Inhibitors of SARM1

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 899,444, filed September 12, 2019, which is incorporated herein by reference in its entirety.

[0003] Sequence Listing

[0004] This application contains a sequence listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy created on September 9, 2020 is named 2012800-0041 SL.txt and is 8,858 bytes in size.

[0005] background

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

[0007] Overview

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

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

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

[0011]

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

[0013] X is N or CR x ;

[0014] R x is selected from hydrogen, halogen, and optionally substituted C1-6 aliphatic groups;

[0015] R a Selected from hydrogen, halogen, CN, CF3, C 1-3 aliphatic groups, and -C(O)N(R a* )2;

[0016] R a* Selected from hydrogen and C 1-3 aliphatic groups;

[0017] R 1 Selected from hydrogen, halogen, N(R)2, OR, C 1-6 aliphatic groups, 3- to 7-membered monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 7- to 8-membered bridged bicyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Each of the aliphatic group, the monocyclic heterocycle or the bridged bicyclic heterocycle, and the heteroaryl ring is optionally substituted by 1-3 R 1* group substituted;

[0018] R 1* is selected from oxo, halogen, N(R)2, OR, C(O)R, S(O)2R, C(O)OR, C(O)N(R)2, optionally substituted C 1-6 aliphatic, and an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0019] R is selected from hydrogen, optionally substituted C 1-6 an aliphatic group, and an optionally substituted 3 to 7 membered saturated monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0020] Two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 3- to 6-membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;

[0021] R 2 is selected from hydrogen, halogen, S(O)2R, C(O)OR, C(O)N(R)2, and an optionally substituted group selected from C 1-6 aliphatic groups, 3- to 7-membered heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

[0022] R 3 Selected from hydrogen, halogen, CN, CF3, C 1-3aliphatic groups, and -C(O)N(R a* )2.

[0023] In some embodiments, provided compounds have the following formula Ia, Ia- i , Ia- ii , Ib, Ib- i , Ib- ii 、Ic、Ic- i 、Ic- ii , II, II-a, II-b, and II-c.

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

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

[0026] In some embodiments, the present disclosure provides compositions comprising and / or delivering a compound of Formula I. In some embodiments, such compositions are pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0027] In some embodiments, provided SARM1 inhibitors reduce or inhibit NAD+ binding by SARM1. In some embodiments, provided SARM1 inhibitors bind to SARM1 within a pocket containing one or more catalytic residues (e.g., the catalytic cleft of SARM1).

[0028] In some embodiments, provided compounds and / or compositions inhibit the activity of SARM1. Alternatively or additionally, in some embodiments, provided compounds alleviate one or more attributes of neurodegeneration. In some embodiments, the disclosure provides methods for treating neurodegenerative diseases or disorders associated with axonal degeneration.

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

[0030] In some embodiments, one or more compounds and / or compositions as described herein can be used for example to treat one or more neurodegenerative diseases, disorders or conditions, which are selected from neuropathy or axonopathy. In some embodiments, one or more compounds and / or compositions as described herein can be used for example to treat neuropathy or axonopathy related to axonal degeneration. In some embodiments, the neuropathy related to axonal degeneration is hereditary or congenital neuropathy or axonopathy. In some embodiments, the neuropathy related to axonal degeneration originates from new mutations or somatic mutations. In some embodiments, the neuropathy related to axonal degeneration is selected from the list contained herein. In some embodiments, neuropathy or axonopathy is related to axonal degeneration, including but not limited to peripheral neuropathy, multiple sclerosis, optic neuropathy such as glaucoma, Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis (ALS), demyelinating disease, ischemia or stroke, chemical injury, thermal injury and AIDS caused by chemotherapy.

[0031] In some embodiments, the object of compound or composition as described herein can be or include suffering from or being susceptible to neurodegenerative disease, disorder or medical condition.In some embodiments, neurodegenerative disease, disorder or medical condition can be or include traumatic neuron injury.In some embodiments, traumatic neuron injury is blunt force trauma, closed brain injury, open head trauma, exposure to concussive force and / or explosive force, penetrating injury in the innervation area of ​​brain cavity or body or penetrating injury to the innervation area of ​​brain cavity or body.In some embodiments, traumatic neuron injury is the force causing axonal deformation, stretching, squeezing (crush) or steering (sheer).

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

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

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

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

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

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

[0039] definition

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

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

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

[0043] Alkenyl: The term "alkenyl" used alone or as part of a larger moiety refers to an optionally substituted straight or branched chain or cyclic hydrocarbon radical having at least one double bond and having 2-12, 2-10, 2-8, 2-6, 2-4 or 2-3 carbon atoms. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having from about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentyl, cyclohexenyl and cycloheptenyl.

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

[0045] Aryl: The term "aryl" refers to monocyclic and bicyclic ring systems with a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, which includes but is not limited to phenyl, biphenyl, naphthyl, anthracenyl, etc., which may be substituted with one or more substituents. The term "aryl" as used herein also includes groups in which aromatic rings are fused to one or more non-aromatic carbocyclic or heterocyclic rings, such as indanyl, phthalimide, naphthalimide, phenanthridinyl, tetrahydronaphthyl, imidazolidinyl, imidazolidin-2-one, etc.

[0046] Combined with:It is to be understood that the term "binding" as used herein generally refers to a non-covalent association between two or more entities. "Direct" binding involves physical contact between the entities or moieties; indirect binding involves physical interaction via physical contact with one or more intermediate entities. Binding between two or more entities can generally be assessed in any of a variety of contexts - including where the interacting entities or moieties are studied in isolation or in the context of a more complex system (e.g., while covalently or otherwise associated with a carrier entity and / or in a biological system or cell).

[0047] Biological samples: The term "biological sample" as used herein generally refers to a sample obtained from or derived from a related biological source as described herein (e.g., tissue or organism or cell culture). In some embodiments, the related source comprises an organism, such as an animal or a human being. In some embodiments, the biological sample is a biological tissue or fluid 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 sample; body fluid containing cells; free nucleic acid; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph fluid; gynecological fluid; skin swab; vaginal swab; oral swab; nasal swab; washing or lavage fluid, such as catheter lavage fluid or bronchoalveolar lavage fluid; aspirate; scrapings; bone marrow sample; tissue biopsy sample; surgical sample; feces, other body fluids, secretions and / or excrement; 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 taken from an individual from a sample. In some embodiments, the sample is a "primary sample" obtained directly from a relevant source by any appropriate means. For example, in some embodiments, the primary biological sample is obtained by a method selected from a biopsy (e.g., fine needle aspiration or tissue biopsy), a surgical operation, a collection of body fluids (e.g., blood, lymph, feces, etc.), etc. In some embodiments, as is clear from the context, the term "sample" refers to a product obtained by processing a primary sample (e.g., by removing one or more components thereof and / or by adding one or more reagents thereto). For example, filtration using a semipermeable membrane. Such a "processed sample" may include, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, separation and / or purification of certain components.

[0048] Biomarkers:The term "biomarker" is used herein to indicate an entity, event or feature whose presence, level, degree, type and / or form is associated with a relevant specific biological event or state so that it is considered a "marker" of the event or state. To name a few, in some embodiments, a biomarker can be or include a marker of a specific disease state, or a marker of the possibility that a specific disease, disorder or condition may develop, occur or recur. In some embodiments, a biomarker can be or include a marker of a specific disease or treatment outcome or its possibility. Therefore, for relevant biological events or relevant states, in some embodiments, a biomarker is predictive, in some embodiments, a biomarker is prognostic, and in some embodiments, a biomarker is diagnostic. A biomarker can be or include an entity of any chemical class, and can be or include a combination of entities. For example, in some embodiments, a biomarker can be or include nucleic acids, polypeptides, lipids, carbohydrates, small molecules, inorganic agents (such as metals or ions) or a combination thereof. In some embodiments, a biomarker is a cell surface marker. In some embodiments, a biomarker is intracellular. In some embodiments, the biomarker is detected extracellularly (e.g., secreted or otherwise produced or present outside the cell, such as in body fluids such as blood, urine, tears, saliva, cerebrospinal fluid, etc.). In some embodiments, the biomarker can be or include a genetic or epigenetic signature. In some embodiments, the biomarker can be or include a gene expression signature.

[0049] In some embodiments, biomarkers can be or include markers of neurodegeneration, or markers of the possibility that a neurodegenerative disease, disorder or condition may develop, occur or recur. In some embodiments, biomarkers can be or include markers of neurodegeneration, treatment outcome or its possibility. Therefore, for neurodegenerative diseases, disorders or conditions, in some embodiments, biomarkers are predictive, in some embodiments, biomarkers are prognostic, and in some embodiments, biomarkers are diagnostic. In some embodiments, changes in biomarker levels can be detected by cerebrospinal fluid (CSF), plasma and / or serum.

[0050] In some embodiments, neurodegeneration can be assessed, for example, by detecting an increase and / or decrease in the concentration of neurofilament light chain (NF-L) and / or neurofilament heavy chain (NF-H) contained in the cerebrospinal fluid of the subject. In some embodiments, the occurrence and / or progression of neurodegeneration can be assessed by positron emission tomography (PET) with synaptic vesicle glycoprotein 2a (SV2A) ligands. In some embodiments, detectable changes in constitutive NAD and / or cADPR levels in neurons can be used to assess neurodegeneration.

[0051] In some embodiments, relative to a healthy reference population, the detectable changes of one or more neurodegeneration-related proteins in the subject can be used as biomarkers of neurodegeneration. Such proteins include but are not limited to albumin, amyloid-β (Aβ) 38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractant protein (MCP) -1, neurogranin, neuron-specific enolase (NSE), soluble amyloid precursor protein (sAPP) α, sAPPβ, soluble triggering receptor expressed on bone marrow cells (sTREM) 2, phosphorylated tau and / or total tau. In some embodiments, cytokines and / or chemokines, including but not limited to Ccl2, Ccl7, Ccl12, Csf1 and / or Il6 increases can be used as biomarkers of neurodegeneration.

[0052] Carrier: The term "carrier" as used herein refers to a diluent, adjuvant, excipient or vehicle for administering a composition. In some exemplary embodiments, the carrier may include sterile liquids, such as water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, the carrier is or includes one or more solid components.

[0053] Combination therapy:The term "combination therapy" as used herein refers to those situations in which a subject is simultaneously exposed to two or more treatment regimens (e.g., two or more therapeutic agents). In some embodiments, two or more regimens may be administered simultaneously; in some embodiments, these regimens may be administered sequentially (e.g., all "doses" of the first regimen are administered before any doses of the second regimen); in some embodiments, these agents are administered in overlapping dosing regimens. In some embodiments, the "administration" of a combination therapy may involve administering one or more agents or modalities to an object receiving other agents or modalities in the combination. For clarity, combination therapy does not require that the individual agents be administered together (or even necessarily simultaneously) in a single composition, although in some embodiments, two or more agents or their active portions may be administered together in a combination composition or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0054] Composition: Those skilled in the art will recognize that the term "composition" can be used to refer to an independent physical entity comprising one or more specified components. Generally speaking, unless otherwise specified, a composition can be in any form - for example, gas, gel, liquid, solid, etc.

[0055] Domain: The term "domain" as used herein refers to a fragment or part of an entity. In some embodiments, a "domain" is associated with a specific structural and / or functional feature of an entity, so that when the domain is physically separated from the rest of its parent entity, it substantially or completely retains the specific structural and / or functional features. Alternatively or additionally, a domain may be or include a part of an entity that substantially retains and / or provides one or more structural and / or functional features unique to the parent entity on the receptor entity when it is separated from the (parent) entity and connected to a different (receptor) entity. In some embodiments, a domain is a fragment or part of a molecule (e.g., a small molecule, a carbohydrate, a lipid, a nucleic acid, or a polypeptide). In some embodiments, a domain is a fragment of a polypeptide; in some such embodiments, a domain is characterized by specific structural elements (e.g., specific amino acid sequences or sequence motifs, α-helical features, β-folding features, coiled coil features, random coil features, etc.) and / or specific functional features (e.g., binding activity, enzymatic activity, folding activity, signal transduction activity, etc.).

[0056] Dosage form or unit dosage form:Those skilled in the art will recognize that the term "dosage form" can be used to represent a physically discrete unit of an active agent (e.g., a therapeutic agent or a diagnostic agent) administered to an object. Typically, each such unit contains a predetermined amount of active agent. In some embodiments, such an amount is a unit dose (or its whole fraction) suitable for administration according to a dosage regimen (i.e., a therapeutic dosage regimen) that has been determined to be associated with a desired or beneficial result when administered to a relevant population. Those of ordinary skill in the art will recognize that the total amount of a therapeutic composition or medicament administered to a particular object is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0057] Dosage regimen or treatment regimen: Those skilled in the art will recognize that the terms "dosage regimen" and "treatment regimen" can be used to refer to a group of unit doses (usually more than one) that are usually administered separately to a subject for a period of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more administrations. In some embodiments, the dosing regimen comprises multiple doses, each separated from other doses in time. In some embodiments, each dose is separated from each other by the same length of time; in some embodiments, the dosing regimen comprises multiple administrations and at least two different time periods for separating each administration. In some embodiments, all administrations within the dosing regimen have the same unit dose. In some embodiments, different administrations within the dosing regimen are different amounts. In some embodiments, the dosing regimen comprises the first administration of a first dose, followed by one or more additional administrations of a second dose different from the first dose. In some embodiments, the dosing regimen comprises the first administration of a first dose, followed by one or more additional administrations of a second dose identical to the first dose. In some embodiments, the dosing regimen is associated with a desired or beneficial result when administered to a relevant population (i.e., a therapeutic dosing regimen).

[0058] excipient: As used herein, refers to non-therapeutic agents that may be included in pharmaceutical compositions, for example, to provide or contribute to the desired consistency or stabilization. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, maltose, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene, glycol, water, ethanol, etc.

[0059] Heteroaryl:The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy" refer to groups having 5 to 10 ring atoms, preferably 5, 6, 9 or 10 ring atoms; having 6, 10 or 14 π-electrons sharing a cyclic array; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl includes, but is not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaryl ring is fused to one or more aryl, alicyclic or heterocyclic rings, wherein the radical or point of attachment is on the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4-dole-4- ... H- The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which includes optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0060] Heterocyclic ring: As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic group" and "heterocyclic ring" are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has, in addition to carbon atoms, one or more, such as 1 to 4 heteroatoms as defined above. The term "nitrogen" when used to refer to a ring atom of a heterocycle includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur and nitrogen, nitrogen can be N (such as in 3,4-dihydro-2H-pyrrolyl), NH (such as in pyrrolidinyl) or NR +(as in N-substituted pyrrolidinyl). Heterocycle can be connected to its side group at any heteroatom or carbon atom producing a stable structure and any ring atom can be optionally substituted. The example of such saturated or partially unsaturated heterocyclic group includes but is not limited to tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolyl, oxazolidinyl, piperazinyl, dioxane-based, dioxolane-based, diazepine-based, oxazepine-based, thiazepine-based, morpholinyl and thiomorpholinyl. Heterocyclic group can be monocyclic, bicyclic, tricyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic, more preferably monocyclic or bicyclic. The term "heterocyclic alkyl" refers to an alkyl substituted by a heterocyclic group, wherein the alkyl and heterocyclic moieties are independently optionally substituted. Additionally, heterocycles also include groups in which a heterocycle is fused to one or more aryl rings (eg, 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[b][1,4]dioxine, etc.).

[0061] Inhibitors: As used herein, the term "inhibitor" refers to an entity, condition, or event whose presence, level, or extent is associated with a reduced target level or activity. In some embodiments, an inhibitor may act directly (in which case it exerts its influence directly on its target, such as by binding to the target); in some embodiments, an inhibitor may act indirectly (in which case it exerts its influence by interacting with and / or otherwise altering a modulator of the target to reduce the level and / or activity of the target). In some embodiments, an inhibitor is an inhibitor whose presence or level is associated with a reduced target level or activity relative to a specific reference level or activity (e.g., observed under appropriate reference conditions, such as the presence of a known inhibitor or the absence of the inhibitor in question, etc.).

[0062] Neurodegeneration:The term "neurodegeneration" as used herein refers to the decline of one or more characteristics, structures or properties of neurons or neuronal tissues. In some embodiments, neurodegeneration is observed as pathological reduction in an organism. Those skilled in the art will recognize that neurodegeneration is related to certain diseases, disorders and conditions, including those affecting mankind. In some embodiments, neurodegeneration may be temporary (e.g., sometimes occurring in association with certain infections and / or chemical or mechanical damage); in some embodiments, neurodegeneration may be chronic and / or progressive (e.g., usually associated with certain diseases, disorders or conditions, such as, but not limited to, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease or Alzheimer's disease). In some embodiments, neurodegeneration can be assessed, for example, by the increase of a biomarker associated with neurodegeneration of a detection object. In some embodiments, neurodegeneration can be assessed, for example, by the reduction of a biomarker associated with neurodegeneration of a detection object. Alternatively or additionally, in some embodiments, neurodegeneration can be assessed by magnetic resonance imaging (MRI), biomarkers containing cerebrospinal fluid, or other biomarkers observed in patients. In some embodiments, neurodegeneration is defined as a score below 24 in the Mini-Mental State Examination. In some embodiments, neurodegeneration refers to synaptic loss. In some embodiments, neurodegeneration refers to a reduction in neural tissue associated with traumatic injury (e.g., exposure to external forces that destroy the integrity of neural tissue). In some embodiments, neurodegeneration refers to a reduction in peripheral neural tissue. In some embodiments, neurodegeneration refers to a reduction in central nervous tissue.

[0063] oral: As used herein, the phrases "oral administration" have their art-understood meanings and refer to administration of a compound or composition by mouth.

[0064] Parenteral: As used herein, the phrases "parenteral administration" have their generally understood meaning in the art and refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0065] Partially unsaturated: As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties as defined herein.

[0066] patient:The term "patient" as used herein refers to any organism to which the provided composition is or can be administered, for example, for experimental, diagnostic, preventive, cosmetic and / or therapeutic purposes. Typical patients include animals (e.g., mammals, such as mice, rats, rabbits, non-human primates and / or humans). In some embodiments, the patient is human. In some embodiments, the patient suffers from or is susceptible to one or more disorders or conditions. In some embodiments, the patient exhibits one or more symptoms of a disorder or condition. In some embodiments, the patient has been diagnosed with one or more disorders or conditions. In some embodiments, the patient is receiving or has received a therapy to diagnose and / or treat a disease, disorder or condition.

[0067] Pharmaceutical composition: The term "pharmaceutical composition" as used herein refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dosage suitable for administration in a treatment or dosing regimen to show a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical compositions can be specially formulated for administration in solid or liquid form, including those suitable for the following administration: oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets, such as those intended for buccal, sublingual and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous or epidural injection, as, for example, sterile solutions or suspensions, or sustained release formulations; topical application, such as as a cream, ointment, or controlled release patch or spray applied to the skin, lungs or mouth; intravaginal or rectal administration, such as as a pessary, cream or foam; sublingual; ocular; transdermal; or nasal, pulmonary and administration to other mucosal surfaces.

[0068] Medicinal use: As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0069] Pharmaceutically acceptable carrier:As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient or solvent encapsulating material, that participates in carrying or delivering the present compound from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; pH buffered solutions; polyesters, polycarbonates, and / or polyanhydrides; and other nontoxic compatible substances used in pharmaceutical formulations.

[0070] Pharmaceutically acceptable salts: As used herein, the term "pharmaceutically acceptable salts" refers to salts of these compounds that are suitable for use in a pharmaceutical setting, i.e., salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. J. Pharmaceutical Sciences, 66: 1-19 (1977) describes pharmaceutically acceptable salts in detail. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. In some embodiments, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed, if appropriate, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates and arylsulfonates.

[0071] prevention: As used herein, the term "prevent" when used in connection with the occurrence of a disease, disorder, and / or condition, refers to reducing the risk of developing the disease, disorder, and / or condition and / or delaying the onset of one or more characteristics or symptoms of the disease, disorder, or condition. Prevention can be considered complete when the onset of the disease, disorder, or condition has been delayed for a predetermined period of time.

[0072] Specificity:The term "specificity" used herein for active agents 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 referred to as "specifically" binding 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 depend on the presence of specific structural features (e.g., epitopes, clefts, binding sites) of the target entity. It is to be understood that specificity does not need to be absolute. In some embodiments, specificity can be assessed relative to the specificity of the binding agent to one or more other potential target entities (e.g., competitors). In some embodiments, specificity is assessed relative to the specificity of a reference specific binding agent. In some embodiments, specificity is assessed relative to the specificity of a reference nonspecific binding agent. In some embodiments, the agent or entity is undetectably bound to a competitive alternative target under conditions of binding to its target entity. In some embodiments, the binding agent is bound to its target entity with a higher on-rate, a lower off-rate, an increased affinity, a reduced dissociation, and / or an increased stability compared to a competitive alternative target.

[0073] Target: The term "subject" as used herein refers to an organism, typically a mammal (e.g., a human, including in some embodiments a prenatal human form). In some embodiments, the subject suffers from a relevant disease, disorder, or condition. In some embodiments, the subject is susceptible to a disease, disorder, or condition. In some embodiments, the subject exhibits one or more symptoms or 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 with one or more features representing a susceptibility to a disease, disorder, or condition or a risk of a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual who is being and / or has been diagnosed and / or treated.

[0074] Substitute or optionally substitute ： As described herein, the compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogen atoms of the designated moiety are replaced with a suitable substituent. "Substitution" applies to one or more hydrogen atoms, whether expressly or impliedly from the structure (e.g., means at least ;and means at least , , or ). Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent at each position may be the same or different. The combinations of substituents contemplated by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable" as used herein refers to compounds that are substantially unchanged when subjected to conditions for their production, detection, and in certain embodiments, their recovery, purification, and use for one or more of the uses disclosed herein.

[0075] Suitable monovalent substituents on the substitutable carbon atoms of the "optionally substituted" group are independently halogen; -(CH2) 0- 4R°; -(CH2) 0-4 OR°; -O(CH2) 0-4 R°, -O-(CH2) 0-4 C(O)OR°; -(CH2) 0-4 CH(OR°)2; -(CH2) 0-4 SR°; -(CH2) substituted by R° 0-4 Ph; -(CH2) substituted by R° 0-4 O(CH2) 0-1 Ph; -CH=CHPh which may be substituted by R°; -(CH2) which may be substituted by R° 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2; -(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°; -(CH2) 0-4 C(O)SR°; -(CH2) 0-4 C(O)OSiR°3; -(CH2) 0-4 OC(O)R°; -OC(O)(CH2) 0- 4SR°; -(CH2) 0-4 SC(O)R°; -(CH2) 0-4C(O)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°, -(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0-4 SSR°; -(CH2) 0-4 S(O)2R°; -(CH2) 0-4 S(O)(NH)R°;-(CH2) 0-4 S(O)2OR°; -(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; SiR°3; -(C 1-4 Straight or branched alkylene)ON(R°)2; or -(C 1-4 linear or branched alkylene) C(O)ON(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5- to 6-membered heteroaryl ring), a 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8- to 10-membered bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independently occurring R° together with the atoms between them form a 3- to 12-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0076] Suitable monovalent substituents on R° (or the ring formed by two independent R° together with the atoms between them) are independently halogen, -(CH2) 0-2 R ● 、-(halogenated R ● )、-(CH2) 0-2 OH, -(CH2) 0-2 OR ● 、-(CH2) 0-2 CH(OR ● )2; -O(halogenated R ● )、-CN、-N3、-(CH2) 0-2 C(O)R ●、-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● 、-(CH2) 0-2 SR ● 、-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● 、-(CH2) 0-2 NR ● 2. -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● 、-(C 1-4 Straight or branched alkylene)C(O)OR ● or -SSR ● , where each R ● is unsubstituted or, when preceded by "halo", is substituted only by one or more halogens, and is independently selected from C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0077] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0 ("oxo"), =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、-O(C(R * 2)) 2-3 O-or-S(C(R * 2)) 2- 3S-, where each independent R * is selected from hydrogen, C which may be substituted as defined below 1-6 an aliphatic group or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents bonded to the ortho-substitutable carbon of the "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independent R * is selected from hydrogen, C which may be substituted as defined below 1-6an aliphatic group or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0078] R * Suitable substituents on the aliphatic group include halogen, -R ● 、-(halogenated R ● ), -OH, -OR ● 、-O(halogenated R ● )、-CN、-C(O)OH、-C(O)OR ● 、-NH2、-NHR ● 、-NR ● 2 or -NO2, where each R ● is unsubstituted or, when preceded by "halo", is substituted only by one or more halogens, and is independently C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0079] Suitable substituents on the substitutable nitrogen of an "optionally substituted" group include -R † 、-NR † 2. -C(O)R † 、-C(O)OR † 、-C(O)C(O)R † 、-C(O)CH2C(O)R † 、-S(O)2R † 、-S(O)2NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R † )S(O)2R † ; Each R † are independently hydrogen, C which may be substituted as defined below 1-6 an aliphatic group, an unsubstituted -OPh or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independent occurrences of R † Together with their intermediate atoms they form an unsubstituted 3- to 12-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0080] R † Suitable substituents on the aliphatic group are independently halogen, -R ● 、-(halogenated R ●), -OH, -OR ● 、-O(halogenated R ● )、-CN、-C(O)OH、-C(O)OR ● 、-NH2、-NHR ● 、-NR ● 2 or -NO2, where each R ● is unsubstituted or, when preceded by "halo", is substituted only by one or more halogens, and is independently C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0081] Therapeutic agents: The phrase "therapeutic agent" as used herein generally refers to any agent that causes a desired pharmacological effect when administered to an organism. In some embodiments, an agent is considered to be a therapeutic agent if it shows a statistically significant effect in an appropriate population. In some embodiments, an appropriate population may be a model organism population. In some embodiments, an appropriate population may be determined by various criteria, such as a specific age group, sex, genetic background, existing clinical condition, etc. In some embodiments, a therapeutic agent is a substance that can be used to alleviate, improve, alleviate, inhibit, prevent one or more symptoms or features of a disease, disorder, and / or condition, delay its onset, reduce its severity, and / or reduce its incidence. In some embodiments, a "therapeutic agent" is an agent that has been or needs to be approved by a government agency before it can be sold for administration to humans. In some embodiments, a "therapeutic agent" is an agent that requires a medical prescription to be administered to humans.

[0082] treat: As used herein, the term "treat" refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not show signs of the disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who only shows early signs of a disease, disorder, and / or condition, e.g., to reduce the risk of development of pathology associated with the disease, disorder, and / or condition.

[0083] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0084] Programmed axonal degeneration and SARM1

[0085] Axonal degeneration is a major pathological feature of neurological diseases such as, but not limited to, Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis, diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, hereditary neuropathies, traumatic brain injury, and / or glaucoma. Damaged or unhealthy axons are eliminated through an intrinsic self-destruction program known as Wallerian degeneration, which is distinct from traditional cell death pathways such as apoptosis (Gerdts, J. et al., Neuron , 2016, 89, 449-460; Whitmore, AV et al., Cell Death Differ ., 2003, 10, 260-261). In Wallerian degeneration, peripheral nerves undergo selective damage to axonal segments distal to the injury, while proximal axonal segments and cell bodies remain intact. Without wishing to be bound by theory, Wallerian degeneration is believed to be characterized first by the depletion of nicotinamide mononucleotide adenylyltransferase (NMNAT), followed by loss of nicotinamide adenine dinucleotide (NAD+), loss of adenosine triphosphate (ATP), proteolysis of neurofilaments, and finally axonal degeneration approximately 8 to 24 hours after injury (Gerdts, J. et al., 2003, 10, 260-261). Neuron , 2016, 89, 449-460).

[0086] NAD+ is a ubiquitous metabolite with key roles in energy metabolism and cell signaling (Belenkey et al., Trends Biochem ., 2007, 32, 12-19; ​​Chiarugi et al., Nat. Rev. Cancer , 2012, 12, 741-752). Homeostatic regulation of NAD+ levels is also responsible for maintaining axonal stability and integrity. (Babetto et al., Cell Rep., 2010, 3, 1422-1429; Sasaki et al., J. Neurosci ., 2009).

[0087] In a genome-wide RNAi screen in primary mouse neurons, Sterile Alpha and TIRmotif-containing 1 (SARM1) was identified, where knockdown of SARM1 resulted in durable protection of sensory neurons from injury-induced axonal degeneration (Gerdts et al., J. Neurosci, 2013, 33, 13569-13580). SARM1 belongs to the cytoplasmic adaptor protein family but is unique among its members in that it is the most evolutionarily ancient adaptor protein that paradoxically inhibits TLR signaling and has been identified as a major executor of the injury-induced axonal death pathway (O'Neill, LA & Bowie, AG, Nat. Rev. Immunol ., 2007, 7, 353-364; Osterloh, JM et al., Science , 2012, 337, 481-484; Gerdts, J. et al., J. Neurosci . 33, 2013, 13569-13580). Activation of SARM1 via axonal injury or forced dimerization of the SARM1-TIR domain promotes rapid and catastrophic depletion of nicotinamide adenine dinucleotide (NAD+), followed shortly thereafter by axonal degeneration. (Gerdts, J. et al., Science , 2015, 348, 453-457). This injury-induced NAD+ depletion requires SARM1 both in vitro and in vivo, and SARM1 activation triggers axonal degeneration by disrupting local NAD(+) (Gerdts et al., Science, 2015 348, 452-457; Sasaki et al., J. Biol. Chem. 2015, 290, 17228-17238; both are incorporated herein by reference in their entirety).

[0088] It is evident from genetic loss-of-function studies that SARM1 acts as a major executioner of the axonal degeneration pathway following injury. Genetic knockout of SARM1 allows axonal preservation for up to 14 days after nerve transection (Osterloh, JM et al., Science , 2012, 337, 481-484; Gerdts, J. et al. J.Neurosci ., 2013, 33, 13569-13580) and also improves functional outcomes in mice after traumatic brain injury (Henninger, N. et al., Brain 139, 2016, 1094-1105). In addition to the role of SARM1 in direct axonal injury, SARM1 is also required for axonal degeneration observed in chemotherapy-induced peripheral neuropathy. Loss of SARM1 blocks chemotherapy-induced peripheral neuropathy, inhibiting axonal degeneration and increased pain sensitivity produced after chemotherapeutic vincristine treatment (Geisler et al., Brain , 2016,139, 3092-3108).

[0089] SARM1 contains multiple conserved motifs, including the SAM domain, ARM / HEAT motif, and TIR domain ( Figure 1 ), to mediate oligomerization and protein-protein interactions (O'Neill, LA & Bowie, AG, Nat. Rev. Immunol .,2007, 7, 353-364;Tewari, R. et al., Trends Cell Biol ., 2010, 20, 470-481;Qiao,F. & Bowie, JU, Sci. STKE TIR domains are commonly found in signaling proteins that function in innate immune pathways, where they serve as scaffolds for protein complexes (O'Neill, LA & Bowie, AG, Nat. Rev. Immunol ., 2007, 7, 353-364). Interestingly, dimerization of the SARM1-TIR domain is sufficient to induce axonal degeneration and rapidly trigger NAD+ degradation by acting as an NAD+ lyase (Milbrandt et al., WO2018 / 057989; Gerdts, J. et al., Science , 2015, 348, 453-457). Given the central role of SARM1 in axonal degeneration pathways and its putative NADase activity, efforts have been made to identify agents that can modulate SARM1 and may serve as useful therapeutic agents, for example, to prevent neurodegenerative diseases, including peripheral neuropathy, traumatic brain injury, and / or neurodegenerative diseases.

[0090] The present disclosure provides, inter alia, certain compounds and / or compositions that function as SARM1 inhibitors (eg, as SARM1 inhibitors), and technologies related thereto.

[0091] Compound

[0092] In some embodiments, the present disclosure provides compounds of Formula I:

[0093]

[0094] or a pharmaceutically acceptable salt thereof, wherein:

[0095] X is N or CR x ;

[0096] R x is selected from hydrogen, halogen, and optionally substituted C 1-6 aliphatic groups;

[0097] R a Selected from hydrogen, halogen, CN, CF3, C 1-3aliphatic groups, and -C(O)N(R a* )2;

[0098] R a* Selected from hydrogen and C 1-3 aliphatic groups;

[0099] R 1 Selected from hydrogen, halogen, N(R)2, OR, C 1-6 aliphatic groups, 3- to 7-membered monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 7- to 8-membered bridged bicyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Each of the aliphatic group, the monocyclic heterocycle or the bridged bicyclic heterocycle, and the heteroaryl ring is optionally substituted by 1-3 R 1* group substituted;

[0100] R 1* is selected from oxo, halogen, N(R)2, OR, C(O)R, S(O)2R, C(O)OR, C(O)N(R)2, optionally substituted C 1-6 aliphatic, and an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0101] R is selected from hydrogen, optionally substituted C 1-6 an aliphatic group, and an optionally substituted 3 to 7 membered saturated monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0102] Two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 3- to 6-membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;

[0103] R 2 is selected from hydrogen, halogen, S(O)2R, C(O)OR, C(O)N(R)2, and an optionally substituted group selected from C 1-6 aliphatic groups, 3- to 7-membered heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

[0104] R 3 Selected from hydrogen, halogen, CN, CF3, C 1-3 aliphatic groups, and -C(O)N(R a* )2.

[0105] As defined generally above, R aSelected from hydrogen, halogen, -CN, -CF3, C 1-3 aliphatic groups, and -C(O)N(R a* )2. In some embodiments, R a is hydrogen. In some embodiments, R a Selected from halogen, -CN, -CF3, C 1-3 aliphatic groups, and -C(O)N(R a* )2. In some embodiments, R a is halogen. In some such embodiments, R a It is chlorine or fluorine.

[0106] In some embodiments, R a It is -CF3.

[0107] In some embodiments, R a Yes-CN.

[0108] In some embodiments, R a It is C 1-3 In some such embodiments, R a It is -CH3, -CH2CH3, -CH(CH3)2, or cyclopropyl.

[0109] In some embodiments, R a Yes-C(O)N(R a* )2.

[0110] As defined generally above, R a* Selected from hydrogen and C 1-3 In some embodiments, R a* is hydrogen. In some embodiments, R a* It is C 1-3 In some such embodiments, R a* It is -CH3, -CH2CH3, -CH(CH3)2, or cyclopropyl.

[0111] In some embodiments, R a is -C(O)NH2. In some embodiments, R a is -C(O)NHCH3. In some embodiments, R a It is -C(O)N(CH3)2.

[0112] As generally defined above, X is N or CR x In some embodiments, X is N. In some embodiments, X is CR x In some embodiments, X is N. In some embodiments, X is CR xThus, in some embodiments, the present disclosure provides compounds of Formula Ia or Ib:

[0113]

[0114] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R x Each of is as defined above and as described below in the classes and subclasses herein.

[0115] As defined generally above, R x is selected from hydrogen, halogen, and optionally substituted C 1-6 In some embodiments, R x is hydrogen. In some embodiments, R x is selected from halogen and optionally substituted C 1-6 In some embodiments, R x is halogen. In some such embodiments, R x is fluorine, chlorine, or bromine.

[0116] In some embodiments, the present disclosure provides compounds of Formula Ic:

[0117]

[0118] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R 3 Each of is as defined above and as described below in the classes and subclasses herein.

[0119] As defined generally above, R 1 Selected from hydrogen, halogen, N(R)2, OR, C 1-6 aliphatic groups, 3- to 7-membered monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 7- to 8-membered bridged bicyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Each of the aliphatic group, the monocyclic heterocycle or the bridged bicyclic heterocycle, and the heteroaryl ring is optionally substituted by 1-3 R 1* In some embodiments, R 1 is hydrogen. In some embodiments, R 1 It is halogen, N(R)2, OR, C 1-6aliphatic groups, 3- to 7-membered monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 7- to 8-membered bridged bicyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Each of the aliphatic group, the monocyclic heterocycle or the bridged bicyclic heterocycle, and the heteroaryl ring is optionally substituted by 1-3 R 1* Group substituted.

[0120] In some embodiments, R 1 is halogen. In some such embodiments, R 1 It's chlorine.

[0121] In some embodiments, R 1 is N(R)2. In some embodiments, R 1 is N(R)2, wherein R is selected from hydrogen and optionally substituted C 1-6 In some embodiments, R 1 is NH2. In some embodiments, R 1 is N(CH3)2. In some such embodiments, R 1 is NHR, wherein R is optionally substituted C 1-6 Aliphatic group.

[0122] In some such embodiments, R 1 Selected from:

[0123]

[0124] In some embodiments, R 1 is N(R)2, wherein R is selected from hydrogen and an optionally substituted 3 to 7 membered saturated monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is NHR, wherein R is an optionally substituted 3 to 7 membered saturated monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is NHR, wherein R is an optionally substituted 5- to 6-membered saturated monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is NHR, wherein R is an optionally substituted 5- to 6-membered saturated monocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur.

[0125] In some embodiments, R 1 Selected from:

[0126]

[0127] In some embodiments, R 1 is OR. In some embodiments, R 1 is OR, wherein R is optionally substituted C 1-6 In some such embodiments, R 1 It is OCH3.

[0128] In some embodiments, R 1 is optionally replaced by 1-3 R 1* C 1-6 In some such embodiments, R 1 It is cyclopropyl.

[0129] In some embodiments, R 1 is a 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic ring is optionally replaced by 1-3 R 1* In some embodiments, R 1 is a 4-membered monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic ring is optionally replaced by 1 R 1* In some embodiments, R 1 yes or .

[0130] In some embodiments, R 1 is a 5-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic ring is optionally replaced by 1-3 R 1* In some embodiments, R 1 is a 5-membered monocyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic ring is optionally replaced by 1-2 R 1* In some embodiments, R 1 is a 5-membered monocyclic heterocyclic ring having 1 nitrogen atom, wherein the heterocyclic ring is optionally replaced by 1 R 1* In some embodiments, R 1 Selected from:

[0131]

[0132] In some embodiments, R 1 is a 6-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic ring is optionally replaced by 1-3 R 1* In some embodiments, R 1is a 6-membered monocyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic ring is optionally replaced by 1-2 R 1* In some embodiments, R 1 is a 6-membered monocyclic heterocyclic ring having 2 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic ring is optionally replaced by 1-2 R 1* Group substituted.

[0133] In some embodiments, R 1 Selected from:

[0134]

[0135] In some embodiments, R 1 is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl ring is optionally replaced by 1-3 R 1* In some embodiments, R 1 is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl ring is optionally substituted by 1-3 R 1* In some embodiments, R 1 is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl ring is optionally replaced by 1-2 R 1* In some embodiments, R 1 Selected from

[0136] .

[0137] In some embodiments, R 1 is a 6-membered heteroaryl ring having 1-2 nitrogen atoms, wherein the heteroaryl ring is optionally substituted by 1-3 R 1* In some embodiments, R 1 yes .

[0138] In some embodiments, R 1 is a 7- to 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the bridged bicyclic heterocyclic ring is optionally replaced by 1-3 R 1* In some embodiments, R 1 is a 7- to 8-membered bridged bicyclic heterocycle having 1-2 nitrogen atoms, wherein the bridged bicyclic heterocycle is optionally substituted by 1-2 R 1* Group substituted.

[0139] In some embodiments, R 1 Selected from:

[0140] .

[0141] As defined generally above, R 1* is selected from oxo, halogen, N(R)2, OR, C(O)R, S(O)2R, C(O)OR, C(O)N(R)2, optionally substituted C 1-6 aliphatic, and optionally substituted 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1* In some embodiments, R 1* is optionally substituted C 1-6 In some such embodiments, R 1* is -CH3 or -CH2CH3. In some embodiments, R 1* is optionally replaced by -(CH2) 0-4 OR° substituted C 1-6 In some such embodiments, R° is hydrogen. Thus, in some such embodiments, R 1* is optionally replaced by -(CH2) 0-4 OH-substituted C 1-6 In some embodiments, R 1* It is -CH2OH.

[0142] In some embodiments, R 1* is optionally replaced by -(CH2) 0-4 C(O)N(R°)2 substituted C 1-6 In some such embodiments, R° is hydrogen. Thus, in some such embodiments, R 1* is optionally replaced by -(CH2) 0-4 C(O)NH2 substituted C 1-6 In some embodiments, R 1* It is -CH2CH2C(O)NH2.

[0143] In some embodiments, R 1* is N(R)2. In some such embodiments, R is selected from hydrogen and optionally substituted C 1-6 In some embodiments, R 1* is NH2. In some embodiments, R 1* is NHR, wherein R is optionally substituted C 1-6 In some embodiments, R 1* is NHR, wherein R is optionally substituted with -(CH2) 0-4 OR° substituted C1-6 In some such embodiments, R° is hydrogen. Thus, in some such embodiments, R 1* is NHR, wherein R is optionally substituted with -(CH2) 0-4 OH-substituted C 1-6 In some embodiments, R 1* It is -NHCH2CH2OH.

[0144] In some embodiments, R 1* In some such embodiments, R is hydrogen or optionally substituted C 1-6 In some embodiments, R 1* It is -OH or -OCH3.

[0145] In some embodiments, R 1* is C(O)N(R)2. In some such embodiments, each R is selected from hydrogen and optionally substituted C 1-6 In some embodiments, R 1* Selected from -C(O)NH2, -C(O)NHCH3, and C(O)N(CH3)2.

[0146] In some embodiments, R 1* is C(O)R. In some such embodiments, R is optionally substituted C 1-6 In some embodiments, R 1* It is -C(O)CH3.

[0147] In some embodiments, R 1* is S(O)2R. In some such embodiments, R is optionally substituted C 1-6 In some embodiments, R 1* It is -S(O)2CH3.

[0148] In some embodiments, R 1* is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1* is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1* is an optionally substituted 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1* yes .

[0149] In some embodiments, R 1*is selected from the group consisting of oxo, -CH3, -CH2CH3, -CH2OH, -CH2CH2C(O)NH2, -OH, -OCH3, -NH2, -NHCH2CH2OH, -C(O)NH2, -C(O)NHCH3, C(O)N(CH3)2, -C(O)CH3, -S(O)2CH3, and .

[0150] As generally defined above, R is selected from hydrogen, optionally substituted C 1-6 aliphatic groups, and optionally substituted 3 to 7 membered saturated monocyclic rings having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 3 to 6 membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C 1-6 An aliphatic group or an optionally substituted 3 to 7 membered saturated monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Or: two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 3 to 6 membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur.

[0151] In some embodiments, R is hydrogen or C 1-6 In some such embodiments, R is hydrogen or -CH3. In some embodiments, R is hydrogen or optionally substituted C 1-6 Aliphatic group.

[0152] In some embodiments, R is C 1-6 In some embodiments, R is -CH3. In some embodiments, R is cyclopropyl.

[0153] In some embodiments, R is optionally selected from -(CH2) 0-4 R°, -(CH2) 0-4 OR°, -(CH2) 0-4 C(O)N(R°)2, and -(CH2) 0-4 N(R°)C(O)N(R°)2 substituted C 1-6 In some such embodiments, R° is selected from hydrogen, C 1-6 aliphatic groups, 5-6 membered saturated, partially unsaturated, or aromatic rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 membered bicyclic aromatic rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R° is selected from -(CH2) 0-2 R ● , -(CH2)0-2 OH, -(CH2) 0-2 OR ● , and -(CH2) 0-2 C(O)NH2, where R ● It is C 1-4 The aliphatic group is radical substituted.

[0154] In some embodiments, R is optionally replaced by -(CH2) 0-4 R° substituted C 1-6 Aliphatic radicals, wherein R° is C 1-6 an aliphatic group, a 5- to 6-membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0155] In some embodiments, R is optionally replaced by -(CH2) 0-4 R° substituted C 1-6 Aliphatic groups, wherein R ° is a 5- to 6-membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is optionally replaced by -(CH2) 0-4 R° substituted C 1-6 aliphatic groups, wherein R° is a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is optionally substituted with -(CH2) 0-4 R° substituted C 1-6 aliphatic group, wherein R ° is a 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is optionally substituted with -(CH2) 0-4 R° substituted C 1-6 an aliphatic group wherein R° is a 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R° is -(CH2) 0-2 R ● In some embodiments, R is optionally substituted , or Substituted C 1-6 Aliphatic group.

[0156] In some embodiments, R is optionally replaced by -(CH2) 0-4 R° substituted C 1-6 aliphatic group, wherein R ° is a 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R is optionally Substituted C 1-6 Aliphatic group.

[0157] In some embodiments, R is optionally replaced by -(CH2) 0-4 R° substituted C 1-6 aliphatic groups, wherein R° is a 5- to 6-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is optionally substituted with -(CH2) 0-4 R° substituted C 1-6 aliphatic group, wherein R ° is a 6-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is optionally replaced by -(CH2) 0-4 R° substituted C 1-6 an aliphatic group wherein R° is a 6-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R° is -(CH2) 0-2 R ● In some embodiments, R is optionally substituted or Substituted C 1-6 Aliphatic group.

[0158] In some embodiments, R is optionally replaced by -(CH2) 0-4 R° substituted C 1-6 an aliphatic group wherein R° is phenyl. In some such embodiments, R° is -(CH2) 0-2 In some embodiments, R is optionally substituted with Substituted C 1-6 Aliphatic group.

[0159] In some embodiments, R is optionally replaced by -(CH2) 0-4 R° substituted C 1-6 aliphatic groups, wherein R° is an 8- to 10-membered bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is optionally substituted with -(CH2) 0-4 R° substituted C 1-6 aliphatic groups, wherein R° is a 9-membered bicyclic aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some such embodiments, R° is -(CH2) 0-2 R ● In some embodiments, R is optionally substituted Substituted C 1-6 Aliphatic group.

[0160] In some embodiments, R is optionally replaced by -(CH2) 0-4 OR° substituted C 1-6 An aliphatic group in which R° is hydrogen or C1-6 In some embodiments, R is C optionally substituted with -OR°. 1-6 An aliphatic group in which R° is hydrogen or C 1-6 In some embodiments, R is C optionally substituted with -OH. 1-6 Aliphatic group.

[0161] In some embodiments, R is optionally replaced by -(CH2) 0-4 C(O)N(R°)2 substituted C 1-6 In some embodiments, R is optionally replaced by -(CH2) 0-4 C(O)N(R°)2 substituted C 1-6 An aliphatic group in which R° is hydrogen or C 1-6 In some embodiments, R is optionally replaced by -(CH2) 0-4 C(O)N(R°)2 substituted C 1-6 An aliphatic group in which R° is hydrogen or optionally substituted by -(CH2) 0-2 OR ● Substituted C 1-6 In some embodiments, R is C optionally substituted with -C(O)N(R°)2. 1-6 An aliphatic group in which R° is hydrogen or optionally substituted by -(CH2) 0-2 OR ● Substituted C 1-6 In some embodiments, R is C optionally substituted with -C(O)NHCH2CH2OCH3. 1-6 In some embodiments, R is C optionally substituted with -C(O)NHCH3. 1-6 Aliphatic group.

[0162] In some embodiments, R is optionally replaced by -(CH2) 0-4 N(R°)C(O)N(R°)2 substituted C 1-6 In some embodiments, R is optionally replaced by -(CH2) 0-4 N(R°)C(O)N(R°)2 substituted C 1-6 An aliphatic group in which R° is hydrogen or C 1-6 In some embodiments, R is C optionally substituted with -NHC(O)N(CH3)2. 1-6 Aliphatic group.

[0163] In some embodiments, R is C optionally substituted with -OH and a 5- to 6-membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.1-6 In some embodiments, R is optionally substituted with -OH and -(CH2) 0-4 C(O)N(R°)2 substituted C 1-6 Aliphatic group.

[0164] In some embodiments, R is an optionally substituted 3 to 7 membered saturated monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 7 membered saturated monocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some such embodiments, R is substituted on a carbon atom having =0. In some embodiments, R is .

[0165] In some embodiments, R is an optionally substituted 3 to 7 membered saturated monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 6 membered saturated monocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some such embodiments, R is -(CH2) 0-4 In some embodiments, R is a 6-membered saturated monocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur, which is substituted with -C(O)NH2. In some embodiments, R is .

[0166] In some embodiments, R is a 6-membered saturated monocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur, wherein R is -(CH2) 0-4 In some such embodiments, R° is substituted with -(CH2) 0-2 R ● Substituted C 1-6 An aliphatic group, wherein R ● is a 3- to 6-membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is .

[0167] In some embodiments, R is a 5-membered saturated monocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some such embodiments, R is ═O and —(CH 2 ) 0-4 In some embodiments, R is .

[0168] In some embodiments, R is selected from hydrogen, C optionally substituted with one or more groups selected from 1-6 Aliphatic groups: -OH, -NHC(O)N(CH3)2, -C(O)NHCH3, -C(O)NHCH2CH2OCH3, , , , , , , ,and , or R is , , ,or .

[0169] In some embodiments, R 1 Selected from hydrogen, halogen, -NH2, -OCH3,

[0170]

[0171]

[0172] .

[0173] As defined generally above, R 2 is selected from hydrogen, halogen, S(O)2R, C(O)OR, C(O)N(R)2, and optionally substituted selected from C 1-6 aliphatic groups, 3 to 7 membered heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5 to 6 membered heteroaryl rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is hydrogen. In some embodiments, R 2 is selected from halogen, S(O)2R, C(O)OR, C(O)N(R)2, and optionally substituted selected from C 1-6 Aliphatic groups, 3 to 7 membered heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5 to 6 membered heteroaryl rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0174] In some embodiments, R 2 is halogen. In some such embodiments, R 2 is fluorine, chlorine or bromine.

[0175] In some embodiments, R 2 is optionally substituted C 1-6 In some such embodiments, R 2 is -CH3 or -CH2CH3. In some embodiments, R 2 In some embodiments, R 2 is optionally replaced by -(CH2) 0-4 OR° substituted C 1-6In some such embodiments, R° is hydrogen. Thus, in some embodiments, R 2 is optionally replaced by -(CH2) 0-4 OH-substituted C 1-6 In some embodiments, R 2 It is -C(OH)(CH3)2.

[0176] In some embodiments, R 2 is C(O)OR. In some such embodiments, R is hydrogen. Thus, in some embodiments, R 2 It is C(O)OH.

[0177] In some embodiments, R 2 is S(O)2R. In some such embodiments, R is optionally substituted C 1-6 In some embodiments, R 2 It is -S(O)2CH3.

[0178] In some embodiments, R 2 is C(O)N(R)2. In some such embodiments, each R is selected from hydrogen and optionally substituted C 1-6 In some embodiments, R 2 is C(O)NH2. 2 is C(O)NHR, wherein R is optionally substituted C 1-6 In some embodiments, R 2 is C(O)NHR, wherein R is optionally substituted with -(CH2) 0-4 OR° substituted C 1-6 In some embodiments, R 2 is C(O)NHR, wherein R is optionally substituted with -(CH2) 0-4 OR° substituted C 1-6 aliphatic group and R° is hydrogen. 2 is C(O)NHR, wherein R is optionally substituted with -(CH2) 0-4 OH-substituted C 1-6 In some embodiments, R 2 It is -C(O)NHCH2CH2OH.

[0179] In some embodiments, R 2 is C(O)N(R)2, wherein the two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 3- to 6-membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur.2 is C(O)N(R)2, wherein the two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 6-membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur. 2 yes .

[0180] In some embodiments, R 2 is an optionally substituted 3 to 7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 4- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 4-membered heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 2 In some embodiments, R 2 is a 5-membered heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 2 In some embodiments, R 2 is a 6-membered heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 2 It is a morpholinyl group.

[0181] In some embodiments, R 2 is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is pyrazolyl. In some such embodiments, R 2 is 3-methyl-1H-pyrazol-4-yl. In some embodiments, R 2 is 1-methyl-1H-pyrazol-4-yl. In some embodiments, R 2 It is 1H-pyrazol-4-yl.

[0182] In some embodiments, R 2 is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogen atoms. 2 In some embodiments, R 2 It is 2-methyl-pyridin-3-yl.

[0183] In some embodiments, R 2is selected from hydrogen, halogen, -CH3, CH2CH3, cyclopropyl, -C(OH)(CH3)2, -C(O)OH, -S(O)2CH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)NHCH2CH2OH, or a group selected from the following:

[0184] .

[0185] As defined generally above, R 3 Selected from hydrogen, halogen, CN, CF3, C 1-3 aliphatic groups, and -C(O)N(R a* )2. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 It is halogen, CN, CF3, C 1-3 aliphatic groups, and -C(O)N(R a* )2. In some embodiments, R 3 is halogen. In some such embodiments, R 3 It is fluorine or chlorine.

[0186] In some embodiments, R 3 is CN. In some embodiments, R 3 is CF3. In some embodiments, R 3 It is C 1-3 In some such embodiments, R 3 is -CH3, -CH2CH3, -CH(CH3)2, or cyclopropyl. 3 Yes-C(O)N(R a* )2. In some embodiments, R 3 is -C(O)NH2. In some embodiments, R 3 is -C(O)NHCH3. In some embodiments, R 3 It is -C(O)N(CH3)2.

[0187] In some embodiments of Formulas Ia, Ib, and Ic, R 3 is hydrogen. Thus, in some embodiments, the present disclosure provides Formula Ia- i , Ib- i , and Ic- i Compounds:

[0188]

[0189] or a pharmaceutically acceptable salt thereof, wherein R 1 , R2 , and R x Each of which is as defined above and as described in the classes and subclasses herein.

[0190] In some embodiments of Formulas Iai, Ibi, and Ici, R 2 is chlorine. Thus, in some embodiments, the present disclosure provides compounds of Formulas Ia-ii, Ib-ii, and Ic-ii:

[0191]

[0192] or a pharmaceutically acceptable salt thereof, wherein R 1 and R x Each of which is as defined above and as described in the classes and subclasses herein.

[0193] In some embodiments, the compound of Formula I is selected from:

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211] In some embodiments, the present disclosure provides compounds having a structure as described in Formula II:

[0212]

[0213] or a pharmaceutically acceptable salt thereof, wherein:

[0214] X is N or CR x ;

[0215] R x is selected from hydrogen, halogen, and optionally substituted C 1-6 aliphatic groups;

[0216] R 1 is selected from 3 to 7 membered monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 to 6 membered heteroaryl rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 7 to 8 membered bridged bicyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Each of the aliphatic group, the monocyclic heterocycle or the bridged bicyclic heterocycle, and the heteroaryl ring is optionally substituted by 1-3 R 1* group substituted;

[0217] R 1* is selected from oxo, halogen, N(R)2, OR, C(O)R, S(O)2R, C(O)OR, C(O)N(R)2, and C 1-6 aliphatic groups;

[0218] R is selected from hydrogen and optionally substituted C 1-6 An aliphatic group, or:

[0219] Two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 3- to 6-membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;

[0220] R 2 is selected from hydrogen, halogen, S(O)2R, C(O)OR, C(O)N(R)2, and an optionally substituted group selected from C 1-6 aliphatic groups, 3- to 7-membered heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

[0221] R 3 Selected from hydrogen, halogen, CN, CF3, C 1-3 aliphatic groups, and -C(O)N(R a* )2.

[0222] In some embodiments, the present disclosure provides compounds having structures as described in Formula II-a, II-b, and II-c:

[0223]

[0224] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R x Each of is as defined above for Formula II and as described above in classes herein.

[0225] List of implementation plans.

[0226] Embodiment 1. Compound of formula I:

[0227]

[0228] or a pharmaceutically acceptable salt thereof, wherein:

[0229] X is N or CR x ;

[0230] R x is selected from hydrogen, halogen, and optionally substituted C 1-6 aliphatic groups;

[0231] R a Selected from hydrogen, halogen, CN, CF3, C 1-3 aliphatic groups, and -C(O)N(R a* )2;

[0232] R a* Selected from hydrogen and C 1-3 aliphatic groups;

[0233] R 1 Selected from hydrogen, halogen, N(R)2, OR, C 1-6 aliphatic groups, 3- to 7-membered monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 7- to 8-membered bridged bicyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Each of the aliphatic group, the monocyclic heterocycle or the bridged bicyclic heterocycle, and the heteroaryl ring is optionally substituted by 1-3 R 1* group substituted;

[0234] R 1*is selected from oxo, halogen, N(R)2, OR, C(O)R, S(O)2R, C(O)OR, C(O)N(R)2, optionally substituted C 1-6 aliphatic, and an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0235] R is selected from hydrogen, optionally substituted C 1-6 an aliphatic group, and an optionally substituted 3 to 7 membered saturated monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0236] Two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 3- to 6-membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;

[0237] R 2 is selected from hydrogen, halogen, S(O)2R, C(O)OR, C(O)N(R)2, and an optionally substituted group selected from C 1-6 aliphatic groups, 3- to 7-membered heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

[0238] R 3 Selected from hydrogen, halogen, CN, CF3, C 1-3 aliphatic groups, and -C(O)N(R a* )2.

[0239] Embodiment 2. The compound according to embodiment 1, wherein R a It is CN.

[0240] Embodiment 3. The compound according to embodiment 2, wherein the compound is a compound of formula Ia or Ib:

[0241]

[0242] or a pharmaceutically acceptable salt thereof.

[0243] Embodiment 4. The compound according to embodiment 3, wherein R x It's a halogen.

[0244] Embodiment 5. The compound according to embodiment 3, wherein R x It's hydrogen.

[0245] Embodiment 6. The compound according to embodiment 5, wherein the compound is a compound of formula Ic:

[0246]

[0247] or a pharmaceutically acceptable salt thereof.

[0248] Embodiment 7. A compound according to any one of embodiments 1-6, wherein R 1 is a 3- to 7-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic ring is optionally replaced by 1-3 R 1* Group substituted.

[0249] Embodiment 8. The compound according to embodiment 7, wherein R 1 is a 5-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic ring is optionally replaced by 1-3 R 1* Group substituted.

[0250] Embodiment 9. The compound according to embodiment 8, wherein R 1 is a 5-membered monocyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic ring is optionally replaced by 1-2 R 1* Group substituted.

[0251] Embodiment 10. The compound according to embodiment 9, wherein R 1 is a 5-membered monocyclic heterocyclic ring having 1 nitrogen atom, wherein the heterocyclic ring is optionally replaced by 1 R 1* Group substituted.

[0252] Embodiment 11. The compound according to embodiment 10, wherein R 1 Selected from

[0253] .

[0254] Embodiment 12. The compound according to Embodiment 7, wherein R 1 is a 6-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic ring is optionally replaced by 1-3 R 1* Group substituted.

[0255] Embodiment 13. The compound according to embodiment 12, wherein R 1 is a 6-membered monocyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic ring is optionally replaced by 1-2 R 1* Group substituted.

[0256] Embodiment 14. The compound according to embodiment 13, wherein R 1 is a 6-membered monocyclic heterocyclic ring having 2 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic ring is optionally replaced by 1-2 R 1* Group substituted.

[0257] Embodiment 15. The compound according to embodiment 14, wherein R 1 Selected from

[0258] .

[0259] Embodiment 16. A compound according to any one of embodiments 1-6, wherein R 1 is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl ring is optionally replaced by 1-3 R 1* Group substituted.

[0260] Embodiment 17. The compound according to embodiment 16, wherein R 1 is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl ring is optionally substituted by 1-3 R 1* Group substituted.

[0261] Embodiment 18. The compound according to embodiment 17, wherein R 1 is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl ring is optionally replaced by 1-2 R 1* Group substituted.

[0262] Embodiment 19. The compound according to embodiment 18, wherein R 1 Selected from

[0263] .

[0264] Embodiment 20. The compound according to embodiment 16, wherein R 1 is a 6-membered heteroaryl ring having 1-2 nitrogen atoms, wherein the heteroaryl ring is optionally substituted by 1-3 R 1* Group substituted.

[0265] Embodiment 21. The compound according to embodiment 20, wherein R 1 yes .

[0266] Embodiment 22. A compound according to any one of embodiments 1-6, wherein R 1 is a 7- to 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the bridged bicyclic heterocyclic ring is optionally replaced by 1-3 R 1* Group substituted.

[0267] Embodiment 23. The compound according to embodiment 22, wherein R 1is a 7- to 8-membered bridged bicyclic heterocycle having 1-2 nitrogen atoms, wherein the bridged bicyclic heterocycle is optionally substituted by 1-2 R 1* Group substituted.

[0268] Embodiment 24. The compound according to embodiment 23, wherein R 1 Selected from

[0269] .

[0270] Embodiment 25. A compound according to any one of Embodiments 7-24, wherein R 1* It is N(R)2.

[0271] Embodiment 26. A compound according to any one of embodiments 7-24, wherein R 1* It is C(O)N(R)2.

[0272] Embodiment 27. A compound according to any one of Embodiments 7-24, wherein R 1* It is OR.

[0273] Embodiment 28. A compound according to any one of embodiments 7-24, wherein R 1* It is C(O)R.

[0274] Embodiment 29. A compound according to any one of Embodiments 7-24, wherein R 1* It is S(O)2R.

[0275] Embodiment 30. A compound according to embodiment 25 or 26, wherein R is selected from hydrogen and optionally substituted C 1-6 Aliphatic group.

[0276] Embodiment 31. A compound according to embodiment 30, wherein each R is hydrogen.

[0277] Embodiment 32. A compound according to Embodiment 30, wherein each R is -CH3.

[0278] Embodiment 33. A compound according to embodiment 30, wherein one R is hydrogen and one R is optionally substituted C 1-6 Aliphatic group.

[0279] Embodiment 34. Compounds according to embodiment 27, wherein R is hydrogen.

[0280] Embodiment 35. A compound according to any one of embodiments 27-29, wherein R is -CH3.

[0281] Embodiment 36. A compound according to any one of embodiments 7-24, wherein R 1* It is C 1-6 Aliphatic group.

[0282] Embodiment 37. The compound according to embodiment 36, wherein R 1* It is -CH3.

[0283] Embodiment 38. A compound according to any one of embodiments 7-24, wherein R 1 Selected from

[0284]

[0285] .

[0286] Embodiment 39. A compound according to any one of embodiments 1-6, wherein R 1 It is N(R)2.

[0287] Embodiment 40. A compound according to Embodiment 39, wherein each R is hydrogen.

[0288] Embodiment 41. A compound according to Embodiment 39, wherein each R is -CH3.

[0289] Embodiment 42. The compound according to embodiment 39, wherein R 1 It is -NHCH3.

[0290] Embodiment 43. The compound according to embodiment 39, wherein R 1 yes .

[0291] Embodiment 44. The compound according to embodiment 39, wherein R 1 yes .

[0292] Embodiment 45. A compound according to any one of embodiments 1-6, wherein R 1 Yes-OR.

[0293] Embodiment 46. A compound according to embodiment 45, wherein R is hydrogen.

[0294] Embodiment 47. A compound according to embodiment 45, wherein R is -CH3.

[0295] Embodiment 48. A compound according to any one of embodiments 1-47, wherein R 2 It's a halogen.

[0296] Embodiment 49. The compound according to embodiment 48, wherein R 2 It's chlorine.

[0297] Embodiment 50. The compound according to embodiment 48, wherein R 2 It's bromine.

[0298] Embodiment 51. The compound according to embodiment 48, wherein R 2 It's fluorine.

[0299] Embodiment 52. A compound according to any one of embodiments 1-47, wherein R 2 It is -CH3.

[0300] Embodiment 53. A compound according to any one of embodiments 1-47, wherein R 2 It's hydrogen.

[0301] Embodiment 54. A compound according to any one of embodiments 1-53, wherein R 3 It's hydrogen.

[0302] Embodiment 54. A compound according to any one of embodiments 1-53, wherein R 3 It's a halogen.

[0303] Embodiment 55. The compound according to embodiment 54, wherein R 3 It's chlorine.

[0304] Embodiment 56. The compound according to embodiment 55, wherein the compound is of formula Ia- ii , Ib- ii , or Ic- ii Compounds:

[0305]

[0306] or a pharmaceutically acceptable salt thereof.

[0307] Embodiment 57. The compound according to embodiment 1, wherein the compound is a compound of formula II:

[0308]

[0309] or a pharmaceutically acceptable salt thereof, wherein:

[0310] X is N or CR x ;

[0311] R x is selected from hydrogen, halogen, and optionally substituted C 1-6 aliphatic groups;

[0312] R1 is selected from 3 to 7 membered monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 to 6 membered heteroaryl rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 7 to 8 membered bridged bicyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Each of the aliphatic group, the monocyclic heterocycle or the bridged bicyclic heterocycle, and the heteroaryl ring is optionally substituted by 1-3 R 1* group substituted;

[0313] R 1* is selected from oxo, halogen, N(R)2, OR, C(O)R, S(O)2R, C(O)OR, C(O)N(R)2, and C 1-6 aliphatic groups;

[0314] R is selected from hydrogen and optionally substituted C 1-6 An aliphatic group, or:

[0315] Two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 3- to 6-membered heterocyclic ring containing 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;

[0316] R 2 is selected from hydrogen, halogen, S(O)2R, C(O)OR, C(O)N(R)2, and an optionally substituted group selected from C 1-6 aliphatic groups, 3- to 7-membered heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

[0317] R 3 Selected from hydrogen, halogen, CN, CF3, C 1-3 aliphatic groups, and -C(O)N(R a* )2.

[0318] Embodiment 58. The compound according to embodiment 57, wherein the compound is a compound of formula II-a, II-b, or II-c:

[0319]

[0320] or a pharmaceutically acceptable salt thereof.

[0321] Composition

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

[0323] In some embodiments, the disclosure provides compositions comprising and / or delivering a compound of Formula I or a compound of Formula II, or an active metabolite thereof, for example, when contacted with or otherwise administered to a system or environment, for example, the system or environment may include SARM1 NADase activity; in some embodiments, such compositions are administered to a system or environment to achieve inhibition of SARM1 activity as described herein.

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

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

[0326] The present disclosure particularly provides a composition comprising a compound of formula I or a compound of formula II or a pharmaceutically acceptable salt or derivative thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in the composition provided is such that it effectively and measurably inhibits axonal degeneration in a biological sample or patient. In certain embodiments, the compound or composition provided is formulated to be administered to a patient in need of such a composition. The compound and composition can be administered using any amount and any route of administration that effectively treats or alleviates the severity of any disease or disorder described herein according to the methods disclosed herein. For ease of administration and dosage uniformity, the compound provided is preferably formulated in a unit dosage form. The expression "unit dosage form" used herein refers to a physically discrete unit of a medicament suitable for a patient to be treated. However, it is to be understood that the total daily dosage of the compound and composition provided will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dosage level for any particular patient or organism will vary from subject to subject, depending on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound being used; the specific composition being used and its route of administration; the species, age, weight, sex, and dietary status of the patient; the general condition of the subject; the time of administration; the rate of excretion of the specific compound being used; the duration of treatment; drugs used in combination or concomitantly with the specific compound being used, etc.

[0327] The provided compositions can be administered orally, parenterally, by inhalation or nasal spray, topically (e.g., by powders, ointments, or drops), rectally, buccally, intravaginally, intraperitoneally, intracisternal, or by implanted reservoirs, depending on the severity of the condition being treated. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. In certain embodiments, provided compounds are administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg of subject body weight per day, once or more per day, to obtain the desired therapeutic effect.

[0328] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarterial, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. The sterile injectable form of the composition provided can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents, for example as solutions in 1,3-butanediol. Available acceptable vehicles and solvents include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspension media.

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

[0330] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

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

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

[0333] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite, and / or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.The active compounds can also be in micro-encapsulated form with one or more excipients as noted above.

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

[0335] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and flavor enhancers.

[0336] Alternatively, the pharmaceutically acceptable compositions described herein can be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the disclosed compounds with suitable non-irritating excipients or carriers that are solid at room temperature but liquid at body (e.g., rectal or vaginal) temperature and thus melt in the rectal or vaginal cavity to release the active compound. Such materials include cocoa butter, suppository waxes (e.g., beeswax), and polyethylene glycols.

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

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

[0339] For topical administration, the pharmaceutically acceptable compositions provided may be formulated in suitable ointments containing active components suspended or dissolved in one or more carriers. Carriers for topical administration of the disclosed compounds include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated in suitable lotions or creams containing active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

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

[0341] The pharmaceutically acceptable compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters for improving bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

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

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

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

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

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

[0347] In some embodiments, a plurality of related compounds or compositions may be analyzed in a particular assay and / or compared to the same reference. In some embodiments, such a plurality of compounds or compositions may be or include a group of compounds or compositions that are considered a "library" because multiple members share one or more characteristics (e.g., structural elements, source identity, synthetic similarity, etc.).

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

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

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

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

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

[0353] SARM1 activity assay

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

[0355] In some embodiments, a method for identifying a SARM1 inhibitor is provided, comprising: a) providing a mixture comprising i) full-length SARM1, ii) NAD+, and iii) a candidate inhibitor, wherein the full-length SARM1 is constitutively active; b) incubating the mixture; c) quantifying NAD+ and ADPR (or cADPR) in the mixture after the incubation; d) determining the molar ratio of NAD+:ADPR (or cADPR); and e) if the molar ratio is greater than a control mixture without the candidate inhibitor, identifying the candidate inhibitor compound as an inhibitor.

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

[0357] SARM1 binding assay

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

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

[0360] Purification of SARM1-TIR domain

[0361] In some embodiments, the SARM1-TIR domain can be engineered with various proteins or epitopes, tags useful, for example, in purification. In some embodiments, the disclosure also provides NRK1-HEK293T cell lines comprising HEK293T cells transformed with nicotinamide riboside kinase 1 (NRK1). In some embodiments, HEK293T cells are transformed or transfected with DNA sequences encoding nicotinamide riboside kinase 1 (NRK1). In some embodiments, the DNA encoding NRK1 can be genomic DNA or cDNA. In some embodiments, HEK293T cells are stably or transiently transfected with DNA encoding NRK1 from a source outside the host cell. In some embodiments, HEK293T cells are stably or transiently transfected with DNA encoding NRK1 so that the cell expresses NRK1 at an elevated level compared to a control cell. In some embodiments, the DNA encoding NRK1 is under the control of one or more exogenous regulatory DNA sequences such as a promoter, an enhancer, or a combination thereof. In some embodiments, the combination of the DNA sequence encoding NRK1 and the regulatory sequence is a non-naturally occurring combination. In some embodiments, the DNA encoding NRK1 (genomic DNA or cDNA) comprises an expression vector, such as an FCIV expression vector. In some embodiments, the DNA encoding NRK1 is derived from genomic DNA or cDNA from a vertebrate or invertebrate species, such as, but not limited to, humans, mice, zebrafish, or fruit flies. In some configurations, the NRK1 DNA is human NRK1 DNA.

[0362] Applications and uses

[0363] The present disclosure provides various uses and applications of the compounds and / or compositions as described herein, for example, according to their activities and / or characteristics as described herein. In some embodiments, such uses may include therapeutic and / or diagnostic uses. Alternatively, in some embodiments, such uses may include research, production and / or other technical uses.

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

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

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

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

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

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

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

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

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

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

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

[0375] Diseases, disorders and conditions

[0376] In some embodiments, the compounds and / or compositions described herein may be administered to a subject suffering from one or more diseases, disorders, or conditions.

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

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

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

[0380] In some embodiments, the condition is a chronic condition affecting the central nervous system, such as Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, or Huntington's disease, Alzheimer's disease.

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

[0382] In some embodiments, the condition is a chronic condition affecting the peripheral nervous system, such as diabetic neuropathy, HIV neuropathy, Charcot-Marie-Tooth disease, or amyotrophic lateral sclerosis.

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

[0384] In some embodiments, the condition is a chronic condition affecting the optic nerve, such as Leber's congenital amaurosis, Leber's hereditary optic neuropathy, primary open-angle glaucoma, and autosomal dominant optic atrophy.

[0385] In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat one or more neurodegenerative diseases, disorders or conditions, selected from neuropathy or axonopathy. In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat neuropathy or axonopathy associated with axonal degeneration. In some embodiments, the neuropathy associated with axonal degeneration is hereditary or congenital neuropathy or axonopathy. In some embodiments, the neuropathy associated with axonal degeneration originates from de novo mutations or somatic mutations. In some embodiments, the neuropathy associated with axonal degeneration is selected from the list contained herein. In some embodiments, neuropathy or axonopathy is associated with axonal degeneration, including but not limited to Parkinson's disease, non-Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating disease, ischemia or stroke, chemical injury, thermal injury and AIDS.

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

[0387] In some embodiments, the neurodegenerative or nervous system disease or disorder is associated with axonal degeneration, axonal injury, axonopathy, demyelinating disease, central pontine myelinolysis, a neurological injury disease or disorder, a metabolic disease, mitochondrial disease, metabolic axonal degeneration, axonal injury from a leukoencephalopathy or a leukodystrophy. In some embodiments, the neurodegenerative or neurological disease or disorder is selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelin breakdown, osmotic hyponatremia, anoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Pelizaeus-Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher disease, Hurler syndrome, traumatic brain injury, post-radiation injury, neurologic complications of chemotherapy (chemotherapy-induced neuropathy; CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 12deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, glaucoma, Leber's hereditary optic atrophy (neuropathy), Leber's congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis encephalitis, viral encephalitis in children, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supranuclear palsy (PSP), Friedrich's ataxia, hereditary ataxias, noise-induced hearing loss, congenital hearing loss, dementia with Lewy bodies, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, severe acute motor axonal neuropathy (AMAN), Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, spinocerebellar ataxia, preeclampsia, hereditary spastic paraplegia, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, and nonalcoholic steatohepatitis (NASH).

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

[0389] In some embodiments, the present disclosure provides methods of treating a neurodegenerative or nervous system disease or disorder associated with axonal degeneration, axonal injury, axonopathy, demyelinating disease, central pontine myelinolysis, a neurological injury disease or disorder, a metabolic disease, mitochondrial disease, metabolic axonal degeneration, axonal injury from leukoencephalopathy or leukodystrophy.

[0390] In some embodiments, neuropathy and axonopathy include any disease or condition involving neurons and / or supporting cells, such as glial cells, muscle cells or fibroblasts, particularly those diseases or conditions involving axonal injury. Axonal injury can be caused by traumatic injury or by non-mechanical injury due to disease, condition or exposure to toxic molecules or drugs. The result of such damage can be the degeneration or dysfunction of axons and the loss of functional neuronal activity. Producing such axonal injury or the disease and condition associated with such axonal injury belong to a large number of neurological diseases and conditions. Such neuropathy can include peripheral neuropathy, central neuropathy and combinations thereof. In addition, peripheral neuropathy performance can be produced by diseases initially focused on the central nervous system, and central nervous system performance can be produced by substantially peripheral or systemic diseases.

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

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

[0393] In some embodiments, the neuropathy includes optic neuropathy, such as glaucoma; retinal ganglion degeneration, such as those associated with retinitis pigmentosa and outer retinal neuropathy; optic neuritis and / or degeneration, including those associated with multiple sclerosis; traumatic injury to the optic nerve, which may include, for example, injury during tumor resection; hereditary optic neuropathy, such as Kjer's disease and Leber's hereditary optic neuropathy; ischemic optic neuropathy, such as those secondary to giant cell arteritis; metabolic optic neuropathy, such as neurodegenerative diseases, including the previously mentioned Leber's neuropathy, nutritional deficiencies, such as vitamin B12 or folic acid deficiency, and toxicity, such as due to ethambutol or cyanide; neuropathy caused by adverse drug reactions and neuropathy caused by vitamin deficiency. Ischemic optic neuropathy also includes non-arteritic anterior ischemic optic neuropathy.

[0394] In some embodiments, neurodegenerative diseases associated with neuropathy or axonopathy in the central nervous system include various diseases. Such diseases include diseases involving progressive dementia, such as Alzheimer's disease, senile dementia, Pick's disease and Huntington's disease; central nervous system diseases that affect muscle function, such as Parkinson's disease, motor neuron disease and progressive ataxia, such as amyotrophic lateral sclerosis; demyelinating diseases, such as multiple sclerosis; viral encephalitis, such as those caused by enterovirus, arbovirus and herpes simplex virus; and prion disease. Mechanical damage, such as glaucoma or trauma to the head and spine can also cause nerve damage and degeneration in the brain and spinal cord. In addition, ischemia and stroke and conditions such as malnutrition and chemical toxicity of chemotherapeutic agents can cause central nervous system neuropathy.

[0395] In some embodiments, the disclosure provides a method for treating a neuropathy or axonopathy associated with axonal degeneration. In some such embodiments, the neuropathy or axonopathy associated with axonal degeneration can be any of many neuropathy or axonopathy, such as hereditary or congenital, or those associated with Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating disease, ischemia or stroke, chemical injury, thermal injury and AIDS. In addition, neurodegenerative diseases not mentioned above and subsets of the diseases mentioned above can also be treated with the methods of the present disclosure. Such a subset of diseases may include Parkinson's disease or non-Parkinson's disease, or Alzheimer's disease.

[0396] Object

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

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

[0399] In some embodiments, the methods provided include administering a compound of Formula I or a compound of Formula II to a patient in need thereof. In some such embodiments, the patient is at risk for developing a condition characterized by axonal degeneration. In some embodiments, the patient has a condition characterized by axonal degeneration. In some embodiments, the patient has been diagnosed with a condition characterized by axonal degeneration.

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

[0401] In some embodiments, the subject is at risk for developing a condition characterized by axonal degeneration. In some embodiments, a subject is identified as being at risk for axonal degeneration, e.g., based on the subject's genotype, diagnosis of a condition associated with axonal degeneration, and / or exposure to agents and / or conditions that induce axonal degeneration.

[0402] In some embodiments, the patient has a risk of developing a neurodegenerative disorder. In some embodiments, the patient is an elderly person. In some embodiments, the patient is known to have a genetic risk factor for neurodegeneration. In some embodiments, the patient has a family history of neurodegenerative diseases. In some embodiments, the patient expresses one or more copies of a known genetic risk factor for neurodegeneration. In some embodiments, the patient is from a population with a high incidence of neurodegeneration. In some embodiments, the patient has a hexanucleotide repeat expansion in chromosome 9 open reading frame 72. In some embodiments, the patient has one or more copies of the ApoE4 allele.

[0403] In some embodiments, the object of being administered a compound or composition as described herein can be or include an object suffering from or susceptible to neurodegenerative disease, disorder or condition. In some embodiments, neurodegenerative disease, disorder or condition can be or include traumatic neuron injury. In some embodiments, traumatic neuron injury is blunt force trauma, closed brain injury, open head trauma, exposure to concussive force and / or explosive force, penetrating injury to the innervation area of ​​the brain cavity or body. In some embodiments, traumatic neuron injury is the force causing axonal deformation, stretching, squeezing (crush) or steering.

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

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

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

[0407] Drug administration

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

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

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

[0411] In some embodiments, the compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or by implanted reservoirs. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarterial, intrasynovial, intrasternal, intrathecal, intrahepatic, intradermal, intraocular, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously.

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

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

[0414] Those additional agents can be administered separately from the provided compounds or compositions thereof as part of a multiple dosage regimen. Alternatively, these agents can be part of a single dosage form, mixed with the provided compounds in a single composition. If administered as part of a multiple dosage regimen, the two active agents can be administered simultaneously, sequentially, or within a certain period of time of each other, typically within 5 hours of each other.

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

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

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

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

[0419] Example 1. Preparation of compounds according to the present invention

[0420] General Synthesis Methods

[0421] Compounds according to the present invention and their intermediates can be obtained using synthetic methods known to those skilled in the art and described in the organic synthesis literature. Preferably, the compound is obtained in a manner similar to the preparation method explained more fully below, particularly as described in the experimental section. In some cases, the order in which the reactions are carried out can vary. Variants of the reaction methods known to those skilled in the art but not described in detail herein can also be used.

[0422] The general method for preparing compounds according to the present invention is apparent to those skilled in the art who study the following scheme. Starting material can be prepared by the method described in the document herein, or can be prepared in a similar or similar manner. Conventional protecting groups can be used to protect any functional group in starting material or intermediate. These protecting groups can be separated again using methods familiar to those skilled in the art at the appropriate stage in the reaction sequence.

[0423] Optimum reaction conditions and reaction times can vary according to the specific reactants used. Unless otherwise indicated, solvent, temperature, pressure and other reaction conditions can be easily selected by those of ordinary skill in the art. Specific procedures are provided in the synthetic examples section. Intermediates and products can be purified by silica gel chromatography, recrystallization and / or reversed phase HPLC (RHPLC). By using chiral HPLC to split the racemic product, separate enantiomers can be obtained. The RHPLC purification method uses acetonitrile / water containing 0.1% formic acid, 0.1-0.01% TFA, 10mM aqueous solution of ammonium bicarbonate or 0.2% aqueous solution of ammonium hydroxide from 0 to 100% of any amount and uses one of the following columns:

[0424] a) Waters Xbridge C18 10μm 30×100 mm column

[0425] b) Waters Sunfire C18 10μm 30×100 mm column

[0426] c) Waters Xbridge C18 3.5μm 50×4.6 mm column

[0427] d) HALO C18 2.7 μm 30 × 4.6 mm column

[0428] e) Waters Sunfire C18 3.5μm 50×4.6 mm column

[0429] LCMS method

[0430] Analytical LC / MS Analysis Method A:

[0431] ESI + / - ion mode 100-1000Da

[0432] Column: XBridge SB-C18, 3.5 μm 4.6 × 50 mm column

[0433] Temperature: 40℃

[0434] gradient:

[0435] Time (min) 10 mM ammonium bicarbonate aqueous solution Acetonitrile Flow rate (mL / min) 0.00 95% 5% 2.0 1.40 5% 95% 2.0 3.00 5% 95% 2.0

[0436] Analytical LC / MS Analysis Method B:

[0437] ESI + / - ion mode 100-1000Da

[0438] Column: Sunfire C18, 3.5 μm 4.6×50 mm column

[0439] Temperature: 50℃

[0440] gradient:

[0441] Time (min) 10 mM ammonium bicarbonate aqueous solution Acetonitrile Flow rate (mL / min) 0.00 95% 5% 2.0 1.40 5% 95% 2.0 3.00 5% 95% 2.0

[0442] Analytical LC / MS Analysis Method C:

[0443] ESI + / - ion mode 100-1000Da

[0444] Column: XBridge SB-C18, 3.5 μm 4.6 × 50 mm column

[0445] Temperature: 40℃

[0446] gradient:

[0447] Time (min) 10 mM ammonium bicarbonate aqueous solution Acetonitrile Flow rate (mL / min) 0.00 95% 5% 2.0 1.20 5% 95% 2.0

[0448] Analytical LC / MS Analysis Method D:

[0449] ESI + / - ion mode 100-1000Da

[0450] Column: XBridge SB-C18, 3.5 μm 4.6 × 50 mm column

[0451] Temperature: 40℃

[0452] gradient:

[0453] Time (min) 0.01% TFA / water Acetonitrile Flow rate (mL / min) 0.00 95% 5% 1.8 1.80 5% 95% 1.8 3.00 5% 95% 1.8

[0454] Analytical LC / MS Analysis Method E:

[0455] ESI + / - ion mode 100-1000Da

[0456] Column: XBridge C18, 3.5 μm 4.6 × 50 mm column

[0457] Temperature: 40℃

[0458] gradient:

[0459] Time (min) 0.01% TFA / water Acetonitrile Flow rate (mL / min) 0.00 95% 5% 2.0 1.30 5% 95% 2.0

[0460] Analytical LC / MS Analysis Method F:

[0461] ESI + / - ion mode 100-1000Da

[0462] Column: XBridge C18, 3.5 μm 4.6 × 50 mm column

[0463] Temperature: 50℃

[0464] gradient:

[0465] Time (min) 10 mM ammonium bicarbonate aqueous solution Acetonitrile Flow rate (mL / min) 0.00 90% 10% 1.5 1.50 5% 95% 1.5

[0466] Analytical LC / MS Method G:

[0467] ESI + / - ion mode 100-1000Da

[0468] Column: XBridge C18, 3.5 μm 4.6 × 50 mm column

[0469] Temperature: 45℃

[0470] gradient:

[0471] Time (min) 0.1% TFA / water Acetonitrile Flow rate (mL / min) 0.00 95% 5% 1.8 1.30 5% 95% 1.8 3.00 5% 95% 1.8

[0472] Analytical LC / MS Analysis Method H:

[0473] ESI + / - ion mode 100-1000Da

[0474] Column: XBridge C18, 3.5 μm 4.6 × 50 mm column

[0475] Temperature: 50℃

[0476] gradient:

[0477] Time (min) 10 mM ammonium bicarbonate aqueous solution Acetonitrile Flow rate (mL / min) 0.00 95% 5% 1.8 1.30 5% 95% 1.8 3.00 5% 95% 1.8

[0478] Analytical LC / MS Analysis Method I:

[0479] ESI + / - ion mode 100-1000Da

[0480] Column: XBridge C18, 3.5 μm 4.6 × 50 mm column

[0481] Temperature: 45℃

[0482] gradient:

[0483] Time (min) 10 mM ammonium bicarbonate aqueous solution Acetonitrile Flow rate (mL / min) 0.00 90% 10% 1.8 1.40 5% 95% 1.8 3.00 5% 95% 1.8

[0484] Analytical LC / MS Analysis Method J:

[0485] ESI + / - ion mode 100-1000Da

[0486] Column: Phenomenex Kinetix-XB C18, 1.7 μm 2.1×100 mm column

[0487] Temperature: 40℃

[0488] gradient:

[0489] Time (min) Water (0.1% formic acid) Acetonitrile (0.1% formic acid) Flow rate (mL / min) 0.00 95% 5% 0.6 5.30 0 100 0.6 5.82 95% 5% 0.6 7.00 95% 5% 0.6

[0490] Synthesis Example

[0491] Synthesis Example A: Synthesis of Example 76

[0492]

[0493] R-2 (53 mg, 0.43 mmol) and K2CO3 (149 mg, 1.1 mmol) were added to a solution of R-1 (80 mg, 0.36 mmol) / DMF (3 mL). The mixture was stirred at 80 ° C for 2 hours, then cooled, treated with H2O (10 mL) and extracted with EtOAc (10 mL×3). The organic layer was washed with brine (30 mL×2), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to give Example 76 (72 mg).

[0494] The following examples were prepared in a similar manner from appropriate reagents: Examples 1-6, 8-14, 16-19, 26-27, 35, 47-64, 67-69, 75-77, and 82-83.

[0495] Synthesis Example B: Synthesis of Example 20

[0496] Step 1

[0497]

[0498] A mixture of R-3 (6.0 g, 26.55 mmol) and R-4 (8.2 g, 79.65 mmol) in acetic acid (25 mL) was stirred at 130 °C for 16 hours. The reaction mixture was cooled and concentrated under reduced pressure to remove acetic acid. The residue was diluted with water (200 mL), neutralized with saturated aqueous NaHCO3 to pH = 7-8 and filtered. The filtrate was acidified with concentrated aqueous HCl to pH = 1-2, filtered and the solid was dried to give I-1 (5.4 g, 76%).

[0499] Step 2

[0500]

[0501] A mixture of I-1 (2.7 g, 10.0 mmol) and PCl5 (5.2 g, 25.0 mmol) / POCl3 (20 mL) was stirred at 110°C for 1.5 hours. The reaction mixture was cooled and concentrated under reduced pressure to give a residue, which was dissolved in THF (30 mL). The mixture was added to a solution of ammonium hydroxide (20 g, 30% aqueous solution, 171.3 mmol) / THF (10 mL) at 0°C. After stirring at 0°C for 0.5 hours, the reaction was concentrated under reduced pressure, filtered, and the resulting solid was washed with water (10 mL) and dried to give a solid.

[0502] The solid was dissolved in CH2Cl2 (40 mL), cooled to 0°C, and then treated with TEA (2.14 mL, 15.4 mmol). After 5 minutes, TFAA (1.3 mL, 9.24 mmol) was slowly added and the mixture was stirred at 0°C for 1 hour. The mixture was neutralized with NaHCO3 to pH = 7, extracted with CH2Cl2 (3×60 mL), dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was washed with EtOAc (10 mL) and the solid was filtered and dried to give I-2 (1.78 g, 68%).

[0503] Step 3

[0504]

[0505] A mixture of I-2 (0.4 g, 1.5 mmol), R-5 (0.36 g, 1.8 mmol) and K2CO3 (1.0 g, 7.5 mmol) / DMF (8 mL) was stirred at 80 °C for 1 hour. The reaction was cooled to room temperature and diluted with EtOAc (150 mL), washed with water (20 mL), brine (4×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the Boc amine intermediate, which was dissolved in CH2Cl2 (20 mL). The mixture was treated with TFA (5 mL) and stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was neutralized with 10% K2CO3 aqueous solution, extracted with EtOAc (3×20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give Example 20 (0.16 g, 33%).

[0506] The following examples were prepared in a similar manner from appropriate reagents: Examples 21-25, 65-66, 72-74, 84-85, 93, 94, 97, 99-130, 132-139, 141-143, 145, 146, and 150-153.

[0507] Synthesis Example C: Synthesis of Example 70

[0508]

[0509] A mixture of R-1 (200 mg, 0.9 mmol) / DMF (3 mL) was added to R-6 (333 mg, 1.8 mmol). The resulting mixture was stirred at 100°C for 2 hours. The reaction mixture was concentrated under vacuum to give a crude product (300 mg), which was dissolved in THF (5 mL) and treated with hydrazine monohydrate (0.3 mL). The resulting mixture was stirred at 80°C for 2 hours. The solvent was removed and the residue was purified by preparative HPLC to give Example 70 (46 mg, 25%).

[0510] Synthesis Example D: Synthesis of Example 71

[0511]

[0512] To a solution of Example 10 (30 mg, 0.12 mmol) / THF (3 mL) was added a solution of LHMDS (1M in THF, 0.06 mL, 0.06 mmol) at -50°C, and the mixture was stirred at -50°C for 1 hour. To this solution was added R-7 (57 mg, 0.18 mmol) and after addition, the mixture was stirred at 0°C for 1 hour and then adjusted to pH=6 by dilute HCl aqueous solution. The mixture was partitioned between water and EtOAc. The organic phase was separated and the aqueous phase was extracted with EtOAc (12 mL×3). The combined organic layers were washed with saturated NaCl aqueous solution, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give Example 71 (0.3 mg, 2%).

[0513] The following examples were prepared in a similar manner from appropriate reagents: Example 89.

[0514] Synthesis Example E: Synthesis of Example 78

[0515]

[0516] Step 1

[0517] R-8 (210 mg, 1.2 mmol) and K2CO3 (691 mg, 5.0 mmol) were added to a solution of R-1 (220 mg, 1.0 mmol) / DMF (4 mL), and then stirred at 80 ° C for 2 hours. The mixture was treated with H2O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (30 mL), dried with Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EtOAc: petroleum ether = 1: 1) to obtain I-3 (310 mg, 95%) [analytical method I, retention time = 2.16 min, m / z = 330.1].

[0518] Step 2

[0519]

[0520] To a solution of I-3 (310 mg, 0.94 mmol) / THF (8 mL) and H2O (2 mL) was added LiOH.H2O (158 mg, 3.76 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 / MeOH=10:1 (100 mL) and filtered. The filtrate was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give I-4 (280 mg, 96%) [Analysis method E, retention time = 1.87 min, m / z = 316.1].

[0521] Step 3

[0522]

[0523] SOCl2 (2.09 g, 17.6 mmol) was added to a solution of I-4 (280 mg, 0.88 mmol) / CH2Cl2 (45 mL). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was dissolved in THF (6 mL), then treated with a solution of ammonium hydroxide (6 mL, 30% aqueous solution, 42.8 mmol) at 0°C and stirred for another 0.5 hours at 0°C. The reaction mixture was concentrated under reduced pressure. The residue was treated with water (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and then purified by preparative HPLC to give Example 78 (130 mg, yield = 48%).

[0524] The following examples were prepared in a similar manner from appropriate reagents: Examples 79-80, 88, 90-92, 95, 96, 98, 131, 140, 144, and 147-149.

[0525] Synthesis Example F: Synthesis of Example 81

[0526]

[0527] A mixture of R-1 (300 mg, 1.35 mmol), R-9 (608 mg, 5.38 mmol), and 2,2,6,6-tetramethylpiperidine (474 ​​mg, 3.36 mmol) was stirred at 230 °C for 7 hours. The reaction mixture was cooled to room temperature and then filtered. The filtrate was directly purified by preparative HPLC to give Example 78 (12.3 mg, 3%).

[0528] Synthesis Example G: Synthesis of Example 87

[0529]

[0530] PdCl2(dppf) (33 mg, 0.045 mmol) and K2CO3 (186.3 mg, 1.35 mmol) were added to a mixture of R-1 (100 mg, 0.45 mmol) and R-2 (102 mg, 0.5 mmol) / 1,4-dioxane (5 mL) and H2O (0.5 mL). The mixture was stirred at 110°C for 2 hours under N2, then cooled, treated with H2O (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 ml×2) and dried over Na2SO4. The organic layer was concentrated under reduced pressure and then purified by preparative HPLC to give Example 87 (25 mg, 21%).

[0531] The following examples were prepared in a similar manner from appropriate reagents: Example 86.

[0532] The results are shown in Table 1:

[0533] Table 1.

[0534]

[0535]

[0536] Example 2: ARM-SAM-TIR SARM1 IC 50 Detection method

[0537] This example describes the ARM-SAM-TIR NADase activity assay and the use of this assay to measure the potency of compounds of Formula I or Formula II in blocking SARM1-mediated NAD+ cleavage. This assay was optimized to characterize the potency of compounds of Formula I or Formula II in inhibiting SARM1 activity and to calculate the IC of each compound. 50 This assay utilizes the full-length SARM1, which contains the ARM, SAM and TIR domains. As demonstrated herein, expression of this fragment without the autoinhibitory N-terminal domain generates a constitutively active enzyme that cleaves NAD+.

[0538] Preparation of ARM-SAM-TIR Lysate (STL)

[0539] NRK1-HEK293T cells were plated at 20 × 10 6 Cells were seeded into 150cm 2 The next day, the cells were transfected with 15 μg of ARM-SAM-TIR expression plasmid, SEQ ID NO: 1:

[0540]

[0541]

[0542] .

[0543] Cultures were supplemented with 1 mM NR at the time of transfection to minimize toxicity from ARM-SAM-TIR overexpression. 48 hours after transfection, cells were harvested, pelleted by centrifugation at 1,000 rpm (Sorvall ST 16R centrifuge, Thermo Fisher), and washed once with cold PBS (0.01 M phosphate buffered saline NaCl 0.138 M; KCl 0.0027 M; pH 7.4). Cells were resuspended in PBS containing protease inhibitors (complete™ protease inhibitor cocktail, Roche product # 11873580001) and cell lysates were prepared by sonication (Branson Sonifer 450, output = 3, 20 episodes of stroke). The lysate was centrifuged (12,000×g for 10 min at 4° C.) to remove cell debris and the supernatant (containing ARM1-SAM-TIR protein) was stored at −80° C. for later use in an in vitro ARM-SAM-TIR NADase assay (see below). Protein concentration was determined by the Bicinchoninic (BCA) method and used to normalize lysate concentrations.

[0544] ARM-SAM-TIR of a compound of formula I or a compound of formula II IC 50 Detection method

[0545] Enzymatic assays were performed in 384-well polypropylene plates in Dulbecco's PBS buffer with a final assay volume of 20 µL. ARM- SAM-TIR lysates were pre-incubated with each compound at 1% DMSO final assay concentration for 2 hours at room temperature. The reaction was initiated by adding 5 μM final assay concentration of NAD+ as a substrate. After 2 hours of incubation at room temperature, the reaction was terminated with 40 μL of 7.5% trichloroacetic acid / acetonitrile stop solution. NAD+ and ADPR concentrations were analyzed using an API4000 triple quadrupole mass spectrometer (AB Sciex Framingham, MA) by a RapidFire HighThroughput Mass Spectrometry System (Agilent Technologies, Santa Clara, CA).

[0546] The results are shown in Table 2 below. Compounds with activity labeled "A" provided IC 50 < 5µM; compounds with activity labeled "B" provide IC 50 5-15 µM; compounds with activity labeled "C" provide IC 50 15.01-30 µM; compounds with activity labeled "D" provide IC 50 >30 µM; nd: not determined.

[0547] Table 2.

[0548]

[0549] . Sequence Listing <110> Disarm Therapeutics, Inc. <120> SARM1 inhibitors <130> X22915 <150> 62 / 899,444 <151> 2019-09-12 <160> 1 <170> PatentIn version 3.5 <210> 1 <211> 6514 <212> DNA <213> Artificial Sequence <220> <223> Chemically Synthesized Oligonucleotide <400> 1 gcgatcgcgg ctcccgacat cttggaccat tagctccaca ggtatcttct tccctctagt 60 ggtcataaca gcagcttcag ctacctctca attcaaaaaa cccctcaaga cccgtttaga 120 ggccccaagg ggttatgcta tcaatcgttg cgttacacac acaaaaaacc aacacacatc 180 catcttcgat ggatagcgat tttattatct aactgctgat cgagtgtagc cagatctagt 240 aatcaattac ggggtcatta gttcatagcc catatatgga gttccgcgtt acataactta 300 cggtaaatgg cccgcctggc tgaccgccca acgacccccg cccattgacg tcaataatga 360 cgtatgttcc catagtaacg ccaataggga ctttccattg acgtcaatgg gtggagtatt 420 tacggtaaac tgcccacttg gcagtacatc aagtgtatca tatgccaagt acgcccccta 480 ttgacgtcaa tgacggtaaa tggcccgcct ggcattatgc ccagtacatg accttatggg 540 actttcctac ttggcagtac atctacgtat tagtcatcgc tattaccatg ctgatgcggt 600 tttggcagta catcaatggg cgtggatagc ggtttgactc acgggattt ccaagtctcc 660 accccattga cgtcaatggg agttgtttt ggcaccaaaa tcaacgggac tttccaaat 720 gtcgtaacaa ctccgcccca tgacgcaa tgggcggtag gcgtgtacgg tgggaggtct 780 atataagcag agctggttta gtgaaccgtc agatcagatc ttgtcgatc ctaccatcca 840 ctcgacacac ccgccagcgg ccgctgccaa gctcgagc tctcgaattc aaaggaggta 900 cccaccatgg ccatgcatca ccaccacat catagctccg gcgtcgacct cggcaccgag 960 aatttatatt tccaagcgg cctcaatgat atcttcgagg cccagagat cgagtggcac 1020 gagggcagct ccgacctcgc cgtgcccggt cccgatggag gcggaggcac tggtccttgg 1080 tgggctgctg gcggcagagg ccctagagaa gtgagccccg gtgctggcac cgaggtgcaa 1140 gacgctctgg agagggctct gcccgaacct cagcaagctc tgtccgctt aaagcaagct 1200 ggaggagcta gagccgtcgg cgccggactg gccgaagtgt tccagctcgt ggaggaagct 1260 tgttattac ccgctgtggg agagaggtc gcccaggtc tgtgtgacgc cattcgtctg 1320 gacggaggtt tagacttatt actgaggctg ctgcaagctc ccgaactgga gacaagggtc 1380 caagctgctc gtctgctgga gcagatcctc gtggccgaga atcgtgacag agtggctaga 1440 atcggtttag gcgtcatcct caatttagcc aaagagaggg agcccgttga gctggccaga 1500 agcgtcgctg gcatcctcga gcacatgttc aagcattccg aggagacttg tcagagactg 1560 gtcgccgccg gaggactcga tgctgtttta tactggtgca gaaggacaga ccccgcttta 1620 ctgaggcatt gtgctctggc cctcggcaat tgcgctttac atggaggcca agccgtccag 1680 agaaggatgg tggagaaaag agccgccgag tggctgttcc ctttagcctt ctccaaagaa 1740 gacgaactgt tacgtctgca tgcttgtctc gctgtcgctg ttttagccac caacaaggag 1800 gtggaaaggg aagtggaaag aagcggaaca ctggctttag tcgaacctct ggtggcttct 1860 ttagatcccg gaaggtttgc cagatgtctg gtcgacgcca gcgatacctc ccaaggaaga 1920 ggccccgacg atctccagag actggtgcct ctgctggaca gcaatcgtct ggaggcccaa 1980 tgtattggcg ccttctatct ctgcgccgaa gccgccatca agtctttaca aggtaagacc 2040 aaggtgttct ccgacattgg agccatccaa tctttaaaga ggctggtgag ctattccacc 2100 aacggcacaa aaagcgcttt agccaaaaga gctttaagac tgctgggcga agaggtgcct 2160 aggcccattt taccttccgt gcctagctgg aaagggccg aggtgcagac ttggctgcag 2220 cagatcggct ttagcaaata ttgcgaatcc tttagggagc agcaagttga cggcgattta 2280 ttattaaggc tgaccgagga agagctccag acagatttag gcatgaaaag cggcatcact 2340 cgtaagaggt tctttcgtga gctcaccgaa ctgaagacct tcgccaacta ctccacttgt 2400 gatcgtagca atttagctga ttggctcgga tccctcgatc ccagatttcg tcagtacacc 2460 tatggactcg tctcttgtgg actggacaga tctttactgc atcgtgtgag cgagcaacag 2520 ctgctgggaag attgcggcat ccatttagga gtgcacagag ccagaattct gaccgccgct 2580 agagagatgc tgcattcccc tctcccttgt accggaggca agcctagcgg agacacccc 2640 gacgtgttca tcagctatcg tagaaacagc ggaagccagc tggcctcttt actgaaggtc 2700 catttacagc tgcacggatt tagcgtcttc atcgacgtgg agaaactgga ggctggcaag 2760 ttcgaggaca agctgatcca gtccgtgatg ggcgctagga atttcgtttt agtgctcagc 2820 cccggcgctc tggataaatg catgcaagat catgactgta aggactgggt ccacaaggaa 2880 atcgtgaccg ctctgtcttg tggcaagaac atcgtcccca tcatcgacgg cttcgaatgg 2940 cccgagcctc aagttctccc cgaagatatg caagctgttt taaccttcaa tggaatcaag 3000 tggagccacg agtaccaaga agccacaatc gagaagatca ttcgttttct gcaaggtaga 3060 tcctccagag attcctccgc tggcagcgac acatctttag agggcgccgc ccctatgggt 3120 cctacctaat aatctagaag ttgtctcctc ctgcactgac tgactgatac aatcgatttc 3180 tggatccgca ggcctctgct agcttgactg actgagatac agcgtacctt cagctcacag 3240 acatgataag atacattgat gagtttggac aaaccacaac tagaatgcag tgaaaaaaat 3300 gctttattg tgaaatttgt gatgctattg ctttatttgt aaccattata agctgcaata 3360 aacaagttaa caacaacaat tgcattcatt tttgtttca ggttcagggg gaggtgtggg 3420 aggtttttta aagcaagtaa aacctctaca aatgtggtat tggcccatct ctatcggtat 3480 cgtagcataa ccccttgggg cctctaaacg ggtcttgagg ggttttttgt gccctcggg 3540 ccggattgct atctaccggc attggcgcag aaaaaaatgc ctgatgcgac gctgcgcgtc 3600 ttactccc acatatgcca gattcagcaa cggatacggc ttccccaact tgcccacttc 3660 catacgtgtc ctccttacca gaaatttatc cttaaggtcg tcagctatcc tgcaggcgat 3720 ctctcgattt cgatcaagac attcctttaa tggtctttc tggacaccac taggggtcag 3780 aagtagttca tcaaactttc ttccctccct aatctcattg gttaccttgg gctatcgaaa 3840 cttaattaac cagtcaagtc agctacttgg cgagatcgac ttgtctgggt ttcgactacg 3900 ctcagaattg cgtcagtcaa gttcgatctg gtccttgcta ttgcacccgt tctccgatta 3960 cgagtttcat ttaaatcatg tgagcaaaag gccagcaaaa ggccaggaac cgtaaaaagg 4020 ccgcgttgct ggcgttttc cataggctcc gcccccctga cgagcatcac aaaaatcgac 4080 gctcaagtca gaggtggcga aacccgacag gactataaag ataccaggcg tttccccctg 4140 gaagctccct cgtgcgctct cctgttccga cctgccgct taccggatac ctgtccgcct 4200 ttctcccttc gggaagcgtg gcgctttctc atagctcacg ctgtaggtat ctcagttcgg 4260 tgtagtcgt tcgctccaag ctgggctgtg tgcacgaacc ccccgttcag cccgaccgct 4320 gcgccttatc cggtaactat cgtcttgagt ccaacccggt aagacacgac ttatcgccac 4380 tggcagcagc cactggtaac aggattagca gagcgaggta tgtaggcggt gctacagagt 4440 tcttgaagtg gtggcctaac tacggctaca ctagaagaac agtatttggt atctgcgctc 4500 tgctgaagcc agttaccttc ggaaaaagag ttggtagctc ttgatccggc aaacaaacca 4560 ccgctggtag cggtggtttt tttgtttgca agcagcagat tacgcgcaga aaaaaaggat 4620 ctcaagaaga tccttgatc ttttctacgg ggtctgacgc tcagtggaac gaaaactcac 4680 gttaagggat tttggtcatg agattatcaa aaaggatctt cacctagatc cttttaaatt 4740 aaaaatgaag ttttaaatca atctaaagta tatatgagta aacttggtct gacagttacc 4800 aatgcttaat cagtgaggca cctatctcag cgatctgtct atttcgttca tccatagttg 4860 catttaaatt tccgaactct ccaaggccct cgtcggaaaa tcttcaaacc ttcgtccga 4920 tccatcttgc aggctacctc tcgaacgaac tatcgcaagt ctcttggccg gccttgcgcc 4980 ttggctattg cttggcagcg cctatcgcca ggtattactc caatcccgaa tatccgagat 5040 cgggatcacc cgagagaagt tcaacctaca tcctcaatcc cgatctatcc gagatccgag 5100 gaatatcgaa atcggggcgc gcctggtgta ccgagaacga tcctctcagt gcgagtctcg 5160 acgatccata tcgttgcttg gcagtcagcc agtcggaatc cagcttggga cccaggaagt 5220 ccaatcgtca gatattgtac tcaagcctgg tcacggcagc gtaccgatct gttaaacct 5280 agatattgat agtctgatcg gtcaacgtat aatcgagtcc tagctttgc aaacatctat 5340 caagagacag gatcagcagg aggctttcgc atgagtattc aacatttccg tgtcgccctt 5400 attcccttt ttgcggcatt ttgccttcct gttttgctc acccagaaac gctggtgaaa 5460 gtaaaagatg ctgaagatca gttgggtgcg cgagtgggtt acatcgaact ggatctcaac 5520 agcggtaaga tccttgagag tttcgcccc gaagaacgct ttccaatgat gagcacttttt 5580 aaagttctgc tatgtggcgc ggtattatcc cgtattgacg ccgggcaaga gcaactcggt 5640 cgccgcatac actattctca gaatgacttg gttgagtatt caccagtcac agaaaagcat 5700 cttacggatg gcatgacagt aagagaatta tgcagtgctg ccataaccat gagtgataac 5760 actgcggcca acttacttct gacaacgatt ggaggaccga aggagctaac cgcttttttg 5820 cacaacatgg gggatcatgt aactcgcctt gatcgttggg aaccggagct gaatgaagcc 5880 ataccaaacg acgagcgtga caccacgatg cctgtagcaa tggcaacaac cttgcgtaaa 5940 ctattaactg gcgaactact tactctagct tcccggcaac agttgataga ctggatggag 6000 gcggataaag ttgcaggacc acttctgcgc tcggcccttc cggctggctg gtttattgct 6060 gataaatctg gagccggtga gcgtgggtct cgcggtatca ttgcagcact ggggccagat 6120 ggtaagccct cccgtatcgt agttatctac acgacgggga gtcaggcaac tatggatgaa 6180 cgaaatagac agatcgctga gataggtgcc tcactgatta agcattggta accgattcta 6240 ggtgcattgg cgcagaaaaa aatgcctgat gcgacgctgc gcgtcttata ctcccacata 6300 tgccagattc agcaacggat acggcttccc caacttgccc acttccatac gtgtcctcct 6360 taccagaaat ttatccttaa gatcccgaat cgtttaaact cgactctggc tctatcgaat 6420 ctccgtcgtt tcgagcttac gcgaacagcc gtggcgctca tttgctcgtc gggcatcgaa 6480 tctcgtcagc tatcgtcagc ttaccttttt ggca 6514

Claims

1. Compounds of formula Ic: or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from hydrogen, halogen, optionally substituted with –(CH2) 0-4 OH-substituted C 1-6 aliphatic groups, 3- to 7-membered heterocyclic rings having 1 oxygen atom, and 5- to 6-membered heteroaryl rings having 1 oxygen atom; R 3 is selected from hydrogen and halogen; and R 1 Selected from 。 2. The compound according to claim 1, wherein R 2 It's a halogen.

3. A compound according to claim 2, wherein R 2 It's chlorine.

4. The compound according to claim 2, wherein R 2 It's bromine.

5. The compound according to claim 2, wherein R 2 It's fluorine.

6. The compound according to claim 1, wherein R 2 It is -CH3.

7. A compound according to claim 1, wherein R 2 It's hydrogen.

8. A compound according to any one of claims 1 to 7, wherein R 3 It's hydrogen.

9. A compound according to any one of claims 1 to 7, wherein R 3 It's a halogen.

10. The compound according to claim 9, wherein R 3 It's chlorine.

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