SARM1 inhibitors

Abstract

The present disclosure provides compounds and methods that can be used to inhibit SARM1 and / or treat and / or prevent axonal degeneration. In some embodiments, the present disclosure provides certain compounds and / or compositions that can be used in medicine, particularly for treating neurodegeneration (e.g., for alleviating axonal degeneration). In some embodiments, the present disclosure provides compounds having a structure as listed in Formula I.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 858,083, filed on June 6, 2019, which is incorporated herein by reference in its entirety.

[0003] Sequence Listing

[0004] This application contains a sequence listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy created on June 3, 2020 is named 2012800-0036_SL.txt and is 13,851 bytes in size.

[0005] background

[0006] Axonal degeneration is a hallmark of several neurological disorders, including peripheral neuropathy, traumatic brain injury, and neurodegenerative diseases (Gerdts et al., SARM1 activation triggers axon degeneration locally via NAD(+) destruction. Science 348 2016, pp. 453-457, the entire text of which is hereby incorporated by reference). Neurodegenerative diseases and injuries are devastating to both patients and caregivers. The costs associated with these diseases currently exceed hundreds of billions of dollars per year in the United States alone. Since the incidence of many of these diseases and disorders increases with age, their incidence is growing rapidly as demographics change.

[0007] Overview

[0008] The present disclosure provides technologies that are particularly useful for treating and / or preventing neurodegeneration (eg, for reducing axonal degeneration). In some embodiments, provided technologies inhibit SARM1.

[0009] In some embodiments, the present disclosure provides certain compounds and / or compositions that are useful in medicine, particularly useful in treating neurodegeneration (eg, for reducing axonal degeneration).

[0010] In some embodiments, the present disclosure provides compounds having a structure as set forth in Formula I:

[0011]

[0012] or a pharmaceutically acceptable salt thereof, wherein

[0013] R 1is selected from -CN, -CON(R)2, -C(=NR)N(R)2, -NO2, -S(O)2R, -S(O)2N(R)2, -C(O)R, -CO2R and a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0014] R 2 Yes-R;

[0015] R 3 Yes - (CH2) 0-2 Cy 1 ;

[0016] R 4 Yes-Cy 2 ;

[0017] Cy 1 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each phenyl and heteroaryl ring is surrounded by 0-4 R x replace;

[0018] Each R x independently selected from halogen, -CN, -NO2, -SR, -N(R)2, -OR, -C(O)R, -SO2R, -CO2R, -SO2N(R)2, -CON(R)2, -N(R)SO2R, -N(R)C(O)R, and optionally substituted C 1-6 aliphatic groups;

[0019] Cy 2 is selected from phenyl, a 3- to 7-membered monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7- to 9-membered bridged bicyclic or spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each of the phenyl, heterocyclic and heteroaryl rings is surrounded by 0-4 R v replace;

[0020] Each R v independently selected from halogen, -CN, -NO2, -SR, -N(R)2, -OR, -C(O)R, -SO2R, -CO2R, -SO2N(R)2, -CON(R)2, -N(R)SO2R, -N(R)C(O)R, optionally substituted C 1-6 aliphatic groups and optionally substituted 5- to 6-membered heteroaryl rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

[0021] Each R is independently hydrogen or optionally substituted C 1-6 An aliphatic group, or:

[0022] Two R's together with the atoms to which they are attached form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring.

[0023] In some embodiments, provided compounds have the following formula Ia, Ia- i , Ia- ii , Ia- iii , Ib, Ib- i , Ib- ii , Ib- iii 、Ic、Ic- i 、Ic- ii and Ic- iii structure.

[0024] In some embodiments, one or more compounds of Formula I are provided and / or used in solid form (eg, crystalline form or amorphous form).

[0025] In some embodiments, the disclosure provides compositions that contain and / or deliver a compound of Formula I (eg, in a form as described herein), a prodrug, or an active metabolite thereof.

[0026] 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.

[0027] In some embodiments, provided SARM1 inhibitors reduce or inhibit NAD+ binding by SARM1. 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).

[0028] 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.

[0029] In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, in medical practice. In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat, prevent, or improve axonal degeneration (e.g., one or more characteristics or properties thereof). In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to inhibit axonal degeneration, including axonal degeneration caused by a reduction or depletion of NAD+. In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to prevent axonal degeneration at the distal end of axonal injury.

[0030] In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat one or more neurodegenerative diseases, disorders or conditions selected from neuropathy or axonopathy. In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat 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 originates from a de novo mutation or a somatic mutation. 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 (ALS), demyelinating disease, ischemia or stroke, chemical injury, thermal injury and AIDS.

[0031] In some embodiments, the object to be administered a compound or composition as described herein may be or include an object 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 brain injury, open head trauma, exposure to concussive force and / or explosive force, penetrating injury in the innervation area of ​​the brain cavity or body, or penetrating injury to the innervation area of ​​the brain cavity or body. In some embodiments, traumatic neuronal injury is a force that causes axonal deformation, stretching, squeezing (crush) or steering (sheer).

[0032] In some embodiments, the methods provided include administering a compound described herein to a patient in need thereof. In some such embodiments, the patient is at risk for developing a condition characterized by axonal degeneration. In some embodiments, the patient has a condition characterized by axonal degeneration. In some embodiments, the patient has been diagnosed with a condition characterized by axonal degeneration.

[0033] In some embodiments, the methods provided include administering a composition as described herein to a patient population in need thereof. In some embodiments, the population is from individuals participating in activities with a high likelihood of traumatic neuronal injury. In some embodiments, the population is from athletes participating in contact sports or other high-risk activities.

[0034] In some embodiments, the patient is at risk for developing a neurodegenerative disorder. In some embodiments, the patient is elderly. In some embodiments, the patient is known to have genetic risk factors for neurodegeneration.

[0035] In certain embodiments, the present disclosure provides compounds that can be used, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present disclosure. The compounds provided by the present disclosure can also be used for the study of SARM1 function in biological and pathological phenomena and the comparative evaluation of novel SARM1 activity inhibitors in vitro or in vivo.

[0036] In some embodiments, one or more compounds and / or compositions as described herein can be used as methods, for example, to inhibit the degeneration of neurons derived from a subject. In some embodiments, one or more compounds and / or compositions as described herein can be used to inhibit the degeneration of neurons or parts thereof cultured in vitro. In some embodiments, one or more compounds and / or compositions as described herein can be used as stabilizers to promote neuronal survival in vitro. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 Illustration of the structure of the SARM1 protein.

[0039] Figure 2 It was shown that the NRK1-HEK293T stable cell line with NR supplementation maintained higher NAD+ levels after SARM1-TIR expression.

[0040] definition

[0041] Aliphatic:The term "aliphatic" refers to a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as "carbocycle" or "alicyclic"), with 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 yet other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle") refers to a monocyclic C3-C8 hydrocarbon or a bicyclic C7-C8 hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic, with a single point of attachment to the rest of the molecule. 10 Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and hybrids thereof.

[0042] 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 of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0043] Alkylene: The term "alkylene" refers to a divalent alkyl group. In some embodiments, an "alkylene" group 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. The optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are optionally replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups, and also include those described in the specification of this article. It is recognized that two substituents of an alkylene group 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.

[0044] 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.

[0045] 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.

[0046] Aryl: The term "aryl" refers to monocyclic and bicyclic ring systems with a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, which includes but is not limited to phenyl, biphenyl, naphthyl, anthracenyl, etc., which may be substituted with one or more substituents. The term "aryl" as used herein also includes groups in which aromatic rings are fused to one or more non-aromatic rings, such as indanyl, phthalimide, naphthalimide, phenanthridinyl or tetrahydronaphthyl, etc.

[0047] Combined with: It is to be understood that the term "binding" as used herein generally refers to a non-covalent association between 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 where the interacting entities or moieties are studied in isolation or in the context of a more complex system (e.g., while covalently or otherwise associated with a carrier entity and / or in a biological system or cell).

[0048] Biological samples:The term "biological sample" as used herein generally refers to a sample obtained from or derived from a relevant biological source as described herein (e.g., a tissue or an organism or a cell culture). In some embodiments, the relevant source 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 comprise 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 fluid; gynecological fluid; skin swab; vaginal swab; oral swab; nasal swab; washings or lavages, such as catheter lavages or bronchoalveolar lavages; aspirates; scrapings; bone marrow samples; tissue biopsy samples; surgical samples; feces, other body fluids, secretions and / or excretions; and / or cells therefrom, etc. In some embodiments, the biological sample is or comprises cells obtained from an individual. In some embodiments, the resulting cells are or include cells from a sample taken from an individual. In some embodiments, a sample is a "primary sample" obtained directly from a relevant source by any appropriate means. For example, in some embodiments, a primary biological sample is obtained by a method selected from a biopsy (e.g., fine needle aspiration or tissue biopsy), a surgical procedure, a collection of body fluids (e.g., blood, lymph, feces, etc.), etc. In some embodiments, as is clear from the context, the term "sample" refers to a preparation obtained by processing a primary sample (e.g., by removing one or more components thereof and / or by adding one or more reagents thereto). For example, filtration using a semipermeable membrane. Such a "processed sample" may include, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, separation and / or purification of certain components.

[0049] Biomarkers:The term "biomarker" is used herein to indicate an entity, event or feature whose presence, level, degree, type and / or form is associated with a relevant specific biological event or state so that it is considered a "marker" of the event or state. To name a few, in some embodiments, a biomarker can be or include a marker of a specific disease state, or a marker of the likelihood that a specific disease, disorder or condition may develop, occur or recur. In some embodiments, a biomarker can be or include a marker of a specific disease or treatment outcome or its likelihood. Therefore, for a relevant biological event or a relevant state, in some embodiments, a biomarker is predictive, in some embodiments, a biomarker is prognostic, and in some embodiments, a biomarker is diagnostic. A biomarker can be or include an entity of any chemical class, and can be or include a combination of entities. For example, in some embodiments, a biomarker can be or include a nucleic acid, 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, the biomarker is detected extracellularly (e.g., secreted or otherwise produced or present outside the cell, such as in a body fluid such as blood, urine, tears, saliva, cerebrospinal fluid, etc.). In some embodiments, the biomarker can be or include a genetic or epigenetic signature. In some embodiments, the biomarker can be or include a gene expression signature.

[0050] In some embodiments, the biomarker can be or include a marker of neurodegeneration, or a marker of the likelihood that a neurodegenerative disease, disorder, or condition may develop, occur, or recur. In some embodiments, the biomarker can be or include a marker of neurodegeneration, treatment outcome, or likelihood thereof. Thus, for neurodegenerative diseases, disorders, or conditions, in some embodiments, the biomarker is predictive, in some embodiments, the biomarker is prognostic, and in some embodiments, the biomarker is diagnostic. In some embodiments, changes in the levels of biomarkers can be detected by cerebrospinal fluid (CSF), plasma, and / or serum.

[0051] 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 onset 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.

[0052] In some embodiments, a detectable change in one or more neurodegeneration-related proteins in a subject relative to a healthy reference population 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 acidic protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractant protein (MCP) -1, neurogranin, neuron-specific enolase (NSE), soluble amyloid precursor protein (sAPP) α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phosphorylated tau and / or total tau. In some embodiments, increases in cytokines and / or chemokines, including but not limited to Ccl2, Ccl7, Ccl12, Csf1 and / or Il6 can be used as biomarkers for neurodegeneration.

[0053] carrier: The term "carrier" as used herein refers to a diluent, adjuvant, excipient or vehicle for administering a composition. In some exemplary embodiments, the carrier may include sterile liquids, such as water and oils, including oils of petroleum, animal, plant 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.

[0054] Combination therapy:The term "combination therapy" as used herein refers to those situations in which a subject is simultaneously exposed to two or more treatment regimens (e.g., two or more therapeutic agents). In some embodiments, two or more regimens may be administered simultaneously; in some embodiments, these regimens may be administered sequentially (e.g., all "doses" of the first regimen are administered before any doses of the second regimen); in some embodiments, these agents are administered in overlapping dosing regimens. In some embodiments, "administration" of a combination therapy may involve administering one or more agents or modalities to a subject receiving other agents or modalities in the combination. For clarity, combination therapy does not require that the individual agents be administered together (or even necessarily simultaneously) in a single composition, although in some embodiments, two or more agents or their active 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).

[0055] Composition: Those skilled in the art will recognize that the term "composition" can be used to refer to a separate physical entity comprising one or more specified components. Generally, unless otherwise specified, a composition can be in any form - eg, gas, gel, liquid, solid, etc.

[0056] Domain: As used herein, the term "domain" refers to a fragment or portion of an entity. In some embodiments, a "domain" is associated with a specific structural and / or functional feature of an entity, such 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 may be or include a portion of an entity that substantially retains and / or provides one or more structural and / or functional features that are unique to the parent entity on the receptor entity when it is separated from the (parent) entity and connected to a different (receptor) entity. In some embodiments, a domain is a fragment 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 fragment of a polypeptide; in some such embodiments, the domain is characterized by specific structural elements (e.g., specific amino acid sequences or sequence motifs, α-helical features, β-folding features, coiled coil features, random coil features, etc.) and / or specific functional features (e.g., binding activity, enzymatic activity, folding activity, signaling activity, etc.).

[0057] Dosage form or unit dosage form:Those skilled in the art will recognize that the term "dosage form" can be used to represent physically discrete units of an active agent (e.g., a therapeutic agent or a diagnostic agent) administered to a subject. Typically, each such unit contains a predetermined amount of an active agent. In some embodiments, such an amount is a unit dose (or its whole fraction) 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 result when administered to a relevant population. Those of ordinary skill in the art will recognize 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.

[0058] Dosage or treatment regimen: Those skilled in the art will recognize that the terms "dosing regimen" and "therapeutic regimen" can be used to refer to a group of unit doses (usually more than one) that are usually administered separately to a subject over a period of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, the dosing regimen comprises multiple doses, each separated from the other doses in time. In some embodiments, each dose is separated from each other by the same length of time; in some embodiments, the dosing regimen comprises multiple doses and at least two different time periods separating each dose. In some embodiments, all doses within the dosing regimen have the same unit dose. In some embodiments, different doses within the dosing regimen are different amounts. In some embodiments, the dosing regimen comprises a first dose of a first dose, followed by one or more additional doses of a second dose different from the first dose. In some embodiments, the dosing regimen comprises a first dose of a first dose, followed by one or more additional doses of a second dose that is the same as the first dose. In some embodiments, the dosing regimen is associated with a desired or beneficial result when administered to a relevant population (i.e., it is a therapeutic dosing regimen).

[0059] excipient: As used herein, refers to non-therapeutic agents that may be included in pharmaceutical compositions, for example, to provide or contribute to the desired consistency or stabilization. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, maltose, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene, glycol, water, ethanol, etc.

[0060] Heteroaryl:The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy" refer to groups having 5 to 10 ring atoms, preferably 5, 6, 9 or 10 ring atoms; having 6, 10 or 14 π-electrons sharing a cyclic array; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl includes, but is not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaryl ring is fused to one or more aryl, alicyclic or heterocyclic rings, wherein the radical or point of attachment is on the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4-dole-4- ... H- Quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which includes optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0061] Heterocyclic: As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic group" and "heterocyclic ring" are used interchangeably and refer to a saturated or partially unsaturated, stable 3- to 8-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety having, in addition to carbon atoms, one or more, such as 1 to 4, heteroatoms as defined above. The term "nitrogen" when used to refer to the ring atoms of the heterocycle includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur and nitrogen, nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR +(such as in N-substituted pyrrolidinyl). The heterocycle can be connected to its side group at any heteroatom or carbon atom that produces a stable structure and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxane, dioxolanyl, diazepine, oxazepine, thiazepine, morpholinyl and thiomorpholinyl. The heterocyclic group can be monocyclic, bicyclic, tricyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic, more preferably monocyclic or bicyclic. The term "heterocyclic alkyl" refers to an alkyl substituted by a heterocyclic group, wherein the alkyl and heterocyclic moieties are independently optionally substituted. Additionally, heterocycles also include groups in which a heterocycle is fused to one or more aryl rings (eg, 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[b][1,4]dioxine, etc.).

[0062] Inhibitors: As used herein, the term "inhibitor" refers to an entity, condition, or event whose presence, level, or extent is associated with a reduced target level or activity. In some embodiments, an inhibitor may act directly (in which case it exerts its influence directly on its target, such as by binding to the target); in some embodiments, an inhibitor may act indirectly (in which case it exerts its influence by interacting with and / or otherwise altering a modulator of the target to reduce the level and / or activity of the target). In some embodiments, an inhibitor is an inhibitor whose presence or level is associated with a reduced target level or activity relative to a specific reference level or activity (e.g., observed under appropriate reference conditions, such as the presence of a known inhibitor or the absence of the inhibitor in question, etc.).

[0063] Neurodegeneration:The term "neurodegeneration" as used herein refers to the reduction of one or more characteristics, structures or properties of neurons or neuronal tissues. In some embodiments, neurodegeneration is observed as a pathological reduction in an organism. Those skilled in the art will recognize that neurodegeneration is related to certain diseases, disorders and conditions, including those affecting humans. In some embodiments, neurodegeneration may be temporary (e.g., sometimes occurring in association with certain infections and / or chemical or mechanical damage); in some embodiments, neurodegeneration may be chronic and / or progressive (e.g., usually associated with certain diseases, disorders or conditions, such as, but not limited to, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease or Alzheimer's disease). In some embodiments, neurodegeneration can be assessed, for example, by an increase in a biomarker associated with neurodegeneration of a subject. In some embodiments, neurodegeneration can be assessed, for example, by a reduction in a biomarker associated with neurodegeneration of a subject. Alternatively or additionally, in some embodiments, neurodegeneration may be assessed by magnetic resonance imaging (MRI), biomarkers containing cerebrospinal fluid, or other biomarkers observed in patients. In some embodiments, neurodegeneration is defined as a score below 24 on the Mini-Mental State Examination. In some embodiments, neurodegeneration refers to synaptic loss. In some embodiments, neurodegeneration refers to a reduction in neural tissue associated with traumatic injury (e.g., exposure to external forces that damage 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.

[0064] oral: As used herein, the phrases "oral administration" have their art-understood meanings and refer to administration of a compound or composition by mouth.

[0065] Parenteral: As used herein, the phrases "parenteral" have their generally understood meanings in the art 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.

[0066] 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.

[0067] patient:The term "patient" as used herein refers to any organism to which the 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 exhibits one or more symptoms of a disorder or condition. In some embodiments, the patient has been diagnosed with one or more disorders or conditions. In some embodiments, the patient is receiving or has received a therapy to diagnose and / or treat a disease, disorder or condition.

[0068] Pharmaceutical composition: The term "pharmaceutical composition" as used herein refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dosage suitable for administration in a treatment or dosing regimen to demonstrate a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical composition can be specially formulated for administration in solid or liquid form, including those suitable for the following administration: oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets, such as those intended for buccal, sublingual and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous or epidural injection, as, for example, sterile solutions or suspensions, or sustained release formulations; topical application, such as as a cream, ointment, or controlled release patch or spray applied to the skin, lungs or mouth; intravaginal or rectal administration, such as as a pessary, cream or foam; sublingual; ocular; transdermal; or nasal, pulmonary and administration to other mucosal surfaces.

[0069] Medicinal use: As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0070] Pharmaceutically acceptable carrier:The term "pharmaceutically acceptable carrier" as used herein refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient or solvent encapsulating material, that participates in carrying or delivering the present compound from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can 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 used in pharmaceutical formulations.

[0071] Pharmaceutically acceptable salts: As used herein, the term "pharmaceutically acceptable salts" refers to salts of these compounds that are suitable for use in a pharmaceutical setting, i.e., salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. J. Pharmaceutical Sciences, 66: 1-19 (1977) describes pharmaceutically acceptable salts in detail. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art, such as ion exchange. In some embodiments, 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-hydroxyethanesulfonate, 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, if appropriate, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates and arylsulfonates.

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

[0073] Specificity:The term "specificity" used herein with respect to an active agent is understood by those skilled in the art to mean that the agent discriminates against a potential target entity or state. For example, in some embodiments, an agent is said to bind to its target "specifically" if it preferentially binds to its target in the presence of one or more competing alternative targets. In many embodiments, specific interactions depend on the presence of specific structural features (e.g., epitopes, clefts, binding sites) of the target entity. It is to be understood that specificity need not 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, the agent or entity is undetectably bound to a competitive alternative target under conditions of binding to its target entity. In some embodiments, the binding agent binds to its target entity with a higher on-rate, a lower off-rate, an increased affinity, a reduced dissociation, and / or an increased stability compared to a competitive alternative target.

[0074] Target: The term "subject" as used herein refers to an organism, typically a mammal (e.g., a human, including in some embodiments a prenatal human form). 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 exhibits one or more symptoms or characteristics of a disease, disorder, or condition. In some embodiments, the subject does not exhibit any symptoms or characteristics of a disease, disorder, or condition. In some embodiments, the subject is an individual with one or more characteristics representing a susceptibility to a disease, disorder, or condition or a risk of 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.

[0075] Substitute or optionally substitute : As described herein, the compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogen atoms of the designated moiety are replaced with a suitable substituent. "Substitution" applies to the replacement of one or more hydrogen atoms, whether expressly or impliedly from the structure (e.g., means at least ;and means at least , , or ). Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent at each position may be the same or different. The combinations of substituents contemplated by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable" as used herein refers to compounds that are substantially unchanged when subjected to conditions for their production, detection, and in certain embodiments, their recovery, purification, and use for one or more of the uses disclosed herein.

[0076] Suitable monovalent substituents on the substitutable carbon atoms of the "optionally substituted" group are independently halogen; -(CH2) 0- 4R o ; -(CH2) 0-4 OR o ; -O(CH2) 0-4 R o 、-O-(CH2) 0-4 C(O)OR°; -(CH2) 0-4 CH(OR o )2; -(CH2) 0-4 SR o ; -(CH2) substituted by R° 0-4 Ph; -(CH2) substituted by R° 0-4 O(CH2) 0-1 Ph; -CH=CHPh which may be substituted by R°; -(CH2) which may be substituted by R° 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2; -(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2; -(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NRo 2;-N(R o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSiR o 3;-(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR°;-(CH2) 0- 4SC(O)R o ;-(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR°、-(CH2) 0-4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ;-(CH2) 0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2;-(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ;-C(NH)NR o 2;-P(O)2R o ;-P(O)R o2;-OP(O)R o 2;-OP(O)(OR o )2;SiR o 3;-(C 1-4 Straight or branched alkylene)ON(R o )2; or -(C 1-4 Straight or branched alkylene)C(O)ON(R o )2, where each R o may be substituted as defined below and are independently hydrogen, C 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5- to 6-membered heteroaryl ring), a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8- to 10-membered bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independent occurrences of R o Together with their intermediate atoms they form a 3- to 12-membered saturated, partially unsaturated or aromatic mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0077] R o (or two independent R o Suitable monovalent substituents on the ring formed by the atoms in the ring are independently halogen, -(CH2) 0-2 R ● 、-(halogenated R ● )、-(CH2) 0-2 OH, -(CH2) 0-2 OR ● 、-(CH2) 0-2 CH(OR ● )2; -O(halogenated R ● )、-CN、-N3、-(CH2) 0-2 C(O)R ● 、-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● 、-(CH2) 0-2 SR ● 、-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● 、-(CH2) 0-2 NR ● 2. -NO2, -SiR ● 3. -OSiR● 3. -C(O)SR ● 、-(C 1-4 Straight or branched alkylene)C(O)OR ● or -SSR ● , where each R ● is unsubstituted or, when preceded by "halo", is substituted only by one or more halogens, and is independently selected from C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0078] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0 ("oxo"), =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、-O(C(R * 2)) 2-3 O-or-S(C(R * 2)) 2- 3S-, where each independent R * is selected from hydrogen, C which may be substituted as defined below 1-6 an aliphatic group or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents bonded to the ortho-substitutable carbon of the "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independent R * is selected from hydrogen, C which may be substituted as defined below 1-6 an aliphatic group or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0079] R * Suitable substituents on the aliphatic group include halogen, -R ● 、-(halogenated R ● ), -OH, -OR ● 、-O(halogenated R ● )、-CN、-C(O)OH、-C(O)OR ● 、-NH2、-NHR ●、-NR ● 2 or -NO2, where each R ● is unsubstituted or, when preceded by "halo", is substituted only by one or more halogens, and is independently C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0080] Suitable substituents on the substitutable nitrogen of an "optionally substituted" group include -R † 、-NR † 2. -C(O)R † 、-C(O)OR † 、-C(O)C(O)R † 、-C(O)CH2C(O)R † 、-S(O)2R † 、-S(O)2NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R † )S(O)2R † ; Each R † are independently hydrogen, C which may be substituted as defined below 1-6 an aliphatic group, an unsubstituted -OPh or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independent occurrences of R † Together with their intermediate atoms they form an unsubstituted 3- to 12-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0081] R † Suitable substituents on the aliphatic group are independently halogen, -R ● 、-(halogenated R ● ), -OH, -OR ● 、-O(halogenated R ● )、-CN、-C(O)OH、-C(O)OR ● 、-NH2、-NHR ● 、-NR ● 2 or -NO2, where each R ● is unsubstituted or, when preceded by "halo", is substituted only by one or more halogens, and is independently C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0082] Therapeutic agents: The phrase "therapeutic agent" as used herein generally refers to any agent that causes a desired pharmacological effect when administered to an organism. In some embodiments, if the agent shows a statistically significant effect in an appropriate population, it is considered a therapeutic agent. In some embodiments, the appropriate population can be a model organism population. In some embodiments, the appropriate population can be determined by various criteria, such as a specific age group, gender, genetic background, existing clinical conditions, 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 characteristics of a disease, disorder and / or condition, delay its onset, reduce its severity and / or reduce its incidence. In some embodiments, a "therapeutic agent" is a medicament that has been or needs to be approved by a government agency before it can be sold for administration to humans. In some embodiments, a "therapeutic agent" is a medicament that requires a medical prescription to be administered to humans.

[0083] treat: The term "treatment" as used herein refers to any method used to partially or completely alleviate, ameliorate, relieve, 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 given to subjects who do not show signs of the disease, disorder, and / or condition. In some embodiments, treatment may be given to subjects who only show early signs of the disease, disorder, and / or condition, for example, to reduce the risk of development of pathology associated with the disease, disorder, and / or condition.

[0084] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0085] Programmed axonal degeneration and SARM1

[0086] Axonal degeneration is a major pathological feature of neurological diseases such as, but not limited to, Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis, diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, hereditary neuropathies, traumatic brain injury, and / or glaucoma. Damaged or unhealthy axons are eliminated through an intrinsic self-destruction program known as Wallerian degeneration, which is distinct from traditional cell death pathways such as apoptosis (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 undergo selective destruction of axonal segments distal to injury, while proximal axonal segments and cell bodies remain intact. This degeneration is characterized by the first depletion of nicotinamide mononucleotide adenylyltransferase (NMNAT), followed by loss of nicotinamide adenine dinucleotide (NAD+), loss of adenosine triphosphate (ATP), proteolysis of neurofilaments, and finally axonal degeneration approximately 8 to 24 hours after injury (Gerdts, J. et al., Neuron , 2016, 89, 449-460).

[0087] NAD+ is a ubiquitous metabolite with key roles 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. Accordingly, manipulations that enhance axonal localization of NMNAT1 provide axonal protection (Babetto et al., Cell Rep., 2010, 3, 1422-1429; Sasaki et al., J. Neurosci ., 2009).

[0088] In a genome-wide RNAi screen in primary mouse neurons, Sterile Alpha and TIRmotif-containing 1 (SARM1) was identified, where knockdown of SARM1 resulted in durable protection of sensory neurons from injury-induced axonal degeneration (Gerdts et al., J. Neurosci , 2013, 33, 13569-13580). SARM1 belongs to the cytoplasmic adaptor protein family but is unique among its members in that it is the most evolutionarily ancient adaptor protein that paradoxically inhibits TLR signaling and has been identified as a major executor of the injury-induced axonal death pathway (O'Neill, LA & Bowie, AG, Nat. Rev. Immunol ., 2007, 7, 353-364; Osterloh, JM et al., Science , 2012, 337, 481-484; Gerdts, J. et al., J. Neurosci. 33, 2013, 13569-13580). Activation of SARM1 via axonal injury or forced dimerization of the SARM1-TIR domain promotes rapid and catastrophic depletion of nicotinamide adenine dinucleotide (NAD+), followed shortly thereafter by axonal degeneration, thus highlighting the central role of NAD+ homeostasis in axonal integrity (Gerdts, J. et al., Science , 2015, 348, 453-457). This injury-induced NAD+ depletion requires SARM1 both in vitro and in vivo, and SARM1 activation triggers axonal degeneration by disrupting local NAD(+) (Gerdts et al., Science, 2015 348, 452-457; Sasaki et al., J. Biol. Chem. 2015, 290, 17228-17238; both are incorporated herein by reference in their entirety).

[0089] It is evident from genetic loss-of-function studies that SARM1 acts as a major executioner of the axonal degeneration pathway following injury. Genetic knockout of SARM1 allows axonal preservation for up to 14 days after nerve transection (Osterloh, JM et al., Science , 2012, 337, 481-484; Gerdts, J. et al. J.Neurosci ., 2013, 33, 13569-13580) and also improves functional outcomes in mice after traumatic brain injury (Henninger, N. et al., Brain 139, 2016, 1094-1105). In addition to the role of SARM1 in direct axonal injury, SARM1 is also required for axonal degeneration observed in chemotherapy-induced peripheral neuropathy. Loss of SARM1 blocks chemotherapy-induced peripheral neuropathy, inhibiting axonal degeneration and increased pain sensitivity produced after chemotherapeutic vincristine treatment (Geisler et al., Brain , 2016,139, 3092-3108).

[0090] SARM1 contains multiple conserved motifs, including the SAM domain, ARM / HEAT motif, and TIR domain ( Figure 1 ), to mediate oligomerization and protein-protein interactions (O'Neill, LA & Bowie, AG, Nat. Rev. Immunol .,2007, 7, 353-364;Tewari, R. et al., Trends Cell Biol ., 2010, 20, 470-481;Qiao,F. & Bowie, JU, Sci. STKE2005, re7, 2005). TIR domains are common in signaling proteins that function in innate immune pathways, where they serve as scaffolds for protein complexes (O'Neill, LA & Bowie, AG, Nat. Rev. Immunol ., 2007, 7, 353-364). Interestingly, dimerization of the SARM1-TIR domain is sufficient to induce axonal degeneration and rapidly trigger NAD+ degradation by acting as an NAD+ lyase (Milbrandt et al., WO2018 / 057989; Gerdts, J. et al., Science , 2015, 348, 453-457). Given the central role of SARM1 in axonal degeneration pathways and its putative NADase activity, efforts have been made to identify agents that can modulate SARM1 and may serve as useful therapeutic agents, for example, to prevent neurodegenerative diseases, including peripheral neuropathy, traumatic brain injury, and / or neurodegenerative diseases.

[0091] The present disclosure provides, inter alia, certain compounds and / or compositions that function as SARM1 inhibitors (eg, as SARM1 inhibitors), and technologies related thereto.

[0092] Compound

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

[0094]

[0095] or a pharmaceutically acceptable salt thereof, wherein

[0096] R 1 is selected from -CN, -CON(R)2, -C(=NR)N(R)2, -NO2, -S(O)2R, -S(O)2N(R)2, -C(O)R, -CO2R and a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0097] R 2 Yes-R;

[0098] R 3 Yes - (CH2) 0-2 Cy 1 ;

[0099] R 4 Yes-Cy 2 ;

[0100] Cy 1is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each phenyl and heteroaryl ring is surrounded by 0-4 R x replace;

[0101] Each R x independently selected from halogen, -CN, -NO2, -SR, -N(R)2, -OR, -C(O)R, -SO2R, -CO2R, -SO2N(R)2, -CON(R)2, -N(R)SO2R, -N(R)C(O)R, and optionally substituted C 1-6 aliphatic groups;

[0102] Cy 2 is selected from phenyl, a 3- to 7-membered monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7- to 9-membered bridged bicyclic or spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each of the phenyl, heterocyclic and heteroaryl rings is surrounded by 0-4 R v replace;

[0103] Each R v independently selected from halogen, -CN, -NO2, -SR, -N(R)2, -OR, -C(O)R, -SO2R, -CO2R, -SO2N(R)2, -CON(R)2, -N(R)SO2R, -N(R)C(O)R, optionally substituted C 1-6 aliphatic groups and optionally substituted 5- to 6-membered heteroaryl rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

[0104] Each R is independently hydrogen or optionally substituted C 1-6 An aliphatic group, or:

[0105] Two R's together with the atoms to which they are attached form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring.

[0106] As generally defined above, R 1 is selected from -CN, -CON(R)2, -C(=NR)N(R)2, -NO2, -S(O)2R, -S(O)2N(R)2, -C(O)R, -CO2R, and a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 Yes-CN.

[0107] In some embodiments, R1 is -CON(R)2. In some such embodiments, each R is independently an optionally substituted C 1-6 In some embodiments, R 1 is -CON(R)2, wherein each R is independently optionally substituted with -(CH2) 0-4 OR o Substituted C 1-6 In some embodiments, R 1 yes .

[0108] In some embodiments, R 1 is -CON(R)2, wherein R is an optionally substituted C 1-6 The two R's, together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 1 yes , or .

[0109] In some embodiments, R 1 Selected from -CN, and .

[0110] In some embodiments, R 1 is -C(=NR)N(R)2. In some embodiments, R 1 is -C(=NR)N(R)2, wherein R is selected from hydrogen and optionally substituted C 1-6 In some embodiments, R 1 is -C(=NR)N(R)2, wherein R is selected from hydrogen and -CH3. In some embodiments, R 1 is -C(=NH)NHCH3. In some embodiments, R 1 is -C(=NH)N(CH3)2. In some embodiments, R 1 is -C(=NR)N(R)2, wherein R is selected from hydrogen and -(CH2) 0-4 OR o Substituted C 1-6 In some embodiments, R 1 is -C(=NR)N(R)2, wherein R is selected from H, -CH3 and -OR o Substituted C 1-6 In some embodiments, R 1 yes or .

[0111] In some embodiments, R 1 is -C(=NH)N(R)2, wherein R is an optionally substituted C 1-6 The two R's, together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 1 yes or .

[0112] In some embodiments, R 1 It is -NO2.

[0113] In some embodiments, R 1 is -S(O)2R. In some such embodiments, R is C 1-6 Aliphatic group.

[0114] In some embodiments, R 1 is -S(O)2N(R)2. In some such embodiments, R is selected from hydrogen and C 1-6 Aliphatic group.

[0115] In some embodiments, R 1 is -C(O)R. In some such embodiments, R is C 1-6 Aliphatic group.

[0116] In some embodiments, R 1 In some such embodiments, R is selected from hydrogen and C 1-6 In some embodiments, R 1 is -CO2R, wherein R is selected from hydrogen and C 1-6 In some embodiments, R 1 is -CO2R, wherein R is selected from hydrogen and -CH3. In some embodiments, R 1 is -CO2H. In some embodiments, R 1 It is -CO2CH3.

[0117] In some embodiments, R 1 is a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0118] In some embodiments, R 1 is a 5-membered heteroaryl ring having 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 yes .

[0119] As generally defined above, R2 As generally defined above, R 2 In some such embodiments, -R is hydrogen. Accordingly, in some embodiments, R 2 is -H. In some embodiments, R 2 is -R, wherein -R is an optionally substituted C 1-6 In some embodiments, R 2 is -R, where -R is C 1-6 In some embodiments, R 2 Yes-C 1-6 In some such embodiments, R 2 It is -CH3.

[0120] As generally defined above, R 3 Yes - (CH2) 0-2 Cy 1 In some embodiments, R 3 Yes-Cy 1 In some embodiments, R 3 Yes -CH2-Cy 1 In some embodiments, R 3 Yes -(CH2)2-Cy 1 .

[0121] As generally defined above, Cy 1 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each phenyl and heteroaryl ring is surrounded by 0-4 R x In some embodiments, Cy 1 In some embodiments, Cy 1 It is 1 R x In some embodiments, Cy 1 It is 2 R x In some embodiments, Cy 1 Selected from

[0122]

[0123] In some embodiments, Cy 1 is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 1 is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 1 1-2 Rx In some embodiments, Cy 1 is a 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 1 is a 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 1 1-2 R x In some embodiments, Cy 1 is a 6-membered heteroaryl ring having 1-2 nitrogen atoms, wherein Cy 1 1-2 R x replace.

[0124] In some embodiments, Cy 1 is an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 1 1-2 R x In some embodiments, Cy 1 is a 9-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 1 is a 9-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 1 1-2 R x In some embodiments, Cy 1 is a 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 1 is a 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 1 1-2 R x In some embodiments, Cy 1 is a 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 1 By 1 R x replace.

[0125] In some embodiments, Cy 1 Selected from

[0126] .

[0127] In some embodiments, Cy 1 Selected from

[0128]

[0129] As generally defined above, Cy 2 is selected from phenyl, a 3- to 7-membered monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7- to 9-membered bridged bicyclic or spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each of the phenyl, heterocyclic and heteroaryl rings is surrounded by 0-4 R v replace.

[0130] In some embodiments, Cy 2 In some embodiments, Cy 2 It is 1 R v In some embodiments, Cy 2 Is 1-2 R v In some embodiments, Cy 2 is a phenyl group fused to a 5- to 6-membered carbocyclic ring. 2 is a phenyl group fused to a 5-membered carbocyclic ring. 2 Selected from

[0131]

[0132] In some embodiments, Cy 2 is a 3- to 7-membered monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 3- to 7-membered monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 By 1 R v In some embodiments, Cy 2 is a 3- to 7-membered monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 By 2 R v In some embodiments, Cy 2 is a 5-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 5-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 1-2 R v In some embodiments, Cy 2is a 5-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 By 1 R v In some embodiments, Cy 2 is a 6-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 6-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 1-2 R v In some embodiments, Cy 2 is a 6-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 By 1 R v replace.

[0133] In some embodiments, Cy 2 is a 5-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy is fused to one or more aryl rings. 2 is a 6-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 Fused to one or more aryl rings.

[0134] In some embodiments, Cy 2 Selected from

[0135]

[0136] In some embodiments, Cy 2 is a 7- to 9-membered bridged bicyclic or spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 7- to 9-membered bridged bicyclic or spirocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 1-2 R v In some embodiments, Cy 2 is a 7-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 7-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 1-2 R v In some embodiments, Cy 2 is a 7-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 By 1 R v replace.

[0137] In some embodiments, Cy 2 is a 7-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 7-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 1-2 R v In some embodiments, Cy 2 is an 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is an 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 1-2 R v In some embodiments, Cy 2 Selected from

[0138]

[0139] In some embodiments, Cy 2 is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 1-2 R v In some embodiments, Cy 2 is a 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 1-2 R v In some embodiments, Cy 2 Selected from

[0140] .

[0141] In some embodiments, Cy 2 is an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 1-2 R v In some embodiments, Cy 2is a 9-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 9-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 1-2 R v In some embodiments, Cy 2 is a 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy 2 1-2 R v replace.

[0142] In some embodiments, Cy 2 Selected from

[0143] .

[0144] As generally defined above, each R x independently selected from halogen, -CN, -NO2, -SR, -N(R)2, -OR, -C(O)R, -SO2R, -CO2R, -SO2N(R)2, -CON(R)2, -N(R)SO2R, -N(R)C(O)R, and optionally substituted C 1-6 In some embodiments, R x is halogen. In some such embodiments, R x It is chlorine or fluorine.

[0145] In some embodiments, R x In some embodiments, R x It is -NO2.

[0146] In some embodiments, R x In some such embodiments, R is C 1-6 In some embodiments, R x Yes - SCH3.

[0147] In some embodiments, R x is -N(R)2. In some such embodiments, R is selected from hydrogen and C 1-6 In some embodiments, R x is -NHCH3. In some embodiments, R x It is -N(CH3)2.

[0148] In some embodiments, R xIn some such embodiments, R is C 1-6 In some embodiments, R x It is -OCH3.

[0149] In some embodiments, R x It is C 1-6 In some embodiments, R x It is C 1-3 In some embodiments, R x is -CH3. In some embodiments, R x It is -CH(CH3)2.

[0150] In some embodiments, R x is an optionally substituted C 1-6 In some embodiments, R x is C optionally substituted by halogen 1-6 In some such embodiments, R x It is -CF3.

[0151] In some embodiments, R x is -C(O)R. In some such embodiments, R is C 1-6 In some embodiments, R x It is -C(O)CH3.

[0152] In some embodiments, R x In some such embodiments, R is C 1-6 In some embodiments, R x It is -SO2CH3.

[0153] In some embodiments, R x In some such embodiments, R is C 1-6 In some embodiments, R x It is -CO2tBu.

[0154] In some embodiments, R x is -SO2N(R)2. In some such embodiments, R is selected from hydrogen and C 1-6 In some embodiments, R x It is -SO2NHCH3.

[0155] In some embodiments, R x is -CON(R)2. In some such embodiments, R is hydrogen. In some embodiments, R x Yes -CONH2.

[0156] In some embodiments, R x In some such embodiments, R is selected from hydrogen and C 1-6 In some embodiments, R x It is -NHSO2CH3.

[0157] In some embodiments, R x is -NRC(O)R. In some such embodiments, R is hydrogen. In some embodiments, R x It is -NHCOCH3.

[0158] As generally defined above, each R v independently selected from halogen, -CN, -NO2, -SR, -N(R)2, -OR, -C(O)R, -SO2R, -CO2R, -SO2N(R)2, -CON(R)2, -N(R)SO2R, -N(R)C(O)R, optionally substituted C 1-6 Aliphatic groups and optionally substituted 5- to 6-membered heteroaryl rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0159] In some embodiments, R v is halogen. In some such embodiments, R v It is chlorine or fluorine.

[0160] In some embodiments, R v Yes-CN.

[0161] In some embodiments, R v It is -NO2.

[0162] In some embodiments, R v In some such embodiments, R is an optionally substituted C 1-6 In some embodiments, R v is -SR, where R is C 1-6 In some embodiments, R v is -SR, wherein R is -CH3. Accordingly, in some embodiments, R v Yes - SCH3.

[0163] In some embodiments, R v is -N(R)2. In some such embodiments, R is selected from hydrogen and optionally substituted C 1-6 In some embodiments, R v is -NH2. In some embodiments, R vis -NHR, where R is C 1-6 In some embodiments, R v is -NHR, wherein R is -CH3. Accordingly, in some embodiments, R v It is -NHCH3.

[0164] In some embodiments, R v In some such embodiments, R is C 1-6 In some embodiments, R v It is -OCH3.

[0165] In some embodiments, R v In some such embodiments, R is selected from hydrogen or an optionally substituted C 1-6 In some embodiments, R v is -SO2N(R)2, wherein R is selected from hydrogen and C 1-6 In some embodiments, R v is -SO2N(R)2, wherein R is selected from hydrogen and -CH3. Accordingly, in some embodiments, R v It is -SO2NHCH3 or -SO2N(CH3)2.

[0166] In some embodiments, R v In some such embodiments, R is selected from hydrogen or optionally substituted C 1-6 In some embodiments, R v is -N(R)SO2R, wherein R is selected from hydrogen and C 1-6 In some embodiments, R v is -N(R)SO2R, wherein R is selected from hydrogen and -CH3. Accordingly, in some embodiments, R v It is -NHSO2CH3 or -N(CH3)SO2CH3.

[0167] In some embodiments, R v is -N(R)C(O)R. In some such embodiments, R is selected from hydrogen or optionally substituted C 1-6 In some embodiments, R v is -N(R)C(O)R, wherein R is selected from hydrogen and C 1-6 In some embodiments, R v is -N(R)C(O)R, wherein R is selected from hydrogen and -CH3. Accordingly, in some embodiments, R v It is -NHC(O)CH3 or -N(CH3)C(O)CH3.

[0168] In some embodiments, R v It is C 1-6 In some embodiments, R v It is C 1-3 In some embodiments, R v is -CH3. In some embodiments, R v It is -CH(CH3)2.

[0169] In some embodiments, R v is an optionally substituted C 1-6 In some embodiments, R v is C optionally substituted by halogen 1-6 In some such embodiments, R v It is -CF3.

[0170] In some embodiments, R v is -C(O)R. In some such embodiments, R is C 1-6 In some embodiments, R v It is -C(O)CH3.

[0171] In some embodiments, R v In some such embodiments, R is C 1-6 In some embodiments, R v It is -SO2CH3.

[0172] In some embodiments, R v In some such embodiments, R is C 1-6 In some embodiments, R v It is -CO2tBu.

[0173] In some embodiments, R v is -CON(R)2. In some such embodiments, R is hydrogen. In some embodiments, R v Yes -CONH2.

[0174] In some embodiments, R v is an optionally substituted 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. v is an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. v yes or .

[0175] In some embodiments, R 3 Selected from

[0176]

[0177] In some embodiments, R 4 Selected from

[0178]

[0179]

[0180] As generally defined above, each R is independently hydrogen or an optionally substituted C 1-6 an aliphatic group; or two R's together with the atoms to which they are attached form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring.

[0181] In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C 1-6 In some such embodiments, R is -C 1-6 In some embodiments, R is -CH3. In some embodiments, R is -C(CH3)3. In some embodiments, R is optionally substituted with -(CH2) 0-4 OR o Substituted C 1-6 In some embodiments, R is optionally substituted with -OR o Substituted C 1-6 In some embodiments, R is C optionally substituted with -OCH3. 1-6 In some embodiments, R is C optionally substituted with -OH. 1-6 Aliphatic group.

[0182] In some embodiments, two R together with the atoms to which they are attached form a 3- to 6-membered saturated or partially unsaturated heterocycle. In some embodiments, two R together with the atoms to which they are attached form a 6-membered saturated or partially unsaturated heterocycle. In some embodiments, two R together with the atoms to which they are attached form a morpholinyl ring.

[0183] In some embodiments of Formula I, R 1 Is -CN. Accordingly, in some embodiments, the present disclosure provides compounds of Formula Ia:

[0184]

[0185] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 and R4 Each is as defined above and as described herein.

[0186] In some embodiments of Formula I, R 1 is -CON(R)2. Accordingly, in some embodiments, the present disclosure provides a compound of Formula Ib:

[0187]

[0188] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 and R are each as defined above and as described herein.

[0189] In some embodiments of Formula I, R 1 Is -C(=NR)N(R)2. Accordingly, in some embodiments, the present disclosure provides a compound of Formula Ic:

[0190]

[0191] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 and R are each as defined above and as described herein.

[0192] In some embodiments of Formula Ia, Ib or Ic, R 2 is H. Accordingly, the present disclosure provides Formula Ia- i , Ib- i or Ic- i Compounds:

[0193]

[0194] or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and R are each as defined above and as described herein.

[0195] In some embodiments of Formula Ia, Ib or Ic, R 3 Yes-Cy 1 , where -Cy 1 is phenyl. Accordingly, in some embodiments, the present disclosure provides formula Ia- ii , Ib- ii or Ic- ii Compounds:

[0196]

[0197] or a pharmaceutically acceptable salt thereof, wherein R 2 , R4 , R and R x Each is as defined above and as described herein.

[0198] In some embodiments of Formula Ia, Ib or Ic, R 3 Yes-Cy 1 , where -Cy 1 is quinolin-5-yl. Accordingly, in some embodiments, the present disclosure provides formula Ia- iii , Ib- iii or Ic- iii Compounds:

[0199]

[0200] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 4 , R and R x Each is as defined above and as described herein.

[0201] In some embodiments, the present disclosure provides a compound selected from:

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208] .

[0209] In some embodiments, one or more compounds of Formula I covalently inhibit SARM1. In some embodiments, one or more compounds of Formula I covalently modify the cysteine ​​residues of SARM1. In some embodiments, one or more compounds of Formula I covalently modify Cys635 of SARM1. In some embodiments, one or more compounds of Formula I covalently modify Cys629 of SARM1. In some embodiments, one or more compounds of Formula I covalently modify Cys649 of SARM1. Not wishing to be bound by any particular theory, but in some embodiments, one or more compounds of Formula I denature SARM1 protein by covalent modification of cysteine ​​residues. In some embodiments, one or more compounds of Formula I denature SARM1 protein by covalent modification of Cys635. In some embodiments, one or more compounds of Formula I denature SARM1 protein by covalent modification of Cys629. In some embodiments, one or more compounds of Formula I denature SARM1 protein by covalent modification of Cys649.

[0210] In some aspects, the present disclosure provides compounds according to the following embodiments:

[0211] Embodiment 1. Compound of formula I:

[0212]

[0213] or a pharmaceutically acceptable salt thereof, wherein

[0214] R 1 is selected from -CN, -CON(R)2, -C(=NR)N(R)2, -NO2, -S(O)2R, -S(O)2N(R)2, -C(O)R, -CO2R and a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0215] R 2 Yes-R;

[0216] R 3 Yes - (CH2) 0-2 Cy 1 ;

[0217] R 4 Yes-Cy 2 ;

[0218] Cy 1 is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each phenyl and heteroaryl ring is surrounded by 0-4 R x replace;

[0219] Each R x independently selected from halogen, -CN, -NO2, -SR, -N(R)2, -OR, -C(O)R, -SO2R, -CO2R, -SO2N(R)2, -CON(R)2, -N(R)SO2R, -N(R)C(O)R, and optionally substituted C 1-6 aliphatic groups;

[0220] Cy 2 is selected from phenyl, a 3- to 7-membered monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7- to 9-membered bridged bicyclic or spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each of the phenyl, heterocyclic and heteroaryl rings is surrounded by 0-4 R v replace;

[0221] Each R v independently selected from halogen, -CN, -NO2, -SR, -N(R)2, -OR, -C(O)R, -SO2R, -CO2R, -SO2N(R)2, -CON(R)2, -N(R)SO2R, -N(R)C(O)R, optionally substituted C 1-6 aliphatic groups and optionally substituted 5- to 6-membered heteroaryl rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

[0222] Each R is independently hydrogen or optionally substituted C 1-6 An aliphatic group, or:

[0223] Two R's together with the atoms to which they are attached form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring.

[0224] Embodiment 2. The compound according to embodiment 1, wherein R 2 Yes -H.

[0225] Embodiment 3. The compound according to embodiment 1, wherein R 2 Yes-R.

[0226] Embodiment 4. The compound according to embodiment 3, wherein -R is C 1-6 Aliphatic group.

[0227] Embodiment 5. The compound according to embodiment 4, wherein R is -C 1-6 alkyl.

[0228] Embodiment 6. A compound according to embodiment 5, wherein R is -CH3.

[0229] Embodiment 7. A compound according to any one of embodiments 1-6, wherein R 1 Yes-CN.

[0230] Embodiment 8. A compound according to any one of embodiments 1-6, wherein R 1 It is -C(O)N(R)2.

[0231] Embodiment 9. A compound according to any one of embodiments 1-6, wherein R 1 It is -C(=NR)C(R)2.

[0232] Embodiment 10. A compound according to any one of embodiments 1-9, wherein R 3 Yes-Cy 1 .

[0233] Embodiment 11. The compound according to embodiment 10, wherein -Cy 1 It is phenyl.

[0234] Embodiment 12. The compound according to embodiment 10, wherein -Cy 1 is a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0235] Embodiment 13. The compound according to embodiment 12, wherein -Cy 1 It is a 6-membered heteroaryl ring having 1-2 nitrogen atoms.

[0236] Embodiment 14. The compound according to embodiment 12, wherein -Cy 1 is a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0237] Embodiment 15. The compound according to embodiment 10, wherein -Cy 1 is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0238] Embodiment 16. The compound according to embodiment 15, wherein -Cy 1 is a 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0239] Embodiment 17. The compound according to embodiment 16, wherein -Cy 1 It is a 10-membered bicyclic heteroaryl ring having 1 nitrogen atom.

[0240] Embodiment 18. The compound according to embodiment 17, wherein -Cy 1 It is quinolinyl.

[0241] Embodiment 19. The compound according to embodiment 10, wherein -Cy 1 Selected from

[0242]

[0243] Embodiment 20. A compound according to any one of embodiments 11-19, wherein R x It's a halogen.

[0244] Embodiment 21. The compound according to embodiment 20, wherein R x It's chlorine.

[0245] Embodiment 22. The compound according to embodiment 20, wherein R x It's fluorine.

[0246] Embodiment 23. A compound according to any one of embodiments 11-19, wherein R x is optionally substituted -C 1-6 Aliphatic group.

[0247] Embodiment 24. The compound according to embodiment 23, wherein R x Yes-C 1-6 alkyl.

[0248] Embodiment 25. The compound according to embodiment 24, wherein R x It is -CH3.

[0249] Embodiment 26. The compound according to embodiment 24, wherein R x It is -CH(CH3)2.

[0250] Embodiment 27. The compound according to embodiment 23, wherein R x is -C optionally substituted by halogen 1-6 Aliphatic group.

[0251] Embodiment 28. The compound according to embodiment 27, wherein R x It is -CF3.

[0252] Embodiment 29. A compound according to any one of embodiments 11-19, wherein R x Yes-OR.

[0253] Embodiment 30. A compound according to embodiment 29, wherein R is an optionally substituted -C 1-6 Aliphatic group.

[0254] Embodiment 31. A compound according to embodiment 30, wherein R is -C 1-6 alkyl.

[0255] Embodiment 32. A compound according to embodiment 31, wherein R is -CH3.

[0256] Embodiment 33. A compound according to embodiment 30, wherein R is -C 1-6 Aliphatic group.

[0257] Embodiment 34. A compound according to embodiment 33, wherein R is -CF3.

[0258] Embodiment 35. A compound according to any one of embodiments 1-34, wherein Cy 2 It is phenyl.

[0259] Embodiment 36. A compound according to any one of embodiments 1-34, wherein Cy 2 is a 3- to 7-membered monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0260] Embodiment 37. The compound according to embodiment 36, wherein Cy 2 is a 5-membered monocyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen and sulfur.

[0261] Embodiment 38. The compound according to embodiment 36, wherein Cy 2 is a 6-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0262] Embodiment 39. A compound according to any one of embodiments 1-34, wherein Cy 2 is a 7- to 9-membered bridged bicyclic or spirocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0263] Embodiment 40. The compound according to embodiment 39, wherein Cy 2 is a 7-membered spiro heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0264] Embodiment 41. A compound according to embodiment 39, wherein Cy 2 is a 7-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0265] Embodiment 42. The compound according to embodiment 39, wherein Cy 2 is an 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0266] Embodiment 36. A compound according to any one of embodiments 1-34, wherein Cy 2is a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0267] Embodiment 37. The compound according to embodiment 36, wherein -Cy 2 It is a 6-membered heteroaryl ring having 1-2 nitrogen atoms.

[0268] Embodiment 38. The compound according to embodiment 36, wherein -Cy 2 is a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0269] Embodiment 39. A compound according to any one of embodiments 1-34, wherein Cy 2 is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0270] Embodiment 40. The compound according to embodiment 39, wherein Cy 2 is a 9-membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0271] Embodiment 41. A compound according to embodiment 40, wherein Cy 2 is a 10-membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0272] Embodiment 42. A compound according to any one of embodiments 1-34, wherein Cy 2 Selected from

[0273]

[0274]

[0275] Embodiment 43. A compound according to any one of embodiments 35-42, wherein R v It is C 1-6 Aliphatic group.

[0276] Embodiment 44. The compound according to embodiment 43, wherein R v It is C 1-3 Aliphatic group.

[0277] Embodiment 45. The compound according to embodiment 44, wherein R v It is -CH3.

[0278] Embodiment 46. The compound according to embodiment 44, wherein R v It is -CH(CH3)2.

[0279] Embodiment 47. A compound according to any one of embodiments 35-42, wherein R v It is -C(O)R.

[0280] Embodiment 48. The compound according to embodiment 47, wherein R v It is -C(O)CH3.

[0281] Embodiment 49. A compound according to any one of embodiments 35-42, wherein R v It is -SO2R.

[0282] Embodiment 50. The compound according to embodiment 49, wherein R v It is -SO2CH3.

[0283] Embodiment 51. A compound according to any one of embodiments 35-42, wherein R v It is -CO2R.

[0284] Embodiment 52. The compound according to embodiment 51, wherein R v It is -CO2tBu.

[0285] Embodiment 53. A compound according to any one of embodiments 35-42, wherein R v Yes-CON(R)2.

[0286] Embodiment 54. The compound according to embodiment 53, wherein R v Yes -CONH2.

[0287] Embodiment 55. A compound according to any one of embodiments 35-42, wherein R v is an optionally substituted 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0288] Embodiment 56. The compound according to embodiment 55, wherein R v is an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0289] Embodiment 57. The compound according to embodiment 56, wherein R v yes or .

[0290] Embodiment 58. A compound according to embodiment 1, wherein

[0291] R 1 is selected from -CN and -CON(R)2; and

[0292] R 2Selected from -H and -CH3.

[0293] Embodiment 59. A compound according to embodiment 1, wherein:

[0294] R 1 Selected from -CN and -CON(R)2;

[0295] R 2 Selected from -H and -CH3;

[0296] R 3 Yes-Cy 1 ;and

[0297] -Cy 1 Selected from

[0298] .

[0299] Embodiment 60. The compound according to embodiment 59, wherein:

[0300] R 1 is-CN; and

[0301] R 2 Yes -H.

[0302] Embodiment 61. The compound according to embodiment 59, wherein:

[0303] R 1 is-CON(R)2; and

[0304] R 2 Yes -H.

[0305] Embodiment 62. A compound according to any one of embodiments 58-61, wherein Cy 2 Selected from

[0306] .

[0307] Embodiment 63. A compound according to any one of embodiments 58-61, wherein Cy 2 Selected from

[0308]

[0309] Embodiment 64. A compound according to any one of embodiments 58-61, wherein Cy 2 Selected from

[0310]

[0311] Embodiment 65. A compound according to any one of embodiments 58-61, wherein Cy 2 Selected from

[0312]

[0313] Preparation of compounds of formula I

[0314] Compounds of formula I can be prepared as shown in Schemes Ia and Ib below.

[0315] Scheme Ia:

[0316]

[0317] In Scheme Ia, thiophosgene A and amine B are coupled together in the presence of a suitable base to produce an isothiocyanate C. Isocyanate C is treated with an amide D in the presence of a suitable base to give a thioamide E, which is treated with bromine to produce a compound of formula I, wherein R 2 is H and R 1 It is -CN or -CONH2, the latter originating from the hydrolysis of CN in this step.

[0318] Scheme Ib:

[0319]

[0320] In Scheme Ib, compound F is treated with a suitable base and compound G (wherein X is a suitable leaving group) to give a compound of Formula I, wherein R 2 Yes-C 1-6 alkyl.

[0321] Composition

[0322] In some embodiments, a compound of Formula I can be provided in a composition, eg, combined (eg, mixed) with one or more other components.

[0323] 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 NADase activity; in some embodiments, such compositions are administered to a system or environment to achieve inhibition of SARM1 activity as described herein.

[0324] In some embodiments, the compositions provided as described herein can be pharmaceutical compositions comprising an active agent and one or more pharmaceutically acceptable excipients; in some such embodiments, provided pharmaceutical compositions comprise a compound of Formula I or an active metabolite thereof and / or deliver a compound of Formula I or an active metabolite thereof to a relevant system or environment as described herein (e.g., to a subject in need thereof).

[0325] In some embodiments, one or more compounds of Formula I are provided and / or used in the form of a pharmaceutically acceptable salt.

[0326] The present disclosure particularly 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 it effectively and measurably inhibits axonal degeneration in a biological sample or patient. In certain embodiments, the compound or composition provided is formulated for administration to a patient in need of such a composition. The compound and composition can be administered using any amount and any route of administration that effectively treats or alleviates the severity of any disease or disorder described herein according to the methods disclosed herein. For ease of administration and dosage uniformity, the compound provided is preferably formulated in a unit dosage form. The expression "unit dosage form" used herein refers to a physically discrete unit of a medicament suitable for a patient to be treated. However, it is to be understood that the total daily dosage of the compound and composition 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 disorder being treated and the severity of the disorder; the activity of the specific compound being used; the specific composition being used and its route of administration; the species, age, weight, sex, and dietary status of the patient; the general condition of the subject; the time of administration; the rate of excretion of the specific compound being used; the duration of treatment; drugs used in combination or concomitantly with the specific compound being used, etc.

[0327] 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 compositions are administered orally, intraperitoneally, or intravenously. In certain embodiments, provided compounds are administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg of subject body weight per day, once or more per day, to obtain the desired therapeutic effect.

[0328] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarterial, 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 formulated 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 solutions in 1,3-butanediol. Available acceptable vehicles and solvents include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspension media.

[0329] For this purpose, any mild fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives can be used to prepare injections, and natural pharmaceutically acceptable oils, such as olive oil or castor oil, can also be used to prepare injections, especially in their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifiers, or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solids, liquids or other dosage forms can also be used for formulation purposes.

[0330] 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 that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0331] In order to prolong the effect of the provided compound, it is usually desirable to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of the compound form for parenteral administration is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the compound / polymer ratio and the properties of the specific polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injection preparations are also prepared by trapping the compound in a liposome or microemulsion compatible with body tissues.

[0332] The pharmaceutically acceptable compositions described herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Conventionally, such dosage forms may also contain additional substances in addition to inert diluents, such as lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavoring agents and / or coloring agents may also be added.

[0333] 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 gum arabic, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators 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 buffering agents.The active compounds can also be in micro-encapsulated form with one or more excipients as noted above.

[0334] Solid compositions of similar types may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols. Solid dosage forms of tablets, lozenges, capsules, pills and granules may be prepared with coatings and shells such as enteric coatings (i.e., buffers) and other coatings well known in the pharmaceutical field. They may optionally contain an emulsifier and may also have a composition that releases the active ingredient only or preferentially in a specific part of the intestinal tract in a delayed manner. Examples of available embedded compositions include polymeric substances and waxes.

[0335] 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, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and flavor enhancers.

[0336] 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 that are solid at room temperature but liquid at body (e.g., rectal or vaginal) temperature and therefore melt in the rectal or vaginal cavity to release the active compound. Such materials include cocoa butter, suppository waxes (e.g., beeswax), and polyethylene glycols.

[0337] The pharmaceutically acceptable compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical administration, including diseases of the eye, the skin, or the lower intestinal tract. Topical application to the lower intestinal tract may be achieved in a rectal suppository formulation (see above) or in a suitable enema formulation.

[0338] The dosage form for topical or transdermal administration of the compound provided includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. The active component is mixed with a pharmaceutically acceptable carrier and any required preservative or buffer as needed under sterile conditions. Ophthalmic preparations, ear drops and eye drops are also considered to be within the scope of the present disclosure. In addition, the present disclosure contemplates the use of transdermal patches, which have the additional advantage of controlled delivery of compounds to the body. Such dosage forms can be prepared by dissolving or distributing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. Rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0339] For topical administration, the pharmaceutically acceptable compositions provided may be formulated in suitable ointments containing active components suspended or dissolved in one or more carriers. Carriers for topical administration of the disclosed compounds 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 compositions provided may be formulated in suitable lotions or creams containing active components 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.

[0340] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[0341] 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 saline using benzyl alcohol or other suitable preservatives, absorption promoters for improving bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

[0342] Most preferably, the pharmaceutically acceptable compositions of the present disclosure are formulated for oral administration.

[0343] Identification and / or characterization of compounds and / or compositions

[0344] The present disclosure provides, inter alia, various techniques for identifying and / or characterizing compounds and / or compositions as described herein.For example, the present disclosure provides various assays for evaluating SARM1 inhibitory activity, inter alia, for evaluating SARM1 inhibitory activity.

[0345] In some embodiments, the performance of one or more related compounds or compositions in a detection method as described herein is compared with an appropriate reference. For example, in some embodiments, the reference can be the absence of a related compound or composition. Alternatively or additionally, in some embodiments, the reference can be the presence of an alternative compound or composition, such as one that has a known performance in a related detection method (e.g., as understood in the art, as a positive control or negative control). In some embodiments, the reference can be an alternative but comparable set of conditions (e.g., temperature, pH, salt concentration, etc.). In some embodiments, the reference can be the performance of a compound or composition to a SARM1 variant.

[0346] Still alternatively or additionally, in some embodiments, the performance of one or more related compounds or compositions in an assay as described herein may be evaluated in the presence of an appropriate reference compound or composition, e.g., to determine the ability of the compound or composition to compete with a reference.

[0347] In some embodiments, a plurality of related compounds or compositions may be analyzed in a particular assay and / or compared to the same reference. In some embodiments, such a plurality of 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 characteristics (e.g., structural elements, source identity, synthetic similarity, etc.).

[0348] Certain exemplary detection methods that can be used in the practice of the present disclosure are exemplified in the following examples. Those skilled in the art reading this disclosure will recognize that useful or relevant systems for identifying and / or characterizing compounds and / or compositions according to the present disclosure are not limited to those included in the examples or otherwise discussed below.

[0349] In some embodiments, compounds and / or compositions can be identified and / or characterized based on one or more activities or characteristics, for example: promoting axonal integrity, cytoskeletal stability and / or neuronal survival. In some embodiments, provided SARM1 inhibitors inhibit NAD+ from being catabolized by SARM1. In some embodiments, provided SARM1 inhibitors slow down the rate of NAD+ catabolism.

[0350] In some embodiments, provided SARM1 inhibitors reduce or inhibit NAD+ binding by SARM1. In some embodiments, provided SARM1 inhibitors bind to SARM1 within a pocket containing one or more catalytic residues (e.g., the catalytic cleft of SARM1). Examples of such catalytic residues include glutamic acid at position 642 (E642).

[0351] In some embodiments, provided SARM1 inhibitors interfere with and / or prevent the multimerization of the TIR1 domain of SARM1. In some embodiments, provided SARM1 inhibitors interfere with the multimerization of the SAM domain. In some embodiments, provided SARM1 inhibitors interfere with the axonal signaling cascade that leads to NAD+ depletion.

[0352] In some embodiments, the disclosure provides detection methods that can be used to identify and / or characterize one or more activities and / or features of related compounds and / or compositions. For example, in some embodiments, the disclosure provides in vitro, cell and / or in vivo systems for assessing one or more such activities and / or features.

[0353] SARM1 activity assay

[0354] In some embodiments, a method for identifying a SARM1 inhibitor comprises: a) providing a mixture comprising i) a mutant or fragment of SARM1, ii) NAD+, and iii) a candidate inhibitor, wherein the mutant or fragment has constitutive activity; b) incubating the mixture; c) quantifying NAD+ in the mixture after incubation; and d) if the amount of NAD+ is greater than a control mixture without the candidate inhibitor, identifying the candidate inhibitor compound as an inhibitor.

[0355] 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 the incubation; d) determining the molar ratio of NAD+:ADPR (or cADPR); and e) if the molar ratio is greater than a control mixture without the candidate inhibitor, identifying the candidate inhibitor compound as an inhibitor.

[0356] In some embodiments, a method for identifying a SARM1 inhibitor is provided, comprising: a) providing a mixture comprising a solid support having bound thereto i) full-length SARM1 and at least one tag, ii) NAD+, and iii) a candidate inhibitor; b) incubating the mixture; c) quantifying the NAD+ after the incubation; and d) if the concentration of NAD+ is greater than a control, identifying the candidate inhibitor compound as a SARM1 inhibitor.

[0357] SARM1 binding assay

[0358] In some embodiments, the efficacy of the provided SARM1 inhibitors may be determined according to, for example, the detection method described in WO 2018 / 057989 published on March 29, 2018, which is incorporated herein by reference in its entirety. In some embodiments, the provided SARM1 inhibitors may be applied to a solution containing SARM1 or a fragment thereof. In some embodiments, the provided SARM1 inhibitors may be applied to an in vitro system. In some embodiments, the provided SARM1 inhibitors may be applied in vivo. In some embodiments, the provided SARM1 inhibitors may be applied to a patient. In some embodiments, the SARM1 inhibitors may be mixed with SARM1 or a fragment thereof that has been labeled with an epitope tag. In some embodiments, the amount of the bound SARM1 inhibitor may be compared with the amount of the unbound SARM1 inhibitor to obtain the affinity for the SARM1 inhibitor.

[0359] In some embodiments, the mutant or fragment of SARM1 is a constitutively active SAM-TIR fragment. Fragments of constitutively active SARM1 include, for example and without limitation, SARM1 with a deleted autoinhibitory domain; at least one point mutation of SARM1 that renders the autoinhibitory domain inactive; a fragment of SARM1 containing a TIR domain; or a fragment of SARM1 consisting of a SAM and TIR domain. In some embodiments, the SARM1 polypeptide may include one or more additional amino acid sequences that may serve 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, at the carboxyl terminus, or a combination thereof. In some embodiments, SARM1 or a fragment thereof labeled with an epitope tag may be used to measure the binding potency of a provided SARM1 inhibitor.

[0360] Purification of SARM1-TIR domain

[0361] In some embodiments, the SARM1-TIR domain can be engineered with various proteins or epitopes, tags useful, for example, in purification. In some embodiments, the present disclosure also provides NRK1-HEK293T cell lines comprising HEK293T cells transformed with nicotinamide riboside kinase 1 (NRK1). In some embodiments, the HEK293T cells are transformed or transfected with a DNA sequence encoding nicotinamide riboside kinase 1 (NRK1). In some embodiments, the DNA encoding NRK1 can be genomic DNA or cDNA. In some embodiments, the HEK293T cells are stably or transiently transfected with DNA encoding NRK1 from a source outside the host cell. In some embodiments, the 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 a promoter, an enhancer, or a combination thereof. In some embodiments, the combination of the DNA sequence encoding NRK1 and the regulatory sequence is a non-naturally occurring combination. In some embodiments, the DNA encoding NRK1 (genomic DNA 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, human, mouse, zebrafish, or fruit fly. In some configurations, the NRK1 DNA is human NRK1 DNA.

[0362] Applications and uses

[0363] The present disclosure provides various uses and applications of the compounds and / or compositions as described herein, for example, according to their activities and / or characteristics 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.

[0364] In one aspect, the disclosure provides methods comprising administering to a subject one or more compounds of Formula I, e.g., to treat, prevent, or reduce the risk of developing one or more conditions characterized by axonal degeneration. In some such embodiments, the compound of Formula I is a SARM1 inhibitor.

[0365] Another embodiment of the present disclosure is directed to a method of inhibiting SARM1 activity in a patient, comprising the step of administering to said patient a provided compound or a composition comprising said compound.

[0366] The inhibition of enzymes in biological samples can be used for various purposes known to those skilled in the art. Examples of such uses include, but are not limited to, biological detection, gene expression studies, and biological target identification.

[0367] In certain embodiments, the disclosure relates to a method for treating axonal degeneration in a biological sample, comprising the step of contacting the biological sample with a compound or composition of Formula I. In some embodiments, one or more compounds and / or compositions as described herein can be used as methods such as inhibiting the degeneration of neurons derived from a subject. In some embodiments, one or more compounds and / or compositions as described herein can be used to inhibit the degeneration of neurons or parts thereof cultured in vitro. In some embodiments, one or more compounds and / or compositions as described herein can be used as stabilizers to promote neuronal survival in vitro.

[0368] In some embodiments, provided compounds and / or compositions inhibit the NADase activity of SARM1. Alternatively or additionally, in some embodiments, provided compounds alleviate one or more attributes of neurodegeneration. In some embodiments, the disclosure provides methods for treating neurodegenerative diseases or disorders associated with axonal degeneration.

[0369] In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, in medical practice. In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat, prevent, or improve axonal degeneration (e.g., one or more characteristics or properties thereof). In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to inhibit axonal degeneration, including axonal degeneration caused by a reduction or depletion of NAD+. In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to prevent axonal degeneration at the distal end of axonal injury.

[0370] In some embodiments, one or more compounds and / or compositions as described herein can be used as methods such as inhibiting the degeneration of peripheral nervous system neurons or parts thereof. In some embodiments, one or more compounds and / or compositions as described herein can be used as methods such as inhibiting or preventing the degeneration of the central nervous system (neurons) or parts thereof. In some embodiments, one or more compounds or compositions as described herein are characterized in that, when administered to a subject population, one or more symptoms or features of neurodegeneration are alleviated. For example, in some embodiments, the relevant symptoms or features can be selected from the degree, rate and / or timing of neuronal destruction.

[0371] In certain embodiments, the present disclosure provides compounds that can be used, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present disclosure. The compounds provided by the present disclosure can also be used for the study of SARM1 activity in biological and pathological phenomena and the comparative evaluation of novel SARM1 activity inhibitors in vitro or in vivo. In certain embodiments, the present disclosure provides assays for identifying and / or characterizing the compounds and / or compositions provided herein. In some embodiments, the assays provided utilize specific reagents and / or systems (e.g., certain vector constructs and / or polypeptides) that can be used to detect SARM1 activity. For example, in some embodiments, the assays provided may utilize, for example, one or more labeled versions of SAM-TIR (in which the SARM1 N-terminal autoinhibitory domain is deleted) and / or TIR domains.

[0372] In some embodiments, one or more compounds and / or compositions as described herein can be used as methods, for example, to inhibit the degeneration of neurons derived from a subject. In some embodiments, one or more compounds and / or compositions as described herein can be used to inhibit the degeneration of neurons or parts thereof cultured in vitro. In some embodiments, one or more compounds and / or compositions as described herein can be used as stabilizers to promote neuronal survival in vitro.

[0373] In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to affect biomarkers associated with neurodegeneration. In some embodiments, changes in biomarkers can be detected systemically or with samples of cerebrospinal fluid (CSF), plasma, serum, and / or tissue from the 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 the subject. In some embodiments, one or more compounds and / or compositions as described herein can affect constitutive NAD and / or cADPR levels in neurons and / or axons.

[0374] In some embodiments, one or more compounds and / or compositions as described herein may affect detectable changes in the level of one or more neurodegeneration-related proteins in a subject. Such proteins include, but are not limited to, albumin, amyloid-β (Aβ) 38, Aβ40, Aβ42, glial fibrillary acidic protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractant protein (MCP) -1, neurogranin, neuron-specific enolase (NSE), soluble amyloid precursor protein (sAPP) α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phosphorylated tau and / or total tau. In some embodiments, one or more compounds and / or compositions as described herein may affect changes in cytokines and / or chemokines, including but not limited to Ccl2, Ccl7, Ccl12, Csf1 and / or Il6.

[0375] Diseases, disorders and conditions

[0376] 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.

[0377] In some embodiments, the condition is an acute condition. In some embodiments, the condition is a chronic condition.

[0378] In some embodiments, the condition is characterized by axonal degeneration in the central nervous system, peripheral nervous system, optic nerves, cranial nerves, or a combination thereof.

[0379] In some embodiments, the condition is or comprises acute injury to the central nervous system, such as injury to the spinal cord and / or traumatic brain injury. In some embodiments, the condition is or comprises chronic injury to the central nervous system, such as injury to the spinal cord, traumatic brain injury, and / or traumatic axonal injury. In some embodiments, the condition is or comprises chronic traumatic encephalopathy (CTE).

[0380] 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.

[0381] In some embodiments, the condition is acute peripheral neuropathy. Chemotherapy-induced peripheral neuropathy (CIPN) is an example of an acute peripheral neuropathy. CIPN can be associated with various drugs, such as, but not limited to, thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

[0382] 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.

[0383] In some embodiments, the condition is an acute condition affecting the optic nerve, such as acute optic neuropathy (AON) or acute angle-closure glaucoma.

[0384] 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.

[0385] In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat one or more neurodegenerative diseases, disorders or conditions, selected from neuropathy or axonopathy. In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat 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 originates from de novo mutations 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.

[0386] In some embodiments, one or more compounds or compositions as described herein are characterized in that, when administered to a subject population, one or more symptoms or features of neurodegeneration are alleviated. For example, in some embodiments, relevant symptoms or features may be selected from the degree, rate and / or opportunity of neuronal destruction. In some embodiments, neuronal destruction may be or include axonal degeneration, synaptic loss, dendrite loss, synaptic density loss, dendritic branch loss, axonal branch loss, neuronal density loss, myelination loss, neuronal cell body loss, synaptic strengthening loss, action potential enhancement loss, cytoskeletal stability loss, axonal transport loss, ion channel synthesis and turnover loss, neurotransmitter synthesis loss, neurotransmitter release and reuptake capacity loss, axonal potential propagation loss, neuronal hyperexcitability and / or neuronal hypoexcitability. In some embodiments, neuronal destruction is characterized in that an appropriate resting neuronal membrane potential cannot be maintained. In some embodiments, neuronal destruction is characterized in that inclusion bodies, plaques and / or neurofibrillary tangles occur. In some embodiments, neuronal destruction is characterized in that stress granules occur. In some embodiments, neuronal destruction is characterized by intracellular activation of one or more members of the cysteine-aspartic acid protease (Caspase) family. In some embodiments, neuronal destruction is characterized by programmed cell death (e.g., apoptosis, pyroptosis, ferroapoptosis, and / or necrosis) and / or inflammation of neurons.

[0387] In some embodiments, the neurodegenerative or nervous system disease or disorder is associated with axonal degeneration, axonal injury, axonopathy, demyelinating disease, central pontine myelinolysis, a neurological injury disease or disorder, a metabolic disease, mitochondrial disease, metabolic axonal degeneration, axonal injury from a leukoencephalopathy or a leukodystrophy. In some embodiments, the neurodegenerative or neurological disease or disorder is selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelin breakdown, osmotic hyponatremia, anoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Pelizaeus-Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher disease, Hurler syndrome, traumatic brain injury, post-radiation injury, neurologic complications of chemotherapy (chemotherapy-induced neuropathy; CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 12deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, glaucoma, Leber's hereditary optic atrophy (neuropathy), Leber's congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis, 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), adrenomyeloneuropathy, progressive supranuclear palsy (PSP), Friedrich's ataxia, hereditary ataxias, noise-induced hearing loss, congenital hearing loss, dementia with Lewy bodies, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, severe acute motor axonal neuropathy (AMAN), Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, spinocerebellar ataxia, preeclampsia, hereditary spastic paraplegia, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, and nonalcoholic steatohepatitis (NASH).

[0388] In some embodiments, the present disclosure provides SARM1 activity inhibitors for treating neurodegenerative or nervous system diseases or disorders involving axonal degeneration or axonopathy. The present disclosure also provides methods of using SARM1 activity inhibitors to treat, prevent or improve axonal degeneration, axonopathy and neurodegenerative or nervous system diseases or disorders involving axonal degeneration.

[0389] 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, mitochondrial disease, metabolic axonal degeneration, axonal injury from leukoencephalopathy or leukodystrophy.

[0390] 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 non-mechanical injury due to disease, condition or exposure to toxic molecules or drugs. The result of such damage can be the degeneration or dysfunction of axons and the loss of functional neuronal activity. Producing such axonal injury or the disease and condition associated with such axonal injury belong to a large number of neurological diseases and conditions. Such neuropathy can include peripheral neuropathy, central neuropathy and combinations thereof. In addition, peripheral neuropathy performance can be produced by diseases initially focused on the central nervous system, and central nervous system performance can be produced by substantially peripheral or systemic diseases.

[0391] In some embodiments, peripheral neuropathy may involve damage to peripheral nerves and / or may be caused by a disease of the nerves or as a result of a systemic disease. Some such diseases may include diabetes, uremia, infectious diseases such as AIDS or leprosy, nutritional deficiencies, vascular or collagen disorders such as atherosclerosis, and autoimmune diseases such as systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, and polyarteritis nodosa. In some embodiments, peripheral nerve degeneration results from traumatic (mechanical) damage to the nerves and chemical or thermal damage to the nerves. Such conditions that damage peripheral nerves include compression or compression injuries such as glaucoma, carpal tunnel syndrome, direct trauma, penetrating injuries, contusions, fractures, or bone dislocations; pressure involving superficial nerves (ulna, radius, or fibula), which may result from prolonged use of crutches or prolonged maintenance of a posture, or from tumors; intraneural bleeding; ischemia; exposure to cold or radiation or certain drugs or toxic substances, such as herbicides or pesticides. In particular, nerve damage may result from chemical damage due to cytotoxic anticancer agents, such as paclitaxel, cisplatin, proteasome inhibitors, or vinca alkaloids such as vincristine. Typical symptoms of such peripheral neuropathy include weakness, numbness, paresthesia (abnormal sensations such as burning, itching, tingling, or tingling) and pain in the arms, hands, legs, and / or feet. In some embodiments, neuropathy is associated with mitochondrial dysfunction. Such neuropathy may manifest as reduced energy levels, i.e., reduced NAD and ATP levels.

[0392] In some embodiments, peripheral neuropathy is metabolic and endocrine neuropathy, which includes a wide range of peripheral nerve disorders related to systemic diseases of metabolic origin. Such diseases include, for example, diabetes, hypoglycemia, uremia, hypothyroidism, liver failure, polycythemia, amyloidosis, acromegaly, porphyria, lipid / glycolipid metabolism disorders, nutrition / vitamin deficiency and mitochondrial disorders, etc. The common hallmark of these diseases is the involvement of peripheral nerves by changes in the structure or function of myelin and axons caused by metabolic pathway disorders.

[0393] In some embodiments, the neuropathy includes optic neuropathy, such as glaucoma; retinal ganglion degeneration, such as those associated with retinitis pigmentosa and outer retinal neuropathy; optic neuritis and / or degeneration, including those 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 those secondary to giant cell arteritis; metabolic optic neuropathy, such as neurodegenerative diseases, including the previously mentioned Leber's neuropathy, nutritional deficiencies, such as vitamin B12 or folic acid deficiency, and toxicity, such as due to 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.

[0394] In some embodiments, neurodegenerative diseases associated with neuropathy or axonopathy in the central nervous system include various 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 those caused by enterovirus, arbovirus and herpes simplex virus; and prion disease. Mechanical damage, such as glaucoma or trauma to the head and spine can also cause nerve damage and degeneration in the brain and spinal cord. In addition, ischemia and stroke and conditions such as malnutrition and chemical toxicity of chemotherapeutic agents can cause central nervous system neuropathy.

[0395] In some embodiments, the 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 many neuropathy or axonopathy, such as hereditary or congenital, or those 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. 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 a subset of diseases may include Parkinson's disease or non-Parkinson's disease, or Alzheimer's disease.

[0396] Object

[0397] In some embodiments, the compounds and / or compositions as described herein are administered to a subject suffering from or susceptible to a disease, disorder, or condition as described herein; in some embodiments, such a disease, disorder, or condition is characterized by axonal degeneration, such as one of the conditions mentioned above.

[0398] In some embodiments, a subject administered a compound or composition as described herein exhibits one or more signs or symptoms associated with axonal degeneration; in some embodiments, the subject does not exhibit any signs or symptoms of neurodegeneration.

[0399] 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 for developing a condition characterized by axonal degeneration. In some embodiments, the patient has a condition characterized by axonal degeneration. In some embodiments, the patient has been diagnosed with a condition characterized by axonal degeneration.

[0400] In some embodiments, the methods provided include administering a composition as described herein to a patient population in need thereof. In some embodiments, the population is from individuals participating in activities with a high likelihood of traumatic neuronal injury. In some embodiments, the population is from athletes participating in contact sports or other high-risk activities.

[0401] In some embodiments, the subject is at risk for developing a condition characterized by axonal degeneration. In some embodiments, a 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.

[0402] In some embodiments, the patient has a risk of developing 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 population with a high incidence of neurodegeneration. In some embodiments, the patient has a hexanucleotide repeat expansion in chromosome 9 open reading frame 72. In some embodiments, the patient has one or more copies of the ApoE4 allele.

[0403] In some embodiments, the object to be administered a compound or composition as described herein may be or include an object 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 brain injury, open head trauma, exposure to concussive force and / or explosive force, penetrating injury to the innervated area of ​​the brain cavity or body. In some embodiments, traumatic neuronal injury is a force that causes axonal deformation, stretching, crushing or steering.

[0404] In some embodiments, the subject participates in activities identified as risk factors for neuronal degeneration, such as the subject's participation in contact sports or an occupation with a high incidence of traumatic neuronal injury.

[0405] For example, the subject can be a patient who is receiving or is required to undergo chemotherapy associated with peripheral neuropathy. Examples of chemotherapeutic agents include, but are not limited to, thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

[0406] In some embodiments, the methods provided include administering a composition as described herein to a patient or patient population based on the presence or absence of one or more biomarkers. In some embodiments, the methods provided further include monitoring the biomarker levels of the patient or patient population and adjusting the dosing regimen accordingly.

[0407] Drug administration

[0408] One skilled in the art will recognize that, in some embodiments, the exact amount of a particular compound included in and / or delivered by administration of a pharmaceutical composition or regimen as described herein may be selected by a physician and may vary from subject to subject, for example, taking into account one or more of the species, age, and general condition of the subject and / or the identity of the particular compound or composition, its mode of administration, etc. Alternatively, in some embodiments, the amount of a particular compound included in and / or delivered by administration of a pharmaceutical composition or regimen as described herein may be standardized across a relevant patient population (e.g., all patients, all patients of a particular age or disease stage or expressing a particular biomarker, etc.).

[0409] For ease of administration and dosage uniformity, the compounds or compositions provided by the present disclosure are preferably formulated in unit dosage forms. The expression "unit dosage form" used herein refers to a physically discrete unit of a medicament suitable for a patient to be treated. However, it is to be understood that the total daily dosage of the compounds or compositions provided by the present disclosure will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dose level for any particular patient or organism depends on various factors, including the disorder to be treated and the severity of the disorder; the clinical condition of the individual patient; the cause of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex and diet of the patient; the time of administration, the delivery location of the medicament, the route of administration and the excretion rate of the specific compound used; the duration of treatment; the drugs used in combination or together with the specific compound used, and similar factors well known in the medical field. The effective amount of the compound to be administered depends on these considerations and is the necessary minimum amount of the inhibition of SARM1 activity required to prevent or treat unwanted diseases or disorders such as neurodegeneration or traumatic nerve injury.

[0410] The pharmaceutically acceptable compositions of the present disclosure can be administered to humans and other animals orally, rectally, intravenously, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., by powders, ointments, or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the disease, disorder, or infection being treated. The daily dose is given in certain embodiments as a single daily dose or 2 to 6 times a day in divided doses, or in a sustained release form. This dosing regimen can be adjusted to provide the best therapeutic response. The compound can be administered in a regimen of 1 to 4 times a day, preferably 1 or 2 times a day.

[0411] In some embodiments, the compositions of the present disclosure can 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, intraarterial, intrasynovial, intrasternal, intrathecal, intrahepatic, intradermal, intraocular, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously.

[0412] In some embodiments, the pharmaceutically acceptable compositions of the present disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical administration, including diseases of the eye, skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0413] Most preferably, the pharmaceutically acceptable compositions of the present disclosure are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present disclosure are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered with food.

[0414] Those additional agents can be administered separately from the provided compounds or compositions thereof as part of a multiple dosage regimen. Alternatively, these 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 dosage regimen, the two active agents can be administered simultaneously, sequentially, or within a certain period of each other, usually within 5 hours of each other.

[0415] It should also be understood that the specific dosage and treatment regimen for any particular patient may depend on various factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. In some embodiments, the amount of the compound of the present disclosure in the composition also depends on the specific compound in the composition.

[0416] In some embodiments, SARM1 inhibition as described herein can be used in combination with one or more other therapies to treat related diseases, disorders or conditions. In some embodiments, the dosage of the SARM1 inhibitor is changed when used for combination therapy compared to when administered as a monotherapy; alternatively or additionally, in some embodiments, the therapy administered in combination with SARM1 inhibition as described herein is administered according to a different regimen or procedure than when administered alone or in combination with one or more non-SARM1 inhibited therapies. In some embodiments, a 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 in lower amounts or less frequently than when used as a monotherapy.

[0417] In some embodiments, the compounds and / or compositions described herein are administered with chemotherapeutic agents, including but not limited to alkylating agents, anthracyclines, taxanes, epothilones, histone deacetylase inhibitors, topoisomerase inhibitors, kinase inhibitors, nucleotide analogs, peptide antibiotics, platinum-based agents, retinoids, vinca alkaloids and derivatives. In some embodiments, the compounds and / or compositions described herein are administered in combination with a PARP inhibitor. Example

[0418] The present teachings include the descriptions provided in the examples, which are not intended to limit the scope of any claim. Unless explicitly expressed in the past tense, inclusion in the examples is not intended to imply that the experiment was actually performed. The following non-limiting examples are provided to further illustrate the present teachings. Those skilled in the art will recognize in light of the present disclosure that many changes can be made in the disclosed specific embodiments and still obtain similar or similar results without departing from the spirit and scope of the present teachings.

[0419] method

[0420] Some of the methods and compositions described herein utilize laboratory techniques well known to the skilled artisan 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 and dosage regimen for drug administration can be determined according to standard principles of pharmacology using 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.

[0421] Example 1: Characterization of compounds

[0422] LCMS method:

[0423] Analytical LC / MS Analysis Method A:

[0424] ESI + / - ion mode 100-1000Da

[0425] Column: XBridge C18, 50 x 4.6 mm, 3.5 um

[0426] Temperature: 40℃

[0427] gradient:

[0428] Time (min) <![CDATA[Water (10 mM NH NH4HCO3)]]> Acetonitrile Flow rate (mL / min) 0 95% 5% 2.0 1.2 5% 95% 2.0 3.0 5% 95% 2.0

[0429] Analytical LC / MS Analysis Method B:

[0430] ESI + / - ion mode 150-850Da

[0431] Column: Phenomenex Kinetix-XB C18, Part No. 00D-4498-AN, 2.1 x 100 mm, 1.7 um

[0432] Temperature: 40℃

[0433] gradient:

[0434] 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

[0435] Analytical LC / MS Analysis Method C:

[0436] ESI + / - ion mode 100-1000Da

[0437] Column: XBridge C18, 50 x 4.6 mm, 3.5 um

[0438] Temperature: 40℃

[0439] gradient:

[0440] Time (min) Water + 0.1% TFA Acetonitrile + 0.1% TFA Flow rate (mL / min) 0 95% 5% 1.8 1.8 5% 95% 1.8 3.0 5% 95% 1.8

[0441] The results are shown in Table 1:

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455] .

[0456] Example 2: SAM-TIR SARM1 IC50 Assay

[0457] This example describes an assay for SAM-TIR NADase activity and the use of this assay to measure the potency of compounds of Formula I in blocking SARM1-mediated NAD+ cleavage. This assay was optimized to characterize the potency of compounds of Formula I in inhibiting SARM1 activity and to calculate the IC50 value of each compound. This assay utilizes a fragment of the SARM1 molecule that contains the SAM and TIR domains. As demonstrated herein, expression of this fragment without the self-inhibiting N-terminal domain generates a constitutively active enzyme that cleaves NAD+.

[0458] Preparation of SARM1 SAM-TIR lysate (STL)

[0459] NRK1-HEK293T cells refer to a cell line that has been stably transfected with an FCIV expression vector expressing 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 Shows that the NRK1-HEK293T stable cell line with NR supplementation maintains higher NAD+ levels after SARM1-TIR expression. Data were 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 t-test.

[0460] NRK1-HEK293T cells represent a cell line that has been stably transfected with an FCIV expression vector expressing human nicotinamide riboside kinase 1 (NRK1), an enzyme that converts the NAD+ biosynthetic precursor nicotinamide riboside (NR) into NMN, the immediate precursor of NAD+.

[0461] NRK1-HEK293T cells were seeded at 20 x 106 cells per plate in 150 cm 2 The next day, cells were transfected with 15 μg of FCIV-SST (SAM-TIR expression plasmid, SEQ ID NO: 1) using X-TREMEGENE™ 9 DNA Transfection Reagent (Roche product #06365787001).

[0462]

[0463]

[0464]

[0465]

[0466] Cultures were supplemented with 1 mM NR at the time of transfection to minimize toxicity from SAM-TIR overexpression. 48 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 PBS containing protease inhibitors (cOmplete™ Protease Inhibitor Cocktail, Roche product # 11873580001) and cell lysates were prepared by sonication (Branson Sonifer 450, output = 3, 20 episodes of stroke). The lysates were centrifuged (12,000 × g for 10 min at 4 °C) to remove cell debris and the supernatant (containing SARM1 SAM-TIR protein) was stored at -80 °C for later use in the in vitro SARM1 SAM-TIR NADase assay (see below). Protein concentration was determined by the Bicinchoninic (BCA) method and used to normalize lysate concentrations.

[0467] SAM-TIR IC50 Assay for Compounds of Formula I

[0468] 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 preincubated with each compound at 1% DMSO final assay concentration for 2 hours at room temperature. Reactions were initiated by the addition of NAD+ as a substrate at a final assay concentration of 5 µM. After a 2-hour room temperature incubation, the reaction was terminated with 40 µL of 7.5% trichloroacetic acid / acetonitrile stop solution. NAD+ and ADPR concentrations were analyzed by RapidFire HighThroughput Mass Spectrometry System (Agilent Technologies, Santa Clara, CA) using an API4000 triple quadrupole mass spectrometer (AB Sciex Framingham, MA).

[0469] The results are shown in Table 2 below. Compounds with activity labeled "A" provided IC 50 < 1µM; compounds with activity labeled “B” provide IC 50 1-5 µM; compounds with activity labeled "C" provide IC 50 > 5 µM.

[0470]

[0471] Example 3: Axonal Degeneration Index

[0472] This example illustrates an in vitro axonal degeneration assay used to characterize compounds of Formula I. This 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.

[0473] Mouse DRG hanging drop cultures: Mouse dorsal root ganglion neurons (DRGs) were dissected from E12.5 CD1 mice (50 ganglia per embryo) and incubated with 0.5% trypsin solution (Gibco) containing 0.02% EDTA at 37°C for 15 min. 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. DRG hanging drop cultures were created by spotting 5000 cells / well into the center of each well of a 96-well tissue culture plate coated with poly-D-lysine (0.1 mg / ml; Sigma) and laminin (3 mg / ml; Invitrogen). Allow cells to adhere to the plate for 15 min in a humidified tissue incubator (5% CO2), then gently add DRG Growth Medium (100 ml per well).

[0474] Axonal degeneration assay Axonal degeneration was stimulated by manual transection of axons using a surgical blade or by chemical toxic stimulation. After the appropriate experimental period, DRG cultures were fixed in 1% PFA and sucrose and stored 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 axonal quantification was performed using an in-house developed script (Acapella, PerkinElmer). Sequence Listing <110> DISARM THERAPEUTICS, INC. <120> SARM1 inhibitors <130> 2012800-0036 <150> 62 / 858,083 <151> 2019-06-06 <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 caaaatgtc 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 gccgaacag ggacttgaaa gcgaaaggga aaccagagga gctctctcga cgcaggactc 1080 ggcttgctga agcgcgcacg gcaagaggcg aggggcggcg actggtgagt acgccaaaaa 1140 ttttgactag cggaggctag aaggagagag atgggtgcga gagcgtcagt attaagcggg 1200 ggagaattag atcgcgatgg gaaaaaattc ggttaaggcc agggggaaag aaaaatata 1260 aattaaaaca tatagtatgg gcaagcaggg 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 tctgtatag tgcagcagca gaacaatttg 1800 ctgagggcta tgaggcgca acaccatctg ttgcactca cagtctgggg catcagcag 1860 ctccaggcaa gatcctggc tgtggaaaga ctccaagg atcacagct cctggggatt 1920 tggggttgct ctggaaaact cattgcacc actgctgtgc cttggaatgc tagttggagt 1980 aaaatctc tggaacagat ttggaatcac acgacctgga tggagtgg cagagaaatt 2040 aaaattaca caagcttaat acaccctta attgagaat cgcaaacca gcaagaaag 2100 atgaacaag attattgga attagaataa tggcaagtt 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 tttatgtac ctatcttctt aagtagctga 3660 agctccggtt ttgaactatg cgctcggggt tggcgagtgt gttttgtgaa gttttttagg 3720 caccttttga aatgtaatca tttgggtcaa tatgtaattt tcagtgttag actagtaaag 3780 cttctgcagg tcgactctag aaaattgtcc gctaaattct ggccgttttt ggctttttg 3840 ttagacgaag cttgggctgc aggtcgactc tagaggatcc ggatccgcca ccatgtcagc 3900 ttggagccac ccacaattcg aaaaggcgg tggctcaggc ggtggctcag gtggctcagc 3960 ttggagccac ccacaattcg aaaaggcgg 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 ccgcgcttc 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 cgctgcttta atgcctttgt atcatgctat tgcttcccgt atggctttca ttttctcctc 5160 cttgtataaa tcctggttgc tgtctcttta tgaggagttg tggcccgttg tcaggcaacg 5220 tggcgtggtg tgcactgtgt ttgctgacgc aacccccact ggttggggca ttgccaccac 5280 ctgtcagctc ctttccgggga ctttcgcttt ccccctccct attgccacgg cggaactcat 5340 cgccgcctgc cttgcccgct gctggacagg ggctcggctg ttgggcactg acaattccgt 5400 ggtgttgtcg gggaaatcat cgtcctttcc ttggctgctc gcctgtgttg ccacctggat 5460 tctgcgcggg acgtccttct gctacgtccc ttcggccctc aatccagcgg accttccttc 5520 ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt cgccttcgcc ctcagacgag 5580 tcggatctcc ctttgggccg cctccccgca tcgataccgt cgacctcgag acctagaaaa 5640 acatggagca atcacaagta gcaatacagc agctaccaat gctgattgtg cctggctaga agcacaagag gaggaggagg tgggttttcc agtcacacct caggtacctt tagcat 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 tgaggtttg acagccgcct agcatttcat cacatggccc gagagctca 6120 tccggactgt actgggtctc tctgggtaga ccagatctga gcctgggagc tctctggcta 6180 actagggaac ccactgctta agcctcaata aagcttgcct tgagtgcttc aagtagtgtg 6240 tgcccgtctg ttgtgtgact ctggtaacta gagatccctc agaccctttt agtcagtgtg 6300 gaaaatctct agcagggccc gtttaaaccc gctgatcagc ctcgactgtg ccttttagtt 6360 gccagccatc tgttgtttgc ccctcccccg tgccttcctt gaccctggaa ggtgccactc 6420 ccactgtcct ttcctaataa aatgaggaaa ttgcatcgca ttgtctgagt aggtgtcatt 6480 ctattctggg gggtggggtg gggcaggaca gcaaggggga ggattgggaa gacaatagca 6540 ggcatgctgg ggatgcggtg ggctctatg cttctgaggc ggaaagaacc agctggggct 6600 ctagggggta tccccacgcg ccctgtagcg gcgcattaag cgcggcggt gtggtggtta 6660 cgcgcagcgt gaccgctaca cttgccagcg cctagcgcc cgctccttc gctttcttcc 6720 cttccttct cgccacgtc gccggctttc cccgtcaagc tctaaatcgg gggctccct 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 cgggttctc 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 atatacga tacgggagg cttaccatct ggccccagtg ctgcaatgat accgcgagac 9480 ccacgctcac cggctccaga tttatcagca ataaaccagc cagccggaag ggccgagcgc 9540 agaagtggtc ctgcaacttt atccgcctcc atccagtcta ttaattgttg ccgggaagct 9600 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. Compounds of formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from -CN or -CON(R)2; R 2 Yes - H; R 3 Yes-Cy 1 ; R 4 Yes-Cy 2 ; Cy 1 is selected from phenyl and an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each phenyl and heteroaryl ring is surrounded by 0-4 R x replace; Each R x are independently selected from halogen, -OR, and C optionally substituted by halogen 1-6 aliphatic groups; Cy 2 is selected from phenyl, a 3- to 7-membered monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7- to 9-membered bridged bicyclic or spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each of the phenyl, heterocyclic and heteroaryl rings is surrounded by 0-4 R v replace; Each R v independently selected from -C(O)R, -SO2R, -CO2R, -CON(R)2, C 1-6 aliphatic groups and 5- to 6-membered heteroaryl rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and Each R is independently hydrogen or C optionally substituted with -OCH3 1-6 An aliphatic group, or: Two R's together with the atoms to which they are attached form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring.

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 is -CN or -CON(R)2; R 2 Yes - H; R 3 Yes-Cy 1 ;and -Cy 1 Selected from 。 3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 is-CON(R)2; and R 2 Yes -H.

4. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Cy 2 Selected from 。 5. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Cy 2 Selected from 。 6. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Cy 2 Selected from 。 7. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing a condition characterized by axonal degeneration.

8. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for preparing a medicament for treating or preventing axonal degeneration.

9. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for preparing a medicament for inhibiting SARM1.

Images