SARM1 inhibitor

Abstract

The present disclosure provides compounds and methods that can be used to inhibit SARM1 and / or treat and / or prevent axonal degeneration.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 861,501, filed on June 14, 2019, the entire content of which is incorporated herein by reference.

[0003] Sequence Listing

[0004] This application contains a sequence listing, which has been electronically submitted in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy was created on June 10, 2020, named 2012800 - 0037_SL.txt, and is 8,858 bytes in size. Background of the Invention

[0006] Axon 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 nicotinamide adenine dinucleotide (NAD+) destruction, Science 348 2016, pages 453 - 457, which is incorporated herein by reference in its entirety). Neurodegenerative diseases and injuries are devastating to patients and caregivers. Currently, in the United States alone, the costs associated with these diseases exceed hundreds of billions of dollars annually. Since the incidence of most of these diseases and disorders increases with age, their incidence is increasing rapidly with the changing demographics. Summary of the Invention

[0008] The present disclosure provides techniques that can be used to treat and / or prevent neurodegeneration (e.g., for reducing axon degeneration), etc. In some embodiments, the provided techniques inhibit SARM1.

[0009] 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 axon degeneration).

[0010] In some embodiments, the present disclosure provides compounds having the structure shown in Formula I:

[0011]

[0012] or a pharmaceutically acceptable salt thereof, wherein:

[0013] X 1 is N or C - R x1;

[0014] X 2 is N or C-R x2 ;

[0015] X 3 is N or C-R x3 ;

[0016] X 4 is N or C-R x4 ;

[0017] Provided that X 1 , X 2 , X 3 and X 4 one or two of which are N;

[0018] R x1 , R x2 , R x3 and R x4 each independently selected from -R or -OR;

[0019] L 1 is selected from a covalent bond, -O-, -N(R)-, -C(O)N(R)-, -S(O)2- and -S(O)2N(R)-;

[0020] L 2 is selected from a covalent bond, -O-, -N(R)-, -N(R)C(O)- and -N(R)S(O)2-;

[0021] R 1 is selected from halogen, CN and -R;

[0022] R 2 is -R; and

[0023] R is selected from hydrogen or an optionally substituted group selected from C 1-6 aliphatic group, phenyl, a 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, and an 8-10 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0024] In some embodiments, the provided compounds have the structures of Formulas I-a, I-a-i, I-a-ii, I-a-iii, I-a-iv, I-a-v, I-b, I-b-i, I-b-ii, I-b-iii, I-b-iv, I-b-v, I-c, I-c-i, I-c-ii, I-c-iii, I-c-iv and I-c-v as described herein.

[0025] In some embodiments, one or more compounds of Formula I are provided and / or used in solid form (e.g., crystalline form or amorphous form).

[0026] In some embodiments, the present disclosure provides compositions that comprise and / or deliver a compound of Formula I (e.g., in a form as described herein), a prodrug thereof, or an active metabolite.

[0027] In some embodiments, the present disclosure provides a composition that comprises and / or delivers a compound of Formula I. In some embodiments, the composition is a pharmaceutical composition that comprises at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0028] 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 in a pocket that comprises one or more catalytic residues (e.g., the catalytic cleft of SARM1).

[0029] 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.

[0030] In some embodiments, one or more of the compounds and / or compositions described herein can be used, for example, in pharmaceutical practice. 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 of its characteristics or properties). In some embodiments, one or more of the compounds and / or compositions 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 of the compounds and / or compositions described herein can be used, for example, to prevent axonal degeneration distal to axonal injury.

[0031] In some embodiments, one or more of the compounds and / or compositions 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 of the compounds and / or compositions 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 (ALS), demyelinating diseases, ischemia or stroke, chemical injury, thermal injury, and AIDS.

[0032] In some embodiments, the individual to whom the compounds or compositions described herein are administered can be or include an individual having or at risk of having a neurodegenerative disease, condition, or disorder. In some embodiments, the neurodegenerative disease, disorder, or condition 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, or penetrating injury within or to the body's cranial cavity or innervated regions. In some embodiments, the traumatic neuronal injury is a force that causes axonal deformation, stretching, crushing, or shearing.

[0033] In some embodiments, the provided method includes administering a compound 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.

[0034] In some embodiments, the provided method includes administering a composition as described herein to a group of patients in need thereof. In some embodiments, the group is selected from individuals engaged in activities with a high likelihood of traumatic neuronal injury. In some embodiments, the group is selected from athletes engaged in contact sports or other high-risk activities.

[0035] 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.

[0036] In certain embodiments, the present disclosure provides compounds that are useful as, for example, analytical tools, probes in biassays, or therapeutic agents according to the present disclosure. The compounds provided by the present disclosure can also be used to study the function of SARM1 in biological and pathological phenomena and to comparatively evaluate new SARM1 activity inhibitors in vitro or in vivo.

[0037] In some embodiments, one or more of the compounds and / or compositions described herein can be used, for example, as a method of inhibiting the degradation of neurons derived from an individual. In some embodiments, one or more of the compounds and / or compositions 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 described herein can be used as a stabilizer to promote neuron survival in vitro. Brief Description of the Drawings

[0039] Figure 1 Illustrates the structure of the SARM1 protein.

[0040] Definitions

[0041] Aliphatic: The term "aliphatic" 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 "alicyclic"), having a single point of attachment to the remainder of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (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, having a single point of attachment to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and their hybrids.

[0042] Alkyl: The term "alkyl," used alone or as part of a larger structural moiety, refers to a saturated, optionally substituted, straight-chain or branched 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 of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0043] 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 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 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 for substituted aliphatic groups below and also those described in this specification. It should be understood that two substituents on the alkylene group can combine together to 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.

[0044] Alkenyl: The term "alkenyl", used alone or as part of a larger structural 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 containing at least one carbon-carbon double bond and having from about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentyl, cyclohexenyl, and cycloheptenyl.

[0045] Alkynyl: The term "alkynyl", used alone or as part of a larger structural 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.

[0046] Aryl: The term "aryl" refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the ring system is aromatic and wherein each ring in the ring system contains three to seven ring members. The term "aryl" can be used interchangeably with the term "aromatic ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, anthracenyl, etc., which may bear one or more substituents. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic carbocyclic or heterocyclic rings, such as indanyl, phthalimido, naphthalimido, phenanthridinyl, tetrahydronaphthyl, imidazolidinyl, imidazolidin-2-one, etc.

[0047] 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 groups; indirect binding involves physical interaction by way of 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 where the interacting entities or groups are studied alone or in a more complex system (such as when covalently or otherwise bound to a carrier entity and / or when in a biological system or cell).

[0048] Biological sample: As used herein, the term "biological sample" generally refers to a sample obtained or derived from a biological source of interest (such as tissue or an organism or cell culture), as described herein. In some embodiments, the source of interest includes an organism, such as an animal or a human. In some embodiments, the biological sample is or comprises a 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; cell-containing body fluids; free-floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; wash or lavage fluids, such as catheter lavage or bronchoalveolar lavage fluid; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and / or excretions; and / or cells therein, etc. In some embodiments, the biological sample is or comprises cells obtained from an individual. In some embodiments, the cells obtained are or include cells from the individual from whom the sample was obtained. In some embodiments, the sample is an "original sample" obtained directly from the source of interest by any suitable means. For example, in some embodiments, the original biological sample is obtained by a method selected from biopsy (such as fine needle aspiration or tissue biopsy), surgery, body fluid collection (such as blood, lymph fluid, feces, etc.). In some embodiments, as will be clear from the context, the term "sample" refers to an article obtained by processing the original sample (such as by removing one or more components and / or by adding one or more substances). For example, filtration using a semipermeable membrane. The "processed sample" can include, for example, nucleic acids or proteins extracted from the sample or obtained by subjecting the original sample to techniques such as amplification or mRNA reverse transcription, separation and / or purification of certain components.

[0049] 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 specific biological event or state of interest, such that it is considered a "marker" of said event or state. By way of just a few examples, in some embodiments, a biomarker can be or include a marker for a particular disease state or a marker for the likelihood of development, occurrence, or recurrence of a particular disease, disorder, or condition. In some embodiments, a biomarker can be or include a marker for a particular disease or its treatment outcome or the likelihood thereof. Thus, in some embodiments, a biomarker predicts a relevant biological event or state of interest, in some embodiments, a biomarker prognosticates a relevant biological event or state of interest, and in some embodiments, a biomarker diagnoses 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 substance (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 outside the cell, such as a biomarker that is secreted or otherwise produced or present outside the cell, for example, in a body fluid such as blood, urine, tears, saliva, cerebrospinal fluid, etc. In some embodiments, a biomarker can be or include a gene or an epigenetic signature. In some embodiments, a biomarker can be or include a gene expression signature.

[0050] In some embodiments, a biomarker can be or include a marker for neurodegeneration or a marker for the likelihood of development, occurrence, or recurrence of a neurodegenerative disease, disorder, or condition. In some embodiments, a biomarker can be or include a marker for a neurodegenerative treatment outcome or the likelihood thereof. Thus, in some embodiments, a biomarker predicts a neurodegenerative disease, disorder, or condition; in some embodiments, a biomarker prognosticates a neurodegenerative disease, disorder, or condition; and in some embodiments, a biomarker diagnoses a neurodegenerative disease, disorder, or condition. In some embodiments, changes in biomarker levels can be detected in cerebrospinal fluid (CSF), plasma, and / or serum.

[0051] In some embodiments, neurodegeneration can be evaluated, for example, by detecting an increase and / or decrease in the concentration of neurofilament light (NF-L) and / or neurofilament heavy (NF-H) contained in the cerebrospinal fluid of an individual. In some embodiments, the occurrence and / or progression of neurodegeneration can be evaluated by positron emission tomography (PET) with 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.

[0052] In some embodiments, detectable changes in one or more neurodegeneration-related proteins of an individual can be used as biomarkers for neurodegeneration relative to a healthy reference population. The 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, phosphorylated-tau, and / or total-tau. In some embodiments, an increase in cytokines and / or chemokines can be used as a biomarker for neurodegeneration, the cytokines and / or chemokines including, but not limited to, Ccl2, Ccl7, Ccl12, Csf1, and / or Il6.

[0053] Vehicle: As used herein, the term "vehicle" refers to a diluent, adjuvant, excipient, or solvent that is administered together 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 comprises one or more solid components.

[0054] Combination Therapy: As used herein, the term "combination therapy" refers to those situations in which an individual is simultaneously exposed to two or more treatment regimens (e.g., two or more therapeutic agents). In some embodiments, the two or more regimens can be administered simultaneously; in some embodiments, such regimens can be administered sequentially (e.g., all "doses" of the first regimen are administered before any dose of the second regimen); in some embodiments, such active agents are administered in an overlapping dosing regimen. In some embodiments, the "administration" of a combination therapy can involve administering one or more active agents or therapies to an individual who is receiving one or more other active agents or therapies in the combination. For clarity, combination therapy does not require that the individual agents be administered together (or even necessarily simultaneously) in a single composition, although in some embodiments, two or more agents or their active moieties can be administered together in a combined composition, or even together in a combined compound (e.g., as part of a single chemical complex or covalent entity).

[0055] 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.

[0056] Domain: The term "domain" as used herein refers to a fragment 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 comprise a portion of an entity that, when separated from the (parent) entity and linked to a different (receiving) entity, substantially retains and / or confers on the receiving entity one or more structural and functional characteristics that are characteristic of its properties in the parent entity. In some embodiments, a domain is a fragment or portion of a molecule (e.g., a small molecule, carbohydrate, lipid, nucleic acid, or polypeptide). In some embodiments, a domain is a fragment 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 characteristics, β-sheet characteristics, coiled-coil characteristics, random coil characteristics, etc.) and / or by specific functional characteristics (e.g., binding activity, enzymatic activity, folding activity, signaling activity, etc.).

[0057] 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 substance (such as a therapeutic or diagnostic substance) for administration to an individual. Generally, each such unit contains a predetermined amount of the active substance. In some embodiments, the amount is an amount that is a unit dose (or a whole part thereof) suitable for administration according to a dosing regimen, which, when administered to a relevant population (i.e., with a therapeutic dosing regimen), has been determined to be associated with an expected or beneficial outcome. Those of ordinary skill in the art understand that the total amount of a therapeutic composition or active agent administered to a particular individual is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0058] 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) administered separately to an individual, usually separated by a time period. 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 in time from the other doses. In some embodiments, the individual doses are separated from each other by the same length of time period; in some embodiments, the dosing regimen includes multiple doses and at least two different time periods for the separated individual doses. In some embodiments, all doses within the dosing regimen are the same unit dose. In some embodiments, the different doses within the dosing regimen have different amounts. In some embodiments, the dosing regimen comprises a first dose of a first amount, followed by one or more additional doses of a second amount different from the first amount. In some embodiments, the dosing regimen comprises a first dose of a first amount, followed by one or more additional doses of a second amount that is the same as the first amount. In some embodiments, when administered to a relevant population, the dosing regimen is associated with an expected or beneficial outcome (i.e., is a therapeutic dosing regimen).

[0059] Excipient: As used herein, refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example to provide or contribute to 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, ethylene glycol, water, ethanol, etc.

[0060] Heteroaryl: The terms "heteroaryl" and "heteroar-" when used alone or as part of a larger structural 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, and 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 a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclic rings, where the linking group or point is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuryl, dibenzofuryl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", and any of said terms includes an optionally substituted ring. The term "heteroalkyl" refers to an alkyl group substituted by a heteroaryl group, where the alkyl and heteroaryl moieties are independently optionally substituted.

[0061] Heterocycle: The terms "heterocycle", "heterocyclic group" and "heterocyclic moiety" as used herein are used interchangeably and refer to a stable 3 - to 8 - membered monocyclic or 7 - to 10 - membered bicyclic heterocyclic moiety which is saturated or partially unsaturated and which has one or more, e.g., one to four, heteroatoms as defined above in addition to carbon atoms. When used in reference to the ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen. For 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, which 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, dioxanyl, dioxolanyl, diaza yl, oxaazanyl yl, thiaazanyl groups, morpholinyl groups, and thiomorpholinyl groups. The heterocyclic group can be mono-, bi-, tri- or polycyclic, preferably mono-, bi- or tricyclic, more preferably mono- 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 aromatic rings (e.g., 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[b][1,4]dioxine, etc.).

[0062] Inhibitor: As used herein, the term "inhibitor" refers to an entity, condition, or event whose presence, level, or degree is associated with a reduced level or activity of a target. In some embodiments, the inhibitor can act directly (in which case it, for example, directly exerts an effect on its target 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 a modulator of the target, thereby reducing the level and / or activity of the target). In some embodiments, the inhibitor is an inhibitor whose presence or level is associated with a reduced target level or activity relative to a specific reference level or activity (e.g., the level or activity observed under appropriate reference conditions, such as the presence of a known inhibitor or the absence of the inhibitor of interest, etc.).

[0063] Neurodegeneration: As used herein, the term "neurodegeneration" refers to a decrease in one or more properties, structures, or characteristics 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 an individual. In some embodiments, neurodegeneration can be evaluated, for example, by detecting a decrease in a biomarker associated with neurodegeneration in an individual. Alternatively or additionally, in some embodiments, neurodegeneration can be assessed by magnetic resonance imaging (MRI), cerebrospinal fluid containing biomarkers, 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 reduction in neural tissue associated with traumatic injury (e.g., exposure to an external force that disrupts the integrity of neural tissue). In some embodiments, neurodegeneration refers to a reduction in peripheral neural tissue. In some embodiments, neurodegeneration refers to a reduction in central neural tissue.

[0064] Oral: The phrases "administered orally" and "orally administered" as used herein have the meaning understood in the art and refer to the administration of a compound or composition by mouth.

[0065] Parenteral: The phrases "administered parenterally" and "parenterally administered" as used herein have the meaning understood in the art and refer to a mode of administration other than enteral and topical administration, typically by injection, and including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0066] Partially unsaturated: As used herein, the term "partially unsaturated" refers to a cyclic structural 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 (e.g., aryl or heteroaryl) structural moieties as defined herein.

[0067] Patient: As used herein, the term "patient" refers to any living organism to which or to whom the provided composition 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 symptoms of one or more disorders or conditions. 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.

[0068] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active substance formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active substance is present in unit doses suitable for administration in a therapeutic or dosing regimen that, when administered to a relevant population, has a statistically significant probability of achieving a predetermined therapeutic effect. In some embodiments, the pharmaceutical composition can be formulated, in particular, for administration in solid or liquid form, including those suitable for: oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets such as those for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, such as sterile solutions or suspensions, or sustained-release formulations; topical administration, such as emulsions, ointments, or controlled-release patches or sprays for application to the skin, lung, or oral cavity; intravaginal or rectal administration, such as pessaries, emulsions, or foams; sublingual administration; ophthalmic administration; transdermal administration; or nasal administration, pulmonary administration, and to other mucosal surfaces.

[0069] 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 human and animal tissues and that do not have excessive toxicity, irritation, allergic response, or other problems or complications and have a reasonable benefit / risk ratio.

[0070] 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 is involved in carrying or transporting the target 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 carrier materials 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; tragacanth powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, 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.

[0071] Pharmaceutically acceptable salts: As used herein, the term "pharmaceutically acceptable salts" refers to salts of the compounds suitable for use in pharmacy, i.e., salts that are suitable for contact with human and lower animal tissues within the scope of reasonable medical judgment, which have no excessive toxicity, irritation, allergic reaction, etc., and have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. described pharmaceutically acceptable salts in detail 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 of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or salts of amino groups formed with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts of amino groups formed by using other methods used in the art such as 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, glucoheptanoates, glycerophosphates, glucuronates, 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, p-toluenesulfonates, undecanoates, valerates, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. In some embodiments, when appropriate, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide ions, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having 1-6 carbon atoms, sulfonate, and arylsulfonate.

[0072] Prevention: As used herein, when used in conjunction with the occurrence of a disease, disorder, and / or condition, the term "prevention" refers to reducing the risk of developing a disease, disorder, and / or condition and / or delaying the onset of one or more characteristics or symptoms of a disease, disorder, or condition. When the onset of a disease, disorder, or condition has been delayed for a predetermined period of time, prevention can be considered to be completed.

[0073] Specific: As used herein in reference to an active substance, one of ordinary skill in the art will understand that the term "specific" means that the substance recognizes a potential target entity or condition. For example, in some embodiments, a substance "specifically" binds to its target if it preferentially binds to that target in the presence of one or more competing candidate targets. In many embodiments, the specific interaction depends 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 is evaluated relative to the specificity of the binding substance 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 binding substance. In some embodiments, specificity is evaluated relative to the specificity of a reference non-specific binding substance. In some embodiments, under conditions for binding to its target entity, the substance or entity does not detectably bind to a competing alternative target. In some embodiments, compared to a competing alternative target, the binding substance binds to its target entity with a higher on-rate, a lower off-rate, increased affinity, decreased dissociation, and / or increased stability.

[0074] Individual: As used herein, the term "individual" refers to an organism, typically a mammal (e.g., a human, including in some embodiments a pre-natal human form). In some embodiments, the individual has a related disease, disorder, or condition. In some embodiments, the individual is predisposed to a disease, disorder, or condition. In some embodiments, the individual exhibits one or more symptoms or characteristics of a disease, disorder, or condition. In some embodiments, the individual does not exhibit any symptoms or characteristics of a disease, disorder, or condition. In some embodiments, the individual is a human having one or more characteristics predisposing to a disease, disorder, or condition or having one or more characteristics conferring a risk of having a disease, disorder, or condition. In some embodiments, the individual is a patient. In some embodiments, the individual is an individual for whom and / or on whom a diagnosis and / or treatment has been performed.

[0075] Substituted or optionally substituted: As described herein, the compounds of the present invention may contain "optionally substituted" structural moieties. Generally, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated structural moiety are replaced by a suitable substituent. "Substituted" applies to moieties that are explicitly or implicitly part of a structure (e.g., means at least and means at least One or more hydrogens of ( ). Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from the specified group, the substituents may be the same or different at each position. Combinations of substituents involved in the present invention are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" refers to a compound that remains substantially unchanged when subjected to conditions that allow its generation, detection, and in certain embodiments, when subjected to conditions that allow its recovery, purification, and application for one or more of the purposes disclosed herein.

[0076] 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 by R o ; -(CH2) o substituted by R 0-4 O(CH2) 0-1 Ph; -CH=CHPh, which may be substituted by R o ; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be substituted by 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(Ro )S(O)2NR o 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 each R o 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 or sulfur), or 8- to 10-membered bicyclic aryl ring (having 0 - 4 heteroatoms independently selected from nitrogen, oxygen or sulfur), or notwithstanding the above definition, two independent occurrences of R o together with the atoms between them form a 3- to 12-membered saturated, partially unsaturated or aryl mono- or bicyclic ring (having 0 - 4 heteroatoms independently selected from nitrogen, oxygen or sulfur), which may be substituted as defined below.

[0077] R o (or the ring formed by two independent occurrences of R o together with the atoms between them) suitable monovalent substituents on are independently halogen, -(CH2) 0-2 R · , -(halo R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · , -(CH2) 0-2 CH(OR · )2; -O(halo 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 linear or branched alkylene)C(O)OR · or -SSR · , where each R · is unsubstituted or, when preceded by "halo-", is substituted by one or more halogens only, 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 or sulfur). Suitable divalent substituents on the saturated carbon atoms of R o include =O and =S.

[0078] 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 occurrence of R * is independently 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 or sulfur). Suitable divalent substituents attached to the ortho-substitutable carbon of an "optionally substituted" group include: -O(CR * 2) 2- 3O-, where each occurrence of R * is independently selected from hydrogen, a C 1-6an aliphatic group, or an unsubstituted 5- or 6-membered saturated, partially unsaturated or aryl ring (with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur).

[0079] 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 each R · is unsubstituted or, when preceded by "halo-", is substituted by one or more halogens only, and is independently a C 1-4 aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring (with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur).

[0080] Suitable substituents on the replaceable nitrogen of an "optionally substituted" group include or where each is independently hydrogen, a C 1-6 aliphatic group which may be substituted as defined below, an unsubstituted -OPh or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring (with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur), or, notwithstanding the above definition, two independently occurring together with their intervening atom 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 or sulfur.

[0081] 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 each R · is unsubstituted or, when preceded by "halo-", is substituted by one or more halogens only, and is independently a C 1-4 aliphatic group, -CH2Ph, -O(CH2)0-1 a Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring (with 0 - 4 heteroatoms independently selected from nitrogen, oxygen or sulfur).

[0082] Therapeutic agent: As used herein, the phrase "therapeutic agent" generally refers to any substance that, when administered to a living organism, elicits an intended pharmacological effect. In some embodiments, a substance is considered a therapeutic agent if it exhibits 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 an age group, sex, 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 one or more symptoms or characteristics of a disease, disorder, and / or condition; delay the onset of one or more symptoms or characteristics of a disease, disorder, and / or condition; reduce the severity of one or more symptoms or characteristics of a disease, disorder, and / or condition; and / or decrease the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition. In some embodiments, a "therapeutic agent" is a substance that has been approved or requires approval by a government agency before it can be marketed for administration to humans. In some embodiments, a "therapeutic agent" is a substance that requires a medical prescription for administration to humans.

[0083] Treatment: As used herein, the term "treatment" refers to any method that is used to partially or completely alleviate, improve, relieve, inhibit, prevent one or more symptoms or characteristics of a disease, disorder, and / or condition; delay the onset of one or more symptoms or characteristics of a disease, disorder, and / or condition; reduce the severity of one or more symptoms or characteristics of a disease, disorder, and / or condition; and / or decrease the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition. Treatment can be administered to an individual who does not show signs of a disease, disorder, and / or condition. In some embodiments, treatment can be administered to an individual who only exhibits early signs of a disease, disorder, and / or condition, for example, for the purpose of reducing the risk of pathogenesis associated with the disease, disorder, and / or condition.

[0084] Detailed description of certain embodiments

[0085] Programmed axonal degeneration and SARM1

[0086] 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, known as 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 breakdown of axonal fragments distal to the injury, while proximal axonal fragments and the cell body remain intact. The hallmarks of this degeneration are first the depletion of nicotinamide mononucleotide adenylyltransferase (NMNAT), followed by loss of nicotinamide adenine dinucleotide (NAD+), loss of adenosine triphosphate (ATP), neurofilament proteolysis, and finally axonal degradation approximately 8-24 hours after injury. (Gerdts, J. et al., Neuron, 2016, 89, 449-460).

[0087] 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 axonal localization of NMNAT1 confer axonal protection (Babetto et al., Cell Rep., 2010, 3, 1422-1429; Sasaki et al., J. Neurosci., 2009).

[0088] In a genome-wide RNAi screen in primary mouse neurons, sterile alpha and TIR motif-containing 1 (SARM1) was identified, and knockdown of SARM1 resulted in long-term protection of sensory neurons against injury-induced axonal degeneration (Gerdts et al., J Neurosci, 2013, 33, 13569-13580). SARM1 belongs to the family of cytoplasmic adaptor proteins but is unique among its members in that it is the most evolutionarily ancient adaptor, which conversely inhibits TLR signaling and has been identified as a central executor of the injury-induced axonal 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 by axonal degeneration, thus highlighting the central role of NAD+ homeostasis in axonal integrity (Gerdts, J. et al., Science, 2015, 348, 453-457). The injury-induced NAD+ depletion requires SARM1 both in vivo and in vitro, and SARM1 activation locally triggers axonal degeneration through NAD(+) disruption (Gerdts et al., Science, 2015 348, 452-457; Sasaki et al., J. Biol. Chem. 2015, 290, 17228-17238; both of which are hereby incorporated by reference in their entirety).

[0089] It is clear from loss-of-function genetic studies that SARM1 acts as the major executor of the axonal degeneration pathway following injury. SARM1 gene knockout can preserve axons for up to 14 days after nerve transection (Osterloh, J.M. et al., Science, 2012, 337, 481-484; Gerdts, J. et al., J. Neurosci., 2013, 33, 13569-13580), and improve 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 both axonal degeneration and enhancing the pain sensation produced after vincristine chemotherapy (Geisler et al., Brain, 2016, 139, 3092-3108).

[0090] SARM1 contains multiple conserved motifs, including the SAM domain, ARM / HEAT motifs, and the TIR domain ( Figure 1 ), which mediate oligomerization and protein-protein interactions (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 it acts as a scaffold for protein complexes (O'Neill, L.A. & Bowie, A.G., Nat. Rev. Immunol., 2007, 7, 353-364). Interestingly, dimerization of the SARM1-TIR domain is sufficient to induce axonal degeneration and rapidly trigger NAD+ degradation by acting as a NAD+ lyase (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 established NADase activity, efforts have been made to identify substances that can modulate SARM1 and may serve as useful therapeutic agents, such as to protect against neurodegenerative diseases, including peripheral neuropathy, traumatic brain injury, and / or neurodegenerative diseases.

[0091] Among them, the present invention provides certain compounds and / or compositions that are used as SARM1 inhibitors (e.g., as SARM1 inhibitors), and related technologies.

[0092] Compound

[0093] In some embodiments, the present disclosure provides a compound of Formula I:

[0094]

[0095] or a pharmaceutically acceptable salt thereof, wherein:

[0096] X 1 is N or C-R x1 ;

[0097] X 2 is N or C-R x2 ;

[0098] X 3 is N or C-R x3 ;

[0099] X 4 is N or C-R x4 ;

[0100] provided that one or two of X 1 , X 2 , X 3 and X 4 are N;

[0101] R x1 , R x2 , R x3 and R x4 each independently is selected from -R or -OR;

[0102] L 1 is selected from a covalent bond, -O-, -N(R)-, -C(O)N(R)-, -S(O)2- and -S(O)2N(R)-;

[0103] L 2 is selected from a covalent bond, -O-, -N(R)-, -N(R)C(O)- and -N(R)S(O)2-;

[0104] R 1 is selected from halogen, CN and -R;

[0105] R 2 is -R; and

[0106] R is selected from hydrogen or an optionally substituted group selected from C 1-6An aliphatic group, a phenyl group, a 4- to 6-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0107] As generally defined above, X 1 is N or C-R x1 . In some embodiments, X 1 is N. In some embodiments, X 1 is C-R x1 . In some embodiments, X 1 is C-R x1 , and one of X 2 , X 3 , and X 4 is N. In some embodiments, X 1 is C-R x1 , and two of X 2 , X 3 , and X 4 are N.

[0108] As generally defined above, X 2 is N or C-R x2 . In some embodiments, X 2 is N. In some embodiments, X 2 is C-R x2 . In some embodiments, X 2 is C-R x2 , and one of X 1 , X 3 , and X 4 is N. In some embodiments, X 2 is C-R x2 , and two of X 1 , X 3 , and X 4 are N.

[0109] As generally defined above, X 3 is N or C-R x3 . In some embodiments, X 3 is N. In some embodiments, X 3 is C-R x3 . In some embodiments, X 3 is C-R x3 , and one of X 1 , X 2 , and X 4 is N. In some embodiments, X 3 is C-R x3, and X 1 , X 2 and X 4 two of which are N.

[0110] As generally defined above, X 4 is N or C-R x4 . In some embodiments, X 4 is N. In some embodiments, X 4 is C-R x4 . In some embodiments, X 4 is C-R x4 , and X 1 , X 2 and X 3 one of which is N. In some embodiments, X 4 is C-R x4 , and X 1 , X 2 and X 3 two of which are N.

[0111] As generally defined above, X 1 , X 2 , X 3 and X 4 one or two of which are N. Thus, it should be understood that in the compounds of formula I, X 1 , X 2 , X 3 and X 4 at least one but no more than two are N.

[0112] As generally defined above, R x1 , R x2 , R x3 and R x4 each independently selected from -R or -OR.

[0113] As generally defined above, R x1 is independently selected from -R or -OR. In some embodiments, R x1 is hydrogen. In some embodiments, R x1 is an optionally substituted C 1-6 aliphatic group. In some embodiments, R x1 is an optionally substituted C 1-3 aliphatic group. In some embodiments, R x1 is -CH3, -CH2CH3 or -CH(CH3)2. In some embodiments, R x1 is -OR. In some embodiments, R x1 is -OH. In some embodiments, R x1 is -OCH3. In some embodiments, Rx1 is

[0114] As generally defined above, R x2 is independently selected from -R or -OR. In some embodiments, R x2 is hydrogen. In some embodiments, R x2 is an optionally substituted C 1-6 aliphatic group. In some embodiments, R x2 is an optionally substituted C 1-3 aliphatic group. In some embodiments, R x2 is -CH3, -CH2CH3 or -CH(CH3)2. In some embodiments, R x2 is -OR. In some embodiments, R x2 is -OH. In some embodiments, R x2 is -OCH3.

[0115] As generally defined above, R x3 is independently selected from -R or -OR. In some embodiments, R x3 is hydrogen. In some embodiments, R x3 is an optionally substituted C 1-6 aliphatic group. In some embodiments, R x3 is an optionally substituted C 1-3 aliphatic group. In some embodiments, R x3 is -CH3, -CH2CH3 or -CH(CH3)2. In some embodiments, R x3 is -OR. In some embodiments, R x3 is -OH. In some embodiments, R x3 is -OCH3.

[0116] As generally defined above, R x4 is independently selected from -R or -OR. In some embodiments, R x4 is hydrogen. In some embodiments, R x4 is an optionally substituted C 1-6 aliphatic group. In some embodiments, R x4 is an optionally substituted C 1-3 aliphatic group. In some embodiments, R x4 is -CH3, -CH2CH3 or -CH(CH3)2. In some embodiments, R x4 is -OR. In some embodiments, R x4 is -OH. In some embodiments, R x4 is -OCH3.

[0117] It should be understood that: R x1 is -OH, and X 2 is N; or R x2 is -OH, and X 1 or X 3 is N; or R x3 is -OH, and X 2 is N; or X 1 is N, and -L 1 -R 1 is -OH; or X 3 is N, and -L 2 -R 2 is -OH can exist in two tautomeric forms, for example:

[0118]

[0119] Similarly, where: X 1 and X 2 is N and R x3 is OH; or X 1 and X 2 is N, and -L 1 -R 1 is OH; or X 2 and X 3 is N, and -L 2 -R 2 is OH; or X 2 and X 3 is N, and R x1 is OH can exist in two tautomeric forms, for example:

[0120]

[0121] The present disclosure contemplates and includes all tautomeric forms of the compounds described herein. In some embodiments, the compound of formula I is described in the pyridin-2(1H)-one or pyridazin-3(2H)-one tautomeric form. In some embodiments, the compound of formula I is described in the pyridin-2-ol or pyridazin-3-ol tautomeric form.

[0122] As generally defined above, L 1 is selected from a covalent bond, -O-, -N(R)-, -C(O)N(R)-, -S(O)2-, and -S(O)2N(R)-. In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 is -C(O)N(R)-. In some such embodiments, L 1 is -C(O)NH-. In some embodiments, L 1is -C(O)N(CH3)-. In some embodiments, L 1 is -S(O)2-. In some embodiments, L 1 is -S(O)2N(R)-. In some such embodiments, L 1 is -S(O)2NH-. In some embodiments, L 1 is -S(O)2N(CH3)-.

[0123] As generally defined above, L 2 is selected from a covalent bond, -O-, -N(R)-, -N(R)C(O)-, and -N(R)S(O)2-. In some embodiments, L 2 is a covalent bond. In some embodiments, L 2 is -O-. In some embodiments, L 2 is -N(R)-. In some embodiments, L 2 is -NH-. In some embodiments, L 2 is -N(CH3)-. In some embodiments, L 2 is -N(R)C(O)-. In some such embodiments, L 2 is -NHC(O)-. In some embodiments, L 2 is -N(CH3)C(O)-. In some embodiments, L 2 is -N(R)S(O)2-. In some such embodiments, L 2 is -NHS(O)2-. In some embodiments, L 2 is -N(CH3)S(O)2-.

[0124] As generally defined above, R 1 is selected from halogen, CN, and -R. In some embodiments, R 1 is halogen. In some such embodiments, R 1 is bromine. In some embodiments, R 1 is chlorine. In some embodiments, R 1 is CN.

[0125] In some embodiments, R 1 is -R. In some embodiments, R 1 is H. In some embodiments, R 1 is an optionally substituted group selected from C 1-6An aliphatic group, a phenyl group, a 4- to 6-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8- to 10-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0126] In some embodiments, R 1 is an optionally substituted C 1-6 aliphatic group. In some embodiments, R 1 is an optionally substituted C 1-2 aliphatic group. In some embodiments, R 1 is an optionally substituted C 3-4 aliphatic group. In some embodiments, R 1 is an optionally substituted C 5-6 aliphatic group. In some embodiments, R 1 is -CH3. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 is -CH2CH2CH3 or -CH(CH3)2. In some embodiments, R 1 is -CH2CH(CH3)2. In some embodiments, R 1 is -(CH2)4CH3. In some embodiments, R 1 is C 1-6 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 or -(CH2) 0-4 N(R o )CO2R o . In some embodiments, R 1 is -CH2-R o , -CH2-OR o , -CH2-N(R o )2 or -CH2-N(R o )CO2R o . In some embodiments, R 1 is -CH2CH2-R o , -CH2CH2-OR o , -CH2CH2-N(R o )2 or -CH2CH2-N(R o )CO2R o . In some embodiments, R1 is -(CH2)3-R o , -(CH2)3-OR o , -(CH2)3-N(R o )2 or -(CH2)3-N(R o )CO2R o . In some embodiments, R 1 is -(CH2)4-R o , -(CH2)4-OR o , -(CH2)4-N(R o )2 or -(CH2)4-N(R o )CO2R o .

[0127] In some embodiments, R 1 is an optionally halogen-substituted C 1-6 aliphatic group. In some embodiments, R 1 is an optionally halogen-substituted C 1-2 aliphatic group. In some embodiments, R 1 is an optionally -R o -substituted C 1-6 aliphatic group, where R o is selected from:

[0128]

[0129] In some embodiments, R 1 is an optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 1 is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 1 is an optionally substituted

[0130] In some embodiments, R 1 is selected from hydrogen, chlorine, bromine, -CN, -CH3, -CH2F, -CH2CH3, -CH2CF3, -CH2CHF2, -CH2CH2CH3, -CH(CH3)2, -(CH2)4CH3, -CH2CH(CH3)2, phenyl or a group selected from:

[0131]

[0132] As generally defined above, R 2 is -R. In some embodiments, R2 is H. In some embodiments, R 2 is an optionally substituted group selected from C 1-6 aliphatic groups, phenyl, 4- to 6-membered heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, and 8- to 10-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0133] In some embodiments, R 2 is an optionally substituted C 1-6 aliphatic group. In some embodiments, R 2 is an optionally substituted C 1-2 aliphatic group. In some embodiments, R 2 is -CH3. In some embodiments, R 2 is -CH2CH3.

[0134] In some embodiments, R 2 is an optionally halogen-substituted C 1-6 aliphatic group. In some embodiments, R 2 is an optionally halogen-substituted C 1-2 aliphatic group. In some embodiments, R 2 is an optionally -R o substituted C 1-6 aliphatic group, where R o is selected from:

[0135]

[0136]

[0137]

[0138] In some such embodiments, R o is not

[0139] In some embodiments, R 2 is an optionally substituted phenyl.

[0140] In some embodiments, R 2 is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 2 is an optionally substituted 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In some embodiments, R 2is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R 2 is an optionally substituted group selected from

[0141] In some embodiments, R 2 is an optionally substituted 8- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 2 is an optionally substituted 10-membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, R 2 is an optionally substituted In some such embodiments, R 2 is

[0142] In some embodiments, R 2 is an optionally substituted 4- to 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 2 is an optionally substituted 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 2 is an optionally substituted 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 2 is In some embodiments, R 2 is not

[0143] In some embodiments, R 2 is selected from hydrogen, -CH3, phenyl,

[0144]

[0145]

[0146]

[0147]

[0148] In some embodiments, R 2 is not In some embodiments, R 2 is not

[0149] As generally defined above, R is selected from hydrogen or an optionally substituted group selected from C 1-6Aliphatic group, phenyl, 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and 8- to 10-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted group selected from C 1-6 Aliphatic group, phenyl, 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and 8- to 10-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0150] In some embodiments, R is an optionally substituted C 1-6 Aliphatic group. In some embodiments, R is an optionally substituted C 1-2 Aliphatic group. In some embodiments, R is an optionally substituted C 3-4 Aliphatic group. In some embodiments, R is an optionally substituted C 5-6 Aliphatic group. In some embodiments, R is -CH3. In some embodiments, R is -CH2CH3. In some embodiments, R is -CH2CH2CH3 or -CH(CH3)2. In some embodiments, R is -CH2CH(CH3)2. In some embodiments, R is -(CH2)4CH3. In some embodiments, R is C 1-6 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 or -(CH2) 0-4 N(R o )CO2R o . In some embodiments, R is -CH2-R o , -CH2-OR o , -CH2-N(R o )2 or -CH2-N(R o )CO2R o . In some embodiments, R is -CH2CH2-R o , -CH2CH2-OR o , -CH2CH2-N(R o )2 or -CH2CH2-N(R o )CO2R o . In some embodiments, R is -(CH2)3-Ro , -(CH2)3-OR o , -(CH2)3-N(R o )2 or -(CH2)3-N(R o )CO2R o . In some embodiments, R is -(CH2)4-R o , -(CH2)4-OR o , -(CH2)4-N(R o )2 or -(CH2)4-N(R o )CO2R o .

[0151] In some embodiments, R is an aliphatic group optionally substituted with halogen 1-6 . In some embodiments, R is an aliphatic group optionally substituted with halogen 1-2 . In some embodiments, R is an aliphatic group optionally substituted with -OH, -R o substituted C 1-6 aliphatic group, wherein R o is selected from:

[0152]

[0153]

[0154]

[0155] In some such embodiments, R o is not

[0156] In some embodiments, R is selected from hydrogen, -CH3, -CH2F, -CH2CH3, -CH2CF3, -CH2CHF2, -CH2CH2CH3, -CH(CH3)2, -(CH2)4CH3, -CH2CH(CH3)2, phenyl or a group selected from:

[0157]

[0158]

[0159]

[0160]

[0161] In some embodiments, R is not

[0162] In some embodiments of Formula I, L 2is -N(R)-. Thus, in some embodiments, the present disclosure provides compounds of formula I-a:

[0163]

[0164] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 , L 1 , R 1 , R 2 and R are each as defined above and as described herein.

[0165] In some embodiments of formula I, L 1 is -O-. Thus, in some embodiments, the present disclosure provides compounds of formula I-b:

[0166]

[0167] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 , L 2 , R 1 and R 2 are each as defined above and as described herein.

[0168] In some embodiments of formula I, L 1 is -O-, and L 2 is -N(R)-. Thus, in some embodiments, the present disclosure provides compounds of formula I-c:

[0169]

[0170] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 , R 1 , R 2 and R are each as defined above and as described herein.

[0171] In some embodiments of formula I, X 2 is N. Thus, in some embodiments, the present disclosure provides compounds of formula I-d:

[0172]

[0173] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 3 , X4 ,L 1 ,L 2 ,R 1 and R 2 each as defined above and described herein.

[0174] In some embodiments of Formulas I-a, I-b, and I-c, X 2 is N. Thus, in some embodiments, the present disclosure provides compounds of Formulas I-a-i, I-b-i, and I-c-i:

[0175]

[0176] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 3 , X 4 , L 1 , L 2 , R 1 , R 2 and R each as defined above and described herein.

[0177] In some embodiments of Formulas I-a-i, I-b-i, and I-c-i, X 4 is N, and each of X 1 and X 3 is CH. Thus, in some embodiments, the present disclosure provides compounds of Formulas I-a-ii, I-b-ii, and I-c-ii:

[0178]

[0179] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 and R each as defined above and described herein.

[0180] In some embodiments of Formulas I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, and I-c-ii, R 2 is an optionally substituted C 1-6 aliphatic group. In some such embodiments, the present disclosure provides compounds of Formulas I-a-iii, I-a-iv, I-a-v, I-b-iii, I-b-iv, I-b-v, I-c-iii, I-c-iv, and I-c-v:

[0181]

[0182] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X3 ,X 4 ,L 1 ,L 2 ,R 1 ,R 2 and R are each as defined above and as described herein.

[0183] In some embodiments, the present disclosure provides compounds selected from:

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195] In some aspects, the present disclosure provides compounds according to the following embodiments:

[0196] Embodiment 1. A compound of formula I:

[0197]

[0198] or a pharmaceutically acceptable salt thereof, wherein:

[0199] X 1 is N or C-R x1 ;

[0200] X 2 is N or C-R x2 ;

[0201] X 3 is N or C-R x3 ;

[0202] X 4 is N or C-R x4 ;

[0203] The condition is that X 1 , X 2 , X 3 and X 4 one or both of which are N;

[0204] R x1 , R x2 , R x3 and R x4 each independently selected from -R or -OR;

[0205] L 1 is selected from a covalent bond, -O-, -N(R)-, -C(O)N(R)-, -S(O)2- and -S(O)2N(R)-;

[0206] L 2 is selected from a covalent bond, -O-, -N(R)-, -N(R)C(O)- and -N(R)S(O)2-;

[0207] R 1 is selected from halogen, CN and -R;

[0208] R 2 is -R; and

[0209] R is selected from hydrogen or an optionally substituted group selected from C 1-6 aliphatic group, phenyl, a 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur and an 8-10 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0210] Embodiment 2. The compound according to Embodiment 1, wherein X 1 is N.

[0211] Embodiment 3. The compound according to Embodiment 1, wherein X 2 is N.

[0212] Embodiment 4. The compound according to Embodiment 1, wherein X 3 is N.

[0213] Embodiment 5. The compound according to Embodiment 1, wherein X 4 is N.

[0214] Embodiment 6. The compound according to any one of Embodiments 1-4, wherein X 4 is N.

[0215] Embodiment 7. The compound according to any one of Embodiments 3-5, wherein X 1It is N.

[0216] Embodiment 8. A compound according to any one of Embodiments 2, 4 and 5, wherein X 2 is N.

[0217] Embodiment 9. A compound according to any one of Embodiments 2, 3 and 5, wherein X 3 is N.

[0218] Embodiment 10. A compound according to any one of Embodiments 1-9, wherein the compound is selected from:

[0219]

[0220] Embodiment 11. A compound according to any one of Embodiments 1-10, wherein L 1 is -O-.

[0221] Embodiment 12. A compound according to Embodiment 11, wherein R 1 is an optionally substituted C 1-6 aliphatic group.

[0222] Embodiment 13. A compound according to Embodiment 12, wherein R 1 is a C 1-6 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 or -(CH2) 0-4 N(R o )CO2R o .

[0223] Embodiment 14. A compound according to Embodiment 13, wherein R 1 is -CH2-R o , -CH2-OR o , -CH2-N(R o )2 or -CH2-N(R o )CO2R o .

[0224] Embodiment 15. A compound according to Embodiment 13, wherein R 1 is -CH2CH2-R o , -CH2CH2-OR o , -CH2CH2-N(R o )2 or -CH2CH2-N(R o )CO2Ro .

[0225] Embodiment 16. A compound according to Embodiment 13, wherein R 1 is -(CH2)3-R o , -(CH2)3-OR o , -(CH2)3-N(R o )2 or -(CH2)3-N(R o )CO2R o .

[0226] Embodiment 17. A compound according to Embodiment 13, wherein R 1 is -(CH2)4-R o , -(CH2)4-OR o , -(CH2)4-N(R o )2 or -(CH2)4-N(R o )CO2R o .

[0227] Embodiment 18. A compound according to Embodiment 13, wherein R 1 is an optionally -R o substituted C 1-6 aliphatic group, wherein R o is selected from:

[0228]

[0229] Embodiment 19. A compound according to any one of Embodiments 11-13, wherein R 1 is selected from hydrogen, -CH3, -CH2F, -CH2CH3, -CH2CF3, -CH2CHF2, -CH2CH2CH3, -CH(CH3)2, -(CH2)4CH3, -CH2CH(CH3)2 or a group selected from the following:

[0230]

[0231] Embodiment 20. A compound according to any one of Embodiments 1-10, wherein L 1 is a covalent bond.

[0232] Embodiment 21. A compound according to Embodiment 20, wherein R 1 is a halogen.

[0233] Embodiment 22. A compound according to Embodiment 20, wherein R 1 is hydrogen.

[0234] Embodiment 23. A compound according to Embodiment 20, wherein R 1is -CN.

[0235] Embodiment 24. The compound according to Embodiment 20, wherein R 1 is an optionally substituted C 1-6 aliphatic group.

[0236] Embodiment 25. The compound according to Embodiment 20, wherein R 1 is selected from hydrogen, chlorine, bromine, -CN, -CH3, -CH2CH3, -CH2CH2CH3,

[0237] Embodiment 26. The compound according to any one of Embodiments 1-10, wherein L 1 is -C(O)N(R)-.

[0238] Embodiment 27. The compound according to Embodiment 26, wherein R is hydrogen.

[0239] Embodiment 28. The compound according to Embodiment 26, wherein R is -CH3.

[0240] Embodiment 29. The compound according to any one of Embodiments 26-28, wherein R 1 is selected from hydrogen, -CH3, phenyl,

[0241] Embodiment 30. The compound according to any one of Embodiments 1-10, wherein L 1 is -S(O)2-.

[0242] Embodiment 31. The compound according to Embodiment 30, wherein R 1 is -CH3.

[0243] Embodiment 32. The compound according to any one of Embodiments 1-10, wherein L 1 is -S(O)2N(R)-.

[0244] Embodiment 33. The compound according to Embodiment 32, wherein R is hydrogen.

[0245] Embodiment 34. The compound according to Embodiment 32, wherein R is -CH3.

[0246] Embodiment 35. The compound according to any one of Embodiments 32-34, wherein R 1 is phenyl or

[0247] Embodiment 36. The compound according to any one of Embodiments 1-10, wherein L 1 is -N(R)-.

[0248] Embodiment 37. The compound according to Embodiment 36, wherein R is hydrogen.

[0249] Embodiment 38. The compound according to Embodiment 36, wherein R is -CH3.

[0250] Embodiment 39. The compound according to any one of Embodiments 36 - 38, wherein R 1 is an optionally substituted C 1-6 aliphatic group.

[0251] Embodiment 40. The compound according to Embodiment 39, wherein R 1 is selected from -CH3, -CH2CH3,

[0252] Embodiment 41. The compound according to any one of Embodiments 1 - 40, wherein L 2 is -N(R)-.

[0253] Embodiment 42. The compound according to Embodiment 41, wherein R is hydrogen.

[0254] Embodiment 43. The compound according to Embodiment 41, wherein R is -CH3.

[0255] Embodiment 44. The compound according to Embodiment 42, wherein R 2 is hydrogen.

[0256] Embodiment 45. The compound according to any one of Embodiments 41 - 43, wherein R 2 is an optionally substituted C 1-6 aliphatic group.

[0257] Embodiment 46. The compound according to Embodiment 45, wherein R 2 is an optionally halogen - substituted C 1-6 aliphatic group.

[0258] Embodiment 47. The compound according to Embodiment 45, wherein R 2 is an optionally -R o substituted C 1-6 aliphatic group, wherein R o is selected from:

[0259]

[0260]

[0261]

[0262]

[0263] Embodiment 48. A compound according to any one of Embodiments 1-40, wherein L 2 is a covalent bond.

[0264] Embodiment 49. A compound according to Embodiment 48, wherein R 2 is an optionally substituted C 1-6 aliphatic group.

[0265] Embodiment 50. A compound according to Embodiment 49, wherein R 2 is

[0266] Embodiment 51. A compound according to any one of Embodiments 1-40, wherein L 2 is -O-.

[0267] Embodiment 52. A compound according to Embodiment 51, wherein R 2 is -CH3.

[0268] Embodiment 53. A compound according to Embodiment 51, wherein R 2 is

[0269] Embodiment 54. A compound according to any one of Embodiments 1-40, wherein L 2 is -N(R)C(O)-.

[0270] Embodiment 55. A compound according to Embodiment 54, wherein R is hydrogen.

[0271] Embodiment 56. A compound according to Embodiment 54, wherein R is -CH3.

[0272] Embodiment 57. A compound according to any one of Embodiments 54-56, wherein R 2 is -CH3, phenyl,

[0273] Embodiment 58. A compound according to any one of Embodiments 1-40, wherein L 2 is -N(R)S(O)2-.

[0274] Embodiment 59. A compound according to Embodiment 58, wherein R is hydrogen.

[0275] Embodiment 60. A compound according to Embodiment 58, wherein R is -CH3.

[0276] Embodiment 61. A compound according to any one of embodiments 58 - 60, wherein R 2 is -CH3, phenyl or

[0277] Embodiment 62. A compound according to embodiment 1, wherein the compound is selected from:

[0278]

[0279] or a pharmaceutically acceptable salt thereof.

[0280] Embodiment 63. A compound according to embodiment 1, wherein the compound is:

[0281]

[0282] or a pharmaceutically acceptable salt thereof.

[0283] Embodiment 64. A compound according to embodiment 62 or embodiment 63, wherein the compound is selected from:

[0284]

[0285] or a pharmaceutically acceptable salt thereof.

[0286] Embodiment 65. A compound according to embodiment 64, wherein the compound is selected from:

[0287]

[0288] or a pharmaceutically acceptable salt thereof.

[0289] Embodiment 66. A compound according to embodiment 62, wherein the compound is selected from:

[0290]

[0291]

[0292] or a pharmaceutically acceptable salt thereof.

[0293] Composition

[0294] In some embodiments, the compound of formula I can be provided in the form of a composition, for example, in combination (e.g., mixed) with one or more other components.

[0295] In some embodiments, the present disclosure provides compositions comprising and / or delivering a Compound of Formula I or an active metabolite thereof, such as when contacted with or otherwise administered to a system or environment, such as the system or environment may include SARM1 NAD enzyme activity; in some embodiments, administering the composition to the system or environment achieves inhibition of SARM1 activity as described herein.

[0296] In some embodiments, the compositions provided herein, as described herein, can be pharmaceutical compositions because they comprise 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 an individual in need thereof).

[0297] In some embodiments, one or more Compounds of Formula I are provided and / or utilized in the form of pharmaceutically acceptable salts.

[0298] The present disclosure particularly provides compositions comprising a Compound of Formula I or a pharmaceutically acceptable salt or derivative thereof and a pharmaceutically acceptable carrier, excipient, 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. According to the methods of the present disclosure, the compounds and compositions 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 compounds are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the expression "dosage unit form" refers to physically discrete units of medicaments suitable for the patient to be treated. However, it should be understood that the total daily dosage of the provided compounds and compositions 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 with the individual, depending on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed and its route of administration; the species, age, weight, sex, and diet of the patient; the general condition of the individual; the time of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination with or concurrently with the specific compound employed, etc.

[0299] The provided compositions can be administered orally, parenterally, by inhalation or nasal spray, topically (e.g., as a powder, ointment or drops), rectally, sublingually, vaginally, intraperitoneally, intracisternally or by an implanted reservoir, depending on the severity of the condition being treated. Preferably, the compositions are administered orally, intraperitoneally or intravenously. In certain embodiments, the provided compounds are administered orally or parenterally once or more times per day at a dosage level of about 0.01 mg / kg to about 50 mg / kg of the individual body weight to obtain the desired therapeutic effect.

[0300] As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intraliver, intralesional and intracranial injection or infusion techniques. The sterile injectable form of the provided compositions can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersing or wetting agents and suspending agents in accordance with the techniques known in the art. 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. Among the acceptable carriers and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as a solvent or suspending medium.

[0301] For this purpose, any mild fixed oil can be used, including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives, and natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxylated forms, can be used in the preparation of injectables. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersing agents, such as carboxymethyl cellulose or similar dispersing agents, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid or other dosage forms can also be used for formulating purposes.

[0302] The injectable preparation can be rendered sterile, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0303] To prolong the effects of the provided compounds, it is generally desirable to slow the absorption of the compounds from subcutaneous or intramuscular injections. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous substance. The absorption rate of the compound depends on its dissolution rate, which in turn depends on crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oil carrier. Injectable depot forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as poly(lactide-co-glycolide). The release rate of the compound can be controlled according to the ratio of the compound to the polymer and the nature of the specific polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0304] The pharmaceutically acceptable compositions described herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In such solid dosage forms, the active compound can be admixed with at least one inert diluent such as sucrose, lactose or starch. In accordance with conventional 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 may also be added.

[0305] 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 and / or 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) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) adsorbents 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 above excipients.

[0306] Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules, which use excipients such as lactose or lactose and high molecular weight polyethylene glycol, etc. Solid dosage forms such as tablets, troches, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings (i.e., buffering agents) and other coatings 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 preferably in a delayed manner in a certain part of the intestine. Examples of embedding compositions that can be used include polymers and waxes.

[0307] 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 can 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 glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, oral compositions can also include adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and fragrances.

[0308] Alternatively, the pharmaceutically acceptable compositions described herein can be administered rectally or vaginally in the form of suppositories. 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 temperature (e.g., rectal or vaginal), and thus will 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.

[0309] The pharmaceutically acceptable compositions described herein can also be administered topically, especially when the target of treatment includes areas or organs that are readily accessible by topical administration, including diseases of the eye, skin, or lower intestine. Topical application to the lower intestine can be achieved with rectal suppository formulations (see above) or suitable enema formulations.

[0310] Dosage forms for the 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 with a pharmaceutically acceptable carrier and any desired preservatives or buffering agents that may be required under aseptic conditions. Ophthalmic formulations, ear drops, and eye drops are also considered to be within the scope of the present disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0311] For topical application, the provided pharmaceutically acceptable compositions can be formulated as suitable ointments containing the active ingredient suspended or dissolved in one or more carriers. Carriers for the 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, which contain 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.

[0312] For ophthalmic application, 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, which may or may not contain a preservative such as benzalkonium chloride. Alternatively, for ophthalmic application, the pharmaceutically acceptable composition can be formulated as an ointment such as petrolatum.

[0313] The pharmaceutically acceptable compositions of the present disclosure can also be administered by nasal aerosol or inhalant. Such compositions are prepared according to techniques well known in the pharmaceutical formulation art and can be prepared as a saline solution using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0314] Most preferably, the pharmaceutically acceptable compositions of the present disclosure are formulated for oral administration.

[0315] Identification and / or characterization of compounds and / or compositions

[0316] The present disclosure particularly provides various techniques for identifying and / or characterizing the compounds and / or compositions as described herein. For example, the present invention provides various assays for evaluating SARM1 inhibitory activity, particularly for evaluating SARM1 inhibitory activity.

[0317] In some embodiments, the performance of one or more target compounds or compositions in the assays described herein is compared to the performance of a suitable reference. For example, in some embodiments, the reference can be the absence of the relevant compound or composition. Alternatively or additionally, in some embodiments, the reference can 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 understood in the art, as a positive or negative control). In some embodiments, the reference can be a set of alternative but equivalent conditions (e.g., temperature, pH, salt concentration, etc.). In some embodiments, the reference can be the performance of the compound or composition with respect to a SARM1 variant.

[0318] Still further alternatively or additionally, in some embodiments, the performance of one or more target compounds or compositions in the assays described herein can be evaluated in the presence of a suitable reference compound or composition, e.g., to determine the ability of the compound or composition to compete with the reference.

[0319] In some embodiments, multiple target compounds or compositions 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 considered to be a “library” because the multiple members share one or more characteristics (e.g., structural elements, source identity, synthetic similarity, etc.).

[0320] Certain exemplary assays useful for the practice of the present disclosure are illustrated in the following examples. 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 examples or otherwise discussed below.

[0321] In some embodiments, compounds and / or compositions can be identified and / or characterized based on one or more activities or characteristics 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.

[0322] In some embodiments, the provided SARM1 inhibitors reduce or inhibit the binding of SARM1 to NAD+. In some embodiments, the provided SARM1 inhibitors bind to SARM1 in a pocket containing one or more catalytic residues (e.g., the catalytic cleft of SARM1). Examples of such catalytic residues include glutamate at position 642 (E642).

[0323] In some embodiments, the provided SARM1 inhibitors disrupt and / or prevent the oligomerization of the TIR1 domain of SARM1. In some embodiments, the provided SARM1 inhibitors disrupt the oligomerization of the SAM domain. In some embodiments, the provided SARM1 inhibitors disrupt the axonal signaling cascade that results in NAD+ depletion.

[0324] In some embodiments, the present disclosure provides assays that can be used to identify and / or characterize one or more activities and / or properties of a target compound and / or composition. 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 properties.

[0325] SARM1 activity assay

[0326] In some embodiments, a method of 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 incubation; and d) identifying the candidate inhibitor compound as an inhibitor if the amount of NAD+ is greater than the amount in a control mixture that does not contain the candidate inhibitor.

[0327] In some embodiments, a method of identifying a SARM1 inhibitor is provided, which comprises: 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 the NAD+ and ADPR (or cADPR) in the mixture after incubation; d) determining the molar ratio of NAD+:ADPR (or cADPR); and e) identifying the candidate inhibitor compound as an inhibitor if the molar ratio is greater than the molar ratio of a control mixture that does not contain the candidate inhibitor.

[0328] In some embodiments, a method of identifying a SARM1 inhibitor is provided, which comprises: a) providing a mixture comprising a solid support to which is bound i) full-length SARM1 and at least one tag, ii) NAD+, and iii) a candidate inhibitor; b) incubating the mixture; c) quantifying the NAD+ after incubation; and d) identifying the candidate inhibitor compound as a SARM1 inhibitor if the concentration of NAD+ is greater than the concentration of a control.

[0329] SARM1 binding assay

[0330] In some embodiments, the efficacy of the provided SARM1 inhibitor can be determined according to assays such as those 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 inhibitor can be applied to a solution containing SARM1 or a fragment thereof. In some embodiments, the provided SARM1 inhibitor can be applied to an in vitro system. In some embodiments, the provided SARM1 inhibitor can be applied in vivo. In some embodiments, the provided SARM1 inhibitor can be applied to a patient. In some embodiments, the SARM1 inhibitor can be mixed with SARM1 or a fragment thereof that has been labeled with an additional epitope. In some embodiments, the amount of bound SARM1 inhibitor can be compared to the amount of unbound SARM1 inhibitor to yield an affinity for the SARM1 inhibitor.

[0331] In some embodiments, a mutant or fragment of SARM1 is the constitutively active SAM-TIR fragment. Constitutively active SARM1 fragments include, for example but not limited to, SARM1 lacking the autoinhibitory domain; at least one point mutation in SARM1 that inactivates the autoinhibitory domain; an SARM1 fragment containing the TIR domain; or an SARM1 fragment consisting of the SAM and TIR domains. In some embodiments, the SARM1 polypeptide can include one or more additional amino acid sequences that can serve as tags, such as His tags, streptavidin tags, or combinations thereof. In some embodiments, the SARM1 polypeptide can include a tag at the amino terminus, carboxyl terminus, or a combination thereof. In some embodiments, SARM1 or a fragment thereof labeled with an additional epitope can be used to assay the binding potency of the provided SARM1 inhibitor.

[0332] Purification of the SARM1-TIR Domain

[0333] In some embodiments, the SARM1-TIR domain can be engineered with various useful proteins or epitopes, tags, such as proteins or epitopes, tags useful for 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 or cDNA. In some embodiments, HEK293T cells are stably or transiently transfected with DNA encoding NRK1 that is exogenous to 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, whether genomic or cDNA, comprises an expression vector, such as an FCIV expression vector. In some embodiments, the DNA encoding NRK1 is derived from genomic DNA or cDNA of a vertebrate or invertebrate species, such as but not limited to human, mouse, zebrafish, or Drosophila. In some configurations, the NRK1 DNA is human NRK1 DNA.

[0334] Applications and uses

[0335] The present disclosure provides various uses and applications of the compounds and / or compositions described herein, such as according to their activities and / or properties described herein. In some embodiments, the uses can include therapeutic and / or diagnostic uses. Alternatively, in some embodiments, such uses can include research, production, and / or other technical uses.

[0336] In one aspect, the present disclosure provides methods comprising administering to an individual one or more compounds of Formula I, for example, to treat, prevent, or reduce the risk of occurrence of one or more disorders characterized by axonal degeneration. In some such embodiments, the compound of Formula I is a SARM1 inhibitor.

[0337] Another embodiment of the present disclosure relates to methods of inhibiting SARM1 activity in a patient, comprising the step of administering to the patient the provided compound or a composition comprising the compound.

[0338] Inhibition of enzymes in biological samples can be used for a variety of 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.

[0339] In certain embodiments, the present disclosure relates to methods of treating axonal degeneration in a biological sample, the method comprising the step of contacting the biological sample with a compound or composition of Formula I. In some embodiments, one or more of the compounds and / or compositions described herein can be used, for example, in methods for inhibiting the degradation of neurons derived from an individual. In some embodiments, one or more of the compounds and / or compositions 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 described herein can be used as a stabilizer to promote neuronal survival in vitro.

[0340] In some embodiments, the provided compounds and / or compositions inhibit the NADase activity of SARM1. Alternatively 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 disorders associated with axonal degeneration.

[0341] In some embodiments, one or more of the compounds and / or compositions described herein can be used, for example, in pharmaceutical practice. In some embodiments, one or more of the compounds and / or compositions 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 of the compounds and / or compositions 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 of the compounds and / or compositions described herein can be used, for example, to prevent axonal degeneration distal to axonal injury.

[0342] In some embodiments, one or more of the compounds and / or compositions described herein can be used, for example, in methods for inhibiting the degradation of neurons or portions thereof of the peripheral nervous system. In some embodiments, one or more of the compounds and / or compositions described herein can be used, for example, in methods 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 described herein are characterized in that, when administered to a population of individuals, they reduce one or more symptoms or characteristics of neurodegeneration. For example, in some embodiments, the relevant symptoms or characteristics can be selected from the degree, rate, and / or time of neuronal destruction.

[0343] In certain embodiments, the present disclosure provides compounds that can be used, according to the present disclosure, as, for example, analytical tools, probes in biassays, or therapeutic agents. The compounds provided by the present disclosure can also be used to study the activity of SARM1 in biological and pathological phenomena, and to comparatively evaluate the activity of 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 (such as certain vector constructs and / or polypeptides) that can be used to assay SARM1 activity. For example, in some embodiments, the provided assay can utilize, for example, SAM-TIR (wherein the SARM1 N-terminal autoinhibitory domain is deleted), and / or one or more tagged forms of the TIR domain.

[0344] In some embodiments, one or more of the compounds and / or compositions described herein can be used, for example, in methods for inhibiting the degradation of neurons derived from an individual. In some embodiments, one or more of the compounds and / or compositions 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 described herein can be used as stabilizers to promote neuron survival in vitro.

[0345] In some embodiments, one or more of the compounds and / or compositions described herein can be used, for example, to affect biomarkers associated with neurodegeneration. In some embodiments, changes in the biomarkers can be detected systemically or with samples from cerebrospinal fluid (CSF), plasma, serum, and / or tissue from an individual. In some embodiments, one or more of the compounds and / or compositions can be used to affect changes in the concentration of neurofilament light (NF-L) and / or neurofilament heavy (NF-H) contained in the cerebrospinal fluid of an individual. In some embodiments, one or more of the compounds and / or compositions described herein can affect the constitutive NAD and / or cADPR levels in neurons and / or axons.

[0346] 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 an individual. The 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, phosphorylated-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.

[0347] Diseases, disorders and conditions

[0348] In some embodiments, the compounds and / or compositions described herein can be administered to an individual having one or more diseases, disorders, or conditions.

[0349] In some embodiments, the condition is an acute condition. In some embodiments, the condition is a chronic condition.

[0350] In some embodiments, the condition is characterized by axonal degeneration in the central nervous system, peripheral nervous system, optic nerve, cranial nerves, or a combination thereof.

[0351] In some embodiments, the condition is or includes an acute injury to the central nervous system, such as a spinal cord injury and / or a traumatic brain injury. In some embodiments, the condition is or includes a chronic injury to the central nervous system, such as a spinal cord injury, a traumatic brain injury, and / or a traumatic axonal injury. In some embodiments, the condition is or includes chronic traumatic encephalopathy (CTE).

[0352] In some embodiments, the condition is a chronic condition affecting the central nervous system, such as Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, or Huntington's disease, Alzheimer's disease.

[0353] In some embodiments, the disorder is an acute peripheral neuropathy. Chemotherapy-induced peripheral neuropathy (CIPN) is an example of an acute peripheral neuropathy. CIPN can be associated with various drugs, such as but not limited to thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

[0354] In some embodiments, the disorder is a chronic disorder affecting the peripheral nervous system, such as diabetic neuropathy, HIV neuropathy, Charcot-Marie-Tooth disease, or amyotrophic lateral sclerosis.

[0355] In some embodiments, the disorder is an acute disorder affecting the optic nerve, such as acute optic neuropathy (AON) or acute angle-closure glaucoma.

[0356] In some embodiments, the disorder is a chronic disorder affecting the optic nerve, such as Leber's congenital amaurosis, Leber hereditary optic neuropathy, primary open-angle glaucoma, and autosomal dominant optic atrophy.

[0357] In some embodiments, one or more of the compounds and / or compositions described herein can be used, for example, to treat one or more neurodegenerative diseases, disorders, or conditions selected from neuropathies or axonopathies. In some embodiments, one or more of the compounds and / or compositions described herein can be used, for example, to treat neuropathies or axonopathies associated with axonal degeneration. In some embodiments, neuropathies associated with axonal degeneration are hereditary or congenital neuropathies or axonopathies. In some embodiments, neuropathies associated with axonal degeneration are caused by de novo or somatic mutations. In some embodiments, neuropathies associated with axonal degeneration are selected from the list included herein. In some embodiments, neuropathies or axonopathies associated with axonal degeneration include but are not limited to Parkinson's disease, non-Parkinson's disease, Alzheimer's disease, herpes infections, diabetes, amyotrophic lateral sclerosis, demyelinating diseases, ischemia or stroke, chemical injury, thermal injury, and AIDS.

[0358] In some embodiments, one or more of the compounds or compositions described herein are characterized in that, when administered to a population of individuals, they reduce one or more symptoms or features of neurodegeneration. For example, in some embodiments, the relevant symptoms or features may be selected from the degree, rate, and / or timing 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 arborization, 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 capacity, 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.

[0359] In some embodiments, neurodegenerative or neurological diseases or disorders are associated with axonal degeneration, axonal injury, axonopathy, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or conditions, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal injury resulting from 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's 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, chemotherapy neurological complications (chemotherapy-induced neuropathy; CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, glaucoma, Leber's hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis, human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy, West Nile virus encephalitis, La Crosse virus encephalitis, bunyavirus encephalitis, pediatric viral encephalitis, 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, age-related hearing loss, dementia with Lewy bodies, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, intestinal 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 settlement disease, Strumpell-Lorrain disease, and non-alcoholic steatohepatitis (NASH).

[0360] 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.

[0361] In some embodiments, the present disclosure also 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 resulting from leukodystrophy or cerebral leukodystrophy.

[0362] In some embodiments, neuropathy and axonopathy include any disease or condition involving neurons and / or supporting cells such as glia, muscle cells, or fibroblasts, particularly those diseases or conditions associated with axonal injury. Axonal injury can be caused by traumatic injury or non-mechanical injury caused by a disease, condition, or exposure to a toxic molecule or drug. The result of such injury can be axonal degeneration or dysfunction, as well as loss of functional neuronal activity. The diseases and conditions that produce or are associated with such axonal injury are particularly many neurological diseases and conditions. The neuropathy can include peripheral neuropathy, central neuropathy, and combinations thereof. In addition, manifestations of peripheral neuropathy can be produced by diseases primarily focused on the central nervous system, and manifestations of the central nervous system can be produced substantially by peripheral or systemic diseases.

[0363] In some embodiments, peripheral neuropathy can involve damage to the peripheral nerves and / or can be caused by diseases of the nerves or as a result of systemic diseases. Some of the said 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. The said conditions that damage the peripheral nerves include compressive or squeezing injuries such as glaucoma, carpal tunnel syndrome, direct trauma, penetrating injury, contusion, fracture, or bone dislocation; pressure on superficial nerves (ulnar, radial, or peroneal) that can be caused by prolonged use of crutches or staying in one position for too long or tumors; intraneural hemorrhage; ischemia; exposure to cold or radiation or certain drugs or toxic substances such as herbicides or pesticides. In particular, chemical injury caused by cytotoxic anticancer substances such as paclitaxel, cisplatin, proteasome inhibitors, or vinca alkaloids such as vincristine can lead to nerve damage. The typical symptoms of the said peripheral neuropathy include weakness, numbness, sensory disturbances (paresthesias such as burning pain, itching, tingling, or numbness), and pain in the arms, hands, legs, and / or feet. In some embodiments, the neuropathy is associated with mitochondrial dysfunction. The neuropathy can manifest as reduced energy levels, i.e., reduced NAD and ATP levels.

[0364] 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, etc. The common feature of these diseases is that they are related to the peripheral nerves due to structural or functional changes in myelin and axons caused by dysregulation of metabolic pathways.

[0365] In some embodiments, the neuropathy includes optic neuropathy, such as glaucoma; retinal ganglion degeneration, such as those associated with retinitis pigmentosa and outer retinal neuropathy; optic neuritis and / or degeneration, including optic neuritis and / or degeneration associated with multiple sclerosis; traumatic injury to the optic nerve, which can include, for example, injury during tumor removal; hereditary optic neuropathy, such as Kjer disease and Leber hereditary optic neuropathy; ischemic optic neuropathy, such as those secondary to giant cell arteritis; metabolic optic neuropathy, such as neurodegenerative diseases, including the previously mentioned Leber neuropathy, nutritional deficiencies such as vitamin B12 or folic acid deficiency, and toxicities such as those due to 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.

[0366] 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 affecting muscle function, such as Parkinson's disease, motor neuron disease, and progressive ataxia, such as amyotrophic lateral sclerosis; demyelinating diseases, such as multiple sclerosis; viral encephalitis, such as those 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 (such as chemotherapeutic agents), can lead to central nervous system neuropathy.

[0367] In some embodiments, the present disclosure provides methods for treating neuropathy or axonopathy associated with axonal degeneration. In some such embodiments, the neuropathy or axonopathy associated with axonal degeneration can be any of a number of neuropathies or axonopathies, such as those that are hereditary or congenital or associated with 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 diseases mentioned above can also be treated with the methods of the present disclosure. The said subsets of diseases can include Parkinson's disease or non-Parkinson's disease, or Alzheimer's disease.

[0368] Individual

[0369] In some embodiments, a compound and / or composition as described herein is administered to an individual having or at risk of having a disease, disorder, or condition as described herein; in some embodiments, the disease, disorder, or condition is characterized by axonal degeneration, such as one of the conditions mentioned herein.

[0370] In some embodiments, an individual to whom a compound or composition as described herein is administered exhibits one or more signs or symptoms associated with axonal degeneration; in some embodiments, the individual does not exhibit any signs or symptoms of neurodegeneration.

[0371] In some embodiments, the provided methods include administering a compound of Formula I to a patient in need thereof. In some such embodiments, the patient is at risk of developing a disorder characterized by axonal degeneration. In some embodiments, the patient has a disorder characterized by axonal degeneration. In some embodiments, the patient has been diagnosed with a disorder characterized by axonal degeneration.

[0372] In some embodiments, the provided methods include administering a composition as described herein to a population of patients in need thereof. In some embodiments, the population is drawn from individuals engaged in activities with a high likelihood of traumatic neuronal injury. In some embodiments, the population is drawn from athletes engaged in contact sports or other high-risk activities.

[0373] In some embodiments, an individual is at risk of developing a disorder characterized by axonal degeneration. In some embodiments, the individual is identified as being at risk of axonal degeneration, for example, based on the individual's genotype, a diagnosis of a condition associated with axonal degeneration, and / or exposure to an agent and / or condition that induces axonal degeneration.

[0374] In some embodiments, a 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. 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, and in some embodiments, the patient has one or more copies of the ApoE4 allele.

[0375] In some embodiments, an individual to whom a compound or composition as described herein is administered can be or include an individual suffering from or predisposed to a neurodegenerative disease, disorder, or condition. In some embodiments, the neurodegenerative disease, disorder, or condition can be or include traumatic neuronal injury. In some embodiments, traumatic neuronal injury is blunt force trauma, closed head injury, open head injury, exposure to shock and / or blast forces, or a penetrating injury within or reaching into the cranial cavity or innervated regions of the body. In some embodiments, traumatic neuronal injury is a force that causes axonal deformation, stretching, crushing, or shearing.

[0376] In some embodiments, an individual engages in activities identified as risk factors for neuronal degradation, e.g., an individual engaged in contact sports or occupations that have a high chance of traumatic neuronal injury.

[0377] For example, the individual can be a patient receiving or 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).

[0378] In some embodiments, the provided methods include administering a composition as described herein to a patient or patient population based on the presence or absence of one or more biomarkers. In some embodiments, the provided methods further include monitoring the levels of the biomarkers in the patient or patient population and adjusting the dosing regimen accordingly.

[0379] Administration

[0380] 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 can be selected by a practicing physician and can be different for different individuals, e.g., after considering one or more of the species, age, and general condition of the individual and / or the properties of the specific 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 can be standardized within a relevant patient population (e.g., all patients, all patients of a particular age or disease stage, or expressing a particular biomarker, etc.).

[0381] The compounds or compositions provided by the present disclosure are preferably formulated in unit dosage forms for ease of administration and dosage uniformity. The expression "unit dosage form" as used herein refers to physically discrete units of medicaments suitable for the patient to be treated. However, it should be understood that the total daily dosage of the compounds or compositions provided by the present disclosure 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 disorder; the activity of the particular compound used; the specific composition employed; 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 particular compound used; the duration of the treatment; drugs used in combination with or concurrently with the particular compound employed, 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, as required for preventing or treating an undesirable disease or disorder, such as neurodegeneration or traumatic nerve injury.

[0382] The pharmaceutically acceptable compositions of the present disclosure can be administered orally, rectally, intravenously, parenterally, intracisternally, vaginally, intraperitoneally, topically (such as by powder, ointment or drops), sublingually, as an oral or nasal spray, etc. to humans and other animals, depending on the severity of the disease, disorder or infection being treated. In certain embodiments, the daily dosage is administered as a single daily dose or as 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 according to a regimen of once to four times a day, preferably once or twice a day.

[0383] In some embodiments, the compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intradermal, intraocular, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously.

[0384] In some embodiments, the pharmaceutically acceptable compositions of the present disclosure can also be administered topically, especially when the target to be treated includes areas or organs that are readily accessible by topical administration, including diseases of the eye, skin or lower intestine. Suitable topical formulations are readily prepared for each of these areas or organs.

[0385] Most preferably, the pharmaceutically acceptable compositions of the present disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered with food.

[0386] Those additional active agents may be administered separately from the provided compound or its composition as part of a multi-dose regimen. Alternatively, those active agents may 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 may be administered simultaneously, sequentially, or within a period of time, usually within five hours of each other.

[0387] It should also be understood that the specific dosage and treatment regimen for any particular patient may 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 attending physician, as well as the severity of the specific 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.

[0388] In some embodiments, the SARM1 inhibition described herein may be used in combination with one or more other therapies to treat related diseases, disorders, or conditions. In some embodiments, when used in combination therapy, the dose of the SARM1 inhibitor is altered compared to when administered as a single therapy; alternatively or additionally, in some embodiments, the therapies administered in combination with SARM1 inhibition as described herein are administered according to a different protocol or regimen than when administered alone or in combination with one or more therapies that are not SARM1 inhibition. In some embodiments, the composition comprising an additional therapeutic agent, the additional therapeutic agent and the provided compound may act synergistically. In some embodiments, one or both of the therapies used in the combination regimen are administered at a lower level or frequency than when used as a single therapy.

[0389] In some embodiments, the compounds and / or compositions described herein are administered with a chemotherapeutic agent, the chemotherapeutic agent 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

[0390] This teaching includes the descriptions provided in the embodiments, which are not intended to limit the scope of any claims. Unless specifically stated in the past tense, the inclusion of an embodiment is not intended to imply that the experiment was actually completed. The following non-limiting embodiments are provided to further illustrate this teaching. Those skilled in the art should understand according to the present disclosure that many changes can be made in the specific embodiments disclosed without departing from the gist and scope of this teaching, and still obtain the same or similar results.

[0391] Method

[0392] Some of the methods and compositions described herein utilize laboratory techniques well known to those skilled in the art, and such laboratory techniques 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, edited by 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. The methods of administering a drug and the dosage regimen can be determined according to standard pharmacological principles using the methods provided in standard references such as Remington: the Science and Practice of Pharmacy (edited by Alfonso R. Gennaro, 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.

[0393] Example 1: Synthesis of the Compound

[0394] General synthetic methods

[0395] The compounds of the present invention and their intermediates 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. Variants of reaction methods known to those skilled in the art but not described in detail herein can also be used.

[0396] The general methods for preparing the compounds of the present invention will be apparent to those skilled in the art studying the following schemes. The starting materials can be prepared by the 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 using methods familiar to those skilled in the art at appropriate stages within the reaction sequence.

[0397] The optimal reaction conditions and reaction times can vary depending on the specific reactants used. Unless otherwise stated, the solvents, temperature, pressure, and other reaction conditions can be readily selected by those of ordinary skill in the art. 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). The separated enantiomers can be obtained by resolving the racemic products using chiral HPLC. The RP-HPLC purification method anywhere uses a solution of 0 - 100% acetonitrile in water, which contains 0.1% formic acid, 0.1 - 0.01% TFA, 10 mM aqueous ammonium bicarbonate, or 0.2% aqueous ammonium hydroxide, and uses one of the following columns:

[0398] Waters Xbridge C18 10μm 30x100 mm column

[0399] Waters Sunfire C18 10μm 30x100 mm column

[0400] Waters Xbridge C18 3.5μm 50x4.6 mm column

[0401] HALO C18 2.7μm 30x4.6 mm column

[0402] Waters Sunfire C18 3.5μm 50x4.6 mm column

[0403] Synthetic Example A: Synthesis of Example 105

[0404]

[0405] At 0 °C, diisopropyl azodicarboxylate (8.08 g, 40 mmol) was added dropwise to a solution of R-2 (6.63 g, 33 mmol) and triphenylphosphine (10.5 g, 40 mmol) in THF (150 mL). After 5 minutes, a solution of R-2 (4.2 g, 30 mmol) in THF (10 mL) was added. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, petroleum ether:acetone = 2:1) to give I-1 (7.3 g, 75%).

[0406] At room temperature, LiBH4 (11.46 g, 526 mmol) was added portionwise to a solution of I-1 (8.5 g, 26.3 mmol) in anhydrous THF (80 mL). The mixture was stirred at 60 °C for 16 h. The reaction mixture was cooled to 0 °C, then EtOAc (100 mL) was added dropwise, followed by saturated aqueous NH4Cl (100 mL) and water (50 mL) at 0 °C. The mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, acetone:petroleum ether = 1:1) to give I-2 (3.08 g, 41.5%).

[0407] A suspension of manganese(IV) oxide (8.14 g, 93.6 mmol) and I-2 (2.63 g, 9.36 mmol) in acetone (50 mL) was stirred at 60 °C for 6 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, petroleum ether:EtOAc = 1:1) to give I-3 (2.4 g, 92%).

[0408] A solution of I-3 (2.4 g, 8.6 mmol) and Example 159 (1.08 g, 8.6 mmol) in EtOH (40 mL) was stirred at 80 °C overnight. The mixture was cooled to room temperature and sodium triacetoxyborohydride (5.47 g, 25.8 mmol) was added portionwise. The mixture was stirred at room temperature for 16 h, then poured into water (80 mL) and extracted with EtOAc (50 mL x 4). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, petroleum ether:EtOAc = 1:3) to give Example 103 (1.47 g, 44%).

[0409] A solution of Example 103 (1.47 g, 3.78 mmol) in MeOH (20 mL) was added to HCl / dioxane (4 M, 10 mL), and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was purified by preparative-HPLC to give Example 105 (837 mg, 77%).

[0410] The following examples were prepared in a similar manner from the appropriate reagents: Examples 62, 104, 106, 119 - 120, 141 - 142, 147 - 148, and 205.

[0411] Synthesis Example B: Synthesis of Example 20

[0412]

[0413] A mixture of Example 206 (7.0 g, 56 mmol) and R-3 (6.5 g, 68 mmol) in EtOH (50 mL) was stirred overnight at 60 °C. The mixture was cooled to room temperature, and NaBH4 (8.6 g, 224 mmol) was added portionwise. The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (100 mL), and then extracted with EtOAc (300 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, petroleum ether:EtOAc = 1:1) to give the crude product, which was further purified by stirring in EtOAc (50 mL) and petroleum ether (10 mL) at room temperature for 2 h, filtered, and dried to give Example 38 (2.6 g, 21%).

[0414] The following examples were prepared in a similar manner from the appropriate aniline and aldehyde reagents: Examples 7 - 10, 12, 14, 18 - 22, 26 - 27, 33 - 34, 36 - 42, 44, 47 - 61, 64 - 70, 73, 75 - 76, 85 - 93, 97, 100 - 101, 109, 113 - 114, 118, 121, 123, 126 - 132, 143 - 146, 154 - 158, 170, 178 - 179, 181 - 185, 194, 203 - 204, 206, 210, and 214 - 216.

[0415] Synthesis Example C: Synthesis of Example 3

[0416]

[0417] R-4 (50 mg, 0.315 mmol), R-5 (69 mg, 0.315 mmol), triethylamine (88 uL, 0.631 mmol) and NMP (1 mL) were added to a pressure tube and sealed. The reaction was stirred and heated to 160 °C for 24 h. The reaction mixture was cooled to ambient temperature and purified by preparative HPLC to give Example 3 (17 mg, 16%).

[0418] The following examples were prepared in a similar manner from suitable heteroaryl halides and amines: Examples 4 - 6, 180 and 186 - 187.

[0419] Synthetic Example D: Synthesis of Example 111

[0420]

[0421] Example 160 (50 mg, 0.36 mmol) and R-6 (96 mg, 0.539 mmol) were dissolved in CH2Cl2 (1 mL). Triethylamine (0.15 mL, 1.08 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with water (2 mL) and CH2Cl2 (2 mL) and passed through a Telos phase separator. A further 2 mL of CH2Cl2 was passed through the phase separator. The combined organic layers were concentrated in vacuo to give a crude residue which was purified by preparative HPLC to give the title compound, Example 111 (16 mg, 17%).

[0422] The following examples were prepared in a similar manner from suitable anilines and acyl chlorides: Examples 23, 46 and 110.

[0423] Synthetic Example E: Synthesis of Example 71

[0424]

[0425] Aniline (22 mg, 0.241 mmol) and pyridine (0.097 mL, 1.20 mmol) were suspended in CH2Cl2 (5 mL), cooled to 0 °C and stirred for 5 min. R-9 (50 mg, 0.241 mmol) was added to the reaction mixture and the reaction mixture was stirred for 10 min. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give Example 71 (22 mg, 35%).

[0426] Synthetic Example F: Synthesis of Example 11

[0427]

[0428] R-10 (50 mg, 0.359 mmol) and R-11 (69 μL, 0.539 mmol) were dissolved in CH2Cl2 (2 mL). Triethylamine (0.15 mL, 1.08 mmol) was added, and the reaction mixture was stirred at room temperature for 17 h. The mixture was washed with water (2 mL) and then passed through a Telos phase separator. Additional CH2Cl2 (2 mL) was passed through the phase separator. The combined organic layers were concentrated in vacuo to give the crude product. The crude material was purified by preparative HPLC to give Example 11 (6.0 mg, 5.9%).

[0429] The following examples were prepared in a similar manner from the appropriate aniline and sulfonyl chloride: Examples 17, 195, and 207 - 209.

[0430] Synthetic Example G: Synthesis of Example 23

[0431]

[0432] R-12 (5.00 g, 20.6 mmol), triethylamine (8.6 mL, 61.8 mmol) and R-13 (2.29 g, 20.6 mmol) were suspended in DMF (10 mL). The reaction mixture was sealed under a nitrogen atmosphere and stirred at 80 °C for 1 h, then cooled to room temperature and partitioned between EtOAc (20 mL) and brine (20 mL). The organic phase was separated and concentrated in vacuo to give the crude material, which was purified by flash chromatography (KP-NH SiO2, heptane / EtOAc) to give I-4 (1.49, 26%).

[0433] I-4 (45 mg, 0.169 mmol), (1{E},4{E})-1,5-diphenylpenta-1,4-dien-3-one; palladium (7.7 mg, 8.46 μmol), di-tert-butyl-[2-(1,3,5-triphenylpyrazol-4-yl)pyrazol-3-yl]phosphane (8.6 mg, 0.0169 mmol) and potassium hydroxide (11 mg, 0.186 mmol) were suspended in trifluoroethanol (1 mL), and the mixture was degassed with nitrogen for 10 min. The reaction mixture was sealed under a nitrogen atmosphere and stirred at 70 °C for 2 h. The reaction mixture was diluted with EtOAc (5 mL), filtered and reduced in vacuo to give the crude product. The crude material was purified by preparative HPLC to give Example 117 (12 mg, 29%).

[0434] The following examples were prepared in a similar manner from suitable heteroaryl halides, amines, and alcohols: Examples 13, 15, 35, 74, 96, 108, 115 - 116, 140, 151, 153, 161 - 164, 166 - 169, 172 - 174, 177, 190, 198 - 199, and 201 - 202.

[0435] Synthetic Example H: Synthesis of Example 24

[0436]

[0437] At room temperature, R - 12 (100 mg, 0.649 mmol), 1 - [bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5 - b]pyridin - 1 - ium 3 - oxide hexafluorophosphate (370 mg, 0.973 mmol), and N - ethyl - N - isopropyl - propan - 2 - amine (0.34 mL, 1.95 mmol) were suspended in DMF (1 mL) and stirred for 10 minutes. R - 8 (80 mg, 0.714 mmol) was added to the reaction mixture, and the reaction mixture was stirred for 2 hours. The reaction mixture was purified by preparative HPLC to give Example 24 (92 mg, 55%).

[0438] The following examples were prepared in a similar manner from suitable amines and acylating agents: Examples 191 - 193 and 196 - 197.

[0439] Synthetic Example I: Synthesis of Example 31

[0440]

[0441] R-15 (0.14 mL, 1.06 mmol), R-14 (100 mg, 0.529 mmol), potassium hydroxide (33 mg, 0.582 mmol), di-tert-butyl-[2-(1,3,5-triphenylpyrazol-4-yl)pyrazol-3-yl]phosphane (27 mg, 0.0529 mmol), (1{E},4{E})-1,5-diphenylpenta-1,4-dien-3-one; palladium (24 mg, 0.0265 mmol) were suspended and then dissolved in 1,4-dioxane (2 mL). The reaction mixture was purged with N2. The reaction mixture was heated to 100 °C for 18 h. Additional (1{E},4{E})-1,5-diphenylpenta-1,4-dien-3-one; palladium (24 mg, 0.0265 mmol) and di-tert-butyl-[2-(1,3,5-triphenylpyrazol-4-yl)pyrazol-3-yl]phosphane (72 mg, 0.0529 mmol) were added and the reaction was heated to 120 °C for 24 h. The reaction mixture was cooled to room temperature and diluted with water (2 mL). The mixture was extracted with EtOAc (3 x 2 mL), the combined organic layers were passed through a Telos phase separator and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give Example 31 (5.0 mg, 4.1%).

[0442] The following examples were prepared in a similar manner from suitable heteroaryl halides and amines: Examples 16, 25, 30, 32, 43, and 45.

[0443] Synthetic Example J: Synthesis of Example 28

[0444]

[0445] R-16 (100 mg, 0.377 mmol) was dissolved in 1,4-dioxane (3 mL) and pyrazole (51 mg, 0.754 mmol), N,N'-dimethylethane-1,2-diamine (0.020 mL, 0.189 mmol) and cesium carbonate (270 mg, 0.830 mmol) were added. The reaction mixture was degassed for 5 min and then copper(I) iodide (14 mg, 0.0754 mmol) was added. The reaction mixture was stirred at 120 °C for 4 h. The reaction mixture was diluted with EtOAc (10 mL) and filtered through a glass fiber filter paper. The organic phase was washed with saturated aqueous NaHCO3 (2 x 10 mL) and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give Example 28 (68 mg, 70%).

[0446] Synthetic Example K: Synthesis of Example 63

[0447]

[0448] A mixture of R-17 (6.0 g, 33 mmol), concentrated HCl (12 M, 18 mL, 216 mmol), and 10% Pd / C (0.6 g) in MeOH (250 mL) was degassed three times and refilled with H2. The reaction mixture was stirred at room temperature under a H2 balloon for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with EtOAc (100 mL) and dried under vacuum to give I-5 (7.0 g, 95%).

[0449] A mixture of I-5 (33 g, 148 mmol), R-18 (20 g, 134.5 mmol), and DIPEA (122 mL, 740 mmol) in NMP (200 mL) was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (1500 mL), and washed with water (200 mL x 2) and brine (200 mL x 3). The organic layer was concentrated under reduced pressure. The residue was washed with MeOH to give I-6 (32 g, 79%).

[0450] A mixture of I-6 (16 g, 53.7 mmol) in 30% MeONa / MeOH solution (250 mL) was stirred at 50 °C for 18 hours. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was neutralized to pH = 7 with 6 mol / L HCl at 0 °C and then concentrated under reduced pressure to about 200 mL. The solid was filtered and washed with water. The resulting solid was dissolved in DMF (60 mL) and purified by preparative-HPLC to give Example 63 (8.5 g, 54%).

[0451] Example 211 was prepared in a similar manner.

[0452] Synthesis Example L: Synthesis of Example 29

[0453]

[0454] R-16 (100 mg, 0.377 mmol) was dissolved in DMF (2 mL), and sodium methanesulfinate (96 mg, 0.943 mmol) and N,N'-dimethylethane-1,2-diamine (0.020 mL, 0.189 mmol) were added. The reaction mixture was degassed for 5 min and then copper(I) iodide (14 mg, 0.0754 mmol) was added. The reaction mixture was heated to 120 °C and stirred for 3 h. The reaction mixture was diluted with EtOAc (10 mL) and filtered through a glass fiber filter paper. The filtrate was washed with saturated NaHCO3 (10 mL), and the organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give Example 29 (45 mg, 44%).

[0455] Synthesis Example M: Synthesis of Example 72

[0456]

[0457] Cesium carbonate (1027 mg, 3.15 mmol), cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (77 mg, 0.105 mmol) were suspended in DCE (2 mL) and acetic acid (10 μL). The reaction mixture was stirred at room temperature. R-19 (156 mg, 1.05 mmol) and R-12 (240 mg, 1.05 mmol) were added, and the reaction mixture was stirred for 3 h. The reaction mixture was quenched with water (2 mL) and extracted with DCM (3 x 2 mL), and the combined organic layers were passed through a Telos phase separator and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give Example 72 (65 mg, 24%).

[0458] Synthesis Example N: Synthesis of Example 77

[0459]

[0460] Example 74 (38 mg, 0.391 mmol) and morpholine (0.034 mL, 0.391 mmol) were suspended in toluene (2 mL). The reaction mixture was degassed for 5 min and then dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (9.3 mg, 0.0195 mmol) and (1{E},4{E})-1,5-diphenylpenta-1,4-dien-3-one; palladium (8.9 mg, 9.77 μmol) were added. The reaction mixture was heated at 100 °C and stirred for 2 h, then cooled to ambient temperature and partitioned between CH2Cl2 (3 mL) and water (3 mL). The mixture was filtered and concentrated, and then purified by preparative HPLC to give Example 77 (3.0 mg, 5%).

[0461] The following examples were prepared in a similar manner from suitable heteroaryl halides (Example 74 or Example 95) and amines: Examples 78-84, 98-99, 112, and 122.

[0462] Synthetic Example O: Synthesis of Example 107

[0463]

[0464] Example 105 (50 mg, 0.173 mmol) and methanesulfonyl chloride (15 μL, 0.191 mmol) were dissolved in CH2Cl2 (2 mL) and stirred at room temperature. Triethylamine (36 μL, 0.260 mmol) was added, and the reaction mixture was purged with N2 and stirred for 16 h. The reaction was quenched with water (2 mL), and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2 x 2 mL), the combined organic layers were passed through a Telos phase separator, and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give Example 107 (27 mg, 41%).

[0465] The following examples were prepared in a similar manner from suitable sulfonylating or acylating agents and Examples 20, 105, and 118: Examples 133-134, 149-150

[0466] Synthetic Example P: Synthesis of Examples 124 and 125

[0467]

[0468] Example 74 (100 mg, 0.399 mmol), R-20 (134 mg, 0.598 mmol), and 2 M aqueous potassium carbonate (0.40 mL, 0.798 mmol) were suspended in 1,4-dioxane (2 mL). The reaction mixture was degassed with nitrogen for 5 min, then cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (29 mg, 0.0399 mmol) was added, and degassed for an additional 5 min. The vial was sealed and stirred at 100 °C (externally) for 18 h. The reaction mixture was diluted with CH2Cl2, washed with brine, separated through a hydrophobic frit, the retained aqueous solution was washed with CH2Cl2, and separated. The combined organics were concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give Example 124 (79 mg, 64%).

[0469] Example 124 (79 mg, 0.254 mmol) was dissolved in ethanol (5 mL), and sodium acetate (63 mg, 0.761 mmol) and Pd / C (10%, 27 mg, 0.0254 mmol) were added. The reaction mixture was stirred under a H2 atmosphere for 24 hours. The reaction mixture was filtered through a Celite pad, washed with methanol, and the filtrate was concentrated under vacuum to give the crude product. The crude product was purified by preparative HPLC to give Example 125 (65 mg, 82%).

[0470] Synthesis method Q: Synthesis of Example 136

[0471]

[0472] A solution of R-21 (1.0 g, 7.75 mmol) in MeOH (20 ml) was added to MeONa (1.255 g, 23.25 mmol), and then stirred at 75 °C overnight. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, eluting with 65% EtOAc in petroleum ether) to give I-7 (500 mg, 51%).

[0473] A mixture of I-7 (306 mg, 2.4 mmol) and DIPEA (1.55 g, 12 mmol) in CH2Cl2 (15 ml) was added to R-22 (344 mg, 2.4 mmol), and then stirred at room temperature for 2 hours. The mixture was diluted with water (40 ml) and extracted with CH2Cl2 (150 ml x 4). The combined organic layers were washed with water and brine, dried, and concentrated under reduced pressure. The residue was purified by preparative-HPLC to give Example 136 (100 mg, 18%).

[0474] Example 137 was prepared in a similar manner from a suitable acylating agent.

[0475] Synthesis method R: Synthesis of Example 175

[0476]

[0477] To a solution of R-23 (5.5 g, 37.6 mmol) in methanol (100 ml) were added DIPEA (9.6 g, 75 mmol) and I-5 (7.0 g, 37.6 mmol). The reaction mixture was heated at 80 °C overnight. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0 to 15% methanol in dichloromethane) to give I-8 (3.4 g, 30%).

[0478] A suspension of I-8 (3.4 g, 11.4 mmol) in a solution of MeONa in methanol (30%, 10 mL, 57 mmol) was stirred at 80 °C overnight. Water (2 mL) was added, and then the mixture was concentrated under vacuum. The residue was purified by flash chromatography (SiO2, 0 to 20% methanol in dichloromethane) to give Example 175 (1.2 g, 36%).

[0479] The following examples were prepared from the appropriate amines in a similar manner: Example 95 and 176.

[0480] Synthetic Method S: Synthesis of Example 138

[0481]

[0482] EtMgBr (3 mol / L in THF, 3.3 mL, 9.9 mmol) was added dropwise to a solution of R-18 (1 g, 6.75 mmol) and iron(III) acetylacetonate (119 mg, 0.33 mmol) in THF (5 mL) and NMP (0.5 mL) at 0 °C, and then the mixture was stirred at 0 °C for 3 h. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (20 mL), and extracted with EtOAc (20 mL x 2). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to give I-9, which was used without further purification.

[0483] A solution of I-9 (150 mg, 1 mmol), R-24 (130 mg, 1.2 mmol), BINAP (62 mg, 0.1 mmol), Pd(dba)3 (45.8 mg, 0.05 mmol) and t-BuONa (144 mg, 1.5 mmol) in dioxane (3 mL) was stirred at 85 °C under a N2 atmosphere for 2 h. The mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc (20 mL) and water (15 mL). The organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative-HPLC to give Example 138 (55 mg, 24.3%).

[0484] Example 200 was prepared in a similar manner.

[0485] Synthetic Method T: Synthesis of Example 139

[0486]

[0487] A mixture of R-18 (5.0 g, 33.7 mmol), R-24 (4.37 g, 40.5 mmol) and K2CO3 (7.0 g, 50.6 mmol) in 1,4-dioxane (100 ml) was stirred overnight at 100 °C and then concentrated to dryness under reduced pressure. The residue was partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was washed with brine and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, ethyl acetate) to give I-10 (3.0 g, yield = 40%).

[0488] To a solution of I-10 (3.0 g, 13.6 mmol) in DMF (20 ml) and methanol (5 ml) was added Mo(CO)6 (2.15 g, 8.16 mmol), d2(dba)3 (1.2 g, 1.36 mmol) and dppf (1.5 g, 2.72 mmol). The mixture was purged with N2 and then sealed. The mixture was stirred overnight at 130 °C. The mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with water and brine and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 0 to 10% methanol in DCM) to give I-11 (2.2 g, 67%).

[0489] To a solution of methylamine in tetrahydrofuran (1 mol / L, 2 mL, 2 mmol) was added I-11 (100 mg, 0.41 mmol), and the mixture was then stirred at room temperature for 4 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 7% methanol in dichloromethane) to give Example 139 (20 mg, 20%).

[0490] The following examples were prepared in a similar manner: Examples 212 - 213.

[0491] Synthetic Method U: Synthesis of Example 94

[0492]

[0493] A suspension of R-25 (1.8 g, 14 mmol) in phosphorus oxychloride (25 ml) was rapidly heated to 75 °C under nitrogen and stirred until all solids had dissolved in the reaction mixture. The mixture was cooled to room temperature and then concentrated in vacuo. The residue was diluted with dichloromethane (100 ml) and washed with water (60 ml x 2). The organic layer was filtered through a silica pad. The silica gel was washed with EtOAc:petroleum ether (1:1). The filtrate was concentrated in vacuo to give I-12 (1.09 g, 52%).

[0494] A mixture of I-12 (200 mg, 1.4 mmol), R-24 (0.19 mL, 1.4 mmol), BINAP (173 mg, 0.27 mmol), t-BuONa (200 mg, 2 mmol) and Pd3(dba)2 (127 mg, 0.14 mmol) in dioxane (4 mL) was refluxed at 100 °C under nitrogen for 1 h. The mixture was added to water (30 mL) and extracted with EtOAc (50 mL×2). The organic phase was concentrated in vacuo and the residue was purified by preparative-HPLC to give Example 94 (20 mg, 15%).

[0495] Example 135 was prepared from the appropriate amine in a similar manner.

[0496] Synthetic Method V: Synthesis of Examples 188 and 189

[0497]

[0498] R-26 (0.22 mL, 1.03 mmol) and R-27 (113 mg, 1.03 mmol) were suspended in 1,4-dioxane (2 mL) and sodium hydride (60%, 45 mg, 1.14 mmol) was added thereto. The resulting mixture was placed at room temperature and stirred under a nitrogen atmosphere for 2 h. The reaction mixture was cooled to room temperature and quenched with water (5 mL) and partitioned between ethyl acetate (20 mL) and brine (20 mL). The organic phase was separated and concentrated in vacuo. The crude material was purified by preparative HPLC to give Example 188 (26 mg, 9.4%) and Example 189 (35 mg, 15%).

[0499] Example 2. Characterization of the compound

[0500] LCMS method:

[0501] Analytical LC / MS analysis method A:

[0502] ESI+ / - ion mode 150 - 850 Da

[0503] Column: Phenomenex Kinetix-XB C18, Part No. 00D-4498-AN, 2.1 x 100 mm, 1.7 μm

[0504] Temperature: 40 °C

[0505] Gradient:

[0506] Time (min) 0.1% formic acid aqueous solution Acetonitrile Flow rate (mL / min) 0 95％ 5％ 0.6 5.30 0％ 100％ 0.6 5.80 0％ 100％ 0.6 5.82 95％ 5％ 0.6 7.00 95％ 5％ 0.6

[0507] Analytical LC / MS analysis method B:

[0508] ESI + / - ion mode 150 - 850 Da

[0509] Column: Waters BEH TM C18, Part No. 186002352, 2.1 x 100 mm, 1.7 μm

[0510] Temperature: 40 °C

[0511] Gradient:

[0512]

[0513]

[0514] Analytical LC / MS analysis method C:

[0515] ESI + / - ion mode 100 - 1000 Da

[0516] Column: HALO C18 2.7 μm 30 x 4.6 mm column

[0517] Temperature: 40 °C

[0518] Gradient:

[0519] Time (min) 0.01% TFA aqueous solution Acetonitrile with 0.01% TFA Flow rate (mL / min) 0 95％ 5％ 2.2 1.0 5％ 95％ 2.2

[0520] Analytical LC / MS analysis method D:

[0521] ESI + / - ion mode 150 - 850 Da

[0522] Column: Phenomenex Gemini NX C18, Part No. 00D - 4453 - B0, 3.0 μm 2.0 x 100 mm column

[0523] Temperature: 40 °C

[0524] Gradient:

[0525]

[0526] Analytical LC / MS analysis method E:

[0527] ESI + / - ion mode 100 - 1000 Da

[0528] Column: XBridge C18, 3.5 μm 4.6 x 50 mm column

[0529] Temperature: 50 °C

[0530] Gradient:

[0531]

[0532] Analysis of LC / MS analysis method F:

[0533] ESI+ / - ion mode 100 - 1000 Da

[0534] Column: XBridge C18, 3.5μm 4.6x50mm column

[0535] Temperature: 40 °C

[0536] Gradient:

[0537]

[0538] Analysis of LC / MS analysis method G:

[0539] ESI+ / - ion mode 100 - 1000 Da

[0540] Column: XBridge SB-C18, 3.5μm 4.6x50mm column

[0541] Temperature: 40 °C

[0542] Gradient:

[0543]

[0544] Analysis of LC / MS analysis method H:

[0545] ESI+ / - ion mode 100 - 1000 Da

[0546] Column: XBridge C18, 3.5μm 4.6x50mm column

[0547] Temperature: 40 °C

[0548] Gradient:

[0549]

[0550] Analysis of LC / MS analysis method I:

[0551] ESI+ / - ion mode 100 - 1000 Da

[0552] Column: XBridge C18, 3.5μm 4.6x50mm column

[0553] Temperature: 50 °C

[0554] Gradient:

[0555]

[0556] Analysis of LC / MS analysis method J:

[0557] ESI+ / - ion mode 100 - 1000 Da

[0558] Column: Zorbox SB - C18, 1.8μm 4.6 x 30 mm column

[0559] Temperature: 40 °C

[0560] Gradient:

[0561] Time (min) 0.01% TFA aqueous solution Acetonitrile with 0.01% TFA Flow rate (mL / min) 0.00 95％ 5％ 1.8 1.30 5％ 95％ 1.8 2.00 5％ 95％ 1.8

[0562] The results are listed in Table 1:

[0563] Table 1.

[0564]

[0565]

[0566]

[0567] Example 3: Determination of IC50 of ARM - SAM - TIR SARM1

[0568] This example describes the determination of ARM - SAM - TIR NAD enzyme activity and the use of this determination to measure the efficacy of a compound of formula I in blocking SARM1 - mediated NAD+ cleavage. This determination was optimized to characterize the potency of a compound of formula I in inhibiting SARM1 activity and to calculate the IC50 value of each compound. This determination utilizes full - length SARM1 containing the ARM, SAM, and TIR domains. As demonstrated herein, expression of this fragment without the auto - inhibitory N - terminal domain produces a constitutively active enzyme that cleaves NAD+.

[0569] Preparation of ARM - SAM - TIR lysate (STL)

[0570] Seed NRK1 - HEK293T cells at 20×10 6 cells / plate into 150 cm 2 plates. The next day, transfect the cells with 15 μg of the ARM - SAM - TIR expression plasmid SEQ ID NO: 1.

[0571]

[0572]

[0573]

[0574] At the time of transfection, the culture was supplemented with 1 mM NR to minimize the toxicity of overexpressed ARM-SAM-TIR. 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, 0.138 M NaCl; 0.0027 M KCl; pH 7.4). The cells were resuspended in PBS containing protease inhibitors (cOmpleteTM protease inhibitor cocktail, Roche product #11873580001) and cell lysates were prepared by sonication (Branson Sonifer 450, output = 3, 20 stroke events). The lysates were centrifuged (12,000×g, 4 °C, 10 minutes) to remove cell debris and the supernatant (containing ARM-SAM-TIR protein) was stored at -80 °C for later use in in vitro ARM-SAM-TIR NADase assays (see below). Protein concentration was determined by the Bicinconinic (BCA) method and used to normalize lysate concentration.

[0575] Determination of the ARM-SAM-TIR IC50 of the compound of formula I.

[0576] The enzyme assay was performed in 384-well polypropylene plates in Dulbecco's PBS buffer with a final assay volume of 20 μL. ARM-SAM-TIR lysate at a final concentration of 5 μg / mL was pre-incubated with each compound at a final assay concentration of 1% DMSO for 2 hours at room temperature. The reaction was initiated by adding NAD+ at a final assay concentration of 5 μM as the substrate. After incubation at room temperature for 2 hours, the reaction was terminated with 40 μL of 7.5% trichloroacetic acid in acetonitrile. NAD+ and ADPR concentrations were analyzed by a RapidFire high-throughput mass spectrometry system (Agilent Technologies, Santa Clara, CA) using an API 4000 triple quadrupole mass spectrometer (AB Sciex, Framingham, MA).

[0577] The results are listed in Table 2 below. Compounds with activity designated "A" provided an IC 50 <5 μM; compounds with activity designated "B" provided an IC of 5 - 15 μM 50 ; compounds with activity designated "C" provided an IC of 15.01 - 30 μM 50 ; compounds with activity designated "D" provided an IC 50 > 30 μM; nd: not determined.

[0578] Table 2.

[0579]

[0580]

[0581]

[0582] Example 4: Axonal degeneration index

[0583] This example illustrates an in vitro axonal degeneration assay for characterizing the compounds of Formula I. This assay is used to test the efficacy of the compounds of Formula I in preventing axonal degeneration in mouse dorsal root ganglion (DRG) explant cultures.

[0584] Mouse DRG hanging drop culture : Mouse dorsal root ganglion neurons (DRGs) 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. Then, the cells were triturated by gentle pipetting and washed three times with DRG growth medium (Neurobasal medium (Gibco) containing 2% B27 (Invitrogen), 100 ng / ml 2.5S NGF (Harland Bioproducts), 1 mM 5-fluoro-2'-deoxyuridine (Sigma), penicillin, and streptomycin). The cells were suspended in DRG growth medium. DRG explant cultures were created 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 per well) was slowly added.

[0585] Axonal degeneration assay: Axonal degeneration was induced by either manual axotomy using a scalpel blade or chemical toxic stimulation. After an appropriate experimental time period, the DRG cultures were fixed in 1% PFA plus sucrose and stored in the refrigerator prior to imaging. Brightfield images of DRG axons and cell bodies were collected using a 20x water immersion lens on a Phenix automated confocal microscope (PerkinElmer), and axon quantification was completed using an in-house developed script (Acapella, PerkinElmer).

Claims

1. Use of a compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing axonal degeneration, wherein the compound is selected from:

Images