SARM1 inhibitors

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 682,045, filed on June 7, 2018, which is incorporated herein by reference in its entirety.

[0003] Sequence Listing

[0004] This application contains a sequence listing, which is submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy created on June 6, 2019, named 2012800-0023_SL.txt, is 13,851 bytes in size. Background Art

[0005] Axon degeneration is a hallmark of a variety of neurological disorders including peripheral neuropathy, traumatic brain injury and neurodegenerative diseases (Gerdts et al., SARM1 activation triggers axon degeneration locally via NAD(+)destruction. Science 348, 2016, pp. 453-457, hereby incorporated 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 per year. Since the incidence of many of these diseases and disorders increases with age, their incidence is increasing rapidly as the population structure changes. Summary of the invention

[0006] The present disclosure provides technologies for, among other things, treating and / or preventing neurodegeneration (eg, for reducing axonal degeneration). In some embodiments, provided technologies inhibit SARM1.

[0007] In some embodiments, the present disclosure provides certain compounds and / or compositions that are useful in medicine, particularly for treating neurodegeneration (eg, for reducing axonal degeneration).

[0008] In some embodiments, the present disclosure provides a compound having a structure as shown in Formula I:

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein:

[0011] X 1 and X2 one of is selected from C and N and the other is C;

[0012] Y 1 Selected from N, and CR y1 ;

[0013] Y 2 Selected from N and CR y2 ;

[0014] Y 3 Selected from N, O, S and S(O)2;

[0015] Z 2 Selected from N and CR z2 ;

[0016] Z 3 Selected from N and CR z3 ;

[0017] Z 4 Selected from N and CR z4 ;

[0018] Each independently selected from hydrogen and C optionally substituted by -OR, -C(O)N(R)2 or -C(O)OR 1-6 Fat;

[0019] R y1 , R y2 , R z1 , R z2 , R z3 and R z4 Each of the following is independently selected from hydrogen, halogen, -CN, -OR, -C(O)OR, and C(O)OR optionally substituted with halogen, -CN, -OR, -N(R)2, -C(O)OR, or -C(O)N(R)2. 1-6 aliphatic; and

[0020] Each R is independently selected from hydrogen and C 1-6 Fat;

[0021] or two R instances together with the atoms to which they are attached form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring.

[0022] In some embodiments, provided compounds have a structure of Formula II, II-a, II-b, II-c, II-d, II-e, III, III-a, III-b, IV, IV-a, or IV-b as described below.

[0023] In some embodiments, one or more compounds of Formula I are provided and / or utilized in solid form (eg, crystalline form or amorphous form).

[0024] In some embodiments, the disclosure provides compositions comprising and / or delivering a compound of Formula I (eg, in a form described herein), a prodrug or an active metabolite thereof.

[0025] In some embodiments, the present disclosure provides compositions comprising and / or delivering a compound of Formula I. In some embodiments, such compositions are pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0026] In some embodiments, provided SARM1 inhibitors reduce or inhibit SARM1 binding to NAD+. In some embodiments, provided SARM1 inhibitors bind to SARM1 within a pocket comprising one or more catalytic residues (e.g., the catalytic cleft of SARM1).

[0027] In some embodiments, provided compounds and / or compositions inhibit the activity of SARM1. Alternatively or additionally, in some embodiments, provided compounds alleviate one or more attributes of neurodegeneration. In some embodiments, the disclosure provides methods for treating neurodegenerative diseases or disorders associated with axonal degeneration.

[0028] In some embodiments, one or more compounds and / or compositions described herein can be used, for example, in medical practice. In some embodiments, one or more compounds and / or compositions described herein can be used, for example, to treat, prevent or improve axonal degeneration (e.g., one or more features or characteristics thereof). In some embodiments, one or more compounds and / or compositions described herein can be used, for example, to inhibit axonal degeneration, including axonal degeneration caused by reduction or depletion of NAD+. In some embodiments, one or more compounds and / or compositions described herein can be used, for example, to prevent axonal degeneration at the distal end of axonal injury.

[0029] In some embodiments, one or more compounds and / or compositions described herein can be used, for example, to treat one or more neurodegenerative diseases, disorders or conditions selected from the group consisting of neuropathy or axonopathy. In some embodiments, one or more 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 hereditary or congenital neuropathy or axonopathy. In some embodiments, the neuropathy associated with axonal degeneration is caused by new or somatic mutations. In some embodiments, the neuropathy associated with axonal degeneration is selected from the list included herein. In some embodiments, neuropathy or axonopathy is associated with axonal degeneration, including but not limited to Parkinson's disease, non-Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis (ALS), demyelinating disease, ischemia or stroke, chemical injury, thermal injury and AIDS.

[0030] In some embodiments, the subject to whom the compounds or compositions described herein are applied may be or include a subject suffering from or susceptible to a neurodegenerative disease, disorder or condition. In some embodiments, a neurodegenerative disease, disorder or condition may be or include traumatic neuronal injury. In some embodiments, traumatic neuronal injury is blunt force trauma, closed head injury, open head injury, exposure to concussive and / or explosive forces, in or to a penetrating injury to a brain cavity or a body innervation area. In some embodiments, traumatic neuronal injury is a force that causes axonal deformation, stretching, extrusion or shearing.

[0031] In some embodiments, the methods provided include administering a compound of Formula I to a patient in need thereof. In some such embodiments, the patient is at risk of suffering from a condition characterized by axonal degeneration. In some embodiments, the patient suffers from a condition characterized by axonal degeneration. In some embodiments, the patient has been diagnosed with a condition characterized by axonal degeneration.

[0032] In some embodiments, the method provided comprises administering the compositions described herein to a patient population in need thereof. In some embodiments, the population is from individuals in activities with a high probability of participating in traumatic neuronal injury. In some embodiments, the population is from athletes participating in contact sports or other high-risk activities.

[0033] In some embodiments, the patient is at risk for a neurodegenerative disorder. In some embodiments, the patient is elderly. In some embodiments, the patient is known to have a genetic risk factor for neurodegeneration.

[0034] In certain embodiments, the present disclosure provides compounds useful as, for example, analytical tools, probes in biological assays, or therapeutic agents according to the present disclosure. The compounds provided by the present disclosure can also be used to study the function of SARM1 NAD enzymes in biological and pathological phenomena and to compare and evaluate new SARM1 activity inhibitors in vitro or in vivo.

[0035] In some embodiments, one or more compounds and / or compositions described herein can be used as methods such as inhibiting neuronal degeneration from a subject. In some embodiments, one or more compounds and / or compositions described herein can be used to inhibit the degeneration of neurons cultured in vitro or a portion thereof. In some embodiments, one or more compounds and / or compositions described herein can be used as stabilizers to promote neuronal survival in vitro.

[0036] BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The structure of the SARM1 protein is shown.

[0038] Figure 2 It was shown that the NRK1-HEK293T stable line with NR supplementation maintained higher NAD+ levels after SARM1-TIR expression.

[0039] definition

[0040] 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 or bicyclic hydrocarbon (also referred to herein as "carbocycle" or "cycloaliphatic") that is completely saturated or contains one or more unsaturated units but is not aromatic, and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle") refers to a monocyclic C3-C8 hydrocarbon or a bicyclic C7-C8 hydrocarbon. 10 A hydrocarbon which is fully saturated or contains one or more unsaturated units, but which is not aromatic and which has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl, alkenyl, alkynyl, and hybrids thereof.

[0041] Alkyl: The term "alkyl", used alone or as part of a larger moiety, refers to a saturated, optionally substituted, straight or branched chain or cyclic hydrocarbon radical having 1-12, 1-10, 1-8, 1-6, 1-4, 1-3 or 1-2 carbon atoms. The term "cycloalkyl" refers to an optionally substituted saturated ring system having from about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0042] Alkylene: The term "alkylene" refers to a divalent alkyl group. In some embodiments, an "alkylene" is a divalent straight or branched chain alkyl group. In some embodiments, an "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, wherein n is a positive integer, such as 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. Optionally substituted alkylene chains are polymethylenes in which one or more methylene hydrogen atoms are optionally replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups, and also include those described in this specification. It should be understood that two substituents of alkylene can form a ring system together. In certain embodiments, two substituents can form a 3- to 7-membered ring together. The substituents can be on the same or different atoms.

[0043] Alkenyl: The term "alkenyl," used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain or cyclic hydrocarbon radical 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.

[0044] Alkynyl: The term "alkynyl" used alone or as part of a larger moiety refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having 2-12, 2-10, 2-8, 2-6, 2-4 or 2-3 carbon atoms.

[0045] Binding: It will be understood that the term "binding" as used herein generally refers to a non-covalent association between or among two or more entities. "Direct" binding involves physical contact between the entities or moieties; indirect binding involves physical interaction via physical contact with one or more intermediate entities. Binding between two or more entities can generally be assessed in any of a variety of contexts, including studying the interacting entities or moieties in isolation or in more complex systems (e.g., when covalently or otherwise associated with a carrier entity and / or in a biological system or cell).

[0046] Biological sample: As used herein, the term "biological sample" generally refers to a sample obtained or derived from a biological source of interest (e.g., a tissue or organism or cell culture) as described herein. In some embodiments, the source of interest comprises an organism, such as an animal or a human. In some embodiments, the biological sample is or comprises a biological tissue or fluid. In some embodiments, the biological sample can be or comprises bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; body fluids containing cells; free nucleic acids; sputum; saliva; urine; cerebrospinal fluid; peritoneal fluid, pleural fluid; feces; lymph; gynecological fluid; skin swab; vaginal swab; oral swab; nasal swab; washing or lavage fluid, such as catheter lavage fluid or bronchoalveolar lavage fluid; aspirate; scraping; bone marrow specimen; tissue biopsy specimen; surgical specimen; feces, other body fluids, secretions and / or excretions; and / or cells obtained therefrom, etc. In some embodiments, the biological sample is or comprises cells obtained from an individual. In some embodiments, the cell obtained is or includes the cell of the individual from which the sample is obtained. In some embodiments, the sample is the "original sample" obtained directly from the source of interest by any appropriate means. For example, in some embodiments, the original biological sample is obtained by the method selected from the group consisting of biopsy (for example, fine needle aspiration or tissue biopsy), surgery, collection of body fluids (for example, blood, lymph, feces, etc.). In some embodiments, as will be known from the context, the term "sample" refers to the preparation obtained by processing the original sample (for example, by removing one or more components of the original sample and / or by adding one or more reagents thereto). For example, a semipermeable membrane is used for filtration. Such "processed sample" can include, for example, nucleic acid or protein extracted from the sample or obtained by the original sample being subjected to amplification or reverse transcription of mRNA, separation and / or purification of certain components.

[0047] Biomarker: The term "biomarker" is used herein to refer to an entity, event or feature whose presence, level, degree, type and / or form is associated with a particular biological event or state of interest, so it is considered a "marker" for the event or state. To name just a few examples, in some embodiments, a biomarker may be or include a marker of a particular disease state, or a marker of the likelihood that a particular disease, disorder or condition may develop, occur or recur. In some embodiments, a biomarker may be or include a marker of a particular disease or its treatment outcome or likelihood. Therefore, in some embodiments, a biomarker is a prediction of a relevant biological event or state of interest, in some embodiments, a biomarker is a prognosis of a relevant biological event or state of interest, and in some embodiments, a biomarker is a diagnosis of a relevant biological event or state of interest. A biomarker may be or include an entity of any chemical class, and may be or include a combination of entities. For example, in some embodiments, a biomarker may be or include a nucleic acid, a polypeptide, a lipid, a carbohydrate, a small molecule, an inorganic agent (e.g., a metal or ion) or a combination thereof. In some embodiments, a biomarker is a cell surface marker. In some embodiments, a biomarker is intracellular. In some embodiments, a biomarker is detected extracellularly (e.g., is secreted or otherwise produced or present extracellularly, such as in a body fluid, such as blood, urine, tears, saliva, cerebrospinal fluid, etc.). In some embodiments, a biomarker can be or comprise a genetic or epigenetic signature. In some embodiments, a biomarker can be or comprise a gene expression signature.

[0048] In some embodiments, biomarkers can be or include markers of neurodegeneration, or markers of the possibility that a neurodegenerative disease, disorder or condition may develop, occur or recur. In some embodiments, biomarkers can be or include markers of neurodegeneration, its treatment outcome or possibility. Therefore, in some embodiments, biomarkers are predictions of neurodegenerative diseases, disorders or conditions, in some embodiments, biomarkers are prognoses of neurodegenerative diseases, disorders or conditions, and in some embodiments, biomarkers are diagnosis of neurodegenerative diseases, disorders or conditions. In some embodiments, changes in biomarker levels can be detected by cerebrospinal fluid (CSF), plasma and / or serum.

[0049] In some embodiments, neurodegeneration can be assessed, for example, by detecting an increase and / or decrease in the concentration of neurofilament light chain (NF-L) and / or neurofilament heavy chain (NF-H) contained in the cerebrospinal fluid of the subject. In some embodiments, the occurrence and / or progression of neurodegeneration can be assessed by positron emission tomography (PET) with synaptic vesicle glycoprotein 2a (SV2A) ligand. In some embodiments, detectable changes in constitutive NAD and / or cADPR levels in neurons can be used to assess neurodegeneration.

[0050] In some embodiments, relative to a healthy reference population, detectable changes in one or more neurodegeneration-related proteins in a subject can be used as a biomarker for neurodegeneration. Such proteins include, but are not limited to, albumin, amyloid-β (Aβ) 38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractant protein (MCP) -1, neurogranulin, 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, including but not limited to Ccl2, Ccl7, Ccl12, Csf1 and / or Il6, can be used as a biomarker for neurodegeneration.

[0051] Carrier: As used herein, the term "carrier" refers to a diluent, adjuvant, excipient or vehicle with which the composition is administered. In some exemplary embodiments, the carrier may 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, etc. In some embodiments, the carrier is or includes one or more solid components.

[0052] Combination therapy: As used herein, the term "combination therapy" refers to those situations in which a subject is exposed to two or more treatment regimens (e.g., two or more therapeutic agents) simultaneously. In some embodiments, two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all "doses" of the first regimen are administered before any doses of the second regimen are administered); in some embodiments, such agents are administered with overlapping dosing regimens. In some embodiments, the "administration" of a combination therapy may involve administering one or more agents or signs to a subject receiving other agents or signs in the combination. For clarity, combination therapy does not require that the individual agents be administered together in a single composition (or even must be administered simultaneously), although in some embodiments, two or more agents or their active portions may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0053] Composition: Those skilled in the art will appreciate that the term "composition" may be used to refer to a discrete physical entity comprising one or more specified components. Generally, unless otherwise specified, a composition may be in any form, such as gas, gel, liquid, solid, etc.

[0054] Domain: As used herein, the term "domain" refers to a segment or portion of an entity. In some embodiments, a "domain" is associated with a specific structural and / or functional feature of an entity, so that when the domain is physically separated from the rest of its parent entity, it substantially or completely retains the specific structural and / or functional feature. Alternatively or additionally, a domain can be or include a portion of an entity that, when separated from the (parent) entity and attached to a different (receptor) entity, substantially retains and / or confers one or more structural and / or functional features to the receptor entity that are characteristic of the parent entity. In some embodiments, a domain is a segment or portion of a molecule (e.g., a small molecule, a carbohydrate, a lipid, a nucleic acid, or a polypeptide). In some embodiments, a domain is a segment of a polypeptide; in some such embodiments, the domain is characterized by specific structural elements (e.g., specific amino acid sequences or sequence motifs, alpha-helical features, beta-pleated features, coiled coil features, random coil features, etc.), and / or by specific functional features (e.g., binding activity, enzymatic activity, folding activity, signaling activity, etc.).

[0055] Dosage form or unit dosage form: It will be appreciated by those skilled in the art that the term "dosage form" can be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic agent or a diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of active agent. In some embodiments, such an amount is a unit dose (or all fractions thereof) suitable for administration according to a dosing regimen (i.e., a therapeutic dosing regimen) that has been determined to be associated with a desired or beneficial outcome when administered to a relevant population. It is understood by those of ordinary skill in the art that the total amount of a therapeutic composition or medicament administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0056] Dosing regimen or treatment regimen: It will be understood by those skilled in the art that the terms "dosing regimen" and "treatment regimen" can be used to refer to a group of unit doses (usually more than one) administered individually to a subject, which are usually separated by time periods. 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 of which is separated from the other doses in time. In some embodiments, each dose is separated from each other by a time period of the same length; in some embodiments, the dosing regimen includes multiple doses and at least two different time periods separating each dose. In some embodiments, all doses within the dosing regimen have the same amount of unit dose. In some embodiments, different doses within the dosing regimen have different amounts. In some embodiments, the dosing regimen comprises a first dose in the amount of a first dose, followed by one or more additional doses in the amount of a second dose different from the amount of the first dose. In some embodiments, the dosing regimen comprises a first dose in the amount of a first dose, followed by one or more additional doses in the amount of a second dose that is the same as the amount of the first dose. In some embodiments, when administered in a related population, the dosing regimen is associated with a desired or beneficial outcome (i.e., a therapeutic dosing regimen).

[0057] Excipient: As used herein, refers to non-therapeutic agents that may be included in a pharmaceutical composition, for example, to provide or promote desired consistency or stabilization. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, ethylene glycol, water, ethanol, etc.

[0058] Heterocycle: As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has, in addition to carbon atoms, one or more, such as one to four heteroatoms, as defined above. The term "nitrogen" when used to refer to the ring atoms of the heterocycle includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur and nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in the pyrrolidinyl substituted by N-).Heterocycle can be connected to its side group at any heteroatom or carbon atom, so as to produce a stable structure, and any ring atom can be optionally substituted.The example of this kind of saturated or partially unsaturated heterocyclic radical includes but is not limited to tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepine, oxazapine, thiazopine, morpholinyl and thiamorpholinyl.Heterocyclic radical can be monocyclic, bicyclic, tricyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic, more preferably monocyclic or bicyclic.Term " heterocyclic alkyl " refers to the alkyl substituted by heterocyclic radical, wherein alkyl and heterocyclic radical part are optionally substituted independently.In addition, heterocyclic also includes the group in which heterocyclic is fused with one or more aromatic rings.

[0059] Inhibitor: As used herein, the term "inhibitor" refers to an entity, condition, or event whose presence, level, or extent is associated with a reduced level or activity of a target. In some embodiments, an inhibitor may act directly (in which case it exerts an effect directly on its target, such as by binding to the target); in some embodiments, an inhibitor may act indirectly (in which case it exerts an effect by interacting with and / or otherwise altering a modulator of the target, causing a reduced level and / or activity of the target). In some embodiments, an inhibitor is an inhibitor whose presence or level is associated with a reduced level or activity of a target relative to a particular reference level or activity (e.g., a level or activity observed under appropriate reference conditions, such as the presence of a known inhibitor, or the absence of the inhibitor in question).

[0060] Neurodegeneration: As used herein, the term "neurodegeneration" refers to a reduction in one or more characteristics, structures or properties of neurons or neuronal tissues. In some embodiments, neurodegeneration is observed as a pathological reduction of an organism. It will be appreciated by those skilled in the art 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 damage); in some embodiments, neurodegeneration can be chronic and / or progressive (e.g., often associated with certain diseases, disorders or conditions, such as, but not limited to, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington disease or Alzheimer's disease). In some embodiments, neurodegeneration can be assessed, for example, by detecting an increase in biomarkers associated with neurodegeneration in a subject. In some embodiments, neurodegeneration can be assessed, for example, by detecting a reduction in biomarkers associated with neurodegeneration in a subject. Alternatively or additionally, in some embodiments, neurodegeneration can be assessed by magnetic resonance imaging (MRI), cerebrospinal fluid containing biomarkers, or other biomarkers observed in patients. In some embodiments, neurodegeneration is defined as a score of less than 24 on a 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 external forces that destroy 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 nervous tissue.

[0061] Oral: As used herein, the phrases "oral administration" and "administered orally" have their art-understood meanings and refer to administration of a compound or composition via the oral cavity.

[0062] Parenteral: As used herein, the phrases "parenteral administration" and "administered parenterally" have their art-understood meanings and refer to modes of administration other than enteral and topical administration (usually by injection), and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0063] Partially unsaturated: As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties as defined herein.

[0064] Patient: As used herein, the term "patient" refers to any organism to which a provided composition is or can be administered, e.g., for experimental, diagnostic, preventive, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals, such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is human. In some embodiments, the patient suffers from or is susceptible to one or more disorders or conditions. In some embodiments, the patient displays one or more symptoms of a disorder or condition. In some embodiments, the patient has been diagnosed with one or more disorders or conditions. In some embodiments, the patient is receiving or has received certain therapies to diagnose and / or treat a disease, disorder, or condition.

[0065] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in an amount suitable for a unit dose administered in a treatment or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical composition can be specifically formulated for administration in solid or liquid form, including pharmaceutical compositions suitable for oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets, such as tablets targeted for buccal, sublingual and systemic absorption, boluses, powders, granules, pastes applied to the tongue; parenteral administration, such as, for example, as a sterile solution or suspension or sustained release formulation, by subcutaneous, intramuscular, intravenous or epidural injection; topical administration, such as, for example, as a cream, ointment or controlled release patch or spray applied to the skin, lungs or oral cavity; intravaginal or rectal, such as as a pessary, cream or foam; sublingual; ocular; transdermal; or nasal, pulmonary and other mucosal surfaces.

[0066] Pharmaceutically acceptable: As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without causing excessive toxicity, irritation, allergic response, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0067] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, component, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; pH buffered solutions; polyesters, polycarbonates, and / or polyanhydrides; and other nontoxic, compatible substances employed in pharmaceutical formulations.

[0068] Pharmaceutically acceptable salts: The term "pharmaceutically acceptable salts" as used herein refers to salts of such compounds suitable for use in a pharmaceutical context, i.e., salts suitable for use in contact with the tissues of humans and lower animals, without excessive toxicity, irritation, allergic reactions, etc., and commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe 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 with inorganic acids or with organic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed by using other methods used in the art, such as ion exchange methods. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. In some embodiments, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates, and arylsulfonates, as appropriate.

[0069] Prevent or prevention: As used herein, the terms "prevent" or "prevention," when used in conjunction with the occurrence of a disease, disorder, and / or condition, refer 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. Prevention may be considered accomplished when the onset of a disease, disorder, or condition has been delayed for a predetermined period of time.

[0070] Specificity: The term "specificity", when used herein to refer to an active agent, will be understood by those skilled in the art to mean that the agent distinguishes between potential target entities or states. For example, in some embodiments, if an agent preferentially binds to its target in the presence of one or more competing alternative targets, the agent is said to "specifically" bind to the target. In many embodiments, specific interactions depend on the presence of specific structural features of the target entity (e.g., epitopes, crevices, binding sites). It should be understood that specificity does not have to be absolute. In some embodiments, specificity can be assessed relative to the specificity of the binding agent for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is assessed relative to the specificity of a reference specific binding agent. In some embodiments, specificity is assessed relative to the specificity of a reference nonspecific binding agent. In some embodiments, an agent or entity will not detect binding to a competitive alternative target under conditions of binding to its target entity. In some embodiments, a binding agent binds to its target entity with a higher binding rate, a lower dissociation rate, increased affinity, reduced dissociation, and / or increased stability compared to a competitive alternative target.

[0071] Subject: As used herein, the term "subject" refers to an organism, typically a mammal (e.g., a human, including prenatal human forms in some embodiments). In some embodiments, the subject suffers from a relevant disease, disorder, or condition. In some embodiments, the subject is susceptible to a disease, disorder, or condition. In some embodiments, the subject displays one or more symptoms or characteristics of a disease, disorder, or condition. In some embodiments, the subject does not display any symptoms or characteristics of a disease, disorder, or condition. In some embodiments, the subject is a person with one or more characteristics of susceptibility or risk for a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual who is being and / or has been diagnosed and / or treated.

[0072] Therapeutic agent: As used herein, the phrase "therapeutic agent" generally refers to any agent that causes a desired pharmacological effect when administered to an organism. In some embodiments, an agent is considered to be a therapeutic agent if it shows a statistically significant effect in an appropriate population. In some embodiments, an appropriate population may be a population of a model organism. In some embodiments, an appropriate population may be defined by various criteria, such as a certain 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, alleviate, inhibit, prevent one or more symptoms or features of a disease, disorder, and / or condition, delay its onset, reduce its severity, and / or reduce its incidence. In some embodiments, a "therapeutic agent" refers to an agent that has been or needs to be approved by a government agency before it can be sold to humans for administration. In some embodiments, a "therapeutic agent" is an agent that requires a medical prescription to be administered to humans.

[0073] Treatment: As used herein, the terms "treat," "treatment," or "treating" refer to any method used to partially or completely alleviate, ameliorate, alleviate, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not show signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who only shows early signs of a disease, disorder, and / or condition, for example, for the purpose of reducing the risk of developing pathology associated with the disease, disorder, and / or condition. DETAILED DESCRIPTION

[0074] Programmed axon degeneration and SARM1

[0075] 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 intrinsic self-destruction program, which is different from the traditional cell death pathway, such as apoptosis known as Wallerian degeneration. (Gerdts, J. et al., Neuron, 2016, 89, 449-460; Whitmore, AV et al., Cell Death Differ., 2003, 10, 260-261). In Wallerian degeneration, peripheral nerves selectively decompose at the distal end of the injured axon segment, while the proximal axon segment and cell body remain intact. This degeneration is characterized by the depletion of nicotinamide mononucleotide adenylyltransferase (NMNAT), followed by nicotinamide adenine dinucleotide (NAD+) depletion, adenosine triphosphate (ATP) depletion, neurofilament proteolysis, and finally axonal degeneration approximately 8 to 24 hours after injury (Gerdts, J. et al., Neuron, 2016, 89, 449-460).

[0076] 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. Therefore, manipulations that increase NMNAT1 axonal localization confer axonal protection (Babetto et al., Cell Rep., 2010, 3, 1422-1429; Sasaki et al., J. Neurosci., 2009).

[0077] In a genome-wide RNAi screen of primary mouse neurons, SARM1 (Sterile Alpha and TIR motif-containing 1) was identified, where knockdown of SARM1 resulted in long-lasting protection of sensory neurons against injury-induced axonal degeneration (Gerdts et al., Journal of Neuroscience, 2013, 33, 13569-13580). SARM1 belongs to the cytoplasmic adaptor protein family, but is unique among its members in that it is the evolutionarily oldest adaptor, paradoxically inhibits TLR signaling, and has been identified as a core executioner of injury-induced axon death pathways (O'Neill, LA and Bowie, AG, Nat. Rev. Immunol., 2007, 7, 353-364; Osterloh, JM et al., Science, 2012, 337, 481-484; Gerdts, J. et al., Journal of Neuroscience 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 quickly by axonal degeneration, highlighting the central role of NAD+ homeostasis in axonal integrity. (Gerdts, J. et al., Science, 2015, 348, 453-457). SARM1 is essential for this injury-induced NAD+ depletion in vivo and in vitro, and activation of SARM1 triggers axonal degeneration locally via the destruction of NAD(+) (Gerdts et al., Science, 2015 348, 452-457; Sasaki et al., J. Biol. Chem. 2015, 290, 17228-17238; both are hereby incorporated by reference in their entirety).

[0078] It is clear from the study of genetic loss of function that SARM1 acts as the core executor of axonal degeneration pathway after injury. Genetic knockout of SARM1 can preserve axons after nerve transection for up to 14 days (Osterloh, JM et al., Science, 2012, 337, 481-484; Gerdts, J. et al., Journal of Neuroscience, 2013, 33, 13569-13580), and can also improve functional outcomes after traumatic brain injury in mice (Henninger, N. et al., Brain 139, 2016, 1094-1105). In addition to the role of SARM1 in direct axonal injury, it is observed that SARM1 is also essential for axonal degeneration in chemotherapy-induced peripheral neuropathy. Loss of SARM1 blocks chemotherapy-induced peripheral neuropathy, inhibiting both axonal degeneration and increased pain sensitivity following treatment with the chemotherapy vincristine (Geisler et al., Brain, 2016, 139, 3092-3108).

[0079] SARM1 contains multiple conserved motifs, including the SAM domain, ARM / HEAT motif, and TIR domain ( Figure 1 ), these motifs mediate oligomerization and protein-protein interactions (O'Neill, LA and Bowie, AG, "Nature Review Immunology", 2007, 7, 353-364; Tewari, R. et al., "Trends Cell Biol.", 2010, 20, 470-481; Qiao, F. and Bowie, JU, "Sci. STKE" 2005, re7, 2005). TIR domains are often found in signaling proteins that function in innate immune pathways, where they serve as scaffolds for protein complexes (O'Neill, LA and Bowie, AG, "Nature Review Immunology", 2007, 7, 353-364). Interestingly, dimerization of the SARM1-TIR domain is sufficient to induce axonal degeneration and rapidly triggers the degradation of NAD+ by acting as an 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 NAD enzyme activity, much effort has been made to identify agents that can regulate SARM1 and may serve as useful therapeutic agents, for example, to prevent the occurrence of neurodegenerative diseases, including peripheral neuropathy, traumatic brain injury and / or neurodegenerative diseases.

[0080] Among other things, the present disclosure provides certain compounds and / or compositions that function as SARM1 inhibitors (eg, as SARM1 inhibitors), and technologies related thereto.

[0081] Compound

[0082] In some embodiments, the present disclosure provides compounds of Formula I:

[0083]

[0084]

[0085] or a pharmaceutically acceptable salt thereof, wherein:

[0086] X 1 and X 2 one of is selected from C and N and the other is C;

[0087] Y 1 Selected from N, and CR y1 ;

[0088] Y 2 Selected from N and CR y2 ;

[0089] Y 3 Selected from N, O, S and S(O)2;

[0090] Z 2 Selected from N and CR z2 ;

[0091] Z 3 Selected from N and CR z3 ;

[0092] Z 4 Selected from N and CR z4 ;

[0093] Each independently selected from hydrogen and C optionally substituted by -OR, -C(O)N(R)2 or -C(O)OR 1-6 Fat;

[0094] R y1 , R y2 , R z1 , R z2 , R z3 and R z4Each of the following is independently selected from hydrogen, halogen, -CN, -OR, -C(O)OR, and C(O)OR optionally substituted with halogen, -CN, -OR, -N(R)2, -C(O)OR, or -C(O)N(R)2. 1-6 aliphatic; and

[0095] Each R is independently selected from hydrogen and C 1-6 Fat;

[0096] or two R instances together with the atoms to which they are attached form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring.

[0097] As generally defined above, X 1 and X 2 One of X is selected from C and N and the other is C. In some embodiments, X 1 is N and X 2 is C. In some embodiments, X 1 is C and X 2 It is N.

[0098] It should be understood that X 1 and X 2 The compound in which one of the N is N has the following structure:

[0099]

[0100] Therefore, it is understandable that due to Y 1 and Y 3 The valence states in this type of compound are (i) Y 1 Selected from N and CR y1 and (ii) Y 3 It is N.

[0101] As generally defined above, each independently selected from hydrogen and C optionally substituted by -OR, -C(O)N(R)2 or -C(O)OR 1-6 In some embodiments, is hydrogen. In some embodiments, is C optionally substituted by -OR, -C(O)N(R)2 or -C(O)OR 1-6 In some embodiments, It is C 1-6 In some such embodiments, It is C 1-6 In some embodiments, is -CH3. In some embodiments, is -CH2CH3. In some embodiments, It is -CH(CH3)2.

[0102] In some embodiments, is C optionally substituted by -OR 1-6 In some embodiments, is C optionally substituted by -OR 1-6 In some embodiments, is C optionally substituted by -OR 1-4 In some embodiments, is C optionally substituted by -OR 1-3 In some embodiments, is C optionally substituted by -OR 1-2 In some embodiments, Yes - (CH2) 1-3 In some embodiments, Yes - (CH2) 2-3 In some embodiments, is -(CH2)2OR. In some embodiments, It is -(CH2)3OR.

[0103] In some embodiments, is C optionally substituted by -C(O)OR 1-6 In some embodiments, is C optionally substituted by -C(O)OR 1-6 In some embodiments, is C optionally substituted by -C(O)OR 1-4 In some embodiments, is C optionally substituted by -C(O)OR 1-3 In some embodiments, is C optionally substituted by -C(O)OR 1-2 In some embodiments, Yes - (CH2) 1-3 C(O)OR. In some embodiments, Yes - (CH2) 2-3 C(O)OR. In some embodiments, is -CH2C(O)OR. In some embodiments, It is -(CH2)2C(O)OR.

[0104] In some embodiments, is C optionally substituted by -C(O)N(R)2 1-6In some embodiments, is C optionally substituted by -C(O)N(R)2 1-6 In some embodiments, is C optionally substituted by -C(O)N(R)2 1-4 In some embodiments, is C optionally substituted by -C(O)N(R)2 1-3 In some embodiments, is C optionally substituted by -C(O)N(R)2 1-2 In some embodiments, Yes - (CH2) 1-3 C(O)N(R)2. In some embodiments, Yes - (CH2) 2-3 C(O)N(R)2. In some embodiments, is -CH2C(O)N(R)2. In some embodiments, It is -(CH2)2C(O)N(R)2.

[0105] As generally defined above, R y1 , R y2 , R z1 , R z2 , R z3 and R z4 Each of the following is independently selected from hydrogen, halogen, -CN, -OR, -C(O)OR, and C(O)OR optionally substituted with halogen, -CN, -OR, -N(R)2, -C(O)OR, or -C(O)N(R)2. 1-6 In some embodiments, R y1 is hydrogen. In some embodiments, R y1 is halogen, -CN, -OR, -C(O)OR or C(O) optionally substituted by halogen, -CN, -OR, -N(R)2, -C(O)OR or -C(O)N(R)2 1-6 In some embodiments, R y1 is hydrogen, halogen or -OR. In some embodiments, R y1 is halogen. In some such embodiments, R y1 In some embodiments, R y1 In some embodiments, R y1 is iodine. In some embodiments, R y1 is -OR. In some embodiments, R y1 It is -CN or -C(O)OR.

[0106] In some embodiments, R y2 is hydrogen. In some embodiments, R y2 is halogen, -CN, -OR, -C(O)OR or C(O) optionally substituted by halogen, -CN, -OR, -N(R)2, -C(O)OR or -C(O)N(R)2 1-6 In some embodiments, R y2 is hydrogen, -CN, -C(O)OR or C 1-6 In some embodiments, R y2 It is C 1-6 In some such embodiments, R y2 It is C 1-6 In some embodiments, R y2 is -CH3. In some embodiments, R y2 In some embodiments, R y2 is -C(O)OR. In some embodiments, R y2 Yes-OR.

[0107] In some embodiments, R z1 is hydrogen. In some embodiments, R z1 is halogen, -CN, -OR, -C(O)OR or C(O) optionally substituted by halogen, -CN, -OR, -N(R)2, -C(O)OR or -C(O)N(R)2 1-6 In some embodiments, R z1 is hydrogen or halogen. In some embodiments, R z1 is halogen. In some such embodiments, R z1 In some embodiments, R z1 is -OR. In some embodiments, R z1 It is -CN or -C(O)OR.

[0108] In some embodiments, R z2 is hydrogen. In some embodiments, R z2 is halogen, -CN, -OR, -C(O)OR or C(O) optionally substituted by halogen, -CN, -OR, -N(R)2, -C(O)OR or -C(O)N(R)2 1-6 In some embodiments, R z2 is C optionally substituted by halogen, -CN, -OR, -N(R)2, -C(O)OR or -C(O)N(R)2 1-6 In some embodiments, R z2 is hydrogen or C 1-6 In some embodiments, R z2It is C 1-6 In some such embodiments, R z2 It is C 1-6 In some embodiments, R z2 is -CH3. In some embodiments, R z2 is -OR. In some embodiments, R z2 It is -CN or -C(O)OR.

[0109] In some embodiments, R z3 is hydrogen. In some embodiments, R z3 is halogen, -CN, -OR, -C(O)OR or C(O) optionally substituted by halogen, -CN, -OR, -N(R)2, -C(O)OR or -C(O)N(R)2 1-6 In some embodiments, R z3 is -OR. In some embodiments, R z3 is -CN or -C(O)OR. In some embodiments, R z3 is C optionally substituted by halogen, -CN, -OR, -N(R)2, -C(O)OR or -C(O)N(R)2 1-6 Fatty.

[0110] In some embodiments, R z4 is hydrogen. In some embodiments, R z4 is halogen, -CN, -OR, -C(O)OR or C(O) optionally substituted by halogen, -CN, -OR, -N(R)2, -C(O)OR or -C(O)N(R)2 1-6 In some embodiments, R z4 is halogen. In some such embodiments, R z4 In some embodiments, R z4 is -OR. In some embodiments, R z4 is C optionally substituted by halogen, -CN, -OR, -N(R)2, -C(O)OR or -C(O)N(R)2 1-6 In some embodiments, R z4 is -C(O)OR. In some embodiments, R z4 Yes-CN.

[0111] As generally defined above, Y 1 Selected from N, and CR y1 In some embodiments, Y 1 is N. In some embodiments, Y 1 yes In some embodiments, Y 1 Yes CR y1 .

[0112] As generally defined above, Y 2 Selected from N and CR y2 In some embodiments, Y 2 is N. In some embodiments, Y 2 Yes CR y2 .

[0113] As generally defined above, Y 3 Selected from N, O, S and S(O)2. In some embodiments, Y 3 Selected from O, S and S(O)2. In some embodiments, Y 3 Selected from O and S. In some embodiments, Y 3 is N. In some embodiments, Y 3 yes In some embodiments, Y 3 is O. In some embodiments, Y 3 is S. In some embodiments, Y 3 It is S(O)2.

[0114] As generally defined above, Z 2 Selected from N and CR z2 In some embodiments, Z 2 is N. In some embodiments, Z 2 Yes CR z2 .

[0115] As generally defined above, Z 3 Selected from N and CR z3 In some embodiments, Z 3 is N. In some embodiments, Z 3 Yes CR z3 .

[0116] As generally defined above, Z 4 Selected from N and CR z4 In some embodiments, Z 4 is N. In some embodiments, Z 4 Yes CR z4 .

[0117] As generally defined above, each R is independently selected from hydrogen and C 1-6In some embodiments, R is hydrogen. In some embodiments, R is C 1-6 In some such embodiments, R is C 1-6 In some embodiments, R is -CH3. In some embodiments, R is selected from hydrogen and -CH3.

[0118] In some embodiments of Formula I, Z 3 is N. Therefore, the present disclosure provides a compound of formula II:

[0119]

[0120] or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments of Formula I, X 1 is N and X 2 is C. Therefore, in some embodiments, the present disclosure provides a compound of formula III:

[0122]

[0123] or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments of Formula I, X 1 is C and X 2 is N. Therefore, in some embodiments, the present disclosure provides compounds of formula IV:

[0125]

[0126] or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the present disclosure provides a compound of any one of Formula II-a, II-b, II-c, II-d, II-e, III-a, III-b, IV-a or IV-b, or a pharmaceutically acceptable salt thereof:

[0128]

[0129]

[0130] Where X 1 , X 2 , Y 1 , Y 2 , Y 3 , Z 2 , Z 4 , R y1 , R z1 and Each of is as defined above and described herein.

[0131] In some embodiments, the present disclosure provides a compound selected from the group consisting of:

[0132]

[0133]

[0134]

[0135]

[0136]

[0137] or a pharmaceutically acceptable salt thereof.

[0138] In some aspects, the present disclosure provides compounds according to the following embodiments:

[0139] Embodiment 1. A compound having Formula I:

[0140]

[0141] or a pharmaceutically acceptable salt thereof, wherein:

[0142] X 1 and X 2 one of is selected from C and N and the other is C;

[0143] Y 1 Selected from N, and CR y1 ;

[0144] Y 2 Selected from N and CR y2 ;

[0145] Y 3 Selected from N, O, S and S(O)2;

[0146] Z 2 Selected from N and CR z2 ;

[0147] Z 3 Selected from N and CR z3 ;

[0148] Z 4 Selected from N and CR z4 ;

[0149] Each independently selected from hydrogen and C optionally substituted by -OR, -C(O)N(R)2 or -C(O)OR 1-6 Fat;

[0150] R y1 , R y2 , R z1 , R z2 , R z3 and R z4 Each of the following is independently selected from hydrogen, halogen, -CN, -OR, -C(O)OR, and C(O)OR optionally substituted with halogen, -CN, -OR, -N(R)2, -C(O)OR, or -C(O)N(R)2. 1-6 aliphatic; and

[0151] Each R is independently selected from hydrogen and C 1-6 Fat;

[0152] or two R instances together with the atoms to which they are attached form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring.

[0153] Embodiment 2. The compound according to Embodiment 1, which has the structure of Formula II:

[0154]

[0155] or a pharmaceutically acceptable salt thereof.

[0156] Embodiment 3. The compound according to Embodiment 1, which has the structure of Formula III:

[0157]

[0158] or a pharmaceutically acceptable salt thereof.

[0159] Embodiment 4. The compound according to Embodiment 1, which has the structure of Formula IV:

[0160]

[0161] or a pharmaceutically acceptable salt thereof.

[0162] Embodiment 5. The compound according to Embodiment 3 or Embodiment 4, wherein Z 3 It is N.

[0163] Embodiment 6. The compound according to Embodiment 3 or Embodiment 4, wherein Z 3 It is N.

[0164] Embodiment 7. A compound according to any one of embodiments 1-6, wherein Y 1 It is N.

[0165] Embodiment 8. A compound according to any one of embodiments 1-6, wherein Y 1 Yes CR y1 .

[0166] Embodiment 9. A compound according to any one of embodiments 1-8, wherein Y 2 It is N.

[0167] Embodiment 10. A compound according to any one of embodiments 1-8, wherein Y 2 Yes CR y2 .

[0168] Embodiment 11. A compound according to any one of embodiments 1-10, wherein Y 3 It is N.

[0169] Embodiment 12. The compound according to Embodiment 1 or Embodiment 2, wherein Y 1 yes

[0170] Embodiment 13. A compound according to Embodiment 1 or Embodiment 2, wherein Y 3 yes

[0171] Embodiment 14. A compound according to Embodiment 1 or Embodiment 2, wherein Y 3 It's O.

[0172] Embodiment 15. The compound according to Embodiment 1 or Embodiment 2, wherein Y 3 It’s S.

[0173] Embodiment 16. A compound according to Embodiment 1 or Embodiment 2, wherein Y 3 It is S(O)2.

[0174] Embodiment 17. A compound according to any one of embodiments 13-16, wherein Y 1 It is N.

[0175] Embodiment 18. A compound according to any one of embodiments 13-16, wherein Y 1 Yes CR y1 .

[0176] Embodiment 19. A compound according to any one of embodiments 13-16, wherein Y 1 yes

[0177] Embodiment 20. A compound according to any one of embodiments 12-19, wherein Y 2 It is N.

[0178] Embodiment 21. A compound according to any one of embodiments 12-19, wherein Y 2 Yes CR y2 .

[0179] Embodiment 22. A compound according to any one of Embodiments 1, 2, 12, 13 and 19, wherein It's hydrogen.

[0180] Embodiment 23. A compound according to any one of Embodiments 1, 2, 12, 13 and 19, wherein It is C 1-6 Fatty.

[0181] Embodiment 24. The compound according to embodiment 23, wherein It is C 1-6 alkyl.

[0182] Embodiment 25. The compound according to embodiment 24, wherein It is -CH3.

[0183] Embodiment 26. The compound according to embodiment 24, wherein It is -CH2CH3.

[0184] Embodiment 27. The compound according to embodiment 24, wherein It is -CH(CH3)2.

[0185] Embodiment 28. A compound according to any one of Embodiments 1, 2, 12, 13 and 19, wherein is C optionally substituted by -C(O)OR or -C(O)N(R)2 1-6 Fatty.

[0186] Embodiment 29. The compound according to embodiment 28, wherein is C optionally substituted by -OR 1-6 Fatty.

[0187] Embodiment 30. The compound according to embodiment 28, wherein is C optionally substituted by -C(O)N(R)2 1-6 Fatty.

[0188] Embodiment 31. A compound according to embodiment 28, wherein is C optionally substituted by -C(O)OR1-6 Fatty.

[0189] Embodiment 32. A compound according to Embodiment 8 or Embodiment 18, wherein R y1 It's hydrogen.

[0190] Embodiment 33. A compound according to Embodiment 8 or Embodiment 18, wherein R y1 It's a halogen.

[0191] Embodiment 34. A compound according to Embodiment 8 or Embodiment 18, wherein R y1 Yes-OR.

[0192] Embodiment 35. A compound according to Embodiment 10 or Embodiment 21, wherein R y2 It's hydrogen.

[0193] Embodiment 36. A compound according to Embodiment 10 or Embodiment 21, wherein R y2 It is C 1-6 Fatty.

[0194] Embodiment 37. The compound according to embodiment 36, wherein R y2 It is C 1-6 alkyl.

[0195] Embodiment 38. The compound according to embodiment 37, wherein R y2 It is -CH3.

[0196] Embodiment 39. The compound according to Embodiment 10 or Embodiment 21, wherein R y2 Yes-CN.

[0197] Embodiment 40. The compound according to Embodiment 10 or Embodiment 21, wherein R y2 It is -C(O)OR.

[0198] Embodiment 41. A compound according to any one of embodiments 1-40, wherein R z1 It's hydrogen.

[0199] Embodiment 42. A compound according to any one of embodiments 1-40, wherein R z1 It's a halogen.

[0200] Embodiment 43. A compound according to any one of embodiments 1-42, wherein Z 2 It is N.

[0201] Embodiment 44. A compound according to any one of embodiments 1-42, wherein Z 2Yes CR z2 .

[0202] Embodiment 45. The compound according to embodiment 44, wherein R z2 It's hydrogen.

[0203] Embodiment 46. The compound according to embodiment 44, wherein R z2 It is C 1-6 Fatty.

[0204] Embodiment 47. The compound according to embodiment 46, wherein R z2 It is C 1-6 alkyl.

[0205] Embodiment 48. The compound according to embodiment 47, wherein R z2 It is -CH3.

[0206] Embodiment 49. A compound according to any one of embodiments 1-48, wherein Z 4 It is N.

[0207] Embodiment 50. A compound according to any one of embodiments 1-48, wherein Z 4 Yes CR z4 .

[0208] Embodiment 51. The compound according to embodiment 50, wherein R z4 It's hydrogen.

[0209] Embodiment 52. The compound according to embodiment 50, wherein R z4 It's a halogen.

[0210] Embodiment 53. A compound according to any one of embodiments 28-31, 34 and 40, wherein R is hydrogen.

[0211] Embodiment 54. A compound according to any one of embodiments 28-31, 34 and 40, wherein R is C 1-6 Fatty.

[0212] Embodiment 55. The compound according to embodiment 54, wherein R is C 1-6 alkyl.

[0213] Embodiment 56. A compound according to Embodiment 55, wherein R is -CH3.

[0214] Embodiment 57. A compound according to Embodiment 55, wherein R is -CH2CH3.

[0215] Embodiment 58. The compound of claim 1, wherein the compound is selected from Formula II-a, II-b, II-c, II-d, II-e, III-a, III-b, IV-a, and IV-b:

[0216]

[0217]

[0218] or a pharmaceutically acceptable salt thereof.

[0219] Composition

[0220] In some embodiments, a compound of Formula I can be provided as a composition, for example, in combination (eg, admixture) with one or more other components.

[0221] In some embodiments, the disclosure provides compositions comprising and / or delivering a compound of Formula I or an active metabolite thereof, for example, when contacted with or otherwise administered to a system or environment, for example, the system or environment may include SARM1 NAD enzyme activity; in some embodiments, administration of the composition to the system or environment can achieve inhibition of SARM1 activity as described herein.

[0222] In some embodiments, the compositions provided herein can be pharmaceutical compositions, wherein the pharmaceutical compositions comprise an active agent and one or more pharmaceutically acceptable excipients; in some such embodiments, the pharmaceutical compositions provided comprise a compound of Formula I or an active metabolite thereof and / or deliver a compound of Formula I or Formula II or an active metabolite thereof to a relevant system or environment described herein (e.g., to a subject in need thereof).

[0223] In some embodiments, one or more compounds of Formula I are provided and / or utilized in the form of a pharmaceutically acceptable salt.

[0224] Among other things, the present disclosure provides a composition comprising a compound of formula I or a pharmaceutically acceptable salt or derivative thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in the composition provided is such that axonal degeneration in a biological sample or patient is effectively and measurably inhibited. In certain embodiments, the compound or composition provided is formulated for administration to a patient in need of such a composition. According to the methods disclosed herein, the compounds and compositions can be administered using any amount and any route of administration effective for treating or alleviating the severity of any disease or condition described herein. The compounds provided are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" used herein refers to a physically discrete dosage unit suitable for a patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions provided will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dosage level for any particular patient or organism will vary from subject to subject, depending on a variety of factors, including the condition being treated and the severity of the condition; 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 subject; the time of administration; the excretion rate of the specific compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed, and the like.

[0225] The provided compositions can be administered orally, parenterally, by inhalation or nasal spray, topically (e.g., by powders, ointments, or drops), rectally, buccally, intravaginally, intraperitoneally, intracisternal, or by implanted reservoirs, depending on the severity of the condition being treated. Preferably, the composition is administered orally, intraperitoneally, or intravenously. In certain embodiments, the provided compounds are administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg of the subject's body weight, once or more per day to obtain the desired therapeutic effect.

[0226] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. The sterile injectable form of the composition provided can be an aqueous or oily suspension. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspension media.

[0227] For this reason, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives can be used to prepare injectables, and natural pharmaceutically acceptable oils, such as olive oil or castor oil, particularly its polyoxyethylated form can also be used to prepare injectables. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants, which are commonly used in preparing pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifiers or bioavailability enhancers, which are commonly used to make pharmaceutically acceptable solids, liquids or other dosage forms, can also be used for formulation purposes.

[0228] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0229] In order to prolong the effect of the compound provided, it is usually desirable to slow down the absorption of the compound injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. Then, the absorption rate of the compound depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of the compound form administered parenterally is achieved by dissolving or suspending the compound in an oily vehicle. The injectable accumulation form is made by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. According to the ratio of the compound to the polymer and the properties of the specific polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Accumulated injectable preparations can also be prepared by encapsulating the compound in a liposome or microemulsion compatible with body tissues.

[0230] The pharmaceutically acceptable compositions described herein can be orally administered in any oral acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also contain additional substances other than inert diluents, such as lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as normal practice. When an oral aqueous suspension is required, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, certain sweeteners, flavoring agents or coloring agents can also be added.

[0231] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders, such as paraffin; f) absorption promoters, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and / or i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer. The active compounds can also be in microencapsulated form with one or more excipients as noted above.

[0232] Solid compositions of similar type can also be used as fillers for soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings (i.e., buffers) and other coatings well known in the art of pharmaceutical formulation. They may optionally contain opacifiers and may also be compositions that release the active ingredient only or preferably in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0233] 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 form may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (particularly 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 inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatics.

[0234] Alternatively, the pharmaceutically acceptable compositions described herein can be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the disclosed compounds with suitable non-irritating excipients or carriers, which are solid at room temperature but liquid at body temperature (e.g., rectal or vaginal temperature) and will therefore melt in the rectum or vaginal cavity to release the active compound. Such materials include cocoa butter, suppository waxes (e.g., beeswax) and polyethylene glycol.

[0235] The pharmaceutically acceptable compositions described herein may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Topical administration to the lower intestinal tract may be achieved in a rectal suppository formulation (see above) or in a suitable enema formulation.

[0236] The dosage form for topical or transdermal administration of the provided compound includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. The active component is mixed with a pharmaceutically acceptable carrier and any desired preservative or buffer that may be needed under aseptic conditions. Ophthalmic preparations, ear drops and eye drops are also considered within the scope of the present disclosure. In addition, the present disclosure also contemplates the use of transdermal patches, which have the additional advantage of controllably delivering the compound to the body. This type of dosage form can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. Rate control can be achieved by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0237] For topical application, the pharmaceutically acceptable composition provided can be formulated into a suitable ointment containing an active component suspended or dissolved in one or more carriers. Carriers for topical application of the disclosed compound include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable composition provided can be formulated into a suitable lotion or cream containing an active component 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 ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0238] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably as solutions in isotonic, pH-adjusted sterile saline, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[0239] The pharmaceutically acceptable compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

[0240] Most preferably, the pharmaceutically acceptable compositions of the present disclosure are formulated for oral administration.

[0241] Identification and / or characterization of compounds and / or compositions

[0242] Among other things, the present disclosure provides various techniques for identifying and / or characterizing the compounds and / or compositions described herein.For example, the present disclosure provides various assays for evaluating SARM1 inhibitory activity, in particular for evaluating SARM1 inhibitory activity.

[0243] In some embodiments, the performance of one or more compounds of interest or compositions in the assays described herein is compared with the performance of appropriate references. For example, in some embodiments, reference may be the absence of a related compound or composition. Alternatively or additionally, in some embodiments, reference may be the presence of an alternative compound or composition, for example, the alternative compound or composition has a known performance in a related assay (for example, as a positive control or negative control, as understood in the art). In some embodiments, reference may be a set of alternative but comparable conditions (for example, temperature, pH value, salt concentration, etc.). In some embodiments, reference may be the performance of a compound or composition relative to a SARM1 variant.

[0244] Further alternatively or additionally, in some embodiments, in the assays described herein, the performance of one or more compounds or compositions of interest can be evaluated in the presence of an appropriate reference compound or composition, for example, to determine the ability of the compound or composition to compete with a reference.

[0245] In some embodiments, multiple compounds or compositions of interest may be analyzed and / or compared to the same reference in a particular assay. In some embodiments, such multiple compounds or compositions may be or include a group of compounds or compositions that are considered a "library" because multiple members share one or more features (e.g., structural elements, source characteristics, synthetic similarity, etc.).

[0246] Certain exemplary assays that can be used in the practice of the present disclosure are described in the Examples below. Those skilled in the art who read this disclosure will appreciate 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 those otherwise discussed below.

[0247] In some embodiments, compounds and / or compositions can be determined based on one or more activities or features, and / or compounds and / or compositions can be characterized by one or more activities or features, such as promoting axonal integrity, cytoskeletal stability and / or neuronal survival. In some embodiments, the SARM1 inhibitors provided inhibit the catabolism of NAD+ by SARM1. In some embodiments, the SARM1 inhibitors provided slow down the rate of NAD+ catabolism.

[0248] In some embodiments, the SARM1 inhibitors provided reduce or inhibit the binding of SARM1 to NAD+. In some embodiments, the SARM1 inhibitors provided bind to SARM1 within a pocket comprising one or more catalytic residues (e.g., the catalytic cleft of SARM1). Examples of such catalytic residues include glutamic acid at position 642 (E642).

[0249] In some embodiments, the SARM1 inhibitors provided disrupt and / or prevent the multimerization of the TIR1 domain of SARM1. In some embodiments, the SARM1 inhibitors provided disrupt the multimerization of the SAM domain. In some embodiments, the SARM1 inhibitors provided disrupt the axonal signaling cascade that leads to NAD+ depletion.

[0250] In some embodiments, the disclosure provides assays that can be used to identify and / or characterize one or more activities and / or features of a compound and / or composition of interest. For example, in some embodiments, the disclosure provides in vitro, cellular, and / or in vivo systems for assessing one or more such activities and / or features.

[0251] SARM1 activity assay

[0252] 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 is constitutively active; b) incubating the mixture; c) quantifying NAD+ in the mixture after incubation; and d) if the amount of NAD+ is greater than the amount of a control mixture that does not comprise the candidate inhibitor, identifying the candidate inhibitor compound as an inhibitor.

[0253] In some embodiments, a method for identifying a SARM1 inhibitor is provided, comprising: a) providing a mixture comprising i) full-length SARM1, ii) NAD+, and iii) a candidate inhibitor, wherein the full-length SARM1 is constitutively active; b) incubating the mixture; c) quantifying NAD+ and ADPR (or cADPR) in the mixture after incubation; d) determining the molar ratio of NAD+:ADPR (or cADPR); and e) if the molar ratio is greater than the molar ratio of a control mixture without the candidate inhibitor, identifying the candidate inhibitor compound as an inhibitor.

[0254] In some embodiments, a method of identifying a SARM1 inhibitor is provided, comprising: a) providing a mixture comprising a solid support bound to i) full-length SARM1 and at least one tag, ii) NAD+, and iii) a candidate inhibitor; b) incubating the mixture; c) quantifying NAD+ after incubation; and d) if the concentration of NAD+ is greater than the concentration of a control, identifying the candidate inhibitor compound as a SARM1 inhibitor.

[0255] SARM1 binding assay

[0256] In some embodiments, the efficacy of the provided SARM1 inhibitor can be determined according to an assay described in, for example, 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 to an in vivo system. In some embodiments, the provided SARM1 inhibitor can be applied to a patient. In some embodiments, the SARM1 inhibitor can be mixed with a SARM1 or a fragment thereof that has been labeled with an epitope tag. In some embodiments, the amount of the bound SARM1 inhibitor can be compared with the amount of the unbound SARM1 inhibitor to derive the affinity for the SARM1 inhibitor.

[0257] In some embodiments, the mutant or fragment of SARM1 is a constitutively active SAM-TIR fragment. Constitutively active SARM1 fragments include, for example, but not limited to, SARM1 lacking an autoinhibitory domain; at least one point mutation of SARM1 that inactivates the autoinhibitory domain; a SARM1 fragment containing a TIR domain; or a SARM1 fragment consisting of a SAM and a TIR domain. In some embodiments, the SARM1 polypeptide may include one or more additional amino acid sequences that may act as tags, such as a His tag, a streptavidin tag, or a combination thereof. In some embodiments, the SARM1 polypeptide may include a tag at the amino terminus, the carboxyl terminus, or a combination thereof. In some embodiments, SARM1 or a fragment thereof labeled with an epitope tag can be used to measure the binding efficacy of a provided SARM1 inhibitor.

[0258] Purification of SARM1-TIR domain

[0259] In some embodiments, the SARM1-TIR domain can be engineered with various protein tags or epitope tags, which can be used, for example, for purification. In some embodiments, the disclosure also provides NRK1-HEK293T cell lines, which include 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 from an exogenous source of a host cell. In some embodiments, HEK293T cells are stably or transiently transfected with DNA encoding NRK1, so that the cells express NRK1 at an elevated level compared to control cells. In some embodiments, the DNA encoding NRK1 is under the control of one or more exogenous regulatory DNA sequences (such as promoters, enhancers, or a combination thereof). In some embodiments, the combination of the DNA sequence encoding NRK1 and the regulatory sequence 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 from a vertebrate or invertebrate species, such as but not limited to humans, mice, zebrafish or fruit flies. In some configurations, the NRK1 DNA is human NRK1 DNA.

[0260] Applications and uses

[0261] The present disclosure provides various uses and applications of the compounds and / or compositions described herein, for example, according to the activity and / or characteristics of these compounds and / or compositions as described herein. In some embodiments, such uses may include therapeutic and / or diagnostic uses. Alternatively, in some embodiments, such uses may include research, production and / or other technical uses.

[0262] In one aspect, the disclosure provides a method comprising administering to a subject one or more compounds of Formula I, for example to treat, prevent or reduce the risk of one or more conditions characterized by axonal degeneration. In some such embodiments, the compound of Formula I is a SARM1 inhibitor.

[0263] Another embodiment of the present disclosure is directed to a method of inhibiting SARM1 activity in a patient, comprising the step of administering to the patient a provided compound or a composition comprising the compound.

[0264] Inhibition of enzymes in biological samples is useful for various purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, bioassays, gene expression studies, and biological target identification.

[0265] In certain embodiments, the disclosure relates to a method for treating axonal degeneration in a biological sample, comprising a step of contacting the biological sample with a compound or composition shown in Formula I. In some embodiments, one or more compounds and / or compositions described herein can be used, for example, to inhibit the degeneration of neurons derived from a subject. In some embodiments, one or more compounds and / or compositions described herein can be used to inhibit the degeneration of neurons or a portion thereof cultured in vitro. In some embodiments, one or more compounds and / or compositions described herein can be used as stabilizers to promote neuronal survival in vitro.

[0266] In some embodiments, provided compounds and / or compositions inhibit the NAD enzyme activity of SARM1. Alternatively or additionally, in some embodiments, provided compounds alleviate one or more attributes of neurodegeneration. In some embodiments, the disclosure provides methods for treating neurodegenerative diseases or disorders associated with axonal degeneration.

[0267] In some embodiments, one or more compounds and / or compositions described herein can be used, for example, in medical practice. In some embodiments, one or more compounds and / or compositions described herein can be used, for example, to treat, prevent or improve axonal degeneration (e.g., one or more features or characteristics thereof). In some embodiments, one or more compounds and / or compositions described herein can be used, for example, to inhibit axonal degeneration, including axonal degeneration caused by reduction or depletion of NAD+. In some embodiments, one or more compounds and / or compositions described herein can be used, for example, to prevent axonal degeneration at the distal end of axonal injury.

[0268] In some embodiments, one or more compounds and / or compositions described herein can be used for example to suppress the method for peripheral nervous system neurons or a part thereof degeneration.In some embodiments, one or more compounds and / or compositions described herein can be used for example to suppress or prevent the method for central nervous system (neurons) or a part thereof degeneration.In some embodiments, one or more compounds or compositions described herein are characterized in that, when applied to subject colony, one or more symptoms or features of neurodegeneration are reduced.For example, in some embodiments, relevant symptoms or features can be selected from the group consisting of the degree, rate and / or opportunity of neuron destruction.

[0269] In certain embodiments, the present disclosure provides compounds described in the present disclosure, for example, for use as analytical tools, as probes in biological assays, or as therapeutic agents. The compounds provided by the present disclosure can also be used to study SARM1 activity in biological and pathological phenomena and to compare and evaluate new SARM1 activity inhibitors in vitro or in vivo. In certain embodiments, the present disclosure provides assays for identifying and / or characterizing the compounds and / or compositions provided herein. In some embodiments, the assays provided utilize specific reagents and / or systems (e.g., certain vector constructs and / or polypeptides) that can be used to assay SARM1 activity. For example, in some embodiments, the assays provided can utilize, for example, SAM-TIRs that lack the SARM1 N-terminal auto-inhibitory domain, and / or one or more tagged versions of the TIR domain.

[0270] In some embodiments, one or more compounds and / or compositions described herein can be used, for example, to inhibit the degeneration of neurons derived from a subject. In some embodiments, one or more compounds and / or compositions described herein can be used to inhibit the degeneration of neurons cultured in vitro or a portion thereof. In some embodiments, one or more compounds and / or compositions described herein can be used as stabilizers to promote neuronal survival in vitro.

[0271] In some embodiments, one or more compounds and / or compositions described herein can be used to, for example, affect biomarkers associated with neurodegeneration. In some embodiments, changes in biomarkers can be detected systemically or with samples of cerebrospinal fluid (CSF), plasma, serum and / or tissue from a subject. In some embodiments, one or more compounds and / or compositions can be used to affect changes in the concentration of neurofilament light chain (NF-L) and / or neurofilament heavy chain (NF-H) contained in the cerebrospinal fluid of a subject. In some embodiments, one or more compounds and / or compositions described herein can affect constitutive NAD and / or cADPR levels in neurons and / or axons.

[0272] In some embodiments, one or more compounds and / or compositions described herein can affect detectable changes in one or more neurodegeneration-related protein levels in a subject. Such proteins include, but are not limited to, albumin, amyloid-β (Aβ) 38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractant protein (MCP) -1, neurogranulin, neuron-specific enolase (NSE), soluble amyloid precursor protein (sAPP) α, sAPPβ, soluble triggering receptors expressed on myeloid cells (sTREM) 2, phosphorylated tau and / or total tau (total-tua). In some embodiments, one or more compounds and / or compositions described herein can affect changes in cytokines and / or chemokines, including but not limited to Ccl2, Ccl7, Ccl12, Csf1 and / or Il6.

[0273] Diseases, Disorders and Conditions

[0274] In some embodiments, the compounds and / or compositions described herein may be administered to a subject suffering from one or more diseases, disorders, or conditions.

[0275] In some embodiments, the condition is an acute condition. In some embodiments, the condition is a chronic condition.

[0276] In some embodiments, the condition is characterized by axonal degeneration of the central nervous system, peripheral nervous system, optic nerves, cranial nerves, or a combination thereof.

[0277] In some embodiments, the condition is or comprises acute damage to the central nervous system, such as damage to the spinal cord and / or traumatic brain injury. In some embodiments, the condition is or comprises chronic damage to the central nervous system, such as damage to the spinal cord, traumatic brain injury and / or traumatic axonal injury. In some embodiments, the condition is or comprises chronic traumatic encephalopathy (CTE).

[0278] 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.

[0279] In some embodiments, the patient's condition is acute peripheral neuropathy. Chemotherapy-induced peripheral neuropathy (CIPN) is an example of acute peripheral neuropathy. CIPN can be associated with a variety of drugs, such as but not limited to thalidomide, epothilone (epothilone) (e.g., ixabepilone), taxane (taxane) (e.g., paclitaxel and docetaxel), vinca alkaloid (vinca alkaloid) (e.g., vinblastine, vinorelbine, vincristine and vindesine), proteasome inhibitors (e.g., bortezomib), platinum drugs (e.g., cisplatin, oxaliplatin and carboplatin).

[0280] In some embodiments, the condition is a chronic condition affecting the peripheral nervous system, such as diabetic neuropathy, HIV neuropathy, Charcot Marie Tooth disease, or amyotrophic lateral sclerosis.

[0281] In some embodiments, the condition is an acute condition affecting the optic nerve, such as acute optic neuropathy (AON) or acute angle-closure glaucoma.

[0282] In some embodiments, the condition is a chronic condition affecting the optic nerve, such as Leber's congenital amaurosis, Leber's hereditary optic neuropathy, primary open-angle glaucoma, and autosomal dominant optic atrophy.

[0283] In some embodiments, one or more compounds and / or compositions described herein can be used, for example, to treat one or more neurodegenerative diseases, disorders or conditions selected from the group consisting of neuropathy or axonopathy. In some embodiments, one or more 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 new or somatic mutations. In some embodiments, the neuropathy associated with axonal degeneration is selected from the list contained herein. In some embodiments, neuropathy or axonopathy is associated with axonal degeneration, including but not limited to Parkinson's disease, non-Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating disease, ischemia or stroke, chemical injury, thermal injury and AIDS.

[0284] In some embodiments, one or more compounds or compositions described herein are characterized in that, when applied to a subject population, one or more symptoms or features of neurodegeneration are reduced. For example, in some embodiments, relevant symptoms or features may be selected from the group consisting of the degree, rate and / or opportunity of neuronal destruction. In some embodiments, neuronal destruction may be or include axonal degeneration, synapse loss, dendrite loss, synaptic density loss, dendrite arbour loss, axonal branch loss, neuronal density loss, myelination loss, neuronal cell body loss, synaptic enhancement loss, action potential enhancement loss, cytoskeleton stability loss, axonal transport loss, ion channel synthesis and turnover loss, neurotransmitter synthesis loss, neurotransmitter release and reuptake ability loss, axonal potential propagation loss, neuronal hyperexcitability and / or neuronal hypoexcitability. In some embodiments, neuronal destruction is characterized by the inability to maintain an appropriate resting neuronal membrane potential. In some embodiments, neuronal destruction is characterized by the occurrence of inclusion bodies, plaques and / or neurofibrillary tangles. In some embodiments, neuronal destruction is characterized by the occurrence of stress granules. In some embodiments, the neuron destruction is characterized by intracellular activation of one or more members of the cysteine-aspartic acid protease (Caspase) family. In some embodiments, the neuron destruction is characterized by programmed cell death (e.g., apoptosis, pyrolysis, ferroptosis and / or necrosis) and / or inflammation of the neurons.

[0285] In some embodiments, the neurodegenerative or nervous system disease or disorder is associated with axonal degeneration, axonal damage, axonopathy, demyelinating disease, central pontine myelinolysis, a nerve damaging disease or disorder, metabolic disease, mitochondrial disease, metabolic axonal degeneration, axonal damage caused by leukoencephalopathy or leukodystrophy. In some embodiments, the neurodegenerative or nervous system disease or disorder is selected from the group consisting of spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, anoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus-Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe's 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-Sacks disease, disease), Gaucher's disease, Hurler syndrome, traumatic brain injury, post-radiation injury, neurologic complications of chemotherapy (chemotherapy-induced neuropathy; CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B 12deficiency, monovitamin E deficiency syndrome, Bassen-Kornzweig syndrome, glaucoma, Leber's hereditary optic atrophy (neuropathy), Leber's congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraplegia, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy, west Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis encephalitis, viral encephalitis in children, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenoleukodystrophy, progressive supranuclear palsy (PSP), Friedrich's ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, spinocerebellar ataxia, preeclampsia, hereditary spastic paraplegia, spastic paraplegia, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, and nonalcoholic steatohepatitis (NASH).

[0286] In some embodiments, the present disclosure provides a SARM1 activity inhibitor for treating a neurodegenerative or nervous system disease or condition involving axonal degeneration or axonopathy. The present disclosure also provides methods of using a SARM1 activity inhibitor to treat, prevent or improve axonal degeneration, axonopathy and a neurodegenerative or nervous system disease or condition involving axonal degeneration.

[0287] In some embodiments, the present disclosure provides methods of treating a neurodegenerative or nervous system disease or disorder associated with axonal degeneration, axonal injury, axonopathy, demyelinating disease, central pontine myelinolysis, a neurological injury disease or disorder, a metabolic disease, a mitochondrial disease, metabolic axonal degeneration, axonal injury caused by leukoencephalopathy or leukodystrophy.

[0288] In some embodiments, neuropathy and axonopathy include any disease or condition involving neurons and / or supporting cells, such as glial cells, muscle cells or fibroblasts, particularly those diseases or conditions involving axonal injury. Axonal injury can be caused by traumatic injury or by disease, condition or exposure to non-mechanical damage caused by toxic molecules or drugs. The result of this damage can be the degeneration or dysfunction of axons and the loss of functional neuronal activity. The disease and condition produced or related to this axonal injury are one of many neurological diseases and conditions. Such neuropathy can include peripheral neuropathy, central neuropathy and combinations thereof. In addition, peripheral neurological manifestations can be mainly produced by diseases concentrated in the central nervous system, and central nervous system manifestations can be basically produced by peripheral or systemic diseases.

[0289] In some embodiments, peripheral neuropathy can be related to damage to peripheral nerves, and / or can be caused by nerve diseases or due to systemic diseases. Some such diseases can include diabetes, uremia, infectious diseases such as AID 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) damage to nerves and chemical or thermal damage to nerves. Such conditions that damage peripheral nerves include compression or pinching, such as glaucoma, carpal tunnel syndrome, direct trauma, penetrating injuries, contusions, fractures or bone dislocations; Pressure involving superficial nerves (ulnar, radial or peroneal nerves), which may be due to long-term use of crutches or staying in one position for too long, or due to tumors; Intraneural bleeding; Local ischemia; Exposure to cold or radiation or certain drugs or toxic substances, such as herbicides or pesticides. In particular, nerve damage may be due to chemical damage by cytotoxic anticancer agents, such as paclitaxel, cisplatin, proteasome inhibitors, or vinca alkaloids such as vincristine. Typical symptoms of this type of peripheral neuropathy include weakness, numbness, paresthesia (abnormal sensations such as burning, itching, tingling, or tingling) and pain in the arms, hands, legs, and / or feet. In some embodiments, neuropathy is associated with mitochondrial dysfunction. This neuropathy can show a decrease in energy levels, i.e., a decrease in NAD and ATP levels.

[0290] In some embodiments, peripheral neuropathy is a metabolic and endocrine neuropathy, which includes a wide range 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 deficiency, and mitochondrial disorders. The common feature of these diseases is that the structural or functional changes of myelin sheaths and axons are affected by dysregulation of metabolic pathways, which in turn affect peripheral nerves.

[0291] In some embodiments, neuropathy includes optic neuropathy, such as glaucoma; retinal ganglion degeneration, such as retinal ganglion degeneration associated with retinitis pigmentosa and outer retinal neuropathy; optic nerve neuritis and / or degeneration, including optic neuritis and / or degeneration associated with multiple sclerosis; traumatic injury to the optic nerve, which may include, for example, injury during tumor resection; hereditary optic neuropathy, such as Kjer's disease and Leber's hereditary optic neuropathy; ischemic optic neuropathy, such as optic neuropathy secondary to giant cell arteritis; metabolic optic neuropathy, such as neurodegenerative diseases, including the aforementioned Leber's neuropathy, nutritional deficiencies, such as vitamin B12 or folic acid deficiency, and poisoning, such as caused by ethambutol or cyanide; neuropathy caused by adverse drug reactions and neuropathy caused by vitamin deficiency. Ischemic optic neuropathy also includes non-arteritic anterior ischemic optic neuropathy.

[0292] In some embodiments, neurodegenerative diseases associated with neuropathy or axonopathy in the central nervous system include a variety of diseases. Such diseases include diseases involving progressive dementia, such as Alzheimer's disease, senile dementia, Pick's disease, and Huntington's disease; central nervous system diseases that affect muscle function, such as Parkinson's disease, motor neuron disease, and progressive ataxia, such as amyotrophic lateral sclerosis; demyelinating diseases, such as multiple sclerosis; viral encephalitis, such as viral encephalitis caused by enterovirus, arbovirus, and herpes simplex virus; and prion diseases. Mechanical damage, such as glaucoma or traumatic injury to the head and spine, can also cause nerve damage and degeneration of the brain and spinal cord. In addition, ischemia and stroke and conditions such as nutritional deficiencies and chemical toxicity (such as chemotherapeutic agents) can also cause central nervous system neuropathy.

[0293] In some embodiments, the present disclosure provides a method for treating a neuropathy or axonopathy associated with axonal degeneration. In some such embodiments, the neuropathy or axonopathy associated with axonal degeneration can be any of a variety of neuropathy or axonopathy, such as those that are hereditary or congenital or are associated with Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating disease, ischemia or stroke, chemical injury, thermal injury, and AIDS-related neuropathy or axonopathy. 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. Such disease subsets can include Parkinson's disease or non-Parkinson's disease, or Alzheimer's disease.

[0294] Subjects

[0295] In some embodiments, the compounds and / or compositions described herein are administered to a subject suffering from or susceptible to a disease, disorder, or condition described herein; in some embodiments, such disease, disorder, or condition is characterized by axonal degeneration, such as one of the conditions mentioned herein.

[0296] In some embodiments, a subject to which a compound or composition described herein is administered exhibits one or more signs or symptoms associated with axonal degeneration; in some embodiments, the subject does not exhibit any signs or symptoms of neurodegeneration.

[0297] In some embodiments, the methods provided include administering a compound of Formula I to a patient in need thereof. In some such embodiments, the patient is at risk of suffering from a condition characterized by axonal degeneration. In some embodiments, the patient suffers from a condition characterized by axonal degeneration. In some embodiments, the patient has been diagnosed with a condition characterized by axonal degeneration.

[0298] In some embodiments, the methods provided include administering the compositions described herein to a patient population in need thereof. In some embodiments, the population is from individuals in activities where the likelihood of traumatic neuronal injury is high. In some embodiments, the population is from athletes participating in contact sports or other high-risk activities.

[0299] In some embodiments, the subject is at risk for a condition characterized by axonal degeneration. In some embodiments, the subject is identified as being at risk for axonal degeneration, e.g., based on the subject's genotype, diagnosis of a condition associated with axonal degeneration, and / or exposure to agents and / or conditions that induce axonal degeneration.

[0300] In some embodiments, the patient has a risk of suffering from a neurodegenerative disorder. In some embodiments, the patient is an elderly person. 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 diseases. In some embodiments, the patient expresses one or more copies of a known genetic risk factor for neurodegeneration. In some embodiments, the patient is from a high-risk population for neurodegeneration. In some embodiments, the patient has a hexanucleotide repeat expansion in chromosome 9 open reading frame 72. In some embodiments, the patient has one or more copies of the ApoE4 allele.

[0301] In some embodiments, the subject to whom the compounds or compositions described herein are applied may be or include a subject suffering from or susceptible to a neurodegenerative disease, disorder or condition. In some embodiments, a neurodegenerative disease, disorder or condition may be or include traumatic neuronal injury. In some embodiments, traumatic neuronal injury is blunt force trauma, closed head injury, open head injury, exposure to concussive and / or explosive forces, penetrating injury to the brain cavity or the innervated area of ​​the body. In some embodiments, traumatic neuronal injury is a force that causes axonal deformation, stretching, extrusion or shearing.

[0302] In some embodiments, the subject engages in an activity identified as a risk factor for neuronal degeneration, for example, a subject who engages in contact sports or an occupation with a high chance of traumatic neuronal injury.

[0303] For example, the subject can be a patient who is receiving or has been prescribed chemotherapy associated with peripheral neuropathy. Examples of chemotherapeutic agents include, but are not limited to, thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), platinum drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

[0304] In some embodiments, the methods provided include administering a composition described herein to a patient or patient population based on the presence or absence of one or more biomarkers. In some embodiments, the methods provided further include monitoring the levels of biomarkers in the patient or patient population and adjusting the dosing regimen accordingly.

[0305] Drug administration

[0306] It will be understood by those skilled in the art that, in some embodiments, the precise amount of a particular compound included in a pharmaceutical composition or regimen described herein and / or delivered by administration may be selected by a medical practitioner and may differ for different subjects, e.g., after considering one or more of the species, age, and general condition of the subject, and / or the characteristics of the particular compound or composition, its mode of administration, etc. Alternatively, in some embodiments, the amount of a particular compound included in a pharmaceutical composition or regimen as described herein and / or delivered by administration may be standardized across a relevant patient population (e.g., all patients, all patients of a particular age or disease stage, or expressing a particular biomarker, etc.).

[0307] The compounds or compositions provided by the present disclosure are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" used herein refers to physically discrete dosage units suitable for patients to be treated. However, it should be understood that the total daily dosage of the compounds and 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 of any particular patient or organism will depend on a variety of factors, including the severity of the disorder and disorder being treated; the clinical condition of the individual patient; the cause of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex and diet of the patient; the administration time of the specific compound used, the delivery site of the agent, the route of administration and the excretion rate; the duration of treatment; the drugs used in combination or simultaneously with the specific compound used, and similar factors well known in medical technology. The effective amount of the compound to be administered will be determined by these considerations and is the minimum amount required to inhibit the activity of SARM1 to prevent or treat undesirable diseases or disorders, such as neurodegeneration or traumatic nerve injury.

[0308] The pharmaceutically acceptable compositions of the present disclosure can be administered to humans and other animals orally, rectally, intravenously, parenterally, intracisternal, intravaginal, intraperitoneal, topically (such as powders, ointments or drops), buccally, as oral or nasal sprays, etc., depending on the severity of the disease, disorder or infection being treated. In certain embodiments, the daily dose is administered in a single daily dose or divided doses twice to six times a day, or in a sustained release form. This dosing regimen can be adjusted to provide the best therapeutic response. The compound can be administered once to four times a day, preferably once or twice a day.

[0309] In some embodiments, the compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or by implanted reservoirs. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intradermal, intraocular, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0310] In some embodiments, the pharmaceutically acceptable compositions of the present disclosure may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Topical formulations suitable for each of these areas or organs are readily prepared.

[0311] Most preferably, the pharmaceutically acceptable compositions of the present disclosure are formulated for oral administration. Such preparations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present disclosure are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered with food.

[0312] Those additional agents can be administered separately from the provided compounds or compositions thereof as part of a multiple dose regimen. Alternatively, those agents can be part of a single dosage form, mixed together with the provided compounds in a single composition. If administered as part of a multiple dose regimen, the two active agents can be provided simultaneously, sequentially, or within a period of time of each other (usually within five hours of each other).

[0313] It is also 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 employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the 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.

[0314] In some embodiments, the SARM1 inhibitors described herein can be used in combination with one or more other therapies to treat related diseases, disorders or conditions. In some embodiments, compared to when used as monotherapy, when using combination therapy, the dosage of the SARM1 inhibitor is changed; alternatively or additionally, in some embodiments, the therapy used in combination with the SARM1 inhibition described herein is administered according to a regimen or treatment process different from that when it is administered alone or in combination with one or more therapies other than SARM1 inhibition. In some embodiments, the composition comprising an additional therapeutic agent, the additional therapeutic agent and the provided compound can act synergistically. In some embodiments, one or both therapies used in the combination regimen are administered at a lower level or less frequently than when used as a monotherapy.

[0315] In some embodiments, the compounds and / or compositions described herein are administered with a chemotherapeutic agent, including but not limited to alkylating agents, anthracyclines, taxanes, epothilones, histone deacetylase inhibitors, topoisomerase inhibitors, kinase inhibitors, nucleotide analogs, peptide antibiotics, platinum agents, retinoids, vinca alkaloids, and derivatives. In some embodiments, the compounds and / or compositions described herein are administered in combination with a PARP inhibitor.

[0316] Example

[0317] This teaching includes the description provided in the examples, which is not intended to limit the scope of any claim. Unless specifically presented in the past tense, it is not intended to imply that experiments were actually performed in the examples. The following non-limiting examples are provided to further illustrate this teaching. According to this disclosure, it should be understood by those skilled in the art that many changes can be made in the specific embodiments disclosed, and similar or similar results can still be obtained without departing from the spirit and scope of this teaching.

[0318] method

[0319] Some of the methods and compositions described herein utilize laboratory techniques that are well known to those skilled in the art and can be found in laboratory manuals such as Sambrook, J. et al., Molecular Cloning: A Laboratory Manual, 3rd ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2001; Methods In Molecular Biology, ed. Richard, Humana Press, NJ, 1995; Spector, DL et al., Cells: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1998; and Harlow, E., Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999. The method of administration and dosage regimen of the drug can be determined according to standard principles of pharmacology using the methods provided in standard reference texts, such as Remington: the Science and Practice of Pharmacy (Alfonso R. Gennaro, ed., 19th ed., 1995); Hardman, JG et al., Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th ed., McGraw-Hill, 1996; and Rowe, RC et al., Handbook of Pharmaceutical Excipients, 4th ed., Pharmaceutical Press, 2003.

[0320] Example 1: Synthesis of Example 14

[0321]

[0322] At 0°C, NaH (60% in oil, 37 mg, 0.92 mmol) was slowly added to a mixture of azaindole 1 (150 mg, 0.615 mmol) in DMF (3 mL), and then stirred at 0°C for 0.5 hours. Iodoethane (144 mg, 0.92 mmol) was slowly added and stirred at ambient temperature for 2 hours. Water (30 ml) was slowly added to quench the reaction and extracted with EtOAc (50 ml × 3). The combined EtOAc was washed with brine and concentrated in vacuo. The residue was purified by preparative HPLC to give Example 14 (32 mg, yield = 18.5%).

[0323] Examples 13-16 and 26 were synthesized in a similar manner.

[0324] Example 2: Synthesis of Example 25

[0325]

[0326] To a mixture of azaindole 1 (150 mg, 0.615 mmol) and 2-bromoethanol (115 mg, 0.923 mmol) in DMF (3 mL) was added KCO (170 mg, 1.23 mmol). The mixture was stirred at 40 ° C for 2 hours, then poured into water (30 mL) and extracted with EtOAc (50 mL×3). The combined EtOAc was washed with brine and concentrated in vacuo. The residue was purified by preparative HPLC to give Example 25 (18 mg, yield=6%).

[0327] Examples 10-12 and 17-25 were synthesized in a similar manner.

[0328] Example 3: Synthesis of Example 36

[0329]

[0330] To a solution of Example 37 (40 mg, 0.27 mmol) in DMF (1 mL) was added N-bromosuccinimide (57 mg, 0.32 mmol). The mixture was stirred at ambient temperature for 2 hours, then diluted with water (1 mL) and directly purified by preparative HPLC to give Example 36 (13 mg, yield = 21%).

[0331] Example 4: Synthesis of Example 40

[0332]

[0333] Example 30 (100 mg, 0.47 mmol) was dissolved in H2O2 aqueous solution (50 wt%, 1 mL) and stirred at ambient temperature for 19 hours. To this mixture was added trifluoroacetic anhydride (0.35 mL, 2.5 mmol) and stirred for 4 days. The mixture was extracted with EtOAc (3×2 mL), dried over MgSO4, filtered and concentrated to give a crude product which was purified by flash chromatography (SiO2, CH2Cl2 containing 0-10% MeOH) to give the title compound Example 40 (11 mg, 9%).

[0334] Example 5: Synthesis of Example 41

[0335]

[0336] Thienopyridazine 2 (30 mg, 0.22 mmol) was dissolved in concentrated H2SO4 (2 mL) and treated with N-iodosuccinimide (0.03 mL, 0.26 mmol). The mixture was stirred at ambient temperature for 2 hours, then diluted with water (5 mL) and the pH was adjusted to pH = 8 with aqueous ammonium hydroxide. The mixture was extracted with EtOAc, dried over MgSO4, filtered and concentrated to give the crude product, which was purified by preparative HPLC to give the title compound Example 41 (5 mg, 9%).

[0337] Example 6: Synthesis of Example 42

[0338]

[0339] Pyrrolopyridazine 3 (50 mg, 0.42 mmol) was dissolved in concentrated H2SO4 (2 mL) and treated with N-iodosuccinimide (0.05 mL, 0.5 mmol). The mixture was stirred at ambient temperature for 2 hours, then diluted with water (5 mL) and the pH was adjusted to pH = 8 with aqueous ammonium hydroxide. The mixture was extracted with EtOAc, dried over MgSO4, filtered and concentrated to give the title compound Example 42 (35 mg, 33%).

[0340] Example 44 was synthesized in a similar manner from pyrrolopyridazine 3 and N-bromosuccinimide.

[0341] Example 7: Characterization of compounds

[0342] LCMS method:

[0343] Analytical LC / MS Analysis Method A:

[0344] ESI + / - ion mode 100-1000Da

[0345] Column: XBridge C18, 50x 4.6mm, 3.5um

[0346] Temperature: 40℃

[0347] gradient:

[0348]

[0349] Analytical LC / MS Analysis Method B:

[0350] ESI + / - ion mode 150-850Da

[0351] Column: Phenomenex Kinetix-XB C18, Part No. 00D-4498-AN, 2.1 x 100 mm, 1.7 um Temperature: 40 °C

[0352] gradient:

[0353] Time (min) Water + 0.1% formic acid Acetonitrile + 0.1% formic acid Flow rate (mL / min) 0.00 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

[0354] Preparative HPLC method:

[0355] UV-directed high pH preparative method

[0356]

[0357]

[0358] UV-directed low pH preparative method

[0359]

[0360] The results are listed in Table 1:

[0361] Table 1.

[0362]

[0363]

[0364]

[0365]

[0366]

[0367] Example 8: SAM-TIR SARM1 IC50 determination

[0368] This example describes an assay for SAM-TIR NADase activity and the use of this assay to measure the efficacy of compounds shown in Formula I in blocking SARM1-mediated NAD+ cleavage. The assay is optimized to characterize the efficacy of compounds shown in Formula I in inhibiting SARM1 activity and calculate the IC50 value for each compound. The assay utilizes a SARM1 molecule fragment containing a SAM and TIR domain. As shown herein, expression of this fragment without an autoinhibitory N-terminal domain produces a constitutively active enzyme that cleaves NAD+.

[0369] Preparation of SARM1 SAM-TIR Lysate (STL)

[0370] NRK1-HEK293T cells refer to a cell line stably transfected with an FCIV expression vector that expresses human nicotinamide riboside kinase 1 (NRK1), an enzyme that converts the NAD+ biosynthetic precursor nicotinamide riboside (NR) into NMN, the direct precursor of NAD+. When NR is provided, this cell line increases intracellular NAD+ levels and maintains cell viability when expressing the SARM1 SAM-TIR. Figure 2 NRK1-HEK293T stable lines with NR supplementation are shown to maintain higher NAD+ levels after SARM1-TIR expression. Data are generated from three independent NAD+ measurements from three independent transfection experiments and normalized to data from a non-transfection experiment run simultaneously. Data are expressed as mean ± SEM; error bars: SEM; ***P < 0.001 two-tailed student's-test.

[0371] NRK1-HEK293T cells represent a cell line stably transfected with an FCIV expression vector that expresses human nicotinamide riboside kinase 1 (NRK1), an enzyme that converts the NAD+ biosynthetic precursor nicotinamide riboside (NR) into NMN, the immediate precursor of NAD+.

[0372] NRK1-HEK293T cells were plated at 20 × 10 6 Cells were seeded into 150cm 2 The next day, use X-TREMEGENE TM The cells were transfected with 15 μg of FCIV-SST (SAM-TIR expression plasmid, SEQ ID NO: 1) using 9DNA transfection reagent (Roche product #06365787001).

[0373]

[0374] The culture was supplemented with 1 mM NR at the time of transfection to minimize the toxicity of SAM-TIR overexpression. Forty-eight hours after transfection, cells were harvested, pelleted by centrifugation at 1,000 rpm (Sorvall ST 16R centrifuge, Thermo Fisher), and washed once with cold PBS (0.01 M phosphate buffered saline; NaCl 0.138 M; KCl 0.0027 M; pH 7.4). Cells were resuspended in 4% paraformaldehyde with protease inhibitors (cOmplete TM Protease inhibitor cocktail, Roche product #11873580001) in PBS and prepared by sonication (Branson Sonifer 450, output = 3, 20 strokes). The lysate was centrifuged (12,000 × g, 10 minutes at 4°C) to remove cell debris, and the supernatant (containing SARM1 SAM-TIR protein) was stored at -80°C for subsequent use in in vitro SARM1 SAM-TIR NADase assay (see below). Protein concentration was determined by the bicinchonaic acid (BCA) method and used for normalization of lysate concentration.

[0375] SAM-TIR IC50 determination of the compound of formula I

[0376] Enzymatic assays were performed in 384-well polypropylene plates in Dulbecco's PBS buffer with a final assay volume of 20 μL. SAM-TIR lysates with a final concentration of 5 μg / mL were pre-incubated with the corresponding compounds at room temperature for 2 hours at a final assay concentration of 1% DMSO. The reaction was initiated by adding 5 μM final assay concentration of NAD+ as a substrate. After 2 hours of incubation at room temperature, the reaction was terminated with 40 μL of 7.5% trichloroacetic acid in acetonitrile. The concentrations of NAD+ and ADPR were analyzed using an API4000 triple quadrupole mass spectrometer (AB Sciex Framingham, MA) by a RapidFire high-throughput mass spectrometry system (Agilent Technologies, Santa Clara, CA).

[0377] The results are listed in Table 2 below. IC values ​​of compounds with activity designated as "A" 50 <10 μM; IC for compounds with activity designated as "B" 50 The IC values ​​of compounds with activity designated as "C" were 10-30 μM. 50 The IC values ​​of compounds with activity designated as "D" were 30.01-50 μM. 50 >50 μM; ND: not determined.

[0378] Table 2.

[0379]

[0380]

[0381]

[0382]

[0383]

[0384] Example 9: Axonal Degeneration Index

[0385] This example illustrates an in vitro axonal degeneration assay used to characterize compounds of Formula I. The assay was used to test the efficacy of compounds of Formula I in preventing axonal degeneration in mouse dorsal root ganglion (DRG) hanging drop cultures.

[0386] Mouse DRG hanging drop culture: Mouse dorsal root ganglion neurons (DRG) were dissected from E12.5 CD1 mice (50 ganglia per embryo) and incubated with 0.5% trypsin solution containing 0.02% EDTA (Gibco) at 37°C for 15 minutes. The cells were then triturated by gentle pipetting and washed three times with DRG growth medium (Neurobasal medium (Gibco) containing 2% B27 (Invitrogen), 100 ng / ml 2.5S NGF (Harland Bioproducts), 1 mM 5-fluoro-2'deoxyuridine (Sigma), penicillin and streptomycin). The cells were suspended in DRG growth medium. 5000 cells / well were spotted into the center of each well of a 96-well tissue culture plate coated with poly-D-lysine (0.1 mg / ml; Sigma) and laminin (3 mg / ml; Invitrogen) to create DRG hanging drop cultures. The cells were allowed to adhere to the plates in a humidified tissue culture incubator (5% CO2) for 15 minutes, after which DRG growth medium (100 ml per well) was gently added.

[0387] Axon degeneration assay: Axon degeneration was stimulated by manual axon transection using a scalpel or by chemotoxic stimulation. After the appropriate experimental time period, DRG cultures were fixed in 1% PFA plus sucrose and kept in the refrigerator before 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 quantification of axons was performed using an in-house developed script (Acapella, PerkinElmer).

[0388] The results are listed in Table 3 below. The compounds described herein demonstrated protection against axonal disruption in cell-based assays and were evaluated by IC 50 10-30μM (B) and <10μM (A) were sorted.

[0389] Table 3.

[0390] Examples <![CDATA[Axonal degeneration IC 50 > 4 A 7 A 30 B Sequence Listing <110> Dasama Therapeutics <120> SARM1 inhibitors <130> 2012800-0023 <150> 62 / 682,045 <151> 2018-06-07 <160> 1 <170> PatentIn version 3.5 <210> 1 <211> 10329 <212> DNA <213> Artificial sequence <220> <223> Chemically synthesized oligonucleotides <400> 1 gtcgacggat cgggagatct cccgatcccc tatggtgcac tctcagtaca atctgctctg 60 atgccgcata gttaagccag tatctgctcc ctgcttgtgt gttggaggtc gctgagtagt 120 gcgcgagcaa aatttaagct acaacaaggc aaggcttgac cgacaattgc atgaagaatc 180 tgcttagggt taggcgtttt gcgctgcttc gcgatgtacg ggccagatat acgcgttgac 240 attgattatt gactagttat taatagtaat caattacggg gtcattagtt catagcccat 300 atatggagtt ccgcgttaca taacttacgg taaatggccc gcctggctga ccgcccaacg 360 acccccgccc attgacgtca ataatgacgt atgttcccat agtaacgcca atagggactt 420 tccattgacg tcaatgggtg gagtatttac ggtaaactgc ccacttggca gtacatcaag 480 tgtatcatat gccaagtacg ccccctattg acgtcaatga cggtaaatgg cccgcctggc 540 attatgccca gtacatgacc ttatgggact ttcctacttg gcagtacatc tacgtattag 600 tcatcgctat taccatggtg atgcggtttt ggcagtacat caatgggcgt ggatagcggt 660 ttgactcacg gggatttcca agtctccacc ccattgacgt caatgggagt ttgttttggc 720 accaaaatca acgggacttt ccaaaatgtc gtaacaactc cgccccattg acgcaaatgg 780 gcggtaggcg tgtacggtgg gaggtctata taagcagcgc gttttgcctg tactgggtct 840 ctctggttag accagatctg agcctgggag ctctctggct aactagggaa cccactgctt 900 aagcctcaat aaagcttgcc ttgagtgctt caagtagtgt gtgcccgtct gttgtgtgac 960 tctggtaact agagatccct cagacccttt tagtcagtgt ggaaaatctc tagcagtggc 1020 gcccgaacag ggacttgaaa gcgaaaggga aaccagagga gctctccga cgcaggactc 1080 ggcttgctga agcgcgcacg gcaagaggcg aggggcggcg actggtgagt acgccaaaaa 1140 ttttgactag cggaggctag aaggagag atgggtgcga gagcgtcagt attaagcggg 1200 ggagaattag atcgcgatgg gaaaaaatttc ggttaaggcc aggggaag aaaaatata 1260 aattaaaaca tatagtatgg gcaagcagggg agctagaacg attcgcagtt aatcctggcc 1320 tgttagaaac atcagaaggc tgtagacaaa tactgggaca gctacaacca tcccttcaga 1380 caggatcaga agaacttaga tcattatata atacagtagc aaccctctat tgtgtgcatc 1440 aaaggaagaaaagaaaaaaaaaaaaaaaaaaaaaaaaggaaaggaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaad imagind haveaaaa aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaees says   cttaagaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaggs ct aaagtaagac caccgcacag caagcggccg ctgatcttca gacctggagg aggagatg 1560 agggacaatt gagaagtga attaataa tataaagtag taaaaattga accattagga 1620 gtagcacca ccaaggcaa gagagagtg gtgcagagag aaaaaagagc agtgggaata 1680 ggagctttgt tccttgggtt cttgggagca gcaggaagca ctatggggcgc agcgtcaatg 1740 acgctgacgg tacaggccag acaattattg tctggtatag tgcagcagca gaacaatttg 1800 ctgagggcta ttgaggcgca acagcatctg ttgcaactca cagtctgggg catcaagcag 1860 ctccaggcaa gaatcctggc tgtggaaaga tacctaaagg atcaacagct cctggggatt 1920 tggggttgct ctggaaaact catttgcacc actgctgtgc cttggaatgc tagttggagt 1980 aataaatctc tggaacagat ttggaatcac acgacctgga tggagtggga cagagaaatt 2040 aacaattaca caagcttaat acactcctta attgaagaat cgcaaacca gcaagaaaag 2100 aatgaacaag aattattgga attagataaa tgggcaagtt tgtggaattg gtttaacata 2160 acaaattggc tgtggtatat aaaattattc ataatgatag taggaggctt ggtaggttta 2220 agaatagttt ttgctgtact ttctatagtg aatagagtta ggcagggata ttcaccatta 2280 tcgtttcaga cccacctccc aaccccgagg ggacccgaca ggcccgaagg aatagaagaa 2340 gaaggtggag agagagacag agacagatcc attcgattag tgaacggatc ggcactgcgt 2400 gcgccaattc tgcagacaaa tggcagtatt catccacaat tttaaaagaa aaggggggat 2460 tggggggtac agtgcagggg aaagaatagt agacataata gcaacagaca tacaaactaa 2520 agaattacaa aaacaaatta caaaaattca aaattttcgg gtttattaca gggacagcag 2580 agatccagtt tggttaatta agggtgcagc ggcctccgcg ccgggttttg gcgcctcccg 2640 cgggcgcccc cctcctcacg gcgagcgctg ccacgtcaga cgaagggcgc aggagcgttc 2700 ctgatccttc cgcccggacg ctcaggacag cggcccgctg ctcataagac tcggccttag 2760 aaccccagta tcagcagaag gacattttag gacgggactt gggtgactct agggcactgg 2820 ttttctttcc agagagcgga acaggcgagg aaaagtagtc ccttctcggc gattctgcgg 2880 agggatctcc gtggggcggt gaacgccgat gattatataa ggacgcgccg ggtgtggcac 2940 agctagttcc gtcgcagccg ggatttgggt cgcggttctt gtttgtggat cgctgtgatc 3000 gtcacttggt gagttgcggg ctgctgggct ggccggggct ttcgtggccg ccgggccgct 3060 cggtgggacg gaagcgtgtg gagagaccgc caagggctgt agtctgggtc cgcgagcaag 3120 gttgccctga actgggggtt ggggggagcg cacaaaatgg cggctgttcc cgagtcttga 3180 atggaagacg cttgtaaggc gggctgtgag gtcgttgaaa caaggtgggg ggcatggtgg 3240 gcggcaagaa cccaaggtct tgaggccttc gctaatgcgg gaaagctctt attcgggtga 3300 gatgggctgg ggcaccatct ggggaccctg acgtgaagtt tgtcactgac tggagaactc 3360 gggtttgtcg tctggttgcg ggggcggcag ttatgcggtg ccgttgggca gtgcacccgt 3420 acctttggga gcgcgcgcct cgtcgtgtcg tgacgtcacc cgttctgttg gcttataatg 3480 cagggtgggg ccacctgccg gtaggtgtgc ggtaggcttt tctccgtcgc aggacgcagg 3540 gttcgggcct agggtaggct ctcctgaatc gacaggcgcc ggacctctgg tgaggggagg 3600 gataagtgag gcgtcagttt ctttggtcgg ttttatgtac ctatcttctt aagtagctga 3660 agctccggtt ttgaactatg cgctcggggt tggcgagtgt gttttgtgaa gttttttagg 3720 caccttttga aatgtaatca tttgggtcaa tatgtaattt tcagtgttag actagtaaag 3780 cttctgcagg tcgactctag aaaattgtcc gctaaattct ggccgttttt ggcttttttg 3840 ttagacgaag cttgggctgc aggtcgactc tagaggatcc ggatccgcca ccatgtcagc 3900 ttggagccac ccacaattcg aaaaaggcgg tggctcaggc ggtggctcag gtggctcagc 3960 ttggagccac ccacaattcg aaaaaggcgg tggctcatct ggcggaggtg gcggtggctc 4020 atctggcgga ggtgctagcg tgcccagctg gaaggaggcc gaggttcaga cgtggctgca 4080 gcagatcggt ttctccaagt actgcgagag cttccgggag cagcaggtgg atggcgacct 4140 gcttctgcgg ctcacggagg aggaactcca gaccgacctg ggcatgaaat cgggcatcac 4200 ccgcaagagg ttctttaggg agctcacgga gctcaagacc ttcgccaact attctacgtg 4260 cgaccgcagc aacctggcgg actggctggg cagcctggac ccgcgcttcc gccagtacac 4320 ctacggcctg gtcagctgcg gcctggaccg ctccctgctg caccgcgtgt ctgagcagca 4380 gctgctggaa gactgcggca tccacctggg cgtgcaccgc gcccgcatcc tcacggcggc 4440 cagagaaatg ctacactccc cgctgccctg tactggtggc aaacccagtg gggacactcc 4500 agatgtcttc atcagctacc gccggaactc aggttcccag ctggccagtc tcctgaaggt 4560 gcacctgcag ctgcatggct tcagtgtctt cattgatgtg gagaagctgg aagcaggcaa 4620 gttcgaggac aaactcatcc agagtgtcat gggtgcccgc aactttgtgt tggtgctatc 4680 acctggagca ctggacaagt gcatgcaaga ccatgactgc aaggattggg tgcataagga 4740 gattgtgact gctttaagct gcggcaagaa cattgtgccc atcattgatg gcttcgagtg 4800 gcctgagccc caggtcctgc ctgaggacat gcaggctgtg cttactttca acggtatcaa 4860 gtggtcccac gaataccagg aggccaccat tgagaagatc atccgcttcc tgcagggccg 4920 ctcctcccgg gactcatctg caggctctga caccagtttg gagggtgctg cacccatggg 4980 tccaacctaa actctagaat tcgatatcaa gcttatcgat aatcaacctc tggattacaa 5040 aatttgtgaa agattgactg gtattcttaa ctatgttgct ccttttacgc tatgtggata 5100 cgctgcttta atgcctttgt atcatgctat tgcttcccgt atggctttca ttttctcctc 5160 cttgtataaa tcctggttgc tgtctcttta tgaggagttg tggcccgttg tcaggcaacg 5220 tggcgtggtg tgcactgtgt ttgctgacgc aacccccact ggttggggca ttgccaccac 5280 ctgtcagctc ctttccggga ctttcgcttt ccccctccct attgccacgg cggaactcat 5340 cgccgcctgc cttgcccgct gctggacagg ggctcggctg ttgggcactg acaattccgt 5400 ggtgttgtcg gggaaatcat cgtcctttcc ttggctgctc gcctgtgttg ccacctggat 5460 tctgcgcgg acgtccttct gctacgtccc ttcggccctc aatccagcgg accttcttc 5520 ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt cgcttcgcc ctcagacgag 5580 tcggatctcc ctttgggccg cctccccgca tcgataccgt cgacctcgag acctagaaaa 5640 acatggagca atcacaagta gcaatacagc agctaccaat gctgattgtg cctggctaga 5700 agcacaagag gagggagg tgggttttcc agtcacacct caggtacctt taagaccaat 5760 gacttacaag gcagctgtag atcttagcca ctttttaaaa gaaaagggg gactggaagg 5820 gctaattcac tcccaacgaa gacaagatat ccttgatctg tggatctacc acacacaagg 5880 ctacttccct gattggcaga actacacacc agggccaggg atcagatatc cactgacctt 5940 tggatggtgc tacaagctag taccagttga gcaagagaag gtagagaag ccaatgaagg 6000 agaagaacacc cgcttgttac accctgtgag cctgcatggg atggatgacc cggagagaga 6060 agtattagag tggaggtttg acagccgcct agcatttcat cacatggccc gagagctgca 6120 tccggactgt actgggtctc tctggttaga ccagatctga gcctgggagc tctctggcta 6180 actagggaac ccactgctta agcctcaata aagcttgcct tgagtgcttc aagtagtgtg 6240 tgcccgtctg ttgtgtgact ctggtaacta gagatccctc agaccctttt agtcagtgtg 6300 gaaaatctct agcagggccc gtttaaaccc gctgatcagc ctcgactgtg ccttctagtt 6360 gccagccatc tgttgtttgc ccctcccccg tgccttcctt gaccctggaa ggtgccactc 6420 ccactgtcct ttcctaataa aatgaggaaa ttgcatcgca ttgtctgagt aggtgtcatt 6480 ctattctggg gggtggggtg gggcaggaca gcaaggggga ggattgggaa gacaatagca 6540 ggcatgctgg ggatgcggtg ggctctatgg cttctgaggc ggaaagaacc agctggggct 6600 ctagggggta tccccacgcg ccctgtagcg gcgcattaag cgcggcgggt gtggtggtta 6660 cgcgcagcgt gaccgctaca cttgccagcg ccctagcgcc cgctcctttc gctttcttcc 6720 cttcctttct cgccacgttc gccggctttc cccgtcaagc tctaaatcgg gggctccctt 6780 tagggttccg atttagtgct ttacggcacc tcgaccccaa aaaacttgat tagggtgatg 6840 gttcacgtag tgggccatcg ccctgataga cggttttcg ccctttgacg ttggagtcca 6900 cgttctttaa tagtggactc ttgttccaaa ctggaacaac actcaaccct atctcggtct 6960 attctttga tttataaggg attttgccga ttcggccta ttggttaaaa aatgagctga 7020 tttaacaaaa atttaacgcg aattaattct gtggaatgtg tgtcagttag ggtgtggaaa 7080 gtccccaggc tccccagcag gcagaagtat gcaaagcatg catctcaatt agtcagcaac 7140 caggtgtgga aagtccccag gctccccagc aggcagaagt atgcaaagca tgcatctcaa 7200 ttagtcagca accatagtcc cgcccctaac tccgcccatc ccgcccctaa ctccgcccag 7260 ttccgcccat tctccgcccc atggctgact aattttttt attatgcag aggccgaggc 7320 cgcctctgcc tctgagctat tccagaagta gtgaggaggc ttttttggag gcctaggctt 7380 ttgcaaaaag ctcccgggag cttgtatatc cattttcgga tctgatcagc acgtgttgac 7440 aattaatcat cggcatagta tatcggcata gtataatacg acaaggtgag gaactaaacc 7500 atggccaagt tgaccagtgc cgttccggtg ctcaccgcgc gcgacgtcgc cggagcggtc 7560 gagttctgga ccgaccggct cgggttctcc cgggacttcg tggaggacga cttcgccggt 7620 gtggtccggg acgacgtgac cctgttcatc agcgcggtcc aggaccaggt ggtgccggac 7680 aacaccctgg cctgggtgtg ggtgcgcggc ctggacgagc tgtacgccga gtggtcggag 7740 gtcgtgtcca cgaacttccg ggacgcctcc gggccggcca tgaccgagat cggcgagcag 7800 ccgtgggggc gggagttcgc cctgcgcgac ccggccggca actgcgtgca cttcgtggcc 7860 gaggagcagg actgacacgt gctacgagat ttcgattcca ccgccgcctt ctatgaaagg 7920 ttgggcttcg gaatcgtttt ccgggacgcc ggctggatga tcctccagcg cggggatctc 7980 atgctggagt tcttcgccca ccccaacttg tttattgcag cttataatgg ttacaaataa 8040 agcaatagca tcacaaattt cacaaataaa gcattttttt cactgcattc tagttgtggt 8100 ttgtccaaac tcatcaatgt atcttatcat gtctgtatac cgtcgacctc tagctagagc 8160 ttggcgtaat catggtcata gctgtttcct gtgtgaaatt gttatccgct cacaattcca 8220 cacaacatac gagccggaag cataaagtgt aaagcctggg gtgcctaatg agtgagctaa 8280 ctcacattaa ttgcgttgcg ctcactgccc gctttccagt cgggaaacct gtcgtgccag 8340 ctgcattaat gaatcggcca acgcgcgggg agaggcggtt tgcgtattgg gcgctcttcc 8400 gcttcctcgc tcactgactc gctgcgctcg gtcgttcggc tgcggcgagc ggtatcagct 8460 cactcaaagg cggtaatacg gttatccaca gaatcagggg ataacgcagg aaagaacatg 8520 tgagcaaaag gccagcaaaa ggccaggaac cgtaaaaagg ccgcgttgct ggcgtttttc 8580 cataggctcc gcccccctga cgagcatcac aaaaatcgac gctcaagtca gaggtggcga 8640 aacccgacag gactataaag ataccaggcg tttccccctg gaagctccct cgtgcgctct 8700 cctgttccga ccctgccgct taccggatac ctgtccgcct ttctcccttc gggaagcgtg 8760 gcgctttctc atagctcacg ctgtaggtat ctcagttcgg tgtaggtcgt tcgctccaag 8820 ctgggctgtg tgcacgaacc ccccgttcag cccgaccgct gcgccttatc cggtaactat 8880 cgtcttgagt ccaacccggt aagacacgac ttatcgccac tggcagcagc cactggtaac 8940 aggattagca gagcgaggta tgtaggcggt gctacagagt tcttgaagtg gtggcctaac 9000 tacggctaca ctagaagaac agtatttggt atctgcgctc tgctgaagcc agttaccttc 9060 ggaaaaagag ttggtagctc ttgatccggc aaacaaacca ccgctggtag cggtggtttt 9120 tttgtttgca agcagcagat tacgcgcaga aaaaaaggat ctcaagaaga tcctttgatc 9180 ttttctacgg ggtctgacgc tcagtggaac gaaaactcac gttaagggat tttggtcatg 9240 agattatcaa aaaggatctt cacctagatc cttttaaatt aaaaatgaag ttttaaatca 9300 atctaaagta tatatgagta aacttggtct gacagttacc aatgcttaat cagtgaggca 9360 cctatctcag cgatctgtct atttcgttca tccatagttg cctgactccc cgtcgtgtag 9420 ataactacga tacgggaggg cttaccatct ggccccagtg ctgcaatgat accgcgagac 9480 ccacgctcac cggctccaga tttatcagca ataaaccagc cagccggaag ggccgagcgc 9540 agaagtggtc ctgcaacttt atccgcctcc atccagtcta ttaattgttg ccgggaagct 9600 agagtaagta gttcgccagt tatagtttg cgcaacgttg ttgccattgc tacaggcatc 9660 gtggtgtcac gctcgtcgtt tggtatggct tcattcagct ccggttccca acgatcaagg 9720 cgagttacat gatcccccat gttgtgcaaa aaagcggtta gctccttcgg tcctccgatc 9780 gttgtcagaa gtaagttggc cgcagtgtta tcactcatgg ttatggcagc actgcataat 9840 tctcttactg tcatgccatc cgtaagatgc tttctgtga ctggtgagta ctcaaccaag 9900 tcattctgag aatagtgtat gcggcgaccg agttgctctt gcccggcgtc aatacgggat 9960 aataccgcgc cacatagcag aactttaaaa gtgctcatca ttggaaaacg ttcttcgggg 10020 cgaaaaactct caaggatctt accgctgttg agatccagtt cgatgtaacc cactcgtgca 10080 cccaactgat cttcagcatc ttttactttc accagcgttt ctgggtgagc aaaaacagga 10140 aggcaaaatg ccgcaaaaaa gggaataagg gcgacacgga aatgttgaat actcatactc 10200 ttcctttttc aatattattg aagcatttat cagggttatt gtctcatgag cggatacata 10260 tttgaatgta tttagaaaaa taaacaaata ggggttccgc gcacatttcc ccgaaaagtg 10320 ccacctgac 10329

Claims

1. Use of a compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing axonal degeneration or for treating a condition selected from chemotherapy-induced peripheral neuropathy, diabetic neuropathy and amyotrophic lateral sclerosis, wherein the compound or a pharmaceutically acceptable salt thereof is selected from: or a pharmaceutically acceptable salt thereof.

Images