Inhibitors of SARM1

Abstract

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

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 958,178, filed on January 7, 2020, and U.S. Provisional Application No. 63 / 065,736, filed on August 14, 2020, which are hereby incorporated herein by reference in their entirety.

[0003] Sequence Listing

[0004] This application contains a Sequence Listing, which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy, created on December 22, 2020, is named 2012800-0069_SL.txt and is 8,857 bytes in size.

[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, which is hereby incorporated herein by reference in its entirety). Neurodegenerative diseases and injuries are devastating to patients and caregivers. In the United States alone, the costs associated with these diseases currently exceed hundreds of billions of dollars annually. As the incidence of many of these diseases and disorders increases with age, their incidence is rapidly increasing with changing demographics.

[0007] BRIEF DESCRIPTION OF THE INVENTION

[0008] The present disclosure provides techniques that can be used, inter alia, to treat and / or prevent neurodegeneration (e.g., to reduce axonal degeneration). In certain embodiments, the techniques provided inhibit SARM1.

[0009] In certain embodiments, the present disclosure provides certain compounds and / or compositions that can be used in medicaments and particularly for treating neurodegeneration (e.g., for reducing axonal degeneration).

[0010] In certain embodiments, the present disclosure provides a compound having the structure shown in Formula I or a pharmaceutically acceptable salt thereof:

[0011]

[0012] Wherein:

[0013] Ring A is a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0014] R 1 is an optionally substituted group selected from: a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0015] Each R x is independently selected from halogen, cyano, OR, SR, N(R)2, or an optionally substituted group selected from: C 1-4 aliphatic group, a 3- to 7-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0016] L is an optionally substituted C 1-4 aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced independently by a group selected from: -O-, -N(R)-, -S-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocycle;

[0017] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; or:

[0018] Two R groups together with the nitrogen atom to which they are attached form an optionally substituted 3- to 7-membered monocyclic heterocycle having 0 to 2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0019] R 2 is hydrogen, halogen, N(R)2, OR, or an optionally substituted group selected from: C 1-6An aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl group, a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8- to 10-membered bicyclic saturated, partially unsaturated, or aryl carbocycle, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; and

[0020] n is 0, 1, or 2.

[0021] In certain embodiments, the present disclosure provides a compound having the structure shown in Formula I’ or a pharmaceutically acceptable salt thereof:

[0022]

[0023] Wherein:

[0024] Ring A is a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0025] R 1 is an optionally substituted group selected from: a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0026] Each R x is independently selected from halogen, cyano, OR, SR, N(R)2, S(O)2N(R)2, C(O)OR, C(O)N(R)2, or an optionally substituted group selected from: C 1-4 an aliphatic group, a 3- to 7-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl group, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0027] L is an optionally substituted C 1-4 aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced independently by a group selected from: -O-, -N(R)-, -S-, -S(O)2-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocycle;

[0028] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic groups, 3- to 7-membered saturated or partially unsaturated heterocycles having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; or:

[0029] Two R groups together with the nitrogen atom to which they are attached form an optionally substituted 3- to 7-membered monocyclic heterocycle having 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0030] R 2 is hydrogen, halogen, N(R)2, OR or an optionally substituted group selected from: C 1-6 aliphatic groups, 3- to 7-membered saturated or partially unsaturated heterocycles having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocycles, 8- to 10-membered bicyclic saturated or partially unsaturated heterocycles having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or 8- to 10-membered bicyclic heteroaryl rings having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; and

[0031] n is 0, 1 or 2.

[0032] In certain embodiments, the provided compounds have the structures of Formulae I-a, I-a- i , I-b, I-b- i , I-c, I-c- i , I-d, I-d- i , I-e, I-e- i , I-f, I-f- i , I-g, I-g- i , I-h, I-h- i , I-i, I-i- i , I-j, I-j- i , I-k, I-k- i , I-l, I-l- i , I-m, I-m- i , I-n, I-n- i , I-o, I-o- i , I-p, I-p- i , I-p- ii , I-q, I-q- i , I-r, I-s, I-t, I-u and I-v.

[0033] In certain embodiments, one or more compounds of Formula I are provided and / or utilized in solid form (e.g., crystalline or amorphous form).

[0034] In certain embodiments, the present disclosure provides compositions that comprise and / or deliver a compound of Formula I (e.g., in a form as described herein), a prodrug thereof, or an active metabolite.

[0035] In certain embodiments, the present disclosure provides compositions that comprise and / or deliver a compound of Formula I. In certain embodiments, such compositions are pharmaceutical compositions that include at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0036] In certain embodiments, the provided SARM1 inhibitors reduce or inhibit the binding of SARM1 to NAD+. In certain embodiments, the provided SARM1 inhibitors bind to SARM1 located within a pocket (e.g., the catalytic cleft of SARM1) that contains one or more catalytic residues.

[0037] In certain embodiments, the provided compounds and / or compositions inhibit the activity of SARM1. Alternatively or additionally, in certain embodiments, the provided compounds mitigate one or more characteristics of neurodegeneration. In certain embodiments, the present disclosure provides methods of treating neurodegenerative diseases or disorders associated with axonal degeneration.

[0038] In certain embodiments, one or more compounds and / or compositions as described herein can be used, for example, in the practice of medicine. In certain embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat, prevent, or ameliorate axonal degeneration (e.g., one or more features or characteristics thereof). In certain 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 certain embodiments, one or more compounds and / or compositions as described herein can be used, for example, to prevent axons distal to an axonal injury from undergoing degeneration.

[0039] In certain 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 certain 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 certain embodiments, the neuropathy associated with axonal degeneration is a hereditary or congenital neuropathy or axonopathy. In certain embodiments, the neuropathy associated with axonal degeneration results from a primary ( de novo) or somatic mutations. In certain embodiments, the neuropathy associated with axonal degeneration is selected from the list contained herein. In certain embodiments, the neuropathy or axonopathy is associated with axonal degeneration, including but not limited to Parkinson's disease, Parkinson's syndrome or Parkinson's plus syndrome such as, for example, multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis (ALS), demyelinating diseases such as, for example, multiple sclerosis, ischemia or stroke, chemical injury, thermal injury, and AIDS.

[0040] In certain embodiments, the subject to which the compounds or compositions described herein are administered can be or include a subject suffering from or susceptible to a neurodegenerative disease, disorder or condition. In certain embodiments, the neurodegenerative disease, disorder or condition can be or include traumatic neuronal injury. In certain embodiments, the traumatic neuronal injury is blunt force trauma, closed head injury, open head injury, exposure to impact and / or blast forces, or penetrating injury in or to the cranial cavity or innervated regions of the body. In certain embodiments, the traumatic neuronal injury is a force that causes axonal deformation, stretching, crushing or breakage.

[0041] In certain embodiments, the methods provided include administering to a patient in need thereof a compound described herein. In certain such embodiments, the patient is at risk of developing a condition characterized by axonal degeneration. In certain embodiments, the patient has a condition characterized by axonal degeneration. In certain embodiments, the patient has been diagnosed with a condition characterized by axonal degeneration.

[0042] In certain embodiments, the methods provided include administering to a population of patients in need thereof a composition as described herein. In certain embodiments, the population is from individuals engaged in activities with a high likelihood of traumatic neuronal injury. In certain embodiments, the population is from athletes engaged in contact sports or other high-risk activities.

[0043] In certain embodiments, the patient is at risk of developing a neurodegenerative disorder. In certain embodiments, the patient is an elderly individual. In certain embodiments, the patient is known to have a genetic risk factor for neurodegeneration.

[0044] In certain embodiments, the present disclosure provides compounds that can be used, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the present disclosure. The compounds provided by the present disclosure can also be used for in vitro or in vivo comparative evaluation of SARM1 function and new SARM1 activity inhibitors in biological and pathological phenomena.

[0045] In certain embodiments, one or more compounds and / or compositions as described herein can be used, for example, in a method for inhibiting the degradation of neurons derived from a subject. In certain embodiments, one or more compounds and / or compositions as described herein can be used to inhibit the degeneration of neurons or portions thereof cultured in vitro. In certain embodiments, one or more compounds and / or compositions as described herein can be used as a stabilizer to promote neuron survival in vitro. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 Illustrates the structure of the SARM1 protein.

[0047] Definitions

[0048] Aliphatic: The term "aliphatic" refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or contains one or more unsaturated units but is non-aromatic (also referred to herein as "carbocyclic" or "cycloaliphatic"). Unless otherwise indicated, aliphatic groups contain 1-6 aliphatic carbon atoms. In certain embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In certain embodiments, "cycloaliphatic" (or "carbocyclic") refers to a completely saturated or monocyclic C3-C8 hydrocarbon or bicyclic C7-C 10 hydrocarbon that contains one or more unsaturated units but is non-aromatic. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene groups and hybrids thereof.

[0049] Alkyl: The term "alkyl", used alone or as part of a larger group, refers to a saturated, optionally substituted, straight-chain or branched or cyclic hydrocarbon group having 1-12, 1-10, 1-8, 1-6, 1-4, 1-3 or 1-2 carbon atoms. The term "cycloalkyl" refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0050] Alkylene: The term "alkylene" refers to a divalent alkyl group. In certain embodiments, "alkylene" is a divalent straight-chain or branched alkyl group. In certain embodiments, an "alkylene chain" is a polymethylene group, i.e., -(CH2) n-, where n is a positive integer, for example, from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. The optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are optionally replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups and also those described in the present specification. It should be understood that two substituents of the alkylene group can together form a ring system. In certain embodiments, the two substituents can together form a 3- to 7-membered ring. The substituents can be on the same or different atoms.

[0051] Alkenyl: The term "alkenyl", used alone or as part of a larger group, refers to an optionally substituted straight-chain, branched-chain, or cyclic hydrocarbon group having at least one double bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having from about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentyl, cyclohexenyl, and cycloheptenyl.

[0052] Alkynyl: The term "alkynyl", used alone or as part of a larger group, refers to an optionally substituted straight-chain or branched-chain hydrocarbon group having at least one triple bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms.

[0053] Aryl: The term "aryl" refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, where at least one ring in the system is aromatic and where each ring in the system contains three to seven 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 including, but not limited to, phenyl, biphenyl, naphthyl, anthracenyl, etc., which can carry one or more substituents. As used herein, groups are also included within the scope of the term "aryl": where the aromatic ring is fused to one or more non-aromatic carbocyclic or heterocyclic rings, such as indanyl, phthalimido, naphthimidyl, phenanthridinyl, tetrahydronaphthyl, imidazolidinyl, imidazolidin-2-one, etc.

[0054] Binding: It should be understood that the term "binding" as used herein generally refers to non-covalent association between two or more entities. "Direct" binding involves physical contact between the entities or moieties; indirect binding involves physical interaction that occurs via physical contact with one or more intermediate entities. Binding between two or more entities can generally be evaluated in any of a variety of contexts - including studying the interacting entities or moieties in isolation or in the context of a more complex system (e.g., when covalently or otherwise associated with a carrier entity and / or in a biological system or cell).

[0055] Biological sample: The term "biological sample" as used herein generally refers to a sample obtained or derived from a biological source of interest (e.g., tissue or organism or cell culture) as described herein. In certain embodiments, the source of interest comprises an organism, such as an animal or a human. In certain embodiments, the biological sample is or comprises a biological tissue or fluid. In certain embodiments, the biological sample can be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; body fluids containing cells; free-floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; 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 derived therefrom, etc. In certain embodiments, the biological sample is or comprises cells obtained from an individual. In certain embodiments, the obtained cells are or include cells from the individual from whom the sample is obtained. In certain embodiments, the sample is a "primary sample" obtained directly from the source of interest by any suitable means. For example, in certain embodiments, the primary biological sample is obtained by a method selected from biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluids (e.g., blood, lymph fluid, feces, etc.), etc. In certain embodiments, as will be clear from the context, the term "sample" refers to an article obtained by processing (e.g., by removing one or more components therefrom and / or by adding one or more reagents thereto) the primary sample. For example, filtration using a semi-permeable membrane. Such a "processed sample" can contain, for example, nucleic acids or proteins extracted from the sample or obtained by techniques such as amplification or reverse transcription of mRNA, separation and / or purification of certain components, etc. of the primary sample.

[0056] Biomarker: The term "biomarker" as used herein refers to an entity, event, or characteristic whose presence, level, degree, type, and / or form is associated with a particular biological event or state of interest, and thus it is considered a "marker" of that event or state. By way of just a few examples, in certain embodiments, a biomarker can be or include a marker of a particular disease state, or a marker of the likelihood of development, occurrence, or recurrence of a particular disease, disorder, or condition. In certain embodiments, a biomarker can be or include a marker of a particular disease or treatment outcome or the likelihood thereof. Thus, for a biological event or state of interest, in certain embodiments, a biomarker is predictive, in certain embodiments, a biomarker is prognostic, and in certain 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 certain embodiments, a biomarker can be or include a nucleic acid, polypeptide, lipid, carbohydrate, small molecule, inorganic reagent (e.g., metal or ion), or a combination thereof. In certain embodiments, a biomarker is a cell surface marker. In certain embodiments, a biomarker is intracellular. In certain embodiments, a biomarker is detected extracellularly (e.g., secreted extracellularly or otherwise produced or present extracellularly, such as in a body fluid such as blood, urine, tears, saliva, cerebrospinal fluid, etc.). In certain embodiments, a biomarker can be or include a genetic or epigenetic feature. In certain embodiments, a biomarker can be or include a gene expression signature.

[0057] In certain embodiments, a biomarker can be or include a marker of neurodegeneration, or a marker of the likelihood of development, occurrence, or recurrence of a neurodegenerative disease, disorder, or condition. In certain embodiments, a biomarker can be or include a marker of a neurodegenerative treatment outcome or the likelihood thereof. Thus, for a neurodegenerative disease, disorder, or condition, in certain embodiments, a biomarker is predictive, in certain embodiments, a biomarker is prognostic, and in certain embodiments, a biomarker is diagnostic. In certain embodiments, changes in biomarker levels can be detected by cerebrospinal fluid (CSF), plasma, and / or serum.

[0058] In certain embodiments, neurodegeneration can be evaluated, for example, by detecting an increase and / or decrease in the concentration of neurofilament light chain (NF-L) and / or neurofilament heavy chain (NF-H) (or its phosphorylated form (pNF-H)) contained in the cerebrospinal fluid of an object. In certain embodiments, the incidence and / or progression of neurodegeneration can be evaluated by positron emission tomography (PET) with respect to a synaptic vesicle glycoprotein 2a (SV2A) ligand. In certain embodiments, detectable changes in the constitutive NAD and / or cADPR levels in neurons can be used to evaluate neurodegeneration.

[0059] In certain embodiments, detectable changes in one or more neurodegeneration-related proteins in an object relative to a healthy reference population can be used as biomarkers of neurodegeneration. Such proteins include, but are not limited to, albumin, amyloid-β (Aβ) 38, Aβ40, Aβ42, glial fibrillary acidic protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractant protein (MCP)-1, neurogranin, neuron-specific enolase (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phosphorylated-tau protein (phospho-tau), and / or total-tau protein (total-tau). In certain embodiments, an increase in cytokines and / or chemokines including, but not limited to, Ccl2, Ccl7, Ccl12, Csf1, and / or Il6 can be used as a biomarker of neurodegeneration.

[0060] Vehicle: As used herein, the term "vehicle" refers to a diluent, adjuvant, excipient, or medium with which a composition is administered. In certain exemplary embodiments, the vehicle can include sterile liquids such as, for example, water and oils, including oils of petroleum, animal, vegetable, or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. In certain embodiments, the vehicle is or includes one or more solid components.

[0061] Combination Therapy: As used herein, the term "combination therapy" refers to those situations in which a subject is simultaneously exposed to two or more treatment regimens (e.g., two or more therapeutic agents). In certain embodiments, two or more regimens may be administered simultaneously; in certain embodiments, such regimens may be administered sequentially (e.g., all "doses" of a first regimen are administered before any dose of a second regimen); in certain embodiments, such agents are administered in an overlapping dosing regimen. In certain embodiments, "administration" of a combination therapy may involve administering one or more agents or modalities to a subject who has received other agents or modalities in the combination. For clarity, combination therapy does not require that the individual agents be administered together (or even simultaneously, if necessary) in a single composition, although in certain embodiments, two or more agents or their active moieties may be administered together in a combined composition or even in a combined compound (e.g., as part of a single chemical complex or covalent entity).

[0062] Composition: Those skilled in the art will understand that the term "composition" can be used to refer to a discrete physical entity that contains one or more specific components. Generally, unless otherwise indicated, a composition can be in any form - e.g., gas, gel, liquid, solid, etc.

[0063] Domain: As used herein, the term "domain" refers to a segment or portion of an entity. In certain embodiments, a "domain" is associated with specific structural and / or functional characteristics of the entity such that when the domain is physically separated from the remainder of its parent entity, it substantially or completely retains the specific structural and / or functional characteristics. Alternatively or additionally, a domain can be or include a portion of an entity that, when separated from the (parent) entity and attached to a different (recipient) entity, substantially retains and / or confers upon the recipient entity one or more structural and / or functional characteristics that characterize it in the parent entity. In certain embodiments, a domain is a segment or portion of a molecule (e.g., small molecule, carbohydrate, lipid, nucleic acid, or polypeptide). In certain embodiments, a domain is a portion of a polypeptide; in certain such embodiments, a domain is characterized by specific structural elements (e.g., specific amino acid sequence or sequence motif, α-helical character, β-sheet character, coiled-coil character, random coil character, etc.), and / or specific functional characteristics (e.g., binding activity, enzymatic activity, folding activity, signaling activity, etc.).

[0064] Dosage form or unit dosage form: Those skilled in the art will understand that the term "dosage form" can be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic agent or a diagnostic agent) for administration to a subject. Generally, each such unit contains a predetermined amount of the active agent. In certain embodiments, such an amount is a unit dose amount (or a whole part thereof) suitable for administration according to a dosing regimen, which amount has been determined to be associated with a desired or beneficial outcome when administered to the relevant population (i.e., for a therapeutic dosing regimen). Those of ordinary skill in the art understand that the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0065] Dosing regimen or treatment regimen: Those skilled in the art will understand that the terms "dosing regimen" and "treatment regimen" can be used to refer to a set of unit doses (usually more than one) administered separately to a subject, usually separated by a period of time. In certain embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In certain embodiments, the dosing regimen comprises multiple doses, where each dose is separated from the other doses in time. In certain embodiments, the individual doses are separated from each other by the same length of time period; in certain embodiments, the dosing regimen comprises multiple doses and at least two different time periods separating the individual doses. In certain embodiments, all the doses in the dosing regimen have the same unit dose amount. In certain embodiments, the different doses in the dosing regimen have different amounts. In certain embodiments, the dosing regimen comprises a first dose at a first dose amount, followed by one or more additional doses at a second dose amount different from the first dose amount. In certain embodiments, the dosing regimen comprises a first dose at a first dose amount, followed by one or more additional doses at a second dose amount the same as the first dose amount. In certain embodiments, when administered to the relevant population, the dosing regimen is associated with a desired or beneficial outcome (i.e., is a therapeutic dosing regimen).

[0066] Excipient: As used herein, refers to a non-therapeutic agent that can be included in a pharmaceutical composition, e.g., to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, ethylene glycol, water, ethanol, etc.

[0067] Heteroaryl: The terms "heteroaryl" and "heteroar-" as used alone or as part of a larger group (e.g., "heteroalkyl" or "heteroalkoxy") refer to groups having 5 to 10 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π-electrons shared in a cyclic array; and having one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of basic nitrogen. Heteroaryl includes, but is not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-" as used herein also include groups in which the heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 H -quinazinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of which includes an optionally substituted ring. The term "heteroalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl moieties are independently optionally substituted.

[0068] Heterocycle: The terms "heterocycle", "heterocyclic group", "heterocyclic radical", and "heterocyclic ring" as used herein are used interchangeably and refer to stable 3- to 8-membered monocyclic or 7- to 10-membered bicyclic heterocyclic groups that are saturated or partially unsaturated and have one or more heteroatoms such as one to four heteroatoms as defined above in addition to carbon atoms. When used with respect to the ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 - 3 heteroatoms selected from oxygen, sulfur, and nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR +(e.g., in an N-substituted pyrrolidinyl). The heterocycle can attach its side group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, 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 "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein the alkyl and heterocyclyl moieties are independently optionally substituted. Additionally, heterocycles also include groups in which the heterocycle is fused to one or more aryl rings (e.g., 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[b][1,4]dioxine, etc.).

[0069] Inhibitor: As used herein, the term "inhibitor" refers to an entity, condition, or event whose presence, level, or degree is associated with a reduced target level or activity. In certain embodiments, the inhibitor can act directly (in which case it directly exerts an effect on its target, e.g., by binding to the target); in certain embodiments, the inhibitor can act indirectly (in which case it exerts its effect by interacting with a regulator of the target and / or otherwise altering the regulator of the target, thereby reducing the level and / or activity of the target). In certain embodiments, the inhibitor is an agent whose presence or level is associated with a reduced target level or activity relative to a specific reference level or activity (e.g., the level or activity observed under appropriate reference conditions, such as the presence of a known inhibitor or the absence of the inhibitor being discussed, etc.).

[0070] Neurodegeneration: As used herein, the term "neurodegeneration" refers to a decrease in one or more characteristics, structures, functions, or properties of neurons or neuronal tissue. In certain embodiments, neurodegeneration is observed as a pathological decrease in an organism. One of ordinary skill in the art will understand that neurodegeneration is associated with certain diseases, disorders, and conditions, including those that affect humans. In certain embodiments, neurodegeneration can be transient (e.g., sometimes occurring in association with certain infections and / or chemical or mechanical disruptions); in certain embodiments, neurodegeneration can be chronic and / or progressive (e.g., often associated with certain diseases, disorders, or conditions such as, but not limited to, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, or Alzheimer's disease). In certain embodiments, neurodegeneration can be evaluated, for example, by detecting an increase in a biomarker associated with neurodegeneration in a subject. In certain embodiments, neurodegeneration can be evaluated, for example, by detecting a decrease in a biomarker associated with neurodegeneration in a subject. Alternatively or additionally, in certain embodiments, neurodegeneration can be evaluated by magnetic resonance imaging (MRI), a biomarker contained in cerebrospinal fluid, or other biomarkers observed in a patient. In certain embodiments, neurodegeneration is defined as a score below 24 on the Mini-Mental State Examination. In certain embodiments, neurodegeneration refers to the loss of synapses. In certain embodiments, neurodegeneration refers to a decrease in neural tissue associated with a traumatic injury (e.g., exposure to an external force that disrupts the integrity of neural tissue). In certain embodiments, neurodegeneration refers to a decrease in peripheral neural tissue. In certain embodiments, neurodegeneration refers to a decrease in central neural tissue.

[0071] Oral: As used herein, the phrases "administered orally" and "administered by mouth" have their understood meaning in the art and refer to the oral administration of a compound or composition.

[0072] Parenteral: As used herein, the phrases "administered parenterally" and "administered by parenteral means" have their understood meaning in the art and refer to a mode of administration other than enteral and topical administration that is typically by injection and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, trans-tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0073] Partially unsaturated: As used herein, the term "partially unsaturated" refers to a cyclic group that includes at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to include rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) groups as defined herein.

[0074] Patient: The term "patient" as used herein refers to any organism to which the provided composition is administered or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In certain embodiments, the patient is a human. In certain embodiments, the patient has or is susceptible to one or more disorders or conditions. In certain embodiments, the patient exhibits one or more symptoms of a disorder or condition. In certain embodiments, the patient has been diagnosed with one or more disorders or conditions. In certain embodiments, the patient is receiving or has received certain therapies for diagnosing and / or treating a disease, disorder, or condition.

[0075] Pharmaceutical composition: The term "pharmaceutical composition" as used herein refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In certain embodiments, the active agent is present in a unit dosage amount suitable for administration in a therapeutic or dosing regimen that, when administered to the relevant population, has a statistically significant probability of achieving a predetermined therapeutic effect. In certain embodiments, the pharmaceutical composition can be formulated specifically for administration in solid or liquid form, including those suitable for: oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or a sustained release formulation; topical application, e.g., as a cream, ointment, or controlled release patch or spray applied to the skin, lung, or mouth; vaginally or rectally, e.g., as a pessary, cream, or foam; sublingually; ophthalmically; transdermally; or nasally, pulmonary, and applied to other mucosal surfaces.

[0076] Pharmaceutically acceptable: The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0077] Pharmaceutically Acceptable Carrier: The term "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or a solvent encapsulating material that participates in the transport or conveyance of the subject compound from one organ or body part to another. Each carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and not harmful 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; diols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; pH buffering solutions; polyesters, polycarbonates, and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0078] Pharmaceutically Acceptable Salt: The term "pharmaceutically acceptable salt" as used herein refers to salts of such compounds that are suitable for use in a pharmaceutical environment, i.e., salts that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals, without undue toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. in J . Pharmaceutical Sciences, pharmaceutically acceptable salts are described in detail in 66:1-19 (1977). In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts formed by reacting an amino group with an acid such as an inorganic acid like hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or an organic acid such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods employed in the art (such as ion exchange). In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, glucuronates, hemi-sulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. In certain embodiments, pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide ions, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having 1-6 carbon atoms, sulfonate, and arylsulfonate.

[0079] Prevention: When used in connection with the occurrence of a disease, disorder, and / or condition, the term "prevention" as used herein refers to reducing the risk of developing a disease, disorder, and / or condition and / or delaying the onset of one or more characteristics or symptoms of a disease, disorder, or condition. Prevention can be considered complete when the onset of a disease, disorder, or condition has been delayed for a predetermined period of time.

[0080] Specific: When used herein with reference to an active agent, the term "specific" is understood by those skilled in the art to mean that the agent distinguishes between potential target entities or states. For example, in certain embodiments, if an agent preferentially binds to its target in the presence of one or more competing alternative targets, the agent is said to "specifically" bind to the target. In many embodiments, specific interactions depend on the presence of specific structural features (e.g., epitopes, clefts, binding sites) of the target entity. It should be understood that specificity does not need to be absolute. In certain embodiments, specificity can be evaluated relative to the specificity of the binding agent for one or more other potential target entities (e.g., competitors). In certain embodiments, specificity is evaluated relative to the specificity of a reference specific binding agent. In certain embodiments, specificity is evaluated relative to the specificity of a reference nonspecific binding agent. In certain embodiments, the agent or entity will not detectably bind to a competitive alternative target under conditions of binding to its target entity. In certain embodiments, a binding agent binds to its target entity with a higher on-rate, lower off-rate, increased affinity, reduced dissociation, and / or increased stability compared to a competing alternative target.

[0081] Subject: The term "subject" as used herein refers to an organism, typically a mammal (e.g., a human, including prenatal human forms in certain embodiments). In certain embodiments, the subject is suffering from the disease, disorder, or condition of interest. In certain embodiments, the subject is susceptible to the disease, disorder, or condition. In certain embodiments, the subject exhibits one or more symptoms or characteristics of the disease, disorder, or condition. In certain embodiments, the subject does not exhibit any symptoms or characteristics of the disease, disorder, or condition. In certain embodiments, the subject is a person with one or more characteristics specific to a susceptibility or risk for a disease, disorder, or condition. In certain embodiments, the subject is a patient. In certain embodiments, the subject is an individual to whom a diagnosis and / or therapy is administered and / or has been administered.

[0082] Substituted or optionally substituted: As described herein, the compounds of the invention may contain "optionally substituted" groups. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogen atoms of the designated group are replaced with a suitable substituent. "Substituted" applies to one or more hydrogen atoms that are explicitly or implicitly replaced by the structure (e.g., At least ;and At least , or )。Unless otherwise specified, an "optionally substituted" group may have appropriate substituents at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified set, the substituents at each position may be the same or different. Combinations of substituents contemplated by the present invention are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that permit its production, detection, and in some embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0083] Suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group are independently: halogen; -(CH2) 0-4 R ○ ; -(CH2) 0-4 OR ○ ; -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR ○ ; -(CH2) 0-4 CH(OR ○ )2; -(CH2) 0-4 SR ○ ; -(CH2) 0-4 Ph, which may be substituted by R ○ ; -(CH2) 0-4 O(CH2) 0-1 Ph, which may be substituted by R ○ ; -CH=CHPh, which may be substituted by R ○ ; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be substituted by R ○ ; -NO2; -CN; -N3; -(CH2) 0-4 N(R ○ )2; -(CH2) 0-4 N(R ○ )C(O)R ○ ; -N(R ○ )C(S)R ○ ; -(CH2) 0-4 N(R ○ )C(O)NR ○ 2; -N(R ○ )C(S)NR ○ 2; -(CH2) 0-4 N(R ○ )C(O)OR ○; -N(R ○ )N(R ○ )C(O)R ○ ; -N(R ○ )N(R ○ )C(O)NR ○ 2; -N(R ○ )N(R ○ )C(O)OR ○ ; -(CH2) 0-4 C(O)R ○ ; -C(S)R ○ ; -(CH2) 0-4 C(O)OR ○ ; -(CH2) 0-4 C(O)SR ○ ; -(CH2) 0-4 C(O)OSiR ○ 3; -(CH2) 0-4 OC(O)R ○ ; -OC(O)(CH2) 0-4 SR ○ ; -(CH2) 0-4 SC(O)R ○ ; -(CH2) 0-4 C(O)NR ○ 2; -C(S)NR ○ 2; -C(S)SR ○ ; -SC(S)SR ○ 、-(CH2) 0-4 OC(O)NR ○ 2; -C(O)N(OR ○ )R ○ ; -C(O)C(O)R ○ ; -C(O)CH2C(O)R ○ ; -C(NOR ○ )R ○ ; -(CH2) 0-4 SSR ○ ; -(CH2) 0-4 S(O)2R ○ ; -(CH2) 0-4 S(O)(NH)R ○ ; -(CH2) 0-4 S(O)2OR ○ ; -(CH2) 0-4 OS(O)2R ○ ; -S(O)2NR ○ 2; -(CH2) 0-4 S(O)R ○ ; -N(R○ )S(O)2NR ○ 2; -N(R ○ )S(O)2R ○ ; -N(OR ○ )R ○ ; -C(NH)NR ○ 2; -P(O)2R ○ ; -P(O)R ○ 2; -OP(O)R ○ 2; -OP(O)(OR ○ )2; SiR ○ 3; -(C 1-4 linear or branched alkylene)O-N(R ○ )2; or -(C 1-4 linear or branched alkylene)C(O)O-N(R ○ )2, where each R ○ may be substituted as defined below and is independently: hydrogen, C 1-6 aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5- to 6-membered heteroaryl ring), 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 definition, but R ○ in two independent occurrences together with their inserted atoms forms a 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 - 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0084] In R ○ (or in the ring formed by combining two independent occurrences of R ○ with their inserted atoms), suitable monovalent substituents are independently halogen, -(CH2) 0-2 R ● , -(haloalkyl R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -O(haloalkyl R ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ●, -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR ● , -(C 1-4 linear or branched alkylene)C(O)OR ● or -SSR ● , where each R ● is unsubstituted or, in the case of being preceded by "halo-", is substituted by one or more halogens only, and is independently selected from C 1-4 aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on the saturated carbon atoms of R ○ include =O and =S.

[0085] Suitable divalent substituents on the saturated carbon atoms of "optionally substituted" groups include the following: =O ("oxo"), =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 S-, where each independent occurrence of R * is selected from: hydrogen, a C 1-6 aliphatic group which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on the vicinal displaceable carbon atoms bonded to the "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independent occurrence of R * is selected from: hydrogen, a C 1-6An aliphatic group, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0086] Suitable substituents on the aliphatic group of R * include halogen, -R ● , -(haloalkylR ● ), -OH, -OR ● , -O(haloalkylR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2 or -NO2, where each R ● is unsubstituted or, in the case where it is preceded by "halo", is substituted only by one or more halogens and is independently a C 1-4 aliphatic group, -CH2Ph, -O(CH2) 0- 1Ph or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0087] Suitable substituents on the replaceable 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 † ; where each R † is independently: hydrogen, a C 1-6 aliphatic group that can be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independently occurring R † together with their intervening atoms form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0088] Suitable substituents on the aliphatic group of R † are independently halogen, -R● 、 -(haloR ● ), -OH, -OR ● 、 -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● 、 -NH2, -NHR ● 、 -NR ● 2 or -NO2, where each R ● is unsubstituted or, in the case of being preceded by "halo", is substituted by one or more halogens only, and independently is C 1-4 aliphatic group, -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.

[0089] Therapeutic agent: The phrase "therapeutic agent" as used herein generally refers to any agent that elicits a desired pharmacological effect when administered to a living organism. In certain embodiments, an agent is considered a therapeutic agent if it shows a statistically significant effect in an appropriate population. In certain embodiments, the appropriate population can be a population of model organisms. In certain embodiments, the appropriate population can be defined by various criteria, such as a certain age group, gender, genetic background, pre-existing clinical condition, etc. In certain embodiments, a therapeutic agent is a substance that can be used to alleviate, improve, relieve, inhibit, prevent one or more symptoms or characteristics of a disease, disorder and / or condition, delay its onset, reduce its severity and / or reduce its incidence. In certain embodiments, a "therapeutic agent" is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans. In certain embodiments, a "therapeutic agent" is an agent that requires a medical prescription for administration to a human.

[0090] Treatment: The term "treatment" as used herein refers to any method used to partially or completely alleviate, improve, relieve, 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. Treatment can be administered to an object that does not exhibit the signs of a disease, disorder and / or condition. In certain embodiments, treatment can be administered to an object that exhibits only early signs of a disease, disorder and / or condition, for example, for the purpose of reducing the risk of developing a pathology associated with the disease, disorder and / or condition.

[0091] In addition, unless otherwise indicated, in certain embodiments, the structures described herein also include compounds that differ only in the presence of one or more isotopically enriched or isotopically labeled atoms. Isotopically labeled compounds can have one or more atoms replaced by atoms having an atomic mass or mass number that is normally found in nature. Examples of isotopes present in the compounds of Formula I or I' and the subgenera described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, and 18 F. Certain isotopically labeled compounds of Formula I or I' and the subgenera described herein can be used in addition to being used as therapeutic agents for drug and / or substrate tissue distribution assays, as analytical tools, or as probes in other biological assays. In one aspect of the invention, tritiated (e.g., 3 H) and carbon-14 (e.g., 14 C) isotopes are useful because they are readily detectable. In another aspect of the invention, replacing one or more hydrogen atoms with a heavier isotope such as deuterium (e.g., 2 H) can provide certain therapeutic benefits.

[0092] Detailed description of certain embodiments

[0093] Programmed axonal degeneration and SARM1

[0094] Axonal degeneration is a major pathological feature of neurological diseases such as, but not limited to, Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis, diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, hereditary neuropathy, traumatic brain injury, and / or glaucoma. Damaged or unhealthy axons are eliminated through an intrinsic self-destruction program that is different from traditional cell death pathways such as apoptosis, known as Wallerian degeneration (Gerdts, J., et al., Neuron , 2016, 89, 449-460; Whitmore, A.V. et al., Cell Death Differ, 2003, 10,260 - 261). In Wallerian degeneration, the axonal segments of the peripheral nerve distal to the injury are selectively degraded, while the proximal axonal segments and the cell body remain intact. The characteristics of this degeneration are first the depletion of nicotinamide mononucleotide adenylyltransferase (NMNAT), followed by the loss of nicotinamide adenine dinucleotide (NAD+), the loss of adenosine triphosphate (ATP), the proteolysis of neurofilaments, and finally the axonal degradation approximately 8 to 24 hours after injury (Gerdts, J., et al., Neuron, 2016, 89, 449 - 460).

[0095] NAD+ is a ubiquitous metabolite that plays a key role in energy metabolism and cell signaling (Belenkey et al., Trends Biochem , 2007, 32, 12 - 19; Chiarugi et al., Nat. Rev. Cancer , 2012, 12, 741 - 752). The homeostatic regulation of NAD+ levels is also responsible for maintaining axonal stability and integrity. Therefore, manipulations that increase the axonal localization of NMNAT1 confer axonal protection (Babetto et al., Cell Rep., 2010, 3, 1422 - 1429; Sasaki et al., J. Neurosci , 2009).

[0096] In a genome-wide RNAi screen of primary mouse neurons, sterile alpha and TIR motif-containing 1 (SARM1) was identified, and the knockdown of SARM1 resulted in long-term protection of sensory neurons against injury-induced axonal degeneration (Gerdts et al., J Neurosci , 2013, 33, 13569 - 13580). SARM1 belongs to the family of cytosolic adaptor proteins but is unique among its members in that it is the most evolutionarily ancient adaptor, paradoxically inhibiting TLR signaling and has been identified as the central executioner of the injury-induced axonal death pathway (O'Neill, L.A. & Bowie, A.G., Nat . Rev . Immunol , 2007, 7, 353 - 364; Osterloh, J.M., et al., Science , 2012, 337,481 - 484; Gerdts, J., et al., J . Neurosci. 33, 2013, 13569-13580). Activation of SARM1 by axonal injury or forced dimerization of the SARM1-TIR domain promotes rapid and catastrophic depletion of nicotinamide adenine dinucleotide (NAD+), followed soon after by axonal degradation, thus highlighting the central role of NAD+ homeostasis in axonal integrity (Gerdts, J., et al., Science , 2015, 348, 453-457). In vitro and in vivo, this injury-induced NAD+ depletion requires SARM1, and SARM1 activation locally triggers axonal degeneration through NAD(+) breakdown (Gerdts et al., Science, 2015 348, 452-457; Sasaki et al., J . Biol . Chem .2015, 290, 17228-17238; both of which are hereby incorporated by reference in their entirety).

[0097] It is clear from genetic loss-of-function studies that SARM1 acts as a central executor of the axonal degeneration pathway after injury. Gene knockout of SARM1 allows axons to be preserved for 14 days or longer after nerve transection (Osterloh, J.M., et al., Science , 2012, 337, 481-484; Gerdts, J., et al. J. Neurosci , 2013, 33, 13569-13580), and also improves the functional outcome in mice after traumatic brain injury (Henninger, N. et al., Brain 139, 2016, 1094-1105). In addition to its role in direct axonal injury, SARM1 is also required for the axonal degeneration observed in chemotherapy-induced peripheral neuropathy. Loss of SARM1 blocks chemotherapy-induced peripheral neuropathy, inhibiting both axonal degeneration and the enhanced pain sensitivity that appears after treatment with the chemotherapy vincristine (Geisler et al., Brain , 2016, 139, 3092-3108).

[0098] SARM1 contains multiple conserved motifs, including an SAM domain, an ARM / HEAT motif, and a TIR domain ( Figure 1 ), which mediate oligomerization and protein-protein interactions (O'Neill, L.A.&Bowie, A.G., Nat. Rev. Immunol ,2007, 7, 353-364; Tewari, R., et al., Trends Cell Biol, 2010, 20, 470 - 481; Qiao, F. & Bowie, J.U., Sci. STKE 2005, re7, 2005). The TIR domain is typically present in signaling proteins that function in the innate immune pathway, where it acts as a scaffold for protein complexes (O'Neill, L.A. & Bowie, A.G., Nat . Rev . Immunol ., 2007, 7, 353 - 364). Intriguingly, dimerization of the SARM1 - TIR domain is sufficient to induce axonal degeneration and rapidly trigger the degradation of NAD+ by acting as a NAD+ lyase (Milbrandt et al., WO 2018 / 057989; Gerdts, J., et al., Science , 2015, 348, 453 - 457). Given the central role of SARM1 in the axonal degeneration pathway and its identified NADase activity, efforts have been made to identify agents that can modulate SARM1 and may act as useful therapeutic agents, e.g., to guard against neurodegenerative diseases, including peripheral neuropathy, traumatic brain injury, and / or neurodegenerative disorders.

[0099] Among other things, the present disclosure provides certain compounds and / or compositions that act as SARM1 inhibitors (e.g., as SARM1 inhibitors) and related technologies.

[0100] Compound

[0101] In certain embodiments, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0102]

[0103] Wherein:

[0104] Ring A is a 5 - to 6 - membered heteroaryl ring having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0105] R 1 is an optionally substituted group selected from: a 3 - to 7 - membered saturated or partially unsaturated heterocycle having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 5 - to 6 - membered heteroaryl ring having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0106] Each R x is independently selected from halogen, cyano, OR, SR, N(R)2, or an optionally substituted group selected from: C 1-4An aliphatic group, a 3- to 7-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl group, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0107] L is optionally substituted C 1-4 aliphatic chain, wherein one or two carbon atoms in said aliphatic chain are optionally replaced independently by a group selected from: -O-, -N(R)-, -S-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocycle;

[0108] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 an aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl group, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; or:

[0109] Two R groups together with the nitrogen atom to which they are attached form an optionally substituted 3- to 7-membered monocyclic heterocycle having 0 to 2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0110] R 2 is hydrogen, halogen, N(R)2, OR, or an optionally substituted group selected from: C 1-6 an aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl group, a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8- to 10-membered bicyclic saturated, partially unsaturated, or aryl carbocycle, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; and

[0111] n is 0, 1, or 2.

[0112] In certain embodiments, the present disclosure provides a compound of formula I' or a pharmaceutically acceptable salt thereof:

[0113]

[0114] Wherein:

[0115] Ring A is a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0116] R 1 is an optionally substituted group selected from: a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0117] Each R x is independently selected from halogen, cyano, OR, SR, N(R)2, S(O)2N(R)2, C(O)OR, C(O)N(R)2, or an optionally substituted group selected from: C 1-4 aliphatic group, 3- to 7-membered saturated or partially unsaturated carbocycle, 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0118] L is an optionally substituted C 1-4 aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced independently by a group selected from: -O-, -N(R)-, -S-, -S(O)2-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocycle;

[0119] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic group, 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; or:

[0120] Two R groups together with the nitrogen atom to which they are attached form an optionally substituted 3- to 7-membered monocyclic heterocycle having 0 to 2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0121] R 2 is hydrogen, halogen, N(R)2, OR, or an optionally substituted group selected from: C 1-6An aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl group, a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8- to 10-membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; and

[0122] n is 0, 1, or 2.

[0123] As generally defined above, ring A is a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, ring A is a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, ring A is pyrrolyl, furyl, or thienyl. In certain embodiments, ring A is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, ring A is a group selected from pyrazolyl, imidazolyl, isothiazolyl, and thiazolyl.

[0124] In certain embodiments, ring A is a 5-membered heteroaryl ring having 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain such embodiments, ring A is a group selected from triazolyl and thiadiazolyl.

[0125] In certain embodiments, ring A is a 6-membered heteroaryl ring having 1 to 2 nitrogen atoms. In certain embodiments, ring A is pyridyl. In certain embodiments, ring A is pyridine-2(1 H )-one group.

[0126] In certain embodiments, ring A is selected from

[0127]

[0128]

[0129]

[0130]

[0131] .

[0132] In certain embodiments, ring A is selected from

[0133]

[0134] wherein R x is an optionally substituted group selected from C1-4 aliphatic groups, 3- to 7-membered saturated or partially unsaturated carbocyclic rings, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, phenyl, and 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0135] In certain embodiments, Ring A is selected from

[0136] .

[0137] In certain embodiments, Ring A is selected from

[0138]

[0139] in:

[0140] R on nitrogen atom x is selected from an optionally substituted group selected from C 1-4 aliphatic groups, 3- to 7-membered saturated or partially unsaturated carbocyclic rings, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, phenyl, and 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur; and

[0141] R on the carbon atom x is selected from halogen, cyano, OR, SR, N(R)2 or an optionally substituted group selected from: C 1-4 aliphatic groups, 3- to 7-membered saturated or partially unsaturated carbocyclic rings, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, phenyl, and 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0142] In certain embodiments, Ring A is selected from , , , , , , , and .

[0143] In certain embodiments, Ring A is selected from and .

[0144] In certain particularly preferred embodiments, Ring A is selected from and .

[0145] In certain embodiments, Ring A is selected from and .

[0146] As generally defined above, R 1 is an optionally substituted group selected from: a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0147] In certain embodiments, R 1 is an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 1 is an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 1 is an optionally substituted group selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.

[0148] In certain embodiments, R 1 is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0149] In certain embodiments, R 1 is an optionally substituted 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 1 is an optionally substituted 5-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 1 is an optionally substituted group selected from pyrazolyl, thiazolyl, and thiophenyl rings. In certain embodiments, R 1 is an optionally substituted group selected from imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, and thiophenyl rings.

[0150] In certain embodiments, R 1 is an optionally substituted 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In certain embodiments, R 1 is an optionally substituted 6-membered heteroaryl ring having 1 to 2 nitrogen atoms. In certain embodiments, R 1 is an optionally substituted group selected from pyridinyl, pyrimidinyl, and pyridazinyl.

[0151] In certain embodiments, R 1 is selected from

[0152]

[0153] 。

[0154] In certain embodiments, R 1 is selected from

[0155] 。

[0156] In certain particularly preferred embodiments, R 1 is selected from and 。

[0157] As generally defined above for formula I, each R x is independently selected from halogen, cyano, OR, SR, N(R)2 or an optionally substituted group selected from: C 1-4 aliphatic groups, 3- to 7-membered saturated or partially unsaturated carbocycles, 3- to 7-membered saturated or partially unsaturated heterocycles having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. As generally defined above for formula I', each R x is independently selected from halogen, cyano, OR, SR, N(R)2, S(O)2N(R)2, C(O)OR, C(O)N(R)2 or an optionally substituted group selected from: C 1-4 aliphatic groups, 3- to 7-membered saturated or partially unsaturated carbocycles, 3- to 7-membered saturated or partially unsaturated heterocycles having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0158] In certain embodiments of formula I or formula I', R x is halogen. In certain such embodiments, R x is chlorine or bromine. In certain embodiments of formula I or formula I', R x is fluorine.

[0159] In certain embodiments of formula I or formula I', R x is cyano.

[0160] In certain embodiments of formula I or formula I', R x is OR. In certain embodiments of formula I or formula I', R x is OR, where R is selected from hydrogen and an optionally substituted C 1-6 aliphatic group. In certain embodiments of formula I or formula I', R xis OR, where R is selected from hydrogen and optionally substituted C 1-4 aliphatic groups. In certain embodiments of Formula I or Formula I', R x is selected from OH, OCH3, and OCH2CH3.

[0161] In certain embodiments of Formula I or Formula I', R x is SR. In certain embodiments of Formula I or Formula I', R x is SR, where R is selected from hydrogen and optionally substituted C 1-6 aliphatic groups. In certain embodiments of Formula I or Formula I', R x is SR, where R is selected from hydrogen and optionally substituted C 1-4 aliphatic groups. In certain embodiments of Formula I or Formula I', R x is selected from SH, SCH3, and SCH2CH3.

[0162] In certain embodiments of Formula I or Formula I', R x is N(R)2. In certain embodiments of Formula I or Formula I', R x is N(R)2, where R is selected from hydrogen and optionally substituted C 1-6 aliphatic groups. In certain embodiments of Formula I or Formula I', R x is N(R)2, where R is selected from hydrogen and optionally substituted C 1-4 aliphatic groups. In certain embodiments of Formula I or Formula I', R x is selected from NH2, NHCH3, NHCH2CH3, N(CH3)2, and N(CH2CH3)2.

[0163] In certain embodiments of Formula I or Formula I', R x is optionally substituted C 1-4 aliphatic groups. In certain embodiments of Formula I or Formula I', R x is CH3, CD3, or CH2CH3. In certain embodiments of Formula I or Formula I', R x is optionally substituted C 3-4 aliphatic groups. In certain such embodiments, R x is selected from tert-butyl, , and . In certain embodiments of Formula I or Formula I', R x is .

[0164] In certain embodiments of Formula I or Formula I', R x is C optionally substituted with a group selected from the following 1-4Aliphatic groups: halogen, -(CH2) 0-4 R ○ 、-(CH2) 0-4 OR ○ 、-(CH2) 0-4 N(R ○ )2, -(CH2) 0-4 C(O)OR ○ and -(CH2) 0-4 C(O)NR ○ 2. In certain such embodiments, R ○ Selected from hydrogen, C 1-6 Aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5- to 6-membered heteroaryl ring), a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8- to 10-membered bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or: two independent occurrences of R ○ Together with their intervening atoms they form a 3- to 12-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0165] In certain embodiments of Formula I or Formula I', R x is C optionally substituted by a group selected from the following 1-4 Aliphatic groups: halogen, -R ○ 、-OR ○ 、-N(R ○ )2. -C(O)OR ○ and -C(O)NR ○ 2. In certain embodiments of Formula I or Formula I', R x is C optionally substituted by halogen 1-4 In certain such embodiments, R x In certain embodiments of Formula I or Formula I', R x Selected from -CH3, -CD3, -CF3, -CHF2 and CH2F.

[0166] In certain embodiments of Formula I or Formula I', R x Selected from -CH2R ○ 、-CH2OR ○ 、-CH2N(R ○ )2, -CH2C(O)OR ○ and -CH2C(O)N(R ○ ) 2. In certain such embodiments, R xSelected from -CH2OH, -CH2OCH3, -CH2C(O)NH2, -CH2C(O)NHCH3, and -CH2C(O)N(CH3)2. In certain embodiments of Formula I or Formula I', R x is CH2C(O)OR ○ . In certain such embodiments, R x is CO2CH3 or CO2CH2CH3.

[0167] In certain embodiments of Formula I or Formula I', R x is a C 1-4 aliphatic group optionally substituted with a group selected from: halogen, -R ○ , -OR ○ , -N(R ○ )2, -C(O)OR ○ and -C(O)NR ○ 2.

[0168] In certain embodiments of Formula I', R x is selected from S(O)2N(R)2, C(O)OR, and C(O)N(R)2. In certain embodiments of Formula I', R x is S(O)2N(R)2. In certain such embodiments, R is hydrogen. In certain embodiments of Formula I', R x is SO2NH2. In certain embodiments of Formula I', R x is C(O)OR. In certain such embodiments, R is selected from hydrogen, CH3, and CH2CH3. In certain embodiments of Formula I', R x is C(O)OCH2CH3. In certain embodiments of Formula I', R x is C(O)N(R)2. In certain such embodiments, R is hydrogen or CH3. In certain embodiments of I', R x is C(O)NH2 or R x is C(O)N(CH3)2. In certain embodiments of Formula I or Formula I', R x is an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocycle. In certain embodiments of Formula I or Formula I', R x is an optionally substituted 5- to 7-membered saturated or partially unsaturated carbocycle. In certain embodiments of Formula I or Formula I', R x is an optionally substituted 5- to 7-membered saturated carbocycle. In certain such embodiments, R x is selected from an optionally substituted cyclopentyl or cyclohexyl.

[0169] In certain embodiments of Formula I or Formula I', R xis an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments of Formula I or Formula I’, R x is an optionally substituted 3- to 4-membered saturated heterocycle having 1 heteroatom selected from oxygen, nitrogen, and sulfur. In certain embodiments of Formula I or Formula I’, R x is an optionally substituted 5- to 7-membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments of Formula I or Formula I’, R x is an optionally substituted 5- to 7-membered saturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain such embodiments, R x is selected from optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.

[0170] In certain embodiments of Formula I or Formula I’, R x is an optionally substituted phenyl.

[0171] In certain embodiments of Formula I or Formula I’, R x is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments of Formula I or Formula I’, R x is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments of Formula I or Formula I’, R x is an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain such embodiments, R x is selected from optionally substituted pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, and thiazolyl.

[0172] In certain embodiments of Formula I or Formula I’, R x is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogen atoms. In certain embodiments of Formula I or Formula I’, R x is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. In certain such embodiments, R x is selected from optionally substituted pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0173] As generally defined above for Formula I, L is optionally substituted C 1-4An aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally independently replaced by a group selected from: -O-, -N(R)-, -S-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle.

[0174] As generally defined above for formula I', L is optionally substituted C 1-4 An aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally independently replaced by a group selected from: -O-, -N(R)-, -S-, -S(O)2-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2- and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle.

[0175] In certain embodiments of formula I or formula I', L is optionally substituted C 1-2 An aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally independently replaced by a group selected from: -O-, -N(R)-, -S-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle. In certain embodiments of formula I or formula I', L is optionally substituted C 1-2 An aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally independently replaced by a group selected from: -O-, -N(R)-, -S-, -C(O)- and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle. In certain embodiments of formula I or formula I', L is optionally substituted C 1-2 An aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally independently replaced by a group selected from: -O-, -N(H)-, -S-, -C(O)- and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle.

[0176] In certain embodiments of formula I or formula I', L is optionally substituted C 3-4An aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally independently replaced by a group selected from: -O-, -N(R)-, -S-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle. In certain embodiments of Formula I or Formula I', L is optionally substituted C 3-4 An aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally independently replaced by a group selected from: -O-, -N(R)-, -S-, -C(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle. In certain embodiments of Formula I or Formula I', L is optionally substituted C 3-4 An aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally independently replaced by a group selected from: -O-, -N(H)-, -S-, -C(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle.

[0177] In certain embodiments of Formula I or Formula I', L is optionally substituted C 1-4 An aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)-, and one additional carbon atom is optionally replaced by a group selected from -O-, -N(R)-, -S-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle.

[0178] In certain embodiments of Formula I or Formula I', L is optionally substituted C 1-4 An aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)-, and one additional carbon atom is optionally replaced by a group selected from: -O-, -N(R)-, -S-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle. In certain embodiments of Formula I or Formula I', L is optionally substituted C 1-4 An aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)-, and one additional carbon atom is optionally replaced by a group selected from: -O-, -N(H)-, -S-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle.

[0179] In certain embodiments of Formula I or Formula I', L is optionally substituted C 3-4an aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by -C(O)-, and an additional carbon atom is optionally replaced by a group selected from -O-, -N(R)-, -S-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring. In certain embodiments of Formula I or Formula I', L is an optionally substituted C 3-4 An aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by -C(O)-, and an additional carbon atom is optionally replaced by a group selected from the group consisting of -O-, -N(H)-, -S-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocyclic ring.

[0180] In certain embodiments of Formula I or Formula I', L is selected from

[0181]

[0182] .

[0183] In certain embodiments of Formula I', L is selected from

[0184] .

[0185] In certain particularly preferred embodiments of Formula I or Formula I', L is selected from and In certain particularly preferred embodiments of Formula I or Formula I', L is selected from , and .

[0186] As generally defined above, each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic groups, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, phenyl, and 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur; or two R groups together with the nitrogen atom to which they are attached form an optionally substituted 3- to 7-membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from oxygen, nitrogen and sulfur. In certain embodiments, R is hydrogen. In certain embodiments, R is an optionally substituted group selected from C 1-6 an aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, a phenyl group, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur; or two R groups together with the nitrogen atom to which they are attached form an optionally substituted 3- to 7-membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0187] In certain embodiments, R is an optionally substituted C 1-6 aliphatic group. In certain embodiments, R is an optionally oxo- and OR ○ substituted C 1-6 aliphatic group, wherein R ○ is a C 1-6 aliphatic group. In certain such embodiments, R is -C(O)OtBu.

[0188] In certain embodiments, R is a C 1-6 aliphatic group. In certain such embodiments, R is methyl or ethyl.

[0189] In certain embodiments, R is selected from hydrogen and an optionally substituted C 1-6 aliphatic group. In certain such embodiments, R is selected from hydrogen, methyl or ethyl.

[0190] As generally defined above, R 2 is hydrogen, halogen, N(R)2, OR or an optionally substituted group selected from: C 1-6 aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, phenyl, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, an 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0191] In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is halogen, N(R)2, OR or an optionally substituted group selected from: C 1-6 aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, phenyl, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, an 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0192] In certain embodiments, R 2 is halogen. In certain embodiments, R 2is N(R)2. In certain such embodiments, R 2 is NH2. In certain embodiments, R 2 is OR. In certain such embodiments, R 2 is OH.

[0193] In certain embodiments, R 2 is an optionally substituted C 1-6 aliphatic group. In certain such embodiments, R 2 is an optionally substituted group selected from cyclopentyl or cyclohexyl. In certain embodiments, R 2 is C 1-6 aliphatic group. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is ethyl. In certain embodiments, R 2 is tert-butyl. In certain embodiments, R 2 is neopentyl (i.e., 2,2-dimethylpropyl). In certain embodiments, R 2 is cyclohexyl.

[0194] In certain embodiments, R 2 is an optionally substituted phenyl.

[0195] In certain embodiments, R 2 is an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 2 is an optionally substituted 3-membered saturated heterocycle having 1 heteroatom selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 2 is an optionally substituted 4-membered saturated heterocycle having 1 heteroatom selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 2 is an optionally substituted 5-membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 2 is an optionally substituted 6-membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 2 is an optionally substituted group selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.

[0196] In certain embodiments, R 2 is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 2is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 2 is an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain such embodiments, R 2 is an optionally substituted group selected from thienyl, pyrazolyl, and imidazolyl.

[0197] In certain embodiments, R 2 is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogen atoms. In certain embodiments, R 2 is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. In certain such embodiments, R 2 is an optionally substituted group selected from pyridyl or pyrimidinyl.

[0198] In certain embodiments, R 2 is an optionally substituted 8- to 10-membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring. In certain embodiments, R 2 is an optionally substituted 9-membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring. In certain such embodiments, R 2 is an optionally substituted 2,3-dihydro-1H-indenyl. In certain embodiments, R 2 is an optionally substituted 10-membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring. In certain such embodiments, R 2 is an optionally substituted group selected from 1,2,3,4-tetrahydronaphthyl and naphthyl.

[0199] In certain embodiments, R 2 is an optionally substituted 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 2 is an optionally substituted 9-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 2 is an optionally substituted 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain such embodiments, R 2 is an optionally substituted group selected from chromanyl, isochromanyl, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, and 2H-benzo[b][1,4]oxazin-3(4H)-one.

[0200] In certain embodiments, R2 is an optionally substituted 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, R 2 is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain such embodiments, R 2 is an optionally substituted group selected from indolyl, benzopyrazolyl, benzimidazolyl, and imidazo[1,2-a]pyridinyl.

[0201] In certain embodiments, R 2 is selected from:

[0202]

[0203]

[0204]

[0205]

[0206] .

[0207] In certain embodiments, R 2 is selected from:

[0208]

[0209] .

[0210] In certain particularly preferred embodiments, R 2 is selected from , and . In certain embodiments, R 2 is selected from , , , , and .

[0211] In certain embodiments of Formula I or Formula I', L is . Thus, in certain embodiments, the present disclosure provides a compound of Formula I-a or a pharmaceutically acceptable salt thereof:

[0212]

[0213] wherein ring A, R x , R 1 , R 2Each of 、R and n is as defined above and as described herein.

[0214] In certain embodiments of Formula I or Formula I', L is . Thus, in certain embodiments, the present disclosure provides a compound of Formula I-b or a pharmaceutically acceptable salt thereof:

[0215]

[0216] wherein ring A, R x 、R 1 、R 2 、R and n are each as defined above and as described herein.

[0217] In certain embodiments of Formula I or Formula I', R 1 is . Thus, in certain embodiments, the present disclosure provides a compound of Formula I-c or a pharmaceutically acceptable salt thereof:

[0218]

[0219] wherein ring A, R x 、L、R 2 、R and n are each as defined above and as described herein.

[0220] In certain embodiments of Formula I or Formula I', R 1 is . Thus, in certain embodiments, the present disclosure provides a compound of Formula I-d or a pharmaceutically acceptable salt thereof:

[0221]

[0222] wherein ring A, R x 、L、R 2 、R and n are each as defined above and as described herein.

[0223] In certain embodiments of Formula I or Formula I', ring A is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. Thus, in certain embodiments, the present disclosure provides a compound of Formula I-e, I-f, I-g, I-h, I-i, I-j, I-k, I-l, I-m, I-n, or I-o or a pharmaceutically acceptable salt thereof:

[0224]

[0225]

[0226] wherein L, R 1 、R2 Each of R and in R is as defined above and as described herein.

[0227] In certain embodiments of Formula I or Formula I’, L is Accordingly, in certain embodiments, the present disclosure provides a compound of Formula I-p or a pharmaceutically acceptable salt thereof:

[0228]

[0229] wherein each of ring A, R x , R 1 , R 2 , R and n is as defined above and as described herein.

[0230] In certain embodiments, the present disclosure provides a compound of the following formula or a pharmaceutically acceptable salt thereof

[0231]

[0232] wherein each of R x , R 1 , R 2 and R is as defined above and as described herein.

[0233] In certain embodiments, the present disclosure provides compounds of Formula I-a- i , I-b- i , I-c- i , I-d- i , I-e- i , I-f- i , I-g- i , I-h- i , I-i- i , I-j- i , I-k- i , I-l- i , I-m- i , I-n- i , I-o- i , I-p- i or I-p- ii or a pharmaceutically acceptable salt thereof:

[0234]

[0235]

[0236]

[0237] wherein ring A, R x , L, R 1 , R2 Each of Rand n is as defined above and as described herein.

[0238] In certain embodiments, the present disclosure provides a compound of Formula I-q or I-q- i or a pharmaceutically acceptable salt thereof:

[0239]

[0240] wherein R 1 , R 2 and R each is as defined above and as described herein.

[0241] In certain embodiments of any one of Formulae I, I-b, I-b- i , I-c or I-c- i , ring A is not .

[0242] In certain embodiments of any one of Formulae I, I-b or I-b- i , ring A is not or .

[0243] In certain embodiments of Formula I-e or Formula I-e- i , L is not .

[0244] In certain embodiments of Formula I-h or Formula I-h- i , L is not .

[0245] In certain embodiments of any one of Formulae I, I-b, I-e, I-e- i , I-h or I-h- i , R 1 is not .

[0246] In certain embodiments, the present disclosure provides a compound selected from:

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289] or a pharmaceutically acceptable salt thereof.

[0290] In certain embodiments, the present disclosure provides a compound selected from the following

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303] or a pharmaceutically acceptable salt thereof.

[0304] In certain particularly preferred embodiments, the present disclosure provides compounds selected from:

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313] or a pharmaceutically acceptable salt thereof.

[0314] In certain embodiments, the present disclosure provides compounds selected from:

[0315]

[0316] or a pharmaceutically acceptable salt thereof.

[0317] In certain embodiments, the present disclosure provides compounds selected from:

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328] or a pharmaceutically acceptable salt thereof.

[0329] In some aspects, the present disclosure provides compounds according to the following embodiments:

[0330] Embodiment 1. A compound of formula I or a pharmaceutically acceptable salt thereof:

[0331]

[0332] Wherein:

[0333] Ring A is a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0334] R 1 is an optionally substituted group selected from: a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0335] Each R x is independently selected from halogen, cyano, OR, SR, N(R)2, or an optionally substituted group selected from: C 1-4 aliphatic group, a 3- to 7-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0336] L is an optionally substituted C 1-4 aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced independently by a group selected from: -O-, -N(R)-, -S-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocycle;

[0337] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; or:

[0338] Two R groups together with the nitrogen atom to which they are attached form an optionally substituted 3- to 7-membered monocyclic heterocycle having 0 to 2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0339] R 2 is hydrogen, a halogen, N(R)2, OR or an optionally substituted group selected from: C 1-6 an aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, phenyl, a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, an 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocycle, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur; and

[0340] n is 0, 1 or 2.

[0341] Embodiment 2. The compound according to Embodiment 1, wherein Ring A is a 6-membered heteroaryl ring having 1 to 2 nitrogen atoms.

[0342] Embodiment 3. The compound according to Embodiment 1, wherein Ring A is a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0343] Embodiment 4. The compound according to Embodiment 3, wherein Ring A is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0344] Embodiment 5. The compound according to Embodiment 3, wherein Ring A is a 5-membered heteroaryl ring having 3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0345] Embodiment 6. The compound according to Embodiment 1, wherein Ring A is selected from

[0346]

[0347]

[0348] .

[0349] Embodiment 7. The compound according to Embodiment 6, wherein Ring A is selected from and .

[0350] Embodiment 7a. The compound according to Embodiment 6, wherein Ring A is selected from and .

[0351] Embodiment 8. The compound according to Embodiment 1, wherein Ring A is selected from

[0352]

[0353]

[0354]

[0355] 。

[0356] Embodiment 9. A compound according to Embodiment 1, wherein Ring A is selected from

[0357]

[0358] wherein R x is an optionally substituted group selected from C 1-4 aliphatic groups, 3- to 7-membered saturated or partially unsaturated carbocycles, 3- to 7-membered saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0359] Embodiment 10. A compound according to Embodiment 1, wherein Ring A is selected from

[0360] 。

[0361] Embodiment 11. A compound according to Embodiment 1, wherein Ring A is selected from

[0362]

[0363]

[0364] wherein:

[0365] R on the nitrogen atom x is selected from optionally substituted groups selected from C 1-4 aliphatic groups, 3- to 7-membered saturated or partially unsaturated carbocycles, 3- to 7-membered saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; and

[0366] R on the carbon atom x is selected from halogen, cyano, OR, SR, N(R)2 or an optionally substituted group selected from: C 1-4 aliphatic groups, 3- to 7-membered saturated or partially unsaturated carbocycles, 3- to 7-membered saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0367] Embodiment 12. A compound according to any one of Embodiments 1-11, wherein R x is a halogen.

[0368] Embodiment 13. A compound according to any one of Embodiments 1-11, wherein R x is a cyano group.

[0369] Embodiment 14. A compound according to any one of Embodiments 1-11, wherein R x is OR.

[0370] Embodiment 15. A compound according to any one of Embodiments 1-11, wherein R x is SR.

[0371] Embodiment 16. A compound according to any one of Embodiments 1-11, wherein R x is N(R)2.

[0372] Embodiment 17. A compound according to any one of Embodiments 14-16, wherein R is selected from hydrogen and an optionally substituted C 1-6 aliphatic group.

[0373] Embodiment 18. A compound according to Embodiment 17, wherein R is selected from hydrogen and an optionally substituted C 1-4 aliphatic group.

[0374] Embodiment 19. A compound according to any one of Embodiments 14, 17 and 18, wherein R x is OH, OCH3 and OCH2CH3.

[0375] Embodiment 20. A compound according to any one of Embodiments 15, 17 and 18, wherein R x is SH, SCH3 and SCH2CH3.

[0376] Embodiment 21. A compound according to any one of Embodiments 16-18, wherein R x is selected from NH2, NHCH3, NHCH2CH3, N(CH3)2 and N(CH2CH3)2.

[0377] Embodiment 22. A compound according to any one of Embodiments 1-11, wherein R x is an optionally substituted C 1-4 aliphatic group.

[0378] Embodiment 23. A compound according to Embodiment 22, wherein R x is an optionally substituted C3-4 Aliphatic group.

[0379] Embodiment 24. The compound according to Embodiment 23, wherein R x is selected from tert-butyl, , and .

[0380] Embodiment 25. The compound according to Embodiment 22, wherein R x is a C 1-4 aliphatic group optionally substituted with a group selected from the following: halogen, -(CH2) 0-4 R ○ , -(CH2) 0-4 OR ○ , -(CH2) 0-4 N(R ○ )2, -(CH2) 0-4 C(O)OR ○ and -(CH2) 0-4 C(O)NR ○ 2.

[0381] Embodiment 26. The compound according to Embodiment 25, wherein R ○ is selected from hydrogen, C 1-6 aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5- to 6-membered heteroaryl ring), a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8- to 10-membered bicyclic aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or: two independently occurring R ○ together with their intervening atoms form a 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0382] Embodiment 27. The compound according to Embodiment 22, wherein R x is a C 1-4 aliphatic group optionally substituted with a group selected from the following: halogen, -R ○ , -OR ○ , -N(R ○ )2, -C(O)OR ○ and -C(O)NR ○ 2.

[0383] Embodiment 28. The compound according to Embodiment 22, wherein R x is a C 1-4 aliphatic group optionally substituted with halogen.

[0384] Embodiment 29. A compound according to Embodiment 28, wherein R x is selected from -CH3, -CF3, -CHF2, and CH2F.

[0385] Embodiment 29a. A compound according to Embodiment 28, wherein R x is selected from -CH3, -CD3, -CF3, -CHF2, and CH2F.

[0386] Embodiment 30. A compound according to Embodiment 22, wherein R x is selected from -CH2R ○ , -CH2OR ○ , -CH2N(R ○ )2, -CH2C(O)OR ○ and -CH2C(O)N(R ○ )2.

[0387] Embodiment 31. A compound according to Embodiment 30, wherein R x is selected from -CH2OH, -CH2OCH3, -CH2C(O)NH2, -CH2C(O)NHCH3, and -CH2C(O)N(CH3)2.

[0388] Embodiment 32. A compound according to any one of Embodiments 1 - 31, wherein R 1 is an optionally substituted 5 - to 6 - membered heteroaryl ring having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0389] Embodiment 33. A compound according to Embodiment 32, wherein R 1 is an optionally substituted 5 - membered heteroaryl ring having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0390] Embodiment 34. A compound according to Embodiment 33, wherein R 1 is an optionally substituted 5 - membered heteroaryl ring having 1 - 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0391] Embodiment 35. A compound according to Embodiment 32, wherein R 1 is an optionally substituted 6 - membered heteroaryl ring having 1 - 3 nitrogen atoms.

[0392] Embodiment 36. A compound according to Embodiment 35, wherein R 1 is an optionally substituted 6 - membered heteroaryl ring having 1 - 2 nitrogen atoms.

[0393] Embodiment 37. A compound according to Embodiment 32, wherein R 1 is selected from

[0394]

[0395] .

[0396] Embodiment 38. A compound according to Embodiment 37, wherein R 1 is selected from and .

[0397] Embodiment 39. A compound according to any one of Embodiments 1-38, wherein L is an optionally substituted C 1-2 aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced independently by a group selected from: -O-, -N(R)-, -S-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle.

[0398] Embodiment 40. A compound according to Embodiment 39, wherein L is an optionally substituted C 1-2 aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced independently by a group selected from: -O-, -N(R)-, -S-, -C(O)- and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle.

[0399] Embodiment 41. A compound according to Embodiment 38 or 39, wherein L is an optionally substituted C 1-2 aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced independently by a group selected from: -O-, -N(H)-, -S-, -C(O)- and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle.

[0400] Embodiment 42. A compound according to any one of Embodiments 1-38, wherein L is an optionally substituted C 3-4 aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced independently by a group selected from: -O-, -N(R)-, -S-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle.

[0401] Embodiment 43. The compound according to embodiment 42, wherein L is an optionally substituted C 3-4 aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced independently by a group selected from: -O-, -N(R)-, -S-, -C(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0402] Embodiment 44. The compound according to embodiment 42 or 43, wherein L is an optionally substituted C 3-4 aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced independently by a group selected from: -O-, -N(H)-, -S-, -C(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0403] Embodiment 45. The compound according to any one of embodiments 1-38, wherein L is an optionally substituted C 1-4 aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)-, and one additional carbon atom is optionally replaced by a group selected from: -O-, -N(R)-, -S-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0404] Embodiment 46. The compound according to embodiment 45, wherein L is an optionally substituted C 1-4 aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)-, and one additional carbon atom is optionally replaced by a group selected from: -O-, -N(R)-, -S-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0405] Embodiment 47. The compound according to embodiment 45 or 46, wherein L is an optionally substituted C 1-4 aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)-, and one additional carbon atom is optionally replaced by a group selected from: -O-, -N(H)-, -S-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

[0406] Embodiment 48. The compound according to embodiment 45 or 46, wherein L is an optionally substituted C 3-4An aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by -C(O)-, and an additional carbon atom is optionally replaced by a group selected from the group consisting of -O-, -N(R)-, -S-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocyclic ring.

[0407] Embodiment 49. The compound according to embodiment 48, wherein L is optionally substituted C 3-4 An aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by -C(O)-, and an additional carbon atom is optionally replaced by a group selected from the group consisting of -O-, -N(H)-, -S-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocyclic ring.

[0408] Embodiment 50. A compound according to any one of embodiments 1-38, wherein L is selected from

[0409]

[0410] .

[0411] Embodiment 50a. A compound according to any one of Embodiments 1-38, wherein L is selected from

[0412]

[0413] .

[0414] Embodiment 51. A compound according to embodiment 50, wherein L is selected from and .

[0415] Embodiment 51a. A compound according to embodiment 50, wherein L is selected from , and .

[0416] Embodiment 52. Compounds according to any one of embodiments 1-51a, wherein R is hydrogen.

[0417] Embodiment 53. A compound according to any one of embodiments 1-51a, wherein R is -CH3.

[0418] Embodiment 54. A compound according to any one of embodiments 1-51a, wherein R is optionally substituted C 1-6 Aliphatic group.

[0419] Embodiment 55. The compound according to embodiment 54, wherein R is optionally oxo-substituted and OR ○ Substituted aliphatic groups.

[0420] Embodiment 56. The compound according to embodiment 55, wherein R ○ is C 1-6 aliphatic group.

[0421] Embodiment 57. The compound according to embodiment 54, wherein R is methyl or ethyl.

[0422] Embodiment 58. The compound according to any one of embodiments 1-57, wherein R 2 is hydrogen.

[0423] Embodiment 59. The compound according to any one of embodiments 1-57, wherein R 2 is halogen, N(R)2, OR or an optionally substituted group selected from: C 1-6 aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, phenyl, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, an 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0424] Embodiment 60. The compound according to embodiment 59, wherein R 2 is N(R)2.

[0425] Embodiment 61. The compound according to embodiment 60, wherein R is NH2.

[0426] Embodiment 62. The compound according to embodiment 59, wherein R 2 is an optionally substituted C 1-6 aliphatic group.

[0427] Embodiment 63. The compound according to embodiment 62, wherein R 2 is methyl or ethyl.

[0428] Embodiment 64. The compound according to embodiment 59, wherein R 2 is an optionally substituted cyclohexyl.

[0429] Embodiment 65. The compound according to embodiment 59, wherein R 2 is an optionally substituted phenyl.

[0430] Embodiment 66. The compound according to embodiment 59, wherein R 2is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0431] Embodiment 67. The compound according to embodiment 66, wherein R 2 is an optionally substituted 5-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0432] Embodiment 68. The compound according to embodiment 66 or 67, wherein R 2 is an optionally substituted group selected from thienyl, pyrazolyl, and imidazolyl.

[0433] Embodiment 69. The compound according to embodiment 66, wherein R 2 is an optionally substituted 6-membered heteroaryl ring having 1 to 3 nitrogen atoms.

[0434] Embodiment 70. The compound according to embodiment 69, wherein R 2 is an optionally substituted 6-membered heteroaryl ring having 1 to 2 nitrogen atoms.

[0435] Embodiment 71. The compound according to embodiment 70, wherein R 2 is an optionally substituted group selected from pyridyl or pyrimidinyl.

[0436] Embodiment 72. The compound according to embodiment 59, wherein R 2 is an optionally substituted 8- to 10-membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring.

[0437] Embodiment 73. The compound according to embodiment 72, wherein R 2 is an optionally substituted 9-membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring.

[0438] Embodiment 74. The compound according to embodiment 73, wherein R 2 is an optionally substituted 2,3-dihydro-1H-indenyl.

[0439] Embodiment 75. The compound according to embodiment 72, wherein R 2 is an optionally substituted 10-membered bicyclic saturated, partially unsaturated, or aryl carbocyclic ring.

[0440] Embodiment 76. The compound according to embodiment 75, wherein R 2 is an optionally substituted group selected from 1,2,3,4-tetrahydronaphthalenyl or naphthalenyl.

[0441] Embodiment 77. The compound according to Embodiment 59, wherein R 2 is an optionally substituted 8- to 10-membered bicyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0442] Embodiment 78. The compound according to Embodiment 77, wherein R 2 is an optionally substituted 9-membered bicyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0443] Embodiment 79. The compound according to Embodiment 77, wherein R 2 is an optionally substituted 10-membered bicyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0444] Embodiment 80. The compound according to Embodiment 79, wherein R 2 is an optionally substituted group selected from chromanyl, isochromanyl, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, and 2H-benzo[b][1,4]oxazin-3(4H)-one.

[0445] Embodiment 81. The compound according to Embodiment 59, wherein R 2 is an optionally substituted 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0446] Embodiment 82. The compound according to Embodiment 81, wherein R 2 is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0447] Embodiment 83. The compound according to Embodiment 81 or 82, wherein R 2 is an optionally substituted group selected from indolyl, benzopyrazolyl, benzimidazolyl, and imidazo[1,2-a]pyridinyl.

[0448] Embodiment 84. The compound according to Embodiment 59, wherein R 2 is selected from

[0449]

[0450]

[0451]

[0452]

[0453] 。

[0454] Embodiment 84a. A compound according to Embodiment 59, wherein R 2 is selected from

[0455]

[0456]

[0457]

[0458]

[0459]

[0460] 。

[0461] Embodiment 85. A compound according to Embodiment 84, wherein R 2 is selected from , , and 。

[0462] Embodiment 85a. A compound according to Embodiment 84a, wherein R 2 is selected from 、 、 、 、 、 and 。

[0463] Embodiment 86. A compound according to Embodiment 1, wherein the compound is:

[0464]

[0465] or a pharmaceutically acceptable salt thereof.

[0466] Embodiment 87. A compound according to Embodiment 1, wherein the compound is:

[0467]

[0468] or a pharmaceutically acceptable salt thereof.

[0469] Embodiment 88. A compound according to Embodiment 1, wherein the compound is:

[0470]

[0471] or a pharmaceutically acceptable salt thereof.

[0472] Embodiment 89. The compound according to Embodiment 1, wherein the compound is:

[0473]

[0474] or a pharmaceutically acceptable salt thereof.

[0475] Embodiment 90. The compound according to Embodiment 1, wherein the compound is selected from:

[0476]

[0477]

[0478] or a pharmaceutically acceptable salt thereof.

[0479] Embodiment 90a. The compound according to Embodiment 1, wherein the compound is:

[0480]

[0481] or a pharmaceutically acceptable salt thereof.

[0482] Embodiment 91. The compound according to Embodiment 1, wherein the compound is selected from:

[0483]

[0484]

[0485] or a pharmaceutically acceptable salt thereof.

[0486] Embodiment 91a. The compound according to Embodiment 1, wherein the compound is:

[0487]

[0488] or a pharmaceutically acceptable salt thereof.

[0489] Embodiment 92. A pharmaceutical composition comprising a compound according to any one of Embodiments 1 - 91a and a pharmaceutically acceptable carrier.

[0490] Embodiment 93. A method comprising the steps of:

[0491] administering to a subject a compound according to any one of Embodiments 1 - 91a, wherein the subject (i) has a disorder characterized by axonal degeneration or (ii) is at risk of developing a disorder characterized by axonal degeneration.

[0492] Embodiment 94. A method of treating or preventing axonal degeneration, the method comprising administering to a subject in need thereof a compound according to any one of Embodiments 1-91a.

[0493] Embodiment 95. A method of inhibiting SARM1, the method comprising contacting a biological sample with a compound according to any one of Embodiments 1-91a.

[0494] Embodiment 96. A compound of formula I' or a pharmaceutically acceptable salt thereof:

[0495]

[0496] Wherein:

[0497] Ring A is a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0498] R 1 is an optionally substituted group selected from: a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0499] Each R x is independently selected from halogen, cyano, OR, SR, N(R)2, S(O)2N(R)2, C(O)OR, C(O)N(R)2, or an optionally substituted group selected from: C 1-4 aliphatic group, a 3- to 7-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0500] L is an optionally substituted C 1-4 aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced independently by a group selected from: -O-, -N(R)-, -S-, -S(O)2-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocycle;

[0501] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6An aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl group, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; or:

[0502] Two R groups together with the nitrogen atom to which they are attached form an optionally substituted 3- to 7-membered monocyclic heterocycle having 0 to 2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur;

[0503] R 2 is hydrogen, halogen, N(R)2, OR, or an optionally substituted group selected from: C 1-6 An aliphatic group, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl group, a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8- to 10-membered bicyclic saturated, partially unsaturated, or aryl carbocycle, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; and

[0504] n is 0, 1, or 2.

[0505] Embodiment 97. The compound according to Embodiment 96, wherein Ring A is a 6-membered heteroaryl ring having 1 to 2 nitrogen atoms.

[0506] Embodiment 98. The compound according to Embodiment 96, wherein Ring A is a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0507] Embodiment 99. The compound according to Embodiment 98, wherein Ring A is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0508] Embodiment 100. The compound according to Embodiment 98, wherein Ring A is a 5-membered heteroaryl ring having 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0509] Embodiment 101. The compound according to Embodiment 96, wherein Ring A is selected from

[0510]

[0511]

[0512] .

[0513] Embodiment 102. The compound according to Embodiment 101, wherein Ring A is selected from and .

[0514] Embodiment 103. The compound according to Embodiment 101, wherein Ring A is selected from and .

[0515] Embodiment 104. The compound according to Embodiment 96, wherein Ring A is selected from

[0516]

[0517]

[0518]

[0519]

[0520] .

[0521] Embodiment 105. The compound according to Embodiment 96, wherein Ring A is selected from

[0522]

[0523] wherein R x is an optionally substituted group selected from C 1-4 aliphatic groups, 3- to 7-membered saturated or partially unsaturated carbocycles, 3- to 7-membered saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and 5- to 6-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0524] Embodiment 106. The compound according to Embodiment 96, wherein Ring A is selected from

[0525] .

[0526] Embodiment 107. The compound according to Embodiment 96, wherein Ring A is selected from

[0527]

[0528]

[0529] wherein:

[0530] R on the nitrogen atom x is selected from optionally substituted groups selected from C 1-4An aliphatic group, a 3- to 7-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl group, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; and

[0531] R on a carbon atom x Selected from halogen, cyano, OR, SR, N(R)2, or an optionally substituted group selected from: C 1-4 An aliphatic group, a 3- to 7-membered saturated or partially unsaturated carbocycle, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a phenyl group, and a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0532] Embodiment 108. A compound according to any one of Embodiments 96 - 107, wherein R x is halogen.

[0533] Embodiment 109. A compound according to any one of Embodiments 96 - 107, wherein R x is cyano.

[0534] Embodiment 110. A compound according to any one of Embodiments 96 - 107, wherein R x is OR.

[0535] Embodiment 111. A compound according to any one of Embodiments 96 - 107, wherein R x is SR.

[0536] Embodiment 112. A compound according to any one of Embodiments 96 - 107, wherein R x is N(R)2.

[0537] Embodiment 113. A compound according to any one of Embodiments 110 - 112, wherein R is selected from hydrogen and an optionally substituted C 1-6 aliphatic group.

[0538] Embodiment 114. The compound according to Embodiment 113, wherein R is selected from hydrogen and an optionally substituted C 1-4 aliphatic group.

[0539] Embodiment 115. The compound according to any one of Embodiments 110, 113, and 114, wherein R x is OH, OCH3, and OCH2CH3.

[0540] Embodiment 116. A compound according to any one of Embodiments 111, 113, and 114, wherein R x is SH, SCH3, and SCH2CH3.

[0541] Embodiment 117. A compound according to any one of Embodiments 112 - 114, wherein R x is selected from NH2, NHCH3, NHCH2CH3, N(CH3)2, and N(CH2CH3)2.

[0542] Embodiment 118. A compound according to any one of Embodiments 96 - 107, wherein R x is an optionally substituted C 1-4 aliphatic group.

[0543] Embodiment 119. The compound according to Embodiment 118, wherein R x is an optionally substituted C 3-4 aliphatic group.

[0544] Embodiment 120. The compound according to Embodiment 119, wherein R x is selected from tert-butyl, , , and .

[0545] Embodiment 121. The compound according to Embodiment 118, wherein R x is a C 1-4 aliphatic group optionally substituted with a group selected from: halogen, -(CH2) 0-4 R ○ , -(CH2) 0-4 OR ○ , -(CH2) 0-4 N(R ○ )2, -(CH2) 0-4 C(O)OR ○ and -(CH2) 0-4 C(O)NR ○ 2.

[0546] Embodiment 122. The compound according to Embodiment 121, wherein R ○ is selected from hydrogen, C 1-6 aliphatic group, -CH2Ph, -O(CH2) 0-1Ph, -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: two independently occurring R ○ which together with their intervening atoms form a 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0547] Embodiment 123. A compound according to Embodiment 118, wherein R x is a C 1-4 aliphatic group optionally substituted with a group selected from: halogen, -R ○ , -OR ○ , -N(R ○ )2, -C(O)OR ○ and -C(O)NR ○ 2.

[0548] Embodiment 124. A compound according to Embodiment 118, wherein R x is a C 1-4 aliphatic group optionally substituted with halogen.

[0549] Embodiment 125. A compound according to Embodiment 124, wherein R x is selected from -CH3, -CF3, -CHF2 and CH2F.

[0550] Embodiment 126. A compound according to Embodiment 124, wherein R x is selected from -CH3, -CD3, -CF3, -CHF2, CH2F, CH2CH3.

[0551] Embodiment 127. A compound according to Embodiment 118, wherein R x is selected from -CH2R ○ , -CH2OR ○ , -CH2N(R ○ )2, -CH2C(O)OR ○ and -CH2C(O)N(R ○ )2.

[0552] Embodiment 128. A compound according to Embodiment 127, wherein R x is selected from -CH2OH, -CH2OCH3, -CH2CO2CH3, CH2CO2CH2CH3, -CH2C(O)NH2, -CH2C(O)NHCH3 and -CH2C(O)N(CH3)2.

[0553] Embodiment 129. A compound according to any one of embodiments 96 - 107, wherein R x is selected from S(O)2N(R)2, C(O)OR, and C(O)N(R)2.

[0554] Embodiment 130. The compound according to embodiment 129, wherein R x is S(O)2N(R)2.

[0555] Embodiment 131. The compound according to embodiment 130, wherein R x is SO2NH2.

[0556] Embodiment 132. The compound according to embodiment 129, wherein R x is C(O)OR.

[0557] Embodiment 133. The compound according to embodiment 132, wherein R x is selected from CO2CH3 and CO2CH2CH3.

[0558] Embodiment 134. The compound according to embodiment 129, wherein R x is C(O)N(R)2.

[0559] Embodiment 135. The compound according to embodiment 134, wherein R x is selected from C(O)NH2 and C(O)N(CH3)2.

[0560] Embodiment 136. The compound according to any one of embodiments 96 - 135, wherein R 1 is an optionally substituted 5 - to 6 - membered heteroaryl ring having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0561] Embodiment 137. The compound according to embodiment 136, wherein R 1 is an optionally substituted 5 - membered heteroaryl ring having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0562] Embodiment 138. The compound according to embodiment 137, wherein R 1 is an optionally substituted 5 - membered heteroaryl ring having 1 - 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0563] Embodiment 139. The compound according to embodiment 136, wherein R 1 is an optionally substituted 6 - membered heteroaryl ring having 1 - 3 nitrogen atoms.

[0564] Embodiment 140. The compound according to embodiment 139, wherein R 1 is an optionally substituted 6-membered heteroaryl ring having 1 to 2 nitrogen atoms.

[0565] Embodiment 141. A compound according to embodiment 136, wherein R 1 Selected from

[0566]

[0567] .

[0568] Embodiment 142. The compound according to embodiment 141, wherein R 1 Selected from and .

[0569] Embodiment 143. A compound according to any one of embodiments 96-142, wherein L is optionally substituted C 1-2 An aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from the group consisting of —O—, —N(R)—, —S—, —S(O)2—, —C(O)—, —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)2N(R)—, —N(R)S(O)2—, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocyclic ring.

[0570] Embodiment 144. The compound according to embodiment 143, wherein L is optionally substituted C 1-2 An aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from the group consisting of -O-, -N(R)-, -S-, -S(O)2-, -C(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocyclic ring.

[0571] Embodiment 145. A compound according to embodiment 143 or 144, wherein L is optionally substituted C 1-2 An aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from the group consisting of -O-, -N(H)-, -S-, -S(O)2-, -C(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocyclic ring.

[0572] Embodiment 146. A compound according to any one of embodiments 96-142, wherein L is optionally substituted C 3-4An aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally independently replaced by a group selected from the following: -O-, -N(R)-, -S-, -S(O)2-, -C(O)-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle.

[0573] Embodiment 147. The compound according to Embodiment 146, wherein L is optionally substituted C 3-4 An aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally independently replaced by a group selected from the following: -O-, -N(R)-, -S-, -S(O)2-, -C(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle.

[0574] Embodiment 148. The compound according to Embodiment 146 or 147, wherein L is optionally substituted C 3-4 An aliphatic chain, wherein one or two carbon atoms in the aliphatic chain are optionally independently replaced by a group selected from the following: -O-, -N(H)-, -S-, -S(O)2-, -C(O)-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle.

[0575] Embodiment 149. The compound according to any one of Embodiments 96 - 142, wherein L is optionally substituted C 1-4 An aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)-, and one additional carbon atom is optionally replaced by a group selected from the following: -O-, -N(R)-, -S-, -S(O)2-, -C(O)N(R)-, -N(R)C(O)-, -C(O)O-, -OC(O)-, -S(O)2N(R)-, -N(R)S(O)2-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle.

[0576] Embodiment 150. The compound according to Embodiment 149, wherein L is optionally substituted C 1-4 An aliphatic chain, wherein one carbon atom in the aliphatic chain is replaced by -C(O)-, and one additional carbon atom is optionally replaced by a group selected from the following: -O-, -N(R)-, -S-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocycle.

[0577] Embodiment 151. The compound according to Embodiment 149 or 150, wherein L is optionally substituted C 1-4An aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by -C(O)-, and an additional carbon atom is optionally replaced by a group selected from the group consisting of -O-, -N(H)-, -S-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocyclic ring.

[0578] Embodiment 152. A compound according to embodiment 149 or 150, wherein L is optionally substituted C 3-4 An aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by -C(O)-, and an additional carbon atom is optionally replaced by a group selected from the group consisting of -O-, -N(R)-, -S-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocyclic ring.

[0579] Embodiment 153. The compound according to embodiment 152, wherein L is optionally substituted C 3-4 An aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by -C(O)-, and an additional carbon atom is optionally replaced by a group selected from the group consisting of -O-, -N(H)-, -S-, and a divalent 3- to 5-membered monocyclic, bicyclic or bridged bicyclic carbocyclic ring.

[0580] Embodiment 154. A compound according to any one of embodiments 96-142, wherein L is selected from

[0581]

[0582]

[0583] .

[0584] Embodiment 155. A compound according to any one of embodiments 96-142, wherein L is selected from

[0585]

[0586]

[0587]

[0588] .

[0589] Embodiment 156. A compound according to embodiment 155, wherein L is selected from and .

[0590] Embodiment 157. A compound according to embodiment 155, wherein L is selected from , ,and .

[0591] Embodiment 158. A compound according to any one of embodiments 96 - 157, wherein R is hydrogen.

[0592] Embodiment 159. A compound according to any one of embodiments 96 - 157, wherein R is -CH3.

[0593] Embodiment 160. A compound according to any one of embodiments 96 - 157, wherein R is an optionally substituted C 1-6 aliphatic group.

[0594] Embodiment 161. A compound according to embodiment 160, wherein R is an aliphatic group optionally substituted with oxo and OR ○ substituted.

[0595] Embodiment 162. A compound according to embodiment 161, wherein R ○ is C 1-6 aliphatic group.

[0596] Embodiment 163. A compound according to embodiment 160, wherein R is methyl or ethyl.

[0597] Embodiment 164. A compound according to any one of embodiments 96 - 163, wherein R 2 is hydrogen.

[0598] Embodiment 165. A compound according to any one of embodiments 96 - 163, wherein R 2 is halogen, N(R)2, OR or an optionally substituted group selected from: C 1-6 aliphatic group, a 3 - to 7 - membered saturated or partially unsaturated heterocycle having 1 - 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, phenyl, a 5 - to 6 - membered heteroaryl ring having 1 - 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, an 8 - to 10 - membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, an 8 - to 10 - membered bicyclic saturated or partially unsaturated heterocycle having 1 - 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, or an 8 - to 10 - membered bicyclic heteroaryl ring having 1 - 3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0599] Embodiment 166. A compound according to embodiment 165, wherein R 2 is N(R)2.

[0600] Embodiment 167. A compound according to embodiment 166, wherein R is NH2.

[0601] Embodiment 168. A compound according to embodiment 165, wherein R2 is an optionally substituted C 1-6 aliphatic group.

[0602] Embodiment 169. The compound according to embodiment 168, wherein R 2 is selected from methyl, ethyl, tert-butyl and neopentyl.

[0603] Embodiment 170. The compound according to embodiment 165, wherein R 2 is an optionally substituted cyclohexyl.

[0604] Embodiment 171. The compound according to embodiment 165, wherein R 2 is an optionally substituted phenyl.

[0605] Embodiment 172. The compound according to embodiment 165, wherein R 2 is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0606] Embodiment 173. The compound according to embodiment 172, wherein R 2 is an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0607] Embodiment 174. The compound according to embodiment 172 or 173, wherein R 2 is an optionally substituted group selected from thienyl, pyrazolyl and imidazolyl.

[0608] Embodiment 175. The compound according to embodiment 172, wherein R 2 is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogen atoms.

[0609] Embodiment 176. The compound according to embodiment 175, wherein R 2 is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms.

[0610] Embodiment 177. The compound according to embodiment 176, wherein R 2 is an optionally substituted group selected from pyridyl or pyrimidinyl.

[0611] Embodiment 178. The compound according to embodiment 165, wherein R 2 is an optionally substituted 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring.

[0612] Embodiment 179. The compound according to embodiment 178, wherein R2 is an optionally substituted 9-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring.

[0613] Embodiment 180. The compound according to Embodiment 179, wherein R 2 is an optionally substituted 2,3-dihydro-1H-indenyl.

[0614] Embodiment 181. The compound according to Embodiment 178, wherein R 2 is an optionally substituted 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring.

[0615] Embodiment 182. The compound according to Embodiment 181, wherein R 2 is an optionally substituted group selected from 1,2,3,4-tetrahydronaphthyl or naphthyl.

[0616] Embodiment 183. The compound according to Embodiment 165, wherein R 2 is an optionally substituted 8- to 10-membered bicyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0617] Embodiment 184. The compound according to Embodiment 183, wherein R 2 is an optionally substituted 9-membered bicyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0618] Embodiment 185. The compound according to Embodiment 183, wherein R 2 is an optionally substituted 10-membered bicyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0619] Embodiment 186. The compound according to Embodiment 185, wherein R 2 is an optionally substituted group selected from chromanyl, isochromanyl, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl and 2H-benzo[b][1,4]oxazin-3(4H)-one.

[0620] Embodiment 187. The compound according to Embodiment 165, wherein R 2 is an optionally substituted 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0621] Embodiment 188. The compound according to Embodiment 187, wherein R 2is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0622] Embodiment 189. The compound according to embodiment 187 or 188, wherein R 2 is an optionally substituted group selected from indolyl, benzopyrazolyl, benzimidazolyl and imidazo[1,2-a]pyridinyl.

[0623] Embodiment 190. The compound according to embodiment 165, wherein R 2 Selected from

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631] .

[0632] Embodiment 191. A compound according to embodiment 165, wherein R 2 Selected from

[0633]

[0634]

[0635]

[0636]

[0637]

[0638] .

[0639] Embodiment 192. The compound according to embodiment 190, wherein R 2 Selected from , and .

[0640] Embodiment 193. The compound according to embodiment 191, wherein R2 Selected from , , , , , and .

[0641] Embodiment 194. A compound according to Embodiment 96, wherein the compound is:

[0642]

[0643] or a pharmaceutically acceptable salt thereof.

[0644] Embodiment 195. A compound according to Embodiment 96, wherein the compound is:

[0645]

[0646] or a pharmaceutically acceptable salt thereof.

[0647] Embodiment 196. A compound according to Embodiment 96, wherein the compound is:

[0648]

[0649] or a pharmaceutically acceptable salt thereof.

[0650] Embodiment 197. A compound according to Embodiment 96, wherein the compound is:

[0651]

[0652] or a pharmaceutically acceptable salt thereof.

[0653] Embodiment 198. A compound according to Embodiment 96, wherein the compound is selected from:

[0654]

[0655] or a pharmaceutically acceptable salt thereof.

[0656] Embodiment 199. A compound according to Embodiment 96, wherein the compound is:

[0657]

[0658] or a pharmaceutically acceptable salt thereof.

[0659] Embodiment 200. A compound according to Embodiment 96, wherein the compound is selected from:

[0660]

[0661] or a pharmaceutically acceptable salt thereof.

[0662] Embodiment 201. A compound according to Embodiment 96, wherein the compound is selected from:

[0663]

[0664]

[0665] or a pharmaceutically acceptable salt thereof.

[0666] Embodiment 202. A compound according to any one of Embodiments 1, 3, 4, 8, 12 - 89, 90a, 91, 96, 98, 99, 101, 104, 108 - 197, 199 and 201, wherein Ring A is .

[0667] Embodiment 203. A compound according to Embodiment 202, wherein the compound is:

[0668]

[0669] or a pharmaceutically acceptable salt thereof.

[0670] Embodiment 204. A compound according to Embodiment 202, wherein the compound is:

[0671]

[0672] or a pharmaceutically acceptable salt thereof.

[0673] Embodiment 205. A compound according to Embodiment 202, wherein the compound is

[0674]

[0675] or a pharmaceutically acceptable salt thereof.

[0676] Embodiment 206. A compound according to Embodiment 202, wherein the compound is

[0677]

[0678] or a pharmaceutically acceptable salt thereof.

[0679] Embodiment 207. A compound according to Embodiment 202, wherein the compound is

[0680]

[0681] or a pharmaceutically acceptable salt thereof.

[0682] Embodiment 208. A compound according to Embodiment 202, wherein the compound is

[0683]

[0684] or a pharmaceutically acceptable salt thereof.

[0685] Embodiment 209. A compound according to Embodiment 202, wherein the compound is

[0686]

[0687] or a pharmaceutically acceptable salt thereof.

[0688] Embodiment 210. A compound according to Embodiment 202, wherein the compound is

[0689]

[0690] or a pharmaceutically acceptable salt thereof.

[0691] Embodiment 211. A compound according to Embodiment 202, wherein the compound is

[0692]

[0693] or a pharmaceutically acceptable salt thereof.

[0694] Embodiment 212. A pharmaceutical composition comprising a compound according to any one of Embodiments 96 - 211 and a pharmaceutically acceptable carrier.

[0695] Embodiment 213. A method comprising the steps of:

[0696] administering to a subject a compound according to any one of Embodiments 96 - 211, wherein the subject (i) has a disorder characterized by axonal degeneration or (ii) is at risk of developing a disorder characterized by axonal degeneration.

[0697] Embodiment 214. A method of treating or preventing axonal degeneration, the method comprising administering to a subject in need thereof a compound according to any one of Embodiments 96 - 211.

[0698] Embodiment 215. The method according to Embodiment 94 or Embodiment 214, wherein the axonal degeneration is associated with a neurodegenerative disease or disorder.

[0699] Embodiment 216. The method according to Embodiment 215, wherein the neurodegenerative disease or disorder is selected from acute or chronic diseases or disorders of the peripheral nervous system (PNS), acute or chronic diseases or disorders of the central nervous system (CNS), or diseases associated with neurodegeneration.

[0700] Embodiment 217. The method according to Embodiment 215 or Embodiment 216, wherein the neurodegenerative disease or disorder is selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy, and chemotherapy-induced peripheral neuropathy.

[0701] Embodiment 218. The method according to Embodiment 217, wherein the neurodegenerative disease or disorder is amyotrophic lateral sclerosis (ALS).

[0702] Embodiment 219. The method according to Embodiment 217, wherein the neurodegenerative disease or disorder is multiple sclerosis (MS).

[0703] Embodiment 220. The method according to Embodiment 217, wherein the neurodegenerative disease or disorder is diabetic neuropathy.

[0704] Embodiment 221. The method according to Embodiment 217, wherein the neurodegenerative disease or disorder is chemotherapy-induced peripheral neuropathy.

[0705] Embodiment 222. A method of inhibiting SARM1, the method comprising contacting a biological sample with a compound according to any one of Embodiments 96-211.

[0706] Composition

[0707] In certain embodiments, a compound of Formula I or Formula I' can be provided in a composition, for example, in combination (e.g., mixed) with one or more other components.

[0708] In certain embodiments, the present disclosure provides a composition that comprises and / or delivers a compound of Formula I or Formula I' or an active metabolite thereof, such as when contacted with or otherwise administered to a system or environment, for example, the system or environment can include SARM1 NADase activity; in certain embodiments, administration of such a composition to a system or environment effects inhibition of SARM1 activity as described herein.

[0709] In certain embodiments, the compositions provided as described herein can be pharmaceutical compositions as they comprise an active agent and one or more pharmaceutically acceptable excipients; in certain such embodiments, the provided pharmaceutical composition comprises a compound of Formula I or Formula I' or an active metabolite thereof and / or delivers a compound of Formula I or Formula I' or an active metabolite thereof to a relevant system or environment as described herein (e.g., to a subject in need thereof).

[0710] In certain embodiments, one or more compounds of Formula I or Formula I' are provided and / or utilized in the form of a pharmaceutically acceptable salt.

[0711] The present disclosure particularly provides compositions that comprise a compound of Formula I or Formula I' or a pharmaceutically acceptable salt or derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the provided composition is such that it effectively and measurably inhibits axonal mutagenesis in a biological sample or a patient. In certain embodiments, the provided compound or composition is formulated for administration to a patient in need of such a composition. According to the methods of the present disclosure, the compounds and compositions can be administered in any amount and by any route of administration effective to treat or alleviate the severity of any disease or disorder described herein. For ease of administration and uniformity of dosage, it is preferred to formulate the provided compound in dosage unit form. As used herein, the expression "dosage unit form" refers to physically discrete units of medicament suitable for the patient to be treated. However, it should be understood that the total daily usage of the provided compounds and compositions will be decided by the attending physician within the scope of reasonable medical judgment. The specific effective dose level for any particular patient or organism will vary depending on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed and its route of administration; the species, age, weight, sex, and diet of the patient; the general condition of the subject; the time of administration; the excretion rate of the specific compound employed; the duration of the treatment; drugs used in combination with or concurrently with the specific compound employed, etc.

[0712] The provided composition can be administered orally, parenterally, by inhalation or nasal spray, topically (e.g., by powder, ointment, or drops), rectally, buccally, vaginally, intraperitoneally, intrathecally, or by an implanted reservoir, depending on the severity of the condition being treated. Preferably, the composition is administered orally, intraperitoneally, or intravenously. In certain embodiments, the provided compound is administered orally or parenterally at a dose level of about 0.01 mg / kg to about 50 mg / kg of the subject body weight per day, one or more times per day, to obtain the desired therapeutic effect.

[0713] As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intraliver, intralesional and intracranial injection or infusion techniques. The sterile injectable form of the provided compositions can be aqueous or oleaginous suspensions. These suspensions can be prepared according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be employed include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly employed as a solvent or suspending medium.

[0714] For this purpose, any mild fixed oil can be employed, including synthetic mono- or di-glycerides of fatty acids. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersing agent such as carboxymethylcellulose or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants (such as Tweens, Spans and other emulsifying agents or bioavailability enhancers) commonly used in the preparation of pharmaceutically acceptable solid, liquid or other dosage forms can also be used for the purposes of formulation.

[0715] The injectable preparation can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporation of a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0716] To prolong the effect of the compounds provided, it is often necessary to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution which in turn depends upon crystal size and form. Alternatively, delayed absorption of a compound form administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming microcapsule matrices of the compound in a biodegradable polymer such as polylactide-polyglycolide. The rate of release of the compound can be controlled according to the ratio of the compound to the polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable preparations are also prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissue.

[0717] The pharmaceutically acceptable compositions described herein can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In such solid dosage forms, the active compound can be admixed with at least one inert diluent such as sucrose, lactose or starch. In accordance with conventional practice, such dosage forms may also contain additional substances in addition to the inert diluent, e.g., lubricants and other tabletting aids such as magnesium stearate and microcrystalline cellulose. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0718] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dibasic calcium phosphate and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite, and / or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. The active compounds can also be in microencapsulated form with one or more of the excipients as described above.

[0719] Using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc., similar types of solid compositions can also be used as fillers in soft or hard gelatin capsules. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings (i.e., buffering agents) and other coatings well known in the art of pharmaceutical formulation. They may optionally contain opacifying agents and may also be compositions that release the active ingredient only or preferentially in a delayed manner in a particular part of the intestine. Examples of embedding compositions that can be used include polymeric materials and waxes.

[0720] Liquid dosage forms for oral administration include, but are not limited to: pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art (such as, for example, water or other solvents), solubilizing agents, and emulsifying agents (such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butanediol, dimethylformamide, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof). In addition to the inert diluent, the oral compositions may further contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0721] Alternatively, the pharmaceutically acceptable compositions described herein may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the compounds of the present disclosure with a suitable non - irritating excipient or carrier that is solid at room temperature but liquid at body (e.g., rectal or vaginal) temperature and will thus melt in the rectal or vaginal cavity to release the active compound. Such materials include cocoa butter, suppository waxes (e.g., beeswax), and polyethylene glycols.

[0722] The pharmaceutically acceptable compositions described herein may also be administered topically, particularly when the treatment target includes areas or organs that can be readily accessed by topical administration, including diseases of the eye, skin, or lower intestine. Topical application for the lower intestine can be achieved in rectal suppository formulations (see above) or in suitable enema formulations.

[0723] Dosage forms for topical or transdermal administration of the provided compounds include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. Under sterile conditions, the active ingredient is mixed with a pharmaceutically acceptable carrier and any preservatives or buffers that may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate - controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0724] For topical application, the provided pharmaceutically acceptable compositions can be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to: mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0725] For ophthalmic applications, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably, as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic applications, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[0726] The pharmaceutically acceptable compositions of the present disclosure can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical formulation art, using benzyl alcohol or other suitable preservatives, absorption enhancers (to enhance bioavailability), fluorocarbons, and / or other conventional solubilizing or dispersing agents, and can be prepared as solutions in saline.

[0727] Most preferably, the pharmaceutically acceptable compositions of the present disclosure are formulated for oral administration.

[0728] Identification and / or characterization of compounds and / or compositions

[0729] The present disclosure particularly provides various techniques for identifying and / or characterizing the compounds and / or compositions described herein. For example, the present disclosure provides various assays for evaluating SARM1 inhibitory activity, and particularly for evaluating SARM1 inhibitory activity.

[0730] In certain embodiments, the performance of one or more compounds or compositions of interest in an assay as described herein is compared to an appropriate reference. For example, in certain embodiments, the reference can be the absence of the relevant compound or composition. Alternatively or additionally, in certain embodiments, the reference can be the presence of an alternative compound or composition, such as the alternative compound or composition having a known performance in the relevant assay (e.g., as understood in the art, as a positive or negative control). In certain embodiments, the reference can be an alternative but comparable set of conditions (e.g., temperature, pH, salt concentration, etc.). In certain embodiments, the reference can be the performance of a compound or composition relative to a SARM1 variant.

[0731] Still further alternatively or additionally, in certain embodiments, the performance of one or more compounds or compositions of interest in an assay as described herein can 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 the reference.

[0732] In certain embodiments, multiple compounds or compositions of interest can be analyzed in a particular assay and / or compared to the same reference. In certain embodiments, such multiple compounds or compositions can be or include a set of compounds or compositions that are considered a "library" due to multiple members sharing one or more characteristics (e.g., structural elements, source identity, synthetic similarity, etc.).

[0733] Certain exemplary assays useful in the practice of the present disclosure are illustrated in the Examples below. Those skilled in the art reading the present disclosure will recognize that useful or relevant systems for identifying and / or characterizing compounds and / or compositions according to the present disclosure are not limited to those included in the Examples or otherwise discussed below.

[0734] In certain embodiments, compounds and / or compositions can be identified and / or characterized based on one or more activities or features, such as, for example: promoting axonal integrity, cytoskeletal stability, and / or neuronal survival. In certain embodiments, the provided SARM1 inhibitors inhibit the catabolism of NAD+ by SARM1. In certain embodiments, the provided SARM1 inhibitors slow the rate of NAD+ catabolism.

[0735] In certain embodiments, the provided SARM1 inhibitors reduce or inhibit the binding of SARM1 to NAD+. In certain embodiments, the provided SARM1 inhibitors bind to SARM1 within a pocket (e.g., the catalytic cleft of SARM1) that contains one or more catalytic residues. Examples of such catalytic residues include Glutamate at position 642 (E642).

[0736] In certain embodiments, the provided SARM1 inhibitors disrupt and / or prevent the polymerization of the TIR1 domain of SARM1. In certain embodiments, the provided SARM1 inhibitors disrupt the polymerization of the SAM domain. In certain embodiments, the provided SARM1 inhibitors disrupt the axonal signaling cascade that results in NAD+ consumption.

[0737] In certain embodiments, the present disclosure provides assays that can be used to identify and / or characterize one or more activities and / or properties of a compound and / or composition of interest. For example, in certain embodiments, the present disclosure provides in vitro, cellular, and / or in vivo systems for evaluating one or more such activities and / or properties.

[0738] SARM1 activity assay

[0739] In certain 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 intrinsic activity; b) incubating the mixture; c) quantifying the NAD+ in the incubated mixture; and d) identifying the candidate inhibitor compound as an inhibitor if the amount of NAD+ is greater than the amount in a control mixture that does not contain the candidate inhibitor.

[0740] In certain embodiments, a method for identifying a SARM1 inhibitor is provided, which comprises: a) providing a mixture comprising i) full-length SARM1, ii) NAD+, and iii) a candidate inhibitor, wherein the full-length SARM1 has intrinsic activity; b) incubating the mixture; c) quantifying the NAD+ and ADPR (or cADPR) in the incubated mixture; d) determining the molar ratio of NAD+:ADPR (or cADPR); and e) identifying the candidate inhibitor compound as an inhibitor if the molar ratio is greater than the molar ratio of a control mixture that does not contain the candidate inhibitor.

[0741] In certain embodiments, methods for identifying SARM1 inhibitors are provided, which include: a) providing a mixture comprising a solid support to which is bound i) full-length SARM1 and at least one tag, ii) NAD+, and iii) a candidate inhibitor; b) incubating the mixture; c) quantifying the NAD+ after incubation; and d) identifying the candidate inhibitor compound as a SARM1 inhibitor if the concentration of NAD+ is greater than the concentration of a control.

[0742] SARM1 binding assay

[0743] In certain embodiments, the potency of the provided SARM1 inhibitor can be determined according to assays described, for example, in WO 2018 / 057989 published on March 29, 2018, which is hereby incorporated by reference in its entirety. In certain embodiments, the provided SARM1 inhibitor can be applied to a solution containing SARM1 or a fragment thereof. In certain embodiments, the provided SARM1 inhibitor can be applied to an in vitro system. In certain embodiments, the provided SARM1 inhibitor can be applied in vivo. In certain embodiments, the provided SARM1 inhibitor can be applied to a patient. In certain embodiments, the SARM1 inhibitor can be mixed with SARM1 or a fragment thereof that has been labeled with an epitope tag. In certain embodiments, the amount of the bound SARM1 inhibitor can be compared with the amount of the unbound SARM1 inhibitor to generate an affinity for the SARM1 inhibitor.

[0744] In certain embodiments, a mutant or fragment of SARM1 is the SAM-TIR fragment with intrinsic activity. Fragments of SARM1 with intrinsic activity include, for example and without limitation, SARM1 with the autoinhibitory domain deleted; at least one point mutation in SARM1 that inactivates the autoinhibitory domain; a fragment of SARM1 containing the TIR domain; or a fragment of SARM1 consisting of the SAM and TIR domains. In certain embodiments, the SARM1 polypeptide can include one or more additional amino acid sequences that can serve as tags, such as His tags, streptavidin tags, or combinations thereof. In certain embodiments, the SARM1 polypeptide can include a tag at the amino terminus, at the carboxyl terminus, or a combination thereof. In certain embodiments, SARM1 or a fragment thereof labeled with an epitope tag can be used to measure the binding potency of the provided SARM1 inhibitor.

[0745] Purification of the SARM1-TIR domain

[0746] In certain embodiments, the SARM1-TIR domain can be engineered with various proteins or epitopes, tags useful in purification, for example. In certain embodiments, the present disclosure also provides an NRK1-HEK293T cell line comprising HEK293T cells transformed with nicotinamide riboside kinase 1 (NRK1). In certain embodiments, HEK293T cells are transformed or transfected with a DNA sequence encoding nicotinamide riboside kinase 1 (NRK1). In certain embodiments, the DNA encoding NRK1 can be genomic or cDNA. In certain embodiments, HEK293T cells are stably or transiently transfected with DNA encoding NRK1 from a source outside the host cell. In certain embodiments, HEK293T cells are stably or transiently transfected with DNA encoding NRK1 such that the cells express NRK1 at elevated levels compared to control cells. In certain embodiments, the DNA encoding NRK1 is under the control of one or more exogenous regulatory DNA sequences such as a promoter, enhancer, or combination thereof. In certain embodiments, the combination of the DNA sequence encoding NRK1 and the regulatory sequence is a non-naturally occurring combination. In certain embodiments, the DNA encoding NRK1 (genomic or cDNA) comprises an expression vector such as an FCIV expression vector. In certain 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 Drosophila. In certain configurations, the NRK1 DNA is human NRK1 DNA.

[0747] Applications and uses

[0748] The present disclosure provides various uses and applications of the compounds and / or compositions described herein, for example, based on their activities and / or characteristics as described herein. In certain embodiments, such uses can include therapeutic and / or diagnostic uses. Alternatively, in certain embodiments, such uses can include research, production, and / or other technical uses.

[0749] In one aspect, the present disclosure provides a method comprising administering to a subject one or more compounds of Formula I or Formula I' to, for example, treat, prevent, or reduce the risk of developing one or more conditions characterized by axonal degeneration. In certain such embodiments, the compound of Formula I or Formula I' is a SARM1 inhibitor.

[0750] Another embodiment of the present disclosure relates to a method of inhibiting SARM1 activity in a patient, comprising the step of administering to the patient the provided compound or a composition comprising the compound.

[0751] Inhibition of enzymes in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, biological assays, gene expression studies, and identification of biological targets.

[0752] In certain embodiments, the present disclosure relates to methods of treating axonal degeneration in a biological sample, which include the step of contacting the biological sample with a compound or composition of Formula I or Formula I'. In certain embodiments, one or more compounds and / or compositions as described herein can be used, for example, as a method of inhibiting the degradation of neurons derived from a subject. In certain embodiments, one or more compounds and / or compositions as described herein can be used to inhibit the degeneration of neurons or portions thereof cultured in vitro. In certain embodiments, one or more compounds and / or compositions as described herein can be used as a stabilizer to promote the survival of neurons in vitro.

[0753] In certain embodiments, the provided compounds and / or compositions inhibit the NADase activity of SARM1. Alternatively or additionally, in certain embodiments, the provided compounds mitigate one or more characteristics of neurodegeneration. In certain embodiments, the present disclosure provides methods of treating neurodegenerative diseases or disorders associated with axonal degeneration.

[0754] In certain embodiments, one or more compounds and / or compositions as described herein can be used, for example, in medical practice. In certain embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat, prevent, or improve axonal degeneration (e.g., one or more of its characteristics or properties). In certain 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 decrease or depletion of NAD+. In certain embodiments, one or more compounds and / or compositions as described herein can be used, for example, to prevent axons distal to an axonal injury from undergoing degeneration.

[0755] In certain embodiments, one or more compounds and / or compositions as described herein can be used, for example, as a method of inhibiting the degradation of neurons or portions thereof in the peripheral nervous system. In certain embodiments, one or more compounds and / or compositions as described herein can be used, for example, as a method of inhibiting or preventing the degeneration of neurons or portions thereof in the central nervous system. In certain embodiments, one or more compounds or compositions as described herein are characterized in that, when administered to a population of subjects, they reduce one or more symptoms or characteristics of neurodegeneration. For example, in certain embodiments, the relevant symptoms or characteristics can be selected from the degree, rate, and / or timing of neuronal destruction.

[0756] In certain embodiments, the present disclosure provides compounds that can be used, according to the present disclosure, as, for example, analytical tools, as probes in biological assays, or as therapeutic agents. The compounds provided by the present disclosure can also be used for the study of SARM1 activity in biological and pathological phenomena and for the comparative evaluation of new SARM1 activity inhibitors in vitro or in vivo. In certain embodiments, the present disclosure provides assays for identifying and / or characterizing the compounds and / or compositions provided herein. In certain embodiments, the provided assays utilize specific reagents and / or systems (e.g., certain vector constructs and / or polypeptides) that can be used to assay SARM1 activity. For example, in certain embodiments, the provided assays can utilize, for example, SAM-TIR (wherein the SARM1 N-terminal autoinhibitory domain has been deleted) and / or one or more labeled versions of the TIR domain.

[0757] In certain embodiments, one or more compounds and / or compositions as described herein can be used, for example, in a method for inhibiting the degradation of neurons derived from a subject. In certain embodiments, one or more compounds and / or compositions as described herein can be used to inhibit the degeneration of neurons or portions thereof cultured in vitro. In certain embodiments, one or more compounds and / or compositions as described herein can be used as stabilizers to promote neuron survival in vitro.

[0758] In certain embodiments, one or more compounds and / or compositions as described herein can be used, for example, to affect biomarkers associated with neurodegeneration. In certain embodiments, changes in biomarkers can be detected systemically or with samples from cerebrospinal fluid (CSF), plasma, serum, and / or tissue from a subject. In certain embodiments, one or more compounds and / or compositions can be used to affect changes in the concentration of neurofilament light chain (NF-L) and / or neurofilament heavy chain (NF-H) contained in the cerebrospinal fluid of a subject. In certain embodiments, one or more compounds and / or compositions as described herein can affect constitutive NAD and / or cADPR levels in neurons and / or axons.

[0759] In certain embodiments, one or more biomarkers of neurodegeneration comprise: the concentration of neurofilament light chain protein (NF-L) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from a subject; the concentration of neurofilament heavy chain protein (NF-H) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from a subject; the concentration of ubiquitin C-terminal hydrolase L1 (UCH-L1) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from a subject; the concentration of α-synuclein in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from a subject; the constitutive NAD+ level in neurons and / or axons of a subject; the constitutive cADPR level in neurons and / or axons of a subject; the levels of albumin, amyloid-β (Aβ) 38, Aβ40, Aβ42, glial fibrillary acidic protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractant protein (MCP)-1, neurogranin, neuron-specific enolase (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phosphorylated-tau protein (phospho-tau), and / or total-tau protein (total-tau) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, a skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from a subject; and the levels of C-C motif chemokine ligand (CCL) 2, CCL7, CCL12, colony stimulating factor (CSF) 1, or interleukin (IL) 6 in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, a skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from a subject.

[0760] In certain embodiments, one or more compounds and / or compositions as described herein can effect a detectable change in the levels 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 protein (phospho-tau), and / or total-tau protein (total-tau). In certain embodiments, one or more compounds and / or compositions as described herein can effect a change in cytokines and / or chemokines (including, but not limited to, Ccl2, Ccl7, Ccl12, Csf1, and / or Il6).

[0761] Diseases, disorders, and conditions

[0762] In certain embodiments, a compound and / or composition as described herein can be administered to a subject suffering from one or more diseases, disorders, or conditions. In certain embodiments, the one or more diseases, disorders, or conditions are mediated by SARM1.

[0763] In certain embodiments, a neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.

[0764] In certain embodiments, the neurodegenerative disease or disorder comprises an acute disease or disorder of the PNS. In certain embodiments, the acute disease or disorder of the PNS is the result of a mechanical injury, a thermal injury, or an injury caused by a chemical agent or chemotherapy. In certain embodiments, the mechanical injury comprises a compression or crush injury or a pressure injury. In certain embodiments, the compression or crush injury comprises carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture, or a dislocated bone. In certain embodiments, the pressure injury comprises pressure involving a superficial nerve, pressure from a tumor, or increased intraocular pressure. In certain embodiments, the chemical agent or chemotherapy comprises a cytotoxic anti-cancer agent, thalidomide, epothilone, taxane, vinca alkaloid, proteasome inhibitor, platinum-based drug, or auristatin. In certain embodiments, the epothilone is ixabepilone. In certain embodiments, the taxane is paclitaxel or docetaxel. In certain embodiments, the vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine. In certain embodiments, the proteasome inhibitor is bortezomib. In certain embodiments, the platinum-based drug is cisplatin, oxaliplatin, or carboplatin. In certain embodiments, the auristatin is conjugated monomethyl auristatin E.

[0765] In certain embodiments, the neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS. In certain embodiments, the chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder.

[0766] In certain embodiments, the chronic disease or disorder of the PNS comprises a hereditary neuropathy, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathy, or other peripheral neuropathies.

[0767] In certain embodiments, the systemic disorder comprises diabetes, uremia, AIDS, leprosy, malnutrition, atherosclerosis, intestinal neuropathy, axonalopathy, Guillain-Barré syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.

[0768] In certain embodiments, pain disorders include chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, cancer pain, arthritis, sciatica, headache, surgical pain, muscle spasm, back pain, visceral pain, injury pain, toothache, neuropathic pain, neuralgia, neuroinflammation, nerve injury, shingles, herniated disc, torn ligament, or diabetes.

[0769] In certain embodiments, metabolic diseases or disorders include diabetes, hypoglycemia, uremia, hypothyroidism, liver failure, polycythemia, amyloidosis, acromegaly, porphyria, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), disorders of lipid / glycolipid metabolism, malnutrition, vitamin deficiency, or mitochondrial disease.

[0770] In certain embodiments, neurodegenerative diseases or disorders include acute diseases or disorders of the CNS. In certain embodiments, acute diseases or disorders of the CNS include ischemia, traumatic CNS injury, injury caused by chemical agents, thermal injury, or viral encephalitis.

[0771] In certain embodiments, ischemia includes cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.

[0772] In certain embodiments, traumatic CNS injury includes spinal cord injury, TBI, mechanical injury to the head and / or spine, traumatic injury to the head and / or spine, blunt force trauma, closed head injury, open head injury, exposure to impact and / or blast forces, penetrating injury to the CNS, increased intraocular pressure, or injury caused by forces that cause axonal deformation, stretch, crush, or breakage.

[0773] In certain embodiments, viral encephalitis includes enteroviral encephalitis, arboviral encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).

[0774] In certain embodiments, neurodegenerative diseases or disorders include chronic diseases or disorders of the CNS.

[0775] In certain embodiments, chronic diseases or disorders of the CNS include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, dementia with Lewy bodies, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig Syndrome, transverse myelitis, motor neuron disease, spinocerebellar ataxia, preeclampsia, hereditary spastic paraplegia, spastic paraparesis, familial spastic paraplegia, French Settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supranuclear palsy (PSP), Friedreich's ataxia or spinal cord injury. In certain embodiments, the chronic disease or disorder of the CNS is neurotoxic hearing loss. In certain such embodiments, the neurotoxic hearing loss is caused by chemotherapy or antibiotics.

[0776] In certain embodiments, the chronic disease or disorder of the CNS includes optic nerve disorders, traumatic CNS injury or metabolic diseases or disorders.

[0777] In certain embodiments, the optic nerve disorders include acute optic neuropathy (AON), hereditary or idiopathic retinal disorders, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, outer retinal neuropathy, optic neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, ischemic optic neuropathy, vitamin B12 deficiency, folate (vitamin B9) deficiency, isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol or exposure to cyanide.

[0778] In certain embodiments, the disease or disorder of the CNS is a Tauopathy. In certain such embodiments, the Tauopathy occurs as a result of progressive supranuclear palsy or corticobasal degeneration.

[0779] In certain embodiments, the neurodegenerative disease or disorder is caused or induced by protein misfolding.

[0780] In certain embodiments, the neurodegenerative disease or disorder is a synucleinopathy, such as, for example, the abnormal accumulation of aggregates of α-synuclein protein in neurons.

[0781] In certain embodiments, the neurodegenerative disease or disorder is multiple system atrophy.

[0782] In certain embodiments, the traumatic CNS injury includes traumatic brain injury (TBI), spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE).

[0783] In certain embodiments, the metabolic disease or disorder includes diabetes, hypoglycemia, Batten-Korn syndrome, uremia, hypothyroidism, liver failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid / glycolipid metabolism, nutritional / vitamin deficiencies and mitochondrial diseases.

[0784] In certain embodiments, the neurodegenerative disease or disorder includes diseases associated with neurodegeneration. In certain embodiments, the neurodegenerative disease or disorder is caused by coagulation problems, inflammation, obesity, aging, stress, cancer or diabetes.

[0785] In certain embodiments, the disorder is acute peripheral neuropathy. Chemotherapy-induced peripheral neuropathy (CIPN) is an example of acute peripheral neuropathy. CIPN can be associated with various drugs, such as, but not limited to, thalidomide, epothilones (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).

[0786] In certain embodiments, one or more of the compounds and / or compositions described herein can be used, for example, to treat one or more neurodegenerative diseases, disorders, or conditions selected from neuropathy or axonopathy. In certain embodiments, one or more of the compounds and / or compositions described herein can be used, for example, to treat neuropathy or axonopathy associated with axonal degeneration. In certain embodiments, the neuropathy associated with axonal degeneration is a hereditary or congenital neuropathy or axonopathy. In certain embodiments, the neuropathy associated with axonal degeneration results from a primary or somatic mutation. In certain embodiments, the neuropathy associated with axonal degeneration is selected from the list contained herein. In certain embodiments, the neuropathy or axonopathy associated with axonal degeneration includes, but is not limited to, Parkinson's disease, non-Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating diseases, ischemia or stroke, chemical injury, thermal injury, and AIDS.

[0787] In certain embodiments, one or more compounds or compositions as described herein are characterized by reducing one or more symptoms or features of neurodegeneration when administered to a population of subjects. For example, in certain embodiments, the relevant symptoms or features may be selected from the degree, rate, and / or timing of neuronal destruction. In certain embodiments, neuronal destruction may be or include axonal degradation, loss of synapses, loss of dendrites, loss of synaptic density, loss of dendritic branching, loss of axonal branching, loss of neuronal density, loss of myelination, loss of neuronal cell bodies, loss of synaptic potentiation, loss of action potential enhancement, loss of cytoskeletal stability, loss of axonal transport, loss of ion channel synthesis and turnover, loss of neurotransmitter synthesis, loss of neurotransmitter release and reuptake capabilities, loss of axonal potential propagation, neuronal hyperexcitability, and / or neuronal hypoexcitability. In certain embodiments, neuronal destruction is characterized by the inability to maintain an appropriate neuronal membrane resting potential. In certain embodiments, neuronal destruction is characterized by the appearance of inclusion bodies, plaques, and / or neurofibrillary tangles. In certain embodiments, neuronal destruction is characterized by the appearance of stress granules. In certain embodiments, neuronal destruction is characterized by the intracellular activation of one or more members of the cysteine-aspartic protease (caspase) family. In certain embodiments, neuronal destruction is characterized by the occurrence of programmed cell death (e.g., apoptosis, pyroptosis, ferroapoptosis, and / or necrosis) and / or inflammation of neurons.

[0788] In certain embodiments, a neurodegenerative or neurological disease or disorder is associated with: axonal degeneration, axonal injury, axonopathy, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal injury caused by leukodystrophy or leukodystrophy. In certain embodiments, the neurodegenerative or neurological disease or disorder is selected from: spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Pelizaeus-Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Huntington disease, Alzheimer disease, Parkinson disease, Tay-Sachs disease, Gaucher disease, Hurler syndrome, traumatic brain injury, post-radiation injury, neurological complications of chemotherapy (chemotherapy-induced neuropathy; CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Barré-Cornil syndrome, glaucoma, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy, West Nile virus encephalitis, La Crosse virus encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supranuclear palsy (PSP), Friedreich ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, severe acute motor axonal neuropathy (AMAN), Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, spinocerebellar ataxia, preeclampsia, hereditary spastic paraplegia, spastic paraparesis, familial spastic paraplegia, French Settlement disease, Strumpell-Lorrain disease, and non-alcoholic steatohepatitis (NASH).

[0789] In certain embodiments, the present disclosure provides inhibitors of SARM1 activity for treating neurodegenerative or neurological diseases or disorders involving axonal degeneration or axonopathy. The present disclosure also provides methods of treating, preventing or ameliorating axonal degeneration, axonopathy, and neurodegenerative or neurological diseases or disorders involving axonal degeneration using inhibitors of SARM1 activity.

[0790] In certain embodiments, the present disclosure provides methods of treating neurodegenerative or neurological diseases or disorders associated with axonal degeneration, axonal injury, axonopathy, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal injury caused by leukodystrophy or leukodystrophy.

[0791] In certain embodiments, neuropathy and axonopathy include any disease or condition involving neurons and / or supporting cells such as, for example, glia, muscle cells or fibroblasts, and particularly those diseases or conditions involving axonal injury. Axonal injury can be caused by traumatic injury or non-mechanical injury attributable to a disease, condition or exposure to a toxic molecule or drug. The result of such injury can be degeneration or dysfunction of the axon and loss of functional neuronal activity. Diseases and conditions that produce such axonal injury or are associated with such axonal injury fall within a large number of neuropathic diseases and conditions. Such neuropathies can include peripheral neuropathies, central neuropathies and combinations thereof. In addition, peripheral neuropathy manifestations can be produced by diseases initially concentrated in the central nervous system, and central nervous system manifestations can be produced by diseases that are primarily peripheral or systemic.

[0792] In certain embodiments, peripheral neuropathy can involve damage to the peripheral nerves, and / or can be caused by diseases of the nerves or as a result of systemic diseases. Some such diseases can include diabetes, uremia, infectious diseases such as AIDS or leprosy, malnutrition, vascular or collagen disorders such as atherosclerosis, and autoimmune diseases such as systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, and polyarteritis nodosa. In certain embodiments, peripheral nerve degeneration results from traumatic (mechanical) injury to the nerves as well as chemical or thermal injury to the nerves. Conditions that damage peripheral nerves include compressive or crush injuries such as glaucoma, carpal tunnel syndrome, direct trauma, penetrating injuries, contusions, fractures or dislocations of bone; pressure on superficial nerves (ulnar, radial, or peroneal), which can result from prolonged use of axillary crutches or maintaining a position for too long, or from tumors; intraneural hemorrhage; ischemia; exposure to cold or radiation or certain pharmaceuticals or toxic substances such as herbicides or pesticides. In particular, nerve injury can result from chemical injury, which is attributed to cytotoxic anticancer agents such as, for example, Taxol, cisplatin, proteasome inhibitors, or vinca alkaloids such as vincristine. Typical symptoms of such peripheral neuropathy include weakness, numbness, paresthesia (abnormal sensations such as burning, itching, tingling, or prickling), and pain in the arms, hands, legs, and / or feet. In certain embodiments, neuropathy is associated with mitochondrial dysfunction. Such neuropathy can exhibit reduced energy levels, i.e., reduced NAD and ATP levels.

[0793] In certain embodiments, peripheral neuropathy is metabolic and endocrine neuropathy, which includes a wide range of peripheral nerve disorders associated with systemic diseases of metabolic origin. These diseases include, for example, diabetes, hypoglycemia, uremia, hypothyroidism, liver failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid / glycolipid metabolism, nutritional / vitamin deficiencies, and mitochondrial diseases, among others. A common hallmark of these diseases is the involvement of the peripheral nerves through changes in the structure or function of myelin and axons caused by abnormal regulation of metabolic pathways.

[0794] In certain embodiments, neuropathies include optic neuropathies such as glaucoma; retinal ganglion degenerations such as those associated with retinitis pigmentosa and outer retinal neuropathies; optic neuritis and / or degeneration, including those associated with multiple sclerosis; traumatic injuries to the optic nerve, which can include, for example, injuries during tumor removal; hereditary optic neuropathies such as Kjer's disease and Leber's hereditary optic neuropathy; ischemic optic neuropathies such as those secondary to giant cell arteritis; metabolic optic neuropathies such as neurodegenerative diseases, including the previously mentioned Leber's neuropathy, nutritional deficiencies such as deficiencies of vitamin B12 or folic acid, and toxicities such as those attributed to ethambutol or cyanide; neuropathies caused by adverse drug reactions and neuropathies caused by vitamin deficiencies. Ischemic optic neuropathies also include non-arteritic anterior ischemic optic neuropathy. In certain embodiments, the optic neuropathy is age-related macular degeneration.

[0795] In certain embodiments, neurodegenerative diseases associated with neuropathies or axonopathies in the central nervous system include a variety of diseases. Such diseases include: diseases involving progressive dementia, such as, for example, Alzheimer's disease, senile dementia, Pick's disease, and Huntington's disease; central nervous system diseases affecting muscle function, such as, for example, Parkinson's disease, motor neuron diseases, and progressive ataxias such as amyotrophic lateral sclerosis; demyelinating diseases such as, for example, multiple sclerosis; viral encephalitides such as those caused by enteroviruses, arboviruses, and herpes simplex virus; and prion diseases. Mechanical injuries such as glaucoma or traumatic injuries to the head and spine can also cause nerve damage and degeneration in the brain and spinal cord. In addition, ischemia and stroke, as well as conditions such as nutritional deficiencies and chemical toxicities such as chemotherapeutic agents, can cause central nervous system neuropathies.

[0796] In certain embodiments, the present disclosure provides a method of treating a neuropathy or axonopathy associated with axonal degeneration. In certain such embodiments, the neuropathy or axonopathy associated with axonal degeneration can be any of a number of neuropathies or axonopathies, such as, for example, those that are hereditary or congenital, or those associated with Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating diseases, ischemia or stroke, chemical injury, thermal injury, and AIDS. In addition, neurodegenerative diseases not mentioned above, as well as subsets of the diseases mentioned above, can also be treated by the methods of the present disclosure. Such subsets of diseases can include Parkinson's disease or non-Parkinson's disease or Alzheimer's disease.

[0797] Subject

[0798] In certain embodiments, a compound and / or composition as described herein is administered to a subject suffering from or susceptible to a disease, disorder, or condition as described herein; in certain embodiments, such a disease, disorder, or condition is characterized by axonal degeneration, such as one of the conditions mentioned herein.

[0799] In certain embodiments, the subject to which the compound or composition is administered as described herein exhibits one or more signs or symptoms associated with axonal degeneration; in certain embodiments, the subject does not exhibit any signs or symptoms of neurodegeneration.

[0800] In certain embodiments, the provided method comprises administering a compound of Formula I or Formula I' to a patient in need thereof. In certain such embodiments, the patient is at risk of developing a condition characterized by axonal degeneration. In certain embodiments, the patient has a condition characterized by axonal degeneration. In certain embodiments, the patient has been diagnosed with a condition characterized by axonal degeneration.

[0801] In certain embodiments, the provided method comprises administering a composition as described herein to a population of patients in need thereof. In certain embodiments, the population is from individuals engaged in activities with a high likelihood of traumatic neuronal injury. In certain embodiments, the population is from athletes engaged in contact sports or other high-risk activities.

[0802] In certain embodiments, the subject is at risk of developing a condition characterized by axonal degeneration. In certain embodiments, the subject is identified as being at risk of 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.

[0803] In certain embodiments, the patient is at risk of developing a neurodegenerative disorder. In certain embodiments, the patient is elderly. In certain embodiments, the patient is known to have a genetic risk factor for neurodegeneration. In certain embodiments, the patient has a family history of neurodegenerative disease. In certain embodiments, the patient expresses one or more copies of a known genetic risk factor for neurodegeneration. In certain embodiments, the patient is from a population with a high incidence of neurodegeneration. In certain embodiments, the patient has a hexanucleotide repeat expansion in chromosome 9 open reading frame 72. In certain embodiments, the patient has one or more copies of the ApoE4 allele.

[0804] In certain embodiments, the subject to which the compounds or compositions described herein are administered can be or can include a subject suffering from or susceptible to a neurodegenerative disease, disorder, or condition. In certain embodiments, the neurodegenerative disease, disorder, or condition can be or can include traumatic neuronal injury. In certain embodiments, the traumatic neuronal injury is blunt force trauma, closed head injury, open head injury, exposure to impact and / or blast forces, penetrating injury to the cranial cavity or innervated regions of the body. In certain embodiments, the traumatic neuronal injury is a force that causes axonal deformation, stretching, crushing, or breakage.

[0805] In certain embodiments, the subject engages in activities identified as risk factors for neuronal degradation, e.g., a subject participating in a contact sport or having an occupation with a high likelihood of traumatic neuronal injury.

[0806] For example, the subject can be a patient receiving or prescribed chemotherapy associated with peripheral neuropathy. Examples of chemotherapeutic agents include, but are not limited to, thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

[0807] In certain embodiments, the provided method includes administering to a patient or patient population a composition as described herein based on the presence or absence of one or more biomarkers. In certain embodiments, the provided method further includes monitoring biomarker levels in the patient or patient population and adjusting the dosing regimen accordingly.

[0808] Dosage

[0809] Those skilled in the art will understand that in certain embodiments, the exact amount of a particular compound included in and / or delivered by administration of a pharmaceutical composition or regimen as described herein can be selected by a medical practitioner and can vary for different subjects, e.g., taking into account one or more of the following: the species, age, and general condition of the subject; and / or the properties of the particular compound or composition, its mode of administration, etc. Alternatively, in certain embodiments, the amount of a particular compound included in and / or delivered by administration of a pharmaceutical composition or regimen as described herein can 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.).

[0810] For ease of administration and uniformity of dosage, the provided compounds or compositions of the present disclosure are preferably formulated in unit dosage form. As used herein, the expression "unit dosage form" refers to physically discrete units of medicament suitable for the patient to be treated. However, it should be understood that the total daily dosage of the provided compounds or compositions will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the clinical condition of the individual patient; the cause of the disorder; the activity of the specific compound being used; the specific composition being used; the age, weight, general health, sex and diet of the patient; the time of administration, the site of delivery of the medicament, the route of administration and the rate of excretion of the specific compound being employed; the duration of the treatment; drugs used in combination with or concurrently with the specific compound being used, and similar factors well known in the medical arts. The effective amount of the compound to be administered will depend on such considerations and is the minimum amount necessary to inhibit SARM1 activity as required for the prevention or treatment of an undesirable disease or disorder, such as, for example, neurodegeneration or traumatic nerve injury.

[0811] The pharmaceutically acceptable compositions of the present disclosure can be administered orally, rectally, intravenously, parenterally, intracisternally, vaginally, intraperitoneally, topically (such as by powder, ointment or drops), sublingually, as an oral or nasal spray, etc., depending on the severity of the disease, disorder or infection being treated. In certain embodiments, the daily dose is administered as a single daily dose, or in divided doses two to six times a day, or in a sustained release form. The dosing regimen can be adjusted to provide optimal efficacy. The compounds can be administered according to a regimen of 1 - 4 times a day, preferably once or twice a day.

[0812] In certain embodiments, the compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, sublingually, vaginally or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intraliver, intradermal, intraocular, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

[0813] In certain embodiments, the pharmaceutically acceptable compositions of the present disclosure can also be administered topically, particularly when the treatment target includes regions or organs that can be readily accessed by topical administration, including diseases of the eye, skin or lower intestine. Suitable topical formulations can be readily prepared for each of these regions or organs.

[0814] Most preferably, the pharmaceutically acceptable compositions of the present disclosure are formulated for oral administration. Such formulations may be administered with or without food. In certain 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.

[0815] Those additional agents may be administered separately from the provided compound or its composition as part of a multi-dose regimen. Alternatively, those agents may be part of a single dosage form, mixed with the provided compound in a single composition. If administered as part of a multi-dose regimen, the two active agents may be administered simultaneously, sequentially, or within a certain time of each other (usually within five hours of each other).

[0816] It should also be understood that the specific dosage and treatment regimen for any particular patient may depend on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. In certain embodiments, the amount of the compound of the present disclosure in the composition also depends on the specific compound in the composition.

[0817] In certain embodiments, SARM1 inhibition as described herein may be used in combination with one or more other therapies to treat related diseases, disorders, or conditions. In certain embodiments, the dosage of the SARM1 inhibitor is altered when used in combination therapy compared to when administered as a single therapy; alternatively or additionally, in certain embodiments, the therapies administered in combination with SARM1 inhibition as described herein are administered according to a specific protocol or procedure that is different from its protocol or procedure when administered alone or in combination with one or more therapies other than SARM1 inhibition. In certain embodiments, a composition comprises an additional therapeutic agent, and the additional therapeutic agent and the provided compound may act synergistically. In certain embodiments, one or both of the therapies used in the combination regimen are administered at a lower level or frequency compared to when it is used as a single therapy.

[0818] In certain embodiments, the compounds and / or compositions described herein are administered with a chemotherapeutic agent, which includes but is not limited to alkylating agents, anthracycline antibiotics, taxanes, epothilones, histone deacetylase inhibitors, topoisomerase inhibitors, kinase inhibitors, nucleotide analogs, peptide antibiotics, platinum-based agents, retinoids, vinca alkaloids, and derivatives. In certain embodiments, the compounds and / or compositions described herein are administered in combination with a PARP inhibitor.

[0819] Examples

[0820] This teaching includes the descriptions provided in the embodiments, which are not intended to limit the scope of any claims. Unless explicitly stated in the past tense, the content included in the embodiments is not intended to imply that the experiments were actually conducted. The following non-limiting embodiments are provided to further illustrate this teaching. Those skilled in the art will understand from this disclosure that many changes can be made in the specific embodiments disclosed and still obtain similar or comparable results without departing from the spirit and scope of this teaching.

[0821] Methods

[0822] Some of the methods and compositions described herein utilize laboratory techniques well known to those of ordinary skill in the art and can be found in laboratory manuals such as Sambrook, J., et al., Molecular Cloning: A Laboratory Manual, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 2001; Methods In Molecular Biology, ed. Richard, Humana Press, NJ, 1995; Spector, D. L., et al., Cells: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1998; and Harlow, E., Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1999. Methods for determining the method of administration and dosing regimen of a drug can be determined according to standard pharmacological principles using methods provided in standard reference textbooks such as Remington: the Science and Practice of Pharmacy (19th ed., ed. Alfonso R. Gennaro, 1995); Hardman, J.G., et al., Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th ed., McGraw-Hill, 1996; and Rowe, R.C., et al., Handbook of Pharmaceutical Excipients, 4th ed., Pharmaceutical Press, 2003.

[0823] Example 1: Synthesis of Compounds

[0824] General synthetic methods

[0825] The compounds according to the invention and their intermediates can be obtained using synthetic methods known to those skilled in the art and described in the organic synthesis literature. Preferably, the compounds are obtained in a manner similar to the preparation methods explained more fully below, in particular as described in the experimental section. In certain cases, the order in which the reaction steps are carried out can be changed. Variants of the reaction methods known to those skilled in the art but not described in detail herein can also be used.

[0826] The general methods for preparing the compounds according to the invention will be apparent to those skilled in the art studying the following schemes. The starting materials can be prepared by the methods described in the literature or herein, or can be prepared in a similar or analogous manner. Any functional groups in the starting materials or intermediates can be protected using conventional protecting groups. These protecting groups can be cleaved again using methods familiar to those skilled in the art at appropriate stages within the reaction sequence.

[0827] The optimal reaction conditions and reaction times can vary depending on the specific reactants used. Unless otherwise indicated, the solvents, temperature, pressure, and other reaction conditions can be readily selected by those of ordinary skill in the art. Specific procedures are provided in the synthetic examples section. The intermediates and products can be purified by chromatography on silica gel, recrystallization, and / or reverse-phase HPLC (RHPLC). The separated enantiomers can be obtained by resolving racemic products using chiral HPLC. The RHPLC purification method uses anywhere from 0 - 100% acetonitrile in water containing 0.1% formic acid, 0.1 - 0.01% TFA, 10 mM aqueous ammonium bicarbonate, or 0.2% aqueous ammonium hydroxide and uses one of the following columns:

[0828] a) Waters Xbridge C18 10μm 30x100 mm column

[0829] b) Waters Sunfire C18 10μm 30x100 mm column

[0830] c) Waters Xbridge C18 3.5μm 50x4.6 mm column

[0831] d) HALO C18 2.7μm 30x4.6 mm column

[0832] e) Waters Sunfire C18 3.5μm 50x4.6 mm column.

[0833] Synthetic Examples

[0834] The carboxylic acids used to prepare the compounds disclosed herein are commercially available, can be readily prepared by those skilled in the art, or can be prepared using one of the following methods. The acid chlorides used to prepare the compounds disclosed herein can be readily prepared by those skilled in the art from carboxylic acids using reagents such as oxalyl chloride and sulfonyl chloride.

[0835] Method A

[0836]

[0837] Piperidine (53 μL, 0.539 mmol) was added to a solution of R-1 (0.97 g, 5.39 mmol) and malonic acid (0.81 mL, 8.08 mmol) in pyridine (3.15 mL). The reaction mixture was stirred at 115 °C for 19 h. After this time, the reaction mixture was concentrated in vacuo. The residue was acidified to pH = 4 with 1 M aqueous HCl and the resulting solid was filtered in vacuo and then triturated from acetonitrile / water to afford a solid (1.2 g), which was dissolved in methanol (19.7 mL) and nickel(II) chloride hexahydrate (291 mg, 1.21 mmol) was added. The reaction mixture was cooled to 0 °C and sodium borohydride (307 mg, 8.10 mmol) was added slowly. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. The reaction mixture was acidified with 2 M aqueous HCl (10 mL) and extracted with (3:1) CHCl3:IPA (3 x 20 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo to afford R-2 (0.59 g, 44%).

[0838] Method B

[0839]

[0840] To a solution of ethyl (diethoxyphosphoryl)acetate (0.60 mL, 3.01 mmol) cooled to 0 °C in THF (13 mL) was added sodium hydride (60% in oil, 115 mg, 2.88 mmol) in one portion. The mixture was stirred at 0 °C for 20 min. A solution of R-3 (500 mg, 2.74 mmol) in THF (3 mL) was added over 2 min, and the mixture was stirred at 0 °C for 1 h and then at room temperature for 24 h. The reaction mixture was poured onto saturated aqueous sodium bicarbonate (20 mL), and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 7% to 40% EtOAc in heptane) to afford R-4 (120 mg, 15%) as a 2:1 mixture of positional isomers.

[0841] To a solution of R-4 (85 mg, 0.334 mmol) in methanol (3 mL) at room temperature was added nickel(II) chloride hexahydrate (24 mg, 0.01 mmol), followed by sodium borohydride (25 mg, 0.66 mmol). The mixture was stirred at room temperature for 3 h, then treated with water (5 mL) and poured into saturated aqueous sodium bicarbonate (10 mL). The aqueous phase was extracted with EtOAc (3 x 20 mL), washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (SiO2, 2% to 30% EtOAc in heptane) to afford ethyl 2-(7-chloro-3,4-dihydro-2H-1-benzopyran-4-yl)acetate (60 mg, 47%).

[0842] To a solution of ethyl 2-(7-chloro-3,4-dihydro-2H-1-benzopyran-4-yl)acetate (60 mg, 0.22 mmol) in THF (2 mL) and water (0.2 mL) was added lithium hydroxide hydrate (19 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 20 h and then quenched by addition of 1 M aqueous HCl (10 mL). The aqueous layer was extracted with EtOAc (3 x 8 mL), the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford R-5 (50 mg, 94%).

[0843] Method C

[0844]

[0845] To a solution of 3-ethoxy-3-oxopropanoic acid (0.63 mL, 5.30 mmol) in pyridine (2 mL) was added piperidine (35 uL, 0.35 mmol) and R-6 (500 mg, 3.53 mmol). The reaction mixture was stirred at 115 °C for 2 h. After this time, the reaction mixture was cooled and then neutralized with 2 M aqueous HCl. The aqueous mixture was extracted with EtOAc (3 x 20 mL), the organic phase was dried (Na2SO4) and concentrated in vacuo. The crude was purified by flash column chromatography using a gradient of (SiO2, 0% to 50% EtOAc in heptane) to afford the ethyl ester (448 mg, 50%).

[0846] To a solution of the ethyl ester (400 mg, 1.89 mmol) in methanol (3.3 mL) was added nickel(II) chloride hexahydrate (227 mg, 0.95 mmol). The reaction mixture was cooled to 0 °C and sodium borohydride (143 mg, 3.78 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with EtOAc (20 mL) and filtered through a glass fiber filter paper. The filtrate was washed with saturated aqueous sodium bicarbonate (2 x 10 mL), brine (10 mL), dried (Na2SO4) and concentrated in vacuo to afford the saturated ethyl ester (212 mg, 52%).

[0847] To a solution of the saturated ethyl ester (212 mg, 0.84 mmol) in THF (1 mL) and methanol (1 mL) was added 2 M aqueous LiOH (0.42 mL, 0.84 mmol). The reaction mixture was stirred at room temperature for 3 h, then the volatiles were concentrated in vacuo. The remaining aqueous mixture was acidified to pH 3 with 2 M aqueous HCl, then extracted with (3:1) DCM:MeOH (3 x 10 mL), dried (Na2SO4) and concentrated in vacuo to afford R-7 (93 mg, 56%).

[0848] Synthesis of Amines

[0849] The amines used to prepare the final compounds of the present invention are commercially available, can be readily prepared by those skilled in the art, or can be prepared using one of the following methods.

[0850] Method D

[0851]

[0852] A mixture of R-8 (500 mg, 3.88 mmol) and aminoguanidine hydrochloride (853 mg, 7.76 mmol) was stirred at 190 °C for 2 h. The reaction mixture was cooled to room temperature, then water (5 mL) was added and the mixture was neutralized with aqueous NaOH (6 mol / L). The mixture was filtered and the filtrate was purified by preparative HPLC to give R-9 (60 mg, 10%).

[0853] Method E

[0854]

[0855] A solution of methyl isonicotinate (4 g, 29 mmol) in anhydrous THF (40 mL) was cooled to -60 °C in a dry ice / ethanol bath under N2 protection. LHMDS (1.0 M, 43.6 ml) was added dropwise while maintaining the temperature below -55 °C. After stirring at -60 °C for 1.5 h, propionitrile (3 mL, 43.6 mmol) was added slowly. The reaction mixture was stirred at -60 °C for an additional 1.5 h and then warmed to room temperature. THF was removed under reduced pressure and the residue was treated with CH2Cl2 (50 mL) and the resulting solid was filtered, washed with cold CH2Cl2 (50 mL) and dried to yield the lithium salt intermediate (5 g).

[0856] The lithium salt (1 g, 6.25 mmol) in ethanol (100 ml) was treated slowly with AcOH (375 mg, 6.25 mmol), followed by hydrazine hydrate (98 wt%, 1.17 g, 18.75 mmol). The reaction mixture was stirred at reflux overnight. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (SiO2, 8% MeOH in CH2Cl2) to give R-11 (672 mg).

[0857] Synthesis of Exemplary Compounds

[0858] Method F: Synthesis of Example 17

[0859]

[0860] Dissolve R-13 (0.30 g, 1.87 mmol) and R-12 (22 uL, 1.87 mmol) in DMF (2.0 mL), and add N-ethyl-N-isopropyl-propan-2-amine (654 uL, 3.75 mmol) and propanephosphonic anhydride (50% in ethyl acetate, 1.67 mL, 2.81 mmol). Stir the reaction mixture at 100 °C for 24 h. After this time, dilute the reaction mixture with ethyl acetate, and wash the organic matter with saturated aqueous sodium bicarbonate, dry (MgSO4) and concentrate in vacuo. Recrystallize the crude product from methanol to afford the title compound (323 mg, 52%).

[0861] The following compounds were prepared in a similar manner from the appropriate carboxylic acids and amines: Examples 1, 12 - 13, 15 - 17, 20 - 23, 29, 37 - 39, 44 - 46, 48 - 50, 52 - 55, 57 - 58, 61, 64 - 66, 70, 76 - 81, 83 - 87, 97, 101 - 108, 116 - 120, 158, 159, 161, 162, 167 - 173, 177 - 182, 186 - 197, 202 - 215, 220 - 222, 224, 227 - 237, 263 - 266, 270 - 273, 278 - 280, 282 - 285, 295, 297, 301 - 306, 309 - 312, 316, 319 and 321 - 323.

[0862] Method G: Synthesis of Example 146

[0863]

[0864] To a mixture of R-14 (150 mg, 0.93 mmol) and DIPEA (488 μL, 2.79 mmol) in CH2Cl2 (2.5 mL), add R-13 (138 μL, 0.93 mmol) and stir the reaction mixture at room temperature for 30 min. Dilute the reaction mixture with CH2Cl2, filter and wash the solid with CH2Cl2. Subsequently, heat the solid residue to 250 °C for 30 min. Purify the crude product by preparative HPLC to afford the title compound (72 mg, 26%).

[0865] The following compounds were prepared in a similar manner from the appropriate carboxylic acids and amines: Examples 113, 121 - 123, 127 - 128, 133 and 143 - 145.

[0866] Method H: Synthesis of Example 27

[0867]

[0868] To a solution of R-15 (160 mg, 0.86 mmol), R-11 (150 mg, 0.86 mmol), and DIPEA (0.30 mL, 1.72 mmol) in anhydrous DMF (3 mL) was added propanephosphonic anhydride (50% in ethyl acetate, 0.77 mL, 1.29 mmol). The mixture was purged with nitrogen and stirred at room temperature in a sealed vial for 1 h. After this time, saturated aqueous sodium bicarbonate (10 mL) and water (10 mL) were added. The mixture was extracted with DCM (3 x 10 mL) and the combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 0 - 10% MeOH in CH2Cl2) to give a solid, which was triturated in CH2Cl2 (5 mL), collected by vacuum filtration, washed with CH2Cl2 (3 x 10 mL), and dried in a vacuum drying oven at 40 °C for 7 days to afford the title compound (115 mg, 38%).

[0869] The following compounds were prepared from the appropriate carboxylic acids and amines in a similar manner: Examples 2, 5, 8 - 11, 14, 18, 34 - 36, 51, 59 - 60, 148, 150 - 155, 199, 200, 219, 250, 261, 262, 267, 268, 269, 274, and 291 - 293.

[0870] Method I: Synthesis of Example 75

[0871]

[0872] To a mixture of R-16 (402 mg, 1.86 mmol) and N-ethyl-N-isopropylpropan-2-amine (683 μL, 3.91 mmol) in DCM (2 mL) at 0 °C was added oxalyl chloride (182 μL, 2.05 mmol), followed by R-17 (300 mg, 1.86 mmol). The reaction mixture was stirred at room temperature for 1 h and then allowed to stand at room temperature for 48 h. The reaction mixture was diluted with DCM and water, filtered, and the solid was washed with additional DCM to give a solid (324 mg), which was then heated to 250 °C in a sealed vial for 5 min. The crude residue was purified by flash column chromatography (SiO2, 0% to 100% ethyl acetate in heptane, then 0% to 20% MeOH in DCM) to afford a crude product, which was further purified by trituration with methanol and then with DCM to give the title compound (9 mg, 2%).

[0873] The following compounds were prepared from the appropriate carboxylic acids and amines in a similar manner: Examples 73 - 75, 93 - 96, 109, 124 - 126, 129 - 132, and 134 - 142.

[0874] Method J: Synthesis of Example 114

[0875]

[0876] To a mixture of R - 17 (29 μL, 0.54 mmol), R - 13 (100 mg, 0.542 mmol), and N - ethyl - N - isopropylpropan - 2 - amine (279 μL, 1.60 mmol) in anhydrous DMF (1 mL) was added HATU (304 mg, 0.80 mmol), and the reaction mixture was stirred in a sealed vial at room temperature for 3 h. The reaction mixture was washed with DCM and brine, separated through a hydrophobic frit, and the retained aqueous layer was washed and separated with DCM. The combined organic layers were concentrated in vacuo and purified by preparative HPLC to afford a solid. The resulting solid was heated at 250 °C for 15 min in a sealed test tube. The reaction mixture was cooled to room temperature and the solid was triturated with acetonitrile and filtered in vacuo to afford the title compound (25 mg, 14%).

[0877] Method K: Synthesis of Example 62

[0878]

[0879] To a solution of R - 17 (73 mg, 0.46 mmol) and R - 18 (100 mg, 0.46 mmol) in pyridine (3.2 mL) was added 1 - ethyl - 3 - (3 - dimethylaminopropyl)carbodiimide (71 mg, 0.46 mmol), and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with DCM, washed with brine, separated through a hydrophobic frit, and the retained aqueous solution was washed and separated with DCM. The combined organic layers were concentrated in vacuo and purified by preparative HPLC to afford the title compound (3 mg, 2%).

[0880] The following compound was prepared from the appropriate carboxylic acid and amine in a similar manner: Example 47.

[0881] Method L: Synthesis of Example 30

[0882]

[0883] R-18 (22 μL, 3.71 mmol), R-19 (601 mg, 3.71 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.3 mL, 7.43 mmol) were dissolved in DMF (6.0 mL) and propanephosphonic anhydride (50%, 3.32 mL, 5.57 mmol) was added. The reaction mixture was stirred at 100 °C for 18 h in a sealed vial. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated aqueous sodium bicarbonate (3 x 100 mL), brine (50 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography using a gradient of 0% to 100% EtOAc in heptane to afford R-20 (580 mg, 38%) [LCMS method G, retention time = 0.84 min, mol ion = 362.1, 364.1].

[0884] To a suspension of R-20 (930 mg, 2.57 mmol) in chloroform (10 mL) was added 4-methylbenzenesulfonic acid hydrate (1:1) (49 mg, 0.26 mmol) and 3,4-dihydro-2H-pyran (0.23 mL, 2.57 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography (SiO2, 0 to 100% EtOAc in heptane) to afford a mixture of R-21 and R-22 (3:1) (750 mg, 63%)[LCMS method G, retention time = 1.00, mol ion = 446.1, 448.1].

[0885] To a mixture of R-21 and R-22 (750 mg, 1.68 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (364 mg, 1.76 mmol) in 1,4-dioxane (5.2 mL) and 2 M aqueous potassium carbonate (2.6 mL, 5.20 mmol) was added cyclopentyl(diphenyl)phosphane; palladium dichloride; iron (146 mg, 0.20 mmol). The reaction mixture was degassed for 5 min and then stirred in a sealed vial at 100 °C for 2 h. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (30 mL) and the layers were separated. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, 0% to 100% EtOAc in heptane, then 0% to 20% methanol in EtOAc) to afford a mixture of isomers (510 mg, 68%). The isomers were dissolved in MeOH (5 mL) and treated with 4 M HCl in dioxane (5.0 mL, 20.0 mmol) and the mixture was left to stand at room temperature for 20 min. The reaction mixture was concentrated in vacuo, then triturated with water, filtered in vacuo, washed with acetonitrile and dried in a vacuum drying oven for 18 h to afford the title compound (320 mg, 77%).

[0886] The following compounds were prepared in a similar manner from the appropriate carboxylic acids and boronic esters or acids: Examples 19, 24 - 26, 31, 40, 163, 198, 225, 238, 239, 260, 281, 286, 294, 298, 299, 300, 307, 308, 313, 314, 315, 318, 320, 324 and 325.

[0887] Method M: Synthesis of Example 32

[0888]

[0889] At 0 °C, sodium hydride (60% in oil, 3.53 g, 88.2 mmol) was added portionwise to a suspension of R-23 (20.0 g, 88.2 mmol) in THF (200 mL), and the reaction mixture was stirred under nitrogen at room temperature for 30 min. The reaction mixture was cooled to 0 °C, [2-(chloromethoxy)ethyl](trimethyl)silane (17 mL, 97.0 mmol) was added, and the reaction mixture was stirred under nitrogen for 18 h. The reaction was quenched with water, diluted with EtOAc, the layers were separated, and the organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, 0% to 50% EtOAc in heptane) to afford the protected triazole (30.0 g, 95%) [LCMS method G, retention time = 1.07 min, mol ion = 355.9, 357.9].

[0890] To a solution of the protected triazole (9.00 g, 25.2 mmol) in NMP (4 mL) was added potassium carbonate (8.71 g, 63 mmol) and 1-(4-methoxyphenyl)methanamine (3.44 mL, 26.3 mmol). The reaction mixture was stirred in a sealed vial at 140 °C for 2 h. The reaction mixture was diluted with ethyl acetate, washed with brine, the organic layer was dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, 0% to 100% EtOAc in heptane) to afford R-24 (9.6 g, 78%) [LCMS method G, retention time = 1.35 min, mol ion = 414.8].

[0891] To a solution of R-24 (7.31 g, 16.1 mmol) in DMF (80 mL) was added sodium hydride (60% in oil, 650 mg, 16.2 mmol) portionwise, and the reaction mixture was stirred under nitrogen at room temperature for 15 min. R-13 (2.91 mL, 16.2 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with water, separated through a hydrophobic frit, and the retained aqueous solution was washed with DCM and separated. The combined organic layers were concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, 0% to 100% EtOAc in heptane) to afford the intermediate amide (5.4 g, 52%) [LCMS method G, retention time = 1.26 min, mol ion = 579.1, 581.1].

[0892] A solution of intermediate amide (500 mg, 0.862 mmol) and (2-methoxy-4-pyridyl)boronic acid (132 mg, 0.862 mmol) in 2 M potassium carbonate (1.3 mL, 2.60 mmol) and 1,4-dioxane (2.6 mL) was degassed with nitrogen for 5 minutes and then cyclopentyl(diphenyl)phosphane; palladium dichloride; iron (75 mg, 0.102 mmol) were added. The reaction mixture was stirred at 100 °C for 10 h in a sealed tube. The reaction mixture was washed with brine, separated through a hydrophobic frit, and the retained aqueous solution was washed with additional DCM and further separated. The combined organics were concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, 0% to 100% EtOAc in heptane) to afford intermediate pyridine (140 mg, 26%) [LCMS method G, retention time = 1.14 min, mol ion = 608.3].

[0893] Trifluoromethanesulfonic acid (72 μL, 0.46 mmol) was added to a solution of intermediate pyridine (141 mg, 0.23 mmol) in (1:1) DCM / TFA (1 mL), and the reaction mixture was stirred at room temperature for 1 h. The crude residue was purified by Biotage ISOLUTE® SCX-2 chromatography, eluting with MeOH and then with 7 M NH3 in MeOH. The ammonia-containing fractions were combined and concentrated in vacuo and then triturated from acetonitrile / water to afford the title compound (43 mg, 52%).

[0894] The following compounds were prepared in a similar manner from the appropriate carboxylic acids and boronic esters or acids: Examples 33 and 42 - 43, 156, 157, and 217.

[0895] Method N: Synthesis of Example 41

[0896]

[0897] At 0 °C, sodium hydride (60% in oil, 3.53 g, 88.2 mmol) was added portionwise to a suspension of R-23 (20.0 g, 88.2 mmol) in THF (200 mL), and the reaction mixture was stirred under nitrogen at room temperature for 30 min. The reaction mixture was cooled to 0 °C, [2-(chloromethoxy)ethyl](trimethyl)silane (17 mL, 97.0 mmol) was added, and the reaction mixture was stirred under nitrogen for 18 h. The reaction was quenched with water and diluted with EtOAc, the layers were separated, the organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, 0% to 50% EtOAc in heptane) to afford the protected triazole (30.0 g, 95%) [LCMS method G, retention time = 1.07 min, molecular ion = 355.9, 357.9].

[0898] A solution of the protected triazole (5.00 g, 14.0 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.87 g, 14.0 mmol) in aqueous 2M potassium carbonate (21 mL, 42.0 mmol) and 1,4-dioxane (30 mL) was degassed with nitrogen for 5 min and then cyclopentyl(diphenyl)phosphine; palladium dichloride; iron (1.03 g, 1.40 mmol) was added. The reaction mixture was stirred in a sealed tube at 100 °C for 2 h. The reaction mixture was diluted with EtOAc (25 mL) and the organic layer was washed with 1 x 20 mL saturated aqueous brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, 0% to 10% EtOAc in heptane, then 0% to 20% MeOH in EtOAc) to afford R-25 (2.80 g, 56%) [LCMS method G, retention time = 0.99 min, molecular ion = 355.1, 357.1].

[0899] A mixture of R-25 (200 mg, 0.563 mmol) and 3-(4-chlorophenyl)propan-1-amine (0.10 mL, 0.62 mmol) was dissolved in anhydrous NMP (1 mL) and potassium carbonate (0.47 g, 3.38 mmol) was added. The reaction mixture was stirred at 140 °C for 3 h in a sealed tube. The reaction mixture was diluted with EtOAc (10 mL) and washed successively with water (2 x 5 mL) and brine (5 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 0% to 10% EtOAc in heptane, then 0% to 20% MeOH in EtOAc) to afford the protected triazole (60 mg, 22%) [LCMS method G, retention time = 1.29 min, molecular ion = 445], which was dissolved in DCM (1 mL) and trifluoroacetic acid (45 μL, 0.61 mmol) was added. The reaction mixture was stirred at room temperature for 20 h and then concentrated in vacuo. The crude residue was purified by preparative HPLC and lyophilized to afford the title compound (8 mg, 20%).

[0900] The following compounds were prepared from the appropriate amines in a similar manner: Examples 28 and 317.

[0901] Method O: Synthesis of Example 92

[0902]

[0903] To a mixture of R-14 (300 mg, 1.86 mmol) and N-ethyl-N-isopropylpropan-2-amine (683 μL, 3.91 mmol) in DCM (2 mL) at 0 °C was added R-14 (312 mg, 1.86 mmol). The reaction mixture was stirred at room temperature for 1 h and then left to stand at room temperature for 16 h. The reaction mixture was diluted with DCM and water, filtered and the solid was washed with DCM. Subsequently, the solid residue was heated to 250 °C in a sealed vial for 15 min and then purified by preparative HPLC to afford the title compound (31 mg, 5%).

[0904] The following compounds were prepared from the appropriate amines in a similar manner: Examples 7, 160, 164, 165, 166, 183 - 185, 226, 276, 277 and 296.

[0905] Method P: Synthesis of Example 6

[0906]

[0907] R-17 (250 mg, 1.56 mmol) was suspended in anhydrous DMF (1 mL), and 4-nitrophenyl chloroformate (76 μL, 1.56 mmol) and N-ethyl-N-isopropylpropan-2-amine (572 μL, 3.28 mmol) were added. The reaction mixture was stirred at room temperature for 30 min, then 1-(4-chlorophenyl)-N-methylmethanamine (243 mg, 1.56 mmol) was added, and the reaction mixture was stirred at room temperature for an additional 30 min. The reaction mixture was then stirred at 90 °C for 4 h. The reaction mixture was diluted with DCM, washed with water, separated through a hydrophobic frit, and the retained aqueous layer was washed and separated with DCM. The organics were concentrated in vacuo, and the crude residue was heated to 250 °C in a sealed vial for 20 min. The crude product was purified by preparative HPLC to afford the title compound (11 mg, 2%).

[0908] The following compounds: Example 174, 216, and 218 were prepared from the appropriate amines in a similar manner.

[0909] Method Q: Synthesis of Example 99

[0910]

[0911] To a mixture of R-27 (29 μL, 0.54 mmol), R-13 (100 mg, 0.54 mmol), and N-ethyl-N-isopropylpropan-2-amine (279 μL, 1.60 mmol) in anhydrous DMF (1 mL) was added HATU (304 mg, 0.80 mmol), and the reaction mixture was stirred in a sealed vial at room temperature for 17 h. After this time, the reaction mixture was diluted with DCM, washed with brine, separated through a hydrophobic frit, and the retained aqueous solution was washed and separated with DCM. The combined organics were concentrated in vacuo and then purified by preparative HPLC to afford the title compound (13 mg, 7%).

[0912] The following compounds: Example 100 and 115 were prepared from the appropriate amines in a similar manner.

[0913] Method R: Synthesis of Examples 98, 110 and 111

[0914]

[0915] To a solution of Example 136 (50%, 295 mg, 0.503 mmol) in anhydrous DMF (1 mL) was added sodium hydride (60% in mineral oil, 60 mg, 1.51 mmol), and the reaction mixture was stirred at room temperature for 15 min. Methyl iodide (94 uL, 1.51 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was purified by preparative HPLC to afford the title compounds Example 98 (12 mg, 8%), Example 110 (13 mg, 8%) and Example 111 (9 mg, 6%).

[0916] The following compounds were prepared from the appropriate amines in a similar manner: Example 287 and 288.

[0917] Method S: Synthesis of Example 82

[0918]

[0919] To a solution of R-14 (269 mg, 1.67 mmol) and R-28 (22 uL, 1.67 mmol) in DMF (4.35 mL) was added N-ethyl-N-isopropyl-propan-2-amine (0.58 mL, 3.34 mmol) and propanephosphonic anhydride (50%, 1.5 mL, 2.50 mmol). The reaction mixture was stirred at 100 °C for 20 h. The reaction mixture was diluted with EtOAc (20 mL) and washed successively with saturated aqueous sodium bicarbonate (2 x 10 mL), brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The crude was purified by flash column chromatography (SiO2, 0% to 100% EtOAc in heptane) to afford the Boc-amine (327 mg, 39%), which was dissolved in DCM (3 mL) and TFA (0.45 mL, 6.1 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The crude residue was purified by preparative HPLC and then lyophilized to afford the title compound (42 mg, 20%).

[0920] The following compounds were prepared from the appropriate amines in a similar manner: Example 3, 4, 56, 63, 69, 175, 176, 201, 223, 275, 289 and 290.

[0921] Method T: Resolution of Examples 67 and 68

[0922] Example 117 (95 mg, 0.30 mmol) was dissolved in a mixture of methanol / acetonitrile and purified by supercritical fluid chromatography on a Chiralpak OD-H, 10 x 250 mm, 5 μm column, eluting with a gradient of 0% to 15% methanol in CO2 at a flow rate of 15 mL / min to afford the title compound.

[0923] Method U: Resolution of Examples 71 and 72

[0924] Example 109 (226 mg, 0.67 mmol) was dissolved in a mixture of methanol, acetonitrile, IPA and formic acid and purified by flash column chromatography on a Chiralpak OD-H, 20 x 250 mm, 5 μm column, eluting with methanol at a flow rate of 9 mL / min to afford the title compound.

[0925] Method V: Resolution of Examples 88 and 89

[0926] Example 131 (82 mg, 0.257 mmol) was dissolved in a mixture of methanol, IPA and formic acid and purified by flash column chromatography on a Chiralpak AD-H, 20 x 250 mm, 5 μm column, eluting with methanol at a flow rate of 9 mL / min to afford the title compound.

[0927] Method W: Resolution of Examples 90 and 91

[0928] Example 132 (21 mg, 0.063 mmol) was dissolved in a mixture of methanol and IPA and purified by flash column chromatography on a Chiralpak AD-H, 20 x 250 mm, 5 μm column, eluting with methanol at a flow rate of 9 mL / min to afford the title compound.

[0929] Example 2. Characterization of the Compounds

[0930] LCMS method:

[0931] Analytical LC / MS method A:

[0932] ESI+ / - ion mode 150 - 850 Da

[0933] Column: Phenomenex Kinetix-XB C18, Part No.00D-4498-AN, 2.1 x 100 mm, 1.7 μm

[0934] Temperature: 40 °C

[0935] Gradient:

[0936] Time (min) 0.1% Formic acid in water Acetonitrile Flow rate (mL / min) 0 95% 5% 0.6 5.30 0% 100% 0.6 5.80 0% 100% 0.6 5.82 95% 5% 0.6 7.00 95% 5% 0.6

[0937] Analytical LC / MS Analysis Method B:

[0938] ESI+ / - Ion Mode 150 - 850 Da

[0939] Column: Phenomenex Gemini-NX C18, Part No. 00D-4453-B0, 2.0 x 100 mm, 3.0μm

[0940] Temperature: 40°C

[0941] Gradient:

[0942] Time (min) 2 mM ammonium bicarbonate aqueous solution Acetonitrile Flow rate (mL / min) 0 95% 5% 0.6 5.50 0% 100% 0.6 5.90 0% 100% 0.6 5.92 95% 5% 0.6 7.00 95% 5% 0.6

[0943] Analytical LC / MS Analysis Method C:

[0944] ESI+ / - Ion Mode 100 - 1000 Da

[0945] Column: Waters UPLC®BEH TM C18, Part No. 186002352, 2.1 x 100 mm, 1.7 μm

[0946] Temperature: 40°C

[0947] Gradient:

[0948] Time (min) 2 mM ammonium bicarbonate aqueous solution Acetonitrile Flow rate (mL / min) 0 95% 5% 0.6 5.30 0% 100% 0.6 5.80 0% 100% 0.6 5.82 95% 5% 0.6 7.00 95% 5% 0.6

[0949] Analytical LC / MS Analysis Method D:

[0950] ESI+ / - Ion Mode 100 - 1000 Da

[0951] Column: XBridge C18, 3.5 μm 4.6x50mm column

[0952] Temperature: 40°C

[0953] Gradient:

[0954] Time (min) 10 mM ammonium bicarbonate aqueous solution Acetonitrile Flow rate (mL / min) 0.00 95% 5% 2.0 1.20 5% 95% 2.0

[0955] Analytical LC / MS Analysis Method E:

[0956] ESI+ / - Ion Mode 100 - 1000 Da

[0957] Column: XBridge SB-C18, 3.5 μm 4.6x50mm column

[0958] Temperature: 40 °C

[0959] Gradient:

[0960] Time (min) 10 mM ammonium bicarbonate aqueous solution Acetonitrile Flow rate (mL / min) 0.00 95% 5% 2.0 1.40 5% 95% 2.0 4.30 5% 95% 2.0

[0961] Analytical LC / MS analysis method F:

[0962] ESI+ / - ion mode 100 - 1000 Da

[0963] Column: Sunfire C18, 3.5 μm 4.6x50mm column

[0964] Temperature: 50 °C

[0965] Gradient:

[0966] Time (min) 10 mM ammonium bicarbonate aqueous solution Acetonitrile Flow rate (mL / min) 0.00 95% 5% 2.0 1.40 5% 95% 2.0 3.00 5% 95% 2.0

[0967] Analytical LC / MS analysis method G:

[0968] ESI+ / - ion mode 100 - 1000 Da

[0969] Column: Waters UPLC®BEH TM C18, Part No. 186005297, 1.7 μm 2.1x50mm column

[0970] Temperature: 40 °C

[0971] Gradient:

[0972] Time (min) 0.1% Formic acid in water 0.1% Formic acid in acetonitrile Flow rate (mL / min) 0.00 95% 5% 0.9 1.10 0% 100% 0.9 1.35 0% 100% 0.9 1.40 95% 5% 0.9 1.50 95% 5% 0.9

[0973] The results are presented in Table 1:

[0974]

[0975]

[0976]

[0977]

[0978] Example 3: ARM - SAM - TIR SARM1 IC50 determination

[0979] This example describes the determination of ARM-SAM-TIR NADase activity and the use of this assay to measure the potency of compounds of Formula I or I' to block SARM1-mediated NAD+ cleavage. The assay was optimized to characterize the potency of compounds of Formula I or I' to inhibit SARM1 activity and to calculate the IC50 value for each compound. The assay utilizes full-length SARM1, which includes the ARM, SAM, and TIR domains. As demonstrated herein, expression of this fragment without the autoinhibitory N-terminal domain produces an enzyme with intrinsic activity to cleave NAD+.

[0980] Preparation of ARM-SAM-TIR Lysate (STL)

[0981] NRK1-HEK293T cells were seeded at 20 × 106 cells per plate in 150 cm 2 plates. The next day, the cells were transfected with 15 μg of the ARM-SAM-TIR expression plasmid (SEQ ID NO: 1):

[0982]

[0983]

[0984]

[0985]

[0986] .

[0987] At the time of transfection, the cultures were supplemented with 1 mM NR to minimize the toxicity from ARM-SAM-TIR overexpression. Forty-eight hours after transfection, the cells were harvested, pelleted by centrifugation at 1,000 rpm (Sorvall ST 16R centrifuge, ThermoFisher), and washed once with cold PBS (0.01 M phosphate buffered saline, 0.138 M NaCl; 0.0027 M KCl; pH 7.4). The cells were resuspended in PBS containing protease inhibitors (cOmplete™ protease inhibitor cocktail, Roche product #11873580001) and cell lysates were prepared by sonication (Branson Sonifer 450, output = 3, 20 strikes). The lysates were centrifuged (centrifuged at 12,000 × g for 10 min at 4 °C) to remove cell debris and the supernatants (containing ARM-SAM-TIR protein) were stored at -80 °C for later use in the in vitro ARM-SAM-TIR NADase assay (see below). Protein concentrations were determined by the Bicinchoninic (BCA) method and used to normalize the lysate concentrations.

[0988] ARM-SAM-TIR IC50 assay for compounds of Formula I or Formula I’

[0989] Enzyme assays were performed in 384-well polypropylene plates in Dulbecco's PBS buffer with a final assay volume of 20 μL. ARM-SAM-TIR lysates with a final concentration of 5 μg / mL were pre-incubated with each compound at a final assay concentration of 1% DMSO for 2 hours at room temperature. The reaction was initiated by adding NAD⁺ at a final assay concentration of 5 μM as a substrate. After a 2-hour incubation at room temperature, the reaction was terminated with 40 μL of stop solution (7.5% trichloroacetic acid in acetonitrile). NAD⁺ and ADPR concentrations were analyzed by a RapidFire High Throughput Mass Spectrometry System (Agilent Technologies, Santa Clara, CA) using an API 4000 triple quadrupole mass spectrometer (AB Sciex Framingham, MA).

[0990] The results are presented in Table 2 below. Compounds with activity designated as "A" provided an IC 50 < 5 μM; compounds with activity designated as "B" provided an IC 50 5 - 15 μM; compounds with activity designated as "C" provided an IC 50 15.01 - 30 μM; compounds with activity designated as "D" provided an IC 50 >30 μM; nd: not determined.

[0991]

[0992]

[0993]

[0994] Example 4: Axonal Degeneration Index

[0995] This example illustrates an in vitro axonal degeneration assay for characterizing compounds of Formula I or Formula I'. This assay is used to test the efficacy of compounds of Formula I or Formula I' in preventing axonal degeneration in mouse dorsal root ganglion (DRG) hanging drop cultures.

[0996] Mouse DRG hanging drop culture: Mouse dorsal root ganglion neurons (DRGs) were dissected from E12.5 CD1 mice (50 ganglia per embryo) and incubated with 0.5% trypsin solution containing 0.02% EDTA (Gibco) 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 onto the center of each well of a 96-well tissue culture plate coated with poly-D-lysine (0.1 mg / ml; Sigma) and laminin (3 mg / ml; Invitrogen). The cells were allowed to adhere to the plate for 15 min in a humidified tissue culture incubator (5% CO2), and then DRG growth medium (100 μl per well) was gently added.

[0997] Axonal degeneration assay: Axonal degeneration was stimulated by manually transecting the axons with a surgical blade or by chemical toxic stimulation. After an appropriate experimental time period, the DRG cultures were fixed in 1% PFA plus sucrose and stored in the refrigerator before imaging. Bright-field images of DRG axons and cell bodies were collected using a 20x water immersion lens of a Phenix automated confocal microscope (PerkinElmer), and axons were quantified using an in-house developed script (Acapella, PerkinElmer). Sequence Listing <110> Disarm Therapeutics, Inc. <120> Inhibitors of SARM1 <130> 2012800-0069 <150> 62 / 958178 <151> 2020-01-07 <160> 1 <170> PatentIn version 3.5 <210> 1 <211> 6514 <212> DNA <213> Artificial Sequence <220> <223> Chemically synthesized oligonucleotide <400> 1 gcgatcgcgg ctcccgacat cttggaccat tagctccaca ggtatcttct tccctctagt 60 ggtcataaca gcagcttcag ctacctctca attcaaaaaa cccctcaaga cccgtttaga 120 ggccccaagg ggttatgcta tcaatcgttg cgttacacac acaaaaaacc aacacacatc 180 catcttcgat ggatagcgat tttattatct aactgctgat cgagtgtagc cagatctagt 240 aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 300 cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 360 cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 420 tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt acgcccccta 480 ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttatggg 540 actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg ctgatgcggt 600 tttggcagta catcaatggg cgtggatagc ggtttgactc acggggattt ccaagtctcc 660 accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat 720 gtcgtaacaa ctccgcccca ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct 780 atataagcag agctggttta gtgaaccgtc agatcagatc tttgtcgatc ctaccatcca 840 ctcgacacac ccgccagcgg ccgctgccaa gcttccgagc tctcgaattc aaaggaggta 900 cccaccatgg ccatgcatca ccaccaccat catagctccg gcgtcgacct cggcaccgag 960 aatttatatt tccaaagcgg cctcaatgat atcttcgagg cccagaagat cgagtggcac 1020 gagggcagct ccgacctcgc cgtgcccggt cccgatggag gcggaggcac tggtccttgg 1080 tgggctgctg gcggcagagg ccctagagaa gtgagccccg gtgctggcac cgaggtgcaa 1140 gacgctctgg agagggctct gcccgaactg cagcaagctc tgtccgcttt aaagcaagct 1200 ggaggagcta gagccgtcgg cgccggactg gccgaagtgt tccagctcgt ggaggaagct 1260 tggttattac ccgctgtggg aagagaggtc gcccaaggtc tgtgtgacgc cattcgtctg 1320 gacggaggtt tagacttatt actgaggctg ctgcaagctc ccgaactgga gacaagggtc 1380 caagctgctc gtctgctgga gcagatcctc gtggccgaga atcgtgacag agtggctaga 1440 atcggtttag gcgtcatcct caatttagcc aaagagaggg agcccgttga gctggccaga 1500 agcgtcgctg gcatcctcga gcacatgttc aagcattccg aggagacttg tcagagactg 1560 gtcgccgccg gaggactcga tgctgtttta tactggtgca gaaggacaga ccccgcttta 1620 ctgaggcatt gtgctctggc cctcggcaat tgcgctttac atggaggcca agccgtccag 1680 agaaggatgg tggagaaaag agccgccgag tggctgttcc ctttagcctt ctccaaagaa 1740 gacgaactgt tacgtctgca tgcttgtctc gctgtcgctg ttttagccac caacaaggag 1800 gtggaaaggg aagtggaaag aagcggaaca ctggctttag tcgaacctct ggtggcttct 1860 ttagatcccg gaaggtttgc cagatgtctg gtcgacgcca gcgatacctc ccaaggaaga 1920 ggccccgacg atctccagag actggtgcct ctgctggaca gcaatcgtct ggaggcccaa 1980 tgtattggcg ccttctatct ctgcgccgaa gccgccatca agtctttaca aggtaagacc 2040 aaggtgttct ccgacattgg agccatccaa tctttaaaga ggctggtgag ctattccacc 2100 aacggcacaa aaagcgcttt agccaaaaga gctttaagac tgctgggcga agaggtgcct 2160 aggcccattt taccttccgt gcctagctgg aaggaggccg aggtgcagac ttggctgcag 2220 cagatcggct ttagcaaata ttgcgaatcc tttagggagc agcaagttga cggcgattta 2280 ttattaaggc tgaccgagga agagctccag acagatttag gcatgaaaag cggcatcact 2340 cgtaagaggt tctttcgtga gctcaccgaa ctgaagacct tcgccaacta ctccacttgt 2400 gatcgtagca atttagctga ttggctcgga tccctcgatc ccagatttcg tcagtacacc 2460 tatggactcg tctcttgtgg actggacaga tctttactgc atcgtgtgag cgagcaacag 2520 ctgctggaag attgcggcat ccatttagga gtgcacagag ccagaattct gaccgccgct 2580 agagagatgc tgcattcccc tctcccttgt accggaggca agcctagcgg agacaccccc 2640 gacgtgttca tcagctatcg tagaaacagc ggaagccagc tggcctcttt actgaaggtc 2700 catttacagc tgcacggatt tagcgtcttc atcgacgtgg agaaactgga ggctggcaag 2760 ttcgaggaca agctgatcca gtccgtgatg ggcgctagga atttcgtttt agtgctcagc 2820 cccggcgctc tggataaatg catgcaagat catgactgta aggactgggt ccacaaggaa 2880 atcgtgaccg ctctgtcttg tggcaagaac atcgtcccca tcatcgacgg cttcgaatgg 2940 cccgagcctc aagttctccc cgaagatatg caagctgttt taaccttcaa tggaatcaag 3000 tggagccacg agtaccaaga agccacaatc gagaagatca ttcgttttct gcaaggtaga 3060 tcctccagag attcctccgc tggcagcgac acatctttag agggcgccgc ccctatgggt 3120 cctacctaat aatctagaag ttgtctcctc ctgcactgac tgactgatac aatcgatttc 3180 tggatccgca ggcctctgct agcttgactg actgagatac agcgtacctt cagctcacag 3240 acatgataag atacattgat gagtttggac aaaccacaac tagaatgcag tgaaaaaaat 3300 gctttatttg tgaaatttgt gatgctattg ctttatttgt aaccattata agctgcaata 3360 aacaagttaa caacaacaat tgcattcatt ttatgtttca ggttcagggg gaggtgtggg 3420 aggtttttta aagcaagtaa aacctctaca aatgtggtat tggcccatct ctatcggtat 3480 cgtagcataa ccccttgggg cctctaaacg ggtcttgagg ggttttttgt gcccctcggg 3540 ccggattgct atctaccggc attggcgcag aaaaaaatgc ctgatgcgac gctgcgcgtc 3600 ttatactccc acatatgcca gattcagcaa cggatacggc ttccccaact tgcccacttc 3660 catacgtgtc ctccttacca gaaatttatc cttaaggtcg tcagctatcc tgcaggcgat 3720 ctctcgattt cgatcaagac attcctttaa tggtcttttc tggacaccac taggggtcag 3780 aagtagttca tcaaactttc ttccctccct aatctcattg gttaccttgg gctatcgaaa 3840 cttaattaac cagtcaagtc agctacttgg cgagatcgac ttgtctgggt ttcgactacg 3900 ctcagaattg cgtcagtcaa gttcgatctg gtccttgcta ttgcacccgt tctccgatta 3960 cgagtttcat ttaaatcatg tgagcaaaag gccagcaaaa ggccaggaac cgtaaaaagg 4020 ccgcgttgct ggcgtttttc cataggctcc gcccccctga cgagcatcac aaaaatcgac 4080 gctcaagtca gaggtggcga aacccgacag gactataaag ataccaggcg tttccccctg 4140 gaagctccct cgtgcgctct cctgttccga ccctgccgct taccggatac ctgtccgcct 4200 ttctcccttc gggaagcgtg gcgctttctc atagctcacg ctgtaggtat ctcagttcgg 4260 tgtaggtcgt tcgctccaag ctgggctgtg tgcacgaacc ccccgttcag cccgaccgct 4320 gcgccttatc cggtaactat cgtcttgagt ccaacccggt aagacacgac ttatcgccac 4380 tggcagcagc cactggtaac aggattagca gagcgaggta tgtaggcggt gctacagagt 4440 tcttgaagtg gtggcctaac tacggctaca ctagaagaac agtatttggt atctgcgctc 4500 tgctgaagcc agttaccttc ggaaaaagag ttggtagctc ttgatccggc aaacaaacca 4560 ccgctggtag cggtggtttt tttgtttgca agcagcagat tacgcgcaga aaaaaaggat 4620 ctcaagaaga tcctttgatc ttttctacgg ggtctgacgc tcagtggaac gaaaactcac 4680 gttaagggat tttggtcatg agattatcaa aaaggatctt cacctagatc cttttaaatt 4740 aaaaatgaag ttttaaatca atctaaagta tatatgagta aacttggtct gacagttacc 4800 aatgcttaat cagtgaggca cctatctcag cgatctgtct atttcgttca tccatagttg 4860 catttaaatt tccgaactct ccaaggccct cgtcggaaaa tcttcaaacc tttcgtccga 4920 tccatcttgc aggctacctc tcgaacgaac tatcgcaagt ctcttggccg gccttgcgcc 4980 ttggctattg cttggcagcg cctatcgcca ggtattactc caatcccgaa tatccgagat 5040 cgggatcacc cgagagaagt tcaacctaca tcctcaatcc cgatctatcc gagatccgag 5100 gaatatcgaa atcggggcgc gcctggtgta ccgagaacga tcctctcagt gcgagtctcg 5160 acgatccata tcgttgcttg gcagtcagcc agtcggaatc cagcttggga cccaggaagt 5220 ccaatcgtca gatattgtac tcaagcctgg tcacggcagc gtaccgatct gtttaaacct 5280 agatattgat agtctgatcg gtcaacgtat aatcgagtcc tagcttttgc aaacatctat 5340 caagagacag gatcagcagg aggctttcgc atgagtattc aacatttccg tgtcgccctt 5400 attccctttt ttgcggcatt ttgccttcct gtttttgctc acccagaaac gctggtgaaa 5460 gtaaaagatg ctgaagatca gttgggtgcg cgagtgggtt acatcgaact ggatctcaac 5520 agcggtaaga tccttgagag ttttcgcccc gaagaacgct ttccaatgat gagcactttt 5580 aaagttctgc tatgtggcgc ggtattatcc cgtattgacg ccgggcaaga gcaactcggt 5640 cgccgcatac actattctca gaatgacttg gttgagtatt caccagtcac agaaaagcat 5700 cttacggatg gcatgacagt aagagaatta tgcagtgctg ccataaccat gagtgataac 5760 actgcggcca acttacttct gacaacgatt ggaggaccga aggagctaac cgcttttttg 5820 cacaacatgg gggatcatgt aactcgcctt gatcgttggg aaccggagct gaatgaagcc 5880 ataccaaacg acgagcgtga caccacgatg cctgtagcaa tggcaacaac cttgcgtaaa 5940 ctattaactg gcgaactact tactctagct tcccggcaac agttgataga ctggatggag 6000 gcggataaag ttgcaggacc acttctgcgc tcggcccttc cggctggctg gtttattgct 6060 gataaatctg gagccggtga gcgtgggtct cgcggtatca ttgcagcact ggggccagat 6120 ggtaagccct cccgtatcgt agttatctac acgacgggga gtcaggcaac tatggatgaa 6180 cgaaatagac agatcgctga gataggtgcc tcactgatta agcattggta accgattcta 6240 ggtgcattgg cgcagaaaaa aatgcctgat gcgacgctgc gcgtcttata ctcccacata 6300 tgccagattc agcaacggat acggcttccc caacttgccc acttccatac gtgtcctcct 6360 taccagaaat ttatccttaa gatcccgaat cgtttaaact cgactctggc tctatcgaat 6420 ctccgtcgtt tcgagcttac gcgaacagcc gtggcgctca tttgctcgtc gggcatcgaa 6480 tctcgtcagc tatcgtcagc ttaccttttt ggca 6514

Claims

1. A compound or a pharmaceutically acceptable salt thereof, the compound being: Wherein: R 1 is L is R 2 is phenyl or pyridyl optionally substituted with one or more halogens.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is phenyl.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is a pyridyl group optionally substituted with one or more halogens.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is selected from:

5. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof.

6. A compound, which is or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 - 6 and a pharmaceutically acceptable carrier.

8. Use of the compound according to any one of claims 1 - 6 in the preparation of a medicament for the treatment or prevention of axonal degeneration.

9. Use of the compound according to any one of claims 1 - 6 in the preparation of a medicament for the treatment or prevention of a disease or disorder selected from amyotrophic lateral sclerosis, multiple sclerosis, diabetic peripheral neuropathy, and chemotherapy-induced neuropathy.

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