2 is an optionally substituted group selected from 1,2,3,4-tetrahydronaphthyl and naphthyl.

[0121] In some embodiments, R 2is an optionally substituted 8- to 10-membered bicyclic saturated or partially unsaturated heterocycle having 1 to 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 heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 2 is an optionally substituted 10-membered bicyclic saturated or partially unsaturated heterocycle 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)-one.

[0122] In some embodiments, R 2 is an optionally substituted 8- to 10-membered bicyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and 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.

[0123] In some embodiments, R 2 is selected from

[0124]

[0125] In some embodiments, –L-R 2 is selected from:

[0126]

[0127] As generally defined above, each R y is independently selected from halogen, cyano, OR, SR, N(R)2, and an optionally substituted C 1-4 aliphatic group.

[0128] In some embodiments, R y is halogen. In some such embodiments, R y is chlorine or bromine.

[0129] In some embodiments, R y is cyano.

[0130] In some embodiments, R y is OR. In some embodiments, Ry is OR, where R is selected from hydrogen or an optionally substituted C 1-6 aliphatic group. In some embodiments, R y is OR, where R is selected from hydrogen or an optionally substituted C 1-4 aliphatic group. In some embodiments, R y is selected from OH, OCH3, and OCH2CH3.

[0131] In some embodiments, R y is SR. In some embodiments, R y is SR, where R is selected from hydrogen or an optionally substituted C 1-6 aliphatic group. In some embodiments, R y is SR, where R is selected from hydrogen or an optionally substituted C 1-4 aliphatic group. In some embodiments, R y is selected from SH, SCH3, and SCH2CH3.

[0132] In some embodiments, R y is N(R)2. In some embodiments, R y is N(R)2, where R is selected from hydrogen or an optionally substituted C 1-6 aliphatic group. In some embodiments, R y is N(R)2, where R is selected from hydrogen or an optionally substituted C 1-4 aliphatic group. In some embodiments, R y is selected from NH2, NHCH3, NHCH2CH3, N(CH3)2, and N(CH2CH3)2.

[0133] In some embodiments, R y is an optionally substituted C 1-4 aliphatic group. In some embodiments, R y is methyl, ethyl, or isopropyl. In some embodiments, R y is an optionally substituted C 3-4 aliphatic group. In some such embodiments, R y is selected from tert-butyl,

[0134] In some embodiments, R y is C 1-4 aliphatic group, which is optionally substituted with a group selected from halogen, –(CH2) 0–4 R o –(CH2) 0–4 OR o –(CH2) 0–4 N(R o )2, –(CH2) 0–4C(O)OR o and –(CH2) 0–4 C(O)NR o 2 groups. In some such embodiments, R o is selected from hydrogen, C 1–6 aliphatic group, –CH2Ph, –O(CH2) 0–1 Ph, -CH2-(5- to 6-membered heteroaryl ring), 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 8- to 10-membered bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two independently occurring R o together with the intervening atoms form a 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0135] In some embodiments, R y is an optionally substituted C o aliphatic group substituted with a group selected from halogen, –R o , –OR o , -N(R o )2, –C(O)OR o and –C(O)NR 1-4 2. In some embodiments, R y is an optionally halogen-substituted C 1-4 aliphatic group. In some such embodiments, R y is selected from –CH3, –CF3, -CHF2 and CH2F.

[0136] In some embodiments, R y is selected from –CH2R o , –CH2OR o , –CH2N(R o )2, –CH2C(O)OR o and –CH2C(O)N(R o )2. In some such embodiments, R y is selected from –CH2OH, -CH2OCH3, -CH2C(O)NH2, -CH2C(O)NHCH3 and -CH2C(O)N(CH3)2.

[0137] As generally defined above, each R is independently hydrogen or an optionally substituted group selected from C 1-6An aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl group, and a 5- to 6-membered heteroaryl having 1 to 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- to 7-membered monocyclic ring having 0 to 2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted group selected from C 1-6 An aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl group, and a 5- to 6-membered heteroaryl having 1 to 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- to 7-membered monocyclic heterocycle having 0 to 2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0138] In some embodiments, R is an optionally substituted C 1-6 aliphatic group. In some embodiments, R is an optionally oxo- and OR o substituted C 1-6 aliphatic group, wherein R o is C 1-6 aliphatic group. In some such embodiments, R is –C(O)OtBu.

[0139] In some embodiments, R is C 1-6 aliphatic group. In some such embodiments, R is methyl or ethyl.

[0140] In some embodiments, R is selected from hydrogen or an optionally substituted C 1-6 aliphatic group. In some such embodiments, R is selected from hydrogen, methyl, and ethyl.

[0141] In some embodiments, the present disclosure provides compounds of formulae I-a-i, I-b-i, I-c-i, I-e-i, I-f-i, I-h-i, and I-j-i:

[0142]

[0143] or a pharmaceutically acceptable salt thereof, wherein L, R 1 , R 2 , R y and n are each as defined above and as described herein.

[0144] In some embodiments, the present disclosure provides compounds selected from:

[0145]

[0146] or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, the present disclosure provides compounds of the following embodiments:

[0148] Embodiment 1. A compound of Formula I:

[0149]

[0150] or a pharmaceutically acceptable salt thereof, wherein:

[0151] Ring A together with the fused carbon atoms is a 6-membered aryl ring or a 6-membered heteroaryl ring having 1 - 3 nitrogen atoms;

[0152] L is an optionally substituted C 1-4 aliphatic chain, wherein one carbon atom on the aliphatic chain is optionally replaced by a group 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 an optionally substituted divalent 3- to 6-membered monocyclic ring having 0 - 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0153] R 1 is an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and a 5- to 6-membered heteroaryl having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0154] R 2 is an optionally substituted group selected from a C 1-6 aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, a 5- to 6-membered heteroaryl having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocycle having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0155] R y are each independently selected from halogen, cyano, OR, SR, N(R)2, and an optionally substituted C 1-4 aliphatic group;

[0156] Each R is independently hydrogen or an optionally substituted group selected from a C 1-6an aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl group, and a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; or:

[0157] two R groups together with the nitrogen atom to which they are attached form an optionally substituted 3- to 7-membered monocyclic heterocycle having 0 to 2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; and

[0158] n is 0, 1, or 2.

[0159] Embodiment 2. The compound of Embodiment 1, wherein Ring A is a 6-membered aryl ring.

[0160] Embodiment 3. The compound of Embodiment 1, wherein Ring A is a 6-membered heteroaryl ring having 1 to 3 nitrogen atoms.

[0161] Embodiment 4. The compound of Embodiment 1, wherein Ring A is a 6-membered heteroaryl ring having 1 nitrogen atom.

[0162] Embodiment 5. The compound of Embodiment 1, wherein Ring A is a 6-membered heteroaryl ring having 2 nitrogen atoms.

[0163] Embodiment 6. The compound of Embodiment 1, wherein the compound is a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, I-l, I-m, and I-n:

[0164]

[0165] or a pharmaceutically acceptable salt thereof.

[0166] Embodiment 7. The compound of any one of Embodiments 1-6, wherein R 1 is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0167] Embodiment 8. The compound of Embodiment 7, wherein R 1 is an optionally substituted 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0168] Embodiment 9. The compound of Embodiment 8, wherein R 1 is an optionally substituted 5-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0169] Embodiment 10. The compound of Embodiment 7, wherein R 1 is an optionally substituted 6-membered heteroaryl ring having 1 to 3 nitrogen atoms.

[0170] Embodiment 11. The compound of Embodiment 10, wherein R 1 is an optionally substituted 6-membered heteroaryl ring having 1 to 2 nitrogen atoms.

[0171] Embodiment 12. The compound of Embodiment 7, wherein R 1 is selected from

[0172]

[0173] Embodiment 13. The compound of Embodiment 12, wherein R 1 is selected from

[0174] Embodiment 14. The compound of any one of Embodiments 1-13, wherein L is an optionally substituted C 1-4 aliphatic chain, wherein one carbon atom on the aliphatic chain is optionally replaced by a group 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 an optionally substituted divalent 3- to 6-membered monocyclic ring having 0 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0175] Embodiment 15. The compound of Embodiment 14, wherein L is an optionally substituted C 1-2 aliphatic chain, wherein one carbon atom on the aliphatic chain is replaced by a group selected from -O- or -N(R)-.

[0176] Embodiment 16. The compound of Embodiment 14 or 15, wherein L is an optionally substituted C 1-2 aliphatic chain, wherein one carbon atom on the aliphatic chain is replaced by a group selected from -O- or -N(H)-.

[0177] Embodiment 17. The compound of Embodiment 14 or 15, wherein L is an optionally substituted C 1-2 aliphatic chain, wherein one carbon atom on the aliphatic chain is replaced by –O-.

[0178] Embodiment 18. The compound of Embodiment 16, wherein L is an optionally substituted C 1-2 aliphatic chain, wherein one carbon atom on the aliphatic chain is replaced by -N(H)-.

[0179] Embodiment 19. The compound of any one of Embodiments 1-13, wherein L is selected from

[0180]

[0181] Embodiment 20. A compound according to any one of Embodiments 1-15 or 19, wherein R is hydrogen.

[0182] Embodiment 21. A compound according to any one of Embodiments 1-15 or 19, wherein R is an optionally substituted C 1-6 aliphatic group.

[0183] Embodiment 22. The compound of Embodiment 21, wherein R is methyl or ethyl.

[0184] Embodiment 23. A compound according to any one of Embodiments 1-22, wherein R 2 is an optionally substituted group selected from C 1-6 aliphatic group, 3- to 7-membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, phenyl, 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocycle, 8- to 10-membered bicyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0185] Embodiment 24. The compound of Embodiment 23, wherein R 2 is an optionally substituted C 1-6 aliphatic group.

[0186] Embodiment 25. The compound of Embodiment 24, wherein R 2 is methyl or ethyl.

[0187] Embodiment 26. The compound of Embodiment 24, wherein R 2 is an optionally substituted cyclohexyl.

[0188] Embodiment 27. The compound of Embodiment 23, wherein R 2 is an optionally substituted phenyl.

[0189] Embodiment 28. The compound of Embodiment 23, wherein R 2 is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0190] Embodiment 29. The compound of Embodiment 28, wherein R 2 is an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0191] Embodiment 30. The compound of Embodiment 28 or 29, wherein R 2is an optionally substituted group selected from thienyl, pyrazolyl and imidazolyl.

[0192] Embodiment 31. The compound of Embodiment 28, wherein R 2 is an optionally substituted 6-membered heteroaryl ring having 1 to 3 nitrogen atoms.

[0193] Embodiment 32. The compound of Embodiment 31, wherein R 2 is an optionally substituted 6-membered heteroaryl ring having 1 to 2 nitrogen atoms.

[0194] Embodiment 33. The compound of Embodiment 32, wherein R 2 is an optionally substituted group selected from pyridyl or pyrimidinyl.

[0195] Embodiment 34. The compound of Embodiment 23, wherein R 2 is selected from

[0196]

[0197] Embodiment 35. The compound of any one of Embodiments 1-34, wherein R y is a halogen.

[0198] Embodiment 36. The compound of any one of Embodiments 1-34, wherein R y is a cyano group.

[0199] Embodiment 37. The compound of any one of Embodiments 1-34, wherein R y is OR.

[0200] Embodiment 38. The compound of any one of Embodiments 1-34, wherein R y is SR.

[0201] Embodiment 39. The compound of any one of Embodiments 1-34, wherein R y is N(R)2.

[0202] Embodiment 40. The compound of any one of Embodiments 37-39, wherein R is selected from hydrogen or an optionally substituted C 1-6 aliphatic group.

[0203] Embodiment 41. The compound of Embodiment 40, wherein R is selected from hydrogen or an optionally substituted C 1-4 aliphatic group.

[0204] Embodiment 42. The compound of any one of Embodiments 37, 40 and 41, wherein R y is OH, OCH3 and OCH2CH3.

[0205] Embodiment 43. A compound according to any one of embodiments 38, 40, and 41, wherein R y is SH, SCH3, and SCH2CH3.

[0206] Embodiment 44. A compound according to any one of embodiments 39 - 41, wherein R y is selected from NH2, NHCH3, NHCH2CH3, N(CH3)2, and N(CH2CH3)2.

[0207] Embodiment 45. A compound according to any one of embodiments 1 - 34, wherein R y is an optionally substituted C 1-4 aliphatic group.

[0208] Embodiment 46. The compound of embodiment 45, wherein R y is an optionally substituted C 3-4 aliphatic group.

[0209] Embodiment 47. The compound of embodiment 46, wherein R y is selected from tert-butyl,

[0210] Embodiment 48. The compound of embodiment 45, wherein R y is a C 1-4 aliphatic group, which is optionally substituted with a group selected from halogen, –(CH2) 0–4 R o –(CH2) 0–4 OR o –(CH2) 0–4 N(R o )2, –(CH2) 0–4 C(O)OR o and –(CH2) 0–4 C(O)NR o 2.

[0211] Embodiment 49. The compound of embodiment 48, wherein R o is selected from hydrogen, C 1–6 aliphatic group, –CH2Ph, –O(CH2) 0–1 Ph, -CH2-(5- to 6-membered heteroaryl ring), a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 - 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic aryl ring having 0 - 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two independently occurring R o together with the intervening atoms form a 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 - 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0212] Embodiment 50. The compound of Embodiment 45, wherein R y is an optionally C o -aliphatic group substituted with a group selected from halogen, –R o , –OR o , -N(R o )2, –C(O)OR o and –C(O)NR 1-4 2.

[0213] Embodiment 51. The compound of Embodiment 45, wherein R y is an optionally halogen-substituted C 1-4 -aliphatic group.

[0214] Embodiment 52. The compound of Embodiment 51, wherein R y is selected from –CH3, –CF3, -CHF2 and CH2F.

[0215] Embodiment 53. The compound of Embodiment 50, wherein R y is selected from –CH2R o , –CH2OR o , –CH2N(R o )2, –CH2C(O)OR o and –CH2C(O)N(R o )2.

[0216] Embodiment 54. The compound of Embodiment 53, wherein R y is selected from –CH2OH, -CH2OCH3, -CH2C(O)NH2, -CH2C(O)NHCH3 and -CH2C(O)N(CH3)2.

[0217] Embodiment 55. The compound of Embodiment 1, wherein the compound is a compound of formula I-a-i, I-b-i, I-c-i, I-e-i, I-f-i, I-h-i and I-j-i:

[0218]

[0219] or a pharmaceutically acceptable salt thereof.

[0220] Embodiment 56. A pharmaceutical composition comprising the compound of any one of Embodiments 1-55 and a pharmaceutically acceptable carrier.

[0221] Embodiment 57. A method comprising the step of administering to a subject a compound of any one of Embodiments 1-55, wherein the subject (i) has a condition characterized by axonal degeneration or (ii) is at risk of developing a condition characterized by axonal degeneration.

[0222] Embodiment 58. A method of treating or preventing axonal degeneration, comprising administering to a subject in need thereof a compound of any one of Embodiments 1-55.

[0223] Embodiment 59. A method of inhibiting SARM1, comprising contacting a biological sample with a compound of any one of Embodiments 1-55.

[0224] Embodiment 60. A compound of any one of Embodiments 1-55 for use in a medicament.

[0225] Embodiment 61. A compound of any one of Embodiments 1-55 for use in treating one or more diseases, disorders or conditions mediated by SARM1.

[0226] Embodiment 62. A compound of any one of Embodiments 1-55 for use in treating or preventing axonal degeneration.

[0227] Composition

[0228] In some embodiments, a compound of Formula I can be provided in a composition, for example in combination (e.g., as a mixture) with one or more other ingredients.

[0229] In some embodiments, the present disclosure provides a composition comprising and / or delivering a compound of Formula I or an active metabolite thereof, for example, when contacted with or otherwise administered to a system or environment, the system or environment can include SARM1 NADase activity; in some embodiments, administering such a composition to a system or environment achieves inhibition of SARM1 activity as described herein.

[0230] In some embodiments, a composition provided as described herein can be a pharmaceutical composition as it comprises an active agent and one or more pharmaceutically acceptable excipients; in some such embodiments, the provided pharmaceutical composition comprises and / or delivers a compound of Formula I or an active metabolite thereof to a relevant system or environment as described herein (e.g., to a subject in need thereof).

[0231] In some embodiments, one or more compounds of Formula I are provided and / or utilized in the form of a pharmaceutically acceptable salt.

[0232] Among them, the present disclosure provides a composition comprising a compound of formula I or a pharmaceutically acceptable salt or derivative thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in the provided composition is such that axonal degeneration in a biological sample or patient is effectively and measurably inhibited. 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 of the methods of the present disclosure can be administered in any amount and by any route of administration effective to treat or alleviate the severity of any disease or disorder described herein. The provided compound is preferably formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the expression "unit dosage form" refers to physically discrete units suitable for the patient to be treated. However, it should be understood that the total daily dosage of the provided compound and composition will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dosage level for any particular patient or organism will vary depending 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 species, age, weight, sex and diet of the patient; the general condition of the subject; the time of administration; the excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used, etc.

[0233] The provided composition can be administered orally, parenterally, by inhalation or nasal spray, topically (e.g., by powder, ointment or drops), rectally, orally, intravaginally, intraperitoneally, intracisternally or by an implanted reservoir, depending on the severity of the disorder being treated. Preferably, the composition is administered orally, intraperitoneally or intravenously. In certain embodiments, the provided compound is administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg of the subject's body weight per day, once or more times a day, to obtain the desired therapeutic effect.

[0234] As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. The sterile injectable form of the provided composition can be an aqueous or oily suspension. These suspensions can be formulated according to techniques known in the art, using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile non-volatile oils are commonly used as solvents or suspending media.

[0235] For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and their glyceride derivatives can be used in the preparation of injectables, as can natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants such as carboxymethyl cellulose or similar dispersants commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans and other emulsifiers or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid or other dosage forms can also be used for formulating purposes.

[0236] Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporation of a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or some other sterile injectable medium before use.

[0237] To prolong the action of the compounds provided, it is generally necessary to slow down the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous material. The absorption rate of the compound then depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as poly(lactide-co-glycolide). The rate of release of the compound can be controlled according to the ratio of the compound to the polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable preparations are also prepared by entrapping the compound in liposomes or microemulsions compatible with body tissues.

[0238] The pharmaceutically acceptable compositions described herein can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In such solid dosage forms, the active compound can be admixed with at least one inert diluent such as sucrose, lactose or starch. As is normal practice, such dosage forms may also contain other substances in addition to the inert diluent, such as lubricants and other tabletting aids such as magnesium stearate and microcrystalline cellulose. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.

[0239] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or calcium phosphate dibasic and / or the following: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders such as paraffin; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite; 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 form may also contain buffering agents. The active compounds can also be in microencapsulated form with one or more of the excipients as described above.

[0240] Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coating materials and shells such as enteric coating materials (i.e., buffering agents) and other coating materials well known in the pharmaceutical formulation art. They can optionally contain opacifying agents and can also be compositions that release the active ingredient only or preferentially in a certain part of the intestine, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0241] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may also contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents, and emulsifying agents such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan and mixtures thereof. In addition to the inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and fragrances.

[0242] Alternatively, the pharmaceutically 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 a suitable non-irritating excipient or carrier that is solid at room temperature but liquid at body (e.g., rectal or vaginal) temperature and will thus melt in the rectal or vaginal cavity to release the active compound. Such materials include cocoa butter, suppository waxes (e.g., beeswax), and polyethylene glycols.

[0243] The pharmaceutically acceptable compositions described herein can also be administered topically, particularly when the treatment target includes a region or organ that is easily accessible for topical administration, including eye, skin, or lower intestinal diseases. Topical administration to the lower intestine can be achieved in the form of a rectal suppository formulation (see above) or in a suitable enema formulation.

[0244] 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 pharmaceutically acceptable carrier and any required preservatives or buffering agents that may be needed. Ophthalmic formulations, otic drops, and eye drops are also considered within the scope of the present disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the additional advantage of providing a controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispensing the compound in a suitable medium. Penetration enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0245] For topical administration, the provided pharmaceutically acceptable compositions can be formulated as suitable ointments containing the active component 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 pharmaceutically acceptable compositions can be formulated as suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0246] For ophthalmic use, the provided pharmaceutically acceptable compositions can 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 benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[0247] The pharmaceutically acceptable compositions of the present disclosure can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0248] Most preferably, the pharmaceutically acceptable compositions of the present disclosure are formulated for oral administration.

[0249] Identification and / or characterization of compounds and / or compositions

[0250] Wherein, 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, particularly for evaluating SARM1 inhibitory activity.

[0251] In some embodiments, the performance of one or more compounds or compositions of interest in the assays described herein is compared to the performance of a suitable reference. For example, in some embodiments, the reference may be the absence of the relevant compound or composition. Alternatively or additionally, in some embodiments, the reference may be the presence of an alternative compound or composition, e.g., the alternative compound or composition has known performance in the relevant assay (e.g., as a positive or negative control, as understood in the art). In some embodiments, the reference may be an alternative but equivalent set of conditions (e.g., temperature, pH, salt concentration, etc.). In some embodiments, the reference may be the performance of the compound or composition with respect to a SARM1 variant.

[0252] Still further optionally or additionally, in some embodiments, the performance of one or more compounds or compositions of interest in the assays described herein can be evaluated in the presence of a suitable reference compound or composition, e.g., such that the ability of the compound or composition to compete with the reference can be determined.

[0253] In some embodiments, multiple compounds or compositions of interest can be analyzed in a particular assay and / or compared to the same reference. In some embodiments, such multiple compounds or compositions can be or include a set of compounds or compositions that are considered a "library" because multiple members share one or more characteristics (e.g., structural units, source identity, synthetic similarity, etc.).

[0254] Certain exemplary assays that can be used to implement the present disclosure are exemplified in the embodiments below. Those skilled in the art reading the present 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 embodiments or otherwise discussed below.

[0255] In some embodiments, compounds and / or compositions can be identified and / or characterized based on one or more activities or features, such as: promoting axonal integrity, cytoskeletal 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 the rate of NAD+ catabolism.

[0256] In some embodiments, the provided SARM1 inhibitors reduce or inhibit the binding of NAD+ through SARM1. In some embodiments, the provided SARM1 inhibitors bind to SARM1 within a pocket (e.g., the catalytic cleft of SARM1) containing one or more catalytic residues. Examples of such catalytic residues include glutamate at position 642 (E642).

[0257] In some embodiments, the provided SARM1 inhibitors disrupt and / or prevent the polymerization of the TIR1 domain of SARM1. In some embodiments, the provided SARM1 inhibitors disrupt the polymerization of the SAM domain. In some embodiments, the provided SARM1 inhibitors disrupt the axonal signaling cascade that leads to NAD+ depletion.

[0258] In some embodiments, the present disclosure provides assays that can be used to identify and / or characterize one or more activities and / or features 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 evaluating one or more such activities and / or features.

[0259] SARM1 activity assay

[0260] In some embodiments, a method for identifying a SARM1 inhibitor comprises: 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 the incubation; and d) identifying the candidate inhibitor compound as an inhibitor if the amount of NAD+ is greater than the amount of NAD+ in a control mixture without the candidate inhibitor.

[0261] In some embodiments, methods for identifying SARM1 inhibitors are provided, which include: 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 the incubation; d) determining the molar ratio of NAD+:ADPR (or cADPR); and e) if the molar ratio is greater than the molar ratio of a control mixture without the candidate inhibitor, identifying the candidate inhibitor compound as an inhibitor.

[0262] In some embodiments, methods for identifying SARM1 inhibitors are provided, the methods including: a) providing a mixture comprising a solid support to which i) full-length SARM1 and at least one tag, ii) NAD+, and iii) a candidate inhibitor are bound; b) incubating the mixture; c) quantifying the NAD+ after the incubation; and d) if the concentration of NAD+ is greater than the concentration of a control, identifying the candidate inhibitor compound as a SARM1 inhibitor.

[0263] SARM1 binding assay

[0264] In some embodiments, the efficacy of the provided SARM1 inhibitors can be determined according to, for example, the assay described in WO 2018 / 057989, published on March 29, 2018, which is incorporated herein by reference in its entirety. In some embodiments, the provided SARM1 inhibitors can be administered 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 administered to a patient. In some embodiments, an SARM1 inhibitor can be mixed with SARM1 or a fragment thereof that has been labeled with an epitope tag. In some embodiments, the amount of bound SARM1 inhibitor can be compared with the amount of unbound SARM1 inhibitor to obtain the affinity for the SARM1 inhibitor.

[0265] In some embodiments, mutants or fragments of SARM1 are constitutively active SAM-TIR fragments. Constitutively active SARM1 fragments include, for example but not limited to, SARM1 lacking its autoinhibitory domain; at least one point mutation in SARM1 that inactivates the autoinhibitory domain; SARM1 fragments containing the TIR domain; or SARM1 fragments consisting of the SAM and TIR domains. In some embodiments, the SARML polypeptide may include one or more additional amino acid sequences that can act as tags, such as His tags, streptavidin tags, or combinations thereof. In some embodiments, the SARML polypeptide may include tags at the amino terminus, carboxyl terminus, or combinations thereof. In some embodiments, SARML or fragments thereof labeled with an epitope tag can be used to measure the binding efficacy of provided SARML inhibitors. Purification of the SARM1-TIR domain

[0266] In some embodiments, the SARM1-TIR domain can be engineered with various protein or epitope tags useful for, for example, purification. In some embodiments, the present disclosure also provides an NRK1-HEK293T cell line comprising HEK293T cells transformed with nicotinamide riboside kinase 1 (NRK1). In some embodiments, 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 DNA or cDNA. In some embodiments, HEK293T cells are stably or transiently transfected with DNA encoding NRK1 from an exogenous source of the host cell. In some embodiments, HEK293T cells are stably or transiently transfected with DNA encoding NRK1 such that the cells express NRK1 at elevated levels 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 promoters, enhancers, or combinations thereof. In some embodiments, the combination of the DNA sequence encoding NRK1 and the regulatory sequences is a non-naturally occurring combination. In some embodiments, the DNA encoding NRK1 (genomic or cDNA) comprises an expression vector, such as an FCIV expression vector. In some embodiments, the DNA encoding NRK1 is derived from cDNA or genomic DNA from vertebrate or invertebrate species (e.g., but not limited to human, mouse, zebrafish, or Drosophila). In some configurations, the NRK1 DNA is human NRK1 DNA.

[0267] Applications and uses

[0268] The present disclosure provides various uses and applications of the compounds and / or compositions described herein, such as according to 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.

[0269] In one aspect, the present invention provides a method comprising administering one or more compounds of Formula I to a subject, such as 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 is a SARM1 inhibitor.

[0270] Another embodiment of the present disclosure relates to a method of inhibiting SARM1 activity in a patient, comprising the step of administering to the patient the provided compound or a composition comprising the compound.

[0271] Inhibiting an enzyme in a biological sample can be used for various purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, biological assays, gene expression studies, and biological target identification.

[0272] In certain embodiments, the present disclosure relates to a method of treating axonal degeneration in a biological sample, comprising the step of contacting the biological sample with a compound or composition of Formula I. In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, as a method of inhibiting the degradation of neurons derived from a subject. In some embodiments, one or more compounds and / or compositions as described herein can be used to inhibit the degeneration of neurons or portions thereof in vitro culture. In some embodiments, one or more compounds and / or compositions as described herein can be used as a stabilizer to promote neuronal survival in vitro.

[0273] In some embodiments, the provided compounds and / or compositions inhibit the NAD enzymatic activity of SARM1. Optionally or additionally, in some embodiments, the provided compounds mitigate one or more attributes of neurodegeneration. In some embodiments, the present disclosure provides methods of treating neurodegenerative diseases or conditions associated with axonal degeneration.

[0274] In some embodiments, one or more of the compounds and / or compositions described herein can be used, for example, in the practice of medicine. In some embodiments, one or more of the compounds and / or compositions as described herein can be used, for example, to treat, prevent, or ameliorate axonal degeneration (e.g., one or more characteristics or properties thereof). In some embodiments, one or more of the compounds and / or compositions as described herein can be used, for example, to inhibit axonal degeneration, including axonal degeneration caused by reduction or depletion of NAD+. In some embodiments, one or more of the compounds and / or compositions as described herein can be used, for example, to prevent axonal degeneration distal to axonal injury.

[0275] In some embodiments, one or more of the compounds and / or compositions as described herein can be used as a method for inhibiting the degradation of neurons or portions thereof in the peripheral nervous system, for example. In some embodiments, one or more of the compounds and / or compositions as described herein can be used as a method for inhibiting or preventing the degeneration of the central nervous system (neurons) or portions thereof. In some embodiments, one or more of the compounds or compositions as described herein are characterized in that when administered to a population of subjects, one or more symptoms or characteristics of neurodegeneration are alleviated. For example, in some embodiments, the relevant symptoms or characteristics can be selected from the degree, rate, and / or time of neuronal destruction.

[0276] In certain embodiments, the present disclosure provides compounds that can be used, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the present disclosure. The compounds provided by the present disclosure can also be used to study SARM1 activity in biological and pathological phenomena, and to comparatively evaluate new 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., certain vector constructs and / or polypeptides) that can be used to assay SARM1 activity. For example, in some embodiments, the provided assays can utilize: for example, SAM-TIR, in which the SARM1 N-terminal autoinhibitory domain is deleted; and / or one and / or more labeled forms of the TIR domain.

[0277] In some embodiments, one or more of the compounds and / or compositions as described herein can be used as a method for inhibiting the degradation of neurons derived from a subject, for example. In some embodiments, one or more of the compounds and / or compositions as described herein can be used to inhibit the degeneration of neurons or portions thereof cultured in vitro. In some embodiments, one or more of the compounds and / or compositions as described herein can be used as a stabilizer to promote the survival of neurons in vitro.

[0278] In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to affect biomarkers associated with neurodegeneration. In some embodiments, changes in biomarkers can be detected systemically or with samples from cerebrospinal fluid (CSF), plasma, serum, and / or tissue from a subject. In some embodiments, one or more compounds and / or compositions can be used to affect changes in the concentration of neurofilament light chain (NF-L) and / or neurofilament heavy chain (NF-H) contained in the cerebrospinal fluid of a subject. In some embodiments, one or more compounds and / or compositions as described herein can affect constitutive NAD and / or cADPR levels in neurons and / or axons.

[0279] In some embodiments, one or more biomarkers of neurodegeneration include: the 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 a subject; the 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 a subject; the 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 a subject; the concentration of α-synuclein in one or more of a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from a subject; the constitutive NAD+ level in neurons and / or axons of a subject; the constitutive cADPR level in neurons and / or axons of a subject; the level of 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 or total-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 nerve biopsy sample, and a brain biopsy sample from a subject; and the level of C-C motif chemokine ligand (CCL)2, CCL7, CCL12, colony-stimulating factor (CSF)1, or interleukin (IL)6 in one or more of a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, a skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from a subject.

[0280] In some embodiments, one or more of the compounds and / or compositions described herein can effect a detectable change in the level of one or more neurodegeneration-related proteins in a subject. 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, one or more of the compounds and / or compositions described herein can effect a change in cytokines and / or chemokines, including but not limited to Ccl2, Ccl7, Ccl12, Csf1, and / or Il6.

[0281] Diseases, disorders and conditions

[0282] In some embodiments, the compounds and / or compositions described herein can be administered to a subject having one or more diseases, disorders, or conditions. In some embodiments, the one or more diseases, disorders, or conditions are mediated by SARM1. In some embodiments, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in a medicament. In some embodiments, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of one or more diseases, disorders, or conditions mediated by SARM1. In some embodiments, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of neurodegeneration. In some embodiments, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of neurodegenerative diseases or disorders.

[0283] In some embodiments, the neurodegenerative disease or condition includes an acute or chronic disease or condition of the peripheral nervous system (PNS), an acute or chronic disease or condition of the central nervous system (CNS), or a disease associated with neurodegeneration.

[0284] In some embodiments, the neurodegenerative disease or disorder includes 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 agent or chemotherapy. In some embodiments, the mechanical injury includes compression or nerve entrapment injury or pressure injury. In some embodiments, the compression or nerve entrapment injury includes carpal tunnel syndrome, direct trauma, penetrating injury, contusion, fracture, or dislocated bone. In some embodiments, the pressure injury includes pressure involving superficial nerves, pressure from a tumor or increased intraocular pressure. In some embodiments, the chemical agent or chemotherapy includes cytotoxic anticancer agents, thalidomide, epothilones, taxanes, vinca alkaloids, proteasome inhibitors, platinum-based drugs, or auristatins. 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.

[0285] In some embodiments, the neurodegenerative disease or disorder includes a chronic disease or disorder of the PNS. In some embodiments, the chronic disease or disorder of the PNS includes a systemic disorder, a pain disorder, or a metabolic disease or disorder.

[0286] In some embodiments, the chronic disease or disorder of the PNS includes hereditary neuropathy, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathy, or other peripheral neuropathies.

[0287] In some embodiments, the systemic disorder includes diabetes, uremia, AIDS, leprosy, nutritional deficiency, atherosclerosis, intestinal neuropathy, axonopathy, Guillain-Barré syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.

[0288] In some embodiments, the pain disorder includes chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, cancer pain, arthritis, sciatica, headache, surgical pain, muscle spasm, back pain, visceral pain, injury pain, toothache, neuropathic pain, neuropathic pain, neuroinflammation, nerve injury, shingles, herniated disc, ligament tear, or diabetes.

[0289] In some embodiments, the metabolic disease or disorder includes diabetes, hypoglycemia, uremia, hypothyroidism, liver failure, polycythemia, amyloidosis, acromegaly, porphyria, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lipid / glycolipid metabolism disorder, nutritional deficiency, vitamin deficiency, or mitochondrial disorder.

[0290] In some embodiments, the neurodegenerative disease or disorder includes an acute disease or disorder of the CNS. In some embodiments, the acute disease or disorder of the CNS includes ischemia, traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis.

[0291] In some embodiments, ischemia includes cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.

[0292] In some embodiments, the traumatic CNS injury includes spinal cord injury, traumatic brain injury (TBI), mechanical injury of the head and / or spine, traumatic injury of the head and / or spine, blunt force trauma, closed head injury, open head injury, exposure to shock and / or blast forces, penetrating injury of the CNS, increased intraocular pressure, or injury from a force that causes axonal deformation, stretch, crush, or torsion.

[0293] In some embodiments, the viral encephalitis includes enteroviral encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).

[0294] In some embodiments, the neurodegenerative disease or disorder includes a chronic disease or disorder of the CNS.

[0295] In some embodiments, chronic diseases or disorders of the CNS include 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 syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, 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-Merzbacher disease, periventricular leukomalacia, 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's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spasticparaparesis), familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supranuclear palsy (PSP), Friedrich’s ataxia, or spinal cord injury.

[0296] In some embodiments, the chronic disease or disorder of the CNS comprises an optic nerve disorder, a traumatic CNS injury, or a metabolic disease or disorder.

[0297] In some embodiments, the optic nerve disease comprises acute optic neuropathy, a hereditary or idiopathic retinal disorder, Leber congenital amaurosis (LCA), Leber 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 nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer'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.

[0298] In some embodiments, the traumatic CNS injury comprises traumatic brain injury, spinal cord injury, traumatic axonal injury, or chronic traumatic encephalopathy (CTE).

[0299] In some embodiments, the metabolic disease or disorder comprises diabetes, hypoglycemia, Barré-Cornil syndrome, uremia, hypothyroidism, liver failure, polycythemia, amyloidosis, acromegaly, porphyria, lipid / glycolipid metabolism disorders, nutritional / vitamin deficiencies, and mitochondrial disorders.

[0300] In some embodiments, the neurodegenerative disease or disorder comprises a disease associated with neurodegeneration. In some embodiments, the neurodegenerative disease or disorder is caused by a blood clotting problem, inflammation, obesity, aging, stress, cancer, or diabetes.

[0301] In some embodiments, the disorder is acute peripheral neuropathy. Chemotherapy-induced peripheral neuropathy (CIPN) is an example of acute peripheral neuropathy. CIPN can be associated with various drugs, such as but not limited to thalidomide, epothilones (such as ixabepilone), taxanes (such as paclitaxel and docetaxel), vinca alkaloids (such as vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (such as bortezomib), platinum-based drugs (such as cisplatin, oxaliplatin, and carboplatin).

[0302] In some embodiments, one or more compounds and / or compositions as described herein are used, for example, to treat one or more neurodegenerative diseases, disorders, or conditions selected from neuropathy and axonopathy. In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat neuropathy or axonopathy associated with axonal degeneration. In some embodiments, the neuropathy associated with axonal degeneration is a hereditary or congenital neuropathy or axonopathy. In some embodiments, the neuropathy associated with axonal degeneration is caused by de novo or somatic mutations. In some embodiments, the neuropathy associated with axonal degeneration is selected from the list included herein. In some embodiments, the neuropathy or axonopathy associated with axonal degeneration includes, but is not limited to, Parkinson's disease, non-Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating diseases, ischemia or stroke, chemical injury, thermal injury, and AIDS.

[0303] In some embodiments, one or more compounds or compositions as described herein are characterized by alleviating one or more symptoms or features of neurodegeneration when administered to a population of subjects. For example, in some embodiments, the relevant symptoms or features may be selected from the degree, rate, and / or time of neuronal damage. In some embodiments, neuronal damage may be or include axonal degradation, synaptic loss, dendritic loss, loss of synaptic density, loss of dendritic arborization, loss of axonal branching, loss of neuronal density, loss of myelination, loss of neuronal cell bodies, 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 ability, loss of axonal potential propagation, neuronal hyperexcitability, and / or neuronal hypoexcitability. In some embodiments, neuronal damage is characterized by the inability to maintain an appropriate resting neuronal membrane potential. In some embodiments, neuronal damage is characterized by the presence of inclusion bodies, plaques, and / or neurofibrillary tangles. In some embodiments, neuronal damage is characterized by the appearance of stress granules. In some embodiments, neuronal damage is characterized by the intracellular activation of one or more members of the cysteine-aspartic protease (caspase) family. In some embodiments, neuronal damage is characterized by neurons undergoing programmed cell death (e.g., apoptosis, pyroptosis, ferroptosis, and / or necrosis) and / or inflammation.

[0304] In some embodiments, the neurodegenerative or neurological disease or disorder is associated with axonal degeneration, axonal injury, axonopathy, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal injury caused by leukoencephalopathy or leukodystrophy. In some embodiments, the neurodegenerative or neurological disease or disorder is selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Pelizaeus-Merzbacher disease, periventricular leukomalacia, globoid 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's disease, Hurler syndrome, traumatic brain injury, post-radiation injury, neurological complications of chemotherapy (chemotherapy-induced neuropathy; CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B 12Deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, glaucoma, Leber hereditary optic neuropathy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, Tembusu virus encephalitis, Bunyavirus encephalitis, viral encephalitis in children, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supranuclear palsy (PSP), Friedrich's ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, severe acute motor axonal neuropathy (AMAN), Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, spinocerebellar ataxia, preeclampsia, hereditary spastic paraplegia, spastic paraparesis, familial spastic paraplegia, French Guiana disease, Strumpell-Lorrain disease, and non-alcoholic steatohepatitis (NASH).

[0305] In some embodiments, the present disclosure provides inhibitors of SARM1 activity for treating neurodegenerative or neurological diseases or disorders involving axonal degeneration or axonopathy. The present disclosure also provides methods of using inhibitors of SARM1 activity to treat, prevent, or ameliorate axonal degeneration, axonopathy, and neurodegenerative or neurological diseases or disorders involving axonal degeneration.

[0306] In some embodiments, the present disclosure provides methods of treating neurodegenerative or neurological diseases or disorders associated with axonal degeneration, axonal injury, axonopathy, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal injury caused by leukodystrophy or leukodystrophy.

[0307] In some embodiments, neuropathies and axonopathies include any disease or disorder involving neurons and / or supporting cells, such as glia, muscle cells, or fibroblasts, particularly those diseases or disorders involving axonal injury. Axonal injury can be caused by traumatic injury or non-mechanical injury caused by a disease, disorder, or exposure to toxic molecules or drugs. The result of such injury can be axonal degeneration or dysfunction and loss of functional neuronal activity. A large number of neurological diseases and disorders result in such axonal injury or are associated therewith. Such neuropathies can include peripheral neuropathies, central neuropathies, and combinations thereof. In addition, peripheral neurological manifestations can be produced by diseases primarily concentrated in the central nervous system, and central nervous system manifestations can be produced by diseases that are primarily peripheral or systemic.

[0308] In some embodiments, peripheral neuropathy can involve injury to the peripheral nerves, and / or can be caused by a neurological disease or as a result of a systemic disease. Some such diseases can include diabetes, uremia, infectious diseases such as AIDS or leprosy, nutritional deficiencies, 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 is caused by traumatic (mechanical) injury to the nerve as well as chemical or thermal injury to the nerve. Conditions that damage the peripheral nerves include compression or nerve crush injuries, such as glaucoma, carpal tunnel syndrome, direct trauma, penetrating injuries, contusions, fractures, or dislocated bones; pressure on superficial nerves (ulnar, radial, or peroneal nerves), which can be caused by prolonged use of a crutch or staying in one position for too long or by a tumor; intraneural hemorrhage; ischemia; exposure to cold or radiation or certain drugs or toxic substances such as herbicides or insecticides. In particular, nerve injury can be caused by chemical injury caused by cytotoxic anti-cancer agents (such as paclitaxel, cisplatin, proteasome inhibitors, or vinca alkaloids such as vincristine). Typical symptoms of such peripheral neuropathy include weakness, numbness, paresthesia (abnormal sensations such as burning, itching, stabbing, or tingling), and pain in the arms, hands, legs, and / or feet. In some embodiments, neuropathy is associated with mitochondrial dysfunction. Such neuropathies can exhibit reduced energy levels, i.e., reduced levels of NAD and ATP.

[0309] In some embodiments, peripheral neuropathy is metabolic and endocrine neuropathy, which includes a broad spectrum of peripheral nerve disorders associated with systemic diseases of metabolic origin. These diseases include, for example, diabetes, hypoglycemia, uremia, hypothyroidism, liver failure, polycythemia, amyloidosis, acromegaly, porphyria, lipid / glycolipid metabolism disorders, nutritional / vitamin deficiencies, and mitochondrial disorders, among others. A common hallmark of these diseases is involvement of the peripheral nerves by altering the structure or function of myelin and axons due to dysregulation of metabolic pathways.

[0310] In some embodiments, the neuropathy includes optic neuropathies such as glaucoma; retinal ganglion degeneration, such as those associated with retinitis pigmentosa and external retinal neuropathy; optic neuritis and / or degeneration, including those associated with multiple sclerosis; traumatic injury to the optic nerve, which can include, for example, injury during tumor resection; hereditary optic neuropathies, such as Kjer disease and Leber hereditary optic neuropathy; ischemic optic neuropathies, such as those secondary to giant cell arteritis; metabolic optic neuropathies, such as neurodegenerative diseases, including the aforementioned Leber neuropathy, nutritional deficiencies such as vitamin B12 or folate deficiency, and toxicities such as those caused by ethambutol or cyanide; neuropathy caused by adverse drug reactions and neuropathy caused by vitamin deficiencies. Ischemic optic neuropathy also includes non-arteritic anterior ischemic optic neuropathy.

[0311] In some embodiments, neurodegenerative diseases associated with neuropathy or axonopathy in the central nervous system include a variety of diseases. These diseases include those involving 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 diseases, and progressive ataxia, such as amyotrophic lateral sclerosis; demyelinating diseases, such as multiple sclerosis; viral encephalitis, such as viral encephalitis caused by enteroviruses, arboviruses, and herpes simplex virus; and prion diseases. Mechanical injuries such as glaucoma or traumatic injuries to the head and spine can also cause nerve damage and degeneration in the brain and spinal cord. In addition, ischemia and stroke, as well as conditions such as nutritional deficiencies and chemical toxicities (e.g., chemotherapeutic agents), can cause central nervous system neuropathy.

[0312] In some embodiments, the present disclosure provides methods for treating a neuropathy or axonopathy associated with axonal degeneration. In some such embodiments, the neuropathy or axonopathy associated with axonal degeneration can be any one of a number of neuropathies or axonopathies, such as those associated with a genetic or congenital condition or Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating diseases, ischemia or stroke, chemical injury, thermal injury, and AIDS. In addition, neurodegenerative diseases not mentioned above and subsets of the above diseases can also be treated by the methods of the present disclosure. Such subsets of diseases can include Parkinson's disease or non-Parkinson's disease or Alzheimer's disease.

[0313] Subject

[0314] In some embodiments, the compounds and / or compositions described herein are administered to a subject having or at risk of having 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.

[0315] In some embodiments, a subject to whom a compound or composition is administered as described herein exhibits one or more signs or symptoms associated with axonal degeneration; in some embodiments, the subject does not exhibit any signs or symptoms of neurodegeneration.

[0316] In some embodiments, the methods provided include administering a compound of Formula I to a patient in need. 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.

[0317] In some embodiments, the methods provided include administering the compositions described herein to a population of patients in need. In some embodiments, the population is from individuals who participate in activities with a high likelihood of traumatic neuronal injury. In some embodiments, the population is from athletes who participate in contact sports or other high-risk activities.

[0318] In some embodiments, a subject is at risk of developing a condition characterized by axonal degeneration. In some embodiments, the subject is identified as being at risk of axonal degeneration, for example, based on the subject's genotype, diagnosis of a condition associated with axonal degeneration, and / or exposure to an agent and / or condition that induces axonal degeneration.

[0319] In some embodiments, the patient is at risk of developing a neurodegenerative disease. In some embodiments, the patient is a middle-aged or elderly individual. 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 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 drawn from a population with a high incidence of neurodegeneration. In some embodiments, the patient has a hexanucleotide repeat expansion in chromosome 9 open reading frame 72. In some embodiments, the patient has one or more copies of the ApoE4 allele.

[0320] In some embodiments, the subject to whom the compounds or compositions described herein are administered can be or include a subject having or predisposed to a neurodegenerative disease, disorder, or condition. In some embodiments, the neurodegenerative disease can be or include traumatic neuronal injury. In some embodiments, the traumatic neuronal injury is blunt force trauma, closed head injury, open head injury, exposure to shock and / or blast forces, penetrating injury to the cranial cavity or innervated regions of the body. In some embodiments, the traumatic neuronal injury is a force that causes axonal deformation, stretching, crushing, or kinking.

[0321] In some embodiments, the subject engages in activities identified as risk factors for neuronal degradation. For example, subjects engaged in contact sports or occupations have a high chance of traumatic neuronal injury.

[0322] For example, the subject can be a patient who is receiving or has been prescribed chemotherapy associated with peripheral neuropathy. Examples of chemotherapeutic agents include, but are 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).

[0323] In some embodiments, the provided method includes 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 provided method further includes monitoring the level of the biomarker in the patient or patient population and adjusting the dosing regimen accordingly.

[0324] Administration

[0325] Those skilled in the art will understand that in some embodiments, the exact amount of a particular compound included in and / or delivered by the pharmaceutical compositions or regimens described herein and / or by administering the pharmaceutical compositions or regimens described herein can be selected by a medical practitioner and can be different for different subjects, e.g., when considering one or more of the species, age, and general condition of the subject and / or the properties of the particular compound or composition, its mode of administration, etc. Alternatively, in some embodiments, the amount of a particular compound included in and / or delivered by the pharmaceutical compositions or regimens described herein and / or by administering the pharmaceutical compositions or regimens described herein can be standardized within a relevant patient population (e.g., all patients, patients of a particular age or disease stage, or all patients expressing a particular biomarker, etc.).

[0326] The compounds or compositions provided by the present disclosure are preferably formulated in unit dosage form for ease of administration and uniform dosing. As used herein, the expression "unit dosage form" refers to physically discrete units of a medicament suitable for the patient to be treated. However, it should be understood that the total daily dosage of the compounds or compositions of the present disclosure provided will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dosage level for 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 disease; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex, and diet of the patient; the time of administration, the site of delivery of the medicament, the route of administration, and the rate of excretion of the specific compound used; the duration of treatment; drugs used in combination with or concurrently 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 determined by these considerations and is the minimum amount required to inhibit SARM1 activity to prevent or treat an undesirable disease or disorder (e.g., neurodegeneration or traumatic nerve injury).

[0327] The pharmaceutically acceptable compositions of the present disclosure can be administered to humans and other animals orally, rectally, intravenously, parenterally, intracisternally, vaginally, intraperitoneally, topically (such as by powder, ointment, or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the disease, disorder, or infection being treated. In certain embodiments, the daily dose is given as a single daily dose or in divided doses two to six times a day or in a sustained release form. The dosage regimen can be adjusted to provide an optimal therapeutic response. The compound can be administered in a regimen of 1 to 4 times a day, preferably once or twice a day.

[0328] In some embodiments, the compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or by an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intraliver, intradermal, intraocular, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0329] In some embodiments, the pharmaceutically acceptable compositions of the present disclosure can also be administered topically, particularly when the treatment target includes areas or organs that are readily accessible to topical administration, including eye, skin, or lower intestinal disorders. For each of these areas or organs, suitable topical formulations are readily prepared.

[0330] Most preferably, the pharmaceutically acceptable compositions of the present disclosure are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present disclosure are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered with food.

[0331] As part of a multi-dose regimen, those additional agents can be administered separately from the provided compound or its composition. Alternatively, those agents can be part of a single dosage form, mixed with the provided compound in a single composition. If administered as part of a multi-dose regimen, the two active agents can be administered simultaneously, sequentially, or at intervals from each other, typically within 5 hours of each other.

[0332] It should also be understood that the specific dosage and treatment regimen for any particular patient can depend on a variety of factors, including the activity of the specific compound used, age, 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 the compound of the present disclosure in the composition will also depend on the specific compound in the composition.

[0333] In some embodiments, the SARM1 inhibition described herein can be used in combination with one or more other therapies to treat related diseases, disorders, or conditions. In some embodiments, the dosage of the SARM1 inhibitor is altered when used in a combination therapy compared to when administered as a single therapy; optionally or additionally, in some embodiments, a therapy administered in combination with the SARM1 inhibition described herein is administered according to a different regimen than when administered alone or in combination with one or more therapies other than SARM1 inhibition. In some embodiments, a composition comprising an additional therapeutic agent, and the additional therapeutic agent and the provided compound can act synergistically. In some embodiments, one or both of the therapies used in the combination regimen are administered at a lower level or at a lower frequency than when used as a single therapy.

[0334] 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

[0335] The teachings, including the descriptions provided in the examples, are not intended to limit the scope of any claims. Unless presented in the past tense specifically, including in the examples is not intended to imply that the experiments were actually conducted. The following non-limiting examples are provided to further illustrate the teachings. Those skilled in the art will understand, in accordance with the present disclosure, that many changes can be made to the specific embodiments disclosed without departing from the spirit and scope of the teachings and still obtain the same or similar results.

[0336] Methods

[0337] Some of the methods and compositions described herein utilize laboratory techniques well known to those skilled 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, N.Y., 2001; Methods In Molecular Biology, ed. Richard, Humana Press, NJ, 1995; Spector, D.L. et al., Cells: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1998; and Harlow, E., Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1999. Methods of administration and dosage regimens of drugs can be determined according to standard principles of pharmacology, using methods provided by standard references such as Remington: the Science and Practice of Pharmacy (Alfonso R. Gennaro ed., 19th ed., 1995); Hardman, J.G. et al., Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th ed., McGraw-Hill, 1996; and Rowe, R.C. et al., Handbook of Pharmaceutical Excipients, 4th ed., Pharmaceutical Press, 2003.

[0338] Example 1: Synthesis of Compounds

[0339] General synthetic methods

[0340] The compounds and their intermediates according to the present invention can be obtained using synthetic methods known to those skilled in the art and described in the organic synthesis literature. Preferably, the compounds are obtained in a manner similar to the preparation methods more fully explained below, particularly as described in the experimental section. In some cases, the order of performing the reaction steps can be varied. Variations of reaction methods known to those skilled in the art but not described in detail herein can also be used.

[0341] The general methods for preparing the compounds of the present invention will become apparent to those skilled in the art studying the following schemes. The starting materials can be prepared by methods described in the literature or herein, or can be prepared in a similar or analogous manner. Any functional groups in the starting materials or intermediates can be protected using conventional protecting groups. These protecting groups can be cleaved again at appropriate stages within the reaction sequence using methods well known to those skilled in the art.

[0342] The optimal reaction conditions and reaction times can vary depending on the specific reactants used. Unless otherwise stated, those of ordinary skill in the art can readily select the solvent, temperature, pressure, and other reaction conditions. Specific methods are provided in the synthetic examples section. The intermediates and products can be purified by silica gel chromatography, recrystallization, and / or reverse-phase HPLC (RP-HPLC). Discrete enantiomers can be obtained by resolving the racemic products using chiral HPLC. The RP-HPLC purification method uses an aqueous solution of 0 - 100% acetonitrile containing 0.1% formic acid, 0.1 - 0.01% TFA, 10 mM ammonium bicarbonate aqueous solution, or 0.2% ammonium hydroxide aqueous solution in any case, and uses one of the following columns:

[0343] Waters Xbridge C18 10μm 30x100mm column

[0344] Waters Sunfire C18 10μm 30x100mm column

[0345] Waters Xbridge C18 3.5μm 50x4.6mm column

[0346] HALO C18 2.7μm 30x4.6mm column

[0347] Waters Sunfire C18 3.5μm 50x4.6mm column

[0348] Synthesis of exemplary compounds

[0349] Method A: Synthesis of I-1

[0350]

[0351] Add R-2 (2.0 g, 9.22 mmol, 1.00 eq) and R-1 (1.29 g, 9.22 mmol, 1.00 eq) to a flask, and then purge with N2 three times. Add the solvent EtOH (30 mL) to the flask, and cool the mixture to 0 °C in an ice bath. Add dropwise an aqueous solution of NaOH (554 mg, 13.83 mmol, 1.50 eq) in H2O (8 mL). After the addition is complete, stir the reaction mixture at 0 °C for 20 min, and then warm to room temperature for 1 h. Monitor the progress of the reaction by LCMS. After the reaction is complete, filter the reaction mixture to collect the solid, wash it three times with brine, and dry it to obtain Int-1 (2.75 g, 88%).

[0352] To a solution of Int-1 (1 g, 2.90 mmol), pyridin-4-ylboronic acid (541.2 mg, 4.4 mmol), dioxane (10 mL), and H2O (1.5 mL), add PdCl2(dppf) (212 mg, 0.29 mmol) and K2CO3 (1.2 g, 8.7 mmol, 3 eq). Stir the mixture at 110 °C in a N2 atmosphere for 2 h. Monitor the progress of the reaction by LCMS. After the reaction is complete, treat the mixture with H2O (20 mL), extract with EtOAc (20 mL x 3), wash with an aqueous NaCl solution, and dry with Na2SO4. Concentrate the organic layer and purify it by flash chromatography (SiO2, petroleum ether / ethyl acetate, v / v, 4 / 5) to obtain Int-2 (700 mg, 70%).

[0353] To a solution of Int-2 (500 mg, 1.48 mmol) in THF (10 mL), add 10% Pd / C (50 mg), and then stir the reaction mixture at 25 °C in a H2 atmosphere for 1 h. Monitor the progress of the reaction by LCMS and TLC. Filter the reaction solution to remove the solid, collect the filtrate, and concentrate it under reduced pressure to obtain a residue. Purify it by flash chromatography (SiO2, petroleum ether / ethyl acetate, v / v, 1 / 1) to obtain Int-3 (250 mg, 50%).

[0354] To a solution of Int-3 (150 mg, 0.44 mmol) in DMSO (3 mL), add hydrazine hydrate (119.46 mg, 2.21 mmol), and then stir the mixture at 120 °C for 16 h. Monitor the progress of the reaction by LCMS. Purify the reaction solution by preparative-HPLC to obtain the title compound I-1 (82.5 mg, 56%).

[0355] Method B: Synthesis of I-2

[0356]

[0357] Add R-2 (2.0 g, 9.22 mmol, 1.00 eq), R-1 (1.31 g, 9.22 mmol, 1.00 eq) and MeOH (30 mL) to a flask. Cool the flask to 0 °C and treat with NaOH (554 mg, 13.83 mmol, 1.50 eq) dissolved in H2O (8 mL) by dropping into the above mixture. After the addition is complete, stir the reaction mixture at 0 °C for 20 min, then warm to room temperature and stir for 2 h. Monitor the progress of the reaction by LCMS. Filter the reaction mixture, wash with brine, collect the filter cake, dry to obtain Int-4 (1.1 g, 36%).

[0358] Add Pd(dppf)Cl2 (235 mg, 0.33 mmol), K2CO3 (1.37 g, 9.91 mmol) and pyridin-4-ylboronic acid (487 mg, 3.96 mmol) to a mixture of Int-4 (1.1 g, 3.30 mmol) in dioxane (15 mL) and H2O (3 mL). Degas the mixture three times with N2 and stir at 110 °C for 16 h. Monitor the progress of the reaction by LCMS. Dilute the reaction mixture with water and EtOAc. Separate the mixture and extract the aqueous phase twice with EtOAc. Dry the combined organic layers, filter and concentrate in vacuo to obtain a crude product, which is purified by flash chromatography (SiO2, petroleum ether / ethyl acetate, v / v = 2:1) to obtain Int-5 (700 mg, crude product).

[0359] Add 10% Pd / C (300 mg) to a solution of Int-5 (650 mg, 1.92 mmol) in THF (20 mL) and MeOH (2 mL), then stir the resulting mixture at room temperature under H2 protection for 2 h. Monitor the progress of the reaction by LCMS. Filter the reaction mixture to remove palladium, concentrate the filtrate, and then purify by flash chromatography (SiO2, petroleum ether / ethyl acetate, v / v, 1 / 1) to obtain Int-6 (340 mg, 42%).

[0360] Add tert-butyl hydrazinecarboxylate (174 mg, 1.32 mmol) to a mixture of Int-6 (150 mg, 0.35 mmol) in MeOH (3 mL) and AcOH (0.5 mL). Then stir the resulting mixture at 100 °C for 2 h. Monitor the progress of the reaction by LCMS. Concentrate the reaction mixture, dilute with water (5 mL), and extract twice with EtOAc (10 mL). Dry the combined organic layers with MgSO4, filter, and concentrate in vacuo to obtain a crude product, which is purified by flash chromatography (SiO2, petroleum ether / ethyl acetate, v / v, 1 / 1) to obtain the Boc-hydrazine compound (200 mg, 65% purity, 81%).

[0361] The Boc-hydrazine compound (150 mg, 65% purity, 0.21 mmol) in DBU (2 mL) in a sealed vial was heated at 150 °C under microwave conditions for 30 min. The progress of the reaction was monitored by LCMS and TLC. The reaction mixture was diluted with water (10 mL) and extracted 3 times with EtOAc (15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (SiO2, dichloromethane / methanol 99 / 1 - 5 / 1) to give the crude product, which was further purified by preparative-HPLC to give the title compound I-2 (14.5 mg, 21%).

[0362] Example 2. Characterization of the compound

[0363] LCMS method:

[0364] Analytical LC / MS analysis method A:

[0365] ESI+ / - ion mode 100 - 1000 Da

[0366] Column: XBridge SB-C18, 3.5 μm 4.6 x 50 mm

[0367] Temperature: 40 °C

[0368] Gradient:

[0369] Time (min) 10 mM aqueous ammonium bicarbonate solution Acetonitrile Flow rate (mL / min) 0.00 95％ 5％ 2.0 1.40 5％ 95％ 2.0 3.00 5％ 95％ 2.0

[0370] Analytical LC / MS analysis method B:

[0371] ESI+ / - ion mode 100 - 1000 Da

[0372] Column: XBridge SB-C18, 3.5 μm 4.6 x 50 mm

[0373] Temperature: 40 °C

[0374] Gradient:

[0375] Time (min) Water (0.05% TFA) Acetonitrile (0.05% TFA) Flow rate (mL / min) 0 95％ 5％ 2.0 1.3 5％ 95％ 2.0 4.2 5％ 95％ 2.0

[0376] The results are shown in Table 1:

[0377] Table 1.

[0378] Compound LCMS method RT (min) Molecular ion (m / z) I-1 B 1.36 334.9 I-2 A 1.58 333.9

[0379] Example 3: ARM-SAM-TIR SARM1 IC50 determination

[0380] This example describes the determination of ARM-SAM-TIR NADase activity and the use of this determination to measure the efficacy of compounds of formula I in blocking SARM1-mediated NAD+ cleavage. The assay was optimized to characterize the efficacy of compounds of formula I in inhibiting SARM1 activity and to calculate the IC50 value for each compound. The assay utilizes full-length SARM1, which contains ARM, SAM, and TIR domains. As demonstrated herein, expression of this fragment without the autoinhibitory N-terminal domain produces a constitutively active enzyme that cleaves NAD+.

[0381] Preparation of ARM-SAM-TIR lysate (STL)

[0382] NRK1-HEK 293T cells were seeded at 20 × 106 cells per plate into 150 cm 2 plates. The next day, the cells were transfected with 15 μg of the ARM-SAM-TIR expression plasmid SEQ ID NO:1.

[0383]

[0384]

[0385]

[0386]

[0387] At the time of transfection, the cultures were supplemented with 1 mM NR to minimize toxicity from ARM-SAM-TIR overexpression. Forty-eight hours after transfection, the 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). The cells were resuspended in PBS containing protease inhibitor (cOmplete TM Protease Inhibitor Cocktail, Roche product #11873580001) and cell lysates were prepared by sonication (Branson Sonifer 450, output = 3, 20 episodes of stroke). The lysates were centrifuged (12,000 × g for 10 min at 4 °C) to remove cell debris, and the supernatant (containing ARM-SAM-TIR protein) was stored at -80 °C for later use in the in vitro ARM-SAM-TIR NADase assay (see below). Protein concentration was determined by the Bicinchoninic (BCA) method and used to calibrate the lysate concentration.

[0388] ARM-SAM-TIR IC50 assay of compounds of formula I

[0389] Enzyme assays were performed in Dulbecco's PBS buffer in 384-well polypropylene plates 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 a substrate. After incubation at room temperature for 2 h, the reaction was terminated with 40 μL of a 7.5% trichloroacetic acid solution in acetonitrile. NAD⁺ and ADPR concentrations were analyzed using an API 4000 triple quadrupole mass spectrometer (AB Sciex, Framingham, MA) via a RapidFire high-throughput mass spectrometry system (Agilent Technologies, Santa Clara, CA).

[0390] The results are shown in Table 2 below. Compounds with the designated activity "A" have an IC 50 < 50 nM; compounds with the designated activity "B" have an IC 50 51 - 100 nM; compounds with the designated activity "C" have an IC 50 101 - 500 nM; compounds with the designated activity "D" have an IC 50 501 - 1000 nM; compounds with the designated activity "E" have an IC 50 > 1000 nM; nd: not determined.

[0391] Table 2.

[0392] Compound <![CDATA[SARM1 IC 50 (nM)]]> I-1 C I-2 C

[0393] Example 4: Axonal degeneration index

[0394] This example illustrates an in vitro axonal mutagenicity assay for characterizing compounds of Formula I. This assay is used to test the efficacy of compounds of Formula I in preventing axonal mutagenesis in mouse dorsal root ganglion (DRG) explant cultures.

[0395] Mouse DRG hanging drop culture: Mouse dorsal root ganglion neurons were dissected from E12.5 CD1 mice (50 ganglia per embryo) and incubated with 0.5% trypsin solution (Gibco) containing 0.02% EDTA at 37 °C for 15 min. The cells were then triturated by gentle pipetting and washed 3 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). The cells were suspended in DRG growth medium. DRG hanging drop cultures were generated by spotting 5000 cells / well onto 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). The cells were allowed to adhere to the plate in a humidified tissue culture incubator (5% CO2) for 15 min, and then DRG growth medium (100 μL / well) was gently added.

[0396] Axonal degeneration assay: Axonal degeneration was induced by manual axotomy using a scalpel blade or chemical toxic stimulation. After the appropriate experimental time period, the DRG cultures were fixed in 1% PFA + sucrose and kept in the refrigerator until imaging. Bright-field images of DRG axons and cell bodies were collected using a 20x water immersion lens of a Phenix automated confocal microscope (PerkinElmer), and axons were quantified using an in-house developed protocol (Acapella, PerkinElmer). Sequence Listing <110> DisArm Therapeutics, Inc <120> SARM1 Inhibitor <130> X22937 <150> 63 / 122682 <151> 2020-12-08 <160> 1 <170> PatentIn version 3.5 <210> 1 <211> 6514 <212> DNA <213> Artificial Sequence <220> <223> Chemically Synthesized Nucleotides <400> 1 gcgatcgcgg ctcccgacat cttggaccat tagctccaca ggtatcttct tccctctagt 60 gcgatcgcgg ctcccgacat cttggaccat tagctccaca ggtatcttct tccctctagt 60 ggtcataaca gcagcttcag ctacctctca attcaaaaaa cccctcaaga cccgtttaga 120 ggtcataaca gcagcttcag ctacctctca attcaaaaaa cccctcaaga cccgtttaga 120 ggccccaagg ggttatgcta tcaatcgttg cgttacacac acaaaaaacc aacacacatc 180 ggccccaagg ggttatgcta tcaatcgttg cgttacacac acaaaaaacc aacacacatc 180 catcttcgat ggatagcgat tttattatct aactgctgat cgagtgtagc cagatctagt 240 catcttcgat ggatagcgat tttattatct aactgctgat cgagtgtagc cagatctagt 240 aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 300 aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 300 cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 360 cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 360 cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 420 cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 420 tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt acgcccccta 480 tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt acgcccccta 480 ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttatggg 540 ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttatggg 540 actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg ctgatgcggt 600 actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg ctgatgcggt 600 tttggcagta catcaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 660 tttggcagta catcaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 660 accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 720 accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 720 gtcgtaacaa ctccgcccca ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct 780 atataagcag agctggttta gtgaaccgtc agatcagatc tttgtcgatc ctaccatcca 840 ctcgacacac ccgccagcgg ccgctgccaa gcttccgagc tctcgaattc aaaggaggta 900 cccaccatgg ccatgcatca ccaccaccat catagctccg gcgtcgacct cggcaccgag 960 aatttatatt tccaaagcgg cctcaatgat atcttcgagg cccagaagat cgagtggcac 1020 gagggcagct ccgacctcgc cgtgcccggt cccgatggag gcggaggcac tggtccttgg 1080 tgggctgctg gcggcagagg ccctagagaa gtgagccccg gtgctggcac cgaggtgcaa 1140 gacgctctgg agagggctct gcccgaactg cagcaagctc tgtccgcttt aaagcaagct 1200 ggaggagcta gagccgtcgg cgccggactg gccgaagtgt tccagctcgt ggaggaagct 1260 tggttattac ccgctgtggg aagagaggtc gcccaaggtc tgtgtgacgc cattcgtctg 1320 gacggaggtt tagacttatt actgaggctg ctgcaagctc ccgaactgga gacaagggtc 1380 caagctgctc gtctgctgga gcagatcctc gtggccgaga atcgtgacag agtggctaga 1440 atcggtttag gcgtcatcct caatttagcc aaagagaggg agcccgttga gctggccaga 1500 agcgtcgctg gcatcctcga gcacatgttc aagcattccg aggagacttg tcagagactg 1560 gtcgccgccg gaggactcga tgctgtttta tactggtgca gaaggacaga ccccgcttta 1620 ctgaggcatt gtgctctggc cctcggcaat tgcgctttac atggaggcca agccgtccag 1680 agaaggatgg tggagaaaag agccgccgag tggctgttcc ctttagcctt ctccaaagaa 1740 gacgaactgt tacgtctgca tgcttgtctc gctgtcgctg ttttagccac caacaaggag 1800 gtggaaaggg aagtggaaag aagcggaaca ctggctttag tcgaacctct ggtggcttct 1860 ttagatcccg gaaggtttgc cagatgtctg gtcgacgcca gcgatacctc ccaaggaaga 1920 ggccccgacg atctccagag actggtgcct ctgctggaca gcaatcgtct ggaggcccaa 1980 tgtattggcg ccttctatct ctgcgccgaa gccgccatca agtctttaca aggtaagacc 2040 aaggtgttct ccgacattgg agccatccaa tctttaaaga ggctggtgag ctattccacc 2100 aacggcacaa aaagcgcttt agccaaaaga gctttaagac tgctgggcga agaggtgcct 2160 aggcccattt taccttccgt gcctagctgg aaggaggccg aggtgcagac ttggctgcag 2220 cagatcggct ttagcaaata ttgcgaatcc tttagggagc agcaagttga cggcgattta 2280 ttattaaggc tgaccgagga agagctccag acagatttag gcatgaaaag cggcatcact 2340 cgtaagaggt tctttcgtga gctcaccgaa ctgaagacct tcgccaacta ctccacttgt 2400 gatcgtagca atttagctga ttggctcgga tccctcgatc ccagatttcg tcagtacacc 2460 tatggactcg tctcttgtgg actggacaga tctttactgc atcgtgtgag cgagcaacag 2520 ctgctggaag attgcggcat ccatttagga gtgcacagag ccagaattct gaccgccgct 2580 agagagatgc tgcattcccc tctcccttgt accggaggca agcctagcgg agacaccccc 2640 gacgtgttca tcagctatcg tagaaacagc ggaagccagc tggcctcttt actgaaggtc 2700 catttacagc tgcacggatt tagcgtcttc atcgacgtgg agaaactgga ggctggcaag 2760 ttcgaggaca agctgatcca gtccgtgatg ggcgctagga atttcgtttt agtgctcagc 2820 cccggcgctc tggataaatg catgcaagat catgactgta aggactgggt ccacaaggaa 2880 atcgtgaccg ctctgtcttg tggcaagaac atcgtcccca tcatcgacgg cttcgaatgg 2940 cccgagcctc aagttctccc cgaagatatg caagctgttt taaccttcaa tggaatcaag 3000 tggagccacg agtaccaaga agccacaatc gagaagatca ttcgttttct gcaaggtaga 3060 tcctccagag attcctccgc tggcagcgac acatctttag agggcgccgc ccctatgggt 3120 cctacctaat aatctagaag ttgtctcctc ctgcactgac tgactgatac aatcgatttc 3180 tggatccgca ggcctctgct agcttgactg actgagatac agcgtacctt cagctcacag 3240 acatgataag atacattgat gagtttggac aaaccacaac tagaatgcag tgaaaaaaat 3300 gctttatttg tgaaatttgt gatgctattg ctttatttgt aaccattata agctgcaata 3360 aacaagttaa caacaacaat tgcattcatt ttatgtttca ggttcagggg gaggtgtggg 3420 aggtttttta aagcaagtaa aacctctaca aatgtggtat tggcccatct ctatcggtat 3480 cgtagcataa ccccttgggg cctctaaacg ggtcttgagg ggttttttgt gcccctcggg 3540 ccggattgct atctaccggc attggcgcag aaaaaaatgc ctgatgcgac gctgcgcgtc 3600 ttatactccc acatatgcca gattcagcaa cggatacggc ttccccaact tgcccacttc 3660 catacgtgtc ctccttacca gaaatttatc cttaaggtcg tcagctatcc tgcaggcgat 3720 ctctcgattt cgatcaagac attcctttaa tggtcttttc tggacaccac taggggtcag 3780 aagtagttca tcaaactttc ttccctccct aatctcattg gttaccttgg gctatcgaaa 3840 cttaattaac cagtcaagtc agctacttgg cgagatcgac ttgtctgggt ttcgactacg 3900 ctcagaattg cgtcagtcaa gttcgatctg gtccttgcta ttgcacccgt tctccgatta 3960 cgagtttcat ttaaatcatg tgagcaaaag gccagcaaaa ggccaggaac cgtaaaaagg 4020 ccgcgttgct ggcgtttttc cataggctcc gcccccctga cgagcatcac aaaaatcgac 4080 gctcaagtca gaggtggcga aacccgacag gactataaag ataccaggcg tttccccctg 4140 gaagctccct cgtgcgctct cctgttccga ccctgccgct taccggatac ctgtccgcct 4200 ttctcccttc gggaagcgtg gcgctttctc atagctcacg ctgtaggtat ctcagttcgg 4260 tgtaggtcgt tcgctccaag ctgggctgtg tgcacgaacc ccccgttcag cccgaccgct 4320 gcgccttatc cggtaactat cgtcttgagt ccaacccggt aagacacgac ttatcgccac 4380 tggcagcagc cactggtaac aggattagca gagcgaggta tgtaggcggt gctacagagt 4440 tcttgaagtg gtggcctaac tacggctaca ctagaagaac agtatttggt atctgcgctc 4500 tgctgaagcc agttaccttc ggaaaaagag ttggtagctc ttgatccggc aaacaaacca 4560 ccgctggtag cggtggtttt tttgtttgca agcagcagat tacgcgcaga aaaaaaggat 4620 ctcaagaaga tcctttgatc ttttctacgg ggtctgacgc tcagtggaac gaaaactcac 4680 gttaagggat tttggtcatg agattatcaa aaaggatctt cacctagatc cttttaaatt 4740 aaaaatgaag ttttaaatca atctaaagta tatatgagta aacttggtct gacagttacc 4800 aatgcttaat cagtgaggca cctatctcag cgatctgtct atttcgttca tccatagttg 4860 catttaaatt tccgaactct ccaaggccct cgtcggaaaa tcttcaaacc tttcgtccga 4920 tccatcttgc aggctacctc tcgaacgaac tatcgcaagt ctcttggccg gccttgcgcc 4980 ttggctattg cttggcagcg cctatcgcca ggtattactc caatcccgaa tatccgagat 5040 cgggatcacc cgagagaagt tcaacctaca tcctcaatcc cgatctatcc gagatccgag 5100 gaatatcgaa atcggggcgc gcctggtgta ccgagaacga tcctctcagt gcgagtctcg 5160 acgatccata tcgttgcttg gcagtcagcc agtcggaatc cagcttggga cccaggaagt 5220 ccaatcgtca gatattgtac tcaagcctgg tcacggcagc gtaccgatct gtttaaacct 5280 agatattgat agtctgatcg gtcaacgtat aatcgagtcc tagcttttgc aaacatctat 5340 caagagacag gatcagcagg aggctttcgc atgagtattc aacatttccg tgtcgccctt 5400 attccctttt ttgcggcatt ttgccttcct gtttttgctc acccagaaac gctggtgaaa 5460 gtaaaagatg ctgaagatca gttgggtgcg cgagtgggtt acatcgaact ggatctcaac 5520 agcggtaaga tccttgagag ttttcgcccc gaagaacgct ttccaatgat gagcactttt 5580 aaagttctgc tatgtggcgc ggtattatcc cgtattgacg ccgggcaaga gcaactcggt 5640 cgccgcatac actattctca gaatgacttg gttgagtatt caccagtcac agaaaagcat 5700 cttacggatg gcatgacagt aagagaatta tgcagtgctg ccataaccat gagtgataac 5760 actgcggcca acttacttct gacaacgatt ggaggaccga aggagctaac cgcttttttg 5820 cacaacatgg gggatcatgt aactcgcctt gatcgttggg aaccggagct gaatgaagcc 5880 ataccaaacg acgagcgtga caccacgatg cctgtagcaa tggcaacaac cttgcgtaaa 5940 ctattaactg gcgaactact tactctagct tcccggcaac agttgataga ctggatggag 6000 gcggataaag ttgcaggacc acttctgcgc tcggcccttc cggctggctg gtttattgct 6060 gataaatctg gagccggtga gcgtgggtct cgcggtatca ttgcagcact ggggccagat 6120 ggtaagccct cccgtatcgt agttatctac acgacgggga gtcaggcaac tatggatgaa 6180 cgaaatagac agatcgctga gataggtgcc tcactgatta agcattggta accgattcta 6240 ggtgcattgg cgcagaaaaa aatgcctgat gcgacgctgc gcgtcttata ctcccacata 6300 tgccagattc agcaacggat acggcttccc caacttgccc acttccatac gtgtcctcct 6360 taccagaaat ttatccttaa gatcccgaat cgtttaaact cgactctggc tctatcgaat 6420 ctccgtcgtt tcgagcttac gcgaacagcc gtggcgctca tttgctcgtc gggcatcgaa 6480 tctcgtcagc tatcgtcagc ttaccttttt ggca 6514

Claims

1. Compound: or a pharmaceutically acceptable salt thereof, wherein: L is a saturated C 1-4 aliphatic chain; R 1 is an optionally halogen-substituted 6-membered heteroaryl having 1 to 2 nitrogen heteroatoms; R 2 is an optionally halogen-substituted phenyl or an optionally halogen-substituted 6-membered heteroaryl having 1 to 2 nitrogen heteroatoms; n is 0.

2. The compound of claim 1, wherein L is or a pharmaceutically acceptable salt thereof.

3. The compound according to any one of claims 1-2, wherein R 1 is selected from: or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1-2, wherein R 2 is selected from: or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1-2, which is: or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5, which is:

7. The compound according to any one of claims 1-2, which is: or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7, which is:

9. A pharmaceutical composition comprising the compound according to any one of claims 1-8 and a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disorder characterized by axonal degeneration or for reducing the risk of developing a disorder characterized by axonal degeneration in a subject in need thereof.

11. Use of the compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing axonal degeneration in a subject in need thereof.

12. A non-therapeutic or non-diagnostic method of inhibiting SARM1, comprising contacting a biological sample with the compound according to any one of claims 1-8.

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