KCNT1 inhibitor and method of use

Abstract

The present invention is directed, in part, to compounds and compositions useful for preventing and / or treating neurological diseases or disorders, diseases or conditions associated with excessive neural excitability and / or gain-of-function mutations in genes (e.g., KCNT1).Methods for treating neurological diseases or disorders, diseases or conditions associated with excessive neural excitability and / or gain-of-function mutations in genes such as KCNT1 are also provided herein.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority and the benefit of U.S. Provisional Patent Application No. 62 / 982,838, filed on February 28, 2020, U.S. Provisional Patent Application No. 62 / 982,830, filed on February 28, 2020, and U.S. Provisional Patent Application No. 62 / 982,804, filed on February 28, 2020, the contents of each of which are incorporated herein by reference in their entirety.

Background Art

[0002] KCNT1 encodes a sodium - activated potassium channel known as Slack (a sequence like a calcium - activated K + channel). These channels are found in neurons throughout the brain and can mediate the sodium - activated potassium current I KNa . This delayed outward current can regulate neuronal excitability and the adaptation rate in response to sustained stimulation. Abnormal Slack activity has been associated with the onset of early - onset epilepsy and intellectual disability. Thus, pharmaceutical compounds that selectively modulate sodium - activated potassium channels, e.g., abnormal KCNT1, abnormal I KNa , are useful for treating neurological diseases or disorders, or diseases or conditions associated with excessive neuronal excitability and / or gain - of - function mutations in KCNT1.

Summary of the Invention

[0003] Described herein are compounds and compositions useful for preventing and / or treating diseases, disorders, or conditions, such as neurological diseases or disorders, excessive neuronal excitability, and / or diseases, disorders, or conditions associated with gain - of - function mutations in a gene, e.g., KCNT1.

[0004] In one aspect, the present disclosure features a pharmaceutical composition comprising a compound of formula I - I below or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient: [Chemical] In the formula, L is a bond or C 1-6 alkyl, X is CH or N; when X is CH in the formula, the hydrogen of CH may be substituted by R5, G is selected from the group consisting of phenyl, C 3-10 cycloalkyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl, R2 is hydrogen, R3 is C 1-6 alkyl optionally substituted with C 1-6 alkoxy, R4 is hydrogen, Each R5 is independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-10 cycloalkyl, Each R6 is independently selected from hydrogen or C 1-6 alkyl, R 12 are each independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, S(O)2(C 1-6 alkyl), -S(O)2(C 3-6 cycloalkyl), -C(O)C 1-6 alkyl, -C(O)N(R6)2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, and phenyl, and z is 0, 1, 2, 3, or 4.

[0005] In another aspect, provided herein is a pharmaceutical composition comprising a compound of formula I-I-I below or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient: [Chemical formula] In the formula, G is selected from the group consisting of phenyl, a 5- to 10-membered heterocyclyl containing at least one unsaturated bond in the heterocyclic ring, and a 5- to 10-membered heteroaryl; R2 is hydrogen; R3 is C 1-6 alkyl optionally substituted with alkoxy; 1-6 alkyl; R4 is hydrogen; R5 is selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-10 cycloalkyl; Each R6 is independently selected from hydrogen or C 1-6 alkyl; R 12 are each independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, S(O)2(C 1-6 alkyl), -S(O)2(C 3-6 cycloalkyl), -C(O)C 1-6 alkyl, -C(O)N(R6)2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, and phenyl; and z is 0, 1, 2, 3, or 4.

[0006] In some embodiments, the compound of formula I-I-I is a compound of formula I-I-Ia or formula I-I-Ib, or a pharmaceutically acceptable salt thereof. [Chemical formula]

[0007] In another aspect, provided herein is a pharmaceutical composition comprising a compound of formula I-I-II or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient:

Chemical formula

[0008] In some embodiments, the compound is a compound of formula I-I-IIa or a pharmaceutically acceptable salt thereof. [Chemistry]

[0009] In some embodiments, the compound is a compound of formula I-I-IIb or formula I-I-IIc, or a pharmaceutically acceptable salt thereof: [Chemistry]

[0010] In some embodiments, the compound is a compound of formula I-I-IId, or a pharmaceutically acceptable salt thereof. [Chemistry]

[0011] In some embodiments, the compound is a compound of formula I-I-IIe or formula I-I-IIf, or a pharmaceutically acceptable salt thereof: [Chemistry]

[0012] In another aspect, the present disclosure features a pharmaceutical composition comprising a compound of formula II-I below or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient: [Chemistry] wherein, each R1 is independently halogen, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, R2 is hydrogen or C 1-4 alkyl, R3 is C 1-6 alkyl optionally substituted with C1-6 is alkyl, R4 is C 1-6 hydrogen or C optionally substituted with alkoxy 1-6 is alkyl, R5 and R6 are each independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, where in this case, C 1-6 alkyl, C 3-10 cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl may optionally be substituted with one or more of halogen, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, aryl, C 3-10 cycloalkyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, and wherein both R5 and R6 are not hydrogen, or R5 and R6, together with the nitrogen to which they are attached, optionally form a 3- to 10-membered heterocyclyl ring substituted with one or more of halogen, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, aryl, C 3-10 cycloalkyl, or 3- to 10-membered heterocyclyl, and n is 1 or 2.

[0013] In some embodiments, the compound of formula II-I is a compound of formula II-I-a, or a pharmaceutically acceptable salt thereof.

Chemical formula

[0014] In some embodiments, the compound of formula II-I is a compound of formula II-I-b, or a pharmaceutically acceptable salt thereof.

Chemical formula

[0015] In some embodiments, the compound of formula II-I is a compound of formula II-I-c, or a pharmaceutically acceptable salt thereof.

Chemical formula

[0016] In some embodiments, the compound of formula II-I is a compound of formula II-I-d, or a pharmaceutically acceptable salt thereof.

Chemical formula

[0017] In another aspect, the present disclosure features a compound of formula III-I, or a pharmaceutically acceptable salt thereof:

Chemical formula

[0018] In some embodiments of Formula III-I, the compound of Formula III-I is a compound of Formula III-Ia, or a pharmaceutically acceptable salt thereof.

Chemical formula

[0019] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula III-I (e.g., Formula III-Ia) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0020] In one aspect, the present disclosure provides a method for treating a neurological disease or disorder, the method comprising administering to a subject in need thereof a compound disclosed herein (e.g., a compound of Formula (I-I), (I-I-2), (I-I-I), (I-I-I2), (I-I-I3), (I-I-II), (I-I-II2), (II-I) or (III-I), or a pharmaceutical composition disclosed herein (e.g., a compound of Formula (I-I), (I-I-2), (I-I-I), (I-I-I2), (I-I-I3), (I-I-II), (I-I-II2), (II-I) or (III-I), or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a pharmaceutically acceptable excipient).

[0021] In another aspect, the present disclosure provides a method for treating a disease or condition associated with excessive neuronal excitability, the method comprising administering to a subject in need thereof a compound disclosed herein (e.g., a compound of formula (I-I), (I-I-2), (I-I-I), (I-I-I2), (I-I-I3), (I-I-II), (I-I-II2), (II-I) or (III-I)), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of formula (I-I), (I-I-2), (I-I-I), (I-I-I2), (I-I-I3), (I-I-II), (I-I-II2), (II-I) or (III-I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient).

[0022] In another aspect, the present disclosure provides a method for treating a disease or condition associated with a gain-of-function mutation of a gene (e.g., KCNT1), the method comprising administering to a subject in need thereof a compound disclosed herein (e.g., a compound of formula (I-I), (I-I-2), (I-I-I), (I-I-I2), (I-I-I3), (I-I-II), (I-I-II2), (II-I) or (III-I)), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of formula (I-I), (I-I-2), (I-I-I), (I-I-I2), (I-I-I3), (I-I-II), (I-I-II2), (II-I) or (III-I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient).

[0023] In some embodiments, the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation of a gene (e.g., KCNT1) is epilepsy, epileptic syndrome, or encephalopathy.

[0024] In some embodiments, the neurological disease or disorder, disease or condition associated with excessive neuronal excitability, or disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is genetic or childhood epilepsy, or a genetic or childhood epilepsy syndrome.

[0025] In some embodiments, the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in a gene (eg, KCNT1) is cardiac dysfunction.

[0026] In some embodiments, the neurological disease or disorder, disease or condition associated with excessive neuronal excitability, or disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from epilepsy and other encephalopathies (e.g., epilepsy of infancy with migratory focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, Lennox Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia).

[0027] In some embodiments, the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from the group consisting of cardiac arrhythmia, sudden unexpected death in epilepsy, Brugada syndrome, and myocardial infarction.

[0028] In some embodiments, the neurological disease or disorder, disease or condition associated with excessive neural excitability, or disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.).

[0029] In some embodiments, the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is a muscular disorder (e.g., myotonia, neuromyotonia, muscle cramps, spasticity).

[0030] In some embodiments, the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from pruritus and prurigo, ataxia, and cerebellar ataxia.

[0031] In some embodiments, the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from mental disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia).

[0032] In some embodiments, the neurological disease or disorder, or the disease or condition associated with excessive neuronal excitability and / or a gain-of-function mutation in a gene (e.g., KCNT1) is selected from the group consisting of learning disabilities, fragile X, neural plasticity, and autism spectrum disorder.

[0033] In some embodiments, neurological diseases or disorders, diseases or conditions associated with excessive neuronal excitability, or diseases or conditions associated with gain-of-function mutations in genes (e.g., KCNT1) are selected from the group consisting of epilepsy encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, nodding epilepsy, benign familial neonatal-infantile seizures, SCN2A epilepsy encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic childhood partial epilepsy with SCN3A mutation, SCN8A epilepsy encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures in infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epilepsy encephalopathy, and KCNT1 epilepsy encephalopathy.

[0034] Other objects and advantages will become apparent to those skilled in the art from a consideration of the following detailed description, examples, and claims for carrying out the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0035] As generally described herein, the present invention provides compounds and compositions useful for preventing and / or treating diseases, disorders, or conditions described herein, such as diseases, disorders, or conditions associated with excessive neuronal excitability and / or diseases, disorders, or conditions associated with gain-of-function mutations in KCNT1. Exemplary diseases, disorders, or conditions include epilepsy and other encephalopathies (e.g., epilepsy of infancy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathies, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, and Lennox syndrome. Gastaut syndrome, seizures, leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic seizures, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia, asymmetric tonic seizures), as well as cardiac dysfunction (e.g., cardiac arrhythmias, 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, muscle spasms, spasticity), itch and pruritus, ataxia and cerebellar ataxia, and psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia).

[0036] definition chemical definition Definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Ed., 1999; and specific functional groups are generally defined as described therein. thEdition, 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.

[0037] The compounds described herein may contain one or more asymmetric centers and, therefore, may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from the mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC), as well as the formation and crystallization of chiral salts, or the preferred isomers can be prepared by asymmetric synthesis. 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). In addition, the invention encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0038] As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., is enantiomerically pure). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is thus enantiomerically pure with respect to the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 98.5%, greater than 99%, greater than 99.2%, greater than 99.5%, greater than 99.6%, greater than 99.7%, greater than 99.8%, or greater than 99.9% enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0039] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R compound can contain, for example, about 90% excipient and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition can contain, for example, at least about 95% R compound and at most about 5% S compound, by total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S compound can contain, for example, about 90% excipient and about 10% enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition can contain, for example, at least about 95% S compound and at most about 5% R compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0040] The compounds described herein can also contain one or more isotope substitutions. For example, H can be 1 H, 2 H (D or deuterium), and 3It may be in any isotopic form containing H (tritium or hydrogen), and C is 12 C, 13 C, and 14 It may be in any isotopic form containing C, and O is 16 O and 18 It may be in any isotopic form containing O, and F is 18 F and 19 It may be in any isotopic form containing F, etc.

[0041] The following terms are intended to have the meanings presented below and are useful for understanding the description and intended scope of the present invention. When describing an invention that may include a compound and its pharmaceutically acceptable salts, a pharmaceutical composition containing such a compound, and methods of using such compounds and compositions, the following terms, when present and unless otherwise indicated, have the following meanings. Also, as described herein, it should be understood that any of the moieties defined below may be substituted with various substituents and that the substituted moieties thus formed are intended to be included within the ranges described for each of their definitions below. Unless otherwise specified, the term "substituted" is defined as described below. It should be further understood that the terms "group" and "radical" may be considered interchangeable as used herein. The articles "a" and "an" may be used herein to refer to one or 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.

[0042] When a range of values is recited, it is intended to include each value and subrange within the range. For example, "C 1-6 alkyl" means 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 , C2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 is intended to include alkyl.

[0043] As used herein, "alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having, for example, 1 to 20 carbon atoms ("C 1-20 alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C 1-10 alkyl"). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1-9 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 alkyl"). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom (C1 alkyl). C 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0044] The term "heteroalkyl" as used herein refers to an "alkyl" group in which at least one carbon atom is replaced by an O or S atom. Heteroalkyl is, for example, -O-C1-C 10It may also be an alkyl group, a -C1-C6 alkylene-O-C1-C6 alkyl group, or a C1-C6 alkylene-OH group. In certain embodiments, "heteroalkyl" may be a 2- to 8-membered heteroalkyl, indicating that the heteroalkyl contains 2 to 8 atoms selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. In still other embodiments, heteroalkyl may be a 2- to 6-membered, 4- to 8-membered, or 5- to 8-membered heteroalkyl group (which may contain, for example, one or two heteroatoms selected from oxygen groups and nitrogen groups). In certain embodiments, heteroalkyl is an "alkyl" group in which 1 to 3 carbon atoms are replaced by oxygen atoms. One type of heteroalkyl group is an "alkoxy" group.

[0045] As used herein, "alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group having 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 2-20 alkenyl"). In certain embodiments, alkenyl does not contain a triple bond. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2-10 alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2-9 alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4 alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C2-3 "alkenyl"). In some embodiments, the alkenyl group has 2 carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. C 2-6 Examples of 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), octatrieneyl (C8), and the like.

[0046] As used herein, "alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having 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, the alkynyl does not contain a double bond. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C 2-10 alkynyl"). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C 2-9 alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2-8 alkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2-7 alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2-6 alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2-5 alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C2-4 (alkynyl). In some embodiments, the alkynyl group has 2 to 3 carbon atoms (C 2-3 alkynyl). In some embodiments, the alkynyl group has 2 carbon atoms (C2 alkynyl). One or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. C 2-6 Examples of 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.

[0047] As used herein, "alkylene", "alkenylene", and "alkynylene" each 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 can be substituted with one or more substituents described herein or can be unsubstituted.

[0048] As used herein, "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) 4n+2 aromatic ring system radical having 6 to 14 ring carbon atoms and 0 heteroatoms provided in an aromatic ring system (C 6-14 aryl). In some embodiments, the aryl group has 6 ring carbon atoms (C6 aryl, e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (C 10"Aryl", e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl", e.g., anthracyl). "Aryl" also includes cases where the aryl ring defined above is fused to one or more carbocyclic or heterocyclic groups, and the radical or point of attachment is on the aryl ring. In such cases, the ring system is included where the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, acenaphthylene, 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 groups derived from trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0049] As used herein, "heteroaryl" refers to a radical (a "5- to 10-membered heteroaryl") of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., having 6 or 10 electrons shared in a cyclic arrangement). In a heteroaryl group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. A heteroaryl bicyclic ring system can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, the point of attachment being on the heteroaryl ring, and in such examples, the number of ring members continues to specify the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which the heteroaryl ring as defined above is fused to one or more aryl groups, the point of attachment being on either the aryl or heteroaryl ring, and in such examples, the number of ring members specifies the number of ring members in the fused (aryl / heteroaryl) ring system. For a bicyclic heteroaryl group in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., either the ring bearing the heteroatom (e.g., 2-indolyl) or the ring not containing a heteroatom (e.g., 5-indolyl).

[0050] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system (a "5- to 10-membered heteroaryl") having ring carbon atoms provided in the aromatic ring system and 1 to 4 ring heteroatoms each independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system (a "5- to 8-membered heteroaryl") having ring carbon atoms provided in the aromatic ring system and 1 to 4 ring heteroatoms each independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system (a "5- to 6-membered heteroaryl") having ring carbon atoms provided in the aromatic ring system and 1 to 4 ring heteroatoms each independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0051] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-fused bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-fused bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0052] Examples of representative heteroaryls include the following:

Chemical formula

[0053] As used herein, "carbocyclic" or "carbocyclic ring" refers to a radical of a non-aromatic ring system having 3 to 10 ring carbon atoms ("C 3-10 carbocyclic") and 0 heteroatoms. In some embodiments, the carbocyclic group has 3 to 8 ring carbon atoms ("C 3-8 carbocyclic"). In some embodiments, the carbocyclic group has 3 to 6 ring carbon atoms ("C 3-6 carbocyclic"). In some embodiments, the carbocyclic group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclic"). Exemplary C 3-6 carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-8 carbocyclic groups include, but are not limited to, the aforementioned C 3-6 carbocyclic groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrieneyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 carbocyclic groups include, but are not limited to, the aforementioned C 3-8 carbocyclic groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10 )), spiro[4.5]decanil (C 10 ), etc. As illustrated by the foregoing examples, in certain embodiments, the carbocyclic group is either monocyclic ("monocyclic carbocyclic") or contains a fused, bridged, or spiro ring system such as a bicyclic system ("bicyclic carbocyclic"), and may be saturated or partially unsaturated. "Carbocyclic" also includes ring systems in which the carbocyclic ring defined above is fused to one or more aryl or heteroaryl groups and the point of attachment is on the carbocyclic ring, and in such examples, the number of carbons continues to specify the number of carbons in the carbocyclic ring system.

[0054] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbons, and herein, for example, "C 4-8 cycloalkyl" derived from cycloalkanes is referred to. Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane. Unless otherwise specified, the cycloalkyl group is optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amide, amidino, amino, aryl, arylalkyl, azide, carbamic acid, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamide, sulfonyl, or thiocarbonyl. The cycloalkyl group may be fused to another cycloalkyl, aryl, or heterocyclyl group. In certain embodiments, the cycloalkyl group is unsubstituted, i.e., non-substituted.

[0055] As used herein, "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system (a "3- to 10-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In a heterocyclyl group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as valence permits. The heterocyclyl group can be monocyclic ("monocyclic heterocyclyl"), or any of a fused, bridged, or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. The bicyclic heterocyclic ring system can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes cases where the heterocyclyl ring defined above is fused to one or more carbocyclic groups, the point of attachment is on either the carbocyclic or heterocyclyl ring or ring system, the heterocyclyl ring defined above is fused to one or more aryl or heteroaryl groups, the point of attachment is on the heterocyclyl ring, and in such examples, ring systems where the number of ring members continues to designate the number of ring members in the heterocyclyl ring system are included.

[0056] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system (a "5- to 10-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system (a "5- to 8-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system (a "5- to 6-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0057] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiirenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, 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, but are not limited to, 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, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0058] When used to describe a compound or a group present in a compound, "hetero" means that one or more carbon atoms in the compound or group are replaced by heteroatoms of nitrogen, oxygen, or sulfur. Hetero may be applied to any of the above-described hydrocarbyl groups, such as, for example, alkyl, such as heteroalkyl; carbocyclic, such as heterocyclic; aryl, such as heteroaryl; and the like having 1 to 5, particularly 1 to 3 heteroatoms.

[0059] As used herein, "cyano" refers to -CN.

[0060] 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.

[0061] As used herein, "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0062] As used herein, "nitro" refers to -NO2.

[0063] As used herein, "oxo" refers to -C=O.

[0064] Generally, the term "substituted", whether or not preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced by an acceptable substituent, i.e., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, or other reactions. Unless otherwise indicated, a "substituted" group has substituents at one or more substitutable positions of the group, and when two or more positions of any given structure are substituted, the substituents are either the same or different at each position.

[0065] The nitrogen atom can be substituted or unsubstituted as long as the valence permits, and includes primary, secondary, tertiary, and quaternary 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 carbocyclic, 3- to 14-membered heterocyclic, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups attached to the nitrogen atom are joined to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc , and R dd are as defined above.

[0066] These and other exemplary substituents are described in more detail in the "Modes for Carrying Out the Invention", "Examples", and "Claims". The present invention is not intended to be limited in any way by the exemplary listing of substituents above.

[0067] Other definitions The term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are those 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 salts of amino groups formed 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, laurylsulfate, 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, etc. Pharmaceutically acceptable salts derived from appropriate bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4Examples of the (alkyl)4 salts include. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0068] As used herein, the "subject" for which administration is contemplated includes, but is not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents), or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)), and / or non-human animals, such as mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, 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.

[0069] Diseases, disorders, and conditions are used interchangeably herein.

[0070] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" are intended to have an effect (also "therapeutic treatment") that occurs while the subject is suffering from a specified disease, disorder, or condition and that reduces the severity of the disease, disorder, or condition, or delays or retards the progression of the disease, disorder, or condition.

[0071] Generally, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.

[0072] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound 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 means the amount of the therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves the overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0073] In an alternative embodiment, the present invention contemplates administering a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, as a prophylactic agent, prior to a subject beginning to suffer from a designated disease, disorder, or condition. As used herein, "prophylactic treatment" contemplates an action that occurs prior to a subject beginning to suffer from a designated disease, disorder, or condition. As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or to prevent its recurrence. A prophylactically effective amount of a compound means the amount of the therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves the overall prophylaxis, or enhances the prophylactic efficacy of another prophylactic agent.

[0074] As used herein, a "disease or condition associated with a gain-of-function mutation in KCNT1" refers to a disease or condition associated with a mutation in KCNT1 that results in a gain-of-function phenotype, i.e., an increase in the activity of the potassium channel encoded by KCNT1 that results in an increase in whole-cell current, or one or more symptoms that are partially or completely caused by, or associated with, such an increase.

[0075] As used herein, "gain-of-function mutation" is a mutation in KCNT1 that results in an increase in the activity of the potassium channel encoded by KCNT1. Activity can be evaluated by, for example, an ion flux assay or electrophysiological methods (such as 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 the potassium channel encoded by wild-type KCNT1.

[0076] Compounds and Compositions In one aspect, the invention features a compound of formula (I-I), or a pharmaceutically acceptable salt thereof:

Chemical Formula

[0077] In another aspect, the present invention features a compound of formula (I-I-2), or a pharmaceutically acceptable salt thereof:

Chemical formula

[0078] In some embodiments of formula (I-I) or (I-I-2), R5 is selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkoxy, and C 3-10 cycloalkyl. For example, R5 is -F, -CF3, cyclopropyl, -OCH2CH3, or -OCH(CH3)3. In some embodiments of formula (I-I) or (I-I-2), R5 is -F. In some embodiments of formula (I-I) or (I-I-2), R5 is -CF3. In some embodiments of formula (I-I) or (I-I-2), R5 is cyclopropyl.

[0079] In some embodiments of formula (I-I) or (I-I-2), R3 is methyl or ethyl. In some embodiments of formula (I-I) or (I-I-2), R3 is methyl. In some embodiments of formula (I-I) or (I-I-2), R3 is ethyl.

[0080] In some embodiments of formula (I-I) or (I-I-2), G is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, thiazolyl, pyridyl, tetrahydropyranyl, thiophenyl, isoxazolyl, isothiazolyl, pyridazinyl, piperidinyl, pyrrolidinyl, triazolyl, benzothiophenyl, pyrimidinyl, bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl,

Chemical formula

[0081] In some embodiments of formula (I-I) or (I-I-2), z is 0, 1 or 2. For example, z is 0. In another example, z is 1 or 2.

[0082] In some embodiments of formula (I-I) or (I-I-2), R 12 are each independently halogen, cyano, hydroxyl, oxo, -S(O)2CH3, -S(O)2CH2CH3, -S(O)2(cyclopropyl), -C(O)CH3, -C(O)NH2, -C(O)N(CH3) -2 , methyl, ethyl, propyl, butyl, isopropyl, isobutyl, -CF3, -OCF3, -OCH3, cyclopropyl, cyclobutyl and phenyl. In some embodiments of formula (I-I) or (I-I-2), R 12 are each independently selected from the group consisting of -F, Cl, -Br, -CF3, cyano, oxo, methyl, and ethyl. In some embodiments of formula (I-I) or (I-I-2), R 12 are each independently selected from the group consisting of methyl, ethyl, phenyl, and -CF3.

[0083] In another aspect, the present invention features a compound of formula (I-I-I), or a pharmaceutically acceptable salt thereof:

Chemical formula

[0084] In another aspect, the present invention features a compound of formula I-I-I2, or a pharmaceutically acceptable salt thereof:

Chemical formula

[0085] In another aspect, the present invention features a compound of formula I-I-I3, or a pharmaceutically acceptable salt thereof:

Chemical formula

[0086] In some embodiments, the compound of formula I-I-I, I-I-I2, or I-I-I3 is a compound of formula I-I-Ia or formula I-I-Ib, or a pharmaceutically acceptable salt thereof:

Chemical formula

[0087] In some embodiments of formula (I-I-I), (I-I-I2), (I-I-I3), (I-I-Ia), or (I-I-Ib), R5 is selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkoxy, and C 3-10 cycloalkyl. For example, R5 is -F, -CF3, cyclopropyl, -OCH2CH3, or -OCH(CH3)3. In some embodiments of formula (I-I-I), (I-I-I2), (I-I-I3), (I-I-Ia), or (I-I-Ib), R5 is halogen. In some embodiments of formula (I-I-I), (I-I-I2), (I-I-I3), (I-I-Ia), or (I-I-Ib), R5 is -F.

[0088] In some embodiments of formula (I-I-I), (I-I-I2), (I-I-I3), (I-I-Ia), or (I-I-Ib), R3 is methyl or ethyl. In some embodiments of formula (I-I-I), (I-I-I2), or (I-I-I3), R3 is methyl. In some embodiments of formula (I-I-I), (I-I-I2), or (I-I-I3), R3 is ethyl.

[0089] In some embodiments of formula (I-I-I), (I-I-I2), (I-I-I3), (I-I-Ia), or (I-I-Ib), G is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, thiazolyl, pyridyl, tetrahydropyranyl, thiophenyl, isoxazolyl, isothiazolyl, pyridazinyl, piperidinyl, pyrrolidinyl, triazolyl, benzothiophenyl, pyrimidinyl, bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl,

Chemical formula

[0090] In some embodiments of formula (I-I-I), (I-I-I2), (I-I-I3), (I-I-Ia), or (I-I-Ib), z is 0, 1, or 2. For example, z is 0. In another example, z is 1 or 2. In some embodiments of formula (I-I-I), (I-I-I2), (I-I-I3), (I-I-Ia), or (I-I-Ib), z is 1. In some embodiments of formula (I-I-I), (I-I-I2), (I-I-I3), (I-I-Ia), or (I-I-Ib), z is 2.

[0091] In some embodiments of formula (I-I-I), (I-I-I2), (I-I-I3), (I-I-Ia), or (I-I-Ib), R 12Each independently is halogen, cyano, hydroxyl, oxo, -S(O)2CH3, -S(O)2CH2CH3, -S(O)2(cyclopropyl), -C(O)CH3, -C(O)NH2, -C(O)N(CH3) -2 , methyl, ethyl, propyl, butyl, isopropyl, isobutyl, -CF3, -OCF3, -OCH3, cyclopropyl, cyclobutyl and phenyl. In some embodiments of formula (I-I-I), (I-I-I2), (I-I-I3), (I-I-Ia) or (I-I-Ib), R 12 Each independently is selected from the group consisting of -F, Cl, -Br, -CF3, cyano, oxo, methyl, phenyl and ethyl. In some embodiments of formula (I-I-I), (I-I-I2), (I-I-I3), (I-I-Ia) or (I-I-Ib), R 12 Each independently is selected from the group consisting of -F, -Cl, -Br, -CF3, cyano, oxo, methyl, and ethyl. In some embodiments of formula (I-I-I), (I-I-I2), (I-I-I3), (I-I-Ia) or (I-I-Ib), R 12 Each independently is selected from the group consisting of methyl, ethyl, phenyl, and -CF3.

[0092] The present invention also provides a compound of the following formula I-I-II, or a pharmaceutically acceptable salt thereof:

Chemical formula

[0093] In another aspect, the present invention also provides a compound of formula I-I-II2, or a pharmaceutically acceptable salt thereof:

Chemical formula

[0094] In some embodiments, the compound is a compound of formula I-I-IIa, or a pharmaceutically acceptable salt thereof.

Chemical formula

[0095] In some embodiments, the compound is a compound of formula I-I-IIb or formula I-I-IIc, or a pharmaceutically acceptable salt thereof.

Chemical formula

[0096] In some embodiments, the compound is a compound of formula I-I-IId, or a pharmaceutically acceptable salt thereof.

Chemical formula

[0097] In some embodiments, the compound is a compound of formula I-I-IIe or formula I-I-IIf, or a pharmaceutically acceptable salt thereof. [Chemistry]

[0098] In some embodiments of formula (I-I-II), (I-I-II2), (I-I-IIa), (I-I-IIb), (I-I-IIc), (I-I-IId), (I-I-IIe) or (I-I-IIf), R5 is halogen, C 1-6 haloalkyl, C 1-6 alkoxy, and C 3-10 selected from the group consisting of cycloalkyl. For example, R5 is -F, -CF3, cyclopropyl, -OCH2CH3, or -OCH(CH3)3.

[0099] In some embodiments of formula (I-I-II), (I-I-II2), (I-I-IIa), (I-I-IIb), (I-I-IIc), (I-I-IId), (I-I-IIe), or (I-I-IIf), R3 is methyl or ethyl.

[0100] In some embodiments of formula (I-I-II), (I-I-II2), (I-I-IIa), (I-I-IIb), (I-I-IIc), (I-I-IId), (I-I-IIe) or (I-I-IIf), G is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, thiazolyl, pyridyl, tetrahydropyranyl, thiophenyl, isoxazolyl, isothiazolyl, pyridazinyl, piperidinyl, pyrrolidinyl, triazolyl, benzothiophenyl, pyrimidinyl, bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, [Chemistry] selected from the group consisting of.

[0101] In some embodiments of formula (I-I-II), (I-I-II2), (I-I-IIa), (I-I-IIb), (I-I-IIc), (I-I-IId), (I-I-IIe), or (I-I-IIf), z is 0, 1, or 2. For example, z is 0. In another example, z is 1 or 2. In some embodiments of formula (I-I-II), (I-I-II2), (I-I-IIa), (I-I-IIb), (I-I-IIc), (I-I-IId), (I-I-IIe), or (I-I-IIf), z is 1. In some embodiments of formula (I-I-II), (I-I-II2), (I-I-IIa), (I-I-IIb), (I-I-IIc), (I-I-IId), (I-I-IIe), or (I-I-IIf), z is 2.

[0102] In some embodiments of formula (I-I-II), (I-I-II2), (I-I-IIa), (I-I-IIb), (I-I-IIc), (I-I-IId), (I-I-IIe) or (I-I-IIf), R 12 is each independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, -S(O)2CH3, -S(O)2CH2CH3, -S(O)2(cyclopropyl), -C(O)CH3, -C(O)NH2, -C(O)N(CH3) -2 , methyl, ethyl, propyl, butyl, isopropyl, isobutyl, -CF3, -OCF3, -OCH3, cyclopropyl, cyclobutyl, and phenyl. In some embodiments of formula (I-I-II), (I-I-II2), (I-I-IIa), (I-I-IIb), (I-I-IIc), (I-I-IId), (I-I-IIe) or (I-I-IIf), R 12 is each independently selected from the group consisting of -F, Cl, -Br, -CF3, cyano, oxo, methyl, and ethyl. In some embodiments of formula (I-I-II), (I-I-II2), (I-I-IIa), (I-I-IIb), (I-I-IIc), (I-I-IId), (I-I-IIe) or (I-I-IIf), R 12 is each independently selected from the group consisting of methyl, ethyl, phenyl, and -CF3.

[0103] In some embodiments of Formula I-I, the compound is selected from the group consisting of or a pharmaceutically acceptable salt thereof:

Chemical formula

[0104] In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I-I), (I-I-I) or (I-I-II) (e.g., (I-I-Ia), (I-I-Ib), (I-I-IIa), (I-I-IIb), (I-I-IIc), (I-I-IId), (I-I-IIe) or (I-I-IIf)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0105] In another aspect, the present invention features a compound of formula (II-I), or a pharmaceutically acceptable salt thereof:

Chemical formula

[0106] In some embodiments of Formula II-I, the compound of Formula II-I is a compound of Formula II-I-a, or a pharmaceutically acceptable salt thereof.

Chemical formula

[0107] In some embodiments of Formula II-I, the compound of Formula II-I is a compound of Formula II-I-b, or a pharmaceutically acceptable salt thereof.

Chemical formula

[0108] In some embodiments of Formula II-I, the compound of Formula II-I is a compound of Formula II-I-c or a pharmaceutically acceptable salt thereof.

Chem.

[0109] In some embodiments of Formula II-I, the compound of Formula II-I is a compound of Formula II-I-d or a pharmaceutically acceptable salt thereof.

Chem.

[0110] In some embodiments of Formula II-I (e.g., Formula II-I-a or Formula II-I-b), R3 is C 1-6 alkyl and R4 is hydrogen.

[0111] In some embodiments of Formula II-I (e.g., Formula II-I-a or Formula II-I-b), R2 is hydrogen.

[0112] In some embodiments of Formula II-I (e.g., Formula II-I-a), n is 1.

[0113] In some embodiments of Formula II-I (e.g., Formula II-I-a, II-I-b, II-I-c, or II-I-d), R5 is hydrogen and R6 is C 1-6 alkyl. In some embodiments of Formula II-I (e.g., Formula II-I-a, II-I-b, II-I-c, or II-I-d), R5 and R6 are each independently C 1-6 alkyl. In some embodiments of Formula II-I (e.g., Formula II-I-a, II-I-b, II-I-c, or II-I-d), R5 is C 1-6is alkyl and R6 is phenyl. In some embodiments of formula II-I (e.g., formula II-I-a, II-I-b, II-I-c, or II-I-d), R5 and R6, together with the nitrogen to which R5 and R6 are attached, form a 3- to 10-membered heterocyclyl. In some embodiments, the 3- to 10-membered heterocyclyl is selected from the group consisting of 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 1,2,3,4-tetrahydroisoquinolinyl, and piperdinyl.

[0114] In some embodiments of formula II-I (e.g., formula II-I-a, II-I-b, II-I-c, or II-I-d), R1 is C 1-6 haloalkyl, C 1-6 alkoxy, and C 3-10 selected from the group consisting of cycloalkyl. In some embodiments of formula II-I (e.g., formula II-I-a, II-I-b, II-I-c, or II-I-d), R1 is selected from the group consisting of cyclopropyl, isopropoxyl, and -CF3.

[0115] In some embodiments of formula II-I, the compound is

Chemical formula

[0116] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (II-I) (e.g., formula (II-I-a), (II-I-b), (II-I-c), or (II-I-d)), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient.

[0117] In another aspect, the present invention features a compound of formula (III-I) or a pharmaceutically acceptable salt thereof:

Chemical formula

[0118] In some embodiments of Formula III-I, the compound of Formula III-I is a compound of Formula III-Ia or a pharmaceutically acceptable salt thereof.

Chemical Formula

[0119] In some embodiments of Formula III-I (e.g., Formula III-Ia), R5 is C 1-6 haloalkyl or C 3-10 cycloalkyl. In some embodiments of Formula III-I (e.g., Formula III-Ia), R5 is C 1-6 haloalkyl. In some embodiments of Formula III-I (e.g., Formula III-Ia), R5 is CF3. In some embodiments of Formula III-I (e.g., Formula III-Ia), R5 is cyclopropyl.

[0120] In some embodiments of Formula III-I (e.g., Formula III-Ia), R1 is one or more halogens, cyano, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or N(R a )(R b )-optionally substituted C 2-6 alkyl. In some embodiments of Formula III-I (e.g., Formula III-Ia), R1 is C 2-6 alkyl optionally substituted with one or more halogens. In some embodiments of Formula III-I (e.g., Formula III-Ia), R1 is C a alkyl substituted with N(R b )(R 1-6 ). In some embodiments of Formula III-I (e.g., Formula III-Ia), R1 is C 4-6 alkyl. In some embodiments of Formula III-I (e.g., Formula III-Ia), R1 is t-butyl.

[0121] In some embodiments of Formula III-I, R3 is C 1-6 alkyl. In some embodiments of Formula III-I, R3 is methyl.

[0122] In some embodiments of Formula III-I (e.g., Formula III-Ia), R a and R b are each independently C 1-6 alkyl or phenyl.

[0123] In some embodiments of Formula III-I, the compounds of Formula III-I are selected from the group consisting of or a pharmaceutically acceptable salt thereof.

Chemical formula

[0124] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (III-I) (e.g., formula (III-Ia))), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0125] General synthetic scheme Exemplary methods for preparing the compounds described herein are illustrated in the following synthetic schemes. These schemes are provided for illustrative purposes of the present invention and should not be construed as limiting the scope or spirit of the present invention in any way.

[0126] Scheme I-1

Chemical formula

[0127] Scheme I-2

Chemical formula

[0128] Scheme II-1 [Chem.] The synthetic route illustrated in Scheme II-1 shows an exemplary procedure for the preparation of II-G (the compound of formula II-I). In the first step, cyanopyridine II-A is reacted with hydroxylamine to obtain nicotimidamide II-B. Next, oxadiazole II-D is obtained by cyclization of II-B with glycine II-C mediated by N,N'-dicyclohexylcarbodiimide (DCC). Deprotection of II-D under acidic conditions gives the amine-substituted oxadiazole intermediate II-E, which is then treated with amine II-F to obtain II-G (the compound of formula II-I).

[0129] Scheme III-1 [Chem.] The synthetic route illustrated in Scheme III-1 shows an exemplary procedure for the preparation of intermediate III-E. In the first step, III-A is treated with hydroxylamine to obtain III-B. Next, oxadiazole III-D is obtained by cyclization of III-B with glycine III-C mediated by HATU or EDCI. Deprotection of III-D under acidic conditions gives intermediate III-E.

[0130] [Chem.] The synthetic route illustrated in Scheme III-2 shows an exemplary procedure for the preparation of III-G (the compound of formula III-I). Compound III-G (the compound of formula III-I) is obtained by coupling intermediate III-E with carboxylic acid III-F using standard peptide coupling procedures (e.g., a dichloromethane solution of HATU in the presence of DIPEA).

[0131] Treatment method The compounds and compositions described above and herein can be used to treat neurological diseases or disorders, or diseases or conditions associated with excessive neuronal excitability and / or gain-of-function mutations in genes (e.g., KCNT1). Exemplary diseases, disorders, or conditions include epilepsy and other encephalopathies (e.g., epilepsy of infancy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathies, developmental and epileptic encephalopathies (DEE), early infantile onset epileptic encephalopathy (EIEE), generalized epilepsy, focal epilepsy, multifocal epilepsy, temporal lobe epilepsy, Ohtahara syndrome, early myoclonic encephalopathy, and Lennox syndrome. Gastaut syndrome, drug-resistant epilepsy, seizures (e.g., frontal lobe seizures, generalized tonic-clonic seizures, asymmetric tonic seizures, focal seizures, leukodystrophies, myelinating leukodystrophies, leukoencephalopathy, and sudden unexpected death in epilepsy, cardiac dysfunction (e.g., cardiac arrhythmias, Brugada syndrome, myocardial infarction), pulmonary vascular disorders / bleeding, pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.), muscle disorders (e.g., myotonia, neuromyotonia, muscle spasms, spasticity), itch and pruritus, movement disorders (e.g., ataxia, and cerebellar ataxia), psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia, attention deficit hyperactivity disorder), neurodevelopmental disorders, learning disabilities, intellectual disability, fragile X, neuroplasticity, and autism spectrum disorders.

[0132] In some embodiments, the neurological disease or disorder, or disease or condition associated with excessive neural excitability and / or gain-of-function mutations in genes (e.g., KCNT1), is selected from EIMFS, ADNFLE, and West syndrome. In some embodiments, the neurological disease or disorder, or disease or condition associated with excessive neural excitability and / or gain-of-function mutations in genes (e.g., KCNT1), is selected from infantile spasms, epileptic encephalopathy, focal epilepsy, Otahara syndrome, developmental and epileptic encephalopathy, and Lennox Gastaut syndrome. In some embodiments, the neurological disease or disorder, or disease or condition associated with excessive neural excitability and / or gain-of-function mutations in genes (e.g., KCNT1), is seizures. In some embodiments, the neurological disease or disorder, or disease or condition associated with excessive neural excitability and / or gain-of-function mutations in genes (e.g., KCNT1), is selected from cardiac arrhythmia, Brugada syndrome, and myocardial infarction.

[0133] In some embodiments, the neurological disease or disorder, or disease or condition associated with excessive neuronal excitability and / or a gain-of-function mutation in a gene (e.g., KCNT1), is selected from the group consisting of learning disabilities, fragile X, intellectual disability, neuroplasticity, psychotic disorders, and autism spectrum disorders.

[0134] Thus, the compounds and compositions thereof can be administered to subjects with a neurological disease or disorder, or a disease or condition associated with excessive neuronal excitability and / or gain-of-function mutations in genes such as KCNT1 (e.g., EIMFS, ADNFLE, West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, and Lennox-Gastaut syndrome, seizures, cardiac arrhythmias, Brugada syndrome, and myocardial infarction).

[0135] EIMFS is a rare and debilitating genetic condition characterized by early onset (before 6 months of age) of mostly continuous, heterogeneous focal seizures that appear to migrate from one brain region and hemisphere to another. Patients with EIMFS generally have intellectual disability, speech impairment, and gait disturbances. To date, several genes have been implicated, but the gene most commonly associated with EIMFS is KCNT1. Several novel 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 are dominant (i.e., present in only one allele) gain-of-function missense mutations, and when tested in Xenopus oocytes or mammalian expression systems, they cause changes in the function of the encoded potassium channels and a significant increase in whole-cell current (see, for example, 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).

[0136] ADNFLE has a later onset than EIMFS, generally presenting in mid-childhood and generally in a less severe state. It is characterized by nocturnal frontal lobe seizures and can cause mental, behavioral, and cognitive impairments in affected patients. ADNFLE is associated with genes encoding several neuronal nicotinic acetylcholine receptor subunits, although mutations in the KCNT1 gene are involved in more severe cases of the disease (Heron et al. (2012) Nat Genet. 44:1188-1190). Functional studies of the mutant KCNT1 gene associated with ADNFLE have shown that the underlying mutations (M896I, R398Q, Y796H, and R928C) are 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).

[0137] West syndrome is a severe form of epilepsy composed of three features: nodding seizures, an interictal electroencephalogram (EEG) pattern called hypsarrhythmia, and mental retardation, although a diagnosis can be made if one of these elements is lacking. Mutations in KCNT1, including G652V and R474H, are associated with West syndrome (Fukuoka et al. (2017) Brain Dev 39:80 - 83 and Ohba et al. (2015) Epilepsia 56:el21 - el28). Treatments targeting the KCNT1 channel suggest that these mutations are gain - of - function mutations (Fukuoka et al. (2017) Brain Dev 39:80 - 83).

[0138] In one aspect, the present invention provides a method for treating diseases or conditions associated with excessive neuronal excitability and / or gain-of-function mutations in genes such as, for example, KCNT1, including epilepsies and other encephalopathies (e.g., epilepsy of infancy with migratory focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathies, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies (DEE), and Lennox syndrome. Gastaut syndrome, seizures, leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic seizures, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia, asymmetric tonic seizures), cardiac dysfunction (e.g., cardiac arrhythmias, 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, muscle spasms, spasticity), itch and pruritus, ataxia and cerebellar ataxia, psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia), learning disabilities, fragile X, neuroplasticity, and autism spectrum disorders). The present invention also features a method of treating a subject in need thereof, the method comprising administering a compound disclosed herein (e.g., a compound of Formula (II), (II-2), (III), (II-I2), (II-I3), (II-II), (II-II2), (II-I) or (III-I), or a pharma- ceutically 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 (II), (II-2), (III), (II-I2), (II-I3), (II-II), (II-II2), (II-I) or (III-I), or a pharma- ceutically acceptable salt thereof) and a pharma- ceutically acceptable excipient).

[0139] In some embodiments, a subject presenting a disease or condition 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 a compound and its composition. For example, whole exome sequencing may be performed on the subject. Gain-of-function mutations associated with EIMFS 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 include, but are not limited to, M896I, R398Q, Y796H, R928C, and G288S. Gain-of-function mutations associated with West syndrome include, but are not limited to, G652V and R474H. Gain-of-function mutations associated with temporal lobe epilepsy include, but are not limited to, R133H and R565H. Gain-of-function mutations associated with Lennox-Gastaut include, but are not limited to, R209C. Gain-of-function mutations associated with seizures include, but are not limited to, A259D, G288S, R474C, R474H. Gain-of-function mutations associated with leukodystrophy include, but are not limited to, G288S and Q906H. Gain-of-function mutations associated with multifocal epilepsy include, but are not limited to, V340M. Gain-of-function mutations associated with EOE include, but are not limited to, F346L and A934T. Gain-of-function mutations associated with early-onset epileptic encephalopathy (EOEE) include, but are not limited to, R428Q. Gain-of-function mutations associated with developmental and epileptic encephalopathy include, but are not limited to, F346L, R474H, and A934T.Examples of gain-of-function mutations associated with epileptic encephalopathy include, but are not limited to, L437F, Y796H, P924L, and R961H. Examples of gain-of-function mutations associated with early infantile epileptic encephalopathy (EIEE) include, but are not limited to, M896K. Examples of gain-of-function mutations associated with drug-resistant epilepsy and tonic-clonic status epilepticus include, but are not limited to, F346L. Examples of gain-of-function mutations associated with migrating partial seizures in infants include, but are not limited to, R428Q. Examples of gain-of-function mutations associated with leukoencephalopathy include, but are not limited to, F932I. Examples of gain-of-function mutations associated with NFLE include, but are not limited to, A934T and R950Q. Examples of gain-of-function mutations associated with Ohtahara syndrome include, but are not limited to, A966T. Examples of gain-of-function mutations associated with salaam seizures include, but are not limited to, P924L. Examples of gain-of-function mutations associated with Brugada syndrome include, but are not limited to, R1106Q. Examples of gain-of-function mutations associated with Brugada syndrome include, but are not limited to, R474H.

[0140] In other embodiments, the subject is first genotyped to identify the presence of a mutation in KCNT1, and then a standard in vitro assay, such as the assay described in Milligan et al. (2015) Ann Neurol. 75(4):581-590, is used to confirm that the mutation is a gain-of-function mutation. Typically, when evaluated using whole-cell electrophysiological methods (e.g., the methods 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), if the expression of the mutant KCNT1 allele results in an increase in whole-cell current compared to the whole-cell current arising from the expression of wild-type KCNT1, the presence of a gain-of-function mutation is confirmed. This increase in whole-cell current can be, for example, an increase of at least or about 50%, 100%, 150%, 200%, 250%, 300%, 350%, 400% or more. It can then be confirmed that the subject has a disease or condition associated with a gain-of-function mutation in KCNT1.

[0141] In certain embodiments, the subject is confirmed to have 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).

[0142] A compound disclosed herein (e.g., a compound of formula (II), (II-2), (III), (II-I2), (II-I3), (II-II), (II-II2), (II-I) or (III-I), or a pharma- ceutically 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 (II), (II-2), (III), (II-I2), (II-I3), (II-II), (II-II2), (II-I) or (III-I), or a pharma- ceutically acceptable salt thereof), and a pharma- ceutically acceptable excipient) may 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 if the disease is not the result of increased KCNT1 expression and / or activity, inhibition of KCNT1 expression and / or activity may still result in reduced neuronal excitability, thereby providing a therapeutic effect. Thus, the compounds disclosed herein (e.g., compounds of formula (II), (II-2), (III), (II-I2), (II-I3), (II-II), (II-II2), (II-I) or (III-I), or a pharma- ceutical acceptable salt thereof) or pharmaceutical compositions disclosed herein (e.g., compounds disclosed herein (e.g., compounds of formula (II), (II-2), (III), (II-I2), (II-I3), (II-II), (II-II2), (II-I) or (III-I)) may be used to treat or prevent the onset of neuronal excitability. A pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable excipient, may be used to treat subjects having conditions associated with excessive neuroexcitability, such as epilepsy and other encephalopathies (e.g., infantile epilepsy with migratory focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ANDFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, and Lennox Gastaut syndrome, seizures), or cardiac dysfunction (e.g., cardiac arrhythmia, Brugada syndrome, myocardial infarction), whether or not the disease or disorder is associated with a gain-of-function mutation in KCNT1.

[0143] Pharmaceutical Composition and Route of Administration The compounds provided according to the present invention are usually administered in the form of pharmaceutical compositions. Accordingly, the present invention provides a pharmaceutical composition comprising, as an active ingredient, one or more of the described compounds, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers comprising inert solid diluents and fillers, diluents comprising sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. The pharmaceutical composition can be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner known in the pharmaceutical art (see, for example, Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.)).

[0144] The pharmaceutical composition can be administered by any of the acceptable modes of administration of a drug, including, for example, by intravenous injection, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or, for example, by rectal, oral, intranasal, and transdermal routes, or via an impregnated or coated device such as a stent, or an arterial insertion cylindrical polymer, having a usefulness similar to that described in the patents and patent applications incorporated herein by reference, either as a single or multiple dose.

[0145] One mode of administration is parenteral, particularly by injection. Forms in which the novel compositions of the invention can be incorporated for administration by injection include aqueous or oily suspensions, or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in physiological saline are also conventionally used for injection but are less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Suitable fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be brought about, for example, by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0146] Sterile injectable solutions are prepared by incorporating the required amount of the compound according to the invention in a suitable solvent containing, if desired, various other ingredients enumerated above, and then filtering the solution sterilize. In general, dispersions are prepared by incorporating various sterilized active ingredients in a sterile vehicle containing a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization techniques which yield a powder of the active ingredient and any additional desired ingredients from its sterile solution which has been previously sterilized by filtration.

[0147] Oral administration is another route for the administration of the compounds according to the present invention. The administration can be via capsules or enteric-coated tablets, etc. In the preparation of a pharmaceutical composition containing at least one compound described herein, the active ingredient is usually diluted with an excipient and / or enclosed within such a carrier which can be in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, the excipient can be in the form of a solid, semi-solid, or liquid material (as described above) acting as a vehicle, carrier, or medium for the active ingredient. Thus, the composition 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), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0148] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can further contain lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl and propyl hydroxy-benzoates, sweetening agents, and flavoring agents.

[0149] The compositions of the present invention can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are described in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods of the present invention employs a transdermal delivery device ("patch"). Such transdermal patches can be used to provide a continuous or discontinuous infusion of the compounds of the present invention in a controlled amount. The construction and use of transdermal patches for delivering pharmaceuticals are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches can be constructed for continuous, pulsed, or on-demand delivery of pharmaceuticals.

[0150] The compositions are preferably formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active substance calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient (e.g., tablets, capsules, ampules). The compounds are generally administered in pharmaceutically effective amounts. Preferably, for oral administration, each dosage unit contains from 1 mg to 2 g of the compounds described herein, and for parenteral administration, preferably from 0.1 to 700 mg of the compounds described herein. However, it will be understood that the actual amount of compound administered will usually be determined by the physician in view of relevant circumstances including the condition being treated, the route of administration selected, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0151] To prepare solid compositions such as tablets, the active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of the compounds of the invention. When referring to these pre-formulation compositions being homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, whereby the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0152] The tablets or pills of the invention can be formulated by coating or other means to provide a dosage form that produces the advantage of long-term action or to protect from the acidic conditions of the stomach. For example, the tablets or pills can include an inner dosage component and an outer dosage component, the latter being in the form of a coating that covers the former. The two components can be separated by an enteric layer that functions to withstand disintegration in the stomach and to allow the inner component to pass through the duodenum intact or to be released in a delayed manner. A variety of materials can be used for such enteric layers or coatings, such materials including many polymeric acids, as well as mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0153] Compositions for inhalation or insufflation include solutions, suspensions, and powders in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof. The liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effects. The compositions in pharmaceutically acceptable solvents can preferably be nebulized by the use of an inert gas. The nebulized solution can be inhaled directly from the nebulizing device or the nebulizing device can be attached to a face mask tent or an intermittent positive pressure breathing apparatus. The solution, suspension, or powder composition can be preferably administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0154] In some embodiments, a pharmaceutical composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present disclosure encompasses the embodiments described in the following sections. [Section 1] A pharmaceutical composition comprising a compound of Formula I-I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein TIFF0007699836000052.tif22130 in the formula, L is a bond or C 1-6 alkyl, X is CH or N, and when X is CH in the formula, the hydrogen of CH may be substituted by R 5 ; G is selected from the group consisting of phenyl, C 3-10 cycloalkyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl; R 2 is hydrogen; R 3 is C 1-6 alkyl optionally substituted with C 1-6 alkoxy; R 4 is hydrogen; R 5 are each independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-10 cycloalkyl; R 6 are each independently selected from hydrogen or C 1-6 alkyl; R 12 are each independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, -S(O) 2 (C 1-6 (alkyl), -S(O) 2 (C 3-6 (cycloalkyl), -C(O)C 1-6 (alkyl), -C(O)N(R 6 ) 2 、C 1-6 )(alkyl), C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, and phenyl, and z is 0, 1, 2, 3, or 4. A pharmaceutical composition. [Section 2] A pharmaceutical composition comprising a compound of Formula I-I-I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein TIFF0007699836000053.tif24130 in the formula, G is selected from the group consisting of phenyl, 5- to 10-membered heterocyclyl containing at least one unsaturated bond in the heterocyclic ring, and 5- to 10-membered heteroaryl; R 2 is hydrogen; R 3 is C 1-6 alkyl optionally substituted with C 1-6 alkoxy; R 4 is hydrogen; R 5 is selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-10 cycloalkyl; R 12 are each independently selected from the group consisting of halogen, cyano, oxo, -S(O) 2 (C 1-6 (alkyl), C 1-6 (alkyl), C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, and phenyl, and z is 0, 1, 2, 3, or 4. A pharmaceutical composition. [Section 3] A pharmaceutical composition comprising a compound of Formula I-I-I2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein TIFF0007699836000054.tif22130 in the formula, G is selected from the group consisting of phenyl, 5- to 10-membered heterocyclyl containing at least one unsaturated bond in the heterocyclic ring, and 5- to 10-membered heteroaryl, R 2 is hydrogen, R 3 is C 1-6 alkyl optionally substituted with alkoxy, 1-6 is alkyl, R 4 is hydrogen, R 5 is halogen, R 6 each is independently selected from hydrogen or C 1-6 alkyl, R 12 each is independently selected from halogen, cyano, hydroxyl, oxo, -S(O) 2 (C 1-6 alkyl), -S(O) 2 (C 3-6 cycloalkyl), -C(O)C 1-6 alkyl, -C(O)N(R 6 ) 2 、C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, and phenyl, and z is 0, 1, 2, 3, or 4, a pharmaceutical composition. [Item 4] The pharmaceutical composition according to any one of Items 1 to 3, wherein the compound is a compound of Formula I-IIIa or Formula I-IIIb, or a pharmaceutically acceptable salt thereof. TIFF0007699836000055.tif46129 [Item 5] A pharmaceutical composition comprising a compound of Formula I-IV, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, TIFF0007699836000056.tif25130 wherein, L is a bond or C 1-6 alkyl, G is selected from the group consisting of phenyl, C 3-10 cycloalkyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl, R 2 is hydrogen, R 3 is C 1-6 alkyl optionally substituted with alkoxy, 1-6 is alkyl, R 4 is hydrogen, R 5 is selected from the group consisting of halogen, C 1-6 alkyl, C1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-10 cycloalkyl, R 6 each is independently selected from hydrogen or C 1-6 alkyl, R 12 each is independently selected from halogen, cyano, hydroxyl, oxo, -S(O) 2 (C 1-6 alkyl), -S(O) 2 (C 3-6 cycloalkyl), -C(O)C 1-6 alkyl, -C(O)N(R 6 ) 2 、C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, and phenyl, and z is 0, 1, 2, 3, or 4, a pharmaceutical composition. [Item 6] The pharmaceutical composition according to any one of Item 1 or 5, wherein the compound is a compound of Formula I-IVa, or a pharmaceutically acceptable salt thereof. TIFF0007699836000057.tif25129 [Item 7] The pharmaceutical composition according to any one of Item 1 or 5, wherein the compound is a compound of Formula I-IVb or Formula I-IVc, or a pharmaceutically acceptable salt thereof. TIFF0007699836000058.tif50128 [Item 8] The pharmaceutical composition according to any one of items 1, 5, and 6, wherein the compound is a compound of formula I-I-IId or a pharmaceutically acceptable salt thereof. TIFF0007699836000059.tif24128 [Item 9] The pharmaceutical composition according to any one of items 1, 5, and 7, wherein the compound is a compound of formula I-I-IIe or formula I-I-IIf or a pharmaceutically acceptable salt thereof. TIFF0007699836000060.tif52128 [Item 10] R 5 is halogen, C 1-6 haloalkyl, C 1-6 alkoxy, and C 3-10 The pharmaceutical composition according to any one of items 1 to 9, which is selected from the group consisting of cycloalkyl. [Item 11] R 5 is -F, -CF 3 , cyclopropyl, cyclobutyl, -OCH 2 CH 3 , and -OCH(CH 3 ) 3 The pharmaceutical composition according to any one of items 1 to 10, which is selected from the group consisting of. [Item 12] R 5 The pharmaceutical composition according to any one of items 1 to 11, wherein is -F. [Item 13] R 5 The pharmaceutical composition according to any one of items 1 to 11, wherein is -CF 3 . [Item 14] R 5 The pharmaceutical composition according to any one of items 1 to 11, wherein is cyclopropyl. [Item 15] R 3 The pharmaceutical composition according to any one of items 1 to 3 and 5 to 14, wherein is methyl or ethyl. [Item 16] G is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, thiazolyl, pyridyl, tetrahydropyranyl, thiophenyl, isoxazolyl, isothiazolyl, pyridazinyl, piperidinyl, pyrrolidinyl, triazolyl, benzothiophenyl, pyrimidinyl, bicyclo[2.2.2]octanyl, isocyclo[1.1.1]pentanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, TIFF0007699836000061.tif23128 The pharmaceutical composition according to any one of items 1 to 15, which is selected from the group consisting of. [Item 17] The pharmaceutical composition according to any one of items 1 to 16, wherein Z is 0. [Item 18] The pharmaceutical composition according to any one of items 1 to 16, wherein Z is 1 or 2. [Item 19] The pharmaceutical composition according to any one of items 1 to 16 and 18, wherein Z is 1. [Item 20] The pharmaceutical composition according to any one of items 1 to 16 and 18, wherein Z is 2. [Item 21] R 12 are each independently halogen, cyano, hydroxyl, oxo, -S(O) 2 CH 3 , -S(O) 2 CH 2 CH 3 , -S(O) 2 (cyclopropyl), -C(O)CH 3 , -C(O)NH 2 , -C(O)N(CH 3 ) -2 , methyl, ethyl, propyl, butyl, isopropyl, isobutyl, -CF 3 , -OCF 3 , -OCH 3 The pharmaceutical composition according to any one of items 1 to 16 and 18 to 20, selected from the group consisting of cyclopropyl, cyclobutyl, and phenyl. [Item 22] R 12 Each is independently selected from the group consisting of -F, -Cl, -Br, -CF 3 The pharmaceutical composition according to any one of items 1 to 16 and 18 to 20, selected from the group consisting of cyano, oxo, methyl, and ethyl. [Item 23] R 12 Each is independently selected from the group consisting of methyl, ethyl, phenyl, and -CF 3 The pharmaceutical composition according to any one of items 1 to 16 and 18 to 20, selected from the group consisting of. [Item 24] The compound is TIFF0007699836000062.tif216136TIFF0007699836000063.tif237135TIFF0007699836000064.tif224141TIFF0007699836000065.tif238142TIFF0007699836000066.tif240145TIFF0007699836000067.tif113137 The pharmaceutical composition according to item 1, selected from the group consisting of or a pharmaceutically acceptable salt thereof. [Item 25] A method for treating a neurological disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I-I or a pharmaceutically acceptable salt thereof, TIFF0007699836000068.tif22128 Wherein, L is a bond or C 1-6 Alkyl, X is CH or N, and when X is CH, the hydrogen of CH may be substituted by R 5 And G is selected from the group consisting of phenyl, C 3-10 Cycloalkyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl, R 2 Is hydrogen, R 3 Is C 1-6 Alkyl optionally substituted with C 1-6 Alkyl, R 4 Is hydrogen, R 5 Each is independently selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, and C3-10 Cycloalkyl, R 6 Each is independently selected from hydrogen or C 1-6 Alkyl, R 12 Each is independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, -S(O) 2 (C 1-6 Alkyl), -S(O) 2 (C 3-6 Cycloalkyl), -C(O)C 1-6 Alkyl, -C(O)N(R 6 ) 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, and phenyl, and z is 0, 1, 2, 3, or 4, a method. [Item 26] A method for treating a disease or condition associated with excessive neuronal excitability, the method comprising administering to a subject in need thereof an effective amount of a compound of formula I-I or a pharmaceutically acceptable salt thereof, TIFF0007699836000069.tif23128 Wherein, L is a bond or C 1-6 Alkyl, X is CH or N, and when X is CH, the hydrogen of CH may be substituted by R 5 And G is phenyl, C 3-10 Selected from the group consisting of cycloalkyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl, R 2 is hydrogen, R 3 is C 1-6 alkyl optionally substituted with alkoxy is C 1-6 alkyl, R 4 is hydrogen, R 5 each is independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C3-10 cycloalkyl, R 6 each is independently selected from hydrogen or C 1-6 alkyl, R 12 each is independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, -S(O) 2 (C 1-6 alkyl), -S(O) 2 (C 3-6 cycloalkyl), -C(O)C 1-6 alkyl, -C(O)N(R 6 ) 2 、C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, and phenyl, and z is 0, 1, 2, 3, or 4, a method. [Item 27] A method for treating a disease or condition associated with a gain-of-function mutation of a gene (e.g., KCNT1), the method comprising administering to a subject in need thereof an effective amount of a compound of formula I-I or a pharmaceutically acceptable salt thereof, TIFF0007699836000070.tif23128 wherein, L is a bond or C 1-6 alkyl, X is CH or N, and when X is CH in the formula, the hydrogen of CH may be substituted by R 5 , G is selected from the group consisting of phenyl, C 3-10 cycloalkyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl, R 2 is hydrogen, R 3 is C 1-6 alkyl optionally substituted with alkoxy is C 1-6 alkyl, R 4 is hydrogen, R 5 each is independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C3-10 cycloalkyl, R 6 each is independently selected from hydrogen or C 1-6 alkyl, R 12 each is independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, -S(O) 2 (C 1-6 alkyl), -S(O) 2 (C 3-6 cycloalkyl), -C(O)C 1-6 alkyl, -C(O)N(R 6 ) 2 、C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, and phenyl, and z is 0, 1, 2, 3, or 4, a method. [Item 28] A method for treating a neurological disease or disorder, the method comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition according to any one of Items 1 to 24, [Item 29] A method for treating a disease or condition associated with excessive neural excitability, comprising administering an effective amount of the pharmaceutical composition according to any one of items 1 to 24 to a subject in need thereof. [Section 30] A method for treating a disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1), comprising administering an effective amount of the pharmaceutical composition according to any one of items 1 to 24 to a subject in need thereof. [Section 31] The method according to any one of items 25 to 30, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is epilepsy, an epilepsy syndrome, or an encephalopathy. [Section 32] The method according to any one of items 25 to 30, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is genetic epilepsy or childhood epilepsy, or a genetic epilepsy or childhood epilepsy syndrome. [Section 33] Item 31. The method according to any one of items 25 to 30, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is cardiac dysfunction. [Section 34] The method according to any one of items 25 to 30, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is selected from the group consisting of epilepsy and other encephalopathies (e.g., epilepsy of infancy with migratory focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, Lennox Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, and cerebellar ataxia). [Section 35] The method according to any one of items 25 to 30, wherein the neurological disease or disorder, the disease or condition associated with the excessive neuronal excitability, or the disease or condition associated with the gain-of-function mutation of the gene (e.g., KCNT1) is selected from the group consisting of cardiac arrhythmia, unexpected sudden death in epilepsy, Brugada syndrome, and myocardial infarction. [Item 36] The method according to any one of items 25 to 30, wherein the neurological disease or disorder, the disease or condition associated with the excessive neuronal excitability, or the disease or condition associated with the gain-of-function mutation of the gene (e.g., KCNT1) is selected from pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.). [Item 37] The method according to any one of items 25 to 30, wherein the neurological disease or disorder, the disease or condition associated with the excessive neuronal excitability, or the disease or condition associated with the gain-of-function mutation of the gene (e.g., KCNT1) is a muscle disorder (e.g., myotonia, neuromyotonia, muscle cramps, spasticity). [Item 38] The method according to any one of items 25 to 30, wherein the neurological disease or disorder, the disease or condition associated with the excessive neuronal excitability, or the disease or condition associated with the gain-of-function mutation of the gene (e.g., KCNT1) is selected from itching and pruritus, ataxia, and cerebellar ataxia. [Item 39] The method according to any one of items 25 to 30, wherein the neurological disease or disorder, the disease or condition associated with the excessive neuronal excitability, or the disease or condition associated with the gain-of-function mutation of the gene (e.g., KCNT1) is selected from mental disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia). [Item 40] The method according to any one of items 25 to 30, wherein the neurological disease or disorder, or the disease or condition associated with the excessive neuronal excitability, and / or the gain-of-function mutation in the gene (e.g., KCNT1) is selected from the group consisting of learning disabilities, fragile X, neural plasticity, and autism spectrum disorder. [Item 41] The neurological disease or disorder, the disease or condition associated with the excessive neuronal excitability, or the disease or condition associated with the gain-of-function mutation of the gene (e.g., KCNT1) is selected from the group consisting of epileptic encephalopathy with SCN1A, SCN2A, 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, nodding epilepsy, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic childhood partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures in infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy, and is the method according to any one of items 25 to 30. [Item 42] A pharmaceutical composition comprising a compound of formula II-I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein TIFF0007699836000071.tif21129 In the formula, R 1 each independently represents halogen, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, R 2 represents hydrogen or C 1-4 alkyl, R 3 represents C 1-6 alkyl optionally substituted with C 1-6 alkoxy, R 4 represents hydrogen or C 1-6 alkyl optionally substituted with C 1-6 alkoxy, R 5 and R 6 each independently represents hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, and the C 1-6 alkyl, C 3-10 cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl may be optionally substituted with one or more of halogen, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, aryl, C 3-10 cycloalkyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, and in the formula, both of R 5 and R 6 are not hydrogen, or R 5 and R 6 , together with the nitrogen to which they are attached, may be optionally substituted with halogen, -CN, -OH, C 5 alkyl, C 6 haloalkyl, aryl, C 1-6 alkyl, C 1-6 haloalkyl, aryl, C 3-10 forms a 3- to 10-membered heterocyclic ring substituted with one or more of cycloalkyl or 3- to 10-membered heterocyclyl, and n is 1 or 2, a pharmaceutical composition. [Item 43] The pharmaceutical composition according to item 42, wherein the compound is a compound of formula II-I-a or a pharmaceutically acceptable salt thereof. TIFF0007699836000072.tif22129 [Item 44] The pharmaceutical composition according to item 42 or 43, wherein the compound is a compound of formula II-I-b or a pharmaceutically acceptable salt thereof. TIFF0007699836000073.tif22129 [Item 45] The pharmaceutical composition according to any one of items 42 to 44, wherein the compound is a compound of formula II-I-c or a pharmaceutically acceptable salt thereof. TIFF0007699836000074.tif24129 [Item 46] The pharmaceutical composition according to any one of items 42 to 46, wherein the compound is a compound of formula II-I-d or a pharmaceutically acceptable salt thereof. TIFF0007699836000075.tif24129 [Item 47] R 3 is C 1-6 alkyl, and R 4 is hydrogen, the pharmaceutical composition according to any one of items 42 to 44. [Item 48] R 2 is hydrogen, the pharmaceutical composition according to any one of items 42 to 44. [Item 49] n is 1, the pharmaceutical composition according to item 42 or 43. [Item 50] R 5 is hydrogen, and R 6 is C 1-6 alkyl, the pharmaceutical composition according to any one of items 42 to 49. [Item 51] R 5 and R 6 are each independently C 1-6 alkyl, the pharmaceutical composition according to any one of items 42 to 49. [Item 52] R 5 is C1-6 alkyl, and R 6 is phenyl, the pharmaceutical composition according to any one of items 42 to 49. [Item 53] R 5 and R 6 together with the nitrogen to which R 5 and R 6 are attached form a 3- to 10-membered heterocyclyl, the pharmaceutical composition according to any one of items 42 to 49. [Item 54] R 5 and R 6 together with the nitrogen to which R 5 and R 6 are attached form TIFF0007699836000076.tif22129 , the pharmaceutical composition according to any one of items 42 to 49 and 53. [Item 55] R 1 is selected from the group consisting of C 1-6 haloalkyl, C 1-6 alkoxy, and C 3-10 cycloalkyl, the pharmaceutical composition according to any one of items 42 to 54. [Item 56] R 1 is selected from the group consisting of cyclopropyl, isopropoxyl, and -CF 3 , the pharmaceutical composition according to any one of items 42 to 55. [Item 57] The compound is TIFF0007699836000077.tif207139 or a pharmaceutically acceptable salt thereof, the pharmaceutical composition according to item 42. [Item 58] A method for treating a neurological disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of formula II-I or a pharmaceutically acceptable salt thereof, TIFF0007699836000078.tif21129 In the formula, R 1 each independently represents halogen, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, R 2 represents hydrogen or C 1-4 alkyl, R 3 represents C 1-6 alkyl optionally substituted with C 1-6 alkoxy, R 4 represents hydrogen or C 1-6 alkyl optionally substituted with C 1-6 alkoxy, R 5 and R 6 each independently represent hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, and the C 1-6 alkyl, C 3-10 cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl may optionally be substituted with one or more of halogen, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, aryl, C 3-10 cycloalkyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl. In the formula, both of R 5 and R 6 are not hydrogen, or R 5 and R 6 , together with the nitrogen to which they are attached, optionally form a 3- to 10-membered heterocyclyl ring substituted with one or more of halogen, -CN, -OH, C 5 alkyl, C 6 haloalkyl, aryl, C 1-6 cycloalkyl, or 3- to 10-membered heterocyclyl, and 1-6 n is 1 or 2, a method. 3-10 [Item 59] A method for treating a disease or condition associated with excessive neuronal excitability, the method comprising administering to a subject in need thereof an effective amount of a compound of formula II-I or a pharmaceutically acceptable salt thereof, wherein, each independently represents halogen, -CN, -OH, C TIFF0007699836000079.tif21130 alkyl, C R 1 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, 1-6 represents hydrogen or C 3-10 alkyl, R 2 represents C 1-4 alkyl optionally substituted with C R 3 alkoxy, 1-6 represents hydrogen or C 1-6 alkyl optionally substituted with C R 4 alkoxy, 1-6 and R 1-6 each independently represent hydrogen, C R 5 alkyl, C 6 cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, and the C 1-6 alkyl, C 3-10 cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl may optionally be substituted with one or more of halogen, -CN, -OH, C 1-6 alkyl, C 3-10 ​ 1-6 ​ 1-6 Haloalkyl, C 1-6 Alkoxy, aryl, C 3-10 Cycloalkyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, and may be substituted with one or more thereof, wherein R 5 And R 6 Are not both hydrogen, or R 5 And R 6 Are, together with the nitrogen to which R 5 And R 6 Is attached, optionally halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, aryl, C 3-10 Cycloalkyl, or a 3- to 10-membered heterocyclyl ring substituted with one or more of 3- to 10-membered heterocyclyl, and n is 1 or 2, method. [Item 60] A method for treating a disease or condition associated with a gain-of-function mutation of a gene (e.g., KCNT1), said method comprising administering to a subject in need thereof an effective amount of a compound of formula II-I, or a pharmaceutically acceptable salt thereof, TIFF0007699836000080.tif23130 Wherein R 1 Are each independently halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, R 2 Is hydrogen or C 1-4 Alkyl, R 3 Is C 1-6 Alkyl optionally substituted with C 1-6 Alkoxy, R 4 Is C 1-6 Hydrogen or C optionally substituted with C 1-6 Alkyl, R 5 And R 6 Are each independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, said C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl is optionally halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, aryl, C 3-10 Cycloalkyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, and may be substituted with one or more thereof, wherein R 5 And R 6 Are not both hydrogen, or R 5 And R 6 Are, together with the nitrogen to which R 5 And R 6 Is attached, optionally halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, aryl, C 3-10 Cycloalkyl, or a 3- to 10-membered heterocyclyl ring substituted with one or more of 3- to 10-membered heterocyclyl, and n is 1 or 2, method. [Item 61] A method for treating a neurological disease or disorder, said method comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition according to any one of Items 42 to 57, method. [Item 62] A method for treating a disease or condition associated with excessive neural excitability, comprising administering an effective amount of the pharmaceutical composition according to any one of items 42 to 57 to a subject in need thereof. [Section 63] A method for treating a disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1), comprising administering an effective amount of the pharmaceutical composition according to any one of items 42 to 57 to a subject in need thereof. [Section 64] Item 58 to 63, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is epilepsy, an epilepsy syndrome, or an encephalopathy. [Section 65] Item 58 to 63, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is genetic epilepsy or childhood epilepsy, or a genetic epilepsy or childhood epilepsy syndrome. [Section 66] Item 58 to 63, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is cardiac dysfunction. [Section 67] The method according to any one of items 58 to 63, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is selected from the group consisting of epilepsy and other encephalopathies (e.g., epilepsy of infancy with migratory focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, Lennox Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia). [Section 68] The method according to any one of items 58 to 63, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation of the gene (e.g., KCNT1) is selected from the group consisting of cardiac arrhythmia, unexpected sudden death in epilepsy, Brugada syndrome, and myocardial infarction. [Item 69] The method according to any one of items 58 to 63, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation of the gene (e.g., KCNT1) is selected from pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.). [Item 70] The method according to any one of items 58 to 63, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation of the gene (e.g., KCNT1) is a muscle disorder (e.g., myotonia, neuromyotonia, muscle cramps, spasticity). [Item 71] The method according to any one of items 58 to 63, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation of the gene (e.g., KCNT1) is selected from itching and pruritus, ataxia, and cerebellar ataxia. [Item 72] The method according to any one of items 58 to 63, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation of the gene (e.g., KCNT1) is selected from mental disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia). [Item 73] The method according to any one of items 58 to 63, wherein the neurological disease or disorder, or the excessive neuronal excitability, and / or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is selected from the group consisting of learning disabilities, fragile X, neural plasticity, and autism spectrum disorder. [Item 74] The neurological disease or disorder, the disease or condition associated with the excessive neuronal excitability, or the disease or condition associated with the gain-of-function mutation of the gene (e.g., KCNT1) is selected from the group consisting of epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, nodding epilepsy, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic childhood partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures in infants, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy, and is the method according to any one of items 58 to 63. [Item 75] A compound of formula III-I, or a pharmaceutically acceptable salt thereof, wherein TIFF0007699836000081.tif23130 In the formula, R 1 is one or more halogen, cyano, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C a )(R b alkyl optionally substituted with N(R 1-6 ); R 2 is hydrogen; R 3 is C 1-6 alkyl optionally substituted with C 1-6 alkoxy; R 4 is hydrogen; R 5 is halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, N(Rc )(R d ), and C 3-10 cycloalkyl; and R a and R b are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, and phenyl; R c and R d are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and phenyl; provided that when R is methoxy, R 5 is C 3 alkyl. 1-3 [Item 76] The compound according to item 75, wherein the compound is a compound of formula III-Ia, or a pharmaceutically acceptable salt thereof. [Item 77] TIFF0007699836000082.tif23130 is C R 5 haloalkyl or C 1-6 cycloalkyl, the compound according to item 75 or 76. 3-10 [Item 78] is C R 5 haloalkyl, the compound according to any one of items 75 to 77. 1-6 [Item 79] is CF R 5 , the compound according to any one of items 75 to 78. 3 [Item 80] is cyclopropyl, the compound according to any one of items 75 to 77. R 5 [Item 81] ​ R 1 is C alkyl optionally substituted with one or more halogens 2-6 The compound according to any one of items 75 to 80, which is alkyl [Item 82] R 1 is C alkyl substituted with N(R a )(R b ) 1-6 The compound according to any one of items 75 to 80, which is alkyl [Item 83] R 1 is C alkyl 4-6 The compound according to any one of items 75 to 80, which is alkyl [Item 84] R 1 The compound according to any one of items 75 to 80 and 84, which is t-butyl [Item 85] R a and R b are each independently C alkyl or phenyl 1-6 The compound according to any one of items 75 to 82, which is alkyl or phenyl [Item 86] R 3 is C alkyl 1-6 The compound according to item 75 and any one of items 77 to 85, which is alkyl [Item 87] R 3 The compound according to item 75 and any one of items 77 to 86, which is methyl [Item 88] The compound is TIFF0007699836000083.tif64128 The compound according to item 75, which is selected from the group consisting of or a pharmaceutically acceptable salt thereof [Item 89] A pharmaceutical composition comprising the compound according to any one of items 75 to 88, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient [Item 90] A method for treating a neurological disease or disorder, comprising administering an effective amount of the compound according to any one of items 75 to 88, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 89, to a subject in need thereof [Item 91] A method for treating a disease or condition associated with excessive neuronal excitability, comprising administering an effective amount of the compound according to any one of items 75 to 88, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 89, to a subject in need thereof [Item 92] A method for treating a disease or condition associated with a gain-of-function mutation of a gene (e.g., KCNT1), comprising administering an effective amount of the compound according to any one of items 75 to 88, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 89, to a subject in need thereof [Item 93] The method according to any one of items 90 to 92, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation of the gene (e.g., KCNT1) is epilepsy, epileptic syndrome, or encephalopathy [Item 94] Item 93. The method according to any one of items 90 to 92, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is genetic epilepsy or childhood epilepsy, or a genetic epilepsy or childhood epilepsy syndrome. [Section 95] Item 93. The method according to any one of items 90 to 92, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is cardiac dysfunction. [Section 96] The method according to any one of items 90 to 92, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is selected from the group consisting of epilepsy and other encephalopathies (e.g., epilepsy of infancy with migratory focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, Lennox Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia). [Section 97] The method according to any one of items 90 to 92, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is selected from the group consisting of cardiac arrhythmia, sudden unexpected death in epilepsy, Brugada syndrome, and myocardial infarction. [Section 98] The method according to any one of items 90 to 92, wherein the neurological disease or disorder, the disease or condition associated with excessive neural excitability, or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is selected from pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.). [Section 99] The method according to any one of items 90 to 92, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation of the gene (e.g., KCNT1) is a muscle disorder (e.g., myotonia, neuromyotonia, muscle cramps, spasticity). [Item 100] The method according to any one of items 19 to 23, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation of the gene (e.g., KCNT1) is selected from pruritus and prurigo, ataxia, and cerebellar ataxia. [Item 101] The method according to any one of items 90 to 92, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation of the gene (e.g., KCNT1) is selected from mental disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia). [Item 102] The method according to any one of items 90 to 92, wherein the neurological disease or disorder, or the excessive neuronal excitability, and / or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is selected from the group consisting of learning disabilities, fragile X, neural plasticity, and autism spectrum disorder. [Item 103] The method according to any one of items 90 to 92, wherein the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation of the gene (e.g., KCNT1) is selected from the group consisting of epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, salaam seizures, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic partial childhood epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures in infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

Example

[0155] The following examples are described to enable a more complete understanding of the invention described herein. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed as limiting their scope in any way.

[0156] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be understood that other process conditions may be used as well, unless otherwise specified, when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. Optimal reaction conditions may vary depending on the particular reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art through routine optimization.

[0157] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing unwanted reactions. The selection of suitable protecting groups for a particular functional group, as well as the conditions suitable for protection and deprotection, are well known in the art. For example, numerous protecting groups, as well as 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 the references cited therein.

[0158] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, trituration, high performance liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). Note that flash chromatography can be performed either manually or via an automated system. The compounds provided herein can 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 parts per million (ppm) and are generated using methods well known to those skilled in the art.

[0159] List of Abbreviations THF Tetrahydrofuran TFA Trifluoroacetic acid 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 Propane phosphonic anhydride DCC N,N’-Dicyclohexylcarbodiimide N-Boc-L-alanine (2S)-2-({[(2-Methyl-2-propanyl)oxy]carbonyl}amino)propanoic acid DMSO Dimethyl sulfoxide Pd(OAc)2 Palladium(II) acetate RuPhos 2-Dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl 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 IC 50 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

[0160] Example I-1: (S)-5-(Trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)picolinamide [Chemical formula] To a solution of I-A2 (100 mg, 0.52 mmol) and I-A1 (0.15 g, 0.58 mmol) in DCM (10 mL), DIPEA (0.18 mL, 1.05 mmol) and HATU (298.44 mg, 0.78 mmol) were added at room temperature, and the mixture was stirred at room temperature for 2 hours. Then the reaction solution was quenched with water (100 mL) and diluted with DCM (100 mL x 2). The combined organic layers were dried over sodium sulfate, evaporated to obtain a residue, which was purified by column chromatography using 100 - 200 silica and 30 - 80% EtOAc / hexane eluent to give I-1 (70 mg, 0.16 mmol, 30% yield) as a solid. HPLC: Rt 9.11 min, 99.3%, column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm, mobile phase: A: aqueous solution of 0.1% FA: ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 432.00 (M + H), Rt 2.10 min, column: X-select CSH C18 (3×50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6) δ 9.87 (d, 1H), 9.10 - 9.08 (m, 1H), 9.04 - 8.98 (m, 1H), 8.50 - 8.43 (m, 1H), 8.31 - 8.22 (m, 3H), 5.65 - 5.52 (m, 1H), 1.75 (d, 3H). Chiral method: Rt 3.63 min, 100%, SFC column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5um), mobile phase: A) CO2 B) MeOH + 0.1% NH3, gradient: 10 - 40% B in 5 minutes, maintain 40% B until 9 minutes. 40 - 10% B at 10 minutes. Maintain 10% B until 12 minutes. Wavelength: 264 nm, flow rate: 3 mL / min.

[0161] Example I-2: (S)-3,3-Difluoro-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)cyclobutane-1-carboxamide

Chemical Structure

[0162] Example I-3: (S)-4,4-Difluoro-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)cyclohexane-1-carboxamide

Chemical Structure

[0163] Example I-4: (S)-2-(Trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-1H-imidazole-4-carboxamide [Chemical formula] To a stirred solution of I-A5 (100 mg, 0.56 mmol) and I-A1 (163.63 mg, 0.56 mmol) in DCM (10 mL), DIPEA (0.19 mL, 1.11 mmol) and HATU (316.72 mg, 0.83 mmol) were added at room temperature, and the mixture was stirred at room temperature for 2 hours. Then the reaction solution was quenched with water (100 mL) and diluted with DCM (100 mL x 2). The combined organic layers were dried over sodium sulfate, evaporated to give a residue, which was purified by column chromatography using 100 - 200 silica and 30 - 80% EtOAc / hexane eluent to give I-4 (25 mg, 0.05 mmol, 10% yield) as a solid. HPLC: Rt 7.99 min, 99.6%, column: X-Select CSH C18 (4.6x150) mm, 3.5 μm, mobile phase: A: aqueous solution of 0.1% FA:ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 421.00 (M+H), Rt 1.86 min, column: X-select CSH C18 (3×50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6) δ 14.22 (bs, 1H), 9.08 (d, 1H), 9.01 (d, 1H), 8.3 - 8.22 (m, 2H), 8.01 (s, 1H), 5.54 - 5.42 (m, 1H), 1.70 (d, 3H). Chiral HPLC: Rt: 2.67 min, 100%, column: DIACEL CHIRALPAK-1G (250×4.6 mm, 5um); mobile phase: A) CO2 B) MeOH + 0.1% NH3, gradient: 10 - 40% B in 5 min, maintain 40% B until 9 min. 40 - 10% B at 10 min. Maintain 10% B until 12 min. Wavelength: 280 nm, flow rate: 3 mL / min.

[0164] Example I-5: (S)-4-(Trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)thiazole-2-carboxamide

Chemical Structure

[0165] Example I-6: (S)-N-(1-(3-(2-(Trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)isonicotinamide [Chemical formula] To a stirred solution of I-A7 (100 mg, 0.81 mmol) and I-A1 (230.7 mg, 0.89 mmol) in DCM (5 mL), DIPEA (0.42 mL, 2.44 mmol) and HATU (463.28 mg, 1.22 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 5 h. The reaction mixture was then quenched with water (10 mL×3) containing DCM. The combined organic layers were dried over sodium sulfate and concentrated to give a residue. The residue was purified by column chromatography on silica gel (100 - 200) using MeOH:DCM (2:98) as the eluent to afford I-6 (60 mg, 0.15 mmol, 19% yield) as a solid. HPLC: Rt 7.01 min, 97.0%, column: X-Select CSH C18 (4.6x150) mm, 3.5 μm, mobile phase: A: aqueous solution of 0.1% FA:ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 364.00 (M+H), Rt 1.67 min, column: X-select CSH C18 (3×50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6) δ 9.60 (d, 1H), 9.01 (d, 1H), 8.79 - 8.75 (m, 2H), 8.28 (d, 2H), 7.84 - 7.76 (m, 2H), 5.56 - 5.48 (m, 1H), 1.72 (d, 3H). Chiral HPLC: Rt 4.72 min, 93.6%, SFC column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5um), mobile phase: A) CO2 B) MeOH + 0.1% NH3, gradient: 10 - 40% B in 5 min, maintain 40% B until 9 min. Wavelength: 270 nm, flow rate: 3 mL / min.

[0166] Example I-7: (S)-N-(1-(3-(2-(Trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)picolinamide [Chemical formula] To a stirred solution of I-A8 (100 mg, 0.81 mmol) in DCM (5 mL) were added DIPEA (0.42 mL, 2.44 mmol) and HATU (463.28 mg, 1.22 mmol) at 0 °C. To the resulting reaction mixture was added I-A1 (230.7 mg, 0.89 mmol) at 0 °C, and the mixture was stirred at room temperature for 5 h. The reaction solution was then diluted with water and extracted with DCM (10 mL x 3). The combined organic layers were dried over sodium sulfate and evaporated to give a residue. The residue was purified by column chromatography using silica gel (100 - 200) and an eluent of MeOH:DCM (2:98) to give I-7 (70 mg, 0.18 mmol, 23% yield) as a solid. HPLC: Rt 8.34 min, 99.8%, column: X-Select CSH C18 (4.6 x 150) mm, 5 μm, mobile phase: A: aqueous solution of 0.1% FA:ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 364.05 (M+H), Rt 1.92 min, column: X-select CSH C18 (3×50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6) δ 9.65 (d, 1H), 9.05 - 8.96 (m, 1H), 8.72 - 8.68 (m, 1H), 8.30 - 8.25 (m, 2H), 8.11 - 7.99 (m, 2H), 7.68 - 7.64 (m, 1H), 5.58 - 5.52 (m, 1H), 1.74 (d, 3H). Chiral HPLC: Rt 5.33 min, 99.1%, SFC column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5um), mobile phase: A) CO2 B) MeOH + 0.1% NH3, gradient: 10 - 40% B in 5 min, maintain 40% B until 12 min. Wavelength: 265 nm, flow rate: 3 mL / min.

[0167] Example I-8: (S)-N-(1-(3-(2-(Trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)benzamide [Chemical formula] To a stirred solution of I-A9 (47.71 mg, 0.34 mmol) and I-A1 (0.1 g, 0.34 mmol) in DCM (10 mL) was added TEA (0.05 mL, 0.34 mmol) at room temperature, and the mixture was stirred for 2 h. The reaction solution was then quenched with water (100 mL) and diluted with DCM (100 mL x 2). The combined organic layers were dried over sodium sulfate, evaporated to give a residue, which was purified by column chromatography using 100 - 200 silica and 30 - 80% EtOAc / hexane eluent to give I-8 (22 mg, 0.06 mmol, 18% yield) as a solid. HPLC: Rt: 8.43 min, 99.8%, column: X-Select CSH C18 (4.6x150) mm, 3.5 μm, mobile phase: A: aqueous solution of 0.1% FA: ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 363.20 (M+H), Rt 1.91 min, column: X-select CSH C18 (3×50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6): δ 9.30 (d, 1H), 9.01 (d, 1H), 8.28 - 8.25 (m, 2H), 7.92 - 7.90 (m, 2H), 7.60 - 7.49 (m, 3H), 5.46 - 5.54 (m, 1H), 1.71 (d, 3H). Chiral HPLC: Rt 3.68 min, 100%, SFC column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5um), mobile phase: A) CO2 B) MeOH + 0.1% NH3, gradient: 20 - 40% B in 5 min, maintain 40% B until 9 min. 40 - 20% B at 10 min. Maintain 20% B until 12 min. Wavelength: 266 nm, flow rate: 3 mL / min.

[0168] Example I-9: (S)-N-(1-(3-(2-(Trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)cyclohexanecarboxamide

Chemical Structure

[0169] Example I-10: (S)-2-(Trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)thiazole-4-carboxamide [Chemical formula] To a stirred solution of I-A11 (80.29 mg, 0.41 mmol) and I-A1 (100 mg, 0.34 mmol) in DCM (10 mL) were added DIPEA (0.12 mL, 0.68 mmol) and HATU (193.56 mg, 0.51 mmol) at room temperature, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then quenched with water (100 mL) and diluted with DCM (100 mL x 2). The combined organic layers were dried over sodium sulfate, evaporated to give a residue, which was purified by column chromatography using 100 - 200 silica and 30 - 80% EtOAc / hexane eluent to afford I-10 (43 mg, 0.09 mmol, 28% yield) as a solid. HPLC: Rt 9.17 min, 99.9%, column: X-Select CSH C18 (4.6x150) mm, 5 μm, mobile phase: A: aqueous solution of 0.1% FA:ACN (95:05), B: ACN, flow rate: 1.0 mL / min LCMS: 437.95 (M+H), Rt 2.13 min, column: X-select CSH C18 (3×50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6): δ 9.55 (d, 1H), 9.02 - 9.00 (m, 1H), 8.78 (s, 1H), 8.28 - 8.27 (m, 2H), 5.56 - 5.52 (m, 1H), 1.73 (d, 3H). Chiral method: Rt 3.54 min, 100%, SFC column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5um), mobile phase: A) CO2 B) MeOH + 0.1% NH3, gradient: 10 - 40% B in 5 min, maintain 70% B until 9 min. 40 - 10% B at 10 min. Maintain 10% B until 12 min. Wavelength: 270 nm, flow rate: 3 mL / min.

[0170] Example I-11: (S)-N-(1-(3-(2-(Trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)nicotinamide

Chemical formula

[0171] Example I-12: (S)-N-(1-(3-(2-(Trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide

Chemical Structure

[0172] Example I-13: (S)-2-Phenyl-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)acetamide

Chemical Structure

[0173] Example I-14: (S)-2-(Trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)isonicotinamide

Chemical Structure

[0174] Example I-15: (S)-2-Phenyl-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)propyl)acetamide

Chemical formula

[0175] I-A18: tert-butyl (S)-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)propyl)carbamate To a stirred solution of I-A16 (0.6 g, 2.92 mmol) in 1,4-dioxane (15 mL) were added I-A17 (0.59 g, 2.92 mmol) and DCC (0.6 g, 2.92 mmol) at room temperature, and the mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with water (2 × 15 mL) and brine solution (15 mL). The organic layer was separated, dried over MgSO4 and evaporated to give a residue. The residue was purified by column chromatography using a 50% EtOAc in hexane solution as the eluent to give I-A18 (0.60 g, 1.29 mmol, 44% yield) as a solid.

[0176] I-A19: (S)-1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)propan-1-amine To a stirred solution of I-A18 (0.6 g, 1.61 mmol) in 1,4-dioxane (2 mL) was added a solution of 4 M hydrochloric acid in dioxane (10 mL, 1.61 mmol) at 0 °C, and the mixture was stirred at room temperature for 6 h. Then the reaction mixture was evaporated under reduced pressure to give I-A19 (0.48 g, 1.49 mmol, 92% yield) as a solid.

[0177] I-15: (S)-2-Phenyl-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)propyl)acetamide To a stirred solution of I-A19 (136.04 mg, 0.44 mmol) and 2-phenylacetic acid (50 mg, 0.37 mmol) in DCM (10 mL) was added HATU (167.56 mg, 0.44 mmol), then DIPEA (0.13 mL, 0.73 mmol) at 0 °C and the mixture was stirred at room temperature for 3 h. The reaction mixture was then diluted with DCM (20 mL) and washed with saturated sodium bicarbonate solution (3 × 25 mL), followed by water (3 × 20 mL). The organic layer was separated, dried over Na2SO4 and evaporated to give a residue. The residue was purified by column chromatography using 100 - 200 silica and a hexane solution of 15 - 20% EtOAc as the eluent to give I-15 (50 mg, 0.12 mmol, 34% yield) as a solid. HPLC: Rt 9.49 min, 99.6%, column: X-select CSH C18 (4.6x150) mm, 5 μm, mobile phase: aqueous solution of 10 mM ammonium bicarbonate, B: ACN, flow rate: 1.0 mL / min. LCMS: 391.05 (M+H), Rt 2.14 min, column: X-select CSH C18 (3.0×50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6): δ 9.04 - 8.95 (m, 2H), 8.25 (d, 2H), 7.35 - 7.17 (m, 5H), 5.15 - 5.05 (m, 1H), 3.54 (s, 2H), 2.04 - 1.86 (m, 2H), 0.95 (t, 3H).

[0178] Example I-16. (S)-2-Phenyl-N-((S)-1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)propanamide

Chemical Structure

[0179] Example I-17: (R)-2-Phenyl-N-((S)-1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)propanamide [Chemical formula] To a stirred solution of I-A21 (104.69 mg, 0.70 mmol) and I-A1 (150 mg, 0.58 mmol) in DCM (10 mL) were added DIPEA (0.2 mL, 1.16 mmol) and HATU (265.07 mg, 0.70 mmol) at 0 °C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then quenched with water (15 mL) and diluted with DCM (30 mL). The aqueous layer was washed with DCM (2 × 30 mL). The combined organic layers were dried over sodium sulfate, evaporated to give a residue, which was purified by column chromatography using 100 - 200 silica and a hexane eluent with 25% EtOAc to afford I-17 (40 mg, 0.10 mmol, 17% yield) as a solid. HPLC: Rt 9.43 min, 97.7%, column: X-select CSH C18 (4.6x150) mm, 5 μm, mobile phase: A: aqueous solution of 10 mM ammonium bicarbonate, B: ACN, flow rate: 1.0 mL / min. LCMS: 391.05 (M+H), Rt 2.16 min, column: X-select CSH C18 (3.0x50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6): δ 9.03 (d, 1H), 8.92 (d, 1H), 8.27 (d, 2H), 7.37 - 7.19 (m, 5H), 5.24 - 5.16 (m, 1H), 3.75 - 3.65 (m, 1H), 1.52 (d, 3H), 1.34 (d, 3H). Chiral method: Rt 4.90 min, 100%, SFC column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5um), mobile phase: A) CO2 B) MeOH + 0.1% NH3, gradient: 10 - 40% B in 5 minutes, maintain 40% B until 9 minutes. 40 - 10% B at 10 minutes. Maintain 10% B until 12 minutes. Wavelength: 275 nm, flow rate: 3 mL / min.

[0180] Example I-18: (S)-5-Bromo-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)thiophene-2-carboxamide [Chemical formula] To a stirred solution of I-A22 (100 mg, 0.48 mmol) and I-A1 (149.65 mg, 0.58 mmol) in DCM (5 mL) were added DIPEA (0.25 mL, 1.45 mmol) and HATU (275.46 mg, 0.72 mmol) at 0 °C, and the mixture was stirred at room temperature for 3 hours. The reaction solution was then quenched with water, and the aqueous layer was washed with DCM (2 × 30 mL). The collected organic layer was washed with a saturated brine solution (20 mL), and the combined organic layer was dried over (Na2SO4) and evaporated to give a residue. The residue was then purified by flash column chromatography using a 20% EtOAc in hexane solution as the eluent to give I-18 (30 mg, 0.06 mmol, 13% yield) as a solid. HPLC: Rt 7.76 min, 99.6%, column: X-Bridge C18 (4.6x150) mm, 5 μm; mobile phase: A: aqueous solution of 0.1% NH3, B: ACN, flow rate: 1.2 mL / min. LCMS: 446.84 (M+H), Rt 2.09 min, column: X-select CSH C18 (3.0x50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6): δ 9.40 (d, 1H), 9.01 (d, 1H), 8.28 (d, 2H), 7.76 - 7.69 (m, 1H), 7.34 (d, 1H), 5.48 - 5.42 (m, 1H), 1.69 (d, 3H).

[0181] Example I-19: (S)-4-Methyl-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)cyclohexane-1-carboxamide [Chemical formula] To a stirred solution of I-A23 (100 mg, 0.70 mmol) and I-A1 (217.89 mg, 0.84 mmol) in DCM (5 mL) were added DIPEA (0.37 mL, 2.11 mmol) and HATU (401.09 mg, 1.05 mmol) at 0 °C, and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with DCM (30 mL) and water (15 mL), and washed again with DCM (2 x 30 mL). The collected and combined organic layers were washed with saturated brine solution (20 mL), dried over (Na2SO4), evaporated to give a residue. The residue was then purified by flash column chromatography using a 20% EtOAc in hexane solution as the eluent to give I-19 (45 mg, 0.11 mmol, 16% yield) as a solid. HPLC: Rt 7.91 min, 99.4%, column: X-Bridge C18 (4.6 x 150) mm, 5 μm; mobile phase: A: aqueous solution of 0.1% NH3, B: ACN, flow rate: 1.2 mL / min. LCMS: 383.05 (M+H), Rt 2.09 min, column: X-select CSH C18 (3.0 x 50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6): δ 9.05 - 8.98 (m, 1H), 8.64 - 8.55 (m, 1H), 8.29 - 8.23 (m, 2H), 5.30 - 5.16 (m, 1H), 2.4 - 2.2 (m, 1H), 1.78 - 1.67 (m, 3H), 1.60 - 1.51 (m, 3H), 1.48 - 1.44 (m, 3H), 1.35 - 1.30 (m, 2H), 0.92 - 0.81 (m, 3H). Note: 1H was not observed but may have been merged under the solvent peak.

[0182] Example I-20: (S)-N-(1-(3-(2-(Trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)propyl)cyclohexanecarboxamide

Chemical Structure

[0183] Example I-21: (S)-5-Methyl-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)isoxazole-4-carboxamide

Chemical Structure

[0184] Example I-22: (S)-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)isothiazole-5-carboxamide

Chemical Structure

[0185] Example I-23: (S)-N-(1-(3-(2-(Trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)isothiazole-5-carboxamide

Chemical formula

[0186] Example I-24: (S)-N-(1-(3-(2-(Trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)pyridazine-3-carboxamide

Chemical formula

[0187] Example I-25. (S)-6-(Trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)benzo[b]thiophene-2-carboxamide

Chemical Structure

[0188] Example I-26: trans-4-Methyl-N-((S)-1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)cyclohexane-1-carboxamide [Chemical formula] To a stirred solution of I-A24 (57.9 mg, 0.41 mmol) and I-A1 (HCl salt) (0.1 g, 0.34 mmol) in DCM (10 mL), DIPEA (0.12 mL, 0.68 mmol) and HATU (193.6 mg, 0.51 mmol) were added at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (100 mL) and diluted with DCM (100 mL x 2). The combined organic layers were dried over sodium sulfate, evaporated to give a residue, which was purified by column chromatography using 100 - 200 silica and 30 - 80% EtOAc / hexane eluent to afford I-26 (30 mg, 0.078 mmol, 23% yield) as a solid. HPLC: Rt 9.30 min, 99.5%, column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm, mobile phase: A: aqueous solution of 0.1% FA:ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 382.7 (M+H), Rt 2.18 min, column: X-select CSH C18 (3×50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6): δ 9.00 (d, 1H), 8.61 (d, 1H), 8.26 - 8.22 (m, 2H), 5.21 (d, 1H), 2.16 - 2.08 (m, 1H), 1.78 - 1.63 (m, 4H), 1.54 (d, 3H), 1.40 - 1.25 (m, 3H), 0.97 - 0.81 (m, 5H). Chiral method: Rt 6.85 min, 100%, column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5um), mobile phase: A) n-hexane + 0.1% isopropylamine, B) DCM:MeOH (1:1), isocratic: 20% B, wavelength: 225 nm, flow rate: 1.0 mL / min.

[0189] Example I-29: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-4-methylcyclohexane-1-carboxamide

Chemical Structure

[0190] Example I-30: 2-Methyl-N-((S)-1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)cyclopentane-1-carboxamide [Chemical formula] To a stirred solution of I-A28 (52 mg, 0.41 mmol) and I-A1 (HCl salt) (0.1 g, 0.34 mmol) in DCM (2 mL), DIPEA (0.18 mL, 1.02 mmol) and HATU (193.6 mg, 0.51 mmol) were added at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (2 mL x 3) and diluted with DCM. The organic layer was dried over sodium sulfate and evaporated to give a mixture, which was purified by column chromatography using a 50% ethyl acetate in hexane solution to afford I-30 (45 mg, 0.12 mmol, 36% yield) as a solid. HPLC: Rt 8.99 min, 99.7%, column: X-Select CSH C18 (4.6 x 150) mm, 5 μm, mobile phase: A: aqueous solution of 0.1% FA: ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 369 (M+H), Rt 2.09 min, column: X-select CSH C18 (3×50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (d, 1H), 8.78 - 8.72 (m, 1H), 8.30 - 8.22 (m, 2H), 5.28 - 5.22 (m, 1H), 2.22 - 2.11 (m, 1H), 2.10 - 1.90 (m, 1H), 1.86 - 1.80 (m, 2H), 1.75 - 1.53 (m, 6H), 1.16 - 1.10 (m, 1H), 1.04 - 0.96 (m, 3H).

[0191] Example I-32: (S)-1-Cyano-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)cyclopropane-1-carboxamide

Chemical Structure

[0192] Example I-33. (S)-1-Methyl-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)cyclopropane-1-carboxamide

Chemical Structure

[0193] Example I-34: (R)-6-oxo-N-((S)-1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)piperidine-2-carboxamide [Chemical formula] To a stirred solution of I-A31 (58.3 mg, 0.41 mmol) and I-A1 (HCl salt) (0.1 g, 0.34 mmol) in DCM (10 mL), DIPEA (0.12 mL, 0.68 mmol) and HATU (193.6 mg, 0.51 mmol) were added at room temperature and stirred at room temperature for 2 hours. The reaction mixture was quenched with water (100 mL) and diluted with DCM (100 mL x 2). The organic layer was dried over sodium sulfate, evaporated to give a residue, which was purified by column chromatography using a 30 - 80% ethyl acetate in hexane solution as the eluent to give I-34 (15 mg, 0.039 mmol, 11% yield) as a solid. HPLC: Rt 8.97 min, 99.6%, column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm, mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 384.3 (M + H), Rt 1.68 min, column: X-select CSH C18 (3×50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, 1H), 8.86 (d, 1H), 8.30 - 8.22 (m, 2H), 7.60 - 7.56 (m, 1H), 5.33 - 5.28 (m, 1H), 3.98 - 3.92 (m, 1H), 2.14 (t, 2H), 1.86 - 1.57 (m, 7H). Chiral method: Rt 10.65 min, 93.4%, column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5um), mobile phase: A) n-hexane + 0.1% isopropylamine, B) DCM:MeOH (1:1), isocratic: 50% B, wavelength: 227 nm, flow rate: 1.0 mL / min.

[0194] Example I-35. (S)-2-(Piperidin-1-yl)-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)acetamide

Chemical Structure

[0195] Example I-36: cis-4-Methyl-N-((S)-1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)cyclohexane-1-carboxamide

Chem.

[0196] Example I-37: (R)-N-(1-(3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)-2,4-dimethylthiazole-5-carboxamide

Chemical Structure

[0197] Example I-38: (S)-N-(1-(3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)-1-methyl-3-phenyl-1H-1,2,4-triazole-5-carboxamide [Chemistry] (S)-1-(3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl)ethane-1-amine (150 mg, 0.72 mmol) in a stirred solution of THF (5 mL) was added 1-methyl-3-phenyl-1H-1,2,4-triazole-5-carboxylic acid (161 mg, 0.80 mmol), then T3P (50% in ethyl acetate, 1.29 mL, 2.17 mmol) and Et3N (0.3 mL, 2.17 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 25 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 using 35% EtOAc / PE to give I-38 (35 mg, 0.086 mmol, 11% yield) as a solid. HPLC: Rt 5.30 min, 96.8%, column: X-Bridge C8 (50 x 4.6) mm, 3.5 μm, mobile phase: A: aqueous solution of 0.1% TFA, B: ACN solution of 0.1% TFA, flow rate: 2.0 mL / min. LCMS: 393.1 (M+H), Rt 2.71 min, column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm, mobile phase: A: aqueous solution of 0.1% HCOOH:ACN (95:5), B: ACN, flow rate: 1.5 mL / min Chiral method: Rt2.36 min, SFC column: YMC Cellulose-SC; mobile phase: 70:30 (A:B), A = liquid CO2, B = methanol, flow rate: 3.0 mL / min, wavelength: 210 nm. 1 1H NMR (400 MHz, CDCl3): δ 8.14 - 8.11 (m, 2H), 8.03 (d, 1H), 7.93 - 7.91 (m, 1H), 7.84 - 7.81 (m, 1H), 7.51 - 7.44 (m, 4H), 7.26 - 7.21 (m, 1H), 5.67 - 5.60 (m, 1H), 4.34 (s, 3H), 1.85 (d, 3H).

[0198] Example I-39: (S)-N-(1-(3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)-2,4-dimethylthiazole-5-carboxamide [Chemical formula] (S)-1-(3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl)ethan-1-amine (170 mg, 0.82 mmol) in a stirred solution of THF (5 mL), 2,4-dimethylthiazole-5-carboxylic acid (159 mg, 1.01 mmol), then T3P (50% in ethyl acetate, 1.47 mL, 2.46 mmol) and Et3N (0.34 mL, 2.46 mmol) were added at 0 °C under a nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 25 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 using 35% EtOAc / PE to give I-39 (110 mg, 0.31 mmol, 37% yield) as a solid. HPLC: Rt 3.89 min, 98.0%, column: X-Bridge C8 (50 x 4.6) mm, 3.5 μm, mobile phase: A: aqueous solution of 0.1% TFA, B: ACN solution of 0.1% TFA, flow rate: 2.0 mL / min. LCMS: 347.0 (M+H), Rt 2.05 min, column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm. Mobile phase: A: aqueous solution of 0.1% HCOOH:ACN (95:5), B: ACN, flow rate: 1.5 mL / min Chiral method: Rt2.29 min, SFC column: YMC Cellulose-SC; mobile phase: 70:30 (A:B), A = liquid CO2, B = methanol, flow rate: 3.0 mL / min, wavelength: 210 nm. 1 1H NMR (400 MHz, CDCl3): δ 7.90 - 7.88 (m, 1H), 7.80 - 7.78 (m, 1H), 7.52 - 7.46 (m, 1H), 7.26 - 7.22 (m, 1H), 6.40 (d, 1H), 5.66 - 5.58 (m, 1H), 2.74 (s, 3H), 2.73 (s, 3H), 1.76 (d, 3H).

[0199] Example I-40: (S)-2-Ethyl-N-(1-(3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)-5-methyl-2H-1,2,3-triazole-4-carboxamide [Chemical formula] (S)-1-(3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl)ethan-1-amine (200 mg, 0.97 mmol) in a stirred solution of THF (5 mL) was added 2-ethyl-5-methyl-2H-1,2,3-triazole-4-carboxylic acid (187 mg, 1.21 mmol), then T3P (50% in ethyl acetate, 1.72 mL, 2.9 mmol) and Et3N (0.4 mL, 2.9 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 25 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 using 35% EtOAc / PE to give I-40 (175 mg, 0.49 mmol, 51% yield) as a solid. HPLC: Rt 4.55 min, 98.7%, column: X-Bridge C8 (50 x 4.6) mm, 3.5 μm, mobile phase: A: aqueous solution of 0.1% TFA, B: ACN solution of 0.1% TFA, flow rate: 2.0 mL / min. LCMS: 345.1 (M+H), Rt 2.36 min, column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 μm, mobile phase: A: aqueous solution of 0.1% HCOOH:ACN (95:5), B: ACN, flow rate: 1.5 mL / min. Chiral method: Rt1.79 min, SFC column: YMC Cellulose-SC; mobile phase: 70:30 (A:B), A = liquid CO2, B = methanol, flow rate: 3.0 mL / min, wavelength: 210 nm. 11H NMR (400 MHz, CDCl3): δ 7.92 - 7.89 (m, 1H), 7.83 - 7.80 (m, 1H), 7.50 - 7.45 (m, 1H), 7.32 - 7.28 (m, 1H), 7.25 - 7.20 (m, 1H), 5.70 - 5.62 (m, 1H), 4.45 (q, 2H), 2.56 (s, 3H), 1.78 (d, 3H), 1.61 (t, 3H).

[0200] Example I - 41: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)benzamide [Chemical Structure] (S)-1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethane-1-amine (100 mg, 0.43 mmol) in a stirred solution of THF (8.0 mL) was treated with benzoic acid (84 mg, 0.69 mmol), then Et3N (0.18 mL, 1.3 mmol) and T3P (50% in ethyl acetate, 0.8 mL, 1.3 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to give I-41 (75 mg, 0.22 mmol, 50% yield) as a solid. Preparative HPLC method: Rt 12.5, 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 2.75 min, 98.4%, column: X-Bridge C8 (50 x 4.6) mm, 3.5 μm, mobile phase: A: aqueous solution of 0.1% TFA, B: ACN solution of 0.1% TFA, flow rate: 2.0 mL / min. LCMS: 335.1 (M+H), Rt 1.90 min, column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 μm, mobile phase: A: aqueous solution of 0.1% HCOOH:ACN (95:5), B: ACN, flow rate: 1.5 mL / min Chiral method: Rt2.23 min, SFC column: YMC Amylose-C; mobile phase: 60:40 (A:B), A = liquid CO2, B = methanol solution of 0.5% isopropylamine, flow rate: 3.0 mL / min, wavelength: 210 nm. 1 H NMR (400 MHz, DMSO-d6): 9.28 (d, 1H), 8.60 (d, 1H), 7.92 (d, 2H), 7.86 (s, 1H), 7.66 (dd, 1H), 7.61 - 7.49 (m, 3H), 5.51 - 5.47 (m, 1H), 2.33 - 2.26 (m, 1H), 1.70 (d, 3H), 1.01 - 0.97 (m, 4H).

[0201] Example I-42: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-2-phenylacetamide

Chemical formula

[0202] Example I - 43: (S)-N-(1-(3-(2 - Isopropoxypyridin - 4 - yl)-1,2,4 - oxadiazol - 5 - yl)ethyl)benzamide

Chemical Structure

[0203] I - 43: (S)-N-(1-(3-(2 - Isopropoxypyridin - 4 - yl)-1,2,4 - oxadiazol - 5 - yl)ethyl)benzamide To a stirred solution of I-A37 (160 mg, 0.64 mmol) in THF (5.0 mL) were added benzoic acid (78 mg, 0.64 mmol), then TEA (0.27 mL, 1.92 mmol) and T3P (50% in ethyl acetate, 1.14 mL, 1.92 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to give I-43 (110 mg, 0.31 mmol, 48% yield) as a solid. Preparative HPLC method: Rt 9.75, column: X-Bridge 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 4.55 min, 99.1%, column: X-Bridge C8 (50 x 4.6) mm, 3.5 μm, mobile phase: A: aqueous solution of 0.1% TFA, B: ACN, flow rate: 2.0 mL / min. LCMS: 353.2 (M+H), Rt 2.33 min, column: Zorbax Eclipse Plus C-18 (50×2.1 mm), 1.8 μm. Mobile phase: A: aqueous solution of 0.1% HCOOH:ACN (95:5), B: ACN, flow rate: 0.8 mL / min. Chiral method: Rt 2.66 min, SFC column: Lux C3; mobile phase: 85:15 (A:B), A = liquid CO2, B = methanol, flow rate: 3.0 mL / min, wavelength: 210 nm. 1 H NMR (400 MHz, DMSO-d6): δ 9.27 (d, 1H), 8.36 (d, 1H), 7.92 - 7.90 (m, 2H), 7.61 - 7.46 (m, 4H), 7.21 (s, 1H), 5.50 - 5.47 (m, 1H), 5.33 - 5.27 (m, 1H), 1.69 (d, 3H), 1.32 (d, 6H).

[0204] Example I-44: (S)-N-(1-(3-(2-Ethoxypyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)benzamide

Chemical Structure

[0205] I-44: (S)-N-(1-(3-(2-Ethoxypyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)benzamide To a stirred solution of I-A39 (150 mg, 0.64 mmol) in THF (5.0 mL), benzoic acid (78 mg, 0.64 mmol), then TEA (0.27 mL, 1.92 mmol) and T3P (50% in ethyl acetate, 1.14 mL, 1.92 mmol) were added at 0 °C under a nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 5 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC to give I-44 (152 mg, 0.45 mmol, 70% yield) as a solid. Preparative HPLC method: Rt 11.82, column: Sunfire C18 (150×19 mm), 5.0 μm. Mobile phase: 0.1% TFA in water / acetonitrile, flow rate: 15.0 mL / min. HPLC: Rt 4.24 min, 99.8%, column: X-Bridge C8 (50x4.6) mm, 3.5 μm, mobile phase: A: aqueous solution of 0.1% TFA, B: ACN, flow rate: 2.0 mL / min. LCMS: 339.1 (M+H), Rt 2.27 min, column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm. Mobile phase: A: aqueous solution of 0.1% HCOOH:ACN (95:5), B: ACN, flow rate: 1.5 mL / min. Chiral method: Rt 2.94 min, SFC column: Lux C3; mobile phase: 85:15 (A:B), A = liquid CO2, B = methanol, flow rate: 3.0 mL / min, wavelength: 210 nm. 1 H NMR (400 MHz, DMSO-d6): δ 9.27 (d, 1H), 8.37 (d, 1H), 7.91 (d, 2H), 7.61 - 7.50 (m, 4H), 7.26 (s, 1H), 5.50 - 5.46 (m, 1H), 4.37 (q, 2H), 1.69 (d, 3H), 1.34 (t, 3H).

[0206] Example I-45: (S)-N-(1-(3-(2-Ethoxypyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)cyclopentanecarboxamide

Chemical Structure

[0207] Example I-46: (S)-N-(1-(3-(2-Isopropoxypyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)cyclopentanecarboxamide [Chemical formula] (S)-1-(3-(2-Isopropoxypyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethan-1-amine (160 mg, 0.64 mmol) in a stirred solution of THF (5.0 mL) was added cyclopentanecarboxylic acid (73 mg, 0.64 mmol), then TEA (0.27 mL, 1.92 mmol) and T3P (50% in ethyl acetate, 1.14 mL, 1.92 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to give I-46 (134 mg, 0.72 mmol, 61% yield) as a solid. Preparative HPLC method: Rt 9.90, column: X-Bridge 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 4.59 min, 99.8%, column: X-Bridge C8 (50 x 4.6) mm, 3.5 μm, mobile phase: A: aqueous solution of 0.1% TFA, B: ACN solution of 0.1% TFA, flow rate: 2.0 mL / min. LCMS: 345.0 (M+H), Rt 2.47 min, column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 μm, mobile phase: A: aqueous solution of 0.1% HCOOH:ACN (95:5), B: ACN, flow rate: 1.5 mL / min. Chiral method: Rt 1.87 min, SFC column: Lux C3; mobile phase: 85:15 (A:B), A = liquid CO2, B = methanol, flow rate: 3.0 mL / min, wavelength: 210 nm. 11H NMR (400 MHz, DMSO-d6): δ 8.64 (d, 1H), 8.37 (d, 1H), 7.45 (dd, 1H), 7.19 (s, 1H), 5.34 - 5.17 (m, 2H), 2.67 - 2.63 (m, 1H), 1.80 - 1.76 (m, 2H), 1.68 - 1.55 (m, 9H), 1.34 (d, 6H).

[0208] Example I-47: N-[1-[3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl]ethyl]-2-methyl-6-(trifluoromethyl)pyridine-3-carboxamide [Chemical formula] I-A41: tert-Butyl N-[1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate A mixture of 3-fluoro-N-hydroxy-benzamidine (1.8 g, 11.68 mmol), 2-(tert-butoxycarbonylamino)propanoic acid (2.43 g, 12.85 mmol), and DCC (4.81 g, 23.36 mmol) in 1,4-dioxane (30 mL) was stirred at 100 °C for 16 h. After cooling to room temperature, the mixture was concentrated to give a residue. The residue was diluted with H2O (25 mL), and the mixture was extracted with EtOAc (25 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by flash chromatography on silica gel (EtOAc in PE = 0% - 10% - 30%) to give the product (3 g, 8.26 mmol, 71% yield) as an oil. LCMS R t = 1.5 minutes, chromatograph at 0.91 minutes, 5 - 95 AB, C 15 H 19 Calculated MS ESI for FN3O3[M + H - tBu] 252.1, found 251.8.

[0209] I-A42: 1-[3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl]ethanamine; hydrochloride A mixture of tert-butyl N-[1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (3 g, 9.76 mmol) in 1,4-dioxane (15 mL) was added to 4M HCl / dioxane (20 mL). The mixture was stirred at 20 °C for 16 h. The mixture was concentrated to give the residue (4 g, 15.16 mmol) as an oil. LCMS R t Chromatography with retention time of 0.59 min at 1.5 min, 5 - 95 AB, C 10 H 11 MS ESI calculated value for FN3O [M + H] 208.1, measured value 207.8.

[0210] Example I - 47: N-[1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]ethyl]-2-methyl-6-(trifluoromethyl)pyridine-3-carboxamide A mixture of 2-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid (100 mg, 0.49 mmol), EDCI (186.91 mg, 0.97 mmol), DIPEA (0.26 mL, 1.46 mmol), HOBt (131.75 mg, 0.97 mmol), and 1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]ethanamine; hydrochloride (130.67 mg, 0.54 mmol) in DCM (2 mL) was stirred at 20 °C for 16 h. The residue was diluted with water (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm), A = H2O (10 mM NH4HCO3) and B = CH3CN; 40 - 70% B over 10 min) to give the product (58.6 mg, 0.15 mmol, 30% yield) as a solid. 1 H NMR (400 MHz, CDCl3) δ H= 7.95 (d, 1H), 7.87 (d, 1H), 7.80 - 7.74 (m, 1H), 7.61 (d, 1H), 7.52 - 7.42 (m, 1H), 7.26 - 7.20 (m, 1H), 6.58 (d, 1H), 5.71 - 5.62 (m, 1H), 2.80 (s, 3H), 1.80 (d, 3H). LCMS R t = 1.25 minutes by two - column chromatography, 10 - 80 AB, C 18 H 15 F4N4O2 [M + H] + The calculated value of MS ESI for it is 395.1, and the measured value is 395.1.

[0211] Example I - 48: N - [1 - [3 - (3 - fluorophenyl) - 1,2,4 - oxadiazol - 5 - yl] ethyl] - 2,4 - dimethyl - pyrimidine - 5 - carboxamide

Chemical Structure

[0212] Example I - 49: N - [1 - [3 - (3 - fluorophenyl) - 1,2,4 - oxadiazol - 5 - yl] ethyl] - 3 - methyl - imidazo[1,2 - a]pyridine - 2 - carboxamide

Chemical Structure

[0213] Example I - 50: N - [1 - [3 - (3 - fluorophenyl) - 1,2,4 - oxadiazol - 5 - yl] ethyl] imidazo[1,2 - a] pyridine - 2 - carboxamide

Chemical Structure

[0214] Example I - 51: N - [1 - [3 - (3 - fluorophenyl) - 1,2,4 - oxadiazol - 5 - yl] ethyl] - 2,3 - dihydro - 1,4 - benzodioxine - 6 - carboxamide

Chemical Structure

[0215] Example I - 52: N - [1 - [3 - (3 - fluorophenyl) - 1,2,4 - oxadiazol - 5 - yl] ethyl] - 5,6,7,8 - tetrahydroimidazo[1,2 - a]pyridine - 2 - carboxamide

Chemical Structure

[0216] Example I - 53: (S)-N-(1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-2-methyl-6-(trifluoromethyl)nicotinamide [Chem.] (S)-1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethan-1-amine (100 mg, 0.43 mmol) in a stirred solution of THF (8.0 mL) was treated with 2-methyl-6-(trifluoromethyl)nicotinic acid (126 mg, 0.62 mmol), then Et3N (0.18 mL, 1.3 mmol) and T3P (50% in ethyl acetate, 0.8 mL, 1.3 mmol) were added at 0 °C under a nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to give I-53 (58 mg, 0.13 mmol, 31% yield) as a solid. Preparative HPLC method: Rt 9.8, column: X-Select 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 3.14 min, 99.1%, column: X-Bridge C8 (50 x 4.6) mm, 3.5 μm, mobile phase: A: aqueous solution of 0.1% TFA, B: ACN solution of 0.1% TFA, flow rate: 2.0 mL / min. LCMS: 418.1 (M+H), Rt 2.15 min, column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 μm, mobile phase: A: aqueous solution of 0.1% HCOOH:ACN (95:5), B: ACN, flow rate: 1.5 mL / min Chiral method: Rt 1.46 min, SFC column: YMC Cellulose-SB; mobile phase: 60:40 (A:B), A = liquid CO2, B = methanol solution of 0.5% isopropylamine, flow rate: 3.0 mL / min, wavelength: 220 nm. 1 1H NMR (400 MHz, CD3OD): δ H = 8.56 (s, 1H), 8.07 (d, 1H), 7.87 (s, 1H), 7.78 (s, 2H), 5.59 - 5.57 (m, 1H), 2.74 (s, 3H), 2.23 (m, 1H), 1.79 (d, 3H), 1.11 - 1.06 (m, 4H).

[0217] Example I-54: (S)-5-Oxo-N-((S)-1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)pyrrolidine-2-carboxamide [Chemical formula] To a stirred solution of I-A51 (78.87 mg, 0.61 mmol) in DCM (2 mL) were added DIPEA (0.27 mL, 1.53 mmol) and HATU (290.34 mg, 0.76 mmol) at room temperature, and the mixture was stirred at room temperature for 10 minutes. To this solution was added I-A1 (150 mg, 0.51 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (10 mL x 2) and washed with water (10 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give a residue. The residue was purified by preparative HPLC to give I-54 (115 mg, 0.311 mmol, 61% yield) as a solid. HPLC: Rt 6.432 minutes, 99.8%, column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm, mobile phase: A: 0.1% aqueous formic acid: ACN (95:05), B: ACN, flow rate: 1.0 mL / min LCMS: 369.9 (M+H), Rt 1.677 minutes, column: X-select CSH C18 (3 × 50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6) δ H = 9.02 (d, 1H), 8.93 (d, 1H), 8.28 - 8.25 (m, 2H), 7.86 - 7.84 (m, 1H), 5.31 - 5.27 (m, 1H), 4.12 - 4.06 (m, 1H), 2.33 - 2.29 (m, 1H), 2.16 - 2.08 (m, 2H), 2.00 - 1.92 (m, 1H), 1.59 (d, 3H). Chiral method: Rt 10.681 minutes, 94.7%, column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5um), mobile phase: A) n-hexane + 0.1% isopropylamine, B) DCM:MeOH (1:1), isocratic: 50% B, wavelength: 225 nm, flow rate: 1.0 mL / min.

[0218] Example I-56: (S)-3,3-Dimethyl-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)cyclobutane-1-carboxamide [Chemical formula] To a stirred solution of I-A53 (104.39 mg, 0.81 mmol) in DCM (2 mL) were added DIPEA (0.35 mL, 2.04 mmol) and HATU (387.12 mg, 1.02 mmol) at room temperature, and the mixture was stirred for 10 minutes. To this solution was added I-A1 (200 mg, 0.68 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (10 mL x 2) and washed with water (10 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give a residue. The residue was purified by flash column chromatography using 100 - 200 mesh silica and a hexane solution of 30 - 35% EtOAc as the eluent to give I-56 (110 mg, 0.29 mmol, 42% yield) as a solid. HPLC: Rt 8.8 minutes, 96%, column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm, mobile phase: A: 0.1% aqueous formic acid: ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 369 (M+H), Rt 2.173 minutes, column: X-select CSH C18 (3×50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6) δ H = 9.02 (d, 1H), 8.56 (d, 1H), 8.28 - 8.25 (m, 2H), 5.27 - 5.19 (m, 1H), 3.07 - 2.98 (m, 1H), 1.93 - 1.80 (m, 4H), 1.55 (d, 3H), 1.14 (s, 3H), 1.03 (s, 3H). Chiral method: Rt 7.29 minutes, 95.1%, column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5um), mobile phase: A) n-hexane + 0.1% isopropylamine, B) DCM:MeOH (50:50), isocratic: 20% B, wavelength: 270 nm, flow rate: 1.0 mL / min.

[0219] Example I-57: Synthesis of (S)-5-Bromo-N-(1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)thiophene-2-carboxamide [Chemical formula] To a stirred solution of I-A54 (93.15 mg, 0.45 mmol) in DCM (2 mL) were added DIPEA (0.2 mL, 1.12 mmol) and HATU (213.83 mg, 0.56 mmol) at room temperature, and the mixture was stirred for 10 minutes. To the resulting reaction mixture was added (1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (100 mg, 0.37 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM, and the organic layer was washed with water (2 x 3 mL). The organic layer was dried over sodium sulfate and concentrated completely under reduced pressure to give a residue as a solid. The residue was purified by preparative HPLC to give I-57 (45 mg, 0.10 mmol, 28% yield) as a solid. HPLC: Rt 8.553 minutes, 96.6%, column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm, mobile phase: A: 0.1% formic acid aqueous solution: ACN (95:05), B: ACN, flow rate: 1.0 mL / min LCMS: 419.10 (M+H), Rt 2.03 minutes, column: X-select CSH C18 (3×50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H = 9.36 (d, 1H), 8.61 (d, 1H), 7.86 - 7.84 (m, 1H), 7.71 (d, 1H), 7.68 - 7.65 (m, 1H), 7.34 (d, 1H), 5.45 - 5.40 (m, 1H), 2.33 - 2.25 (m, 1H), 1.67 (d, 3H), 1.04 - 0.96 (m, 4H). Chiral method: Rt15.32 minutes, 91.9%, column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5um), mobile phase: A) n-hexane + 0.1% isopropylamine, B) DCM:MeOH (1:1), isocratic: 20% B, wavelength: 280 nm, flow rate: 1.0 mL / min.

[0220] Example I-58: Synthesis of (R)-N-((S)-1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-2-phenylpropanamide

Chemical formula

[0221] Example I-59: (S)-N-(1-(3-(2-(Trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)bicyclo[2.2.2]octane-1-carboxamide [Chemical formula] To a stirred solution of I-A1 (100 mg, 0.39 mmol) and I-A56 (71.67 mg, 0.46 mmol) in DCM (10 mL) were added HATU (220.89 mg, 0.58 mmol) and DIPEA (0.13 mL, 0.77 mmol) at room temperature. The reaction mixture was 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 separated, dried over anhydrous sodium sulfate, filtered and evaporated to give a residue. The residue was purified by flash column chromatography using 100 - 200 mesh silica and a hexane solution of 25 - 30% EtOAc as the eluent to give I-59 (20 mg, 0.050 mmol, yield 13%). HPLC: Rt 9.522 min, 99.8%, column: X-Select CSH C18 (4.6x150) mm, 5μm, mobile phase: A: 0.1% aqueous formic acid:ACN (95:05), B: ACN, flow rate: 1.0 mL / min LCMS: 394.90 (M+H), Rt 2.202 min, column: X-select CSH C18 (3×50) mm, 2.5μm.1 1H NMR (400 MHz, DMSO-d6) δ H = 9.02 (d, 1H), 8.28 - 8.25 (m, 2H), 8.16 - 8.13 (m, 1H), 5.27 - 5.19 (m, 1H), 1.68 - 1.64 (m, 6H), 1.63 - 1.53 (m, 10H). Chiral method: Rt 7.184 min, 94.4%, column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5 μm), mobile phase: A) n-hexane + 0.1% isopropylamine, B) DCM:MeOH (1:1), isocratic: 20% B, wavelength: 225 nm, flow rate: 1.0 mL / min.

[0222] Example I-60: Synthesis of N-((S)-1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)bicyclo[2.2.2]octane-2-carboxamide

Chemical Structure

[0223] Example I-61: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-4-methoxybenzamide

Chemical formula

[0224] Example I-62: (S)-4-chloro-N-(1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)benzamide [Chemical formula] To a stirred solution of I-A27 HCl salt (0.070 g, 0.262 mmol) and I-A60 (0.049 g, 0.312 mmol) in DCM (10 mL), DIPEA (0.090 mL, 0.520 mmol) was added, followed by HATU (0.149 g, 0.390 mmol) at room temperature, and the mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography with a 30 - 80% ethyl acetate in n-hexane solution using a 100 - 200 mesh size to give I-62 (0.020 g, 0.054 mmol, yield 21%) as a solid. LCMS: 368.90 (M+H), R t = 2.036 min, column: Kinetex EVO-C18 (3.0*50 mm, 2.6μm), mobile phase: A: 0.025% formic acid, B: acetonitrile, T / B%: 0.01 / 5, 3 / 90, 5 / 90, 5.5 / 5, 6 / 5, flow rate: 0.8 mL / min (gradient). HPLC: R t= 8.580 min, 97.0%, Column: X-Select CSH C18 (150 x 4.6 mm, 3.5 μm); Mobile Phase: A: 0.05% TFA: Acetonitrile (95:05), B: Acetonitrile: 0.05% TFA (95:05), Program: T / B%: 0.01 / 10, 12 / 90, 16 / 90. Flow Rate: 1.0 mL / min, Diluent: Acetonitrile: Water. Chiral HPLC: R t = 7.184 min, 94.40%, Column: CHIRAL PAK IG (250×4.6 mm, 5 μm); Mobile Phase: A) n-Hexane + 0.1% Iso-Propyl-Amine B) DCM:MeOH (1:1), Isocratic: 25% B, Wavelength: 292 nm, Flow Rate: 1.0 mL / min. 1 1H NMR (400 MHz, DMSO-d6) δ H = 9.02 (d, 1H), 8.28 - 8.25 (m, 2H), 8.16 - 8.13 (m, 1H), 5.27 - 5.19 (m, 1H), 1.68 - 1.64 (m, 6H), 1.63 - 1.53 (m, 10H).

[0225] Example I-63: 3-Chloro-N-[(1S)-1-[3-(2-Cyclopropyl-4-pyridyl)-1,2,4-oxadiazol-5-yl]ethyl]benzamide

Chemical Structure

[0226] Example I-64: (2S)-N-[(1S)-1-[3-(2-Cyclopropyl-4-pyridyl)-1,2,4-oxadiazol-5-yl]ethyl]-2-phenyl-propanamide

Chemical Structure

[0227] Example I-65: (S)-1-Methyl-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)piperidine-4-carboxamide

Chemical formula

[0228] Example I-66: 1-Methyl-N-((S)-1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)piperidine-2-carboxamide

Chemical Structure

[0229] Example I-67: (S)-4,4-Dimethyl-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)cyclohexane-1-carboxamide

Chem.

[0230] Example I-68: 1-Methyl-N-((S)-1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)piperidine-3-carboxamide

Chemical Structure

[0231] Example I-69: (S)-4-Methoxy-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)cyclohexane-1-carboxamide

Chem.

[0232] Example I-70: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-5-(methylsulfonyl)thiophene-2-carboxamide [Chemical formula] I-A69: Methyl 5-(methylsulfonyl)thiophene-2-carboxylate: To a stirred solution of I-A68 (2.00 g, 9.050 mmol) in DMSO (30 mL) were added sodium methanesulfinate (1.85 g, 18.09 mmol), copper(I) iodide (0.343 g, 1.810 mmol), L-proline (0.208 g, 1.810 mmol), and sodium hydroxide (0.036 g, 0.900 mmol) at room temperature. The reaction mixture was further heated at 100 °C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure to dryness. The residue was diluted with ethyl acetate and washed with water (2 × 10 mL), then with brine (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography eluting with a 0 - 30% ethyl acetate in n-hexane solution to give I-A69 (0.800 g, 3.630 mmol, 40% yield).

[0233] I-A70: 5-(Methylsulfonyl)thiophene-2-carboxylic acid: To a stirred solution of I-A69 (0.800 g, 3.631 mmol) in THF:H2O (7:3 mL) was added LiOH·H2O (0.305 g, 7.264 mmol) at room temperature and the mixture was stirred for 14 h. After completion of the reaction, the mixture was concentrated under reduced pressure to remove THF. The resulting aqueous layer was acidified with 1 N HCl solution, the solid precipitate was filtered off, and dried under vacuum to give I-A70 (0.500 g, 2.424 mmol, 67% yield).

[0234] Example I-70: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-5-(methylsulfonyl)thiophene-2-carboxamide: To a stirred solution of I-A27 HCl salt (0.300 g, 1.120 mmol) and I-A70 (0.278 g, 1.350 mmol) in DCM (10 mL), DIPEA (0.590 mL, 3.370 mmol) was added first, followed by HATU (0.641 g, 1.690 mmol) at room temperature, and the mixture was stirred for 2 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure. The residue was diluted with ethyl acetate, washed with water (2×10 mL), and then with brine (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography eluting with a 0 - 40% ethyl acetate in n-hexane solution to give I-70 (0.204 g, 0.470 mmol, 42% yield) as a solid. LCMS: 419.10 (M+H), R t = 2.252 min, column: Kinetex EVO-C18 (3.0*50 mm, 2.6 μm), mobile phase: A: 0.025% formic acid, B: acetonitrile, T / B%: 0.01 / 5, 3 / 90, 5 / 90, 5.5 / 5, 6 / 5, flow rate: 0.8 mL / min (gradient). HPLC: R t = 5.838 min, 97.38%, column: Atlantis T3 (150x4.6 mm, 3.5 μm); mobile phase: A: 0.05% TFA aqueous solution: acetonitrile (95:05), B: acetonitrile: 0.05% TFA aqueous solution (5:95), program: T / B%: 0.01 / 10, 12 / 90, 16 / 90. Flow rate: 1.0 mL / min, diluent: acetonitrile: water. Chiral HPLC: R t = 15.07 min, 98.24%; column: CHIRAL PAK IC (150×4.6 mm, 3 μm), mobile phase: A) 0.1% DEA in n-hexane solution, B) DCM:MeOH (50:50), A:B::70:30, flow rate: 0.7 mL / min. 1 H NMR (400 MHz, DMSO-d6) δ H = ppm 9.64 (d, 1H), 8.60 (d, 1H), 7.94 (d, 1H), 7.84 - 7.87 (m, 2H), 7.65 (dd, 1H), 5.44 - 5.59 (m, 1H), 3.39 (s, 3H), 2.27 - 2.31 (m, 1H), 1.70 (d, 3H), 0.96 - 1.01 (m, 4H).

[0235] Example I-71: 1-Methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-oxadiazol-5-yl]ethyl]cyclohexanecarboxamide

Chem.

[0236] Example I-72: 3-Methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-oxadiazol-5-yl]ethyl]bicyclo[1.1.1]pentane-1-carboxamide

Chemical Structure

[0237] Example I-73: 1-Acetyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-oxadiazol-5-yl]ethyl]piperidine-4-carboxamide

Chem.

[0238] Example I-74: 3-Methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-oxadiazol-5-yl]ethyl]cyclobutanecarboxamide [Chemical formula] To a stirred solution of Compound I-A1 (100 mg, 0.34 mmol, HCl salt) and I-A74 (38.74 mg, 0.34 mmol) in DCM (2 mL) were added HATU (193.56 mg, 0.51 mmol) and DIPEA (0.18 mL, 1.02 mmol) at room temperature for 10 minutes. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (5 mL) and washed with water (2 x 10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give a residue. The residue was purified by preparative HPLC to give I-74 (67 m, 0.19 mmol, 56% yield) as a solid. HPLC: Rt 8.431 (47%) and 8.476 (53%), total: 99.9%, (Note: cis-trans isomers were not separated); Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm, Mobile phase: A: 0.1% aqueous formic acid: ACN (95:05), B: ACN, Flow rate: 1.0 mL / min. LCMS: 354.9 (M+H), Rt 2.093 min, Column: X-select CSH C18 (3*50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6) δ H = 9.02 (d, 1H), 8.28 - 8.25 (m, 2H), 8.16 - 8.13 (m, 1H), 5.27 - 5.19 (m, 1H), 1.68 - 1.64 (m, 6H), 1.63 - 1.53 (m, 10H). Chiral method: Rt 16.622 min (49.846%) and 20.119 (46.334%). Column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5u), - Mobile phase: A) n-hexane + 0.1% iso-propyl-amine B) DCM:MeOH (1:1), Isocratic: 10% B, Wavelength: 225 nm, Flow rate: 1.0 mL / min Note: cis and trans isomer mixture (approx. 50:50).

[0239] Example I-75: N-[(1S)-1-[3-(2-Cyclopropyl-4-pyridyl)-1,2,4-oxadiazol-5-yl]ethyl]-2-methoxy-benzamide [Chem.] To a stirred solution of I-A27 HCl salt (61.96 mg, 0.41 mmol) and I-A75 (90.52 mg, 0.34 mmol) in DCM (2 mL) were added HATU (193.56 mg, 0.51 mmol) and DIPEA (0.18 mL, 1.02 mmol) at room temperature for 10 minutes. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (5 mL) and washed with water (2 × 10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give a residue. The residue was purified by preparative HPLC to give I-75 (17 mg, 0.0456 mmol, 13% yield) as a solid. HPLC: Rt 8.499 min, 97.8%, column: X-Select CSH C18 (4.6x150) mm, 5 μm, mobile phase: A: 0.1% aqueous formic acid: ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 365 (M+H), Rt 1.994 min, column: X-select CSH C18 (3*50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6) δ H = 9.02 (d, 1H), 8.28 - 8.25 (m, 2H), 8.16 - 8.13 (m, 1H), 5.27 - 5.19 (m, 1H), 1.68 - 1.64 (m, 6H), 1.63 - 1.53 (m, 10H). Chiral method: Rt 11.47 min, 93%, column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5u), - mobile phase: A) n-hexane + 0.1% iso-propyl-amine B) DCM:MeOH (1:1), isocratic: 30% B, wavelength: 290 nm, flow rate: 1.0 mL / min

[0240] Example I-76: N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-oxadiazol-5-yl]ethyl]spiro[3.3]heptane-2-carboxamide [Chem.] To a stirred solution of Compound I-A1 (0.21 g, 0.71 mmol, HCl salt) and I-A76 HCl salt (0.1 g, 0.71 mmol) in DCM (2 mL) were added HATU (0.27 g, 0.71 mmol) and DIPEA (0.25 mL, 1.43 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with DCM (20 mL) and washed with water (10 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give a residue. The residue was purified by flash column chromatography using an 80% EtOAc in hexane solution as the eluent to give I-76 (115 mg, 0.29 mmol, 41% yield). HPLC: Rt 9.018 min, 96.6%, column: X-Select CSH C18 (4.6x150) mm, 5 μm, mobile phase: A: 0.1% formic acid in aqueous solution: ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 381.1 (M+H), Rt 2.181 min, column: X-select CSH C18 (3*50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H = 9.02 (d, 1H), 8.28 - 8.25 (m, 2H), 8.16 - 8.13 (m, 1H), 5.27 - 5.19 (m, 1H), 1.68 - 1.64 (m, 6H), 1.63 - 1.53 (m, 10H). Chiral method: Rt 7.862 min, 95.8%, column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5u), - mobile phase: A) n-hexane + 0.1% iso-propyl-amine B) DCM:MeOH (1:1), isocratic: 20% B, wavelength: 271 nm, flow rate: 1.0 mL / min

[0241] Examples I-77 and I-78: cis-4-Hydroxy-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-oxadiazol-5-yl]ethyl]cyclohexanecarboxamide and trans-4-Hydroxy-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-oxadiazol-5-yl]ethyl]cyclohexanecarboxamide [Chemical] To a stirred solution of Compound I-A1 (100 mg, 0.34 mmol, HCl salt) and I-A77 (0.06 mL, 0.41 mmol) in DCM (2 mL) were added HATU (193.56 mg, 0.51 mmol) and DIPEA (0.18 mL, 1.02 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (3 mL) and washed with water (2 x 3 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated to give a residue. The residue was purified by preparative HPLC and then purified again using chiral column chromatography to give I-77 (34 mg, 0.09 mmol, 26% yield) and I-78 (18 mg, 0.04 mmol, 13% yield) of the cis and trans isomeric products. Note that the stereochemistry was randomly assigned.

[0242] I-77: HPLC: Rt 6.9 min, 99.8%, column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm, mobile phase: A: 0.1% aqueous formic acid: ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 385.15 (M+H), Rt 1.78 min, column: X-select CSH C18 (3*50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6) δ H = 9.02 (d, 1H), 8.65 (d, 1H), 8.28 - 8.24 (m, 2H), 5.24 - 5.20 (m, 1H), 4.55 (d, 1H), 2.15 - 2.08 (m, 1H), 1.86 - 1.84 (m, 2H), 1.18 - 1.70 (m, 2H), 1.54 (d, 3H), 1.43 - 1.30 (m, 2H), 1.17 - 1.08 (m, 2H), 1H was merged with the solvent peak. Chiral method: Rt 7.87 min, 98.9%, column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5u), - mobile phase: A) n-hexane + 0.1% isopropylamine, B) isopropyl alcohol, isocratic: 20% B, wavelength: 270 nm, flow rate: 1.0 mL / min

[0243] I-78: HPLC: Retention time 7.02 minutes, 97.4%, column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm, mobile phase: A: 0.1% formic acid aqueous solution: ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 385.15 (M+H), Retention time 1.90 minutes, column: X-select CSH C18 (3 * 50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H = 9.02 (d, 1H), 8.59 - 8.57 (m, 1H), 8.28 - 8.25 (m, 2H), 5.25 - 5.20 (m, 1H), 4.32 - 4.30 (m, 1H), 3.80 - 3.70 (m, 1H), 2.25 - 2.15 (m, 1H), 1.85 - 1.75 (m, 2H), 1.61 - 1.57 (m, 2H), 1.55 (d, 3H), 1.45 - 1.42 (m, 4H). Chiral method: Retention time 15.167 minutes, 97.2%, column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5u), - mobile phase: A) n-hexane + 0.1% iso-propyl-amine B) DCM:MeOH (50:50), isocratic: 20% B, wavelength: 270 nm, flow rate: 1.0 mL / min

[0244] Example I-79: (N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-oxadiazol-5-yl]ethyl]-3-methoxy-benzamide

Chemical Structure

[0245] Example I-80: 2-Chloro-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-oxadiazol-5-yl]ethyl]benzamide

Chemical Structure

[0246] Example I-81: N-[(1S)-1-[3-(2-Cyclopropyl-4-pyridyl)-1,2,4-oxadiazol-5-yl]ethyl]-3-methyl-benzamide

Chemical formula

[0247] Example A-82: N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-oxadiazol-5-yl]ethyl]spiro[2.4]heptane-7-carboxamide

Chemical Structure

[0248] Example I-83: N-[(1S)-1-[3-(2-Cyclopropyl-4-pyridyl)-1,2,4-oxadiazol-5-yl]ethyl]-2-methyl-benzamide

Chemical Structure

[0249] Example I-84: (1S,4R)-N-((S)-1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-4-methylcyclohexane-1-carboxamide

Chemical Structure

[0250] I-84: HPLC: Rt 8.697 min, 98.4%, Column: X-Select CSH C18 (4.6x150) mm, 3.5 μm, Mobile phase: A: Aqueous solution of 0.1% formic acid:ACN (95:05), B: ACN, Flow rate: 1.0 mL / min. LCMS: 355.05 (M + H), Rt 1.939 min, Column: X-select CSH (3*50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H=8.60 (d, 1H), 8.52 - 8.51 (m, 1H), 7.83 (s, 1H), 7.64 - 7.63 (m, 1H), 5.23 - 5.20 (m, 1H), 2.32 - 2.24 (m, 2H), 1.77 - 1.73 (m, 2H), 1.60 (brs, 1H), 1.54 (d, 3H), 1.50 - 1.46 (m, 4H), 1.33 - 1.30 (m, 2H), 1.04 - 0.97 (m, 4H), 0.88 (d, 3H). Chiral method: Rt 10.318 min, 100%, column: DIACEL CHIRALPAK YMC CHIRAL AMYLOSE - SA (250×4.6 mm, 5u), - mobile phase: A) n - hexane + 0.1% isopropylamine, B) isopropyl alcohol, isocratic: 20%B, wavelength: 220 nm, flow rate: 1.0 mL / min

[0251] Example I - 85: 1 - Acetyl - N - [(1S) - 1 - [3 - [2 - (trifluoromethyl) - 4 - pyridyl] - 1,2,4 - oxadiazol - 5 - yl] ethyl] piperidine - 3 - carboxamide

Chemical formula

[0252] Example I-86: 1-Acetyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-oxadiazol-5-yl]ethyl]piperidine-2-carboxamide

Chemical Structure

[0253] Example I-87: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-4-methylbenzamide: [Chemistry] To a stirred solution of I-A27 (150 mg, 0.56 mmol, HCl salt) and I-A87 (91.88 mg, 0.67 mmol) in DCM (3 mL), HATU (320.74 mg, 0.84 mmol) and DIPEA (0.29 mL, 1.69 mmol) were added at room temperature and stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (5 mL), quenched with water (2 x 10 mL), and the organic layer was separated. The organic layer was dried over Na2SO4, filtered, and evaporated by rotavapor. The reaction mixture was purified by column chromatography using a hexane solution of 25 - 30% ethyl acetate to obtain I-87 (40 mg, 0.1125 mmol, 20% yield) as a solid. HPLC: Rt 8.309 min, 98%, column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm, mobile phase: A: aqueous solution of 0.1% formic acid: ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 349.05 (M+H), Rt 1.950 min, column: X-select CSH C18 (3 * 50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H = 9.17 (d, 1H), 8.59 (d, 1H), 7.85 - 7.80 (m, 3H), 7.65 - 7.64 (m, 1H), 7.31 (d, 2H), 5.48 - 5.44 (m, 1H), 2.36 (s, 3H), 2.28 - 2.27 (m, 1H), 1.68 (d, 3H), 1.00 - 0.97 (m, 4H). Chiral method: Rt 5.785 min, 99.8%, column: DIACEL CHIRALPAK-IG (250×4.6 mm, 5u), - mobile phase: A) n-hexane + 0.1% iso-propyl-amine B) DCM:MeOH (1:1), isocratic: 50% B, wavelength: 292 nm, flow rate: 1.0 mL / min

[0254] Example I-88: (S)-3-Cyano-N-(1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)benzamide [Chemistry] To a stirred solution of I-A27 (70 mg, 0.26 mmol) and I-A88 (46 mg, 0.31 mmol) in DCM (5 mL) were added HATU (7.67 mg, 0.04 mmol) and DIPEA (0.14 mL, 0.79 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (5 mL) and diluted with DCM (3 x 10 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give a residue. The residue was purified by column chromatography using 100 - 200 silica and 5 - 10% EtOAc / hexane as the eluent to give I-88 (50 mg, 0.1387 mmol, 26% yield) as a solid. HPLC: Rt 8.25 min, 99.67%, column: X-Bridge C18 (4.6 x 150) mm, 3.5 μm, mobile phase: A: aqueous solution of 10 mM ammonium bicarbonate, B: ACN, flow rate: 1.0 mL / min. LCMS: 360.05 (M+H), Rt 1.923 min, column: X-select CSH C18 (3 * 50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H = 9.47 (d, 1H), 8.59 (d, 1H), 8.34 (s, 1H), 8.19 (d, 1H), 8.05 (d, 1H), 7.84 (s, 1H), 7.73 (t, 1H), 7.64 (d, 1H), 5.51 - 5.47 (m, 1H), 2.30 - 2.26 (m, 1H), 1.69 (d, 3H), 1.00 - 0.95 (m, 4H).

[0255] Example I-89: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-3-fluorobenzamide

Chemical formula

[0256] Examples I-90 and I-91: Synthesis of (S)-N1-(1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-N3,N3-dimethylisophthalamide and (S)-N-(1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)isophthalamide

Chemical formula

[0257] I-90: (S)-N1-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-N3,N3-dimethylisophthalamide Yield: 21 mg, 0.048 mmol, 13% yield, Appearance: solid, HPLC: Rt 6.411 min, 93.11%, Column: X-Select CSH C18 (4.6x150) mm, 3.5 μm, Mobile phase: A: 0.1% formic acid aqueous solution: ACN (95:05), B: ACN, Flow rate: 1.0 mL / min. LCMS: 406.10 (M+H), Rt 1.939 min, Column: X-select CSH C18 (3*50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6) δ H = 9.37 (d, 1H), 8.61 (d, 1H), 8.01 - 7.92 (m, 2H), 7.87 (s, 1H), 7.69 (d, 1H), 7.64 - 7.52 (m, 2H), 5.50 (p, 1H), 3.00 (s, 3H), 2.91 (s, 3H), 2.29 (q, 1H), 1.69 (d, 3H), 1.03 - 0.98 (m, 4H). Chiral method: Rt 9.640 min, 91.78%, Column: YMC CHIRAL ART CELLULOSE-SC (250x4.6 mm, 5u), Mobile phase: A) n-hexane + 0.1% TFA, B) DCM:MeOH (50:50), Isocratic: 40% B, Wavelength: 288 nm, Flow rate: 1.0 mL / min

[0258] I-91: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)isophthalamide Yield: 15 mg, 0.0387 mmol, 6%, Appearance: Solid, HPLC: Rt 6.346 min, 97.30%, Column: X-Select CSH C18 (4.6x150) mm, 3.5 μm, Mobile phase: A: 0.1% formic acid aqueous solution: ACN (95:05), B: ACN, Flow rate: 1.0 mL / min. LCMS: 378 (M+H), Rt 1.794 min, Column: X-select CSH C18 (3*50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H = 9.40 (d, 1H), 8.61 (d, 1H), 8.41 (s, 1H), 8.11 - 8.00 (m, 3H), 7.87 (s, 1H), 7.68 (d, 1H), 7.59 (t, 1H), 7.50 (s, 1H), 5.51 (p, 1H), 2.30 - 2.28 (m, 1H), 1.71 (d, 3H), 1.04 - 0.95 (m, 4H). Chiral method: Rt 9.988 min, 95.89%, Column: YMC CHIRAL ART CELLULOSE-SC (250x4.6 mm, 5u), Mobile phase: A) n-hexane + 0.1% TFA, B) DCM:MeOH (50:50), Isocratic: 35% B, Wavelength: 288 nm, Flow rate: 1.0 mL / min

[0259] Example I-92: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-3-(methylsulfonyl)benzamide [Chemical formula] To a stirred solution of I-A90 (63.05 mg, 0.31 mmol) in DCM (2 mL) were added HATU (99.79 mg, 0.26 mmol) and DIPEA (0.05 mL, 0.26 mmol), and the mixture was stirred for 15 minutes. To this solution was added I-A27 HCl salt (70 mg, 0.26 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After completion, the reaction mass was diluted with DCM (20 mL) and water (5 mL), and extracted with DCM (3 × 20 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give the desired compound I-92 (40 mg, 0.1 mmol, 37%) as a solid. HPLC: Rt 7.796 min, 99.22%, column: X-Bridge C18 (4.6x150) mm, 5 μm; mobile phase: A: aqueous solution of 10 mM ammonium bicarbonate, B: ACN, flow rate: 1.0 mL / min. LCMS: 412.95 (M+H), Rt 1.775 min. Column: Atlantis Premier BEH C18 (2.1*50 mm), 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H = 9.59 (d, 1H), 8.60 (d, 1H), 8.45 (s, 1H), 8.24 (d, 1H), 8.14 (d, 1H), 7.85 - 7.77 (m, 2H), 7.66 - 7.64 (m, 1H), 5.55 - 5.52 (m, 1H), 3.28 - 3.26 (m, 3H), 2.30 - 2.25 (m, 1H), 1.72 (d, 3H), 1.00 - 0.96 (m, 4H). Chiral method: Rt 7.376 min, 99.07%, column: YMC CHIRAL ART CELLULOSE-SC (250x4.6 mm, 5u), mobile phase: A) n-hexane + 0.1% isopropylamine, B) DCM:MeOH (50:50), isocratic: 40% B, wavelength: 292 nm, flow rate: 1.0 mL / min

[0260] Example I-93: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-5-(ethylsulfonyl)thiophene-2-carboxamide [Chemistry] (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-5-(ethylsulfonyl)thiophene-2-carboxamide (PRX-0003499-001) Synthesis: To a stirred solution of I-A91 (69.37 mg, 0.31 mmol) in DCM (5 mL), HATU (249.47 mg, 0.66 mmol) and DIPEA (0.14 mL, 0.79 mmol) were added and stirred for 15 minutes. To this solution, I-A27 HCl salt (70 mg, 0.26 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After completion, the reaction mass was diluted with DCM (20 mL) and water (5 mL), and extracted with DCM (3 × 20 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to obtain the desired compound I-93 (12 mg, 0.03 mmol, 11%) as a solid. HPLC: Rt 8.159 minutes, 99.27%, column: X-Bridge C18 (4.6x150) mm, 5 μm; mobile phase: A: 10 mM aqueous ammonium bicarbonate, B: ACN, flow rate: 1.0 mL / min. LCMS: 432.90 (M+H), Rt 1.867 minutes. Column: Atlantis Premier BEH C18 (2.1*50 mm), 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H = 9.66 (s, 1H), 8.60 (d, 1H), 7.97 (d, 1H), 7.88 - 7.80 (m, 2H), 7.65 (d, 1H), 5.50 - 5.46 (m, 1H), 3.45 (q, 2H), 2.30 - 2.25 (m, 1H), 1.70 (d, 3H), 1.18 (t, 3H), 1.03 - 0.94 (m, 4H). Chiral method: Rt 7.319 minutes, 97.09%, column: YMC CHIRAL ART CELLULOSE-SC (250x4.6 mm, 5u), mobile phase: A) n-hexane + 0.1% isopropylamine, B) DCM:MeOH (50:50), isocratic: 40%B, wavelength: 262 nm, flow rate: 1.0 mL / min

[0261] Example I-94: (S)-2,4-dichloro-N-(1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)benzamide [Chemical formula] To a stirred solution of I-A92 (60.15 mg, 0.31 mmol) in DCM (5 mL) were added HATU (249.47 mg, 0.66 mmol) and DIPEA (0.14 mL, 0.79 mmol), and the mixture was stirred for 15 minutes. To this solution was added I-A27 HCl salt (70 mg, 0.26 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After completion, the reaction mass was diluted with DCM (20 mL) and water (5 mL), and extracted with DCM (3 × 20 mL). The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give the desired compound I-94 (25 mg, 0.06 mmol, 23%) as a solid. HPLC: Rt 9.010 min, 99.37%, column: X-Bridge C18 (4.6x150) mm, 5 μm; mobile phase: A: aqueous solution of 10 mM ammonium bicarbonate, B: ACN, flow rate: 1.0 mL / min. LCMS: 402.80 (M+H), Rt 2.236 min. Column: Atlantis Premier BEH C18 (2.1*50 mm), 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6) δ H = 9.41 (d, 1H), 8.62 (d, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 7.70 - 7.63 (m, 1H), 7.55 - 7.53 (m, 2H), 5.44 (p, 1H), 2.32 - 2.27 (m, 1H), 1.65 (d, 3H), 1.02 - 0.98 (m, 4H). Chiral method: Rt 9.507 min, 98.01%, column: DIACEL CHIRALPAK-IG, (250x4.6 mm, 5u), mobile phase: A) n-Hexane + 0.1% isopropylamine, B) DCM:MeOH (50:50), isocratic: 30% B, wavelength: 291 nm, flow rate: 1.0 mL / min

[0262] Example I-95: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-3-(trifluoromethyl)benzamide

Chemical formula

[0263] Example I - 96: (S) - N - (1 - (3 - (2 - cyclopropylpyridin - 4 - yl) - 1,2,4 - oxadiazol - 5 - yl)ethyl) - 2 - (trifluoromethyl)isonicotinamide

Chemical Structure

[0264] Example I-97: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-5-(cyclopropylsulfonyl)thiophene-2-carboxamide [Chemical formula] To a stirred solution of I-A27 HCl salt (97.07 mg, 0.36 mmol) and I-A95 (101.44 mg, 0.44 mmol) in DCM (5 mL) were added HATU (166.05 mg, 0.44 mmol) and DIPEA (0.13 mL, 0.73 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After completion, the reaction solution was quenched with water (10 mL) and extracted with DCM (2 x 50 mL). The organic layer was separated, dried over anhydrous Na2SO4, and then filtered. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 30 - 80% EtOAc / hexane as the eluent to give the title compound I-97 (25 mg, 0.05 mmol, 15%) as a solid. HPLC: Rt 7.953 min, 95.09%, column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm, mobile phase: A: 0.1% aqueous formic acid: ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 445 (M+H), Rt 1.934 min, column: X-select CSH C18 (3 * 50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H = 9.64 (d, 1H), 8.60 - 8.58 (m, 1H), 7.96 - 7.94 (m, 1H), 7.86 - 7.82 (m, 2H), 7.66 - 7.64 (m, 1H), 5.50 - 5.46 (m, 1H), 3.10 - 3.00 (m, 1H), 2.30 - 2.25 (m, 1H), 1.70 (d, 3H), 1.22 - 1.10 (m, 4H), 1.05 - 0.98 (m, 4H). Chiral method: Rt: 7.205 min, 97.58%, column: DIACEL CHIRALPAK-IG, (250 x 4.6 mm, 5u), mobile phase: A) n-Hexane + 0.1% isopropylamine, B) DCM:MeOH (50:50), isocratic: 20%B, wavelength: 287 nm, flow rate: 1.0 mL / min

[0265] Example I-98: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)spiro[3.3]heptane-2-carboxamide [Chemistry] To a stirred solution of I-A27 HCl salt (100 mg, 0.37 mmol) and I-A96 (63.07 mg, 0.45 mmol) in DCM (5 mL) were added HATU (171.06 mg, 0.45 mmol) and DIPEA (0.07 mL, 0.37 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After completion, the reaction solution was quenched with water (10 mL) and extracted with DCM (2 x 50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 30 - 80% EtOAc / hexane as the eluent to give the title compound I-98 (28 mg, 0.08 mmol, 21% yield) as an oil. HPLC: Rt 8.436 min, 99.50%, column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm, mobile phase: A: 0.1% aqueous formic acid: ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 353.3 (M+H), Rt 1.999 min, column: X-select CSH C18 (3 * 50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H = 8.59 (d, 1H), 8.52 (d, 1H), 7.82 (s, 1H), 7.62 (d, 1H), 5.22 - 5.18 (m, 1H), 2.95 - 2.85 (m, 1H), 2.30 - 2.25 (m, 1H), 2.10 - 2.05 (m, 4H), 2.00 - 1.95 (m, 2H), 1.85 - 1.70 (m, 4H), 1.52 (d, 3H), 1.05 - 0.95 (m, 4H). Chiral method: Rt: 9.762 min, 99.42%, column: DIACEL CHIRALPAK-IG, (250 x 4.6 mm, 5u), mobile phase: A) n-Hexane + 0.1% isopropylamine, B) DCM:MeOH (50:50), isocratic: 20%B, wavelength: 292 nm, flow rate: 1.0 mL / min

[0266] Example I-99: (S)-2-Cyclopropyl-N-(1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)isonicotinamide

Chemical formula

[0267] Example I - 100: (S) - 3 - chloro - N - (1 - (3 - (2 - cyclobutylpyridin - 4 - yl) - 1,2,4 - oxadiazol - 5 - yl)ethyl)benzamide

Chemical Structure

[0268] I - A100: (Z) - 2 - cyclobutyl - N’ - hydroxyisonicotinimidamide To a stirred solution of I-A99 (2 g, 12.64 mmol) in EtOH (20 mL) were added hydroxylamine hydrochloride (1.32 g, 18.96 mmol) and TEA (2.55 g, 25.28 mmol), and the mixture was stirred at 80 °C for 3 h. The reaction mixture was evaporated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and evaporated to give a residue, which was purified by silica gel column chromatography using 100 - 200 mesh silica and 8% ethyl acetate / hexane as the eluent to afford I-A100 (2 g, 10.47 mmol, 83%) as an oil.

[0269] I-A101: tert-butyl (S)-(1-(3-(2-cyclobutylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate To a stirred solution of I-A100 (2 g, 10.46 mmol) in 1,4-dioxane (20 mL) were added (2S)-2-(tert-butoxycarbonylamino)propanoic acid (2.18 g, 11.5 mmol) and DCC (2.37 g, 11.5 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and evaporated to give a residue, which was purified by combiflash column chromatography using 8% ethyl acetate / hexane as the eluent to afford I-A101 (3 g, 8.71 mmol, 83%) as an oil.

[0270] I-A102: (S)-1-(3-(2-cyclobutylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethane-1-amine To a stirred solution of I-A101 (3 g, 8.71 mmol) in 1,4-dioxane (10 mL) was added a solution of 4 M HCl in 1,4-dioxane (30 mL, 214.94 mmol), and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether to give I-A102 hydrochloride (2.5 g) as a solid.

[0271] I-100: (S)-3-Chloro-N-(1-(3-(2-cyclobutylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)benzamide To a stirred solution of I-A103 (67 mg, 0.43 mmol) in DCM (5 mL) were added HATU (380 mg, 1 mmol) and DIPEA (0.26 mL, 1.49 mmol), and the mixture was stirred at room temperature for 15 minutes. To this solution was added I-A102 (100 mg, 0.41 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After completion, the reaction mass was quenched with water and extracted with DCM (3 x 20 mL). The organic layer was separated, dried over Na2SO4, filtered, and evaporated to give a residue, which was purified by preparative HPLC to afford I-100 (20 mg, 0.05 mmol, 15%) as an oil. HPLC: Rt 9.213 min, 99.25%, column: X-Bridge C18 (4.6 x 150) mm, 5 μm; mobile phase: A: aqueous solution of 10 mM ammonium bicarbonate, B: ACN, flow rate: 1.0 mL / min. LCMS: 382.95 (M+H), Rt 2.258 min, column: X-select CSH C18 (3 * 50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H = 9.38 (d, 1H), 8.74 (d, 1H), 7.97 (s, 1H), 7.86 (d, 1H), 7.75 - 7.70 (m, 2H), 7.66 (d, 1H), 7.55 (t, 1H), 5.50 - 5.46 (m, 1H), 3.80 - 3.75 (m, 1H), 2.32 - 2.26 (m, 4H), 2.06 - 1.98 (m, 1H), 1.87 - 1.85 (m, 1H), 1.69 (d, 3H). Chiral method: Rt 7.590 min, 100%, column: DIACEL CHIRALPAK-IG, (250 x 4.6 mm, 5u), mobile phase: A) n-Hexane + 0.1% TEA, B) DCM:MeOH (50:50), isocratic: 20% B, wavelength: 281 nm, flow rate: 1.0 mL / min

[0272] Example I-101: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-2-methylisonicotinamide [Chemical formula] To a stirred solution of I-A27 HCl salt (100 mg, 0.43 mmol) and I-A104 (71.47 mg, 0.52 mmol) in DCM (5 mL) were added DIPEA (0.23 mL, 1.3 mmol) and HATU (247.69 mg, 0.65 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After completion, the reaction was quenched with water and extracted with DCM. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give I-101 (32.1 mg, 0.09 mmol, 21% yield) of the title compound as a solid. HPLC: Rt 5.253 min, 97.74%, column: X-Select CSH C18 (4.6x150) mm, 3.5 μm, mobile phase: A: 0.1% aqueous formic acid: ACN (95:05), B: ACN, flow rate: 1.0 mL / min. LCMS: 350.1 (M+H), Rt 1.433 min, column: X-select CSH C18 (3*50) mm, 2.5 μm. 1 1H NMR (400 MHz, DMSO-d6) δ H = 9.51 (d, 1H), 8.65 - 8.58 (m, 2H), 7.85 (s, 1H), 7.68 - 7.59 (m, 3H), 5.52 - 5.47 (m, 1H), 2.55 (s, 3H), 2.32 - 2.25 (m, 1H), 1.69 (d, 3H), 1.05 - 0.95 (m, 4H). Chiral method: Rt: 7.814 min, 99.18%, column: DIACEL CHIRALPAK-IG, (250x4.6 mm, 5u), mobile phase: A) n-Hexane + 0.1% isopropylamine, B) DCM:MeOH (50:50), isocratic: 30%B, wavelength: 282 nm, flow rate: 1.0 mL / min

[0273] Example I-102: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-3,5-difluorobenzamide

Chemical Structure

[0274] Example I-103: (S)-N-(1-(3-(2-Cyclopropylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethyl)-3-(trifluoromethoxy)benzamide

Chemical formula

[0275] Example I - 104: (S) - 1 - cyclobutyl - N - (1 - (3 - (2 - cyclopropylpyridin - 4 - yl) - 1,2,4 - oxadiazol - 5 - yl)ethyl) - 1H - imidazole - 2 - carboxamide

Chemical formula

Claims

1. A pharmaceutical composition comprising a compound of formula I-I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein 【Chemical 1】 In the formula,[ L is a bond or C １－６ is alkyl, X is N, G is selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, thiazolyl, pyridyl, tetrahydropyranyl, thiophenyl, isoxazolyl, isothiazolyl, pyridazinyl, piperidinyl, pyrrolidinyl, triazolyl, benzothiophenyl, pyrimidinyl, bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, 【Chemical 2】 Selected from the group consisting of R ２ is hydrogen, and R ３ is a C １－６ alkyl optionally substituted with C １－６ alkoxy and R ４ is hydrogen, and R ５ is selected from the group consisting of halogen, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, and C ３－１０ cycloalkyl, R ６ is each independently selected from hydrogen or C １－６ alkyl, R １２ is each independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, -S(O) ２ (C １－６ alkyl), -S(O) ２ (C ３－６ cycloalkyl), -C(O)C １－６ alkyl, -C(O)N(R ６ ) ２ , C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, C ３－１０ cycloalkyl, and phenyl, and z is 0, 1, 2, 3, or 4, a pharmaceutical composition.

2. A pharmaceutical composition comprising a compound of formula I-III, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein 【Chemical 3】 In the formula,[ G is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, thiazolyl, pyridyl, tetrahydropyranyl, thiophenyl, isoxazolyl, isothiazolyl, pyridazinyl, piperidinyl, pyrrolidinyl, triazolyl, benzothiophenyl, pyrimidinyl, bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, 【Chemical Formula 4】 Selected from the group consisting of R ２ is hydrogen, and R ３ is a C １－６ alkyl optionally substituted with C １－６ alkoxy and R ４ is hydrogen, and R ５ is a halogen, and R １２ is each independently selected from the group consisting of halogen, cyano, oxo, -S(O) ２ (C １－６ alkyl), C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, C ３－１０ cycloalkyl, and phenyl, and z is 0, 1, 2, 3, or 4, a pharmaceutical composition.

3. A pharmaceutical composition comprising a compound of formula I-III2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein [Chemical Formula 5] In the formula,[ G is selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, thiazolyl, pyridyl, tetrahydropyranyl, thiophenyl, isoxazolyl, isothiazolyl, pyridazinyl, piperidinyl, pyrrolidinyl, triazolyl, benzothiophenyl, pyrimidinyl, bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, ​ Selected from the group consisting of R ２ is hydrogen, and R ３ is a C １－６ alkyl optionally substituted with C １－６ alkoxy and R ４ is hydrogen, and R ５ is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C3-10 cycloalkyl, R ６ each independently is hydrogen or C １－６ alkyl selected from, R １２ is each independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, -S(O) ２ (C １－６ alkyl), -S(O) ２ (C ３－６ cycloalkyl), -C(O)C １－６ alkyl, -C(O)N(R ６ ) ２ , C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, C ３－１０ cycloalkyl, and phenyl, and z is 0, 1, 2, 3, or 4, a pharmaceutical composition.

4. The pharmaceutical composition according to claim 2 or 3, wherein the compound is a compound of formula I-IIIa or formula I-IIIb, or a pharmaceutically acceptable salt thereof. [Chemical Formula 7]

5. A pharmaceutical composition comprising a compound of formula I-II-III, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein: 【Chemical 8】 In the formula: L is a bond or C １－６ is alkyl, G is selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, thiazolyl, pyridyl, tetrahydropyranyl, thiophenyl, isoxazolyl, isothiazolyl, pyridazinyl, piperidinyl, pyrrolidinyl, triazolyl, benzothiophenyl, pyrimidinyl, bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl; 【Chemical Formula 9】 Selected from the group consisting of: R ２ is hydrogen, and R ３ is a C １－６ alkyl optionally substituted with C １－６ alkoxy and R ４ is hydrogen, and R ５ is selected from the group consisting of halogen, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, and C ３－１０ cycloalkyl, R ６ is each independently selected from hydrogen or C １－６ alkyl, R １２ is each independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, -S(O) ２ (C １－６ alkyl), -S(O) ２ (C ３－６ cycloalkyl), -C(O)C １－６ alkyl, -C(O)N(R ６ ) ２ , C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, C ３－１０ cycloalkyl, and phenyl, and z is 0, 1, or 2, the pharmaceutical composition.

6. The pharmaceutical composition according to claim 1 or 5, wherein the compound is a compound of formula I-II-IIIa, formula I-II-IIIb, formula I-II-IIIc, formula I-II-III d, formula I-II-IIIe, or formula I-II-IIIf, or a pharmaceutically acceptable salt thereof. 【Chemical 10】

7. The compound is 【Chemical 11】 Or a pharmaceutically acceptable salt thereof, the pharmaceutical composition according to claim 2.

8. The compound is 【Chemical 12】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 Or a pharmaceutically acceptable salt thereof, the pharmaceutical composition according to claim 1.

9. A compound for use in a method of treating a neurological disease or disorder, a disease or condition associated with excessive neuronal excitability, or a disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1), wherein the compound is a compound of formula I-I or a pharmaceutically acceptable salt thereof. 【Chemical 13】 In the formula: L is a bond or C １－６ is alkyl, X is N; G is selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, thiazolyl, pyridyl, tetrahydropyranyl, thiophenyl, isoxazolyl, isothiazolyl, pyridazinyl, piperidinyl, pyrrolidinyl, triazolyl, benzothiophenyl, pyrimidinyl, bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl; 【Chemical 14】 Selected from the group consisting of: R ２ is hydrogen, and R ３ is a C １－６ alkyl optionally substituted with C １－６ alkoxy and R ４ is hydrogen, and R ５ is selected from the group consisting of halogen, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, and C ３－１０ cycloalkyl, R ６ is each independently selected from hydrogen or C １－６ alkyl, R １２ is each independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, -S(O) ２ (C １－６ alkyl), -S(O) ２ (C ３－６ cycloalkyl), -C(O)C １－６ alkyl, -C(O)N(R ６ ) ２ , C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, C ３－１０ cycloalkyl, and phenyl, and z is 0, 1, 2, 3, or 4.

10. 9. The pharmaceutical composition of any one of claims 1 to 8 for use in a method for treating a neurological disease or disorder, a disease or condition associated with excessive neuronal excitability, or a disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1).

11. The neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is selected from the group consisting of epilepsy, epilepsy syndromes, encephalopathies (e.g., epilepsy of infancy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, Lennox syndrome, Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia), genetic or childhood epilepsy, genetic or childhood epilepsy syndromes, cardiac dysfunction, cardiac arrhythmias, sudden unexpected death in epilepsy (SUDEP), Brugada syndrome, myocardial infarction, pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine), muscle disorders (e.g., myotonia, neuromyotonia, muscle spasms, spasticity), itch and pruritus, ataxia and cerebellar ataxia, psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia) , learning disability, fragile X, neuroplasticity, autism spectrum disorder, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile onset epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

12. A pharmaceutical composition comprising a compound of formula II-I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein: 【Chemical Formula 15】 In the formula, R １ is each independently halogen, -CN, -OH, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, C ３－１０ cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, and R ２ is hydrogen or C １－４ alkyl, and R ３ is a C １－６ alkyl optionally substituted with C １－６ alkoxy and R ４ is C １－６ alkyl optionally substituted with C １－６ alkoxy or hydrogen, R ５ and R ６ are each independently hydrogen, C １－６ alkyl, C ３－１０ cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein said C １－６ alkyl, C ３－１０ cycloalkyl, phenyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl may optionally be substituted with one or more of halogen, -CN, -OH, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, aryl, C ３－１０ cycloalkyl, 3- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, and wherein both R ５ and R ６ are not hydrogen, or R ５ and R ６ are, together with the nitrogen bonded to R ５ and R ６ optionally form a 3- to 10-membered heterocyclic ring substituted with one or more of halogen, -CN, -OH, C １－６ alkyl, C １－６ haloalkyl, aryl, C ３－１０ cycloalkyl, or 3- to 10-membered heterocyclyl, and n is 1 or 2, the pharmaceutical composition.

13. The pharmaceutical composition according to claim 12, wherein the compound is a compound of formula II-I-a, formula II-I-b, formula II-I-c, or formula II-I-d, or a pharmaceutically acceptable salt thereof. 【Chemical 16】

14. R ３ is C １－６ alkyl, R ４ is hydrogen, and / or R ２ is hydrogen and / or n is 1, and / or R ５ is hydrogen, and R ６ is C １－６ alkyl, or R ５ and R ６ are each independently C １－６ alkyl, or R ５ is C １－６ alkyl, R ６ is phenyl, or R ５ and R ６ is R ５ and R ６ together with the nitrogen to which they are attached form a 3- to 10-membered heterocyclyl, and / or R １ is selected from the group consisting of C １－６ haloalkyl, C １－６ alkoxy, and C ３－１０ cycloalkyl The pharmaceutical composition according to claim 12 or 13.

15. The compound is 【Chemical 17】 Or a pharmaceutically acceptable salt thereof, the pharmaceutical composition according to claim 12.

16. The pharmaceutical composition according to any one of claims 12 to 15 for use in a method of treating a neurological disease or disorder, a disease or condition associated with excessive neuronal excitability, or a disease or condition associated with a gain-of-function mutation of a gene (e.g., KCNT1).

17. The neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is selected from the group consisting of epilepsy, epilepsy syndromes, and encephalopathies (e.g., epilepsy of infancy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, Lennox syndrome, Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia), genetic or childhood epilepsy, genetic or childhood epilepsy syndromes, cardiac dysfunction, cardiac arrhythmias, sudden unexpected death in epilepsy (SUDEP), Brugada syndrome, myocardial infarction, pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine), muscle disorders (e.g., myotonia, neuromyotonia, muscle spasms, spasticity), itch and pruritus, ataxia and cerebellar ataxia, psychiatric disorders (e.g., major depression, anxiety, bipolar disorder , schizophrenia), learning disabilities, fragile X, neuroplasticity, autism spectrum disorder, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile onset epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

18. A compound of formula III-I, or a pharma- ceutically acceptable salt thereof, 【Chemical Formula 18】 During the ceremony, R １ is C optionally substituted with one or more halogen, cyano, １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, or N(R ａ )(R ｂ ), and is C １－６ alkyl, R ２ is hydrogen, R ３ is a C １－６ alkyl optionally substituted with C １－６ alkoxy and R ４ is hydrogen, and R ５ is selected from the group consisting of halogen, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, N(R ｃ )(R ｄ ), and C ３－１０ cycloalkyl, and R ａ and R ｂ are each independently selected from the group consisting of C １－６ alkyl, C １－６ haloalkyl and phenyl, R ｃ and R ｄ are each independently selected from the group consisting of hydrogen, C １－６ alkyl, C １－６ haloalkyl, C ３－１０ cycloalkyl, and phenyl In the formula, R ５ When is methoxy, R ３ is, C １－３ alkyl, a compound.

19. 19. The compound of claim 18, wherein the compound is of formula III-Ia, or a pharma- ceutically acceptable salt thereof. 【Chemical Formula 19】

20. R ５ is C １－６ haloalkyl or C ３－１０ cycloalkyl, and / or R １ is C alkyl optionally substituted with one or more halogens ２－６ or R １ is C alkyl substituted with N(R ａ )(R ｂ ), and / or １－６ is C alkyl R ３ is C １－６ alkyl 20. A compound according to claim 18 or 19.

21. The compound is 【Chemical 20】 The compound according to claim 18, selected from the group consisting of or pharmaceutically acceptable salts thereof.

22. A pharmaceutical composition comprising the compound according to any one of claims 18 to 21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. The pharmaceutical composition according to claim 22, for use in a method of treating a neurological disease or disorder, a disease or condition associated with excessive neuronal excitability, or a disease or condition associated with a gain-of-function mutation of a gene (e.g., KCNT1).

24. The neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is selected from the group consisting of epilepsy, epilepsy syndromes, and encephalopathies (e.g., epilepsy of infancy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, Lennox syndrome, Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia), genetic or childhood epilepsy, genetic or childhood epilepsy syndromes, cardiac dysfunction, cardiac arrhythmias, sudden unexpected death in epilepsy (SUDEP), Brugada syndrome, myocardial infarction, pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine), muscle disorders (e.g., myotonia, neuromyotonia, muscle spasms, spasticity), itch and pruritus, ataxia and cerebellar ataxia, psychiatric disorders (e.g., major depression, anxiety, bipolar disorder , schizophrenia), learning disabilities, fragile X, neuroplasticity, autism spectrum disorder, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile onset epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

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