SARM1 inhibitor in combination with a neuroprotective agent

Abstract

The present disclosure relates to methods of treating neurodegenerative and neurodegenerative diseases, which comprise administering to a subject in need thereof a combination of a SARM1 inhibitor and a neuroprotective agent.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 782,239, filed on December 19, 2018, the entire content of which is incorporated herein by reference.

[0003] Sequence Listing

[0004] This application contains a sequence listing that has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy created on December 18, 2019 is named 2012800 - 0029_SL.txt and is 2,514 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 nicotinamide adenine dinucleotide (NAD+) destruction. Science 348 2015, pp. 453 - 457, the entire content of which is incorporated herein by reference). Neurodegenerative diseases and injuries are devastating to patients and caregivers alike. The costs associated with these diseases currently exceed hundreds of billions of dollars per year in the United States alone. Since the incidence of many of these diseases and disorders increases with age, their incidence is growing rapidly as demographics change.

[0007] Overview

[0008] Axonal degeneration after injury is characterized by the sequential depletion of nicotinamide mononucleotide adenylyltransferase (NMNAT), NAD+, and adenosine triphosphate (ATP), followed by neurofilament proteolysis and axonal fragmentation approximately 8 to 24 hours after the primary injury (Gerdts, J. et al., Neuron, 2016, 89, 449 - 460, the full text of which is incorporated herein by reference). After axonal injury, Sterile Alpha and TIR motif-containing 1 (SARM1) acts as the central executioner in the axonal degeneration pathway. Activated SARM1 is a highly efficient NADase that depletes local axonal NAD+ reserves within minutes to hours after activation, causing a local bioenergetic crisis followed by rapid axonal degeneration. This disclosure shows the surprising finding that a combination of neuroprotective agents, particularly dual leucine zipper kinase (DLK) inhibitors or NAMPT inhibitors, and SARM1 inhibitors provides much superior and more durable axonal protection than the effect of either agent alone. In some embodiments, such a combination provides a safe and effective method for treating patients with axonopathies.

[0009] Accordingly, in some embodiments, this disclosure involves recognizing that a combination of a DLK inhibitor and an SARM1 inhibitor maintains higher intracellular NAD+ levels, thereby preventing, ameliorating, and / or reducing the progression of axonal degeneration and cell death. In some embodiments, such a combination significantly delays the pathological SARM1-mediated intracellular NAD+ reduction that occurs due to SARM1 activation.

[0010] In some embodiments, this disclosure involves recognizing that a combination of a NAMPT inhibitor and an SARM1 inhibitor provides greater neuroprotection than either therapy alone. In some embodiments, such a combination inhibits the production of nicotinamide mononucleotide (NMN). In some embodiments, such a combination inhibits the production of cyclic adenosine diphosphate ribose (cADPR).

[0011] In some embodiments, this disclosure provides a method of treating, preventing, and / or ameliorating a neurodegenerative disease, disorder, or condition, which comprises administering an SARM1 inhibitor in combination with a DLK inhibitor or a NAMPT inhibitor.

[0012] In some embodiments, the neurodegenerative disease, disorder, or condition is associated with axonal degeneration (such as axonal fragmentation or degeneration). Accordingly, in some embodiments, this disclosure provides a method of treating, preventing, and / or ameliorating axonal degeneration, which comprises administering to a subject in need thereof an SARM1 inhibitor in combination with a DLK inhibitor or a NAMPT inhibitor. In some embodiments, axonal degeneration results from a reduction or depletion of NAD+. In some embodiments, axonal degeneration results from an accumulation of NMN. In some embodiments, axonal degeneration results from an accumulation of cADPR.

[0013] In some embodiments, the provided methods prevent or slow the progression of axonal degeneration distal to axonal injury. In some embodiments, the provided methods treat or prevent secondary conditions associated with neurodegenerative disorders. Such secondary conditions include, but are not limited to, muscle injury, respiratory injury, anxiety, depression, language disorders, pulmonary embolism, arrhythmia, and / or pneumonia.

[0014] In some embodiments, the present disclosure relates to a method of treating, preventing, and / or ameliorating a neurodegenerative disease, disorder, or condition, comprising i) providing a) a subject diagnosed with, at risk of, or exhibiting symptoms of a neurodegenerative disease, disorder, or condition and b) a combination comprising a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor; and ii) administering the combination to the subject under conditions that mitigate the neurodegenerative disease, disorder, or condition.

[0015] In some embodiments, the present disclosure relates to a method of treating, preventing, and / or ameliorating a neurodegenerative disease, disorder, or condition, comprising i) providing a) a subject diagnosed with, at risk of, or exhibiting symptoms of a neurodegenerative disease, disorder, or condition and b) a SARM1 inhibitor; and ii) administering the SARM1 inhibitor to a subject that is or has been exposed to a DLK inhibitor or a NAMPT inhibitor under conditions that mitigate the neurodegenerative disease, disorder, or condition.

[0016] In some embodiments, the present disclosure provides a combination therapy comprising a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor. In some embodiments, the provided combination therapy comprises a SARM1 inhibitor, a DLK inhibitor, and one or more additional therapeutic agents. In some embodiments, the provided combination therapy comprises a SARM1 inhibitor, a NAMPT inhibitor, and one or more additional therapeutic agents. In some embodiments, the provided combination therapy comprises a SARM1 inhibitor, a DLK inhibitor, a NAMPT inhibitor, and one or more additional therapeutic agents.

[0017] In some embodiments, the provided combination therapy can be used to treat, prevent, and / or ameliorate a neurodegenerative disease, disorder, or condition. In some embodiments, the provided combination therapy can be used to treat, prevent, and / or ameliorate axonal degeneration. In some embodiments, the provided combination therapy can be used to prevent or slow the progression of axonal degeneration distal to axonal injury. In some embodiments, the provided combination therapy can be used to maintain axonal function, including but not limited to metabolism, axonal integrity, intracellular trafficking, and axonal potential propagation.

[0018] In some embodiments, a neurodegenerative disease, disorder, or condition is characterized by axons that are vulnerable to damage, degeneration, or pathological stress. In some embodiments, such diseases, disorders, or conditions include, but are not limited to, cancer, diabetes, neurodegenerative diseases, cardiovascular diseases, blood coagulation, inflammation, flushing, obesity, aging, or stress.

[0019] In some embodiments, the neurodegenerative disease, disorder, or condition is selected from neuropathy or axonopathy. In some embodiments, the neuropathy or axonopathy is associated with axonal degeneration.

[0020] In some embodiments, the neuropathy associated with axonal degeneration is a hereditary or congenital neuropathy or axonopathy. In some embodiments, the neuropathy associated with axonal degeneration results from de novo mutations ( de novo ) or somatic mutations. In some embodiments, the neuropathy associated with axonal degeneration results from an idiopathic condition.

[0021] In some embodiments, the neuropathy or axonopathy associated with axonal degeneration includes, but is not limited to, Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis (ALS), multiple sclerosis, demyelinating diseases, ischemia or stroke, traumatic brain injury, chemical injury, thermal injury, and AIDS.

[0022] In some embodiments, the neurodegenerative disease, disorder, or condition can be or include traumatic neuronal injury. In some embodiments, the traumatic neuronal injury is blunt force trauma, closed head injury, open head injury, exposure to shock forces and / or blast forces, penetrating injury in or to the cranial cavity or innervated regions of the body. In some embodiments, the traumatic neuronal injury is a force that causes axonal deformation, stretching, fragmentation, or turning.

[0023] In some embodiments, a subject administered the combination therapy as described herein has or is susceptible to a neurodegenerative disease, disorder, or condition. In some embodiments, the subject is at risk of developing a neurodegenerative disease, disorder, or condition. In some embodiments, the subject is an elderly individual. In some embodiments, the subject has a genetic risk factor for neurodegeneration.

[0024] In some embodiments, the subject is at risk of developing a disease, disorder, or condition characterized by axonal degeneration. In some embodiments, the subject has a disease, disorder, or condition characterized by axonal degeneration. In some embodiments, the subject has been diagnosed with a disease, disorder, or condition characterized by axonal degeneration. In some embodiments, the subject has not been diagnosed with a disease, disorder, or condition characterized by axonal degeneration.

[0025] In some embodiments, the methods provided comprise administering to a subject population in need thereof a combination therapy as described herein. In some embodiments, the subject population is the elderly. In some embodiments, the subject population has a genetic risk factor for neurodegeneration.

[0026] In some embodiments, the subject population is from individuals who engage in activities with a high likelihood of traumatic neuronal injury. In some embodiments, the subject population is athletes who engage in contact sports or other high-risk activities.

[0027] In certain embodiments, a combination comprising a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor can be used, for example, as an analytical tool, as a probe in a biological assay, or as a therapeutic agent according to the present disclosure.

[0028] Such combinations provided by the present disclosure can also be used for the study of SARM1 NADase function in biological and pathological phenomena and for the comparative evaluation of novel SARM1 activity inhibitors in vitro or in vivo. In some embodiments, a combination comprising a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor can be used to study axonal integrity. In some embodiments, such a combination can be used to study apoptosis.

[0029] In some embodiments, the present disclosure provides a method of inhibiting the degeneration of neurons derived from a subject, which comprises administering to the subject a SARM1 inhibitor in combination with a DLK inhibitor or a NAMPT inhibitor.

[0030] In some embodiments, the combinations provided can be used to inhibit the degeneration of neurons or a part thereof. In some embodiments, the combinations provided can be used to treat neurons with damaged axons. In some embodiments, the combinations provided can be used to inhibit the degeneration of neurons or a part thereof in vivo. In some embodiments, the combinations provided can be used as a stabilizer to promote neuronal survival in vitro.

[0031] In some embodiments, the present disclosure relates to a method of increasing the intracellular concentration of NAD+, which comprises contacting a cell with a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor. In some embodiments, the present disclosure relates to a method of preventing an increase in intracellular cADPR, which comprises contacting a cell with a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor.

[0032] In some embodiments, the provided SARM1 inhibitors reduce or inhibit the binding of NAD+ by SARM1. In some embodiments, the provided SARM1 inhibitors bind to SARM1 within a pocket that includes one or more catalytic residues (e.g., the catalytic cleft of SARM1). In some embodiments, the provided SARM1 inhibitors bind to non-catalytic residues. In some such embodiments, the provided SARM1 inhibitors are allosteric modulators of SARM1 activity. Accordingly, in some embodiments, the present disclosure provides a method of reducing or inhibiting the binding of SARM1 by NAD+, which includes administering to a subject in need thereof a combination of a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor. In some embodiments, such a SARM1 inhibitor binds to one or more catalytic residues in the binding pocket of SARM1.

[0033] In some embodiments, the SARM1 inhibitor and the DLK inhibitor are co-administered to a subject. In some embodiments, the SARM1 inhibitor is first administered to the subject, followed by the DLK inhibitor. In some embodiments, the DLK inhibitor is administered before the SARM1 inhibitor. In some embodiments, the SARM1 inhibitor is administered to a subject exposed to the DLK inhibitor.

[0034] In some embodiments, the SARM1 inhibitor and the NAMPT inhibitor are co-administered to a subject. In some embodiments, the SARM1 inhibitor is first administered to the subject, followed by the NAMPT inhibitor. In some embodiments, the NAMPT inhibitor is administered before the SARM1 inhibitor. In some embodiments, the SARM1 inhibitor is administered to a subject exposed to the NAMPT inhibitor.

[0035] In some embodiments, the provided method and / or combination therapy inhibits the activity of SARM1. Alternatively or additionally, in some embodiments, the provided method and / or combination therapy alleviates one or more attributes of neurodegeneration. In some embodiments, the present disclosure provides methods of treating, preventing, and / or ameliorating neurodegenerative diseases, disorders, or conditions associated with axonal degeneration.

[0036] In some embodiments, the SARM1 inhibitor is a small molecule, polypeptide, peptide fragment, nucleic acid (e.g., siRNA, antisense oligonucleotide, microRNA, or aptamer), antibody, dominant negative inhibitor, or ribozyme.

[0037] In some embodiments, the SARM1 inhibitor is a small molecule. In some embodiments, the SARM1 inhibitor is siRNA. In some embodiments, the SARM1 inhibitor is an antisense oligonucleotide. In some embodiments, the SARM1 inhibitor is a polypeptide. In some embodiments, the SARM1 inhibitor is a peptide fragment. In some embodiments, the SARM1 inhibitor is a nucleic acid. In some embodiments, the SARM1 inhibitor is an antisense oligonucleotide.

[0038] In some embodiments, the DLK inhibitor is a small molecule, polypeptide, peptide fragment, nucleic acid (such as siRNA, antisense oligonucleotide, microRNA or aptamer), antibody, dominant negative inhibitor or ribozyme.

[0039] In some embodiments, the DLK inhibitor is a small molecule. In some embodiments, the DLK inhibitor is siRNA. In some embodiments, the DLK inhibitor is an antisense oligonucleotide. In some embodiments, the DLK inhibitor is a polypeptide. In some embodiments, the DLK inhibitor is a peptide fragment. In some embodiments, the DLK inhibitor is a nucleic acid. In some embodiments, the DLK inhibitor is an antisense oligonucleotide.

[0040] In some embodiments, the NAMPT inhibitor is a small molecule, polypeptide, peptide fragment, nucleic acid (such as siRNA, antisense oligonucleotide, microRNA or aptamer), antibody, dominant negative inhibitor or ribozyme.

[0041] In some embodiments, the NAMPT inhibitor is a small molecule. In some embodiments, the NAMPT inhibitor is siRNA. In some embodiments, the NAMPT inhibitor is an antisense oligonucleotide. In some embodiments, the NAMPT inhibitor is a polypeptide. In some embodiments, the NAMPT inhibitor is a peptide fragment. In some embodiments, the NAMPT inhibitor is a nucleic acid. In some embodiments, the NAMPT inhibitor is an antisense oligonucleotide.

[0042] In some embodiments, the NAMPT inhibitor prevents the formation of nicotinamide mononucleotide (NMN). In some embodiments, inhibition of NAMPT inhibits the mammalian NAD+ salvage pathway.

[0043] In some embodiments, the present disclosure provides a composition comprising and / or delivering a SARM1 inhibitor (such as in the form described herein), a prodrug or an active metabolite thereof. In certain embodiments, the composition comprising the SARM1 inhibitor is formulated for co-administration to a subject with a DLK inhibitor or a NAMPT inhibitor.

[0044] In some embodiments, the present disclosure provides a composition comprising a SARM1 inhibitor for use in combination with a DLK inhibitor or a NAMPT inhibitor. In some embodiments, such a composition is a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0045] In some embodiments, a SARM1 inhibitor can be identified according to assays described, for example, in WO 2018 / 057989, published on March 29, 2018, the entire content of which is incorporated herein by reference. Brief Description of the Drawings

[0047] Figure 1A and Figure 1B show that the combination of compound I-26 (a SARM1 inhibitor) and the DLK inhibitor GNE-3511 provides enhanced neuroprotection after axotomy compared to monotherapy. For each concentration of the test compound I-26, the degree of axonal protection of the combination of compound I-26 + DLK inhibitor was compared to the amount of protection produced by the reagent in the combination that alone had the higher protection. Figure 1A and 1B show the degeneration index of DRG axons 16 hours after axotomy. In Figure 1A , 100 nM DLK inhibitor did not provide axonal protection, while compound I-26 showed axonal protection at all test concentrations. Addition of 100 nM DLK inhibitor to the test concentrations of compound I-26 provided further, although not significant, reduction in axonal degeneration. Indicates uncut axons , untreated cut axons , axons treated with 100 nM DLK inhibitor , axons treated with 1.1, 3.3, 10, or 30 μM compound I-26 alone and axons treated with 1.1, 3.3, 10, or 30 μM compound I-26 + 100 nM DLK inhibitor. The degeneration index. In Figure 1B , 300 nM DLK inhibitor alone and 1.1 μM of compound I-26 alone each provided modest protection. Surprisingly, the combination of 1.1 μM compound I-26 + 300 nM DLK inhibitor provided robust and statistically significant protection indistinguishable from control uninjured axons. Moreover, the magnitude of the combined effect of 1.1 μM compound I-26 and 300 nM DLK inhibitor was greater than the sum of the individual effects of either reagent alone, indicating that the effect of combining these reagents is not simply additive but is in fact synergistic and cannot be predicted from the individual effects of the separate reagents. Indicates uncut axons , untreated cut axons Axons treated with 300 nM DLK inhibitor Axons treated with 1.1 µM compound I-26 alone And axons treated with 1.1 µM compound I-26 + 300 nM DLK inhibitor Degeneration index. Statistical significance is indicated by * (p < 0.05); ** (p < 0.01); *** (p < 0.001); and **** (p < 0.0001).

[0048] Figure 2A And Figure 2B Show that the combination of compound I-86 (SARM1 inhibitor) and DLK inhibitor (GNE-3511) provides enhanced neuroprotection after axotomy compared to monotherapy. For the concentrations of compound I-86 tested, the degree of axon protection by the combination of compound I-86 + DLK inhibitor was compared to the amount of protection produced by the reagent with the higher protection in the combination alone. Figure 2A And 2B Show the degeneration index of DRG axons 16 hours after axotomy. In Figure 2A , 100 nM DLK inhibitor did not provide axon protection, while at 1.1 µM, compound I-86 exhibited a small but statistically significant amount of axon protection. Surprisingly, the combination of 1.1 µM compound I-86 + 100 nM DLK inhibitor provided robust and statistically significant axon protection that was greater than the sum of the individual effects of either reagent alone. Indicates uncut axons Uncut axons, untreated cut axons Axons treated with 100 nM DLK inhibitor Axons treated with 1.1 µM compound I-86 alone And axons treated with 1.1 µM compound I-86 + 100 nM DLK inhibitor Degeneration index. Statistical significance is indicated by * (p < 0.05); ** (p < 0.01); *** (p < 0.001); and **** (p < 0.0001). In Figure 2BIn this case, either 300 nM of the DLK inhibitor alone or 1.1 µM of Compound I-86 alone provided moderate axonal protection. Surprisingly, the combination of 1.1 µM of Compound I-86 + 300 nM of the DLK inhibitor provided robust and statistically significant axonal protection. Additionally, the magnitude of the combined effect of 1.1 µM of Compound I-86 and 300 nM of the DLK inhibitor was greater than the sum of the individual effects of either reagent alone, indicating that the effect of combining these reagents was not simply additive, but rather was actually synergistic and could not be predicted from the individual effects of the separate reagents. Indicates uncut axons and untreated transected axons and axons treated with 300 nM of the DLK inhibitor and axons treated with 1.1 µM of Compound I-86 alone and axons treated with 1.1 µM of Compound I-86 + 300 nM of the DLK inhibitor The degeneration index. Statistical significance is indicated by * (p < 0.05); ** (p < 0.01); *** (p < 0.001); and **** (p < 0.0001).

[0049] Figure 3A and Figure 3B show that the combination of Compound II-6 (SARM1 inhibitor) and the DLK inhibitor (GNE-3511) provides enhanced neuroprotection after axotomy compared to monotherapy. For each concentration of the test Compound II-6, the degree of axonal protection of the combination of Compound II-6 + the DLK inhibitor was compared to the amount of protection produced by the individual reagent in the combination that had the higher protective effect alone. Figure 3A and 3B show the degeneration index of DRG axons 16 hours after axotomy. In Figure 3A 100 nM of the DLK inhibitor did not provide axonal protection, while 1.1 or 3.3 µM of Compound II-6 exhibited moderate but statistically significant axonal protection. Surprisingly, the combination of 3.3 µM of Compound II-6 + 100 nM of the DLK inhibitor provided robust and statistically significant protection. Additionally, the magnitude of the combined effect of 3.3 µM of Compound II-6 and 100 nM of the DLK inhibitor was greater than the sum of the individual effects of either reagent alone and exhibited nearly complete injury protection, indicating that the effect of combining these reagents was not simply additive, but rather was actually synergistic and could not be predicted from the individual effects of the separate reagents. Indicates uncut axons and untreated transected axons and axons treated with 100 nM of the DLK inhibitor and axons treated with 1.1 or 3.3 µM of Compound II-6 alone Axons treated with 1.1 or 3.3 μM compound II-6 + 100 nM DLK inhibitor denaturation index. Statistical significance is indicated by * (p < 0.05); ** (p < 0.01); *** (p < 0.001); and **** (p < 0.0001). In Figure 3B , 300 nM DLK inhibitor alone or 3.3 μM compound II-6 alone provided moderate protection. Compared with 300 nM DLK inhibitor alone, the combination of 3.3 μM compound II-6 + 300 nM DLK inhibitor provided robust and statistically significant protection. In addition, the magnitude of the combined effect of 3.3 μM compound II-6 and 300 nM DLK inhibitor was greater than the sum of the individual effects of either reagent alone and exhibited complete injury protection, indicating that the effect of combining these reagents was not simply additive but was actually synergistic and not predictable from the individual effects of the separate reagents. Indicates uncut axons , untreated transected axons , axons treated with 300 nM DLK inhibitor , axons treated with 1.1 or 3.3 μM compound II-6 alone and axons treated with 1.1 or 3.3 μM compound II-6 + 300 nM DLK inhibitor denaturation index. Statistical significance is indicated by * (p < 0.05); ** (p < 0.01); *** (p <0.001); and **** (p < 0.0001).

[0050] Figure 4A and Figure 4B show that the combination of compound II-32 (SARM1 inhibitor) and DLK inhibitor (GNE-3511) prolongs neuroprotection after axotomy compared to monotherapy. For each concentration of compound II-32 tested, the degree of axonal protection of the compound II-32 + DLK inhibitor combination was compared to the amount of protection produced by the reagent with the higher protection alone in the combination. Figure 4A and 4B show the denaturation index of DRG axons 16 hours after axotomy. In Figure 4AIn it, the 100 nM DLK inhibitor did not provide axonal protection, while 0.11, 0.33, or 1.1 μM of Compound II-32 showed moderate but not statistically significant axonal protection at these concentrations. The combination of 0.11, 0.33, or 1.1 μM of Compound II-32 + 100 nM DLK inhibitor provided higher protection than either reagent alone, reaching statistical significance at 1.1 μM of Compound II-32. In addition, the magnitude of the combined effect of 1.1 μM of Compound II-32 and 100 nM DLK inhibitor was greater than the sum of the individual effects of either reagent alone, indicating that the effect of combining these reagents was not simply additive but was actually synergistic and could not be predicted by the individual effects of the separate reagents. Indicates unsevered axons , un-treated severed axons , axons treated with 100 nM DLK inhibitor , axons treated with 0.11, 0.33, or 1.1 μM of Compound II-32 alone and axons treated with 0.11, 0.33, or 1.1 μM of Compound II-32 + 100 nM DLK inhibitor of the degeneration index. Statistical significance is indicated by * (p < 0.05); ** (p < 0.01); *** (p < 0.001); and **** (p < 0.0001). In Figure 4B , the 300 nM DLK inhibitor alone provided a moderate but statistically significant level of axonal protection, while 0.11, 0.33, or 1.1 μM of Compound II-32 alone provided only slight and non-statistically significant protection at these concentrations. However, the combination of 0.33 or 1.1 μM of Compound II-32 + 300 nM DLK inhibitor provided robust and statistically significant protection compared to the 300 nM DLK inhibitor alone. In addition, the magnitude of the combined effect of 0.33 or 1.1 μM of Compound II-32 and 300 nM DLK inhibitor was greater than the sum of the individual effects of either reagent alone, indicating that the effect of combining these reagents was not simply additive but was actually synergistic and could not be predicted by the individual effects of the separate reagents. Indicates unsevered axons , un-treated severed axons , axons treated with 300 nM DLK inhibitor , axons treated with 0.11, 0.33, or 3.3 μM of Compound II-32 alone and axons treated with 0.11, 0.33, or 1.1 μM of Compound II-32 + 300 nM DLK inhibitor Denaturation index. Statistical significance is indicated by * (p < 0.05); ** (p < 0.01); *** (p < 0.001); and **** (p < 0.0001).

[0051] Definition

[0052] Combination It is to be understood that the term "binding" as used herein generally refers to an association (e.g., non-covalent or covalent association) between two or more entities. "Direct" binding involves physical contact between entities or moieties; indirect binding involves physical interaction via physical contact with one or more intermediate entities. Binding between two or more entities can generally be evaluated in a variety of environments - including those in which the interacting entities or moieties are studied in isolation or in more complex systems (e.g., while covalently or otherwise associated with a carrier entity and / or in a biological system or cell).

[0053] Biological sample The term "biological sample" as used herein generally refers to a sample obtained from or derived from a relevant biological source as described herein (e.g., tissue or organism or cell culture). In some embodiments, the relevant source comprises an organism, such as an animal or a human. In some embodiments, the biological sample is or comprises a biological tissue or fluid. In some embodiments, the biological sample can be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free-floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph fluid; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages, such as catheter lavages or bronchoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; other body fluids, secretions, and / or excretions; and / or cells therefrom, etc. In some embodiments, the biological sample is or comprises cells obtained from an individual. In some embodiments, the resulting cells are or include cells from the individual from whom the sample was obtained. In some embodiments, the sample is a "primary sample" obtained directly from the relevant source by any suitable means. For example, in some embodiments, the primary biological sample is obtained by a method selected from biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, body fluid collection (e.g., blood, lymph fluid, feces, etc.), etc. In some embodiments, as is clear from the context, the term "sample" refers to an article obtained by processing (e.g., by removing one or more of its components and / or by adding one or more reagents thereto) the primary sample. For example, filtration using a semipermeable membrane. Such a "processed sample" can contain, for example, nucleic acids or proteins extracted from the sample or obtained by subjecting the primary sample to techniques such as amplification or reverse transcription of mRNA, isolation, and / or purification of certain components, etc.

[0054] Biomarker The term "biomarker" is used herein to denote an entity, event, or characteristic whose presence, level, degree, type, and / or form is associated with a particular biological event or state such that it is regarded as a "marker" of that event or state. By way of example only, in some embodiments, a biomarker can be or include a marker of a particular disease state or the likelihood that a particular disease, disorder, or condition may develop, occur, or recur. In some embodiments, a biomarker can be or include a marker of a particular disease or treatment outcome or the likelihood thereof. Thus, for a relevant biological event or relevant state, in some embodiments, a biomarker is predictive, in some embodiments, a biomarker is prognostic, and in some embodiments, a biomarker is diagnostic. A biomarker can be or include an entity of any chemical species and can be or include a combination of entities. For example, in some embodiments, a biomarker can be or include a nucleic acid, polypeptide, lipid, carbohydrate, small molecule, inorganic reagent (such as a metal or ion), or a combination thereof. In some embodiments, a biomarker is a cell surface marker. In some embodiments, a biomarker is intracellular. In some embodiments, a biomarker is detected extracellularly (e.g., secreted or otherwise generated or present extracellularly, such as in a body fluid such as blood, urine, tears, saliva, cerebrospinal fluid, etc.). In some embodiments, a biomarker can be or include a genetic or epigenetic signature. In some embodiments, a biomarker can be or include a gene expression signature.

[0055] In some embodiments, a biomarker can be or include a marker of neurodegeneration or the likelihood that a neurodegenerative disease, disorder, or condition may develop, occur, or recur. In some embodiments, a biomarker can be or include a marker of neurodegeneration, treatment outcome, or the likelihood thereof. Thus, for a neurodegenerative disease, disorder, or condition, in some embodiments, a biomarker is predictive, in some embodiments, a biomarker is prognostic, and in some embodiments, a biomarker is diagnostic. In some embodiments, changes in biomarker levels can be detected in cerebrospinal fluid (CSF), plasma, and / or serum. In some embodiments, a biomarker can be a detectable signal generated by a medical imaging technique, including but not limited to magnetic resonance imaging (MRI), positron emission tomography (PET), and / or computed tomography (CT). In some embodiments, a biomarker can be a detectable change of electrophysiological nature.

[0056] In some embodiments, neurodegeneration can be assessed, for example, by detecting an increase and / or decrease in the concentration of neurofilament light chain protein (NF-L) and / or neurofilament heavy chain protein (NF-H) contained in a body fluid from a subject, including but not limited to cerebrospinal fluid, blood, serum, and / or plasma. In some embodiments, the occurrence and / or progression of neurodegeneration can be evaluated by positron emission tomography (PET) with a synaptic vesicle glycoprotein 2a (SV2A) ligand. In some embodiments, detectable changes in the constitutive NAD+ and / or cADPR levels in neurons can be used to assess neurodegeneration.

[0057] In some embodiments, detectable changes in one or more neurodegeneration-related proteins in a subject, relative to a healthy reference population, can be used as biomarkers of neurodegeneration. Such proteins include but are not limited to albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acidic protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractant protein (MCP)-1, neurogranin, neuron-specific enolase (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM)2, Phospho-tau, and / or Total-tau. In some embodiments, an increase in cytokines and / or chemokines, including but not limited to Ccl2, Ccl7, Ccl12, Csf1, and / or Il6, can be used as a biomarker of neurodegeneration.

[0058] Carrier As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle administered together with a composition. In some exemplary embodiments, the carrier can include sterile liquids, such as water and oils, including oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. In some embodiments, the carrier is or includes one or more solid components.

[0059] CombinationAs used herein, the term "combination therapy" or "in combination with" refers to those situations in which two or more different agents for treating a disease are administered in an overlapping regimen such that a subject is simultaneously exposed to at least two agents. In some embodiments, the different agents are administered simultaneously. In some embodiments, the administration of one agent overlaps with the administration of at least one other agent. In some embodiments, the different agents are administered sequentially (e.g., all "doses" of a first regimen are administered prior to the administration of any dose of a second regimen) such that the agents have simultaneous biological activity in the subject. In some embodiments, "administration" of a combination therapy may involve administering one or more agents or modalities in combination to a subject who is receiving another agent or modality. For clarity, combination therapy does not require that the individual agents be administered together (or even necessarily simultaneously) in a single composition, although in some embodiments, two or more agents or their active moieties may be administered together in a combination composition or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0060] Composition One of ordinary skill in the art will recognize that the term "composition" can be used to denote an independent physical entity comprising one or more specified components. In general, unless otherwise specified, a composition can be in any form - e.g., gas, gel, liquid, solid, etc.

[0061] Dual leucine zipper kinase (DLK) inhibitor As used herein, the term "dual leucine zipper kinase inhibitor" or "DLK inhibitor" refers to a compound that binds to and / or inhibits the activity of DLK. DLK, also known as MAP3K12, is a member of the mixed lineage kinase (MLK) family that contains an N-terminal kinase domain, followed by two leucine zipper domains and a glycine / serine / proline-rich C-terminal domain. In some embodiments, inhibition of DLK results in a downstream decrease in JNK phosphorylation (e.g., a decrease in JNK2 and / or JNK3 phosphorylation), a downstream decrease in JNK activity (e.g., a decrease in JNK2 and / or JNK3 activity), and / or a downstream decrease in JNK expression (e.g., a decrease in JNK2 and / or JNK3 expression). Accordingly, inhibition of DLK can have an impact on the activity of kinase targets downstream of the DLK signaling cascade, such as (i) a decrease in JNK phosphorylation, JNK activity, and / or JNK expression, (ii) a decrease in cJun phosphorylation, cJun activity, and / or cJun expression, and / or (iii) a decrease in p38 phosphorylation, p38 activity, and / or p38 expression.

[0062] DomainAs used herein, the term "domain" refers to a segment or portion of an entity. In some embodiments, a "domain" is associated with specific structural and / or functional characteristics of the entity such that when the domain is physically separated from the remainder of its parent entity, it substantially or fully retains the specific structural and / or functional characteristics. Alternatively or additionally, a domain can be or include a part of an entity that, when separated from the (parent) entity and attached to a different (recipient) entity, substantially retains and / or confers on the recipient entity one or more of the structural and / or functional characteristics that characterized it in the parent entity. In some embodiments, a domain is a segment or portion of a molecule (e.g., a small molecule, carbohydrate, lipid, nucleic acid, or polypeptide). In some embodiments, a domain is a segment of a polypeptide; in some such embodiments, a domain is characterized by specific structural elements (e.g., a specific amino acid sequence or sequence motif, an α-helical character, a β-sheet character, a coiled-coil character, a random coil character, etc.) and / or specific functional characteristics (e.g., binding activity, enzymatic activity, folding activity, signaling activity, etc.).

[0063] Dosage form or unit dosage form One of ordinary skill in the art will recognize that the term "dosage form" can be used to denote a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) administered to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, such an amount is a unit dose (or an integer part thereof) that is suitable for administration according to a dosing regimen (i.e., a therapeutic dosing regimen) that has been determined to be associated with a desired or beneficial outcome when administered to the relevant population. One of ordinary skill in the art will recognize that the total amount of a therapeutic composition or reagent administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0064] Dosing regimen or treatment regimenThose skilled in the art will recognize that the terms "dosing regimen" and "treatment regimen" can be used to denote a set of unit doses (usually more than one) that are typically administered to a subject separately over a period of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen that may involve one or more doses. In some embodiments, a dosing regimen comprises multiple doses, each separated in time from the other doses. In some embodiments, the doses are separated from each other by the same length of time; in some embodiments, a dosing regimen comprises multiple doses and at least two different lengths of time separating the doses. In some embodiments, all of the doses within a dosing regimen have the same amount of the unit dose. In some embodiments, the different doses within a dosing regimen are different amounts. In some embodiments, a dosing regimen comprises a first, priming dose, followed by one or more booster doses of a second dose that is different from the first dose. In some embodiments, a dosing regimen comprises a first, priming dose, followed by one or more booster doses of a second dose that is the same as the first dose. In some embodiments, a dosing regimen is associated with a desired or beneficial outcome (i.e., is a therapeutic dosing regimen) when administered to a relevant population.

[0065] Excipient As used herein, refers to a non-therapeutic agent that can be included in a pharmaceutical composition, such as 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, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like.

[0066] Inhibitor The term "inhibitor" as used herein refers to an entity, condition, or event whose presence, level, or degree is associated with a reduced level or activity of a target. In some embodiments, an inhibitor can act directly (in which case it exerts its effect directly on its target, e.g., by binding to the target); in some embodiments, an inhibitor can act indirectly (in which case it exerts its effect by interacting with a modulator of the target and / or otherwise altering the modulator of the target to reduce the level and / or activity of the target). In some embodiments, an inhibitor is an inhibitor whose presence or level is associated with a reduced level or activity of a target relative to a specific reference level or activity (e.g., as observed under appropriate reference conditions, such as the presence of a known inhibitor or the absence of the inhibitor in question).

[0067] NeurodegenerationAs used herein, the term "neurodegeneration" refers to the decline of one or more elements, structures, or characteristics of neurons or neuronal tissue. In some embodiments, neurodegeneration is observed as a pathological reduction in an organism. Those skilled in the art will recognize that neurodegeneration is associated with certain diseases, disorders, and conditions, including those that affect humans. In some embodiments, neurodegeneration may be transient (e.g., occurring sometimes in relation to certain infections and / or chemical or mechanical perturbations); in some embodiments, neurodegeneration may be chronic and / or progressive (e.g., typically associated with certain diseases, disorders, or conditions such as, but not limited to, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, or Alzheimer's disease). In some embodiments, neurodegeneration can be assessed, for example, by detecting an increase in a biomarker associated with neurodegeneration in a subject. In some embodiments, neurodegeneration can be assessed, for example, by detecting a decrease in a biomarker associated with neurodegeneration in a subject. Alternatively or additionally, in some embodiments, neurodegeneration can be assessed by magnetic resonance imaging (MRI) of biomarkers contained in cerebrospinal fluid or other biomarkers observed in a subject. In some embodiments, neurodegeneration is defined as a score below 24 on the Mini-Mental State Examination. In some embodiments, neurodegeneration refers to synaptic loss. In some embodiments, neurodegeneration refers to a reduction in neural tissue associated with traumatic injury (e.g., exposure to an external force to disrupt the integrity of neural tissue). In some embodiments, neurodegeneration refers to a reduction in peripheral neural tissue. In some embodiments, neurodegeneration refers to a reduction in central neural tissue.

[0068] Nicotinamide phosphoribosyltransferase (NAMPT) inhibitor : The term "nicotinamide phosphoribosyltransferase inhibitor" or "NAMPT inhibitor" as used herein refers to a compound that binds to NAMPT and / or inhibits the activity of NAMPT. NAMPT is the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway that converts nicotinamide (NAM) to nicotinamide mononucleotide (NMN) in mammals. In some embodiments, inhibition of NAMPT results in a reduction in NMN. In some embodiments, a NAMPT inhibitor blocks the synthesis of NMN. In some embodiments, inhibition of NAMPT inhibits the NAMPT-dependent NAD+ salvage pathway.

[0069] Oral The phrase "oral administration" as used herein has its art-recognized meaning and refers to the administration of a compound or composition by mouth.

[0070] ParenteralAs used herein, the phrase "parenteral administration" has its art-understood meaning and refers to modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0071] Patient As used herein, the term "patient" refers to any organism to which the provided composition has been or can be administered, for example, for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is human. In some embodiments, the patient has or is susceptible to one or more disorders or conditions. In some embodiments, the patient exhibits one or more symptoms of a disorder or condition. In some embodiments, the patient has been diagnosed with one or more disorders or conditions. In some embodiments, the patient is receiving or has received a particular therapy for diagnosing and / or treating a disease, disorder, or condition.

[0072] Pharmaceutical composition As used herein, the term "pharmaceutical composition" refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit doses 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 some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those suitable for: oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets, such as those intended for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, as, for example, a sterile solution or suspension, or a sustained-release formulation; topical application, such as as a cream, ointment, or controlled-release patch, or a spray applied to the skin, lung, or oral cavity; intravaginal or rectal administration, such as as a vaginal pessary, cream, or foam; sublingual; intraocular; transdermal; or nasal, pulmonary, and administration to other mucosal surfaces.

[0073] Pharmaceutically acceptable As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for use in 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.

[0074] Pharmaceutically acceptable carrierAs used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; pH buffering solutions; polyesters, polycarbonates, and / or polyanhydrides; and other non-toxic compatible substances used in pharmaceutical formulations.

[0075] Pharmaceutically acceptable salt As used herein, the term "pharmaceutically acceptable salts" refers to salts of these compounds that are suitable for use in the pharmaceutical field, i.e., salts that are suitable for contact with the tissues of humans and lower animals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, etc., and 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, Medicinally acceptable salts are described in detail in , 66: 1-19 (1977). In some embodiments, medicinally acceptable salts include, but are not limited to, non-toxic acid addition salts which are salts of an amino group formed by using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or using organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. In some embodiments, medicinally acceptable salts include, but are not limited to, adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, glucuronates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. In some embodiments, medicinally acceptable salts include, if appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide ions, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having 1 to 6 carbon atoms, sulfonate and arylsulfonate.

[0076] Prevention As used herein, the term "prevention", when used in relation to the occurrence of a disease, disorder and / or condition, refers to reducing the risk of developing the disease, disorder and / or condition and / or delaying the onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention can be considered complete when the onset of the disease, disorder or condition has been delayed for a predetermined time.

[0077] SpecificityAs used herein, the term "specificity" with respect to an active agent is understood by those skilled in the art to mean that the agent discriminates between potential target entities or states. For example, in some embodiments, an agent is said to "specifically" bind to its target if it preferentially binds to its target in the presence of one or more competing alternative targets. In many embodiments, specific interactions rely on the presence of specific structural features (e.g., epitopes, clefts, binding sites) of the target entity. It is to be understood that specificity need not be absolute. In some embodiments, specificity may be evaluated relative to the specificity of the binding agent for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is evaluated relative to a reference specific binding agent. In some embodiments, specificity is evaluated relative to a reference non-specific binding agent. In some embodiments, the agent or entity binds undetectably to competing alternative targets under conditions where it binds to its target entity. In some embodiments, the binding agent binds to its target entity with a higher on-rate, a lower off-rate, increased affinity, decreased dissociation, and / or increased stability compared to competing alternative targets.

[0078] Subject As used herein, the term "subject" refers to an organism, typically a mammal (e.g., a human, including in some embodiments a prenatal human form). In some embodiments, the subject has a relevant disease, disorder, or condition. In some embodiments, the subject is predisposed to a disease, disorder, or condition. In some embodiments, the subject exhibits one or more symptoms or features of a disease, disorder, or condition. In some embodiments, the subject does not exhibit any symptoms or features of a disease, disorder, or condition. In some embodiments, the subject is an individual having one or more characteristics representative of being predisposed to or at risk of a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual who is being and / or has been diagnosed and / or treated.

[0079] Therapeutic agentAs used herein, the phrase "therapeutic agent" generally refers to any agent that elicits a desired pharmacological effect when administered to a living organism. In some embodiments, an agent is considered a therapeutic agent if it exhibits a statistically significant effect in an appropriate population. In some embodiments, the appropriate population can be a population of model organisms. In some embodiments, the appropriate population can be determined by various criteria, such as a specific age group, gender, genetic background, existing clinical condition, etc. In some embodiments, a therapeutic agent is a substance that can be used to alleviate, improve, relieve, inhibit, prevent, delay onset, reduce severity, and / or reduce incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition. In some embodiments, a "therapeutic agent" is an agent that has been or needs to be approved by a government agency before it can be marketed for administration to humans. In some embodiments, a "therapeutic agent" is an agent that requires a medical prescription for administration to humans.

[0080] Treatment As used herein, the term "treatment" refers to any method for partially or completely alleviating, improving, relieving, inhibiting, preventing, delaying onset, reducing severity, and / or reducing incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition. A subject who does not exhibit signs of a disease, disorder, and / or condition can be treated. In some embodiments, a subject who exhibits only early signs of a disease, disorder, and / or condition can be treated, for example, to reduce the risk of development of the pathology associated with the disease, disorder, and / or condition. In some embodiments, a subject can be treated to prevent the risk of development of a pathology associated with and / or caused by a medical procedure and / or treatment.

[0081] Detailed description of certain embodiments

[0082] Programmed axonal degeneration

[0083] 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 called Wallerian degeneration, which is distinct from traditional cell death pathways such as apoptosis (Gerdts, J. et al., Neuron , 2016, 89, 449-460; Whitmore, A. et al., Cell Death Differ, 2003, 10, 260 - 261, each incorporated herein by reference in its entirety). During Wallerian degeneration, selective breakdown of axons occurs in the distal segment of the injured nerve, while the proximal axon segment and the cell body remain intact. Axonal degeneration after injury is characterized by sequential depletion of NMNAT2, NAD+, and ATP, followed by neurofilament proteolysis and axonal fragmentation approximately 8 to 24 hours after the primary injury (Gerdts, J. et al., Neuron , 2016, 89, 449 - 460, incorporated herein by reference in its entirety).

[0084] The discovery of the Wallerian degeneration slow (Wlds) protein, which acutely delays axonal degeneration after injury, raised the hope that blocking Wallerian degeneration would help treat nerve disorders (Conforti et al., Nat Rev Neurosci . 2014, 15(6), 394 - 409; Mack et al., Nat Neurosci . 2001, 4(12), 1199 - 1206, each incorporated herein by reference in its entirety). The Wlds protein blocks axonal degeneration by mislocalizing the nuclear nicotinamide adenine dinucleotide (NAD+) biosynthetic enzyme NMNAT1 into axons, thereby replacing the loss of the labile axon maintenance factor NMNAT2 and preventing post - injury NAD+ degradation (Araki et al., Science . 2004, 305(5686), 1010 - 1013; Babetto et al., J Neurosci ., 2010, 30(40), 13291 - 13304.; Gilley et al., PLoS Biol. 2010, 8(1), e1000300; Sasaki et al., J Biol Chem., 2010, 285(53), 41211 - 41215, each incorporated herein by reference in its entirety). These results emphasize the importance of NAD+ for maintaining axonal integrity.

[0085] NAD+ is a natural coenzyme that serves as a mediator in cellular oxidation and reduction reactions and as a substrate for ADP - ribosyltransferases. NAD+ has key roles in energy metabolism, ATP synthesis, and cell signaling (Belenkey et al., Trends Biochem ., 2007, 32, 12 - 19; Chiarugi et al., Nat. Rev. Cancer, 2012, 12, 741-752 (each incorporated herein by reference in its entirety). Increasing intracellular NAD+ levels can improve cell health. In addition, homeostatic regulation of NAD+ levels is responsible for maintaining axonal stability and integrity. Accordingly, manipulations that increase the axonal localization of NMNAT, a nicotinamide adenine dinucleotide (NAD+) biosynthetic enzyme, provide axonal protection (Babetto et al., Cell Rep., 2010, 3, 1422-1429; Sasaki et al., J. Neurosci ., 2009, each incorporated herein by reference in its entirety). Exogenous application of NAD+ precursors, which are substrates for these enzymes, including nicotinic acid mononucleotide, nicotinamide mononucleotide, and nicotinamide riboside (NR), can also delay axonal degeneration (Sasaki et al., J. Neurosci , 2006, 26(33):8481-8491, which is incorporated herein by reference in its entirety).

[0086] In most cases, the application of NAD+ or NAD+ precursors has been found to be beneficial to neurons after injury. However, some studies now suggest that an abnormal increase in nicotinamide mononucleotide (NMN), a direct precursor of NAD+, rather than a loss of NAD+ is responsible for mediating neurodegeneration after injury. In fact, one study found that co-administering nicotinic acid riboside (NAR) (a precursor of NAMN) with FK866, an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), the enzyme that produces NMN, protected dorsal root ganglion (DRG) axons from vincristine-induced degeneration (Lie et al., Pro. Nat. Acad. Sci. USA., 2018, 115(42): 10654-10659, which is incorporated herein by reference in its entirety). This study observed that an increase in NMN alone was not sufficient to cause degeneration, but that inhibiting NMN levels could confer axonal protection even at lower NAD+ levels. Blocking NMN formation with a NAMPT inhibitor blocked NAD+ synthesis via the NAMPT-dependent salvage pathway, while other NAD+ synthetic pathways capable of producing NAD+ remained open. Thus, blocking NMN formation can be used to prevent axonal degeneration after injury and to complement neuroprotective agents.

[0087] Pharmacological inhibition or genetic deletion of DLK is also sufficient to attenuate the neuronal injury response and potently protect neurons from degeneration in response to a range of neuronal injuries (Ghosh et al., Cell Biol. 2011, 194, 751-764, the full text of which is incorporated herein by reference). Activation of DLK in neurons triggers stress-specific JNK signaling via MKK4 / 7 and elevates PERK signaling. Induction of these pathways generates a broad transcriptional injury response in neurons by regulating transcription factors, including c-Jun and ATF4, which results in apoptosis and axonal degeneration. Thus, blocking DLK activity can attenuate neuronal injury after injury. In addition, it has also been demonstrated that loss of DLK signaling protects neurons from excitotoxicity-induced degeneration in vitro and in vivo, indicating that DLK function is not limited to axonal injury but is involved in the response to a range of neuronal injuries (Pozniak et al., J. Exp. Med. , 2013, 210, 2553-2567). Thus, DLK has emerged as a drug target for various neurodegenerative disorders and diseases. More recently, it has also been found that knockdown or elimination of SARM1 expression persistently protects sensory neurons from injury-induced axonal degeneration (Gerdts et al., J. Neurosci , 2013, 33, 13569-13580, the full text of which is incorporated herein by reference).

[0088] Activated SARM1 is a highly efficient NADase that depletes local axonal NAD+ stores within minutes to hours after activation, causing a local bioenergetic crisis followed by rapid axonal degeneration. SARM1 belongs to the myeloid differentiation primary response 88 (MYD88)-cytoplasmic adaptor protein family. However, SARM1 is unique within this family in that it is the most evolutionarily ancient adaptor protein, paradoxically inhibits TLR signaling and has been identified as a core executor of the injury-induced axonal death pathway (O'Neill, L.A. & Bowie, A.G., Nat. Rev. Immunol ., 2007, 7, 353-364; Osterloh, J.M. et al., Science , 2012, 337, 481-484; Gerdts, J. et al., J. Neurosci .33, 2013, 13569-13580, each full text of which is incorporated herein by reference). Activation of SARM1 via axonal injury or forced dimerization of the SARM1-TIR domain promotes rapid and catastrophic depletion of nicotinamide adenine dinucleotide (NAD+), followed shortly thereafter by axonal degeneration, thus highlighting the central role of NAD+ homeostasis in axonal integrity (Gerdts, J. et al., Science, 2015, 348, 453-457). This injury-induced NAD+ depletion requires SARM1 both in vitro and in vivo, and SARM1 activation triggers axonal degeneration by disrupting NAD+ locally (Gerdts et al., Science, 2015 348, 452-457; Sasaki et al., J. Biol. Chem. 2015, 290, 17228-17238, each incorporated herein by reference in its entirety).

[0089] Genetic loss-of-function studies have shown that SARM1 acts as a central executor in the axonal degeneration pathway after injury. Gene deletion or knockout of SARM1 enables axons to be preserved for up to 14 days after nerve transection (Osterloh, J.M. et al., Science , 2012, 337, 481-484; Gerdts, J. et al J.Neurosci ., 2013, 33, 13569-13580, each incorporated herein by reference in its entirety) and also improves the functional outcome in mice after traumatic brain injury (Henninger, N. et al., Brain , 139, 2016, 1094-1105, which is incorporated herein by reference in its entirety). In addition to the direct role of SARM1 in axonal injury, SARM1 is also required for the axonal degeneration observed in chemotherapy-induced peripheral neuropathy (CIPN). Loss of SARM1 blocks CIPN, inhibits axonal degeneration and increased pain sensitivity produced after chemotherapeutic vincristine treatment (Geisler et al., Brain , 2016, 139, 3092-3108, which is incorporated herein by reference in its entirety). SARM1 contains multiple conserved motifs, including the SAM domain, ARM / HEAT motifs and the TIR domain, to 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, each incorporated herein by reference in its entirety). The TIR domain is common in signaling proteins that play a role in innate immune pathways, where they act as scaffolds for protein complexes (O'Neill, L.A. & Bowie, A.G., Nat. Rev. Immunol, 2007, 7, 353-364, the full text of which is incorporated herein by reference). Interestingly, dimerization of the SARM1-TIR domain is sufficient to trigger 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, the full text of each of which is incorporated herein by reference). Given the central role of SARM1 in the axonal degeneration pathway and its identified NADase activity, efforts have been made to identify reagents that can modulate SARM1 and may act as useful therapeutic agents to, for example, prevent neurodegenerative diseases, including peripheral neuropathy, traumatic brain injury, and / or neurodegenerative diseases. SARM1-dependent NAD+ consumption is a central biochemical event in the axonal degeneration program. The present disclosure particularly provides methods for inhibiting SARM1. The present disclosure particularly provides combinations of SARM1 inhibitors and DLK inhibitors or NAMPT inhibitors for stabilizing neurons whose axons have been damaged. In some embodiments, such combinations are capable of repairing axons rather than causing them to degenerate.

[0090] Methods for treating neurodegeneration

[0091] DLK is a member of the mixed lineage kinase (MLK) family that contains an N-terminal kinase domain, followed by two leucine zipper domains and a glycine / serine / proline-rich C-terminal domain. Proper function in neurons requires palmitoylation of DLK. Activation of DLK in neurons triggers stress-specific JNK signaling via MKK4 / 7 and enhances PERK signaling. In some embodiments, the DLK inhibitor is a dominant negative inhibitor of DLK.

[0092] NAMPT is the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway that converts nicotinamide (NAM) to nicotinamide mononucleotide (NMN) in mammals. In some embodiments, inhibition of NAMPT results in a decrease in NMN. In some embodiments, the NAMPT inhibitor blocks the synthesis of NMN. In some embodiments, the NAMPT inhibitor is a dominant negative inhibitor of NAMPT. In some embodiments, inhibition of NAMPT inhibits the NAMPT-dependent NAD+ salvage pathway. In some embodiments, the present disclosure provides compounds that inhibit NAMPT.

[0093] In some embodiments, the present disclosure provides a method of treating a subject having one or more diseases, disorders, or conditions. In some embodiments, the one or more diseases, disorders, or conditions are mediated by SARM1.

[0094] In some embodiments, the one or more diseases, disorders, or conditions are acute. In some embodiments, the one or more diseases, disorders, or conditions are chronic.

[0095] In some embodiments, the one or more diseases, disorders, or conditions are characterized by axonal degeneration in the central nervous system, peripheral nervous system, optic nerve, cranial nerves, or a combination thereof.

[0096] In some embodiments, the provided combination therapies and methods promote an increase in the intracellular level of nicotinamide adenine dinucleotide (NAD+) in cells and tissues to improve cell and tissue survival. In some embodiments, the provided combination therapy methods increase the NAD+ levels in cells and tissues. In some embodiments, the provided combination therapies and methods improve cell and tissue survival. In some embodiments, the provided combination therapies and methods stabilize neurons and / or cells until the external environment stabilizes after an acute event.

[0097] In some embodiments, the present disclosure provides a method of treating, preventing, and / or ameliorating a neurodegenerative disease, disorder, or condition, comprising administering a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor. In some embodiments, the neurodegenerative disease, disorder, or condition is associated with axonal degeneration. Accordingly, in some embodiments, the present disclosure provides a method of treating, preventing, and / or ameliorating axonal degeneration, comprising administering to a subject in need thereof a SARM1 inhibitor in combination with a DLK inhibitor or a NAMPT inhibitor.

[0098] In some embodiments, the provided combination therapies and / or methods prevent or slow the degeneration of neurons, a portion of an intact neuron, or a cellular fragment derived from a neuron. In some embodiments, the provided combination and / or method prevents or slows the progression of degeneration of the axonal portion distal to an axonal injury. In some embodiments, the methods and / or combinations provided herein can be used as stabilizers to promote neuron survival. In some embodiments, the provided combination therapies can be used to maintain the function of axons, including but not limited to metabolism, axonal integrity, intracellular transport, and action potential propagation.

[0099] In some embodiments, the provided methods treat or prevent secondary conditions associated with neurodegenerative disorders. Such secondary conditions include but are not limited to muscle injury, respiratory injury, anxiety, depression, language disorders, pulmonary embolism, arrhythmia, and / or pneumonia.

[0100] In some embodiments, the present disclosure relates to a method of treating, preventing, and / or ameliorating a neurodegenerative disease, disorder, or condition, comprising i) providing a) a subject diagnosed with, at risk of, or exhibiting symptoms of a neurodegenerative disease, disorder, or condition and b) a combination comprising a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor; and ii) administering the combination to the subject under conditions that mitigate the neurodegenerative disease, disorder, or condition.

[0101] In some embodiments, the present disclosure provides a combination therapy comprising a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor. In some embodiments, the provided combination therapy comprises a SARM1 inhibitor, a DLK inhibitor, or a NAMPT inhibitor and one or more additional therapeutic agents.

[0102] In some embodiments, the provided combination therapy comprises a SARM1 inhibitor, a DLK inhibitor, or a NAMPT inhibitor and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from acetylcholinesterase inhibitors, NMDA agonists, donepezil, galantamine, memantine, rivastigmine, riluzole, edaravone, levodopa, carbidopa, anticholinergics, bromocriptine, pramipexole, ropinirole, and / or amantadine. In some embodiments, the one or more additional therapeutic agents are selected from immunosuppressive drugs such as prednisone, cyclosporine, or azathioprine, and non-steroidal anti-inflammatory drugs (NSAIDs). In some embodiments, the one or more additional therapeutic agents include antidepressants, anticonvulsants, antiarrhythmic agents (e.g., mexiletine), and anesthetics, tricyclic antidepressants such as amitriptyline, or newer serotonin-norepinephrine reuptake inhibitors such as duloxetine hydrochloride or venlafaxine. In some embodiments, the anticonvulsant is one of the following: gabapentin, pregabalin, topiramate, and carbamazepine. In some embodiments, the one or more additional therapeutic agents combined with the present disclosure include antiepileptic therapy. In some embodiments, the one or more additional therapeutic agents are intravenous immunoglobulin (IV Ig). In some embodiments, the one or more additional therapeutic agents are selected from multiple sclerosis disease-modifying therapies (DMTs), including but not limited to interferon β-1a, interferon β-1b, glatiramer acetate, daclizumab, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, ocrelizumab, and natalizumab.

[0103] In some embodiments, such combination therapies can be used to treat, prevent, and / or ameliorate neurodegenerative diseases, disorders, or conditions. In some embodiments, the provided combination therapies can be used to treat, prevent, and / or ameliorate axonal degeneration. In some embodiments, the provided combination therapies can be used to prevent or slow the progression of axonal degeneration distal to axonal injury.

[0104] In some embodiments, the neurodegenerative disease, disorder, or condition is characterized by axons that are vulnerable to disruption or pathological stress. Such diseases or conditions include, but are not limited to, cancer, diabetes, neurodegenerative diseases, cardiovascular diseases, blood clotting, inflammation, flushing, obesity, aging, or stress.

[0105] In some embodiments, the neurodegenerative disease, disorder, or condition is selected from neuropathy or axonopathy. In some embodiments, an axonopathy or neuropathy is any disease, disorder, or condition that involves neurons and / or supporting cells, such as glia, muscle cells, or fibroblasts, particularly those that involve axonal injury. Axonal injury can be caused by trauma or by 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 neurological diseases and conditions. Such neuropathies can include peripheral neuropathy, central neuropathy, 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 underlying peripheral or systemic diseases.

[0106] In some embodiments, the neurodegenerative disease, disorder, or condition can be traumatic neuronal injury. In some embodiments, injury to the spinal cord and / or traumatic brain injury. In some embodiments, traumatic neuronal injury is blunt force trauma, closed head injury, open head trauma, exposure to shock forces and / or blast forces, penetrating injury in or to the cranial cavity or the innervated regions of the body. In some embodiments, traumatic neuronal injury is a force that causes axonal deformation, stretching, fragmentation, or turning. In some embodiments, the neurodegenerative disease, disorder, or condition is an acute injury to the central nervous system. In some embodiments, the condition is or includes a chronic injury to the central nervous system, such as injury to the spinal cord, traumatic brain injury, and / or traumatic axonal injury. In some embodiments, the condition is or includes chronic traumatic encephalopathy (CTE). In some embodiments, traumatic neuronal injury results from increased intraocular pressure.

[0107] In some embodiments, neurodegenerative or neurological diseases, disorders or conditions are associated with axonal degeneration, axonal injury, axonopathy, demyelinating diseases, central pontine myelinolysis, nerve injury diseases, disorders or conditions, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal injury resulting from leukodystrophy or leukodystrophy.

[0108] In some embodiments, neuropathy or axonopathy is associated with axonal degeneration. In some embodiments, the neuropathy associated with axonal degeneration is a hereditary or congenital neuropathy or axonopathy. In some embodiments, the neuropathy associated with axonal degeneration results from De novo mutation or somatic mutation ... In some embodiments, the neuropathy associated with axonal degeneration results from an idiopathic condition.

[0109] In some embodiments, the methods provided herein can be used, for example, to inhibit or prevent the degeneration of the central nervous system (neurons) or a part thereof. In some embodiments, the present disclosure provides a combination therapy comprising a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor, which can be used, for example, as a method for inhibiting the degeneration of peripheral nervous system neurons or a part thereof.

[0110] In some embodiments, peripheral neuropathy can involve damage to the peripheral nerves and / or can be caused by diseases of the nerves or as a result of systemic diseases. Some such diseases can include diabetes, uremia, infectious diseases such as AIDS or leprosy, nutritional deficiencies, vascular or collagen disorders such as atherosclerosis, and autoimmune diseases such as systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis and polyarteritis nodosa. In some embodiments, peripheral nerve degeneration results from traumatic (mechanical) injury to the nerves as well as chemical or thermal injury to the nerves. Conditions that damage the peripheral nerves include compressive or crush injuries such as carpal tunnel syndrome, direct trauma, penetrating injuries, contusions, fractures or bone dislocations; pressure on superficial nerves (ulnar, radial or peroneal), which can result from prolonged use of crutches or prolonged maintenance of a posture, or from tumors; intraneural hemorrhage; ischemia; exposure to cold or radiation or certain drugs or toxic substances, such as herbicides or pesticides. In particular, nerve injury can result from chemical injury attributed to cytotoxic anticancer agents, such as paclitaxel, cisplatin, proteasome inhibitors or vinca alkaloids, such as vincristine. Typical symptoms of such peripheral neuropathy include weakness, numbness, paresthesia (abnormal sensations, such as burning, itching, stinging or tingling) and pain in the arms, hands, legs and / or feet. In some embodiments, neuropathy is associated with mitochondrial dysfunction. Such neuropathy can exhibit reduced energy levels, i.e., reduced NAD+ and ATP levels.

[0111] In some embodiments, neurodegenerative diseases, disorders, or conditions associated with neuropathy or axonopathy in the central nervous system include diseases involving progressive dementia, such as Alzheimer's disease, senile dementia, Pick's disease, and Huntington's disease; central nervous system diseases affecting muscle function, such as Parkinson's disease, motor neuron, progressive ataxia, and amyotrophic lateral sclerosis; demyelinating diseases, such as multiple sclerosis. Mechanical injury or trauma to the head and spine can also cause nerve injury and degeneration in the brain and spinal cord. In some embodiments, ischemia and / or stroke, as well as conditions such as malnutrition and chemical toxicity, such as chemotherapeutic agents, can cause central nervous system neuropathy.

[0112] In some embodiments, neuropathies or axonopathies associated with axonal degeneration include, but are not limited to, Parkinson's disease, Alzheimer's disease, Huntington's disease, herpes infection, diabetes, amyotrophic lateral sclerosis (ALS), demyelinating diseases, ischemia or stroke, frontotemporal dementia, ataxia, Charcot Marie Tooth, neuromyelitis optica, traumatic brain injury, chemical injury, thermal injury, and AIDS.

[0113] In some embodiments, the subject administered the combination therapy as described herein is a subject having or at risk of having a neurodegenerative disease, disorder, or condition. In some embodiments, the subject is at risk of developing a neurodegenerative disease, disorder, or condition. In some embodiments, the present disclosure provides a method comprising administering to a subject at risk of developing a neurodegenerative disease, disorder, or condition a SARM1 inhibitor in combination with a DLK inhibitor or a NAMPT inhibitor. In some embodiments, the neurodegenerative disease, disorder, or condition is characterized by axonal degeneration.

[0114] In some embodiments, the neurodegenerative or neurological disease, disorder or condition is selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Pelizaeus-Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sachs disease, Gaucher's disease, Hurler syndrome, traumatic brain injury, post-radiation injury, neurological complications of chemotherapy (chemotherapy-induced neuropathy; CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, glaucoma, Leber's hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy, West Nile virus encephalitis, La Crosse virus encephalitis, Bunyavirus encephalitis, viral encephalitis in children, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supranuclear palsy (PSP), Friedrich ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, dementia with Lewy bodies, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, 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).

[0115] In some embodiments, a neurodegenerative disease, disorder or condition includes a condition that produces neuronal or axonal injury or is associated with neuronal or axonal injury. Such neurodegenerative diseases, disorders or conditions can include peripheral neuropathy, central neuropathy and combinations thereof. In some embodiments, peripheral neuropathy can be produced by a disease initially concentrated in the central nervous system, and central nervous system neuropathy can be produced by a primarily peripheral or systemic disease.

[0116] In some embodiments, the neurodegenerative disease, disorder or condition is acute peripheral neuropathy. In some embodiments, the acute peripheral neuropathy is chemotherapy-induced peripheral neuropathy (CIPN). CIPN can be induced by 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), and auristatin (e.g., monomethyl auristatin E conjugate).

[0117] In some embodiments, the present disclosure provides methods for treating, preventing and / or ameliorating neurodegenerative or neurological diseases or conditions associated with axonal degeneration, axonal injury, axonopathy, demyelinating disease, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal injury resulting from leukodystrophy or leukodystrophy. In some embodiments, axonal degeneration results from a decrease or depletion of NAD+.

[0118] In some embodiments, the neurodegenerative disease, disorder or condition is a central nervous system disease or disorder, peripheral neuropathy or disorder, optic nerve disorder, metabolic disorder, traumatic injury, viral encephalitis, exposure to toxic molecules or drugs, neuropathy associated with pain. In some embodiments, viral encephalitis includes those caused by enteroviruses, arboviruses, herpes simplex virus. In some embodiments, viral encephalitis includes West Nile virus encephalitis, La Crosse virus encephalitis, Bunyavirus encephalitis, viral encephalitis in children and AIDS dementia syndrome (also known as HIV dementia, HIV encephalopathy and HIV-associated dementia).

[0119] In some embodiments, a neurodegenerative disease, disorder, or condition is associated with a pain-producing condition. Painful neuropathies treatable according to the methods of the present disclosure include those associated with the following conditions: chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, cancer pain, arthritis, sciatica, headache, surgical pain, muscle spasm, back pain, visceral pain, post-injury pain, toothache, neuralgia such as neurogenic or neuropathic pain, neuroinflammation or injury, shingles, herniated disc, ligament tear, and diabetes.

[0120] In some embodiments, a neurodegenerative disease, disorder, or condition affects the central nervous system. In some embodiments, the neurodegenerative disease, disorder, or condition includes but is not limited to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis, Huntington's disease, senile dementia, Pick's disease, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Bassen-Kornzweig syndrome, Charcot-Marie-Tooth disease, motor neuron disease, hereditary sensory and autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supranuclear palsy (PSP), and / or Friedrich ataxia.

[0121] In some embodiments, a neurodegenerative disease, disorder, or condition affects the peripheral nervous system. In some embodiments, peripheral neuropathy can involve damage to the peripheral nerves and / or can be caused by a disease of the nerves or as a result of a systemic disease. In some embodiments, the peripheral neuropathy is selected from diabetes, uremia, infectious diseases such as AIDS or leprosy, nutritional deficiencies, vascular or collagen disorders such as atherosclerosis, and autoimmune diseases such as systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, and polyarteritis nodosa.

[0122] In some embodiments, a neurodegenerative disease, disorder, or condition affects the optic nerve. In some embodiments, the condition is an acute condition affecting the optic nerve, such as but not limited to acute optic neuropathy (AON) or acute angle-closure glaucoma. In some embodiments, the condition is a hereditary or idiopathic retinal condition. In some embodiments, the condition increases intraocular pressure, such as an increase in intraocular pressure leading to glaucoma. In some embodiments, the neurodegenerative disease, disorder, or condition is a hereditary or idiopathic retinal condition, such as a condition that causes, for example, axonal degeneration of the optic nerve resulting in vision loss. In some embodiments, the condition is a chronic condition affecting the optic nerve, such as but not limited to Leber congenital amaurosis, Leber hereditary optic neuropathy, primary open-angle glaucoma, and autosomal dominant optic atrophy.

[0123] In some embodiments, the optic nerve neuropathy includes, but is not limited to, glaucoma; retinal ganglion degeneration, such as those associated with retinitis pigmentosa and outer retinal neuropathy; optic neuritis and / or degeneration, including those associated with multiple sclerosis. In some embodiments, the optic nerve neuropathy includes neurotraumatic injury to the optic nerve, which can include, for example, injury during tumor resection. In some embodiments, the optic nerve neuropathy is a hereditary optic neuropathy, such as Kjer disease and Leber hereditary optic neuropathy; ischemic optic neuropathy, such as those secondary to giant cell arteritis; metabolic optic neuropathy, such as neurodegenerative diseases, including Leber neuropathy, nutritional deficiencies, such as vitamin B12 or folate deficiency, and toxicities, such as those attributable to ethambutol and cyanide; neuropathy caused by adverse drug reactions and neuropathy caused by vitamin deficiencies. Ischemic optic neuropathy also includes non-arteritic anterior ischemic optic neuropathy.

[0124] In some embodiments, the neurodegenerative disease, disorder or condition is a peripheral neuropathy or a peripheral nervous system disorder. In some embodiments, the peripheral neuropathy is a metabolic and endocrine neuropathy, which includes a broad spectrum of peripheral nerve disorders associated with systemic diseases of metabolic origin. Such diseases and disorders include, for example, diabetes, hypoglycemia, uremia, hypothyroidism, liver failure, polycythemia, amyloidosis, acromegaly, porphyria, lipid / glycolipid metabolism disorders, nutritional / vitamin deficiencies, and mitochondrial disorders, among others. In some embodiments, these peripheral nerve disorders can be identified by the involvement of the peripheral nerves in changes in the structure or function of myelin and axons caused by dysregulation of metabolic pathways.

[0125] In some embodiments, the subject is at risk of developing a condition characterized by axonal degeneration. In some embodiments, the subject is identified as being at risk of axonal degeneration, for example, based on the subject's genotype, a diagnosis of a condition associated with axonal degeneration, and / or exposure to agents and / or conditions that trigger axonal degeneration.

[0126] In some embodiments, the subject has a condition characterized by axonal degeneration. In some embodiments, the subject has been diagnosed with a condition characterized by axonal degeneration.

[0127] In some embodiments, the combination therapy provided herein is characterized in that, when administered to a population of subjects, the combination therapy alleviates one or more symptoms or features of neurodegeneration. For example, in some embodiments, the relevant symptoms or features can be selected from the degree, rate, and / or timing of neuronal destruction.

[0128] In some embodiments, a subject engages in activities that are identified as risk factors for neuronal degeneration, such as the subject engaging in contact sports or occupations with a high likelihood of traumatic neuronal injury. In some embodiments, contact sports include, but are not limited to, American football, basketball, boxing, diving, hockey, soccer, ice hockey, lacrosse, martial arts, rodeo, rugby, ski jumping, water polo, wrestling, baseball, cycling, competitive cheerleading, fencing, track and field, gymnastics, handball, equestrian, ice skating, skiing, skateboarding, softball, squash, ultimate frisbee, volleyball, and / or windsurfing.

[0129] In some embodiments, the methods provided comprise administering to a subject population in need thereof the combination therapy as described herein. In some embodiments, the subject and / or subject population is elderly.

[0130] In some embodiments, the combination therapy provided can be used, for example, to treat a population at risk of developing a condition characterized by axonal and / or neuronal degeneration. In some embodiments, the population is from individuals who engage in activities with a high likelihood of traumatic neuronal injury. In some embodiments, the population is from athletes who engage in contact sports or other high-risk activities. In some embodiments, the subject population is from those who are members of the armed forces or military contractors.

[0131] In some embodiments, the subject and / or subject population is known to have genetic risk factors for neurodegeneration. In some embodiments, the subject and / or subject population has a family history of neurodegenerative disease. In some embodiments, the subject and / or subject population expresses one or more copies of a known genetic risk factor for neurodegeneration. In some embodiments, the subject and / or subject population is from a population with a high incidence of neurodegeneration. In some embodiments, the subject and / or subject population has a hexanucleotide repeat expansion in chromosome 9 open reading frame 72. In some embodiments, the subject and / or subject population has one or more copies of the ApoE4 allele.

[0132] In some embodiments, a subject administered the combination therapy provided exhibits one or more signs or symptoms associated with axonal degeneration. In some embodiments, the subject does not exhibit any signs or symptoms of neurodegeneration.

[0133] In some embodiments, the neurodegenerative disease, disorder, or condition is selected from neuropathy or axonopathy. In some embodiments, the present disclosure provides a combination therapy comprising a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor to treat one or more neurodegenerative diseases, disorders, or conditions selected from neuropathy or axonopathy. In some embodiments, the present disclosure provides a combination therapy comprising a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor, for example, to treat neuropathy or axonopathy associated with axonal degeneration. In some embodiments, the neuropathy associated with axonal degeneration is a hereditary or congenital neuropathy or axonopathy. In some embodiments, the neuropathy associated with axonal degeneration results from de novo mutations or somatic mutations. In some embodiments, the neuropathy associated with axonal degeneration results from an idiopathic condition. In some embodiments, the neuropathy associated with axonal degeneration is selected from the list included herein.

[0134] In some embodiments, the methods provided alleviate one or more symptoms or features of neurodegeneration. For example, in some embodiments, the relevant symptoms or features may be selected from the degree, rate, and / or timing of neuronal destruction. In some embodiments, neuronal destruction may be or include axonal degeneration, synaptic loss, dendritic loss, 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 capacity, loss of axonal potential propagation, neuronal hyperexcitability, and / or neuronal hypoexcitability. In some embodiments, neuronal destruction is characterized by the inability to maintain an appropriate resting neuronal membrane potential. In some embodiments, neuronal destruction is characterized by the presence of inclusion bodies, plaques, and / or neurofibrillary tangles. In some embodiments, neuronal destruction is characterized by the presence of stress granules. In some embodiments, neuronal destruction is characterized by the intracellular activation of one or more members of the cysteine-aspartic protease (Caspase) family. In some embodiments, neuronal destruction is characterized by programmed cell death (e.g., apoptosis, pyroptosis, Ferroapoptosis, and / or necrosis) and / or inflammation of neurons.

[0135] In certain embodiments, the combination comprising a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor can be used, for example, as an analytical tool, as a probe in a biological assay, or as a therapeutic agent according to the present disclosure.

[0136] Such combinations provided by the present disclosure can also be used for the study of SARM1 NADase function in biological and pathological phenomena and the comparative evaluation of novel SARM1 activity inhibitors in vitro or in vivo. In some embodiments, a combination comprising a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor can be used to study axonal integrity. In some embodiments, such a combination can be used to study apoptosis.

[0137] In some embodiments, the provided combination can be used to inhibit the degeneration of a neuron or a part thereof. In some embodiments, the provided combination can be used to treat a neuron whose axon is damaged. In some embodiments, the provided combination can be used to inhibit the degeneration of a neuron or a part thereof in vivo. In some embodiments, the provided combination can be used as a stabilizer to promote neuron survival in vitro.

[0138] In some embodiments, the present disclosure provides a method for inhibiting the degeneration of neurons derived from a subject, which comprises administering to the subject a SARM1 inhibitor in combination with a DLK inhibitor or a NAMPT inhibitor.

[0139] In some embodiments, the provided combination can be used to treat a neuron whose axon is damaged.

[0140] In some embodiments, the present disclosure relates to a method for increasing the intracellular concentration of NAD+, which comprises: contacting a biological sample with a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor. In some embodiments, the present disclosure relates to a method for preventing the increase of intracellular cADPR, which comprises: contacting a cell with a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor.

[0141] In some embodiments, the present disclosure provides a combination therapy comprising a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor, which can be used to affect, for example, biomarkers related to neurodegeneration. In some embodiments, changes in biomarkers can be detected systemically or using samples of cerebrospinal fluid (CSF), blood, plasma, serum, and / or tissue from a subject. In some embodiments, the provided methods described herein can be used to affect changes in the concentration of neurofilament light chain protein (NF-L) and / or neurofilament heavy chain protein (NF-H) contained in the CSF, blood, plasma, serum, and / or tissue of a subject. In some embodiments, the provided methods described herein can affect the constitutive NAD+ and / or cADPR levels in neurons and / or axons.

[0142] In some embodiments, the provided methods comprise administering to a subject or a population of subjects a combination therapy as described herein based on the presence or absence of one or more biomarkers. In some embodiments, the provided methods further comprise monitoring the biomarker levels in the subject and / or the population of subjects and adjusting the dosing regimen accordingly.

[0143] In some embodiments, the methods provided 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, Phospho-tau, and / or Total-tau. In some embodiments, one or more compounds and / or compositions as described herein can effect changes in cytokines and / or chemokines, including but not limited to Ccl2, Ccl7, Ccl12, Csf1, and / or Il6.

[0144] In some embodiments, the provided SARM1 inhibitor reduces or inhibits the binding of NAD+ by SARM1. In some embodiments, the provided SARM1 inhibitor binds to SARM1 within a pocket that includes one or more catalytic residues (e.g., the catalytic cleft of SARM1). In some embodiments, the provided SARM1 inhibitor binds to non-catalytic residues. In some embodiments, the provided SARM1 inhibitor is an allosteric modulator of SARM1 activity. In some embodiments, the provided SARM1 inhibitor reduces SARM1 NADase activity. Accordingly, in some embodiments, the present disclosure provides a method of reducing or inhibiting the binding of SARM1 by NAD+, which comprises administering to a subject in need thereof a combination of a SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor.

[0145] In some embodiments, an SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor are co-administered to a subject. In some embodiments, an SARM1 inhibitor is administered to a subject exposed to a DLK inhibitor or a NAMPT inhibitor. In some embodiments, an SARM1 inhibitor and a DLK inhibitor or a NAMPT inhibitor are each administered sequentially. In some embodiments, a subject is first administered an SARM1 inhibitor, followed by a DLK inhibitor or a NAMPT inhibitor. In some embodiments, a DLK inhibitor or a NAMPT inhibitor is administered before the SARM1 inhibitor. In some embodiments, an SARM1 inhibitor is administered to a subject who is being or has been administered a DLK inhibitor or a NAMPT inhibitor.

[0146] In some embodiments, the methods and / or combination therapies provided inhibit the activity of SARM1. Alternatively or additionally, in some embodiments, the methods and / or combination therapies provided alleviate one or more attributes of neurodegeneration. In some embodiments, the present disclosure provides methods of treating, preventing, and / or ameliorating neurodegenerative diseases, disorders, or conditions associated with axonal degeneration.

[0147] In some embodiments, the SARM1 inhibitor is a small molecule, polypeptide, peptide fragment, nucleic acid (e.g., siRNA, antisense oligonucleotide, microRNA, or aptamer), antibody, dominant negative inhibitor, or ribozyme.

[0148] In some embodiments, the SARM1 inhibitor is a small molecule. In some embodiments, the SARM1 inhibitor is siRNA. In some embodiments, the SARM1 inhibitor is an antisense oligonucleotide. In some embodiments, the SARM1 inhibitor is a polypeptide. In some embodiments, the SARM1 inhibitor is a peptide fragment. In some embodiments, the SARM1 inhibitor is a nucleic acid. In some embodiments, the SARM1 inhibitor is an antisense oligonucleotide.

[0149] In some embodiments, the DLK inhibitor is a small molecule, polypeptide, peptide fragment, nucleic acid (e.g., siRNA, antisense oligonucleotide, microRNA, or aptamer), antibody, dominant negative inhibitor, or ribozyme.

[0150] In some embodiments, the DLK inhibitor is a small molecule. In some embodiments, the DLK inhibitor is siRNA. In some embodiments, the DLK inhibitor is an antisense oligonucleotide. In some embodiments, the DLK inhibitor is a polypeptide. In some embodiments, the DLK inhibitor is a peptide fragment. In some embodiments, the DLK inhibitor is a nucleic acid. In some embodiments, the DLK inhibitor is an antisense oligonucleotide.

[0151] In some embodiments, the NAMPT inhibitor is a small molecule, polypeptide, peptide fragment, nucleic acid (such as siRNA, antisense oligonucleotide, microRNA or aptamer), antibody, dominant negative inhibitor or ribozyme.

[0152] In some embodiments, the NAMPT inhibitor is a small molecule. In some embodiments, the NAMPT inhibitor is siRNA. In some embodiments, the NAMPT inhibitor is an antisense oligonucleotide. In some embodiments, the NAMPT inhibitor is a polypeptide. In some embodiments, the NAMPT inhibitor is a peptide fragment. In some embodiments, the NAMPT inhibitor is a nucleic acid. In some embodiments, the NAMPT inhibitor is an antisense oligonucleotide.

[0153] In some embodiments, the present disclosure provides a composition comprising and / or delivering a SARM1 inhibitor (such as in the form as described herein), a prodrug or an active metabolite thereof. In certain embodiments, the composition comprising the SARM1 inhibitor is formulated for co-administration to a subject with a DLK inhibitor or a NAMPT inhibitor.

[0154] In some embodiments, the provided methods and / or combination therapies promote an increase in the intracellular level of nicotinamide adenine dinucleotide (NAD+) in cells and tissues to improve cell and tissue survival. In some embodiments, the provided methods and / or combination therapies prevent a decrease in the NAD+ level in cells and / or tissues. In some embodiments, the provided methods and / or combination therapies reduce NAD+ catabolism. In further embodiments, the provided methods and / or combination therapies increase the NAD+ level in cells and tissues to improve cell and tissue survival. In some embodiments, the provided methods reduce or inhibit the ability of SARM1 to bind efficiently to NAD+. In some embodiments, the provided methods inhibit SARM1 by a dominant negative mechanism. In some embodiments, the provided combination therapies and / or methods stabilize neurons and / or cells until the external environment stabilizes after an acute event.

[0155] In some embodiments, the present disclosure provides a composition comprising a SARM1 inhibitor for use in combination with a DLK inhibitor or a NAMPT inhibitor. In some embodiments, such a composition is a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the present disclosure provides a composition comprising and / or delivering a compound comprising a SARM1 inhibitor together with a DLK inhibitor or a NAMPT inhibitor. In some embodiments, such a composition is a pharmaceutically acceptable composition comprising at least one pharmaceutically acceptable carrier.

[0156] SARM1 inhibitor

[0157] In some embodiments, the SARM1 inhibitor is a small molecule, polypeptide, peptide fragment, nucleic acid (e.g., siRNA, antisense oligonucleotide, microRNA or aptamer), antibody, dominant negative inhibitor or ribozyme.

[0158] In some embodiments, the SARM1 inhibitor is a small molecule. In some embodiments, the SARM1 inhibitor is siRNA. In some embodiments, the SARM1 inhibitor is an antisense oligonucleotide. In some embodiments, the SARM1 inhibitor is a polypeptide. In some embodiments, the SARM1 inhibitor is a peptide fragment. In some embodiments, the SARM1 inhibitor is a nucleic acid. In some embodiments, the SARM1 inhibitor is an antisense oligonucleotide.

[0159] In some embodiments, the provided SARM1 inhibitor binds to SARM1 within a pocket that includes one or more catalytic residues (e.g., the catalytic cleft of SARM1). In some embodiments, the provided SARM1 inhibitor inhibits SARM1 activity by binding to an allosteric site.

[0160] i. Small molecule SARM1 inhibitors

[0161] In some embodiments, the SARM1 inhibitor is a small molecule.

[0162] In some embodiments, the SARM1 inhibitor is selected from compounds of Formula I, II or III:

[0163]

[0164] or a pharmaceutically acceptable salt thereof, wherein X 1 、X 2 、Y 1 、Y 2 、Y 3 、Z 1 、Z 2 、 、 、R 1 、R 2 、R 3 、R 4 、X a 、X b 、Y a 、Y b 、Y c 、Z b 、Z c 、Z d and R za are each defined below.

[0165] In some embodiments, the SARM1 inhibitor is a compound of Formula I:

[0166]

[0167] or a pharmaceutically acceptable salt thereof, wherein:

[0168] and each independently is a single bond or a double bond;

[0169] X 1 is selected from N and C–R x1 ;

[0170] R x1 is selected from halogen, -CN, -R ' , and –OR ' ;

[0171] X 2 is selected from N and C–R x2 ;

[0172] R x2 is selected from halogen, -CN, -R ' , -OR ' , -N(R ' )2, -SO2R ' , -C(O)R ' , -N(R ' )SO2R ' , -SO2N(R ' )2, -OC(O)R ' , -C(O)OR ' , -N(R ' )C(O)R ' , -C(O)N(R ' )2 and –N(R ' )C(O)N(R ' )2;

[0173] When is a double bond, Y 1 is selected from N and C–R y1 , or when is a single bond, Y 1 is CH(R y1 ) or C(R y1 )2;

[0174] R y1 is selected from halogen, -CN, -R ' , -OR ' and –N(R ' )2;

[0175] When is a double bond, Y 2 is selected from N and C–Ry2 , or when is a single bond, Y 2 is selected from N–R ' and C(O);

[0176] When is a double bond, Y 3 is selected from N and C–R y3 , or when is a single bond, Y 3 is selected from N–R ' and C(O);

[0177] Each R y2 and R y3 are independently selected from halogen, -CN, -R ' , -OR ' and -N(R ' )2; and

[0178] When is a double bond, Z 1 is selected from N and C–R z1 , or when is a single bond, Z 1 is CH(R z1 ) or C(R z1 )2;

[0179] R z1 is selected from halogen, -CN, -NO2, -R ' , -(C 1-6 alkylene)OR ' , -(C 1-6 alkylene)N(R ' )2, -OR ' , -SR ' , -SF5, -N(R ' )2, -C(O)R ' , -C(O)OR ' , -OC(O)R ' , -C(O)N(R ' )2, -N(R ' )C(O)R ' , -SOR ' , -SO2R ' , -N(R)SO2R ' and -SO2N(R ' )2;

[0180] Z 2 is selected from N and C–R z2 ;

[0181] R z2 is selected from halogen, -CN, -R' , -OR ' and -N(R ' )2; and

[0182] each R ' is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl is each optionally substituted with a halogen; or:

[0183] Two instances of R ' , together with the nitrogen atom to which they are attached, form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring.

[0184] In some embodiments, the SARM1 inhibitor is a compound of formula I:

[0185]

[0186] or a pharmaceutically acceptable salt thereof, wherein:

[0187] and are each independently a single bond or a double bond;

[0188] X 1 is selected from N and C–R x1 ;

[0189] R x1 is selected from halogen, -CN, -R ' and -OR ' ;

[0190] X 2 is selected from N and C–R x2 ;

[0191] R x2 is selected from halogen, -CN, -R ' , -OR ' , -N(R ' )2, -SO2R ' , -C(O)R ' , -N(R ' )SO2R ' , -SO2N(R ' )2, -OC(O)R ' , -C(O)OR ' , -N(R ' )C(O)R ' , -C(O)N(R ' )2 and –N(R' )C(O)N(R ' )2;

[0192] When is a double bond, Y 1 is selected from N and C–R y1 , or when is a single bond, Y 1 is CH(R y1 ) or C(R y1 )2;

[0193] R y1 is selected from halogen, -CN, -R ' , -OR ' and –N(R ' )2;

[0194] When is a double bond, Y 2 is selected from N and C–R y2 , or when is a single bond, Y 2 is selected from N–R ' and C(O);

[0195] When is a double bond, Y 3 is selected from N and C–R y3 , or when is a single bond, Y 3 is selected from N–R ' and C(O);

[0196] Each R y2 and R y3 are independently selected from halogen, -CN, -R ' , -OR ' and -N(R ' )2; and

[0197] When is a double bond, Z 1 is selected from N and C–R z1 , or when is a single bond, Z 1 is CH(R z1 ) or C(R z1 )2;

[0198] R z1 is selected from halogen, -CN, -NO2, -R ' , -(C 1-6 alkylene)OR ' , -(C 1-6 alkylene)N(R ' )2, -OR ' , -SR' , -SF5, -N(R ' )2, -C(O)R ' , -C(O)OR ' , -OC(O)R ' , -C(O)N(R ' )2, -N(R ' )C(O)R ' , -SOR ' , -SO2R 'I , -N(R ' )SO2R ' and -SO2N(R ' )2;

[0199] Z 2 is selected from N and C–R z2 ;

[0200] R z2 is selected from halogen, -CN, -R ' , -OR ' and -N(R ' )2; and

[0201] each R ' is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, where C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl is each optionally substituted with halogen; or:

[0202] R ' , together with the nitrogen atom to which it is attached, forms a 3- to 6-membered saturated or partially unsaturated heterocyclic ring.

[0203] As generally defined above for formula I, and are each independently a single bond or a double bond. In some embodiments of formula I, and are each double bonds. In some embodiments of formula I, and are each single bonds. In some embodiments of formula I, is a single bond and is a double bond. In some embodiments of formula I, is a double bond and is a single bond.

[0204] It is to be recognized that compounds of formula I having the following structure

[0205]

[0206] When R ' is H, it can exist in two tautomeric forms:

[0207]

[0208] Correspondingly, it should be recognized that a compound of formula I in which Y 2 is N-H and Y 3 is C(O) can be drawn in either tautomeric form.

[0209] Similarly, a compound of formula I having the following structure

[0210]

[0211] When R ' is H, it can exist in two tautomeric forms:

[0212]

[0213] Correspondingly, it should be recognized that a compound of formula I in which Y 2 is C(O) and Y 3 is N-H can be drawn in either tautomeric form.

[0214] As generally defined for formula I above, X 1 is selected from N and C–R x1 . In some embodiments of formula I, X 1 is N. In some embodiments of formula I, X 1 is C–R x1 .

[0215] As generally defined for formula I above, R x1 is selected from halogen, -CN, -R ' and –OR ' . In some embodiments of formula I, R x1 is –R ' . In some such embodiments of formula I, R ' is H. Correspondingly, in some embodiments of formula I, R x1 is H. In some embodiments of formula I, R x1 is –R ' , where R ' is -C 1-6 alkyl. In some embodiments of formula I, R x1 is –R ' , where R ' is –CH3. Correspondingly, in some embodiments of formula I, R x1is –CH3.

[0216] In some embodiments of Formula I, R x1 is –OR ' . In some embodiments of Formula I, R x1 is –OR ' , where R ' is H. Accordingly, in some embodiments of Formula I, R x1 is –OH.

[0217] As generally defined above for Formula I, X 2 is selected from N and C–R x2 . In some embodiments of Formula I, X 2 is N. In some embodiments of Formula I, X 2 is C–R x2 .

[0218] As generally defined above for Formula I, R x2 is selected from halogen, -CN, -R ' , -OR ' , -N(R ' )2, -SO2R ' , -C(O)R ' , -N(R ' )SO2R ' , -SO2N(R ' )2, -OC(O)R ' , -C(O)OR ' , -N(R ' )C(O)R ' , -C(O)N(R ' )2 and –N(R ' )C(O)N(R ' )2. In some embodiments of Formula I, R x2 is –R ' . In some such embodiments of Formula I, R ' is H. Accordingly, in some embodiments of Formula I, R x2 is H. In some embodiments of Formula I, R x2 is –R ' , where R ' is -C 1-6 alkyl. In some embodiments of Formula I, R x2 is –R ' , where R ' is –CH3. Accordingly, in some embodiments of Formula I, R x2 is –CH3.

[0219] In some embodiments of Formula I, R x2 is a halogen. In some embodiments of Formula I, R x2 is chlorine.

[0220] In some embodiments of Formula I, R x2 is –N(R ' )SO2R ' . In some embodiments of Formula I, R x2 is –NHSO2R ' . In some such embodiments of Formula I, R ' is -C 1-6 alkyl. In some embodiments of Formula I, R x2 is –NHSO2R ' , where R ' is –CH3. In some embodiments of Formula I, R x2 is –NHSO2R ' , where R ' is –CH2CH3. In some embodiments of Formula I, R x2 is –NHSO2R ' , where R ' is cyclopropyl.

[0221] In some embodiments of Formula I, R x2 is –N(R ' )2. In some such embodiments of Formula I, each R ' is H. Accordingly, in some embodiments of Formula I, R x2 is –NH2. In some embodiments of Formula I, R x2 is –N(R ' )2, where each R ' is independently selected from H and -C 1-6 alkyl. In some embodiments of Formula I, R x2 is –N(R ' )2, where each R ' is independently selected from H and –CH3. In some embodiments of Formula I, R x2 is –NHCH3. In some embodiments, R x2 is –N(CH3)2.

[0222] In some embodiments of Formula I, R x2 is –OR ' . In some such embodiments of Formula I, R ' is H. Accordingly, in some embodiments of Formula I, R x2 is –OH. In some embodiments of Formula I, R x2 is –OR' , wherein R ' is -C 1-6 alkyl. In some embodiments of Formula I, R x2 is -OR ' , wherein R ' is -CH3. Accordingly, in some embodiments of Formula I, R x2 is -OCH3.

[0223] In some embodiments of Formula I, R x2 is -N(R ' )C(O)N(R ' )2. In some such embodiments of Formula I, each R ' is independently selected from H and -C 1-6 alkyl. In some embodiments of Formula I, R x2 is -N(R ' )C(O)N(R ' )2, wherein each R ' is independently selected from H and -CH3. In some embodiments of Formula I, R x2 is -NHC(O)NHCH3.

[0224] As generally defined above for Formula I, when is a double bond, Y 1 is selected from N and C-R y1 , or when is a single bond, Y 1 is CH(R y1 ) or C(R y1 )2. In some embodiments of Formula I, is a double bond and Y 1 is N. In some embodiments of Formula I, is a double bond and Y 1 is C-R y1 . In some embodiments of Formula I, is a single bond and Y 1 is CH(R y1 ). In some embodiments of Formula I, is a single bond and Y 1 is C(R y1 )2.

[0225] As generally defined above for Formula I, R y1 is selected from halogen, -CN and -R ' . In some embodiments of Formula I, R y1 is -R ' . In some such embodiments of Formula I, -R 'is H. Accordingly, in some embodiments of Formula I, R y1 is H. In some embodiments of Formula I, R y1 is –N(R ' )2. In some embodiments of Formula I, R y1 is –NH2. In some embodiments of Formula I, R y1 is –OR ' . In some embodiments of Formula I, R y1 is –OCH3. In some embodiments of Formula I, R y1 is –OH. In some embodiments of Formula I, R y1 is halogen. In some such embodiments of Formula I, R y1 is fluorine or bromine.

[0226] As generally defined for Formula I above, when is a double bond, Y 2 is selected from N and C–R y2 , or when is a single bond, Y 2 is selected from N–R ' and C(O). In some embodiments of Formula I, is a double bond and Y 2 is N. In some embodiments of Formula I, is a double bond and Y 2 is C–R y2 . In some embodiments of Formula I, is a single bond and Y 2 is N–R ' . In some embodiments of Formula I, is a single bond and Y 2 is C(O).

[0227] As generally defined for Formula I above, when is a double bond, Y 3 is selected from N and C–R y3 , or when is a single bond, Y 3 is selected from N–R ' and C(O). In some embodiments of Formula I, is a double bond and Y 3 is N. In some embodiments of Formula I, is a double bond and Y 3 is C–R y3 . In some embodiments of Formula I, is a single bond and Y 3 is N–R ' . In some embodiments of Formula I, is a single bond and Y3 is C(O).

[0228] As generally defined above for formula I, each R y2 and R y3 are independently selected from halogen, -CN, -R ' , -OR ' and -N(R ' )2. In some embodiments of formula I, R y2 is –R ' . In some such embodiments of formula I, -R ' is H. Accordingly, in some embodiments of formula I, R y2 is H. In some embodiments of formula I, R y2 is halogen. In some such embodiments of formula I, R y2 is fluorine or bromine. In some embodiments of formula I, R y2 is –OR ' . In some such embodiments of formula I, R ' is H. Accordingly, in some embodiments of formula I, R y2 is –OH. In some embodiments of formula I, R y2 is –OR ' , where R ' is -C 1-6 alkyl. In some embodiments of formula I, R y2 is –OCH3.

[0229] In some embodiments of formula I, R y3 is –R ' . In some such embodiments of formula I, -R ' is H. Accordingly, in some embodiments of formula I, R y3 is H. In some embodiments of formula I, R y3 is –R ' , where R ' is -C 1-6 alkyl. In some such embodiments of formula I, -R ' is CH3. Accordingly, in some embodiments of formula I, R y3 is CH3. In some embodiments of formula I, R y3 is halogen. In some such embodiments of formula I, R y3 is chlorine or bromine. In some embodiments of formula I, R y3 is –OR ' . In some such embodiments of formula I, R ' is H. Accordingly, in some embodiments of formula I, R y3is –OH. In some embodiments of Formula I, R y3 is –OR ' , where R ' is -C 1-6 alkyl. In some embodiments of Formula I, R y3 is –OCH3.

[0230] In some embodiments of Formula I, R y3 is –N(R ' )2. In some such embodiments of Formula I, each R ' is H. Accordingly, in some embodiments of Formula I, R y3 is –NH2. In some embodiments of Formula I, R y3 is –N(R ' )2, where each R ' is independently selected from H and -C 1-6 alkyl. In some such embodiments of Formula I, R y3 is –N(R ' )2, where each R ' is independently selected from H and –CH3. In some embodiments of Formula I, R y3 is –NHCH3. In some embodiments of Formula I, R y3 is –N(R ' )C(O)N(R ' )2. In some such embodiments of Formula I, each R ' is independently selected from H and -C 1-6 alkyl. In some embodiments of Formula I, R y3 is –N(R ' )C(O)N(R ' )2, where each R ' is independently selected from H and –CH3. In some embodiments of Formula I, R y3 is –NHC(O)NHCH3.

[0231] As generally defined above for Formula I, when is a double bond, Z 1 is selected from N and C–R z1 , or when is a single bond, Z 1 is CH(R z1 ) or C(R z1 )2. In some embodiments of Formula I, is a double bond and Z 1 is N. In some embodiments of Formula I, is a double bond and Z 1 is C–R z1. In some embodiments of formula I, is a single bond and Z 1 is CH(R z1 ). In some embodiments of formula I, is a single bond and Z 1 is C(R z1 )2.

[0232] As generally defined above for formula I, R z1 is selected from halogen, -CN, -NO2, -R ' , -(C 1-6 alkylene)OR ' , -(C 1-6 alkylene)N(R ' )2, -OR ' , -SR ' , -SF5, -N(R ' )2, -C(O)R ' , -C(O)OR ' , -OC(O)R ' , -C(O)N(R ' )2, -N(R ' )C(O)R ' , -SOR ' , -SO2R ' , -N(R I )SO2R ' and -SO2N(R ' )2. In some embodiments of formula I, R z1 is –R ' . In some such embodiments of formula I, R ' is H. Accordingly, in some embodiments of formula I, R z1 is H.

[0233] In some embodiments of formula I, R z1 is halogen. In some such embodiments of formula I, R z1 is bromine. In some embodiments of formula I, R z1 is iodine. In some embodiments of formula I, R z1 is chlorine.

[0234] In some embodiments of formula I, R z1 is -NO2.

[0235] In some embodiments of formula I, R z1 is -CF3.

[0236] In some embodiments of formula I, R z1 is -C(O)R' 。In some such embodiments of Formula I, R ' is -C 1-6 alkyl. In some embodiments of Formula I, R z1 is –C(O)CH3.

[0237] In some embodiments of Formula I, R z1 is -C(O)OR ' 。In some such embodiments of Formula I, R ' is selected from H and -C 1-6 alkyl. In some embodiments of Formula I, R z1 is -C(O)OH. In some embodiments of Formula I, R z1 is -C(O)OCH3.

[0238] In some embodiments of Formula I, R z1 is -N(R ' )2. In some such embodiments of Formula I, each R ' is H. Accordingly, in some embodiments of Formula I, R z1 is -NH2.

[0239] In some embodiments of Formula I, R z1 is –R ' , where R ' is -C 1-6 alkyl. In some embodiments of Formula I, R z1 is isopropyl. In some embodiments of Formula I, R z1 is cyclopropyl. In some embodiments of Formula I, R z1 is –R ' , where R ' is -C 1-6 alkynyl. In some embodiments of Formula I, R z1 is –C≡CH.

[0240] In some embodiments of Formula I, R z1 is –OR ' . In some such embodiments of Formula I, R ' is H. Accordingly, in some embodiments of Formula I, R z1 is –OH. In some embodiments of Formula I, R z1 is –OR, where R ' is -C 1-6 alkyl. In some embodiments of Formula I, R z1 is –OCH3. In some embodiments of Formula I, R z1 is –OCH(CH3)2.

[0241] In some embodiments of Formula I, R z1 is –SR ' , where R ' is -C 1-6 alkyl. In some embodiments of Formula I, R z1 is –SCH3.

[0242] In some embodiments of Formula I, R z1 is -(C 1-6 alkylene)OR ' . In some embodiments of Formula I, R z1 is –CH2OR ' . In some such embodiments of Formula I, R ' is H. Accordingly, in some embodiments of Formula I, R z1 is –CH2OH. In some embodiments of Formula I, R z1 is –C(CH3)2OH.

[0243] In some embodiments of Formula I, R z1 is -(C 1-6 alkylene)N(R ' )2. In some embodiments of Formula I, R z1 is -CH2N(R ' )2. In some such embodiments of Formula I, each R ' is H. Accordingly, in some embodiments of Formula I, R z1 is –CH2NH2.

[0244] As generally defined above for Formula I, Z 2 is selected from N and C–R z2 . In some embodiments of Formula I, Z 2 is N. In some embodiments of Formula I, Z 2 is C–R z2 .

[0245] As generally defined above for Formula I, R z2 is selected from halogen, -CN, -R ' , –OR ' and -N(R ' )2. In some embodiments of Formula I, R z2 is –R ' . In some such embodiments of Formula I, R ' is H. Accordingly, in some embodiments, R z2 is H. In some embodiments of Formula I, R z2 is –R ' , where R' is -C 1-6 alkyl. In some embodiments of formula I, R z2 is –CH3. In some embodiments of formula I, R z2 is –CH(CH3)2. In some embodiments of formula I, R z2 is cyclopropyl.

[0246] In some embodiments of formula I, R z2 is halogen. In some embodiments of formula I, R z2 is bromine. In some embodiments of formula I, R z2 is iodine.

[0247] In some embodiments of formula I, R z2 is -OR ' . In some such embodiments of formula I, R ' is H. Accordingly, in some embodiments of formula I, R z2 is -OH. In some embodiments of formula I, R z2 is –OR ' , where R ' is -C 1-6 alkyl. Accordingly, in some embodiments of formula I, R z2 is –OCH3.

[0248] In some embodiments, R z2 is -N(R ' )2. In some such embodiments, each R ' is H. Accordingly, in some embodiments, R z2 is -NH2.

[0249] As generally defined above for formula I, each R ' is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, where C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is each optionally substituted with halogen; or two instances of R ' , together with the nitrogen atom to which they are attached, form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring.

[0250] In some embodiments of formula I, Z 1 is C–R z1 and Z 2 is C–R z2 . Accordingly, the present disclosure provides a compound of formula I-a or a pharmaceutically acceptable salt thereof:

[0251] 。

[0252] In some embodiments of Formula I, Z 1 is C–R z1 , Z 2 is C–R z2 , and and are each double bonds. Accordingly, in some embodiments of Formula I, the SARM1 inhibitor is a compound of Formula I-b or a pharmaceutically acceptable salt thereof:

[0253] 。

[0254] In some embodiments of Formula I, is a double bond, is a single bond, Y 2 is N–R ' , and Y 3 is C(O). Accordingly, in some embodiments of Formula I, the SARM1 inhibitor is a compound of Formula I-c or a pharmaceutically acceptable salt thereof:

[0255] 。

[0256] In some embodiments of Formula I, is a single bond, Y 2 is N–R ' , and Y 3 is C(O). Accordingly, in some embodiments of Formula I, the present disclosure provides a compound of Formula I-d or a pharmaceutically acceptable salt thereof:

[0257] 。

[0258] In some embodiments of Formula I, is a double bond, Y 2 is C(O), and Y 3 is N–R ' . Accordingly, in some embodiments of Formula I, the present disclosure provides a compound of Formula I-e or a pharmaceutically acceptable salt thereof:

[0259] 。

[0260] In some embodiments of Formula I, is a single bond, Y 2 is C(O), and Y 3 is N–R ' . Accordingly, in some embodiments of Formula I, the present disclosure provides a compound of Formula I-f or a pharmaceutically acceptable salt thereof:

[0261] 。

[0262] In some embodiments of Formula I, X 2 is C–R x2 , Y 1 is C–R y1 , Y 2 is C–R y2 , and Y 3 is C–R y3 . Accordingly, in some embodiments of Formula I, the present disclosure provides a compound of Formula I-g or a pharmaceutically acceptable salt thereof:

[0263] .

[0264] In some embodiments of Formula I, R x2 is H. Accordingly, in some embodiments of Formula I, the present disclosure provides a compound of Formula I-h or a pharmaceutically acceptable salt thereof:

[0265] .

[0266] In some embodiments of Formula I, R y1 is H. Accordingly, in some embodiments of Formula I, the present disclosure provides a compound of Formula I-i or a pharmaceutically acceptable salt thereof:

[0267] .

[0268] In some embodiments of Formula I, R y2 is H. Accordingly, in some embodiments of Formula I, the present disclosure provides a compound of Formula I-j or a pharmaceutically acceptable salt thereof:

[0269] .

[0270] In some embodiments of Formula I, R x1 is H. Accordingly, in some embodiments of Formula I, the present disclosure provides a compound of Formula I-k or a pharmaceutically acceptable salt thereof:

[0271] .

[0272] In some embodiments of Formula I, the present disclosure provides compounds of Formula I-b- i , I-b- ii , I-b- iii , I-b- iv , I-b- v , I-b- vi , I-b- vii , I-b- viii , I-b- ix , I-b- x , I-b-xi , Ib- xii , Ib- xiii , Ib- xiv , Ib- xv , Ib- xvi and Ib- xvii Any of the compounds:

[0273]

[0274]

[0275] or a pharmaceutically acceptable salt thereof, wherein R x1 , R x2 , R y1 , R y2 , R y3 , R z1 and R z2 Each is as defined above for Formula I and as described herein.

[0276] In some embodiments of Formula I, the present disclosure provides Formula Ib- xviii , Ib- xix , Ib- xx , Ib- xxi , Ib- xxii , Ib- xxiii , Ib- xxiv , Ib- xxv and Ib- xxvi Any of the compounds:

[0277]

[0278]

[0279] or a pharmaceutically acceptable salt thereof, wherein R x1 , R x2 , R y1 , R y2 , R y3 , R z1 and R z2 Each is as defined above for Formula I and as described herein.

[0280] In some embodiments of Formula I, the present disclosure provides Formula Ia- i , Ia- ii and Ia- iii Any compound or a pharmaceutically acceptable salt thereof:

[0281]

[0282] Where R z1and R ' each as defined above and as described herein.

[0283] In some embodiments, the compound of formula I is selected from:

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295] or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, the SARM1 inhibitor is a compound of formula II:

[0297]

[0298] or a pharmaceutically acceptable salt thereof, wherein

[0299] R 1 is selected from -CN, -NO2, -C(O)R '' , -S(O)2R '' , -CON(R '' )2, -S(O)2N(R '' )2 and -CO2R '' ;

[0300] R 2 is -R '' ;

[0301] R 3 is –(CH2) 0-2 Cy, or:

[0302] R 2 and R 3, together with the nitrogen atoms to which they are attached, form a 4- to 7-membered saturated or partially unsaturated ring fused to Cy or a 4- to 7-membered saturated or partially unsaturated ring substituted with –Cy;

[0303] Cy is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic aryl ring, wherein each phenyl, heteroaryl, and aryl ring is substituted with 0 to 4 R x substituents;

[0304] Each R x is independently selected from halogen, -CN, -NO2, -OR '' , -SR '' , -N(R '' )2, -SO2R '' , -SO2N(R '' )2, -CO2R '' , -CON(R '' )2, -N(R '' )SO2R '' , -N(R '' )C(O)R '' and an optionally substituted C 1-6 aliphatic group;

[0305] R 4 is -R '' ;

[0306] Each R '' is independently hydrogen or an optionally substituted C 1-6 aliphatic group, or:

[0307] Two instances of R '' , together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring.

[0308] As generally defined above for formula II, R 1 is selected from -CN, -NO2, -C(O)R '' , -S(O)2R '' , -CON(R '' )2, -S(O)2N(R '' )2, and -CO2R '' . In some embodiments of formula II, R 1 is selected from –CN, -C(O)N(R '' )2, and –CO2R '' . In some embodiments of formula II, R 1 is –CN. In some embodiments, R1 is –CON(R '' )2. In some such embodiments of Formula II, each R '' is independently selected from hydrogen and C 1-6 aliphatic groups. In some embodiments of Formula II, R 1 is –CON(R '' )2, wherein each R is independently selected from hydrogen and C 1-6 alkyl. In some embodiments of Formula II, R 1 is –CON(R '' )2, wherein each R '' is independently selected from hydrogen and –CH3. In some embodiments of Formula II, R 1 is –CONH2. In some embodiments of Formula II, R 1 is –CO2R '' . In some such embodiments of Formula II, R '' is selected from hydrogen and C 1-6 aliphatic groups. In some embodiments of Formula II, R 1 is –CO2R '' , wherein R '' is selected from hydrogen and C 1-6 alkyl. In some embodiments of Formula II, R 1 is –CO2R '' , wherein R '' is selected from hydrogen and –CH3. In some embodiments of Formula II, R 1 is –CO2H. In some embodiments, R 1 is -NO2. In some embodiments of Formula II, R 1 is -C(O)R '' . In some embodiments of Formula II, R 1 is -S(O)2R '' . In some embodiments of Formula II, R 1 is -S(O)2N(R '' )2.

[0309] As generally defined for Formula II above, R 2 is -R '' . In some such embodiments of Formula II, -R '' is hydrogen. Accordingly, in some embodiments of Formula II, R 2 is –H. In some embodiments of Formula II, R 2 is –R '' , wherein –R '' is an optionally substituted C 1-6 aliphatic group. In some embodiments of Formula II, R2 is –R '' , where –R '' is C 1-6 an aliphatic group. In some embodiments of Formula II, R 2 is –C 1-6 alkyl. In some such embodiments of Formula II, R 2 is –CH3.

[0310] As generally defined above for Formula II, R 3 is –(CH2) 0-2 Cy. In some embodiments of Formula II, R 3 is –Cy. In some embodiments of Formula II, R 3 is –CH2-Cy. In some embodiments of Formula II, R 3 is –(CH2)2-Cy.

[0311] As generally defined above for Formula II, Cy is selected from phenyl, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic aryl ring, wherein each phenyl, heteroaryl, and aryl ring is substituted with 0-4 R x substituents.

[0312] In some embodiments of Formula II, Cy is phenyl. In some embodiments of Formula II, Cy is phenyl substituted with 1 R x substituent. In some embodiments of Formula II, Cy is phenyl substituted with 2 R x substituents. In some embodiments of Formula II, Cy is selected from

[0313]

[0314] In some embodiments of Formula II, Cy is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula II, Cy is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula II, Cy is a 6-membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments of Formula II, Cy is a 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some such embodiments of Formula II, Cy is substituted with 1 R xSubstitution. In some embodiments of Formula II, Cy is pyridyl. In some such embodiments of Formula II, Cy is pyrimidin-2-yl, pyrimidin-3-yl or pyrimidin-4-yl. In some embodiments of Formula II, Cy is pyridazinyl. In some embodiments of Formula II, Cy is pyrazinyl. In some embodiments of Formula II, Cy is pyrimidinyl. In some embodiments of Formula II, Cy is selected from:

[0315]

[0316]

[0317] In some embodiments of Formula II, Cy is an 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments of Formula II, Cy is an 8- to 10-membered bicyclic heteroaryl ring having 1-3 nitrogen atoms. In some embodiments of Formula II, Cy is a 10-membered bicyclic heteroaryl ring having 1-3 nitrogen atoms. In some embodiments of Formula II, Cy is a 10-membered bicyclic heteroaryl ring having 1 nitrogen atom. In some such embodiments of Formula II, Cy is substituted with 1 R x Substitution. In some embodiments of Formula II, Cy is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl or quinolin-8-yl.

[0318] In some embodiments of Formula II, Cy is an 8- to 10-membered bicyclic aryl ring. In some embodiments of Formula II, Cy is a 10-membered bicyclic aryl ring. In some such embodiments of Formula II, Cy is substituted with 1 R x Substitution. In some embodiments, Cy is naphthalen-1-yl. In some embodiments of Formula II, Cy is naphthalen-2-yl.

[0319] In some embodiments of Formula II, R 2 and R 3 , together with the nitrogen atom to which they are attached, form a 4- to 7-membered saturated or partially unsaturated ring fused to Cy or a 4- to 7-membered saturated or partially unsaturated ring substituted with –Cy. In some embodiments of Formula II, R 2 and R 3 , together with the nitrogen atom to which they are attached, form a ring selected from:

[0320] and

[0321] wherein Cy is substituted with 0-4 R x Substitution.

[0322] As generally defined above for Formula II, each R x is independently selected from halogen, -CN, -NO2, -OR '' , -SR '' , -N(R '' )2, -SO2R '' , -SO2N(R '' )2, -CO2R '' , -CON(R '' )2, -N(R)SO2R '' and -N(R '' )C(O)R '' , or an optionally substituted C 1-6 aliphatic group.

[0323] In some embodiments of Formula II, R x is halogen. In some such embodiments of Formula II, R x is fluorine. In some embodiments of Formula II, R x is chlorine.

[0324] In some embodiments of Formula II, R x is an optionally substituted C 1-6 aliphatic group. In some embodiments of Formula II, R x is an optionally substituted -C 1-6 alkyl. In some embodiments of Formula II, R x is an optionally halogen-substituted -C 1-6 alkyl. In some embodiments of Formula II, R x is an optionally substituted –CH3. In some such embodiments of Formula II, R x is –CF3.

[0325] In some embodiments of Formula II, R x is a C 1-6 aliphatic group. In some embodiments of Formula II, R x is -C 1-6 alkyl. In some embodiments of Formula II, R x is –CH3. In some embodiments of Formula II, R x is –CH(CH3)2.

[0326] In some embodiments of Formula II, R x is –OR '' . In some such embodiments of Formula II, R '' is a C 1-6 aliphatic group. In some embodiments of Formula II, R x is –OR '', where R '' is C 1-6 alkyl. In some embodiments of Formula II, R x is –OCH3.

[0327] In some embodiments of Formula II, R x is –OR '' . In some such embodiments of Formula II, R '' is an optionally substituted C 1-6 aliphatic group. In some embodiments of Formula II, R x is –OR '' , where R '' is an optionally substituted C 1-6 alkyl. In some embodiments of Formula II, R x is –OR '' , where R '' is an optionally substituted -CH3. In some embodiments of Formula II, R x is –OR '' , where R '' is –CF3. Accordingly, in some embodiments of Formula II, R x is –OCF3.

[0328] In some embodiments of Formula II, R x is –SO2R '' . In some such embodiments of Formula II, R '' is an optionally substituted C 1-6 aliphatic group. In some embodiments of Formula II, R x is –SO2R '' , where R '' is C 1-6 alkyl. In some embodiments of Formula II, R x is –SO2R '' , where R '' is -CH3. Accordingly, in some embodiments of Formula II, R x is –SO2CH3.

[0329] In some embodiments of Formula II, R x is –SR''. In some such embodiments of Formula II, R '' is an optionally substituted C 1-6 aliphatic group. In some embodiments of Formula II, R x is –SR '' , where R '' is C 1-6 alkyl. In some embodiments of Formula II, R x is –SR'' , wherein R '' is -CH3. Correspondingly, in some embodiments of Formula II, R x is –SCH3.

[0330] As generally defined above for Formula II, R 4 is -R '' . In some embodiments of Formula II, R 4 is –R '' . In some such embodiments of Formula II, -R '' is hydrogen. Correspondingly, in some embodiments of Formula II, R 4 is hydrogen. In some embodiments of Formula II, R 4 is –R '' , wherein R'' is an optionally substituted C 1-6 aliphatic group. In some embodiments of Formula II, R 4 is –R '' , wherein R'' is a C 1-6 aliphatic group. In some embodiments of Formula II, R 4 is –R '' , wherein R '' is a C 1-6 alkyl. In some embodiments, R 4 is –R '' , wherein R '' is CH3. Correspondingly, in some embodiments of Formula II, R 4 is –CH3.

[0331] As generally defined above for Formula II, each R '' is independently hydrogen or an optionally substituted C 1-6 aliphatic group; or two instances of R '' , together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring.

[0332] In some embodiments of Formula II, R '' is hydrogen. In some embodiments of Formula II, R '' is an optionally substituted C 1-6 aliphatic group. In some such embodiments of Formula II, R '' is -C 1-6 alkyl. In some embodiments, R '' is –CH3.

[0333] It is to be recognized that compounds of Formula II having the following structure

[0334]

[0335] When R 4 is H, it can exist in two tautomeric forms:

[0336] .

[0337] Accordingly, it is to be recognized that a compound of Formula II in which R 4 is H can be drawn in either tautomeric form.

[0338] In some embodiments of Formula II, R 1 is –CN. Accordingly, in some embodiments of Formula II, the SARM1 inhibitor is a compound of Formula II-a:

[0339]

[0340] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 and R 4 are each as defined above and as described herein.

[0341] In some embodiments of Formula II, R 1 is –CON(R '' )2. Accordingly, in some embodiments of Formula II, the SARM1 inhibitor is a compound of Formula II-b:

[0342]

[0343] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 and R '' are each as defined above and as described herein.

[0344] In some embodiments of Formula II-a or II-b, R 2 is H. Accordingly, in some embodiments, the SARM1 inhibitor is a compound of Formula II-a- i or II-a- ii :

[0345]

[0346] or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and R '' are each as defined above and as described herein.

[0347] In some embodiments of Formula II-a or II-b, R 3is –Cy, where –Cy is phenyl. Accordingly, in some embodiments, the SARM1 inhibitor is of formula II-b- i or II-b- ii compounds:

[0348]

[0349] or a pharmaceutically acceptable salt thereof, wherein R 2 、R 4 、R '' and R x are each as defined above and as described herein.

[0350] In some embodiments, the compounds of formula II are selected from:

[0351]

[0352]

[0353]

[0354]

[0355] .

[0356] In some embodiments, one or more compounds of formula II covalently inhibit SARM1. In some embodiments, one or more compounds of formula II covalently modify a cysteine residue of SARM1. In some embodiments, one or more compounds of formula II covalently modify Cys635 of SARM1. In some embodiments, one or more compounds of formula II covalently modify Cys629 of SARM1. In some embodiments, one or more compounds of formula II covalently modify Cys649 of SARM1.

[0357] In some embodiments, the SARM1 inhibitor is a compound of formula III:

[0358]

[0359] or a pharmaceutically acceptable salt thereof, wherein:

[0360] X a and X b one of which is selected from C and N and the other is C;

[0361] Y a is selected from N, N–R † and C–R ya ;

[0362] Y b is selected from N and C–Ryb ;

[0363] Y c is selected from N, N–R † , O, S and S(O)2;

[0364] Z b is selected from N and C–R zb ;

[0365] Z c is selected from N and C–R zc ;

[0366] Z d is selected from N and C–R zd ;

[0367] Each R † is independently selected from hydrogen and C ''' optionally substituted by –OR ''' ), -C(O)N(R ''' )2 or -C(O)OR 1-6 aliphatic group;

[0368] R ya , R yb , R za , R zb , R zc and R zd are each independently selected from hydrogen, halogen, -CN, -OR ''' , -C(O)OR ''' and C ''' optionally substituted by halogen, -CN, -OR ''' ), -N(R ''' )2, -C(O)OR ''' or -C(O)N(R 1-6 )2 aliphatic group; and

[0369] each R ''' is independently selected from hydrogen and C 1-6 aliphatic group;

[0370] or two instances of R ''' , together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring.

[0371] As generally defined above for formula III, one of X a and X b is selected from C and N and the other is C. In some embodiments of formula III, X a is N and X b is C. In some embodiments of formula III, X a is C and Xb is N.

[0372] It should be recognized that for a compound of formula III in which one of X a and X b is N, has the structure:

[0373] or

[0374] Thus, it should be understood that due to the valence of Y a and Y c in such a compound of formula III, (i) Y a is selected from N and C–R ya and (ii) Y c is N.

[0375] As generally defined for formula III above, each R † is independently selected from hydrogen and a C ''' aliphatic group optionally substituted with –OR ''' 、-C(O)N(R ''' )2 or -C(O)OR 1-6 . In some embodiments of formula III, R † is hydrogen. In some embodiments of formula III, R † is a C ''' aliphatic group optionally substituted with –OR ''' )2 or -C(O)OR ''' . In some embodiments of formula III, R 1-6 is a C † aliphatic group. In some such embodiments of formula III, R 1-6 is a C † alkyl. In some embodiments of formula III, R 1-6 is –CH3. In some embodiments of formula III, R † is –CH2CH3. In some embodiments of formula III, R † is –CH(CH3)2. † is –CH(CH3)2.

[0376] In some embodiments of formula III, R † is a C ''' aliphatic group optionally substituted with –OR 1-6 . In some embodiments of formula III, R † is a C ''' aliphatic group optionally substituted with –OR 1-6 . In some embodiments of formula III, R † is a C''' Substituted C 1-4 alkylene. In some embodiments of Formula III, R † is optionally C ''' substituted by –OR 1-3 alkylene. In some embodiments of Formula III, R † is optionally C ''' substituted by –OR 1-2 alkylene. In some embodiments, R † is –(CH2) 1-3 OR ''' . In some embodiments of Formula III, R † is –(CH2) 2-3 OR ''' . In some embodiments of Formula III, R † is –(CH2)2OR ''' . In some embodiments of Formula III, R † is –(CH2)3OR ''' .

[0377] In some embodiments of Formula III, R † is optionally C ''' substituted by –C(O)OR 1-6 aliphatic group. In some embodiments of Formula III, R † is optionally C ''' substituted by –C(O)OR 1-6 alkylene. In some embodiments of Formula III, R † is optionally C ''' substituted by –C(O)OR 1-4 alkylene. In some embodiments of Formula III, R † is optionally C ''' substituted by –C(O)OR 1-3 alkylene. In some embodiments of Formula III, R † is optionally C ''' substituted by –C(O)OR 1-2 alkylene. In some embodiments of Formula III, R † is –(CH2) 1-3 C(O)OR ''' . In some embodiments of Formula III, R † is –(CH2) 2-3 C(O)OR ''' . In some embodiments of Formula III, R † is –CH2C(O)OR ''' . In some embodiments of Formula III, R† is –(CH2)2C(O)OR ''' 。

[0378] In some embodiments of Formula III, R † is an optionally –C(O)N(R)2 substituted C 1-6 aliphatic group. In some embodiments of Formula III, R † is an optionally –C(O)N(R ''' )2 substituted C 1-6 alkylene group. In some embodiments of Formula III, R † is an optionally –C(O)N(R ''' )2 substituted C 1-4 alkylene group. In some embodiments of Formula III, R † is an optionally –C(O)N(R ''' )2 substituted C 1-3 alkylene group. In some embodiments of Formula III, R † is an optionally –C(O)N(R ''' )2 substituted C 1-2 alkylene group. In some embodiments of Formula III, R † is –(CH2) 1-3 C(O)N(R ''' )2. In some embodiments of Formula III, R † is –(CH2) 2-3 C(O)N(R ''' )2. In some embodiments of Formula III, R † is –CH2C(O)N(R ''' )2. In some embodiments of Formula III, R † is –(CH2)2C(O)N(R ''' )2.

[0379] As generally defined above for Formula III, R ya , R yb , R za , R zb , R zc and R zd each independently selected from hydrogen, halogen, -CN, -OR ''' , -C(O)OR ''' and an optionally halogen, -CN, -OR ''' , -N(R ''' )2, -C(O)OR ''' or -C(O)N(R ''' )2 substituted C 1-6An aliphatic group. In some embodiments of formula III, R ya is hydrogen. In some embodiments of formula III, R ya is halogen, -CN, -OR ''' -C(O)OR ''' or an aliphatic C ''' substituted optionally with halogen, -CN, -OR ''' , -N(R ''' )2, -C(O)OR ''' or -C(O)N(R 1-6 )2. In some embodiments of formula III, R ya is hydrogen, halogen or -OR ''' . In some embodiments of formula III, R ya is halogen. In some such embodiments of formula III, R ya is chlorine. In some embodiments of formula III, R ya is bromine. In some embodiments of formula III, R ya is iodine. In some embodiments of formula III, R ya is –OR ''' . In some embodiments of formula III, R ya is –CN or –C(O)OR ''' .

[0380] In some embodiments of formula III, R yb is hydrogen. In some embodiments of formula III, R yb is halogen, -CN, -OR ''' , -C(O)OR ''' or an aliphatic C ''' substituted optionally with halogen, -CN, -OR ''' , -N(R ''' )2, -C(O)OR ''' )2 or -C(O)N(R 1-6 )2. In some embodiments of formula III, R yb is hydrogen, -CN, -C(O)OR ''' or a C 1-6 aliphatic group. In some embodiments of formula III, R yb is a C 1-6 aliphatic group. In some such embodiments of formula III, R yb is a C 1-6 alkyl. In some embodiments of formula III, R yb is –CH3. In some embodiments of formula III, R yb is –CN. In some embodiments of formula III, Ryb is -C(O)OR ''' . In some embodiments of Formula III, R yb is –OR ''' .

[0381] In some embodiments of Formula III, R za is hydrogen. In some embodiments of Formula III, R za is halogen, -CN, -OR ''' , -C(O)OR ''' or an aliphatic group optionally substituted with halogen, -CN, -OR ''' , -N(R ''' )2, -C(O)OR ''' or -C(O)N(R ''' )2. In some embodiments of Formula III, R 1-6 is hydrogen or halogen. In some embodiments of Formula III, R za is halogen. In some such embodiments of Formula III, R za is bromine. In some embodiments of Formula III, R za is –OR za . In some embodiments of Formula III, R ''' is –CN or –C(O)OR za . ''' .

[0382] In some embodiments of Formula III, R zb is hydrogen. In some embodiments of Formula III, R zb is halogen, -CN, -OR ''' , -C(O)OR ''' or an aliphatic group optionally substituted with halogen, -CN, -OR ''' , -N(R ''' )2, -C(O)OR ''' or -C(O)N(R ''' )2. In some embodiments of Formula III, R 1-6 is an aliphatic group optionally substituted with halogen, -CN, -OR zb , -N(R ''' )2, -C(O)OR ''' or -C(O)N(R ''' )2. In some embodiments of Formula III, R ''' is hydrogen or a C 1-6 aliphatic group. In some embodiments of Formula III, R zb is a C 1-6 aliphatic group. In some embodiments of Formula III, R zb is a C 1-6An aliphatic group. In some such embodiments of Formula III, R zb is C 1-6 alkyl. In some embodiments of Formula III, R zb is –CH3. In some embodiments of Formula III, R zb is –OR ''' . In some embodiments of Formula III, R zb is –CN or –C(O)OR ''' .

[0383] In some embodiments of Formula III, R zc is hydrogen. In some embodiments of Formula III, R zc is halogen, -CN, -OR ''' , -C(O)OR ''' or an optionally halogen-, -CN-, -OR ''' , -N(R ''' )2, -C(O)OR ''' or -C(O)N(R ''' )2-substituted C 1-6 aliphatic group. In some embodiments of Formula III, R zc is –OR ''' . In some embodiments of Formula III, R zc is –CN or –C(O)OR ''' . In some embodiments of Formula III, R zc is an optionally halogen-, -CN-, -OR ''' , -N(R ''' )2, -C(O)OR ''' or -C(O)N(R ''' )2-substituted C 1-6 aliphatic group.

[0384] In some embodiments of Formula III, R zd is hydrogen. In some embodiments of Formula III, R zd is halogen, -CN, -OR ''' , -C(O)OR ''' or an optionally halogen-, -CN-, -OR ''' , -N(R ''' )2, -C(O)OR ''' or -C(O)N(R ''' )2-substituted C 1-6 aliphatic group. In some embodiments of Formula III, R zd is halogen. In some such embodiments of Formula III, R zd is chlorine. In some embodiments of Formula III, Rzd is –OR ''' . In some embodiments of Formula III, R zd is an optionally halogen, -CN, -OR ''' , -N(R ''' )2, -C(O)OR ''' or -C(O)N(R ''' )2 substituted C 1-6 aliphatic group. In some embodiments of Formula III, R zd is -C(O)OR ''' . In some embodiments of Formula III, R zd is –CN.

[0385] As generally defined above for Formula III, Y a is selected from N, N–R † and C–R ya . In some embodiments of Formula III, Y a is N. In some embodiments of Formula III, Y a is N–R † . In some embodiments of Formula III, Y a is C–R ya .

[0386] As generally defined above for Formula III, Y b is selected from N and C–R yb . In some embodiments of Formula III, Y b is N. In some embodiments of Formula III, Y b is C–R yb .

[0387] As generally defined above for Formula III, Y c is selected from N, N–R † , O, S and S(O)2. In some embodiments of Formula III, Y c is selected from N–R † , O, S and S(O)2. In some embodiments of Formula III, Y c is selected from N–R † , O and S. In some embodiments of Formula III, Y c is N. In some embodiments of Formula III, Y c is N–R † . In some embodiments of Formula III, Y c is O. In some embodiments of Formula III, Y c is S. In some embodiments of Formula III, Y c is S(O)2.

[0388] As generally defined above for formula III, Z b is selected from N and C–R zb . In some embodiments of formula III, Z b is N. In some embodiments of formula III, Z b is C–R zb .

[0389] As generally defined above for formula III, Z c is selected from N and C–R zc . In some embodiments of formula III, Z c is N. In some embodiments of formula III, Z c is C–R zc .

[0390] As generally defined above for formula III, Z d is selected from N and C–R zd . In some embodiments of formula III, Z d is N. In some embodiments of formula III, Z d is C–R zd .

[0391] As generally defined above for formula III, each R ''' is independently selected from hydrogen and C 1-6 aliphatic group, or two instances of R ''' , together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated heterocyclic ring. In some embodiments of formula III, R ''' is hydrogen. In some embodiments of formula III, R ''' is C 1-6 aliphatic group. In some such embodiments of formula III, R ''' is C 1-6 alkyl. In some embodiments of formula III, R ''' is –CH3. In some embodiments of formula III, R ''' is selected from hydrogen and –CH3.

[0392] In some embodiments of formula III, Z c is N. Accordingly, in some embodiments, the SARM1 inhibitor is a compound of formula III-a or a pharmaceutically acceptable salt thereof:

[0393] .

[0394] In some embodiments of formula III, X a is N and X bIt is C. Accordingly, in some embodiments, the SARM1 inhibitor is a compound of Formula III-b or a pharmaceutically acceptable salt thereof:

[0395] .

[0396] In some embodiments of Formula III, X a is C and X b is N. Accordingly, in some embodiments, the SARM1 inhibitor is a compound of Formula III-c or a pharmaceutically acceptable salt thereof:

[0397] .

[0398] In some embodiments of Formula III, the SARM1 inhibitor is a compound of Formula III-a- i , III-a- ii , III-a- iii , III-a- iv , III-a- v , III-b- i , III-b- ii , III-c- i or III-c- ii any one of the compounds:

[0399]

[0400] or a pharmaceutically acceptable salt thereof, wherein X a , X b , Y a , Y b , Y c , Z b , Z d , R ya , R za and R † are each as defined above and as described herein.

[0401] In some embodiments, the compounds of Formula III are selected from:

[0402]

[0403]

[0404]

[0405]

[0406]

[0407] or a pharmaceutically acceptable salt thereof.

[0408] DLK inhibitor

[0409] In some embodiments, the DLK inhibitor is a small molecule, polypeptide, peptide fragment, nucleic acid (e.g., siRNA, antisense oligonucleotide, microRNA, or aptamer), antibody, dominant negative inhibitor, or ribozyme.

[0410] In some embodiments, the DLK inhibitor is a small molecule. In some embodiments, the DLK inhibitor is siRNA. In some embodiments, the DLK inhibitor is an antisense oligonucleotide. In some embodiments, the DLK inhibitor is a polypeptide. In some embodiments, the DLK inhibitor is a peptide fragment. In some embodiments, the DLK inhibitor is a nucleic acid. In some embodiments, the DLK inhibitor is an antisense oligonucleotide.

[0411] In some embodiments, the DLK inhibitor inhibits downstream JNK-phosphorylation by reducing DLK expression.

[0412] In some embodiments, the DLK inhibitor is CGD-0134 (RG6000).

[0413] In some embodiments, the DLK inhibitor is described in Patel et al. J Med Chem. 2015 Jan 8;58(1):401-18, which is incorporated herein by reference in its entirety. For example, in some such embodiments, the DLK inhibitor is GNE-3511.

[0414] In some embodiments, the DLK inhibitor is a compound described in WO 2013 / 177367, which is incorporated herein by reference in its entirety. For example, in some such embodiments, the DLK inhibitor is SR8165.

[0415] In some embodiments, the DLK inhibitor is described in WO 2005 / 021729, WO 2009 / 011546, US 8,754,060, WO 2013 / 174780, WO 2011 / 050192, WO 2013 / 134766, WO 2014 / 111496, US 2016 / 0158234, WO 2014 / 177060, WO 2014 / 177524, US 2015 / 0175619, WO 2015 / 091889, WO 2016 / 142310, WO 2018 / 044808, and US 2018 / 0057507, each of which is incorporated herein by reference in its entirety.

[0416] In some embodiments, the DLK inhibitor is Shu, M. J Med Chem.2018, Patel, S. J Med Chem. 2017, 60(19):8083-8102, Welsbie, D.S., Neuron. 2017, 94(6):1142-1154, Blondeau et al., Neural Dev . 2016, 11(1):13, Yin, C. et al., Neuropharmacology. 2016, 108:316-23, and Holland, S.M. et al., Proc Natl Acad Sci USA. the compounds described in 2016, 113(3):763-8, each incorporated herein by reference in its entirety.

[0417] In some embodiments, the DLK inhibitor is selected from:

[0418]

[0419]

[0420] .

[0421] In some embodiments, the DLK inhibitor is siRNA. In some embodiments, the DLK inhibitor is an siRNA inhibitor selected from:

[0422] .

[0423] In some embodiments, the siRNA targeting DLK is described in Yin, C. et al., Neurobiol Dis. 2017 Jul;103:133-143.

[0424] In some embodiments, the method of DLK inhibition is described in WO 2014 / 134349, which is incorporated herein by reference in its entirety. In some embodiments, the DLK inhibitor is described in Summers, D.W., Proc Natl Acad Sci USA. 2018, 115(37):E8746-E8754, which is incorporated herein by reference in its entirety.

[0425] In some embodiments, the DLK inhibitor is shRNA. In some embodiments, the DLK inhibitor is shRNA having a targeting sequence selected from the following sequences:

[0426] .

[0427] In some embodiments, the DLK inhibitor is as described in Sheu, M.L., Int J Mol Sci.2018, 19(8):E2421 or Simard-Bisson et al., J Invest Dermatol. the shRNA sequences described in 2017, (1):132-141 are each incorporated herein by reference in their entirety.

[0428] NAMPT inhibitor

[0429] In some embodiments, the NAMPT inhibitor is a small molecule, polypeptide, peptide fragment, nucleic acid (such as siRNA, antisense oligonucleotide, microRNA or aptamer), antibody, dominant negative inhibitor or ribozyme.

[0430] In some embodiments, the NAMPT inhibitor is a small molecule. In some embodiments, the NAMPT inhibitor is siRNA. In some embodiments, the NAMPT inhibitor is an antisense oligonucleotide. In some embodiments, the NAMPT inhibitor is a polypeptide. In some embodiments, the NAMPT inhibitor is a peptide fragment. In some embodiments, the NAMPT inhibitor is a nucleic acid. In some embodiments, the NAMPT inhibitor is an antisense oligonucleotide.

[0431] In some embodiments, the NAMPT inhibitor prevents the formation of nicotinamide mononucleotide (NMN). In some embodiments, the inhibition of NAMPT inhibits the mammalian NAD+ salvage pathway.

[0432] In some embodiments, the NAMPT inhibitor is selected from:

[0433]

[0434]

[0435] .

[0436] In some embodiments, the NAMPT inhibitor is Travelli, C. et al., J.Pharmacol.Exp.Ther. 2011, 388(3):829-40; Hasmann, M. and Schemainda, I. Cancer Res. 2003, 63(21):7436-42; Galli et al., ChemMedChem . 2008, 3(5):771-9; Colombano, G. et al., J. Med Chem. 2010, 53(2):616-23; Matheny, C.J. Chem. Biol. 2013, 20(11):1352-63; Chan, D.A. et al., Sci. Trans. Med.2011, 3(94):94ra70; Adams, D.J. et al., ACS Chem. Biol. 2014, 9(10):2247-54; Kroop, E.M. et al., Stem Cells Transl Med. 2015, 4(5):483-93.; von Heideman, A. et al., Cancer Chemother Pharmacol. 2010, 65(6):1165-72.; Lovborg, H. et al., BMC Res Notes. 2009, 2:114.; Olesen, U.H. et al., Biochem Biophys Res Commun. , 2008, 367(4):799-804.; Hassan, S.B. et al., Anticancer Res., 2006, 26(6B):4431-6.; Johanson, V. et al., Neuroendocrinology. 2005, 82(3-4):171-6, Friberg, L.E. et al., Eur J Pharm Sci., 2005, 25(1):163-73; Ravaud, A. et al., Eur J. Cancer. 2005, 41(5):702-7.; Olsen, L.S. et al, Int J. Cancer. 2004,111(2): 198-205; Lovborg, H. et al., Mol Cancer Ther. 2004, 3(5):521-6; Zheng,X., J. Med. Chem. 2013, 56(16): 6413-33; Wang, W. et al, PLoS One , 2014, 9(10)e109366; O’Brien, T. et al., Neoplasia . 2013, 15(12): 1314-29, Xiao, T. et al., Neoplasia. 2013, 15(10): 1151-60; Zhao, G. et al., Cancer Ther . 2017, 16(12):2677-88; Guo, J. et al., Biochem Biophys Res Commun. 2017, 491(3):681-6; Lockman,J.W. et al., J. Med. Chem. , 2010, 53(24):8734-46; Fleischer, T.C. et al., Chem. Biol. 2010, 17(6): 659-64, Bavetsias, V. et al.,J. Med. Chem ., 2002, 45(17):3692 - 702.; Hiorns, L.R. et al., J Inorg Biochem. 1999, 77(1 - 2):95 - 104; Preyat, N. and Leo, O. Biochem Pharmacol. 2016, 101:13 - 26; Chan. M. et al., Cancer Res. 2014,74(21):5948 - 54; Olesen, U.H. et al., BMC Cancer . 2010, 10:677; Bi, T.Q. and Che, X.M. Cancer Biol Ther. 2010, 10(2):119 - 25; Fuchs, D. et al., Int J Cancer . 2010, 126(12):2773 - 89; Kato, H. et al., Clin Cancer Res . 2010, 16(3):898 - 911; Watson, M. et al., Mol Cell Biol. 2009, 29(21):5872 - 88; Beauparlant, P. et al., Anticancer Drugs . 2009, 20(5):346 - 54; Rane, C. et al., Sci Rep . 2017, 7:42555; Fulciniti, M. et al., Blood . 2017, pii: blood - 2016 - 06 - 724831; Aboukameel, A. et al., Mol Cancer Ther . 2017, 16(1):76 - 87; and Abu Aboud, O. et al Mol Cancer Ther. the compounds described in 2016, 15(9):2119 - 29 are each incorporated herein by reference in their entireties.

[0437] Composition

[0438] In some embodiments, the present disclosure provides a composition comprising and / or delivering a SARM1 inhibitor (e.g., in the form as described herein), its prodrug, or an active metabolite. In certain embodiments, the composition comprising the SARM1 inhibitor is formulated for co - administration to a subject with a DLK inhibitor.

[0439] In some embodiments, the present disclosure provides a composition comprising a SARM1 inhibitor for use in combination with a DLK inhibitor. In some embodiments, such a composition is a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the present disclosure provides a composition comprising and / or delivering a compound of Formula I, II, or III together with a DLK inhibitor. In some embodiments, such a composition is a pharmaceutically acceptable composition comprising at least one pharmaceutically acceptable carrier.

[0440] In some embodiments, the provided method comprises administering a composition comprising a SARM1 inhibitor and one or more pharmaceutically acceptable excipients.

[0441] The amount of the SARM1 inhibitor in the provided composition effectively and measurably inhibits axonal degeneration and / or measurably affects the change of a biomarker of neurodegeneration in a biological sample or a subject. In certain embodiments, the composition comprising the SARM1 inhibitor is formulated for administration to a subject in need of such composition. The compound and the composition 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 according to the methods of the present disclosure. For ease of administration and uniformity of dosage, the SARM1 inhibitor is preferably formulated in unit dosage forms. As used herein, the expression "unit dosage form" refers to physically discrete units of the agent suitable for the subject to be treated. However, it is to be understood that the total daily dosage of the SARM1 inhibitor will be decided by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular subject or organism will vary depending on the subject, 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 dietary status of the subject; the general condition of the subject; the time of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination with or together with the specific compound employed, etc. Examples

[0442] This teaching includes the descriptions provided in the examples, which are not intended to limit the scope of any claims. Unless explicitly stated in the past tense, inclusion in the examples is not intended to imply that the experiment was actually conducted. The following non-limiting examples are provided to further illustrate this teaching. Those skilled in the art will recognize, based on the present disclosure, that many changes can be made in the specific embodiments disclosed and still obtain similar or analogous results without departing from the spirit and scope of this teaching.

[0443] Materials and Methods

[0444] The methods and compositions described herein utilize laboratory techniques well known to those of skill in the art and are 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, Richard, Humana Press, NJ, 1995; Spector, D.L. et al., Cells: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1998; and Harlow, E., Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1999. The methods of administering a drug and the dosing regimen can be determined using standard reference texts, such as Remington: the Science and Practice of Pharmacy (Alfonso R. Gennaro, 19th ed., 1995); Hardman, J.G. et al., Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th ed., McGraw-Hill, 1996; and Rowe, R.C. et al., Handbook of Pharmaceutical Excipients, 4th ed., Pharmaceutical Press, 2003, according to standard principles of pharmacology.

[0445] Example 1

[0446] Activated SARM1 is a highly efficient NADase that depletes local axonal NAD+ stores within minutes to hours after activation, creating a local bioenergetic crisis in this important neuronal compartment and followed by rapid axonal degeneration. Axonal degeneration assays as described herein confirm the efficacy of treating damaged axons using an SARM1 inhibitor in combination with a DLK inhibitor.

[0447] Mouse DRG Hanging Drop Culture

[0448] Primary embryonic dorsal root ganglion (DRG) cells were isolated from embryonic day (E) 12.5 CD1 mouse embryos. Mouse dorsal root ganglion neurons (DRGs) (50 ganglia per embryo) were dissected from E12.5 CD1 mice and incubated with 0.5% Trypsin solution (Gibco) containing 0.02% EDTA at 37 °C for 15 minutes. Cells were then dissociated 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). Cells were suspended in DRG growth medium. DRG hanging drop cultures were created by spotting 5000 cells / well into the center of each well of a 96-well tissue culture plate coated with poly-D-lysine (0.1 mg / ml; Sigma) and laminin (3 mg / ml; Invitrogen). Cells were allowed to adhere to the plate for 15 minutes in a humidified tissue culture incubator (5% CO2), and then DRG growth medium (100 μl per well) was gently added. DRG neurons were maintained in Neurobasal medium supplemented with L-glutamine (Invitrogen), 2% (vol / vol) B27 (Invitrogen), 50 ng / mL NGF (Harlan Laboratories), 1 μM 5-fluoro-2'-deoxyuridine, and 1 μM uridine (Sigma) to induce death of mitotic cells. DRG neurons were then plated onto plates pre-coated with poly-D-lysine and laminin.

[0449] Axonal Degeneration Assay

[0450] To study the axon protection effect of combining a DLK inhibitor with a SARM1 inhibitor, 6-day-old mouse DRG hanging drop cultures were pre-incubated with 100 nM or 300 nM DLK inhibitor (GNE-3511) for 24 hours before axotomy. Two hours before axotomy, the DRG cultures were treated with a SARM1 inhibitor in the continued presence of the DLK inhibitor. Potent SARM1 inhibitors were selected from two classes: isoquinoline and isothiazole SARM1 inhibitors. The isoquinoline SARM1 inhibitors tested included I-26 and I-86, while the isothiazole SARM1 inhibitors tested included II-6 and II-32. SARM1 inhibitors were tested at concentrations of 0.1 to 30 μM.

[0451] Manual axotomy was performed by transversely cutting the axons of DRG neurons with a blade at time 0. After axotomy, DRG cultures were maintained exposed to either a SARM1 inhibitor alone, a DLK inhibitor alone, or a combination of a SARM1 inhibitor and a DLK inhibitor. At 16 h, DRG cultures were fixed in a buffer containing 1% PFA and sucrose and stored at 4 °C prior to imaging. Brightfield images of DRG axons and cell bodies were collected using a 20x water immersion lens on a Phenix automated confocal microscope (PerkinElmer), and quantification of axonal injury was performed using an in-house developed script (Acapella, PerkinElmer). The effect of the DLK inhibitor alone on preventing distal axonal fragmentation was determined at concentrations of 100 nM and 300 nM. The effect of combinations of the DLK inhibitor with different concentrations of the SARM1 inhibitor was compared to the individual protective effects of either 100 nM or 300 nM DLK inhibitor alone or the SARM1 inhibitor at equal concentrations alone.

[0452] Results

[0453] The axonal protection effect of SARM1 inhibition when co-administered with the DLK inhibitor GNE-3551 was evaluated using the potent SARM1 inhibitor I-26 in the axonal degeneration assay described herein. As shown in Figure 1, the combination of compound I-26 with the DLK inhibitor improved neuroprotection after axotomy compared to monotherapy. For each concentration of the test compound I-26, the degree of axonal protection of the compound I-26 + DLK inhibitor combination was consistently compared to the amount of protection produced by the reagent in the combination that alone had the higher protective effect. Figure 1A and 1B shows the degeneration index of DRG axons 16 h after axotomy. In Figure 1A , 100 nM DLK inhibitor did not provide axonal protection, while compound I-26 exhibited significant axonal protection at all test concentrations. Addition of 100 nM DLK inhibitor to the test concentrations of compound I-26 provided further, although not significant, reduction of axonal degeneration. In Figure 1B , either 300 nM DLK inhibitor alone or 1.1 μM of compound I-26 alone provided modest protection. Surprisingly, the combination of 1.1 μM compound I-26 + 300 nM DLK inhibitor provided robust and statistically significant protection. Moreover, the magnitude of the combined effect of 1.1 μM compound I-26 and 300 nM DLK inhibitor was greater than the sum of the individual effects of either reagent alone, indicating that the effect of combining these reagents is not simply additive but is in fact synergistic and cannot be predicted by the individual effects of the separate reagents.

[0454] In the axonal degeneration assay described herein, the potent SARM1 inhibitor I-86 was further evaluated for axonal protection provided when administered in combination with the DLK inhibitor GNE-3511. In Figure 2A , the 100 nM DLK inhibitor provided no axonal protection, while at 1.1 µM, compound I-86 exhibited a small but statistically significant amount of axonal protection. Surprisingly, the combination of 1.1 µM compound I-86 + 100 nM DLK inhibitor provided robust and statistically significant axonal protection that was greater than the sum of the individual effects of either reagent alone. In Figure 2B , either 300 nM DLK inhibitor alone or 1.1 µM of compound I-86 alone provided modest protection. Surprisingly, the combination of 1.1 µM compound I-86 + 300 nM DLK inhibitor provided robust and statistically significant protection. Additionally, the magnitude of the combined effect of 1.1 µM compound I-86 and 300 nM DLK inhibitor was greater than the sum of the individual effects of either reagent alone, indicating that the effect of combining these reagents is not simply additive, but rather is actually synergistic and cannot be predicted from the individual effects of the separate reagents.

[0455] The potency of SARM1 inhibitors when administered in combination with DLK inhibitors in the axonal degeneration assay described herein was also tested with two isothiazole compounds. The SARM1 inhibitor II-6 was tested in combination with the DLK inhibitor GNE-3511 in the axonal degeneration assay. Figure 3A and 3B show the degeneration index of DRG axons 16 hours after axotomy. In Figure 3A , the 100 nM DLK inhibitor provided no axonal protection, while 1.1 or 3.3 µM compound II-6 exhibited modest but statistically significant axonal protection. Surprisingly, the combination of 3.3 µM compound II-6 + 100 nM DLK inhibitor provided robust and statistically significant protection. Additionally, the magnitude of the combined effect of 3.3 µM compound II-6 and 100 nM DLK inhibitor was greater than the sum of the individual effects of either reagent alone and exhibited near-complete injury protection, indicating that the effect of combining these reagents is not simply additive, but rather is actually synergistic and cannot be predicted from the individual effects of the separate reagents. In Figure 3BAmong them, 300 nM DLK inhibitor alone or 3.3 µM of Compound II-6 alone provided moderate protection. Compared with 300 nM DLK inhibitor alone, the combination of 3.3 µM Compound II-6 + 300 nM DLK inhibitor provided robust and statistically significant protection. In addition, the magnitude of the combined effect of 3.3 µM Compound II-6 and 300 nM DLK inhibitor was greater than the sum of the individual effects of either reagent alone and showed complete protection against injury, indicating that the effect of combining these reagents was not simply additive but was actually synergistic and could not be predicted by the individual effects of the separate reagents.

[0456] In the axonal degeneration assay described herein, the effect of combining SARM1 inhibitor with DLK inhibitor was further tested using SARM1 inhibitor II-32 in combination with DLK inhibitor GNE-3511. The combination of Compound II-32 + DLK inhibitor provided enhanced neuroprotection after axotomy compared to monotherapy. Figure 4A and 4B show the degeneration index of DRG axons 16 hours after axotomy. In Figure 4A among them, 100 nM DLK inhibitor did not provide axonal protection, while 0.11, 0.33 or 1.1 µM of Compound II-32 showed moderate but not statistically significant axonal protection at these concentrations. The combination of 0.11, 0.33 or 1.1 µM Compound II-32 + 100 nM DLK inhibitor provided higher protection than either reagent alone, reaching statistical significance at 1.1 µM of Compound II-32. In addition, the magnitude of the combined effect of 1.1 µM Compound II-32 and 100 nM DLK inhibitor was greater than the sum of the individual effects of either reagent alone, indicating that the effect of combining these reagents was not simply additive but was actually synergistic and could not be predicted by the individual effects of the separate reagents. In Figure 4B among them, 300 nM DLK inhibitor alone provided a moderate but statistically significant level of axonal protection, while 0.11, 0.33 or 1.1 µM of Compound II-32 alone provided only slight and non-statistically significant protection at these concentrations. However, compared with 300 nM DLK inhibitor alone, the combination of 0.33 or 1.1 µM Compound II-32 + 300 nM DLK inhibitor provided robust and statistically significant protection. In addition, the magnitude of the combined effect of 0.33 or 1.1 µM Compound II-32 and 300 nM DLK inhibitor was greater than the sum of the individual effects of either reagent alone, indicating that the effect of combining these reagents was not simply additive but was actually synergistic and could not be predicted by the individual effects of the separate reagents.

[0457] In summary, these results demonstrate the neuroprotective efficacy of SARM1 inhibitors when provided in combination with DLK inhibitors in the axonal degeneration assay described herein.

[0458] Example 2

[0459] In this example, the ability of SARM1 inhibitors to prevent axonal degeneration in combination with NAMPT inhibitors was demonstrated using the axonal degeneration assay as described herein.

[0460] Mouse DRG Hanging Drop Culture

[0461] Primary embryonic dorsal root ganglion (DRG) cells were isolated from embryonic day (E) 12.5 CD1 mouse embryos. DRG cells were isolated from wild-type embryos at E12.5. The mouse DRGs (50 ganglia per embryo) were dissected and incubated with 0.5% Trypsin solution (Gibco) containing 0.02% EDTA at 37 °C for 15 minutes. The cells were then dissociated by gentle pipetting and washed three times with DRG growth medium (Neurobasal medium (Gibco) containing 2% B27 (Invitrogen), 100 ng / ml 2.5S NGF (Harland Bioproducts), 1 mM 5-fluoro-2'-deoxyuridine (Sigma), penicillin, and streptomycin). The cells were suspended in DRG growth medium. DRG hanging drop cultures were created by spotting 5000 cells / well into the center of each well of a 96-well tissue culture plate coated with poly-D-lysine (0.1 mg / ml; Sigma) and laminin (3 mg / ml; Invitrogen). The cells were allowed to attach to the plate for 15 minutes in a humidified tissue culture incubator (5% CO2), and then DRG growth medium (100 μl per well) was gently added. The DRG neurons were maintained in Neurobasal medium supplemented with L-glutamine (Invitrogen), 2% (vol / vol) B27 (Invitrogen), 50 ng / mL NGF (Harlan Laboratories), 1 μM 5-fluoro-2′-deoxyuridine, and 1 μM uridine (Sigma) to induce the death of mitotic cells. The DRG neurons were seeded onto plates pre-coated with poly-D-lysine and laminin.

[0462] Axonal Degeneration Assay

[0463] The axonal protection effect of combining a NAMPT inhibitor with a SARM1 inhibitor was confirmed using an axonal degeneration assay. 6-day-old mouse DRG hanging drop cultures were pre-incubated with a NAMPT inhibitor for 24 hours before axotomy. Then, 2 hours before axotomy, the DRG cultures were treated with a SARM1 inhibitor in the continued presence of the NAMPT inhibitor. Isoquinoline SARM1 inhibitors included I-26 and I-86, while the tested isothiazole SARM1 inhibitors included II-6 and II-32. SARM1 inhibitors were tested at concentrations of 0.1 to 33 µM. The NAMPT inhibitor was selected from the list of NAMPT inhibitors included herein, including FK866.

[0464] Manual axotomy was performed at time 0 by transecting the axons of DRG neurons with a blade. After axotomy, the DRG cultures were maintained in the presence of the SARM1 inhibitor alone, the NAMPT inhibitor alone, or a combination of the SARM1 inhibitor and the NAMPT inhibitor. At 16 or 24 hours, the DRG cultures were fixed in a buffer containing 1% PFA and sucrose and stored at 4 °C before imaging. Brightfield images of DRG axons and cell bodies were collected using a 20x water immersion lens of a Phenix automated confocal microscope (PerkinElmer), and quantification of axonal damage was performed using an in-house developed script (Acapella, PerkinElmer). The effect of combining the NAMPT inhibitor with different concentrations of the SARM1 inhibitor was compared to the individual protective effects of the NAMPT inhibitor alone or the SARM1 inhibitor at the same concentration alone.

[0465] Results

[0466] Neuroprotection provided by the combination of a SARM1 inhibitor and a NAMPT inhibitor was tested in an acute axotomy assay.

[0467] The isoquinoline SARM1 inhibitors I-26 and I-86 were tested alone or in combination with the NAMPT inhibitor FK866 in an axonal degeneration assay. When I-26 was tested in combination with FK866 in an acute axotomy assay, neuroprotection and axonal protection were enhanced compared to the protection achieved by either reagent alone at their respective single-agent concentrations. Similarly, when I-86 was tested in combination with FK866 in an acute axotomy assay, the degree of neuroprotection and axonal protection was enhanced compared to the protection achieved by either reagent alone at their respective single-agent concentrations.

[0468] Test isoxazole SARM1 inhibitors II-6 and II-32 alone or in combination with a NAMPT inhibitor in the axonal degeneration assay. When II-6 is tested in combination with FK866 in the acute axotomy assay, neuroprotection and axonal protection are increased compared to the protection achieved by either reagent alone at their respective single-agent concentrations. Similarly, when II-32 is tested in combination with FK866 in the acute axotomy assay, the degree of neuroprotection and axonal protection is increased compared to the protection achieved by either reagent alone at their respective single-agent concentrations.

[0469] In summary, these results demonstrate the neuroprotective efficacy of SARM1 inhibitors provided in combination with the NAMPT inhibitor FK866 in the axonal degeneration assays described herein. Both SARM1 inhibitors and NAMPT inhibitors provide neuroprotection after acute axotomy. The combination of a SARM1 inhibitor and a NAMPT inhibitor provides greater neuroprotection than either compound alone.

[0470] Other embodiments

[0471] The recitation of a list of elements in any definition of a variable herein includes definitions of that variable as any single element or combination (or sub-combination) of the listed elements. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or portions thereof.

[0472] The entire disclosures of each patent, patent application, and publication cited herein are incorporated herein by reference. Although the invention has been disclosed with reference to specific embodiments, it will be apparent to other skilled artisans in the art that other embodiments and variations of the invention may be designed without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations. Sequence Listing <110> DisArm Therapeutics, Inc. <120> SARM1 Inhibitors in Combination with Neuroprotective Agents <130> 2012800-0029 <150> 62 / 782,239 <151> 2018-12-19 <160> 11 <170> PatentIn version 3.5 <210> 1 <211> 25 <212> RNA <213> Artificial Sequence <220> <223> Chemically synthesized nucleotide <400> 1 gcucaggcga gagcaagcuu uagaa 25 <210> 2 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Chemically synthesized nucleotide <400> 2 uucuaaagcu ugcucucgcc ugagc 25 <210> 3 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Chemically synthesized nucleotide <400> 3 cccucauguu gcaacuagaa cucaa 25 <210> 4 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Chemically synthesized nucleotide <400> 4 uugaguucua guugcaacau gaggg 25 <210> 5 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Chemically synthesized nucleotide <400> 5 ccaauagugu ccugcagcua cauga 25 <210> 6 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Chemically synthesized nucleotide <400> 6 ucauguagcu gcaggacacu auugg 25 <210> 7 <211> 20 <212> DNA <213> Artificial sequence <220> <223> Chemically synthesized nucleotide <400> 7 catcatctgg gtgtgggaag 20 <210> 8 <211> 29 <212> DNA <213> Artificial sequence <220> <223> Chemically synthesized nucleotide <400> 8 aagttggcag caccaacact gatgagcga 29 <210> 9 <211> 30 <212> DNA <213> Artificial sequence <220> <223> Chemically synthesized nucleotide <400> 9 aaggaggatg tcctggtcta ctgaagtcac 30 <210> 10 <211> 29 <212> DNA <213> Artificial sequence <220> <223> Chemically synthesized nucleotide <400> 10 cctgtctgga caatgattgg caaagccta 29 <210> 11 <211> 29 <212> DNA <213> Artificial sequence <220> <223> Chemically synthesized nucleotide <400> 11 gagtagcctg gatggctcct gaagtgatc 29

Claims

1. A composition comprising a SARM1 inhibitor for use in combination with a DLK inhibitor, wherein the DLK inhibitor is a compound of the following formula or a pharmaceutically acceptable salt thereof: and the SARM1 inhibitor is selected from and pharmaceutically acceptable salts thereof.

2. Use of the composition of claim 1 for the manufacture of a medicament for the treatment and / or prevention of axonal degeneration.

3. Use of the composition of claim 1 for the manufacture of a medicament for the treatment and / or prevention of a neurodegenerative disease or disorder associated with axonal degeneration.

4. Use according to claim 3, wherein the neurodegenerative disease or disorder is selected from acute or chronic peripheral nervous system diseases or disorders, acute or chronic central nervous system diseases or disorders or diseases associated with neurodegeneration.

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