WO2022231872A1 - Kcnt1 inhibitors and methods of use - Google Patents

Abstract

Disclosed herein are compounds and compositions useful for preventing and/or treating a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1). Methods of treating a neurological disorder, a disorder associated with excessive neuronal excitability, or disorder associated with a gain-of-function mutation in a gene such as KCNT1 are also provided herein.

Description

KCNT1 INHIBITORS AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATION [001] This application claims the benefit of, and relies on the filing date of, U.S. provisional patent application number 63/181,498, filed 29 April 2021, the entire disclosure of which is incorporated herein by reference. FIELD OF THE DISCLOSURE [002] The present disclosure is generally directed to KCNT1 inhibitors comprising an oxadiazole core, as well as pharmaceutical compositions and methods of treatment involving the use of such compounds. BACKGROUND OF THE DISCLOSURE [003] Potassium sodium-activated channel subfamily T member 1 (“KCNT1”) is one of the genes in a family of genes responsible for providing the instructions to make potassium channels. KCNT1 encodes sodium-activated potassium channels known as Slack (Sequence like a calcium-activated K⁺ channel). These channels are found in neurons throughout the brain and can mediate a sodium-activated potassium current I_KNa. This delayed outward current can regulate neuronal excitability and the rate of adaption in response to maintained stimulation. Abnormal Slack activity has been associated with development of early onset epilepsies and intellectual impairment. Accordingly, pharmaceutical compounds that selectively regulate sodium-activated potassium channels, e.g., abnormal KCNT1 or abnormal IKNa, are useful in treating a neurological disease or disorder or a disease or condition related to excessive neuronal excitability and/or KCNT1 gain-of-function mutations. SUMMARY OF THE DISCLOSURE [004] Described herein are compounds and compositions useful for preventing and/or treating a disease, disorder, or condition, e.g., a neurological disorder, a disorder associated with excessive neuronal excitability, or disorder associated with a gain-of-function mutation in a gene, for example, KCNT1. [005] In one aspect, the present disclosure features a compound of Formula I having an oxadiazole core:

or a pharmaceutically acceptable salt thereof, wherein R₁ is chosen from a C_1-6alkyl, a C_1-6haloalkyl, or a C_3-10cycloalkyl, wherein the C_1-6alkyl, C_1-6haloalkyl, and C_3-10cycloalkyl optionally comprises a C_1-6alkoxy or N(R₈)₂ substituent; R₂ is chosen from hydrogen or a C_1-4alkyl; R3 is chosen from a C_1-6alkyl optionally comprising a C_1-6alkoxy substituent; R4 is chosen from hydrogen or a C_1-6alkyl; R₅ is chosen from a C_1-6alkyl or a C_1-6haloalkyl; R₆ is chosen from hydrogen, a C_1-6alkyl, a C_3-10cycloalkyl, a phenyl, or a 3-10 membered heterocyclyl, wherein the C_1-6alkyl, C_3-10cycloalkyl, phenyl, or 3-10 membered heterocyclyl may optionally comprise one or more substituents chosen from a halogen, -CN, -OH, a C_1-6alkyl, a C_{1- 6}haloalkyl, a C_1-6alkoxy, a phenyl, a C_3-10cycloalkyl, or a 3-10 membered heterocyclyl; R₇ is chosen from a C_1-6alkyl, a C_3-10cycloalkyl, a phenyl, or a 3-10 membered heterocyclyl, wherein the C_1-6alkyl, C_3-10cycloalkyl, phenyl, or 3-10 membered heterocyclyl may optionally comprise one or more substituents chosen from a halogen, -CN, -OH, a C_1-6alkyl, a C_1-6haloalkyl, a C_1-6alkoxy, a phenyl, a C_3-10cycloalkyl, or a 3-10 membered heterocyclyl; or R₆ and R₇ are taken together with the nitrogen attached to R₆ and R₇ to form a 3-10 membered heterocyclyl ring optionally comprising one or more substituents chosen from a halogen, -CN, -OH, a C_1-6alkyl, a C_1-6haloalkyl, a phenyl, a C_3-10cycloalkyl, or a 3-10 membered heterocyclyl, wherein the C_1-6alkyl is optionally substituted with an oxo; each R₈ is independently chosen from hydrogen or a C_1-6alkyl; and x is 0, 1 or 2. [006] In some embodiments, the compound of Formula I is a compound of Formula I-a:

or a pharmaceutically acceptable salt thereof. [007] In some embodiments, the compound of Formula I is a compound of Formula I-b:

or a pharmaceutically acceptable salt thereof. [008] In some embodiments, the compound of Formula I is a compound of Formula I-c:

or a pharmaceutically acceptable salt thereof. [009] In some embodiments, the compound of Formula I is a compound of Formula I-d or Formula I-e:

or a pharmaceutically acceptable salt thereof. [0010] In certain embodiments disclosed herein, in a compound of the Formula (I) or pharmaceutically acceptable salt thereof, R₃ is C_1-6alkyl and R₄ is hydrogen, and in certain embodiments, R₂ is hydrogen. In certain embodiments, R₁ is C_1-6alkyl, and in certain embodiments, R₁ is methyl. In certain embodiments, x is 1 or 2, such as 1, and in certain embodiments, R₅ is C_1-6haloalkyl, such as -CF₃. In certain aspects, R₆ is hydrogen and R₇ is C_{1- 6}alkyl, and in certain aspects, R₆ and R₇ are each C_1-6alkyl optionally comprising a phenyl substituent. In certain embodiments, R₆ and R₇ are taken together with the nitrogen attached to R₆ and R₇ to form a 3-10 membered heterocyclyl ring optionally comprising one or more substituents chosen from a halogen, a C_1-6alkyl, or a C_1-6haloalkyl. [0011] In certain embodiments, a compound of the Formula (I) is chosen from:

or a pharmaceutically acceptable salt thereof. [0012] In one aspect, the present disclosure provides a method of treating neurological disorder, wherein the method comprises administering to a subject in need thereof a compound disclosed herein (e.g., compound of Formula (I), (e.g., (I-a), (I-b), (I-c), (I-d), or (I-e))) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of Formula (I), (e.g., (I-a), (I-b), (I-c), (I-d), or (I-e)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient). [0013] In another aspect, the present disclosure provides a method of treating a disorder associated with excessive neuronal excitability, wherein the method comprises administering to a subject in need thereof a compound disclosed herein (e.g., compound of Formula (I), (e.g., (I-a), (I-b), (I-c), (I-d), or (I-e))) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of Formula (I), (e.g., (I-a), (I-b), (I-c), (I-d), or (I-e)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient). [0014] In another aspect, the present disclosure provides a method of treating a disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1), wherein the method comprises administering to a subject in need thereof a compound disclosed herein (e.g., a compound of Formula (I), (e.g., (I-a), (I-b), (I-c), (I-d), or (I-e))) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of Formula (I), (e.g., (I-a), (I-b), (I-c), (I-d), or (I-e)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient). [0015] In some embodiments, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is epilepsy, an epilepsy syndrome, or an encephalopathy. [0016] In some embodiments, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is a genetic or pediatric epilepsy or a genetic or pediatric epilepsy syndrome. [0017] In some embodiments, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is a cardiac dysfunction. [0018] In some embodiments, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is selected from epilepsy and other encephalopathies (e.g., malignant migrating focal seizures of infancy (MMFSI) or epilepsy of infancy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, seizures (e.g., Generalized tonic clonic seizures, Asymmetric Tonic Seizures), leukodystrophy, leukoencephalopathy, intellectual disability, Multifocal Epilepsy, Drug resistant epilepsy, Temporal lobe epilepsy, cerebellar ataxia). [0019] In some embodiments, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is chosen from cardiac arrhythmia, Brugada syndrome, and myocardial infarction. [0020] In some embodiments, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is selected from pain and related conditions (e.g., neuropathic pain, acute/chronic pain, migraine, etc.). [0021] In some embodiments, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is a muscle disorder (e.g., myotonia, neuromyotonia, cramp muscle spasms, spasticity). [0022] In some embodiments, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is selected from itch and pruritis, ataxia or cerebellar ataxias. [0023] In some embodiments, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is selected from psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia). [0024] In some embodiments, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is chosen from a learning disorder, Fragile X, neuronal plasticity, or an autism spectrum disorder. [0025] In some embodiments, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is chosen from epileptic encephalopathy with SCN1A, SCN2A, and/or SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy. [0026] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing Detailed Description, Examples, and Claims. DETAILED DESCRIPTION OF THE DISCLOSURE [0027] Provided herein are compounds and compositions useful for preventing and/or treating a disease, disorder, or condition described herein, e.g., a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with gain-of-function mutations in a gene (e.g., KCNT1). Exemplary diseases, disorders, or conditions include epilepsy and other encephalopathies (e.g., MMFSI or EIMFS, ADNFLE, West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, Intellectual disability, Multifocal Epilepsy, Generalized tonic clonic seizures, Drug resistant epilepsy, Temporal lobe epilepsy, cerebellar ataxia, Asymmetric Tonic Seizures), cardiac dysfunctions (e.g., cardiac arrhythmia, Brugada syndrome, sudden unexpected death in epilepsy, myocardial infarction), pain and related conditions (e.g., neuropathic pain, acute/chronic pain, migraine, etc.), muscle disorders (e.g., myotonia, neuromyotonia, cramp muscle spasms, spasticity), itch and pruritis, ataxia and cerebellar ataxias, and psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia). Definitions Chemical definitions [0028] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987. [0029] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods described in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The compounds described herein encompass both individual isomers substantially free of other isomers, and alternatively, mixtures of various isomers. [0030] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound. [0031] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R–compound. In certain embodiments, the enantiomerically pure R–compound in such compositions can, for example, comprise, at least about 95% by weight R–compound and at most about 5% by weight S–compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S–compound. In certain embodiments, the enantiomerically pure S–compound in such compositions can, for example, comprise, at least about 95% by weight S–compound and at most about 5% by weight R–compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier. [0032] Compound described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including ¹H, ²H (D or deuterium), and ³H (T or tritium); C may be in any isotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form, including ¹⁶O and ¹⁸O; F may be in any isotopic form, including ¹⁸F and ¹⁹F; and the like. [0033] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present disclosure. When describing the embodiments, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue. [0034] When a range of values is listed, it is intended to encompass each value and sub– range within the range. For example, “C₁–6 alkyl” is intended to encompass, C₁, C₂, C₃, C₄, C₅, C₆, C_1–6, C_1–5, C_1–4, C_1–3, C_1–2, C_2–6, C_2–5, C_2–4, C_2–3, C_3–6, C_3–5, C_3–4, C_4–6, C_4–5, and C_5–6 alkyl. [0035] As used herein, “alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“C_1–20 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C_1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C_1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C_1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C_1–7 alkyl”). In 2_ome embodiments, an alkyl group has 1 to 6 carbon atoms (“C_1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C_1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C_1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C_1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C_1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). Examples of C_1–6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like. [0036] The term “heteroalkyl” as used herein refers to an “alkyl” group in which at least one carbon atom has been replaced with an O or S atom. The heteroalkyl may be, for example, an –O-C₁-C₁₀alkyl group, an -C₁-C₆alkylene-O-C₁-C₆alkyl group, or a C₁-C₆ alkylene-OH group. In certain embodiments, the “heteroalkyl” may be 2-8 membered heteroalkyl, indicating that the heteroalkyl contains from 2 to 8 atoms selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. In yet other embodiments, the heteroalkyl may be a 2-6 membered, 4-8 membered, or a 5-8 membered heteroalkyl group (which may contain for example 1 or 2 heteroatoms selected from the group oxygen and nitrogen). In certain embodiments, the heteroalkyl is an “alkyl” group in which 1-3 carbon atoms have been replaced with oxygen atoms. One type of heteroalkyl group is an “alkoxy” group. [0037] As used herein, “alkenyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds), and optionally one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds) (“C_1–20alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C_1–10alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C_2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C_2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C_2–7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C_2–6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C_2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C_2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C_2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl). The one or more carbon–carbon double bonds can be internal (such as in 2– butenyl) or terminal (such as in 1–butenyl). Examples of C_2–4 alkenyl groups include ethenyl (C₂), 1–propenyl (C₃), 2–propenyl (C₃), 1–butenyl (C₄), 2–butenyl (C₄), butadienyl (C₄), and the like. Examples of C_2–6 alkenyl groups include the aforementioned C_2–4 alkenyl groups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additional examples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl (C₈), and the like. [0038] As used herein, “alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds), and optionally one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds) (“C_2–20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C_2–10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C_2–9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C_2–8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C_2–7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C_2–6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C_2–5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C_2–4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C_2–3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon–carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C_2–4 alkynyl groups include, without limitation, ethynyl (C₂), 1–propynyl ( C₃), 2–propynyl (C₃), 1–butynyl (C₄), 2–butynyl (C₄), and the like. Examples of C_2–6 alkenyl groups include the aforementioned C_2–4 alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and the like. Additional examples of alkynyl include heptynyl (C₇), octynyl (C₈), and the like. [0039] As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to a divalent radical of an alkyl, alkenyl, and alkynyl group respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” or “alkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” and “alkynylene,” groups may be substituted or unsubstituted with one or more substituents as described herein. [0040] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C_6–14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. [0041] As used herein, “heteroaryl” refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5–10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl). [0042] In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”). In some embodiments, the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. [0043] Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5– membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6–membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6–bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. [0044] Examples of representative heteroaryls include the following:

wherein each Z is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ is independently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ carbocyclyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl, and 5-10 membered heteroaryl. [0045] As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C_3–10 carbocyclyl”) and zero heteroatoms in the non–aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C_3–8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C_3–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C_5–10 carbocyclyl”). Exemplary C_3–6 carbocyclyl groups include, without limitation, cyclopropyl (C₃),cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. Exemplary C_3–8 carbocyclyl groups include, without limitation, the aforementioned C_3–6 carbocyclyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C_3–10 carbocyclyl groups include, without limitation, the aforementioned C_{3– 8} carbocyclyl groups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro–1H–indenyl (C9), decahydronaphthalenyl (C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. [0046] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "C_4-8cycloalkyl," derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes. Unless specified otherwise, cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. Cycloalkyl groups can be fused to other cycloalkyl, aryl, or heterocyclyl groups. In certain embodiments, the cycloalkyl group is not substituted, i.e., it is unsubstituted. [0047] As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3– to 10–membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. [0048] In some embodiments, a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non– aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. [0049] Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2,5–dione. Exemplary 5–membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. [0050] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g,. heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms. [0051] As used herein, “cyano” refers to -CN. [0052] As used herein, “halo” or ”halogen” refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). In certain embodiments, the halo group is either fluoro or chloro. [0053] As used herein, “haloalkyl” refers to an alkyl group substituted with one or more halogen atoms. [0054] As used herein, “nitro” refers to -NO₂. [0055] As used herein, “oxo” refers to -C=O. [0056] In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. [0057] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, –OH, –OR^aa, –N(R^cc)2, –CN, –C(=O)R^aa, –C(=O)N(R^cc)₂, –CO₂R^aa, –SO₂R^aa, –C(=NR^bb)R^aa, –C(=NR^cc)OR^aa, – C(=NR^cc)N(R^cc)₂, –SO₂N(R^cc)₂, –SO₂R^cc, –SO₂OR^cc, –SOR^aa, –C(=S)N(R^cc)₂, – C(=O)SR^cc, –C(=S)SR^cc, –P(=O)₂R^aa, –P(=O)(R^aa)₂, –P(=O)₂N(R^cc)₂, –P(=O)(NR^cc)₂, C_1–10 alkyl, C_1–10 perhaloalkyl, C_2–10 alkenyl, C_2–10 alkynyl, C_3–10 carbocyclyl, 3–14 membered heterocyclyl, C_6–14 aryl, and 5–14 membered heteroaryl, or two R^cc groups attached to a nitrogen atom are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups, and wherein R^aa, R^bb, R^cc and R^dd are as defined above. [0058] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The disclosure is not intended to be limited in any manner by the above exemplary listing of substituents. Other definitions [0059] The terms “in some embodiments,” “in other embodiments,” or the like, refer to embodiments of all aspects of the disclosure, unless the context clearly indicated otherwise. [0060] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, 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. The general concept of pharmaceutically acceptable salts has been discussed in the art, including, for example, Berge et al., which describes pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group 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, oxalic 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. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C_1–4alkyl)₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. [0061] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, an infant, child, adolescent) or an adult subject (e.g., a young adult, middle–aged adult, or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein. [0062] Disease, disorder, and condition are used interchangeably herein. [0063] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (also “therapeutic treatment”). [0064] In general, the “effective amount” of a compound or pharmaceutically acceptable salt thereof refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound or pharmaceutically acceptable salt thereof as disclosed herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound or pharmaceutically acceptable salt thereof, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. [0065] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound or pharmaceutically acceptable salt thereof is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. [0066] In an alternate embodiment, provided herein are methods of treating comprising administering the compounds disclosed herein or a pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof, as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition. As used herein, “prophylactic treatment” contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition. As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound or pharmaceutically acceptable salt thereof is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound or pharmaceutically acceptable salt thereof means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. [0067] As used herein, a “disorder associated with a gain-of-function mutation in KCNT1” refers to a disorder that is associated with, is partially or completely caused by, or has one or more symptoms that are partially or completely caused by, a mutation in KCNT1 that results in a gain- of-function phenotype, i.e. an increase in activity of the potassium channel encoded by KCNT1 resulting in an increase in whole cell current. [0068] As used herein, a “gain-of-function mutation” is a mutation in KCNT1 that results in an increase in activity of the potassium channel encoded by KCNT1. Activity can be assessed by, for example, ion flux assay or electrophysiology (e.g. using the whole cell patch clamp technique). Typically, a gain-of-function mutation results in an increase of at least or about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400% or more compared to the activity of a potassium channel encoded by a wild-type KCNT1. Compounds and Compositions [0069] In one aspect, disclosed herein is a compound of Formula (I) having an oxadiazole core:

or a pharmaceutically acceptable salt thereof, wherein R₁ is chosen from a C_1-6alkyl, a C_1-6haloalkyl, and a C_3-10cycloalkyl, wherein the C_1-6alkyl, C_1-6haloalkyl, and C_3-10cycloalkyl optionally comprises a substituent chosen from a C_1-6alkoxy or N(R₈)₂; R₂ is chosen from hydrogen or a C_1-4alkyl; R₃ is a C_1-6alkyl optionally comprising a C_1-6alkoxy substituent; R₄ is chosen from hydrogen or a C_1-6alkyl; R₅ is chosen from a C_1-6alkyl or a C_1-6haloalkyl; R₆ is chosen from hydrogen, a C_1-6alkyl, a C_3-10cycloalkyl, a phenyl, or a 3-10 membered heterocyclyl, wherein the C_1-6alkyl, C_3-10cycloalkyl, phenyl, or 3-10 membered heterocyclyl may optionally comprise one or more substituents chosen from a halogen, -CN, -OH, a C_1-6alkyl, a C_{1- 6}haloalkyl, a C_1-6alkoxy, a phenyl, a C_3-10cycloalkyl, or a 3-10 membered heterocyclyl; R₇ is chosen from a C_1-6alkyl, a C_3-10cycloalkyl, a phenyl, or a 3-10 membered heterocyclyl, wherein the C_1-6alkyl, C_3-10cycloalkyl, phenyl, or 3-10 membered heterocyclyl may optionally comprise one or more substituents chosen from a halogen, -CN, -OH, a C_1-6alkyl, a C_1-6haloalkyl, a C_1-6alkoxy, a phenyl, a C_3-10cycloalkyl, or a 3-10 membered heterocyclyl; or R₆ and R₇ are taken together with the nitrogen attached to R₆ and R₇ to form a 3-10 membered heterocyclyl ring optionally comprising one or more substituents chosen from a halogen, -CN, -OH, a C_1-6alkyl, a C_1-6haloalkyl, a phenyl, a C_3-10cycloalkyl, or a 3-10 membered heterocyclyl, wherein the C_1-6alkyl is optionally substituted with oxo; each R₈ is independently chosen from hydrogen or a C_1-6alkyl; and x is 0, 1 or 2. [0070] In some embodiments, the compound of Formula I is a compound of Formula I-a:

or a pharmaceutically acceptable salt thereof. [0071] In some embodiments, the compound of Formula I is a compound of Formula I-b:

or a pharmaceutically acceptable salt thereof. [0072] In some embodiments, the compound of Formula I is a compound of Formula I-c:

or a pharmaceutically acceptable salt thereof. [0073] In some embodiments, the compound of Formula I is a compound of Formula I-d or I-e:

or a pharmaceutically acceptable salt thereof. [0074] In some embodiments, R₃ is C_1-6alkyl and R₄ is hydrogen. [0075] In some embodiments, R2 is hydrogen. [0076] In some embodiments, R₁ is C_1-6alkyl. In some embodiments, R₁ is methyl. [0077] In some embodiments, x is 1 or 2. In some embodiments, x is 1. [0078] In some embodiments, R₅ is C_1-6haloalkyl. In some embodiments, R₅ is -CF3. [0079] In some embodiments, R₆ is hydrogen and R₇ is C_1-6alkyl. [0080] In some embodiments, R₆ and R₇ are each C_1-6alkyl optionally comprising a phenyl substituent. [0081] In some embodiments, R₆ and R₇ are taken together with the nitrogen attached to R₆ and R₇ to form a 3-10 membered heterocyclyl ring optionally comprising one or more substituents chosen from a halogen, a C_1-6alkyl, or a C_1-6haloalkyl. [0082] In some embodiments, the compound is chosen from:

, or a pharmaceutically acceptable salt thereof. [0083] In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. General Synthetic Schemes [0084] Exemplary methods for preparing compounds described herein are illustrated in the following synthetic schemes. These schemes are given for the purpose of illustrating exemplary embodiments, and should not be regarded in any manner as limiting the scope or the spirit of the disclosure. SCHEME 1

[0085] The synthetic route illustrated in Scheme 1 depicts an exemplary procedure for preparing intermediate F. In the first step, amine A is treated with cyanogen bromide to provide nitrile B, which is then treated with hydroxylamine to provide N-hydroxyimidamide C. Then, N,N'-dicyclohexylcarbodiimide (DCC)-mediated cyclization of C with glycine D affords oxadiazole E. Deprotection of E under acidic conditions provides intermediate F. SCHEME 2

[0086] The synthetic route illustrated in Scheme 2 depicts an exemplary procedure for preparing H (a compound of Formula I). Coupling of intermediate F with carboxylic acid G using standard peptide coupling procedures (e.g., HATU in dichloromethane in the presence of DIPEA) provides compound H (a compound of Formula I). Methods of Treatment [0087] The compounds and compositions described above and herein can be used to treat a neurological disease, a disorder associated with excessive neuronal excitability, or disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1). Exemplary diseases, disorders, or conditions include epilepsy and other encephalopathies (e.g., MMFSI or EIMFS, ADNFLE, West syndrome, infantile spasms, epileptic encephalopathy, developmental and epileptic encephalopathy (DEE), early infantile epileptic encephalopathy (EIEE), generalized epilepsy, focal epilepsy, multifocal epilepsy, temporal lobe epilepsy, Ohtahara syndrome, early myoclonic encephalopathy, Lennox-Gastaut syndrome, drug-resistant epilepsy, seizures (e.g., frontal lobe seizures, generalized tonic clonic seizures, asymmetric tonic seizures, focal seizures), leukodystrophy, hypomyelinating leukodystrophy, leukoencephalopathy, and sudden unexpected death in epilepsy, cardiac dysfunctions (e.g., cardiac arrhythmia, Brugada syndrome, myocardial infarction), pulmonary vasculopathy / hemorrhage, pain and related conditions (e.g., neuropathic pain, acute/chronic pain, migraine, etc.), muscle disorders (e.g., myotonia, neuromyotonia, cramp muscle spasms, spasticity), itch and pruritis, movement disorders (e.g., ataxia and cerebellar ataxias), psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia, attention-deficit hyperactivity disorder), neurodevelopmental disorder, learning disorders, intellectual disability, Fragile X, neuronal plasticity, and autism spectrum disorders. [0088] In some embodiments, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from EIMFS, ADNFLE and West syndrome. In some embodiments, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, and Lennox-Gastaut syndrome. In some embodiments, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is seizure. In some embodiments, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from cardiac arrhythmia, Brugada syndrome, and myocardial infarction. [0089] In some embodiments, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is chosen from a learning disorder, Fragile X, intellectual function, neuronal plasticity, psychiatric disorders, or an autism spectrum disorder. [0090] Accordingly, the compounds and compositions thereof can be administered to a subject with a neurological disorder, a disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene such as KCNT1 (e.g., EIMFS, ADNFLE, West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, seizures, cardiac arrhythmia, Brugada syndrome, and myocardial infarction). [0091] EIMFS is a rare and debilitating genetic condition characterized by an early onset (before 6 months of age) of almost continuous heterogeneous focal seizures, where seizures appear to migrate from one brain region and hemisphere to another. Patients with EIMFS are generally intellectually impaired, non-verbal and non-ambulatory. While several genes have been implicated to date, the gene that is most commonly associated with EIMFS is KCNT1. Several de novo mutations in KCNT1 have been identified in patients with EIMFS, including V271F, G288S, R428Q, R474Q, R474H, R474C, I760M, A934T, P924L, G243S, H257D, A259D, R262Q, Q270E, L274I, F346L, C377S, R398Q, P409S, A477T, F502V, M516V, Q550del, K629E, K629N, I760F, E893K, M896K, R933G, R950Q, K1154Q. Barcia et al. (2012) Nat Genet. 44: 1255-1260; Ishii et al. (2013) Gene 531:467-471; McTague et al. (2013) Brain. 136: 1578-1591; Epi4K Consortium & Epilepsy Phenome/Genome Project. (2013) Nature 501:217-221; Lim et al. (2016) Neurogenetics; Ohba et al. (2015) Epilepsia 56:el21-el28; Zhou et al. (2018) Genes Brain Behav. e12456; Moller et al. (2015) Epilepsia. e114-20; Numis et al. (2018) Epilepsia.1889-1898; Madaan et al. Brain Dev. 40(3):229-232; McTague et al. (2018) Neurology. 90(1):e55-e66; Kawasaki et al. (2017) J Pediatr. 191:270-274; Kim et al. (2014) Cell Rep. 9(5):1661-1672; Ohba et al. (2015) Epilepsia. 56(9):e121-8; Rizzo et al. (2016) Mol Cell Neurosci. 72:54-63; Zhang et al. (2017) Clin Genet.91(5):717-724; Mikati et al. (2015) Ann Neurol. 78(6):995-9; Baumer et al. (2017) Neurology. 89(21):2212; Dilena et al. (2018) Neurotherapeutics. 15(4):1112-1126. These mutations may be gain-of-function, missense mutations that are dominant (i.e., present on only one allele) and result in change-in-function of the encoded potassium channel that causes a marked increase in whole cell current when tested in Xenopus oocyte or mammalian expression systems (see e.g. Milligan et al. (2015) Ann Neurol.75(4): 581-590; Barcia et al. (2012) Nat Genet.44(11): 1255-1259; and Mikati et al. (2015) Ann Neurol. 78(6): 995-999). [0092] ADNFLE has a later onset than EIMFS, generally in mid-childhood, and is generally a less severe condition. It is characterized by nocturnal frontal lobe seizures and can result in psychiatric, behavioural and cognitive disabilities in patients with the condition. While ADNFLE is associated with genes encoding several neuronal nicotinic acetylcholine receptor subunits, mutations in the KCNT1 gene have been implicated in more severe cases of the disease (Heron et al. (2012) Nat Genet. 44: 1188-1190). Functional studies of the mutated KCNT1 genes associated with ADNFLE indicated that the underlying mutations (M896I, R398Q, Y796H and R928C) were dominant, gain-of-function mutations (Milligan et al. (2015) Ann Neurol. 75(4): 581-590; Mikati et al. (2015) Ann Neurol. 78(6): 995-999). [0093] West syndrome is a severe form of epilepsy composed of a triad of infantile spasms, an interictal electroencephalogram (EEG) pattern termed hypsarrhythmia, and mental retardation, although a diagnosis can be made one of these elements is missing. Mutations in KCNT1, including G652V and R474H, have been associated with West syndrome (Fukuoka et al. (2017) Brain Dev 39:80-83 and Ohba et al. (2015) Epilepsia 56:el21-el28). Treatment targeting the KCNT1 channel suggests that these mutations are gain-of-function mutations (Fukuoka et al. (2017) Brain Dev 39:80-83). [0094] In one aspect, disclosed herein is a method of treating treat a disorder associated with excessive neuronal excitability or a disorder associated with a gain-of-function mutation in a gene such as KCNT1 (for example, epilepsy and other encephalopathies (e.g., MMFSI or EIMFS, ADNFLE, West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, DEE, Lennox-Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, Multifocal Epilepsy, Generalized tonic clonic seizures, drug-resistant epilepsy, Temporal lobe epilepsy, cerebellar ataxia, Asymmetric Tonic Seizures); cardiac dysfunctions (e.g., cardiac arrhythmia, Brugada syndrome, sudden unexpected death in epilepsy, myocardial infarction); pain and related conditions (e.g., neuropathic pain, acute/chronic pain, migraine, etc.); muscle disorders (e.g., myotonia, neuromyotonia, cramp muscle spasms, spasticity); itch and pruritis; ataxia and cerebellar ataxias; psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia), learning disorders, Fragile X, neuronal plasticity, and autism spectrum disorders) comprising administering to a subject in need thereof a compound disclosed herein (e.g., a compound of Formula (I), (e.g., (I-a), (I-b), (I-c), (I-d), or (I- e)) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (I), (e.g., (I-a), (I-b), (I-c), (I-d), or (I-e)) or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable excipient). [0095] In some examples, the subject presenting with a disorder that may be associated with a gain-of-function mutation in KCNT1 is genotyped to confirm the presence of a known gain- of-function mutation in KCNT1 prior to administration of the compounds or a pharmaceutically acceptable salt thereof or and compositions disclosed herein. For example, whole exome sequencing can be performed on the subject. Gain-of-function mutations associated with EIMFS may include, but are not limited to, V271F, G288S, R428Q, R474Q, R474H, R474C, I760M, A934T, P924L, G243S, H257D, A259D, R262Q, Q270E, L274I, F346L, C377S, R398Q, P409S, A477T, F502V, M516V, Q550del, K629E, K629N, I760F, E893K, M896K, R933G, R950Q, and K1154Q. Gain-of-function mutations associated with ADNFLE may include, but are not limited to, M896I, R398Q, Y796H, R928C, and G288S. Gain-of-function mutations associated with West syndrome may include, but are not limited to, G652V and R474H. Gain-of-function mutations associated with temporal lobe epilepsy may include, but are not limited to, R133H and R565H. Gain-of-function mutations associated with Lennox-Gastaut may include, but are not limited to, R209C. Gain-of-function mutations associated with seizures may include, but are not limited to, A259D, G288S, R474C, R474H. Gain-of-function mutations associated with leukodystrophy may include, but are not limited to, G288S and Q906H. Gain-of-function mutations associated with Multifocal Epilepsy may include, but are not limited to, V340M. Gain-of-function mutations associated with early-onset epilepsy (EOE) may include, but are not limited to, F346L and A934T. Gain-of-function mutations associated with Early-onset epileptic encephalopathies (EOEE) may include, but are not limited to, R428Q. Gain-of-function mutations associated with developmental and epileptic encephalopathies may include, but are not limited to, F346L, R474H, and A934T. Gain-of-function mutations associated with epileptic encephalopathies may include, but are not limited to, L437F, Y796H, P924L, and R961H. Gain-of-function mutations associated with Early Infantile Epileptic Encephalopathy (EIEE) may include, but are not limited to, M896K. Gain-of- function mutations associated with drug-resistant epilepsy and generalized tonic-clonic seizure may include, but are not limited to, F346L. Gain-of-function mutations associated with migrating partial seizures of infancy may include, but are not limited to, R428Q. Gain-of-function mutations associated with Leukoencephalopathy may include, but are not limited to, F932I. Gain-of-function mutations associated with NFLE may include, but are not limited to, A934T and R950Q. Gain- of-function mutations associated with Ohtahara syndrome may include, but are not limited to, A966T. Gain-of-function mutations associated with infantile spasms may include, but are not limited to, P924L. Gain-of-function mutations associated with Brugada Syndrome may include, but are not limited to, R1106Q. Gain-of-function mutations associated with Brugada Syndrome may include, but are not limited to, R474H. [0096] In other examples, the subject is first genotyped to identify the presence of a mutation in KCNT1 and this mutation is then confirmed to be a gain-of-function mutation using standard in vitro assays, such as those described in Milligan et al. (2015) Ann Neurol. 75(4): 581- 590. Typically, the presence of a gain-of-function mutation is confirmed when the expression of the mutated KCNT1 allele results an increase in whole cell current compared to the whole cell current resulting from expression of wild-type KCNT1, as may be assessed using whole-cell electrophysiology (such as described in Milligan et al. (2015) Ann Neurol.75(4): 581-590; Barcia et al. (2012) Nat Genet. 44(11): 1255-1259; Mikati et al. (2015) Ann Neurol. 78(6): 995-999; or Rizzo et al. Mol Cell Neurosci. (2016) 72:54-63). This increase of whole cell current can be, for example, an increase of at least or about 50%, 100%, 150%, 200%, 250%, 300%, 350%, 400% or more. The subject can then be confirmed to have a disease or condition associated with a gain-of- function mutation in KCNT1. [0097] In particular examples, the subject is confirmed as having a KCNT1 allele containing a gain-of-function mutation (e.g. V271F, G288S, R398Q, R428Q, R474Q, R474H, R474C, G652V, I760M, Y796H, M896I, P924L, R928C or A934T). [0098] The compounds disclosed herein (e.g., a compound of Formula (I), (e.g., (I-a), (I- b), (I-c), (I-d), or (I-e)) or a pharmaceutically acceptable salt thereof) or the pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (I), (e.g., (I-a), (I-b), (I-c), (I-d), or (I-e)) or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable excipient) can also be used therapeutically for conditions associated with excessive neuronal excitability where the excessive neuronal excitability is not necessarily the result of a gain-of-function mutation in KCNT1. Even in instances where the disease is not the result of increased KCNT1 expression and/or activity, inhibition of KCNT1 expression and/or activity can nonetheless result in a reduction in neuronal excitability, thereby providing a therapeutic effect. Thus, the compounds disclosed herein (e.g., a compound of Formula (I), (e.g., (I-a), (I-b), (I-c), (I-d), or (I-e)) or a pharmaceutically acceptable salt thereof) or the pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (I), (e.g., (I-a), (I-b), (I-c), (I-d), or (I-e)) or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable excipient) can be used to treat a subject with conditions associated with excessive neuronal excitability, for example, epilepsy and other encephalopathies (e.g., EIMFS, ADNFLE, West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, seizures) or cardiac dysfunctions (e.g., cardiac arrhythmia, Brugada syndrome, myocardial infarction), regardless of whether or not the disorder is associated with a gain-of- function mutation in KCNT1. Pharmaceutical Compositions and Routes of Administration [0099] Compounds disclosed herein and pharmaceutically acceptable salts thereof are usually administered in the form of pharmaceutical compositions. Therefore, disclosed herein are pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds described, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions may be prepared in a manner disclosed in the pharmaceutical art, including, for example, in Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa.17^th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3^rd Ed. (G. S. Banker & C. T. Rhodes, Eds.). [00100] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery- inserted cylindrical polymer. [00101] One mode for administration is parenteral, particularly by injection. The forms in which the novel compositions disclosed herein may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. [00102] Sterile injectable solutions are prepared by incorporating a compound or pharmaceutically acceptable salt thereof as disclosed herein in the appropriate solvent with various other ingredients as enumerated above, as desired, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the desired other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, exemplary methods of preparation include vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. [00103] Oral administration is another route for administration of the compounds or pharmaceutically acceptable salts thereof as disclosed herein. Administration may be via capsule or enteric coated tablets, or the like. In making the pharmaceutical compositions that include at least one compound described herein, the active ingredient may be diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders. [00104] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. In certain embodiments, the compositions disclosed herein can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy- benzoates; sweetening agents; and flavoring agents. [00105] The compositions disclosed herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer- coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos.3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another embodiment for use in the methods disclosed herein employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds or pharmaceutically acceptable salts thereof in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is described, for example, in U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents. [00106] The compositions disclosed herein may be formulated in a unit dosage form. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds or pharmaceutically acceptable salt thereof are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from about 1 mg to about 2 g of a compound or pharmaceutically acceptable salt thereof as described herein, and for parenteral administration, preferably from about 0.1 to about 700 mg of a compound or pharmaceutically acceptable salt thereof as described herein. It will be understood, however, that the amount of the compound or pharmaceutically acceptable salt thereof actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or pharmaceutically acceptable salt thereof administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like. [00107] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound or pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. [00108] The tablets or pills disclosed herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. [00109] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In certain embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, such as orally or nasally, from devices that deliver the formulation in an appropriate manner. [00110] In some embodiments, there is provided a pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt thereof, as disclosed herein and a pharmaceutically acceptable carrier. EXAMPLES [00111] In order that the embodiments described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting their scope. [00112] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimal reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization. [00113] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are described in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. [00114] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, trituration, high pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). Note that flash chromatography may either be performed manually or via an automated system. The compounds provided herein may be characterized by known standard procedures, such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS). NMR chemical shifts are reported in part per million (ppm) and are generated using methods described in the art. [00115] List of abbreviations THF tetrahydrofuran TFA trifluoroacetic acid TFAA trifluoroacetic anhydride DMF N,N-dimethylformamide MeOH methanol DCM dichloromethane MeCN or ACN acetonitrile PE petroleum ether EtOAc ethyl acetate DIPEA N,N,-diisopropylethylamine Et₃N or TEA triethylamine HATU o-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate T3P propanephosphonic acid anhydride DCC N,N'-dicyclohexylcarbodiimide N-Boc-L-alanine (2S)-2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)propanoic acid DMSO dimethyl sulfoxide EGTA ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid NMDG N-methyl-D-glucamine HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid IC₅₀ half maximal inhibitory concentration TLC thin layer chromatography LCMS liquid chromatography-mass spectrometry HPLC high-performance liquid chromatography SFC supercritical fluid chromatography MS mass spectrometry NMR nuclear magnetic resonance Example 1. Synthesis of 1-methyl-N-((R)-1-(3-((R)-3-methylpiperidin-1-yl)-1,2,4-oxadiazol- 5-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 1)

Synthesis of tert-butyl ((R)-1-(3-((R)-3-methylpiperidin-1-yl)-1,2,4-oxadiazol-5- yl)ethyl)carbamate (A-1b): [00116] To a stirred solution of A-1a (0.9 g, 5.72 mmol) in 1,4-dioxane (20 mL) was added N-Boc-D-alanine (1.08 g, 5.72 mmol) followed by DCC (1.18 g, 5.72 mmol) at room temperature, and the reaction was stirred at 100 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (30 mL) and washed with water (15 mL). The organic layer was again washed water (10 mL x 2) and brine (10 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated to give the residue. The residue was purified by flash column chromatography using 100-200 mesh silica and 20% EtOAc in hexane as an eluent to give A-1b (0.18 g, 0.34 mmol, 6 % yield) as an oil. Synthesis of (1R)-1-[3-[(3S)-3-methyl-1-piperidyl]-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (A1): [00117] To a stirred solution of A-1b (0.18 g, 0.58 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in dioxane (5 mL) at 0 °C and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to give A1 (0.13 g, 0.35 mmol, 60 % yield) as an oil. Synthesis of Compound 1: [00118] To a stirred solution of A2 (0.1g, 0.52 mmol) in DCM (10 mL) was added A1 (0.13g, 0.52 mmol), HATU (195.88 mg, 0.52 mmol), and DIPEA (0.18 mL, 1.03 mmol) at 0 °C and stirred at room temperature for 6 hours. The reaction mixture was diluted with DCM (10 mL x 2) and water (5 mL). The organic layer was again washed water (10 mL x 2) and brine (10 mL). The organic layer was dried over anhydrous MgSO4, filtered, and evaporated to give the residue. The residue was purified by flash column chromatography using 100-200 mesh silica and 20-25 % EtOAc in hexane to give Compound 1 (30 mg, 0.077 mmol, 15 % yield) as an oil. HPLC: Rt 9.240 min, 99.7%; Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 µm; Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS: 386.8 (M+H), Rt 2.255 min; Column: X-select CSH C18 (3 x 50) mm, 2.5 µm. ¹H NMR (400 MHz, DMSO-d6): δ_H = 9.29 (d, 1H), 7.42 (s, 1H), 5.23-5.19 (m, 1H), 4.12 (s, 3H), 3.74-3.70 (m, 2H), 2.86-2.79 (m, 1H), 1.76-1.44 (m, 7H), 1.13-1.06 (m, 1H), 0.87 (d, 3H), 1H merged in solvent peak. Examples 2 and 3. Synthesis of 1-methyl-N-(1-(3-(4-methylpiperazin-1-yl)-1,2,4-oxadiazol- 5-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 2) and N-(1-(3-(4- acetylpiperazin-1-yl)-1,2,4-oxadiazol-5-yl)ethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole- 5-carboxamide (Compound 3)

Synthesis of tert-butyl N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]carbamate (A-3b) [00119] To a stirred solution of A-3a (10.g, 52.85 mmol) in THF (100 mL) was added N-methylmorpholine (6.39 mL, 58.14 mmol) and ethyl chloroformate (5.53 mL, 58.14 mmol) at -20 ºC under N₂ atmosphere and stirred for 30 minutes. To the reaction mixture, ammonia hydrate (20.36 mL, 528.51 mmol) was added at the -20 ºC and stirred for 5 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL) and washed with 1N KHSO₄, water (100 mL), and brine (100 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated to a give A-3b as a solid. Synthesis of tert-butyl N-[(1S)-1-cyanoethyl]carbamate (A-3c) [00120] To a stirred solution of A-3b (5 g, 26.6 mmol) in THF (40 mL) was added TFAA (5.62 mL, 39.85 mmol) and pyridine (6.3 g, 79.7 mmol) at -10 ºC and stirred at -10 ºC for 3 hours. The solvent was removed under reduced pressure to give a residue, which was dissolved in ethyl acetate, and washed with 1N aqueous KHSO4, water, and brine. The organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated to give a solid, which was recrystallized using ethyl acetate/hexane (2:8) to give A-3c as a solid. Synthesis of (2S)-2-aminopropanenitrile hydrochloride (A-3d) [00121] To a stirred solution of A-3d (500 mg, 2.94 mmol) in 1,4-dioxane (5 mL) was added 4M HCl/dioxane (2 mL, 2.94 mmol) at room temperature and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, dried, triturated with diethyl ether, and dried to give A-3d. Synthesis of N-[(1S)-1-cyanoethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3-carboxamide (A- 3f) [00122] To a stirred solution of A-3d (600 mg, 5.63 mmol) and 2-methyl-5- (trifluoromethyl)pyrazole-3-carboxylic acid (1 g, 5.63 mmol) in DCM (10 mL) was added DIPEA (0.98 mL, 5.63 mmol) and HATU (3.2 g, 8.45 mmol) at room temperature and stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM and washed with brine. The organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated to give a residue, which was purified by column chromatography to afford A-3f (850 mg, 3.45 mmol, 61 % yield) as a solid. Synthesis of N-[(1S)-1-(3-bromo-1,2,4-oxadiazol-5-yl)ethyl]-2-methyl-5- (trifluoromethyl)pyrazole-3-carboxamide (A3) [00123] To a stirred solution of A-3f (2 g, 8.12 mmol) in toluene (30 mL) was added sodium bicarbonate (2.7 g, 32.5mmol) and dibromomethanone oxime (8.2 g, 40.62 mmol), and then the reaction mixture was stirred at 120 ºC for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate thrice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and evaporated to give a residue, which was purified by column chromatography to give A3 (810 mg, 2.2 mmol, 27 % yield) as a solid. Synthesis of Compound 2: [00124] To a stirred solution of A3 (0.15 g, 0.41 mmol) in DMF (2 mL) was added DIPEA (0.14 mL, 0.81 mmol) and heated to 60 °C for 12 hours. The reaction mixture was diluted with water (5 ml) and EtOAc (10 ml), and the organic layer was separated. The organic layer was washed with saturated brine solution (5 mL), separated and dried over MgSO4, and evaporated to give a residue, which was purified by flash column chromatography using 30 % EtOAc in hexane as an eluent to afford a residue. The residue was re-purified by prep HPLC give Compound 2 (8 mg, 0.02 mmol, 4.9 % yield) as a solid. HPLC: Rt 5.241 min, 98.1% Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 µm Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 388.25 (M+H), Rt 1.416 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 µm. ¹H NMR (400 MHz, DMSO-d6) δ_H = 9.30 (d, 1H), 7.42 (s, 1H), 5.24-5.20 (m, 1H), 4.12 (s, 3H), 3.32 (t, 4H), 2.37 (t, 4H), 2.20 (s, 3H), 1.54 (d, 3H). Synthesis of Compound 3: [00125] To a stirred solution of A3 (0.15 g, 0.41 mmol) in DMF (2 mL) was added 1-piperazin-1-ylethanone (0.05 g, 0.41 mmol), DIPEA (0.14 mL, 0.81 mmol) and heated to 60 °C for 12 hours. The reaction mixture was diluted with water (5 ml) and EtOAc (10 ml), and the organic layer was separated. The organic layer was washed with saturated brine solution (1 x 5 mL), separated and dried over MgSO₄, and evaporated to dryness to give a residue, which was purified by flash column chromatography using 30% EtOAc in hexane as an eluent to give a solid, which was re-purified by prep HPLC to give Compound 3 (15 mg, 0.036 mmol, 9 % yield) as a solid. HPLC: Rt 7.160 min, 99.9% Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 µm Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 416.20 (M+H), Rt 1.74 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 µm [00126] ¹H NMR (400 MHz, DMSO-d6) δH = 9.30 (d, 1H), 7.42 (s, 1H), 5.25-5.20 (m, 1H), 4.12 (s, 3H), 3.60-3.50 (m, 4H), 3.38-3.28 (m, 4H), 2.03 (s, 3H), 1.55 (d, 3H). Chiral HPLC shows racemic mixture. Example 4. Synthesis of 1-methyl-N-((S)-1-(3-((R)-2-methylpiperidin-1-yl)-1,2,4-oxadiazol- 5-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 4)

Synthesis of (R)-2-methylpiperidine-1-carbonitrile (A5): [00127] To a stirred solution of A4 (0.65 g, 6.55 mmol) in MeCN (15 mL) was added K₂CO₃ (1.8 g, 13.11 mmol) followed by addition of cyanogen bromide (1.04 g, 9.83mmol) at 0 °C and stirred at room temperature for 16 hours. The residue was diluted with EtOAc (30 mL) and washed with water (15 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated under reduced pressure to give A5 (0.56 g, 4.04 mmol, 62 % yield) as an oil. Synthesis of (R,Z)-N'-hydroxy-2-methylpiperidine-1-carboximidamide (A6): [00128] To a stirred solution of A5 (0.6 mg, 4.51 mmol) in ethanol (10 mL) was added hydroxyl amine hydrochloride (0.38 g, 5.41 mmol) and triethyl amine (0.91 mL, 9.02 mmol). The reaction mixture was stirred at 80 °C for 12 hours. The solvent was evaporated to give A6 (1.1 g), which was used in the next step without further purification. Synthesis of tert-butyl ((S)-1-(3-((R)-2-methylpiperidin-1-yl)-1,2,4-oxadiazol-5- yl)ethyl)carbamate (A7): [00129] To a stirred solution of A6 (1.1 g, 7 mmol) in 1,4-dioxane (25 mL) was added N-Boc-L-alanine (1.32 g, 7 mmol) followed by DCC (1.44 g, 7 mmol) at room temperature and stirred at 100 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with water (20 mL). The organic layer was again washed with water (20 mL x 2) and brine. The organic layer was separated, dried over magnesium sulfate, and filtered. The organic layer was evaporated under reduced pressure to give the residue. The residue was purified by flash column chromatography using 100-200 mesh silica and 30 % EtOAc in hexane as an eluent to give A7 (150 mg, 0.14 mmol) as a liquid. Synthesis of (S)-1-(3-((R)-2-methylpiperidin-1-yl)-1,2,4-oxadiazol-5-yl)ethan-1-amine (A8): [00130] To a stirred solution of A7 (0.15 g, 0.48 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in dioxane (5 mL) at 0 °C and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether to give A8 (100 mg, 0.17 mmol) as a solid. Synthesis of Compound 4: [00131] To a stirred solution of A8 (0.08 g, 0.39 mmol) in DCM (5 mL) was added A2 (0.1 g, 0.39 mmol), HATU (0.16 g, 0.43 mmol) and DIPEA (0.13 mL, 0.77 mmol) at room temperature and stirred for 6 hours. The reaction mixture was diluted with DCM (10 mL) and washed with water (5 mL), and the organic layer was separated. The organic layer was again washed water (10 mL x 2) and brine (10 mL). The organic layer was dried over anhydrous MgSO4, filtered, and evaporated to give the residue. The residue was purified by flash column chromatography using 100-200 mesh silica and 20-25 % EtOAc in hexane. The compound was re- purified by prep. HPLC to give Compound 4 (20 mg, 0.052 mmol, 13 % yield) as an oil. HPLC: Rt 9.234 min, 99.8% Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 µm Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 387.05 (M+H), Rt 2.132 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 µm. ¹H NMR (400 MHz, DMSO-d6) δH = 9.28 (d, 1H), 7.42 (s, 1H), 5.23-5.19 (m, 1H), 4.15-4.10 (m, 4H), 3.63-3.59 (m, 1H), 3.03- 2.96 (m, 1H), 1.70-1.40 (m, 9H), 1.11 (d, 3H). Example 5. Synthesis of 1-methyl-N-((S)-1-(3-((S)-2-methylpiperidin-1-yl)-1,2,4-oxadiazol- 5-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 5)

Synthesis of (S)-2-methylpiperidine-1-carbonitrile (A10): [00132] To a stirred solution of A9 (0.5 g, 5.04 mmol) in MeCN (10 mL) was added K₂CO₃ (1.4 g, 10 mmol) followed by addition of cyanogen bromide (0.8 g, 7.56 mmol) at 0 °C and stirred at room temperature for 16 hours. The residue was diluted with EtOAc (100 mL x 2) and washed with water (10 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated to give a residue, which was purified by column chromatography using 100-200 silica gel and 30-80% EtOAc/Hexane as an eluent to give A10 (0.6 g, 4.25 mmol, 84 % yield) as an oil. Synthesis of (S,Z)-N'-hydroxy-2-methylpiperidine-1-carboximidamide (A11): [00133] To a stirred solution of A10 (0.6 mg, 4.25 mmol) in ethanol (15 mL) was added hydroxyl amine hydrochloride (295.46mg, 4.25mmol) and triethyl amine (1.19 mL, 8.5 mmol). The reaction mixture was stirred at 80 °C for 6 hours. The reaction mixture was quenched using water (10 ml) and diluted with EtOAc (100 mL x 2). The organic layer was separated, dried by Na₂SO₄, filtered, and evaporated to give a residue, which was purified by column chromatography using 100-200 silica and 30-80% EtOAc/Hexane as an eluent to give A11 (600 mg, 3.05 mmol, 72 % yield). Synthesis of tert-butyl ((S)-1-(3-((S)-2-methylpiperidin-1-yl)-1,2,4-oxadiazol-5- yl)ethyl)carbamate (A12): [00134] To a stirred solution of A11 (0.6 g, 3.05 mmol) in 1,4- dioxane (20 mL) was added N-Boc-L-alanine (0.58 g, 3.05 mmol) followed by the addition of DCC (0.63 g, 3.05 mmol) at room temperature and stirred at 100 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL x 2) and washed with water (10 mL). The organic layer was again washed with water (10 mL x 2) and brine (10 mL). The organic layer was separated, dried over sodium sulphate, and filtered. The organic layer was evaporated under reduced pressure to give the residue. The residue was purified by flash column chromatography using 100-200 mesh silica and 30-80 % EtOAc in hexane as an eluent to give A12 (100 mg, 0.13 mmol) as an oil. Synthesis of (S)-1-(3-((S)-2-methylpiperidin-1-yl)-1,2,4-oxadiazol-5-yl)ethan-1-amine (A13): [00135] To a stirred solution of A12 (0.1 g, 0.32 mmol) in 1,4- dioxane (5 mL) was added 4M HCl in dioxane (10 mL) at 0 °C and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether to give A13 (70mg, 0.11 mmol) as an oil. Synthesis of Compound 5: [00136] To a stirred solution of A13 (70 mg, 0.11 mmol) and A2 (26.43 mg, 0.14 mmol) in DCM (10 mL) was added HATU (64.72 mg, 0.17 mmol) and DIPEA (0.04 mL, 0.23 mmol) at room temperature and stirred for 2 hours. The reaction mixture was diluted with DCM (200 mL) and washed with water (100 mL) and brine. The organic layer was again washed with water (10 mL x 2) and brine (10 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated to give the residue. The residue was purified by flash column chromatography using 100-200 mesh silica and 30-80 % EtOAc in hexane as an eluent to give Compound 5 (15 mg, 0.038 mmol, 33.87% yield) as a solid. HPLC: Rt 9.261 min, 99.5% Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 µm Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 387.20 (M+H), Rt 2.17 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 µm.¹H NMR (400 MHz, DMSO-d6) δH = 9.28 (d, 1H), 7.41 (s, 1H), 5.25-5.17 (m, 1H), 4.12 (s, 3H), 3.63-3.59 (m, 1H), 3.03-2.96 (m, 1H), 1.66-1.58 (m, 3H), 1.55-1.53 (m, 5H), 1.45-1.38 (m, 1H), 1.11 (d, 3H), 1.05-0.90 (m, 1H).. Example 6. Synthesis of (S)-N-(1-(3-(isobutyl(methyl)amino)-1,2,4-oxadiazol-5-yl)ethyl)-1- methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 6):

[00137] To a stirred solution of A3 (0.1 g, 0.27 mmol) in DMF (2 mL) was added N,2-dimethylpropan-1-amine (0.04g, 0.41 mmol) and DIPEA (0.09 mL, 0.54 mmol). The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (5 mL) and brine. The organic layer was again washed with brine (10 mL). The organic layer was dried over anhydrous MgSO4, filtered, and evaporated to give the residue. The residue was purified by flash column chromatography using 100-200 mesh silica and 30-80 % EtOAc in hexane. The compound was re-purified by prep. HPLC to give Compound 6 (10 mg, 0.027 mmol, 10 % yield) as an oil. HPLC: Rt 8.902 min, 99.5% Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 µm Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 375.1 (M+H), Rt 2.133 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 µm.¹H NMR (400 MHz, DMSO-d6) δ_H = 9.25 (d, 1H), 7.41 (s, 1H), 5.25-5.15 (m, 1H), 4.12 (s, 3H), 3.12 (d, 2H), 2.91 (s, 3H), 2.00-1.95 (m, 1H), 1.53 (d, 3H), 0.83 (d, H). Example 7. Synthesis of 1-methyl-N-((S)-1-(3-((S)-2-methylmorpholino)-1,2,4-oxadiazol-5- yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 7)

Synthesis of (2R)-2-methylmorpholine-4-carbonitrile (A-14b) [00138] To a stirred solution of A-14a (0.6 g, 5.93 mmol) in DMF (4 mL) was added K₂CO₃ (2.45 g, 17.8 mmol) followed by cyanogen bromide (0.63 g, 5.93 mmol) at 0 °C and stirred at room temperature for 16 hours. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (30 mL) and washed with water (15 mL). The organic layer was again washed water (10 mL x 2) and brine (10 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated to give A-14b (450 mg, 3.57 mmol, 60 % yield) as an oil. Synthesis of rac-(2S)-N-hydroxy-2-methyl-morpholine-4-carboxamidine (A-14c) [00139] To a stirred solution of A-14b (0.63 g, 4.99 mmol) in ethanol (5 mL) was added hydroxylamine hydrochloride (3 g, 14.9 mmol) and triethylamine (2.09 mL, 14.9 mmol). The reaction mixture was stirred at 70 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give A-14c (510 mg, 3.2 mmol, 64 % yield) as a solid, which was used in the next reaction without further purification. Synthesis of tert-butyl N-[(1S)-1-[3-[(2S)-2-methylmorpholin-4-yl]-1,2,4-oxadiazol-5- yl]ethyl]carbamate (A-14d) [00140] To a stirred solution of A-14c (0.5 g, 3.14 mmol) in 1,4-dioxane (7 mL) was added N-Boc-L-alanine (0.59 g, 3.14 mmol) followed by DCC (0.65 g, 3.14 mmol) at room temperature and stirred at 100 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water. The organic layer was again washed water and brine. The organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated to give the residue. The residue was purified by flash column chromatography using 100-200 mesh silica and 7 % EtOAc in hexane as an eluent to give A-14d (509 mg, 1.5 mmol, 48 % yield) as an oil. Synthesis of 1S)-1-[3-[(2S)-2-methylmorpholin-4-yl]-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (A14) [00141] To a stirred solution of A-14d (0.3 g, 0.96 mmol) in 1,4-dioxane (6 mL) was added 4M HCl in dioxane (4 mL) at 0°C and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give A14 (0.21 g, 0.61 mmol, 63 % yield) as an oil, which was used for next step without purification. Synthesis of Compound 7 [00142] To a stirred solution of A14 (150 mg, 0.60 mmol) in DCM (5 mL) was added A2 (175.61 mg, 0.90 mmol), DIPEA (0.32 mL, 1.81 mmol) and HATU (343.98 mg, 0.90 mmol) at room temperature and stirred for 16 hours. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated to give the residue. The residue was purified by to give Compound 7 (20 mg ,0.051 mmol, 8% yield) as an oil. HPLC: Rt 8.13 min, 98.5% Column: X-Select CSH C18 (4.6 x 150) mm, 5 µm Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 389 (M+H), Rt 1.927 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 µm.¹H NMR (400 MHz, DMSO-d6) δH = 9.25 (d, 1H), 7.42 (s, 1H), 5.26-5.18 (m, 1H), 4.12 (s, 3H), 3.88-3.82 (m, 1H), 3.66-3.62 (m, 1H), 3.58-3.50 (m, 3H), 2.98-2.90 (m, 1H), 2.66-2.60 (m, 1H), 1.54 (d, 3H), 1.11 (d, 3H). Example 8. Synthesis of (S)-N-(1-(3-(benzylamino)-1,2,4-oxadiazol-5-yl)ethyl)-1-methyl-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 8)

[00143] To a stirred solution of A3 (25 mg, 0.070 mmol) in DMF (2 mL) was added phenylmethanamine (0.01 mL, 0.10 mmol) and DIPEA (0.02 mL, 0.14 mmol). The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (5 mL) and brine. The organic layer was again washed brine (10 mL). The organic layer was dried over anhydrous MgSO4, filtered, and evaporated to give the residue. The residue was purified by prep HPLC to give Compound 8 (15 mg, 0.038 mmol, 56 % yield) as an oil. HPLC: Rt 8.459 min, 99.9% Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 µm Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 395.20 (M+H), Rt 1.985 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 µm. ¹H NMR (400 MHz, DMSO-d6) δ_H = 9.25 (d, 1H), 7.48-7.44 (m, 1H), 7.41 (s, 1H), 7.32-7.28 (m, 4H), 7.26- 7.21 (m, 1H), 5.22-5.18 (m, 1H), 4.25 (d, 2H), 4.12 (s, 3H), 1.53 (d, 3H). Example 9. Synthesis of (S)-N-(1-(3-(isobutylamino)-1,2,4-oxadiazol-5-yl)ethyl)-1-methyl-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 9)

Synthesis of isobutylcyanamide (A-15b) [00144] To a solution of carbononitridic bromide (5.21 g, 49.22 mmol) in MeCN (30 mL) was added K₂CO₃ (5.7 g, 41.02 mmol) and a solution of A-15a (3 g, 41.02 mmol) in MeCN in a dropwise manner at 0 º C under argon and stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, and insoluble materials were separated by filtration. The organic layer was washed with water and brine, dried over sodium sulphate, and evaporated to give A-15b as a liquid, which was used for next step without further purification. Synthesis of 1-hydroxy-3-isobutyl-guanidine (A-15c) [00145] A mixture of A-15b (1 g, 10.19 mmol), hydroxylamine hydrochloride (0.92 g, 13.25 mmol) and TEA (2.84mL, 20.38mmol) in ethanol (10 mL) was heated at 80 ºC for 16 hours. The solvent was removed, and the residue was triturated with diethyl ether and dried using vacuum to give A-15c as a solid, which was used directly for the next step without further purification. Synthesis of tert-butyl N-[(1S)-1-[3-(isobutylamino)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (A-15e) [00146] A mixture of A-15c (1 g, 7.62 mmol), A-15d (1.59 g, 8.39 mmol), DCC (1.73 g, 8.39 mmol) in 1,4-dioxane (15mL) was heated at 100 º C for 12 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine, dried over sodium sulphate, and evaporated to give residue, which was purified by column chromatography on silica gel using ethyl acetate, hexane to give A-15e as a solid (1 g , 3.52 mmol, 46% yield). Synthesis of 5-[(1S)-1-aminoethyl]-N-isobutyl-1,2,4-oxadiazol-3-amine hydrochloride (A15) [00147] To a stirred solution of A-15e (0.5g, 1.76mmol) in 1,4-dioxane (5mL) was added 4M HCl 1,4-dioxane (5 mL, 1.76 mmol) and stirred reaction at 0 ºC for 2 hours. The reaction mixture was evaporated under vacuum to give a solid, which was washed using diethyl ether to give A15 as a solid (0.3 g, 0.82 mmol, 46% yield). Synthesis of Compound 9 [00148] To a stirred solution of A15 (0.2 g, 0.91 mmol) in DCM (10 mL) was added A2 (211.08 mg, 1.09 mmol), HATU (516.85 mg, 1.36 mmol) and DIPEA (0.32 mL, 1.81 mmol) at room temperature and stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (100 mL x 2) and washed with water (100 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated to give the residue. The residue was purified by flash column chromatography using 100-200 mesh silica and 30-80 % EtOAc in hexane as an eluent to give Compound 9 (20 mg, 0.055 mmol, 6% yield) as a solid. HPLC: Rt 8.576 min, 99.7% Column: X-Select CSH C18 (4.6 x 150) mm, 5 µm. Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 361.05 (M+H), Rt 1.972 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 µm.¹H NMR (400 MHz, DMSO-d6) δ_H = 9.25 (d, 1H), 7.42 (s, 1H), 6.95-6.91 (m, 1H), 5.21-5.18 (m, 1H), 4.15 (s, 3H), 2.86-2.83 (m, 2H), 1.86- 1.80 (m, 1H), 1.55-1.51 (m, 3H), 0.90-0.85 (m, 6H). Example 10. Synthesis of 1-methyl-N-((R)-1-(3-((S)-3-methylpiperidin-1-yl)-1,2,4- oxadiazol-5-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 10)

Synthesis of tert-butyl N-[(1R)-1-[3-[(3S)-3-methyl-1-piperidyl]-1,2,4-oxadiazol-5- yl]ethyl]carbamate (A-16b) [00149] To a stirred solution of A-16a (1 g, 6.36 mmol) in 1,4-dioxane (20 mL) was added N-Boc-D-alanine (1.26 g, 6.36 mmol) followed by DCC (1.31 g, 6.36 mmol) at room temperature and stirred at 100 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (30 mL) and washed with water (15 mL). The organic layer was again washed water (10 mL x 2) and brine (10 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated to give the residue. The residue was purified by flash column chromatography using 100-200 mesh silica and 20 % EtOAc in hexane as an eluent to give A-16b (0.18 g, 0.46 mmol, 7 % yield) as an oil. Synthesis of (1R)-1-[3-[(3S)-3-methyl-1-piperidyl]-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (A16) [00150] To a stirred solution of A-16b (0.18 g, 0.58 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in dioxane (5 mL) at 0 °C and stirred at room temperature 6 hours. The reaction mixture was concentrated under reduced pressure to give A16 (0.16 g,0.52 mmol, 91 % yield) as an oil. Synthesis of Compound 10: [00151] To a stirred solution of A2 (0.1 g, 0.52 mmol) in DCM (15mL) was added A16 (0.13 g, 0.52 mmol), HATU (0.2 g, 0.52 mmol) and DIPEA (0.18 mL, 1.03 mmol) at 0 °C and stirred at room temperature for 6 hours. The reaction mixture was diluted with DCM (10 mL) and washed with water (5 mL). The organic layer was again washed with water (10 mL x 2) and brine (10 mL). The organic layer was dried over anhydrous MgSO₄, filtered, and evaporated to give the residue. The residue was purified by flash column chromatography using 100-200 mesh silica and 20-25 % EtOAc in hexane as an eluent to give Compound 10 (110 mg,0.277 mmol, 54% yield) as an oil. (SOR: 35.95, Concentration 0.261 w/v%). HPLC: Rt 9.257 min, 97.2% [00152] Column: X-Select CSH C18 (4.6 x 150) mm, 5 µm Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 387.25 (M+H), Rt 2.119 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 µm. ¹H NMR (400 MHz, DMSO-d6) δH = 9.29 (d, 1H), 7.42 (s, 1H), 5.23-5.18 (m, 1H), 4.12 (s, 3H), 3.74-3.64 (m, 2H), 2.85-2.78 (m, 1H), 2.54-2.52 (m, 1H), 1.73-1.43 (m, 7H), 1.11-1.06 (m, 1H), 0.87 (d, 3H). Example 11. Synthesis of (S)-N-(1-(3-(benzyl(methyl)amino)-1,2,4-oxadiazol-5-yl)ethyl)-1- methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 11):

Synthesis of benzylcyanamide (A-17b) [00153] To a stirred solution of cyanogen bromide (6.23 g, 58.8 mmol) and sodium carbonate (11.87g, 111.99 mmol) in ether (50mL) was added benzylamine (3.06 mL, 28 mmol) at 0 °C and stirred at room temperature 4 hours. The reaction mixture was filtered on a celite bed, and the filtrate evaporated to give A-17b (3.6 g, 14.4 mmol, 51 % yield) as a solid. Synthesis of benzyl(methyl)cyanamide (A-17c) [00154] To a stirred solution of A-17b (2 g, 15.13 mmol) in DMF (10 mL) was added K₂C_O3 (2.3g, 16.65 mmol) and methyl iodide (0.95 mL, 15.13 mmol) at 0 °C and then stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (30 mL) and water (20 mL), and the organic layer was separated. The organic layer was washed with water (2 x 20 mL) and a saturated brine solution (1 x 20 mL), dried over MgSO₄, and evaporated to give a residue, which was purified by flash column chromatography using 30 % EtOAc in hexane as an eluent to give A-17c (1.2 g, 7.42 mmol, 49 % yield,) as an oil. Synthesis of 1-benzyl-2-hydroxy-1-methyl-guanidine (A-17d) [00155] To a stirred solution of A-17c (1.g, 6.84mmol) in ethanol (20mL) was added hydroxyl amine hydrochloride (0.56 g, 8.07 mmol) and triethylamine (1.38 g, 13.68 mmol) and heated to 80 °C for 12 hours. The reaction mixture was evaporated, and the residue dissolved in EtOAc (50 mL) and diluted with water (20mL). The separated organic layer was dried MgSO₄ and evaporated to dryness to give A-17d (0.9 g, 2.89 mmol, 42 % yield) as an oil. Synthesis of tert-butyl N-[(1S)-1-[3-[benzyl(methyl)amino]-1,2,4-oxadiazol-5- yl]ethyl]carbamate (A-17e) [00156] To a stirred solution of A-17d (0.8g, 4.46mmol) in 1,4-dioxane (20mL) was added N-Boc-L-alanine (0.84 g, 4.46 mmol) and DCC (0.92 g, 4.46 mmol) and heated to 100 °C for 12 hours. The reaction mixture was evaporated, and the residue was dissolved with EtOAc (30 mL) and diluted with water (15 mL). The separated organic layer was washed with water (2 x 10 mL) and saturated brine solution (10 mL). The separated organic layer was dried over MgSO4 and evaporated to give the residue. The residue was then purified by flash column chromatography using 20 % EtOAc in hexane as an eluent to give A-17e (0.23 g,0.61 mmol, 13% yield) as an oil. Synthesis of 5-[(1S)-1-aminoethyl]-N-benzyl-N-methyl-1,2,4-oxadiazol-3-amine hydrochloride (A17) [00157] To a stirred solution of A-17e (0.23 g, 0.69 mmol) in 1,4-dioxane (1mL) was added 4M HCl in dioxane (5.mL, 0.69 mmol) at 0 °C and stirred at room temperature for 4 hours. The reaction mixture was evaporated to give A17 (0.18 g, 0.64 mmol, 93 % yield) as a solid. Synthesis of Compound 11 [00158] To a stirred solution of A2 (0.1 g, 0.52 mmol) in DCM (10 mL) was added A17 (0.17 g, 0.62 mmol), HATU (0.24 g, 0.62 mmol) and DIPEA (0.18 mL, 1.03 mmol) at room temperature and stirred at room temperature for 6 hours. The reaction mixture was diluted with DCM (20 mL) and washed with water (10 mL). The organic layer was washed with brine (10 mL). The organic layer was dried over anhydrous MgSO4, filtered, and evaporated to give the residue. The residue was purified by flash column chromatography using 100-200 mesh silica and 30-35% EtOAc in hexane as an eluent to give Compound 11 (50 mg,0.122 mmol, 24% yield) as an oil. HPLC: Rt 9.021 min, 99.7% Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 µm Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 409.25 (M+H), Rt 2.072 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 µm. ¹H NMR (400 MHz, DMSO-d6) δH = 9.30 (d, 1H), 7.41 (s, 1H), 7.34-7.24 (m, 5H), 5.25-5.20 (m, 1H), 4.52 (s, 2H), 4.12 (s, 3H), 2.86 (s, 3H), 1.56 (d, 3H). Example 12. Synthesis of 1-methyl-N-((S)-1-(3-((R)-3-methylpiperidin-1-yl)-1,2,4- oxadiazol-5-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 12)

Synthesis of (R)-3-methylpiperidine-1-carbonitrile (A19): [00159] To a stirred solution of A18 (1 g, 7.37 mmol) in MeCN (30 mL) was added K₂CO₃ (3.06 g, 22.12 mmol) followed by addition of cyanogen bromide (1.17 g, 11.06 mmol) at 0 °C and stirred at room temperature for 16 hours. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (30 mL) and washed with water (15 mL). The organic layer was again washed water (10 mL x 2) and brine (10 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated to give A19 (0.77 g, 6.2 mmol, 84 % yield) as an oil. Synthesis of (R,Z)-N'-hydroxy-3-methylpiperidine-1-carboximidamide (A20): [00160] To a stirred solution of A19 (0.77 g, 6.2 mmol) in ethanol (20 mL) was added hydroxyl amine hydrochloride (0.47 g, 6.82 mmol) and triethyl amine (1.25 g, 12.4 mmol). The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give A20 (2 g) as a solid. The compound was used in the next reaction without further purification. Synthesis of tert-butyl ((S)-1-(3-((R)-3-methylpiperidin-1-yl)-1,2,4-oxadiazol-5- yl)ethyl)carbamate (A21): [00161] To a stirred solution of A20 (0.9 g, 5.72 mmol) in 1,4- dioxane (20 mL) was added N-Boc-L-alanine (1.08 g, 5.72 mmol) followed by addition of DCC (1.8 g, 5.72 mmol) at room temperature and stirred at 100 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (30 mL) and washed with water (15 mL). The organic layer was again washed with water (10 mL x 2) and brine (10 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated to give the residue. The residue was purified by flash column chromatography using 100-200 mesh silica and 20 % EtOAc in hexane as an eluent to give A22 (0.18 g, 0.45 mmol) as an oil. Synthesis of (S)-1-(3-((R)-3-methylpiperidin-1-yl)-1,2,4-oxadiazol-5-yl)ethan-1-amine; hydrochloride (A22): [00162] To a stirred solution of A21 (0.18 g, 0.58 mmol) in 1,4- dioxane (2 mL) was added 4M HCl in dioxane (5 mL) at 0 °C and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to give A22 (0.13 g, 0.39mmol) as an oil. Synthesis of Compound 12: [00163] To a stirred solution of A2 (0.1 g, 0.52 mmol) in DCM (10 mL) was added A22 (0.13 g, 0.52 mmol), HATU (0.2 g, 0.52 mmol) and DIPEA (0.18 mL, 1.03 mmol) at 0 °C and stirred at room temperature for 6 hours. The reaction mixture was diluted with DCM (10 mL) and washed with water (5 mL). The organic layer was again washed with water (10 mL x 2) and brine (10 mL). The organic layer was dried over anhydrous MgSO₄, filtered, and evaporated to give the residue. The residue was purified by flash column chromatography using 100-200 mesh silica and 20-25% EtOAc in hexane. The compound was re-purified by prep. HPLC to give Compound 12 (57 mg, 0.147 mmol, 29 % yield) as an oil. SOR: -35.22, Concentration 0.2505 w/v%. HPLC: Rt 9.26 min, 99.9%; Column: X-Select CSH C18 (4.6 x 150) mm, 5 µm; Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 386.8 (M+H), Rt 2.246 min; Column: X-select CSH C18 (3 x 50) mm, 2.5 µm. ¹H NMR (400 MHz, DMSO-d6): δH = 9.30 (d, 1H), 7.42 (s, 1H), 5.23-5.19 (m, 1H), 4.12 (s, 3H), 3.74-3.69 (m, 2H), 2.85-2.78 (m, 1H), 2.55-1.44 (m, 7H), 1.15-1.05 (m, 1H), 0.87 (d, 3H), 1H merged in solvent peak. Example 13. Synthesis of 1-methyl-N-((S)-1-(3-((S)-3-methylpiperidin-1-yl)-1,2,4-oxadiazol- 5-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 13)

Synthesis of (S)-3-methylpiperidine-1-carbonitrile (A24): [00164] To a stirred solution of A23 (1 g, 7.37mmol) in MeCN (30 mL) was added K₂CO₃ (3.06 g, 22.12 mmol) followed by addition of cyanogen bromide (1.17 g, 11.06 mmol) at 0 °C and stirred at room temperature for 16 hours. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (30 mL) and washed with water (15 mL). The organic layer was again washed with water (10 mL x 2) and brine (10 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated to give A24 (0.85 g, 6.71 mmol, 91.06% yield) as an oil. Synthesis of (S,Z)-N'-hydroxy-3-methylpiperidine-1-carboximidamide (A25): [00165] To a stirred solution of A24 (0.85 g, 6.84 mmol) in ethanol (20 mL) was added hydroxyl amine hydrochloride (0.48 g, 6.84 mmol) and triethyl amine (1.38 g, 13.69 mmol). The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give A25 (2.2 g) as a solid. The residue was used in the next reaction without further purification. Synthesis of tert-butyl ((S)-1-(3-((S)-3-methylpiperidin-1-yl)-1,2,4-oxadiazol-5- yl)ethyl)carbamate (A26): [00166] To a stirred solution of A25 (1 g, 6.36 mmol) in 1,4- dioxane (20 mL) was added N-Boc-L-alanine (1.2 g, 6.36 mmol) followed by the addition of DCC (1.31 g, 6.36 mmol) at room temperature and then stirred at 100 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (30 mL) and washed with water (15 mL). The organic layer was again washed with water (10 mL x 2) and brine (10 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated to give the residue. The residue was purified by flash column chromatography using 100-200 mesh silica and 20-25 % EtOAc in hexane as an eluent to give A27 (0.2 g,0.55 mmol, 9% yield) as an oil. Synthesis of (S)-1-(3-((S)-3-methylpiperidin-1-yl)-1,2,4-oxadiazol-5-yl)ethan-1-amine (A27): [00167] To a stirred solution of A26 (0.2 g, 0.64 mmol) in 1,4- dioxane (2 mL) was added 4M HCl in dioxane (5mL) at 0 °C and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to give A27 (0.145 g,0.44 mmol) as an oil. Synthesis of Compound 13: [00168] To a stirred solution of A2 (0.1 g, 0.52 mmol) in DCM (10 mL) was added A27 (0.13 g, 0.52 mmol), HATU (0.24 g, 0.62 mmol) and DIPEA (0.18 mL, 1.03 mmol) at 0 °C and stirred at room temperature for 6 hours. The reaction mixture was diluted with DCM (10 mL) and water (5 mL). The organic layer was again washed with water (10 mL x 2) and brine (10 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated to give the residue. The residue was purified by flash column chromatography using 100-200 mesh silica and 20-25 % EtOAc in hexane as an eluent to give Compound 13 (100 mg,0.2536 mmol, 49% yield) as an oil. SOR : - 6.19, Concentration 0.2525 w/v%. HPLC: Rt 9.34 min, 97.9%; Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 µm; Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 387.30 (M+H), Rt 2.12 min; Column: X-select CSH C18 (3 x 50) mm, 2.5 µm.¹H NMR (400 MHz, DMSO-d6) δH = 9.30 (d, 1H), 7.42 (s, 1H), 5.23-5.19 (m, 1H), 4.12 (s, 3H), 3.74-3.70 (m, 2H), 2.86-2.78 (m, 1H), 1.76-1.44 (m, 7H), 1.11- 1.06 (m, 1H), 0.87 (d, 3H), 1H merged in solvent peak. Example 14. Synthesis of Synthesis of (S)-1-methyl-N-(1-(3-(piperidin-1-yl)-1,2,4-oxadiazol- 5-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 14)

Synthesis of piperidine-1-carbonitrile (A28): [00169] To a stirred solution of piperidine (500 mg, 5.87 mmol) in acetone (10 mL) at 0 °C was added K₂CO₃ (973 mg, 7.05 mmol) and cyanogen bromide (622 mg, 5.87 mmol). The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated, treated with water (30 mL), and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated to afford A28 (595 mg) as a liquid. The compound was used in the next step without further purification. Synthesis of (E)-N'-hydroxypiperidine-1-carboximidamide (A29): [00170] To a stirred solution of A28 (595 mg, 5.4 mmol) in ethanol (15.0 mL) was added hydroxylamine hydrochloride (561 mg, 8.07 mmol) and DIPEA (2.67 mL, 16.15 mmol). The reaction mixture was heated at 80 ºC for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated to afford A29 (690 mg) which was used in the next step without further purification. Synthesis of tert-butyl (S)-(1-(3-(piperidin-1-yl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate (A30): [00171] To a stirred solution of A29 (690 mg, 4.82 mmol) in 1,4-dioxane (20.0 mL) was added DCC (1.78 g, 8.67 mmol) and (2S)-2-(tert-butoxycarbonylamino)propanoic acid (1.36 g, 7.23 mmol). The reaction mixture was heated at 100 ºC for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was treated with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel with 38% EtOAc/PE to afford A30 (398 mg, 1.34 mmol, 27% yield). LCMS: 297.2 (M+H), Rt 2.36 min Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 µm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate:1.5 mL/min. Synthesis of (S)-1-(3-(piperidin-1-yl)-1,2,4-oxadiazol-5-yl)ethan-1-amine (A31): [00172] To a stirred solution of A30 (398 mg, 1.34 mmol) in DCM (20.0 mL) was added TFA (1.0 mL) at 0 ºC. The reaction mixture was slowly warmed to room temperature and stirred for 4 hours. The mixture was concentrated under reduced pressure and treated with ice water (20 mL). The mixture was treated with 10% NaHCO3 solution (10 mL) and extracted with DCM (2 x 30 mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄, and concentrated to afford A31 (210 mg). The residue was used in the next step without further purification. Synthesis of Compound 14: [00173] To a stirred solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (208 mg, 1.07 mmol) and A31 (210 mg, 1.07 mmol) in THF (20.0 mL) was added Et3N (0.45 mL, 3.21 mmol) and T3P (50% in EtOAc, 1.91 mL, 3.21 mmol) at 0 ºC. The reaction mixture was slowly warmed to room temperature and stirred for 12 hours. The reaction mixture was treated with water (40 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by preparative HPLC to afford Compound 14 (280 mg, 0.72 mmol, 67% yield) as a solid. Prep. HPLC method: Rt 9.5; Column: X-Bridge (150 x 19 mm), 5.0 µm; Mobile phase: 0.1% TFA in water/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 4.79 min, 96.0% Column: X-Bridge C₈ (50 x 4.6) mm, 3.5 µm Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 373.1 (M+H), Rt 2.39 min, Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 µm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate:1.5 mL/min. ¹H NMR (400 MHz, CD3OD): δH = 7.20 (s, 1H), 5.28 (q, 1H), 4.16 (s, 3H), 3.42-3.39 (m, 4H), 1.65-1.63 (m, 9H). [00174] Example 15. Synthesis of 1-methyl-N-((1S)-1-(3-(3-methylpiperidin-1- yl)-1,2,4-oxadiazol-5-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 15)

Synthesis of 3-methylpiperidine-1-carbonitrile (A32): [00175] To a stirred solution of 3-methylpiperidine (1.0 g, 10.08 mmol) in acetone (20 mL) at 0 °C was added K₂CO₃ (1.67 g, 12.1 mmol) and cyanogen bromide (1.07 g, 10.08 mmol). The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated, treated with water (30 mL), and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated to afford A32 (970 mg) as a liquid. The compound was used in the next step without further purification. Synthesis of (E)-N'-hydroxy-3-methylpiperidine-1-carboximidamide (A33): [00176] To a stirred solution of A32 (970 mg, 7.81 mmol) in ethanol (15.0 mL) was added hydroxylamine hydrochloride (0.81 g, 11.71 mmol) and DIPEA (4.08 mL, 23.42 mmol). The reaction mixture was heated at 80 ºC for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated to afford A33 (1.17 g). It was used for the next step without further purification. Synthesis of tert-butyl ((1S)-1-(3-(3-methylpiperidin-1-yl)-1,2,4-oxadiazol-5- yl)ethyl)carbamate (A34) [00177] To a stirred solution of A33 (1.17 g, 7.46 mmol) in 1,4-dioxane (20.0 mL) was added DCC (1.69 g, 8.21 mmol) and (2S)-2-(tert-butoxycarbonylamino)propanoic acid (1.41 g, 7.46 mmol). The reaction mixture was heated at 100 ºC for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was treated with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel with 35% EtOAc/PE to afford A34 (340 mg, 1.09 mmol, 14% yield). LCMS: 311.3 (M+H), Rt 2.55 min Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 µm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate:1.5 mL/min. Synthesis of (1S)-1-(3-(3-methylpiperidin-1-yl)-1,2,4-oxadiazol-5-yl)ethan-1-amine (A35) [00178] To a stirred solution of A34 (340 mg, 1.09 mmol) in DCM (8.0 mL) was added TFA (3.0 mL) at 0 ºC. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure and treated with ice water (20 mL). The mixture was treated with 10% NaHCO₃ solution (10 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄, and concentrated to afford A35 (198 mg). The residue was used in the next step without further purification. Synthesis of Compound 15: [00179] To a stirred solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (183 mg, 0.94 mmol) and A35 (198 mg, 0.94 mmol) in THF (10.0 mL) was added Et₃N (0.39 mL, 2.83 mmol) and T3P (50% in EtOAc, 1.68 mL, 2.83 mmol) at 0 ºC. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was treated with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by preparative HPLC to afford Compound 15 (170 mg, 0.43 mmol, 46% yield) as a solid. Prep. HPLC method: Rt 10.6; Column: Sunfire C-18 (150 x 19 mm), 5.0 µm; Mobile phase: 0.1% TFA in water/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 5.15 min, 99.7% Column: X-Bridge C₈ (50 x 4.6) mm, 3.5 µm Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 387.2 (M+H), Rt 2.54 min, Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 µm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate:1.5 mL/min. ¹H NMR (400 MHz, DMSO-d6): δ_H = 9.30 (d, 1H), 7.42 (s, 1H), 5.23-5.20 (m, 1H), 4.13 (s, 3H), 3.75-3.71 (m, 2H), 2.86-2.79 (m, 1H), 1.77-1.42 (m, 7H), 1.18-1.08 (m, 1H), 0.89 (d, 3H). Example 16. Synthesis of (S)-N-(1-(3-(3,3-dimethylpiperidin-1-yl)-1,2,4-oxadiazol-5- yl)ethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 16)

Synthesis of 3,3-dimethylpiperidine-1-carbonitrile (A36) [00180] To a stirred solution of Na₂CO₃ (2.83 g, 26.73 mmol) in H2O (4.0 mL) was added 3,3-dimethylpiperidine hydrochloride (1.0 g, 6.68 mmol) at 10 ºC. The reaction mixture was stirred for 5 minutes, and cyanogen bromide (0.85 g, 8.02 mmol) in DCM (20 mL) was added drop-wise. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was treated with water (30 mL) and extracted with DCM (2 x 30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated to afford A36 (820 mg) as a liquid. The compound used in the next step without further purification. Synthesis of N'-hydroxy-3,3-dimethylpiperidine-1-carboximidamide (A37) [00181] To a stirred solution of A36 (820 mg, 5.93 mmol) in ethanol (10.0 mL) was added hydroxylamine hydrochloride (618 mg, 8.9 mmol) and DIPEA (1.8 mL, 17.8 mmol). The reaction mixture was heated at 80 ºC for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with water (20 mL) followed by saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated to afford A37 (170 mg). The compound was used in the next step without further purification. Synthesis of tert-butyl (S)-(1-(3-(3,3-dimethylpiperidin-1-yl)-1,2,4-oxadiazol-5- yl)ethyl)carbamate (A38) [00182] To a stirred solution of A37 (170 mg, 0.99 mmol) in 1,4-dioxane (20.0 mL) was added DCC (245 mg, 1.19 mmol) and (2S)-2-(tert-butoxycarbonylamino)propanoic acid (281 mg, 1.49 mmol). The reaction mixture was heated at 100 ºC for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was treated with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel with 35% EtOAc/PE to afford A38 (320 mg, 0.99 mmol, 99% yield). LCMS: 325.3 (M+H), Rt 2.65 min Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 µm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate:1.5 mL/min. Synthesis of (S)-1-(3-(3,3-dimethylpiperidin-1-yl)-1,2,4-oxadiazol-5-yl)ethan-1-amine (A39) [00183] To a stirred solution of A38 (320 mg, 0.99 mmol) in DCM (8.0 mL) was added TFA (1.0 mL) at 0 ºC. The reaction mixture was slowly warmed to room temperature and stirred for 4 hours. The mixture was concentrated under reduced pressure and treated with ice water (20 mL). The mixture was treated with 10% NaHCO₃ solution (10 mL) and extracted with DCM (2 x 30 mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄, and concentrated to afford A39 (195 mg). The residue was used for the next step without further purification. Synthesis of Compound 16: [00184] To a stirred solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (169 mg, 0.88 mmol) and A39 (195 mg, 0.87 mmol) in THF (10.0 mL) was added Et₃N (0.37 mL, 2.63 mmol) and T3P (50% in EtOAc, 1.56 mL, 2.63 mmol) at 0 ºC. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was treated with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by preparative HPLC to afford Compound 16 (200 mg, 0.49 mmol, 56% yield) as a solid. Prep. HPLC method: Rt 11.31; Column: YMC C-18 (150 x 19 mm), 5.0 µm; Mobile phase: 10 mM NH₄OAc in water/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 5.39 min, 99.7% Column: X- Bridge C₈ (50 x 4.6) mm, 3.5 µm Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 401.2 (M+H), Rt 2.63 min, Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 µm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate:1.5 mL/min. ¹H NMR (400 MHz, CD3OD): δH = 7.20 (s, 1H), 5.28 (q, 1H), 4.17 (s, 3H), 3.38-3.32 (m, 2H), 3.11 (s, 2H), 1.69-1.63 (m, 5H), 1.45 (t, 2H), 0.96 (s, 6H). Example 17. Synthesis of (S)-N-(1-(3-(5-azaspiro[2.5]octan-5-yl)-1,2,4-oxadiazol-5-yl)ethyl)- 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 17)

Synthesis of 5-azaspiro[2.5]octane-5-carbonitrile (A40): [00185] To a stirred solution of sodium carbonate (1.4 g, 13.6 mmol) in water (4 mL) was added 5-azaspiro[2.5]octane hydrochloride (500 mg, 3.4 mmol) at 10 ºC. The reaction mixture was stirred for 5 minutes, and cyanogen bromide (792 mg, 7.48 mmol) in DCM (20.0 mL) was added drop-wise. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was treated with water (30 mL) and extracted with DCM (2 x 30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated to afford A40 (380 mg) as a liquid. The compound was used for the next step without further purification. Synthesis of N'-hydroxy-5-azaspiro[2.5]octane-5-carboximidamide (A41): [00186] To a stirred solution of A40 (380 mg, 2.80 mmol) in ethanol (10.0 mL) was added hydroxylamine hydrochloride (293 mg, 4.23 mmol) and DIPEA (1.47 mL, 8.46 mmol). The reaction mixture was heated at 80 ºC for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with water (20 mL) followed by saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated to afford A41 (275 mg). The compound was used for the next step without further purification. Synthesis of tert-butyl (S)-(1-(3-(5-azaspiro[2.5]octan-5-yl)-1,2,4-oxadiazol-5- yl)ethyl)carbamate (A42): [00187] To a stirred solution of A41 (275 mg, 1.63 mmol) in 1,4-dioxane (10.0 mL) was added DCC (401 mg, 1.95 mmol) and (2S)-2-(tert-butoxycarbonylamino)propanoic acid (460 mg, 2.44 mmol). The reaction mixture was heated at 100 ºC for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was treated with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel with 38% EtOAc/PE to afford A42 (205 mg, 0.64 mmol, 39% yield). LCMS: 323.2 (M+H), Rt 2.52 min Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 µm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate:1.5 mL/min. Synthesis of (S)-1-(3-(5-azaspiro[2.5]octan-5-yl)-1,2,4-oxadiazol-5-yl)ethan-1-amine (A43): [00188] To a stirred solution of A42 (205 mg, 0.64 mmol) in DCM (8.0 mL) was added TFA (2.0 mL) at 0 ºC. The reaction mixture was slowly warmed to room temperature and stirred for 4 hours. The mixture was concentrated under reduced pressure and treated with ice water (10 mL). The mixture was treated with 10% NaHCO₃ solution (8.0 mL) and extracted with DCM (3 x 30 mL). The organic layer was washed with brine (20 mL), dried over Na₂SO₄, and concentrated to afford A43 (100 mg). The residue was used in the next step without further purification. Synthesis of Compound 17: [00189] To a stirred solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (94 mg, 0.48 mmol) and (1S)-1-[3-(5-azaspiro[2.5]octan-5-yl)-1,2,4-oxadiazol-5- yl]ethanamine (100 mg, 0.45 mmol) in THF (10.0 mL) was added Et₃N (0.2 mL, 1.45 mmol) and T3P (50% in EtOAc, 0.86vmL, 1.45 mmol) at 0 ºC. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was treated with water (25 mL) and extracted with ethyl acetate (2 x 40 mL). The organic layer was washed with saturated sodium bicarbonate solution (20 mL), washed with brine (20 mL), dried over Na₂SO₄, and concentrated. The residue was purified by preparative HPLC to afford Compound 17 (140 mg, 0.35 mmol, 72% yield) as a solid. Prep. HPLC method: Rt 6.1; Column: Atlantis C-18 (150 x 19 mm), 5.0 µm; Mobile phase: 0.1% TFA in water/acetonitrile; Flow Rate: 15.0 mL/min. HPLC: Rt 5.17 min, 99.5% Column: X-Bridge C₈ (50 x 4.6) mm, 3.5 µm Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL/min. LCMS: 399.1 (M+H), Rt 2.44 min, Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 µm Mobile Phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow Rate:1.5 mL/min. ¹H NMR (400 MHz, CD₃OD): δ_H = 7.21 (s, 1H), 5.28 (q, 1H), 4.18 (s, 3H), 3.47 (t, 2H), 3.23 (s, 2H), 1.78-1.72 (m, 2H), 1.64 (d, 3H), 1.51 (t, 2H), 0.48- 0.34 (m, 4H). Example 18. Synthesis of (S)-N-(1-(3-(azepan-1-yl)-1,2,4-oxadiazol-5-yl)ethyl)-1-methyl-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (18)

Synthesis of azepane-1-carbonitrile (A45): [00190] To a stirred solution of A44 (5 g, 50.42 mmol), in MeCN (60 mL) was added K₂CO₃ (13.93 g, 100.84 mmol) and cyanogen bromide (8.01 g, 75.63 mmol) at 0 ºC, and then reaction was stirred at room temperature for 16 hours. The reaction mixture was filtered through celite, and the filtrate was evaporated to give a residue, which was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulphate and evaporated to afford A46 (4 g, 32.14 mmol, 63 % yield) as a liquid, which was directly used in the next step. Synthesis of (E)-N'-hydroxyazepane-1-carboximidamide (A46): [00191] A stirred solution of A45 (2 g, 16.11 mmol), TEA (4.5 mL, 32.21 mmol) and hydroxylamine hydrochloride (1.68 g, 24.16 mmol) in ethanol (20 mL) was heated at 80 ºC for 16 hours. The solvent was evaporated to give a solid, which was triturated with diethyl ether and dried to give A46 (800 mg, 5.08 mmol, 31 % yield), which was used directly in the next step. Synthesis of tert-butyl (S)-(1-(3-(azepan-1-yl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate (A47): [00192] To a stirred solution of A45 (500 mg, 3.18 mmol), DCC (720.69 mg, 3.5 mmol) and N-Boc-L-alanine (661.95 mg, 3.5 mmol) in 1,4-dioxane (5 mL) was heated at 100 ºC for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 times). The combined organic layer was washed with water and brine, dried over sodium sulphate, and evaporated to give a residue, which was purified by combi-flash chromatography using ethyl acetate:hexane as an eluent to give the product, which was further purified by prep HPLC to give A47 (600 mg, 1.89 mmol, 59 % yield). Synthesis of (S)-1-(3-(azepan-1-yl)-1,2,4-oxadiazol-5-yl)ethan-1-amine (A48): [00193] To a stirred solution of A47 (400.mg, 1.29 mmol) in 1,4- dioxane (2 mL) was added 4M HCl in 1,4-dioxane (6 mL) at 0 ºC and stirred at room temperature for 2 hours. The solvent was evaporated, and the solid was triturated with diethyl ether and dried to give A48 (200 mg, 0.81 mmol, 62 % yield), which was used for next step without further purification. Synthesis of Compound 18: [00194] To a mixture of A48 (200 mg, 0.81 mmol) and A2 (173.07 mg, 0.89 mmol) in DCM (5 mL) was added HATU (462.3 mg, 1.22 mmol), DIPEA (0.42 mL, 2.43 mmol) at room temperature and stirred for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 5ml). The combined organic layer was washed using saturated brine solution (10 ml), separated, dried over MgSO4, and evaporated to give the residue. The residue was purified by flash column chromatography using EtOAc as an eluent. The fractions were evaporated to dryness, and the residue was then purified by prep HPLC to give Compound 18 (85 mg, 0.22 mmol, 27 % yield) as a solid. HPLC: Rt 9.16 min, 99.8 % Column: X-Select CSH C18 (4.6*150) mm, 3.5 µm Mobile phase: A: 0.1% Formic acid in water B: Acetonitrile (95:05); Flow Rate: 1.0 mL/min. LCMS: 387.25 (M+H), Rt 2.18 min, Column: X-select CSH (3.0*50) mm, 2.5 µm.¹H NMR (400 MHz, DMSO-d6) δ_H = 9.28 (d, 1H), 7.41 (s, 1H), 5.28-5.12 (m, 1H), 4.12 (s, 3H), 3.48-3.38 (m, 4H), 1.72-1.60 (m, 4H), 1.58-1.40 (m, 7H).

Example 19. Synthesis of (S)-1-methyl-N-(1-(3-(pyrrolidin-1-yl)-1,2,4-oxadiazol-5-yl)ethyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 19)

Synthesis of pyrrolidine-1-carbonitrile (A50): [00195] To a stirred solution of A49 (5 g, 70.3 mmol) in THF (50 mL) was added TEA (9.81 mL, 70.3 mmol) and cyanogen bromide (7.45 g, 70.3 mmol) at 0 ºC and stirred at room temperature for 2 days. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulphate, and evaporated to give A50 (2 g, 20.80 mmol, 29 % yield), which was directly used in the next step. Synthesis of (E)-N'-hydroxypyrrolidine-1-carboximidamide (A51): [00196] A stirred solution of A50 (2 g, 20.81 mmol), TEA (5.81 mL, 41.61 mmol) and hydroxylamine hydrochloride (2.17 g, 31.21 mmol) in ethanol (20 mL) was heated at 80 ºC for 16 hours. The solvent was evaporated and the solid was triturated with diethyl ether and dried to give A51 (500 mg, 3.87 mmol, 18 % yield) as a solid, which was used directly in the next step. Synthesis of tert-butyl (S)-(1-(3-(pyrrolidin-1-yl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate (A53): [00197] A stirred solution of A51 (500 mg, 3.87 mmol), DCC (877.21 mg, 4.26 mmol) and N-Boc-L-alanine (805.71 mg, 4.26 mmol) in 1,4-dioxane (5 mL) was heated at 100 ºC for 16 hours. The reaction was diluted with water and extracted with ethyl acetate (3 times). The combined organic layer was washed with water and brine, dried over sodium sulphate, and evaporated to give a residue, which was purified by combi-flash chromatography in ethyl acetate: hexane and further by prep HPLC to afford desired A53 (400 mg, 1.41 mmol, 36 % yield) as a solid. Synthesis of (S)-1-(3-(pyrrolidin-1-yl)-1,2,4-oxadiazol-5-yl)ethan-1-amine (A54): [00198] To a stirred solution of A54 (200 mg, 0.71 mmol) in 1,4- dioxane (2 mL) was added 4M HCl in 1,4-dioxane (6 mL) at 0 ºC and stirred at room temperature for 2 hours. The solvent was evaporated. The solid was triturated with diethyl ether and dried to give A54 (140 mg, 0.64 mmol, 90 % yield) as a solid, which was used in the next step directly. Synthesis of Compound 19: [00199] To a stirred solution of A54 (140 mg, 0.64 mmol) and A2 (136.7 mg, 0.70 mmol) in DCM (5 ml) was added HATU (365.14 mg, 0.96 mmol) followed by DIPEA (0.33 mL, 1.92 mmol) and stirred at room temperature for 3 hours. The reaction mixture was diluted with water and ethyl acetate (3 times). The organic layer was separated, washed with water and brine solution, and dried over Na₂SO₄ to obtain a residue. The residue was purified by combi flash column chromatography using EA:hexane as an eluent to give Compound 19 (85.1 mg, 0.23 mmol, 36 % yield) as a solid. HPLC: Rt 8.31 min, 97.9% Column: X-Select CSH C18 (4.6 x 150) mm, 5 µm Mobile phase: A: 0.1% Formic acid in water : Acetonitrile (95:05); B: Acetonitrile, Flow Rate: 1.0 mL/min. LCMS : 359.15 (M+H), Rt 1.95 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 µm. ¹H NMR (400 MHz, DMSO-d6) δH = 9.30 (d, 1H), 7.42 (s, 1H), 5.26-5.12 (m, 1H), 4.12 (s, 3H), 3.35-3.22 (m, 4H), 1.94 – 1.82 (m, 4H), 1.58-1.48 (m, 3H). Example 20. Synthesis of (S)-N-(1-(3-(3,3-difluoropiperidin-1-yl)-1,2,4-oxadiazol-5- yl)ethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 20)

Synthesis of 3,3-difluoropiperidine-1-carbonitrile (A56): [00200] To a stirred solution of compound 1 (0.65 g, 4.12 mmol) in MeCN (15 mL) was added K₂CO₃ (1.71 g, 12.37 mmol) and cyanogen bromide (0.44 g, 4.12 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (30 mL) and water (15 mL). The separated organic layer was washed with water (10 mL x 2) and saturated brine solution (10 mL), dried over anhydrous sodium sulphate, and evaporated to dryness to give A56 (0.48 g, 3.17 mmol, 77% yield) as a solid. The residue was used without further purification. Synthesis of 3,3-difluoro-N'-hydroxy-piperidine-1-carboxamidine (A57): [00201] To a stirred solution of A56 (0.48 g, 3.28 mmol) in ethanol (10 mL) was added hydroxyl amine hydrochloride (0.23 g, 3.28 mmol) and triethylamine (0.66 g, 6.57 mmol). The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to afford A57 (0.55 g, 2.98 mmol, 91% yield) as a solid. The residue was used without further purification. Synthesis of tert-butyl N-[(1S)-1-[3-(3,3-difluoro-1-piperidyl)-1,2,4-oxadiazol-5- yl]ethyl]carbamate (A58): [00202] To a stirred solution of A57 (0.55 g, 3.07 mmol) in 1,4-dioxane (10 mL) was added N-Boc-L-alanine (0.58 g, 3.07 mmol) and DCC (0.63 g, 3.07 mmol), and the reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and water (20 mL). The separated organic layer was washed with water (20 mL x 2) and saturated brine solution (20 mL), dried over anhydrous MgSO4, and evaporated to dryness to give a residue, which was purified by flash column chromatography using silica gel and 30-35% EtOAc in hexane as an eluent to give A58 (0.4 g, 0.91 mmol) as a solid. Synthesis of (1S)-1-[3-(3,3-difluoro-1-piperidyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (A59): [00203] To a stirred solution of A58 (0.4 g, 1.2 mmol) in 1,4- dioxane (2 mL) was added 4M HCl in dioxane (10 mL) at 0 °C and stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure to obtain a solid, which was triturated with ether to give A59 (0.3 g, 1.05 mmol) as an oil. Synthesis of Compound 20: [00204] To a stirred solution of A2 (0.15 g, 0.77 mmol) in DCM (10 mL) was added A59 (0.23 g, 0.85 mmol), HATU (0.32 g, 0.85 mmol) and DIPEA (0.27 mL, 1.55 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL x 2) and saturated brine solution (10 mL), dried over anhydrous MgSO₄, and evaporated to dryness to give a residue, which was purified by flash column chromatography using 70-80 % EtOAc in hexane as an eluent to give Compound 20 (60 mg, 0.14 mmol, 18% yield) as an oil. HPLC: Rt 8.488 min, 93.7% Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 µm Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 409 (M+H), Rt 2.095 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 µm. ¹H NMR (400 MHz, DMSO-d6) δH = 9.31 (d, 1H), 7.42 (s, 1H), 5.25-5.21 (m, 1H), 4.12 (s, 3H), 3.69 (t, 2H), 3.43-3.40 (m, 2H), 2.12-2.02 (m, 2H), 1.80-1.72 (m, 2H), 1.55 (d, 3H). Example 21. Synthesis of 2-methyl-5-(trifluoromethyl)-N-[(1S)-1-[3-[3-(trifluoromethyl)-1- piperidyl]-1,2,4-oxadiazol-5-yl]ethyl]pyrazole-3-carboxamide (21)

Synthesis of 3-(trifluoromethyl)piperidine-1-carbonitrile (A62): [00205] To a stirred solution of A61 (1.g, 6.53mmol) in MeCN (10 mL) was added K₂CO₃ (1.8 g, 13.06 mmol) and cyanogen bromide (1.0 g, 9.79mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (10 mL), and EtOAc was added (100 mL x 2). The separated organic layer was dried over anhydrous sodium sulphate and evaporated to dryness to give a residue, which was purified by column chromatography using 00-200 silica and 30-80% EtOAc/Hexane as eluent to give A62 (1g, 3.93 mmol, 60 % yield). Synthesis of N'-hydroxy-3-(trifluoromethyl)piperidine-1-carboxamidine (A63): [00206] To a stirred solution of A62 (1.1g, 6.17mmol) in ethanol (20 mL) was added hydroxyl amine hydrochloride (514.89 mg, 7.41 mmol) and triethylamine (514.89 mg, 7.41 mmol). The reaction mixture was stirred at 80 °C for 6 hours. The reaction mixture was quenched using water (10 mL) and diluted with ethyl acetate (100 mL x2), and the organic layer was separated. The organic layer was then dried using sodium sulphate, filtered, and evaporated to give a residue, which was purified using column chromatography using 100-200 silica gel and 30-80% EtOAc/Hexane eluent to give A63 (1.1 g, 3.64 mmol, 59% yield). Synthesis of tert-butyl N-[(1S)-1-[3-[3-(trifluoromethyl)-1-piperidyl]-1,2,4-oxadiazol-5- yl]ethyl]carbamate (A64): [00207] To a stirred solution of A63 (1.g, 4.74mmol)) in 1,4- dioxane (50 mL) was added N-Boc-L-alanine (895.97 mg, 4.74 mmol) and DCC (1063.26 mg, 5.16 mmol), and the reaction mixture was stirred at 100 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL x 2) and water (10 mL). The separated organic layer was dried over anhydrous Na₂SO₄ and evaporated to dryness to give a residue, which was purified by flash column chromatography using silica gel and 30-80% EtOAc/Hexane as an eluent to give A64 (700 mg, 1.34 mmol, 28 % yield) as a solid. Synthesis of (1S)-1-[3-[3-(trifluoromethyl)-1-piperidyl]-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (A65): [00208] To a stirred solution of A64 (800 mg, 2.2 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in dioxane (20 mL, 2.2 mmol) at 0 °C and stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure to obtain a solid which was triturated with ether to give A65 (500 mg, 1.163 mmol, 53 % yield) as an oil. Synthesis of Compound 21: [00209] To a stirred solution of A2 (387.3mg, 2mmol) in DCM (10 mL) was added A65 (500 mg, 1.66 mmol), HATU (948.33 mg, 2.49 mmol) and DIPEA (0.58 mL, 3.33 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (50 mL x 2) and water (10 mL). The organic layer was washed with water (10 mL x 2) and saturated brine solution (10 mL), dried over anhydrous by Na₂SO₄, and evaporated to dryness to give a residue, which was purified by flash column chromatography using 30-80% EtOAc/Hexane eluent as an eluent to give 21 (122 mg, 0.27 mmol, 16 % yield) as a solid. HPLC: Rt 9.368 min, 98.6%; Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 µm; Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min; LCMS : 440.9 (M+H), Rt 2.21 min. Column: X-select CSH C18 (3 x 50) mm, 2.5 µm. ¹H NMR (400 MHz, DMSO-d6) δ_H = 9.31 (d, 1H), 7.42 (s, 1H), 5.24-5.20 (m, 1H), 4.12 (s, 3H), 3.96-3.92 (m, 1H), 3.78-3.75 (m, 1H), 3.03-2.91 (m, 2H), 2.65-2.55 (m, 1H), 2.00-1.95 (m, 1H), 1.80-1.74 (m, 1H), 1.60-1.48 (m, 5H). Example 22. Synthesis of 2-methyl-N-[(1S)-1-[3-(3-methylpyrrolidin-1-yl)-1,2,4-oxadiazol- 5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (22)

Synthesis of 3-methylpyrrolidine-1-carbonitrile (A67) [00210] To a stirred solution of A66 (1 g, 8.22 mmol) in MeCN (20 mL) was added K₂CO₃ (3.41 g, 24.67 mmol) and cyanogen bromide (1.31 g, 12.33 mmol) at 0 °C and stirred at room temperature for 16 hours. The reaction mixture was filtered using celite bed. The filtrate was evaporated, the residue was diluted with EtOAc (30 ml) and water (15 ml), and the organic layer was separated. The organic layer was washed with water (2 x 10 mL) and saturated brine solution (10 mL), separated, dried over anhydrous Na₂SO₄, and evaporated to give A67 (0.88 g, 7.99 mmol, 97 % yield) as a liquid. Synthesis of N'-hydroxy-3-methyl-pyrrolidine-1-carboxamidine (A68) [00211] To a stirred solution of A67 (0.88 g, 7.99 mmol) in ethanol (20 mL) was added hydroxyl amine hydrochloride (0.56 g, 7.99 mmol), triethyl amine (1.61 g, 15.98 mmol) and heated to 80 °C for 12 hours. The reaction mixture was evaporated to give A68 (1 g, 2.84 mmol, 35% yield) as an oil. Synthesis of tert-butyl N-[(1S)-1-[3-(3-methylpyrrolidin-1-yl)-1,2,4-oxadiazol-5- yl]ethyl]carbamate (A69) [00212] To a stirred solution of A68 (1.g, 6.98 mmol) in 1,4-dioxane (15 mL) was added N-Boc-L-alanine (1.45 g, 7.68 mmol), DCC (1.58 g, 7.68 mmol) and heated to 100 °C for 12 hours. The reaction mixture was evaporated, the residue was diluted with EtOAc (50 mL) and water (20 mL), and the organic layer was separated. The organic layer was washed with water (2 x 20 mL) and saturated brine solution (20 mL), dried over MgSO₄, and evaporated to dryness to give a residue. The residue was then purified by flash column chromatography using 30 % EtOAc in hexane as an eluent to give A69 (0.3 g, 0.34 mmol, 5 % yield) as a solid Synthesis of rac-(1S)-1-[3-(3-methylpyrrolidin-1-yl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (A70) [00213] To a stirred solution of A69 (0.3 g, 1.01 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in dioxane (10 mL, 1.01 mmol) at 0 °C and stirred at room temperature for 6 hours. The reaction mixture was evaporated to dryness in vacuo to give A70 (0.18 g, 0.45 mmol, 45 % yield) as a solid. Synthesis of 22: [00214] To a stirred solution of A2 (0.14 g, 0.72 mmol) and A70 ((0.17 g, 0.72 mmol) in DCM (10 mL) was added HATU (0.27 g, 0.72 mmol) and DIPEA (0.25 mL, 1.44 mmol) at 0 °C and stirred at room temperature for 6 hours. The reaction mixture was diluted with DCM (20 mL) and washed with water (10 mL) The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to give the residue. The residue was purified by prep HPLC to give 22 (90 mg, 0.24 mmol, 33% yield) as an oil. HPLC: Rt 8.759 min, 99.8%; Column: X-Select CSH C18 (4.6 x 150) mm, 5 µm; Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 373.05 (M+H), Rt 1.92 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 µm.¹H NMR (400 MHz, DMSO-d6) δH = 9.02 (d, 1H), 7.43 (s, 1H), 5.22-5.18 (m, 1H), 4.12 (s, 3H), 3.50-3.25 (m, 3H), 2.87-2.83 (m, 1H), 2.33-2.27 (m, 1H), 2.07- 2.00 (m, 1H), 1.58-1.49 (m, 4H), 1.03 (d, 3H). Example 23. Synthesis of N-[(1S)-1-[3-(diethylamino)-1,2,4-oxadiazol-5-yl]ethyl]-2-methyl- 5-(trifluoromethyl)pyrazole-3-carboxamide (23)

Synthesis of diethylcyanamide (A72) [00215] To a stirred solution of A71 (1.43 mL, 13.67 mmol) in ACN (20 mL) was added cyanogen bromide (2 g, 20.51 mmol), K₂CO₃ (3.9 g, 27.34 mmol) and stirred for 16 hours at room temperature. The reaction was quenched by water (10mL) and diluted with EtOAc (100 mL x 2). The organic layer was separated, dried over Na₂SO₄, filtered, and evaporated to give a residue, which was purified by column chromatography using 100-200 silica and 30-80% EtOAc/Hexane as an eluent to give A72 (1.1g, 10.08 mmol, 74% yield) as an oil. Synthesis of 1,1-diethyl-2-hydroxy-guanidine (A73) [00216] To a stirred solution of A72 (1.1 g, 10.09 mmol) in ethanol (20 mL) was added hydroxylamine hydrochloride (841.1 mg, 12.1 mmol) and TEA (2.82 mL, 20.17 mmol), and the mixture was stirred at 80 ºC for 6 hours. The reaction mixture was quenched using water (10 mL) and diluted with EtOAc (100 mL x 2). The organic layer was separated, dried over Na₂SO₄, filtered, and evaporated to give a residue. The residue was purified by column chromatography using 100-200 silica and 30-80% EtOAc/hexane as an eluent to give A73 (1.2 g, 8.507 mmol, 84 % yield) as a solid. Synthesis of tert-butyl N-[(1S)-1-[3-(diethylamino)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (A74) [00217] To a stirred solution of A73 (1.g, 7.09 mmol) and (2S)-2-(tert- butoxycarbonylamino)propanoic acid (1341.4 mg, 7.09 mmol) in 1,4-dioxane (50mL) was added DCC (1591.88 mg, 7.73 mmol) and stirred for 12 hours at 100 ºC. The reaction mixture was quenched by water (10mL) and diluted with EtOAc (100 mL x 2). The organic layer was separated, dried over Na₂SO₄, filtered, and evaporated to give a residue, which was purified by column chromatography using 100-200 silica and 30-80% EtOAc/hexane as an eluent to give A74 (200 mg, 0.2391 mmol, 3 % yield) as a solid. Synthesis of 5-[(1S)-1-aminoethyl]-N,N-diethyl-1,2,4-oxadiazol-3-amine hydrochloride (A75) [00218] To a stirred solution of A74 (200 mg, 0.24 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in 1,4-dioxane (10 mL, 0.24 mmol) then stirred at 0 ºC for 2 hours. The reaction mixture was evaporated to give a residue, which was washed by diethyl ether to give A75 (100 mg, 0.1541 mmol, 64% yield) as a solid. Synthesis of 23 [00219] To a stirred solution of A75 (100.mg, 0.15 mmol) and A2 (35.88 mg, 0.18 mmol) in DCM (10 mL) was added HATU (87.86 mg, 0.23 mmol) and DIPEA (0.05 mL, 0.30 mmol) at room temperature and stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and diluted with DCM (50 mL x 2). The organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated to give a residue. The residue was purified by column chromatography using 100-200 silica and 30-80% EtOAc/hexane as an eluent to give 23 (12mg, 0.033 mmol, 21 % yield) as a solid. HPLC: Rt 8.558 min, 99.5%; Column: X- Select CSH C18 (4.6 x 150) mm, 3.5 µm; Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 361.05 (M+H), Rt 1.947 min, Column: X- select CSH (3 x 50) mm, 2.5 µm; ¹H NMR (400 MHz, DMSO-d6) δ_H = 9.27 (d, 1H), 7.40 (s, 1H), 5.19 (quin, 1H), 4.11 (s, 3H), 3.23-3.38 (m, 4H), 1.53 (d, 3H), 1.08 (t, 6H). Example 24. Synthesis of (S)-1-methyl-N-(1-(3-(4-methylpiperidin-1-yl)-1,2,4-oxadiazol-5- yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (24)

Synthesis of 4-methylpiperidine-1-carbonitrile (A77) [00220] To a stirred solution of A76 (1 g, 10.08 mmol) in MeCN (20 mL) was added K₂CO₃ (2.8 g, 20.17mmol) followed by addition of cyanogen bromide (1.07 g, 10.08 mmol) at 0 °C under nitrogen and stirred at room temperature for 16 hours. The residue was diluted with EtOAc, and insoluble material was separated by filtration. The organic layer was washed with water and brine, dried over anhydrous sodium sulphate, filtered, and evaporated under reduced pressure to give A77 (1.1 g, 6.2 mmol, 61 % yield) as a liquid. Synthesis of N'-hydroxy-4-methyl-piperidine-1-carboxamidine (A78) [00221] To a stirred solution of A77 (1.1 g, 6.2 mmol) in ethanol (15 mL) was added hydroxyl amine hydrochloride (0.43 g, 6.2 mmol) and triethyl amine (1.73 mL, 12.4 mmol). The reaction mixture was stirred at 80 °C for 16 hours. The solvent was removed to give a residue, which was triturated with diethyl ether and dried under reduced pressure to give A78 (1.2g, 4.58 mmol, 74 % yield) as a solid which was used for next step without further purification. Synthesis of tert-butyl N-[(1S)-1-[3-(4-methyl-1-piperidyl)-1,2,4-oxadiazol-5- yl]ethyl]carbamate (A79): [00222] To a stirred solution of A78 (1.2g, 4.58mmol) in 1,4-dioxane (30 mL) was added N-Boc-L-alanine (866.6 mg, 4.58 mmol) followed by the addition of DCC (1.0 g, 4.99mmol) at room temperature and stirred at 100 °C for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (3 times). The combined organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was then dried over sodium sulphate and evaporated to give a residue, which was purified by column chromatography using silica gel and ethyl acetate:hexane as an eluent to give A79 (0.3 g, 0.68 mmol, 15 % yield) as a solid. Synthesis of ((1S)-1-[3-(4-methyl-1-piperidyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (A80) [00223] To a stirred solution of A79 (0.3 g, 0.97 mmol) in 1,4-dioxane (10 mL) was added 4M HCl in dioxane (10 mL, 0.97 mmol) at 0 °C and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, triturated with diethyl ether, and dried to give A80 (200 mg, 0.53 mmol, 55 % yield) as a solid, which was used for next step without further purification. Synthesis of 24 [00224] To a stirred solution of A79 (200 mg, 0.53 mmol) in DCM (5 mL) was added A2 (124.61 mg, 0.64 mmol), HATU (305.12 mg, 0.8 mmol) and DIPEA (0.19 mL, 1.07 mmol) in water (1 mL) at room temperature and stirred at room temperature for 2 hours. The reaction mixture was quenched by water and diluted with DCM. The organic layer was dried over sodium sulphate and concentrated to give a residue, which was purified by prep HPLC to give 24 (20 mg, 0.051 mmol, 9 % yield) as a solid. HPLC: Rt 9.411 min, 98.1%; Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 µm; Mobile phase: A: 0.1%; Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 387.30 (M+H), Rt 2.077 min, Column: X-select CSH (3 x 50) mm, 2.5 µm. ¹H NMR (400 MHz, DMSO-d6) δH = 9.29 (d, 1H), 7.42 (s, 1H), 5.21 (quin, 1H), 4.12 (s, 3H), 3.79 (d, 2H), 2.86 (t, 2H), 1.62-1.72 (m, 2H), 1.54 (d, 4H), 1.02-1.30 (m, 2H), 0.91 (d, 3H). Example 25. Synthesis of (S)-N-(1-(3-(4,4-dimethylpiperidin-1-yl)-1,2,4-oxadiazol-5- yl)ethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (25)

Synthesis 4,4-dimethylpiperidine-1-carbonitrile (A82): [00225] To a stirred solution of A81 (500 mg, 4.42 mmol) was added carbononitridic bromide (701.77 mg, 6.63 mmol) and K₂CO₃ (1220.85 mg, 8.83 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched using water (10 mL) and diluted with EtOAc (50 x 2mL). The organic layer was separated, dried over Na₂SO₄, filtered, and evaporated under reduced pressure to get a residue. The residue was purified by column chromatography using 100-200 silica and 30-80% EtOAc/Hexane eluent as an eluent to get A82 (400 mg, 1.74 mmol, 39 % yield) Synthesis of N'-hydroxy-4,4-dimethyl-cyclohexanecarboxamidine (A83): [00226] To a stirred solution of A82 (400 mg, 2.89 mmol) was added hydroxylamine hydrochloride (144.8 mg, 2.08 mmol) and TEA (0.48 mL, 3.47 mmol), and the mixture was stirred for 6 hours at 80 ºC. The reaction mixture was quenched using water (10 mL) and diluted with EtOAc (50x2 ml). The organic layer was separated, dried over Na₂SO₄, filtered, and evaporated to give a residue, which was purified by column chromatography using 100-200 silica and 30-80% EtOAc/Hexane as an eluent to give A83 (450 mg, 1.98 mmol, 68 % yield). Synthesis of tert-butyl N-[(1S)-1-[3-(4,4-dimethyl-1-piperidyl)-1,2,4-oxadiazol-5- yl]ethyl]carbamate (A84): [00227] To a stirred solution of A83 (450 mg, 2.63 mmol) and (2S)-2-(tert- butoxycarbonylamino)propanoic acid (497.22 mg, 2.63 mmol) in 1,4-Dioxane (15 mL) was added DCC (590.07 mg, 2.86 mmol), and the mixture was stirred for 12 hours at 100 ºC. The reaction mixture was quenched with water (10 mL) and diluted with EtOAc (50 x 2mL). The organic layer was separated, dried over Na₂SO₄, filtered, and evaporated under reduced pressure to get a residue, which was purified by column chromatography using 100-200 silica and 30-80% EtOAc/Hexane as an eluent to get A84 (100 mg, 0.123 mmol, 5 % yield) as a solid. Synthesis of (1S)-1-[3-(4,4-dimethyl-1-piperidyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (A85): [00228] To a stirred solution of A84 (100 mg, 0.31 mmol) in 1,4-Dioxane (5 mL) was added 4M HCl in 1,4-dioxane (5.mL, 0.31 mmol) and the mixture was stirred at 0 ºC for 2 hours. The reaction mixture was evaporated under reduced pressure, and the resulting solid was washed using diethyl ether to get A85 (70 mg, 0.08 mmol, 26 % yield) as an oil. Synthesis of (S)-N-(1-(3-(4,4-dimethylpiperidin-1-yl)-1,2,4-oxadiazol-5-yl)ethyl)-1-methyl-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (25): [00229] To a stirred solution of A85 (70 mg, 0.27 mmol) and A2 (62.53 mg, 0.32 mmol) in DCM (10mL) was added HATU (153.11 mg, 0.4 mmol) and DIPEA (0.09 mL, 0.54 mmol) at room temperature, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched using water (10 mL) and diluted with DCM (50mL), and the organic layer was separated. The organic layer was dried over Na₂SO₄, filtered, and evaporated under reduced pressure to get a residue, which was purified by column chromatography using 100- 200 silica and 30-80% EtOAc/Hexane as an eluent to give 25 (5mg, 0.0119mmol, 4 % yield) as a solid. HPLC: Rt 9.395 min, 95.6%; Column: X-Select CSH C18 (4.6 X 150) mm, 3.5 µm; Mobile phase: A: 0.1% Formic acid in water: ACN (95:05), B: ACN; Flow Rate: 1.0 mL/min. LCMS : 399 (M-H), Rt 2.417 min, Column: X-select CSH C18 (3*50) mm, 2.5 µm; ¹H NMR (400 MHz, DMSO-d6) δ_H = 9.29 (d, 1H), 7.42 (s, 1H), 5.22-5.19 (m, 1H), 4.12 (s, 3H), 3.32-3.31 (m, 4H), 1.54 (d, 3H), 1.36-1.33 (m, 4H), 0.94 (s, 6H). Chiral method: Rt 7.534 min, 94.9% min; column: DIACEL CHIRALPAK-IG (250x4.6mm,5u), - Mobile Phase: A) n-Hexane+0.1%Iso-propyl- amine B) DCM: MeOH (1:1), Isocratic:10%B; Wavelength: 254 nm, Flow: 1.0 mL/min. Example 26. Efficacy of exemplary compounds in the inhibition of KCNT1 KCNT1-WT-Basal – Patch Clamp Assay [00230] Inhibition of KCNT1 (of KCNT1 (KNa1.1, Slack) was evaluated using a tetracycline inducible cell line (HEK-TREX). Currents were recorded using the SyncroPatch 384PE automated, patch clamp system. Pulse generation and data collection were performed with PatchController384 V1.3.0 and DataController384 V1.2.1 (Nanion Technologies). The access resistance and apparent membrane capacitance were estimated using built-in protocols. Current were recorded in perforated patch mode (10 µM escin) from a population of cells. The cells were lifted, triturated, and resuspended at 800,000 cells/ml. The cells were allowed to recover in the cell hotel prior to experimentation. Currents were recorded at room temperature. The external solution contained the following (in mM): NaCl 105, NMDG 40, KCl 4, MgCl₂1, CaCl₂ 5 and HEPES 10 (pH = 7.4, Osmolarity ~300 mOsm). The extracellular solution was used as the wash, reference and compound delivery solution. The internal solution contained the following (in mM): NaCl 105, NMDG 40, KCl 4, MgCl₂ 1, CaCl₂ 5 and HEPES 10 (pH = 7.4, Osmolarity ~300 mOsm). The extracellular solution was used as the wash, reference and compound delivery solution. The internal solution contained the following (in mM): NaCl 70, KF 70, KCl 10, EGTA 5, HEPES 5 and Escin 0.01 (pH = 7.2, Osmolarity ~295 mOsm). Escin is made at a 5mM stock in water, aliquoted, and stored at -20°C. The compound plate was created at 2x concentrated in the extracellular solution. The compound was diluted to 1:2 when added to the recording well. The amount of DMSO in the extracellular solution was held constant at the level used for the highest tested concentration. A holding potential of -80 mV with a 100ms step to 0mV was used. Mean current was measured during the step to 0 mV. 100 µM Bepridil was used to completely inhibit KCNT1 current to allow for offline subtraction of non-KCNT1 current. The average mean current from 3 sweeps was calculated and the % inhibition of each compound was calculated. The % Inhibition as a function of the compound concentration was fit with a Hill equation to derive IC₅₀, slope, min and max parameters. If KCNT1 inhibition was less than 50% at the highest tested concentration or if an IC₅₀ could not be calculated, then a percent inhibition was reported in place of the IC₅₀. [00231] Results from this assay are summarized in Table 1 below. In this table, “A” indicates IC₅₀ of less than or equal to1 µM; “B” indicates inhibition of between 1 µM to 20 µM; and “C” indicates inhibition of greater than or equal to 20 µM. N/A indicates not tested. [00232] Table 1

Equivalents and Scope [00232] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. [00233] Furthermore, the embodiments encompass all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the embodiment, or aspects of the embodiment, is/are referred to as comprising particular elements and/or features, certain embodiments or aspects of the embodiments consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub–range within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [00234] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment can be excluded from any claim, for any reason, whether or not related to the existence of prior art. [00235] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

CLAIMS 1. A compound of Formula I having an oxadiazole core:

, or a pharmaceutically acceptable salt thereof, wherein R₁ is chosen from a C_1-6alkyl, a C_1-6haloalkyl, or a C_3-10cycloalkyl, wherein the C_1-6alkyl, C_1-6haloalkyl, and C_3-10cycloalkyl optionally comprises a substituent chosen from C_1-6alkoxy or N(R₈)₂; R² is chosen from hydrogen or a C₁-4alkyl; R³ is chosen from a C_1-6alkyl optionally comprising a C_1-6alkoxy substituent; R₄ is chosen from hydrogen or a C_1-6alkyl; R₅ is chosen from a C_1-6alkyl or a C_1-6haloalkyl; R₆ is chosen from a hydrogen, a C_1-6alkyl, a C_3-10cycloalkyl, a phenyl, or a 3-10 membered heterocyclyl, wherein the C_1-6alkyl, C_3-10cycloalkyl, phenyl, or 3-10 membered heterocyclyl may optionally comprise one or more substituents chosen from a halogen, -CN, - OH, a C_1-6alkyl, a C_1-6haloalkyl, a C_1-6alkoxy, a phenyl, a C_3-10cycloalkyl, or a 3-10 membered heterocyclyl; R₇ is chosen from a C_1-6alkyl, a C_3-10cycloalkyl, a phenyl, or a 3-10 membered heterocyclyl, wherein the C_1-6alkyl, C_3-10cycloalkyl, phenyl, or 3-10 membered heterocyclyl may optionally comprise one or more substituents chosen from a halogen, -CN, -OH, a C_1-6alkyl, a C_1-6haloalkyl, a C_1-6alkoxy, a phenyl, a C_3-10cycloalkyl, or a 3-10 membered heterocyclyl; or R₆ and R₇ are taken together with the nitrogen attached to R₆ and R₇ to form a 3-10 membered heterocyclyl ring optionally comprising one or more substituents chosen from a halogen, -CN, -OH, a C_1-6alkyl, a C_1-6haloalkyl, a phenyl, a C_3-10cycloalkyl, or a 3-10 membered heterocyclyl, wherein the C_1-6alkyl is optionally substituted with oxo; each R₈ is independently chosen from hydrogen or a C_1-6alkyl; and x is 0, 1 or 2.

2. The compound of claim 1, wherein the compound is a compound of Formula I-a:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein the compound is a compound of Formula I-b:

or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-3, wherein the compound is a compound of Formula I-c:

or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-4, wherein the compound is a compound of Formula I-d or Formula I-e:

or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1-3, wherein R₃ is C_1-6alkyl and R₄ is hydrogen.

7. The compound of any one of claims 1-3 and 6, wherein R₂ is hydrogen.

8. The compound of any one of claims 1-7, wherein R₁ is C_1-6alkyl.

9. The compound of any one of claims 1-8, wherein R₁ is methyl.

10. The compound of any one of claims 1-9, wherein x is 1 or 2.

11. The compound of any one of claims 1-10, wherein x is 1.

12. The compound of any one of claims 1-11, wherein R₅ is C_1-6haloalkyl.

13. The compound of any one of claims 1-12, wherein R₅ is -CF₃.

14. The compound of any one of claims 1-13, wherein R₆ is hydrogen and R₇ is C_1-6alkyl.

15. The compound of any one of claims 1-13, wherein R₆ and R₇ are each C_1-6alkyl optionally comprising a phenyl substituent.

16. The compound of any one of claims 1-13, wherein R₆ and R₇ are taken together with the nitrogen attached to R₆ and R₇ to form a 3-10 membered heterocyclyl ring optionally comprising one or more substituents chosen from a halogen, a C_1-6alkyl, or a C_1-6haloalkyl.

17. The compound of claim 1, wherein the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

19. A method of treating a neurological disorder, wherein the method comprises administering to a subject in need thereof an effective amount of a compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 18.

20. A method of treating a disorder associated with excessive neuronal excitability, wherein the method comprises administering to a subject in need thereof an effective amount of a compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 18.

21. A method of treating a disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1), wherein the method comprises administering to a subject in need thereof an effective amount of a compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 18.

22. The method of any one of claims 19-21, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is epilepsy, an epilepsy syndrome, or an encephalopathy.

23. The method of any one of claims 19-21, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is a genetic or pediatric epilepsy or a genetic or pediatric epilepsy syndrome.

24. The method of any one of claims 19-21, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is a cardiac dysfunction.

25. The method of any one of claims 19-21, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is chosen from epilepsy and other encephalopathies (e.g., malignant migrating focal seizures of infancy (MMFSI) or epilepsy of infancy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, and Lennox-Gastaut syndrome), seizures (e.g., Generalized tonic clonic seizures, Asymmetric Tonic Seizures), leukodystrophy, leukoencephalopathy, intellectual disability, Multifocal Epilepsy, drug-resistant epilepsy, Temporal lobe epilepsy, or cerebellar ataxia.

26. The method of any one of claims 19-21, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is chosen from cardiac arrhythmia, Brugada syndrome, and myocardial infarction.

27. The method of any one of claims 19-21, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is selected from pain and related conditions (e.g., neuropathic pain, acute/chronic pain, migraine).

28. The method of any one of claims 19-21, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is a muscle disorder (e.g., myotonia, neuromyotonia, cramp muscle spasms, spasticity).

29. The method of any one of claims 19-21, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is selected from itch and pruritis, ataxia, or cerebellar ataxias.

30. The method of any one of claims 19-21, wherein the neurological, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is selected from psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia).

31. The method of any one of claims 19-21, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is chosen from a learning disorder, Fragile X, neuronal plasticity, or an autism spectrum disorder.

32. The method of any one of claims 19-21, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1) is chosen from epileptic encephalopathy with SCN1A, SCN2A, and/or SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.