KCNT1 inhibitors and methods 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 of 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 to and the benefit of U.S. Provisional Patent Application No. 63 / 048,335, filed July 6, 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] KCNT1 is a sodium-activated potassium channel (calcium-activated K + These channels are found in neurons throughout the brain and encode the sodium-activated potassium current I KNa This delayed outward current can regulate neuronal excitability and adaptation rates in response to sustained stimulation. Abnormal Slack activity is associated with the development of early-onset epilepsy and intellectual disability. Therefore, sodium-activated potassium channels, such as abnormal KCNT1 and abnormal I KNa Pharmaceutical compounds that selectively modulate KCNT1 are useful for treating neurological diseases or disorders or diseases or conditions associated with excessive neuronal excitability and / or KCNT1 gain-of-function mutations. 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, diseases, disorders, or conditions associated with excessive neural excitability and / or gain-of-function mutations in genes, such as KCNT1.

[0004] Thus, in one aspect, the present disclosure provides a compound of formula (A): [ka] wherein the variables are as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0005] In another aspect, the present disclosure provides a compound of formula (A-1), (A-2), or (A-3): [ka] wherein the variables are as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0006] In another aspect, the present disclosure provides a compound of formula (II): [ka] wherein the variables are as defined herein or feature a pharmaceutically acceptable salt thereof.

[0007] In another aspect, the present disclosure provides a compound of formula (II-a): [ka] wherein the variables are as defined herein or feature a pharmaceutically acceptable salt thereof.

[0008] In another aspect, the present disclosure provides a compound of formula (II-b): [ka] wherein the variables are as defined herein or feature a pharmaceutically acceptable salt thereof.

[0009] In another aspect, the present disclosure provides a compound of formula (III): [ka] wherein the variables are as defined herein or feature a pharmaceutically acceptable salt thereof.

[0010] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (II), (II-a), (II-b), or (III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] In another aspect, the disclosure provides a method of 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 (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-b), or (III), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-b), or (III), or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable excipient).

[0012] In another aspect, the disclosure provides a method of treating a disease or condition associated with excessive neural excitability, the method comprising administering to a subject in need thereof a compound disclosed herein (e.g., a compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-b), or (III), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-b), or (III), or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable excipient).

[0013] In another aspect, the present disclosure provides a method of treating a disease or condition associated with a gain-of-function mutation in 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 (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-b), or (III), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-b), or (III), or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable excipient).

[0014] 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 epilepsy, an epilepsy syndrome, or an encephalopathy.

[0015] 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 inherited or childhood epilepsy, or an inherited or childhood epilepsy syndrome.

[0016] 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 (eg, KCNT1) is cardiac dysfunction.

[0017] 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 epilepsy and other encephalopathies (e.g., migratory focal seizures in infancy (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).

[0018] 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 the group consisting of cardiac arrhythmia, sudden unexpected death in epilepsy, Brugada syndrome, and myocardial infarction.

[0019] 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.).

[0020] 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 a muscle disorder (e.g., myotonia, neuromyotonia, muscle spasms, spasticity).

[0021] 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 itch and pruritus, ataxia, and cerebellar ataxia.

[0022] 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 psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia).

[0023] In some embodiments, the neurological disease or disorder, or disease or condition associated with excessive neural 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, neuroplasticity, and autism spectrum disorders.

[0024] 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 the group consisting of epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, The compound is selected from the group consisting of benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCNA8 epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0025] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description, examples, and claims. DETAILED DESCRIPTION OF THE INVENTION

[0026] As generally described herein, the present invention provides compounds and compositions useful for preventing and / or treating the diseases, disorders, or conditions described herein, e.g., diseases, disorders, or conditions associated with excessive neural 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., infantile epilepsy 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, and Lennox-Gastaut syndrome), seizures, leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic seizures, drug-resistant epilepsy, temporal lobe epilepsy, and cerebellar ataxia. , asymmetric tonic seizures) and 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.

[0027] 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, 5 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.

[0028] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can 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 mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric 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 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention additionally encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0029] As used herein, an enantiomerically pure compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that a compound contains more than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.2%, 99.5%, 99.6%, 99.7%, 99.8%, or more than 99.9% by weight of an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0030] In the compositions provided herein, the enantiomerically pure compound may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R compound may contain, for example, about 90% excipients and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may contain, for example, at least about 95% by weight of the R compound and at most about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S compound may contain, for example, about 90% excipients and about 10% of the enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may contain, for example, at least about 95% by weight of the S compound and at most about 5% by weight of the R compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipients or carriers.

[0031] The compounds described herein may also contain one or more isotopic substitutions. For example, H is: 1 H, 2 H (D or deuterium), and 3H (T or tritium) and C may be in any isotopic form. 12 C. 13 C, and 14 C may be in any isotopic form, including O 16 O and 18 F may be in any isotopic form, including O; 18 F and 19 It may be in any isotopic form, including F, etc.

[0032] The following terms are intended to have the meanings presented below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated. It is also to be understood that, as described herein, any of the moieties defined below may be substituted with various substituents, and that each definition is intended to include such substituted moieties within their scope as set forth below. Unless otherwise specified, the term "substituted" is as defined below. It is further to be understood that the terms "group" and "radical" can be considered interchangeable when 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 object of the article. By way of example, "an analogue" means one analogue or more than one analogue.

[0033] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3, C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0034] As used herein, "alkyl" refers to the radical of a linear or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has one carbon atom (C alkyl). 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0035] As used herein, "alkenyl" refers to the 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 In certain embodiments, an alkenyl group does not contain a triple bond. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 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. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc.

[0036] As used herein, "alkynyl" refers to the 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 In certain embodiments, alkynyl groups contain no double bonds. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2-4Examples 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. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), etc. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), etc.

[0037] As used herein, "alkylene," "alkenylene," and "alkynylene" refer to the 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 a linear divalent chain of carbons. "Alkylene," "alkenylene," and "alkynylene" groups can be substituted or unsubstituted with one or more substituents described herein.

[0038] As used herein, "aryl" refers to a radical of a 4n+2 aromatic ring system ("C"), monocyclic or polycyclic (e.g., bicyclic or tricyclic) (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system. 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an 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 ring systems in which the aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such instances the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Exemplary aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0039] As used herein, "heteroaryl" refers to the radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in the cyclic arrangement) 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 ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems may 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 carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case 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 a heteroaryl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring; in such cases, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups 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., on the ring bearing a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0040] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system ("5- to 10-membered heteroaryl") 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. In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system ("5- to 8-membered heteroaryl") 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. In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system ("5- to 6-membered heteroaryl") 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. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0041] 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-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0042] Representative examples of heteroaryls include: [ka] where each Z is a carbonyl, N, NR 65, O, and S; R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Carbocyclyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0043] As used herein, "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 10 ring carbon atoms ("C 3-10 "Carbocyclyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). Exemplary C 3-6 Carbocyclyl 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. 3-8 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3-6 Examples include carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10), spiro[4.5]decanyl (C 10 As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic carbocyclyl"), which may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclyl ring; in such instances, the number of carbons continues to designate the number of carbons in the carbocyclic ring system.

[0044] 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 is used herein to refer to, for example, "C" derived from a cycloalkane. 4-8

[0023] Unless otherwise specified, cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azide, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl, or thiocarbonyl. Cycloalkyl groups can be fused to other cycloalkyl, aryl, or heterocyclyl groups. In certain embodiments, cycloalkyl groups are unsubstituted, i.e., unsubstituted.

[0045] As used herein, "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system ("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 heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, where the point of attachment is on either the carbocyclyl or heterocyclyl ring or ring system, and in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, and in such instances the number of ring members continues to designate the number of ring members in the heterocyclyl ring system.

[0046] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system ("5- to 10-membered heterocyclyl") having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system ("5- to 8-membered heterocyclyl") having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system ("5- to 6-membered heterocyclyl") having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl has 1-3 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, hi some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0047] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. 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 pyrrolyl-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 C aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. 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, etc.

[0048] As used herein, "heterocylene" refers to a divalent radical of a heterocycle.

[0049] "Hetero," when used to describe a compound or a group present in a compound, means that one or more carbon atoms in the compound or group have been replaced with a heteroatom of nitrogen, oxygen, or sulfur. Hetero may apply to any of the hydrocarbyl groups mentioned above, such as alkyl, e.g., heteroalkyl, carbocyclyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, and the like having 1 to 5, especially 1 to 3, heteroatoms.

[0050] As used herein, "cyano" refers to --CN.

[0051] As used herein, "halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is either fluoro or chloro.

[0052] As used herein, "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0053] As used herein, "nitro" refers to --NO.sub.2.

[0054] As used herein, "oxo" refers to -C=O.

[0055] In general, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., 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 reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

[0056] Nitrogen atoms can be substituted or unsubstituted, where valence allows, and include 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 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14aryl, and 5- to 14-membered heteroaryl; or two R cc groups join to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc , and R dd is as defined above.

[0057] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the above exemplary list of substituents.

[0058] Other definitions The term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. in J. Pharmaceutical Sciences (1977) 66:1-19 and Gould in "Salt selection for basic drugs," International Journal of Pharmaceutics, 33 (1986) 201-217, describe pharmaceutically acceptable salts in detail. 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 salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfonate. , lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N. + (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0059] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., 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, e.g., mammals such as 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.

[0060] Disease, disorder, and condition are used interchangeably herein.

[0061] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate the action of reducing the severity of the disease, disorder, or condition or slowing or retarding the progression of the disease, disorder, or condition (also "therapeutic treatment"), occurring while a subject is afflicted with the specified disease, disorder, or condition.

[0062] Generally, an "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of a compound of the invention may 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.

[0063] As used herein, and 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 a disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a 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 overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0064] 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 before a subject begins to suffer from a specified disease, disorder, or condition. As used herein, "prophylactic treatment" contemplates an effect that occurs before a subject begins to suffer from a specified disease, disorder, or condition. As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with a disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of a 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 overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0065] As used herein, "disease or condition associated with a gain-of-function mutation in KCNT1" refers to a disease or condition that is associated with, is partially or completely caused by, or has one or more symptoms that are partially or completely caused by, a mutation in KCNT1 that results in a gain-of-function phenotype, i.e., increased activity of the potassium channel encoded by KCNT1, resulting in an increased whole-cell current.

[0066] As used herein, a "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 assessed, for example, by ion flux assays or electrophysiological methods (e.g., using whole-cell patch clamp techniques). 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.

[0067] Compounds and Compositions In one aspect, the present disclosure provides a compound of formula (A): [ka] During the ceremony, A is phenyl or pyridyl; R1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a C 1-6 The alkyl is optionally C 1-6 substituted with alkoxy, R a is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, or phenyl; C 3-8Cycloalkyl or phenyl may contain one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R2 is hydrogen or C 1-6 is alkyl, R3 and R4 are hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, and C 1-6 are each independently selected from the group consisting of alkoxy; R5 is halogen, cyano, -OH, -NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, and 4- to 8-membered heterocyclyl; C 1-6 Alkyl, C 3-8 The cycloalkyl or 4- to 8-membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R c and R d are each independently hydrogen or C 1-6 is alkyl, R6 is C 1-6 Alkyl or C 1-6 is an alkoxy; t is 0, 1, 2, 3, or 4, and m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof. In one aspect, the present disclosure provides a compound of formula (A-1), (A-2), or (A-3): [ka] During the ceremony, R1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a C 1-6 Alkyl is C 1-6 optionally substituted with alkoxy; R a is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, or phenyl; C 3-8 Cycloalkyl or phenyl may contain one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R5 is halogen, cyano, -OH, -NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, and 4- to 8-membered heterocyclyl; C 1-6 Alkyl, C 3-8 cycloalkyl 、 or 4-8 membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R c and R d are each independently hydrogen or C 1-6 is alkyl, R6 is C 1-6 Alkyl or C 1-6 is an alkoxy; t is 0, 1, 2, 3, or 4, and m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0068] In one aspect, the present disclosure provides a compound of formula (I): [ka] During the ceremony, R1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a is selected from the group consisting of R a is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, or phenyl; C 3-8 Cycloalkyl or phenyl may contain one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R2 is hydrogen; R3 and R4 are hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, and C 1-6 are each independently selected from the group consisting of alkoxy; R5 is halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-OC 1-6 Alkyl, and C 3-8 cycloalkyl; R6 is C 1-6 Alkyl or C 1-6 is an alkoxy; t is 0, 1, 2, 3, or 4, and m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0069] In one aspect, provided herein is a compound of formula (Ia) or formula (Ib): [ka] During the ceremony, R1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a is selected from the group consisting of R a is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, or phenyl, wherein C 3-8 Cycloalkyl or phenyl may contain one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R2 is hydrogen; R3 is hydrogen; R4 is C 1-6 is alkyl, R5 is halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-OC 1-6 Alkyl, and C 3-8 cycloalkyl; R6 is C 1-6 Alkyl or C 1-6 is an alkoxy; t is 0, 1, 2, 3, or 4, and m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0070] In some embodiments of the compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), R is C 1-6 Alkyl or -NHRa In some embodiments of the compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), R is C 1-6 In some embodiments of the compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), R is methyl, ethyl, or isopropyl.

[0071] In some embodiments of the compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), R is -NHR a In some embodiments of compounds of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), R a is C 1-6 In some embodiments of compounds of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), R a is methyl, ethyl, or isopropyl. In some embodiments of compounds of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), R a In some embodiments of compounds of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), R is C 3-8 In some embodiments of a compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of a compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), R is cyclopropyl. In some embodiments of a compound of Formula (A), (A-1), (A-2), or (A-3), R is 、 C 1-6 Alkoxy-substituted C 1-6 In some embodiments of compounds of Formula (A), (A-1), (A-2), or (A-3), R is C substituted with —OCH 1-6It is alkyl.

[0072] In some embodiments of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), R3 is hydrogen. In some embodiments of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), R4 is hydrogen. In some embodiments of Formula (A), (I), (Ia), or (Ib), R4 is methyl, ethyl, or isopropyl. In some embodiments of Formula (A), (I), (Ia), or (Ib), R4 is methyl.

[0073] In some embodiments of the compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), R5 is halogen, cyano, —OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, and C 3-8 cycloalkyl, each independently selected from the group consisting of C 1-6 Alkyl or C 3-8 Cycloalkyl is halogen, cyano, or C 1-6 In some embodiments of the compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), R5 is chloro, fluoro, bromo, cyano, —OH, methyl, ethyl, isopropyl, tert-butyl, —CHCF 2、 -CF3, -OCH 3、 are each independently selected from the group consisting of -OCH2CH3, -OCH(CH3)2, -OCH2CF3, and cyclopropyl optionally substituted with -CF3.

[0074] In some embodiments of a compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), t is 1 or 2. In some embodiments of a compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), t is 1. In some embodiments of a compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), or (Ib), t is 2.

[0075] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R1 is 、 C 1-6 Alkyl or -NHR a In some embodiments of the compound of Formula (I), (Ia), or (Ib), R is C 1-6 In some embodiments of the compound of Formula (I), (Ia), or (Ib), R is methyl.

[0076] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R1 is 、 -NHR a is.

[0077] In some embodiments of compounds of Formula (I), (Ia), or (Ib), R a is C 1-6 In some embodiments of compounds of Formula (I), (Ia), or (Ib), R a is methyl.

[0078] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R3 is hydrogen.

[0079] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R 4 is hydrogen or methyl.

[0080] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R5 is halogen, —OH, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, and C 3-8 In some embodiments of a compound of Formula (I), (Ia), or (Ib), R5 is each independently selected from the group consisting of chloro, fluoro, bromo, —OH, methyl, —CF3, —OCH3, and cyclopropyl.

[0081] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), t is 1 or 2.

[0082] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), m is 0.

[0083] In another aspect, provided herein are compounds of formula II: [ka] During the ceremony, R1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a C 1-6 Alkyl is C 1-6 optionally substituted with alkoxy; R a is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, or phenyl, wherein C 3-8 Cycloalkyl or phenyl may contain one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R2 is hydrogen; R3 and R4 are hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, and C 1-6are each independently selected from the group consisting of alkoxy; R5 is halogen, cyano, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, and 4- to 8-membered heterocyclyl, 1-6 Alkyl, C 3-8 cycloalkyl 、 or 4-8 membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R6 is C 1-6 Alkyl or C 1-6 is an alkoxy; R7 is halogen, cyano, -NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, and C 3-8 cycloalkyl, wherein C 1-6 Alkyl, C 3-8 cycloalkyl 、 or 4-8 membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R c and R d are each independently hydrogen or C 1-6 is alkyl, t is 0, 1, 2, or 3, and m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0084] In another aspect, provided herein is a compound of formula (II): [ka] During the ceremony, R1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a is selected from the group consisting of R a is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, or phenyl, wherein C 3-8 Cycloalkyl or phenyl may contain one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R2 is hydrogen; R3 and R4 are hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, and C 1-6 are each independently selected from the group consisting of alkoxy; R5 is -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-OC 1-6 Alkyl, and C 3-8 cycloalkyl; R6 is C 1-6 Alkyl or C 1-6 is an alkoxy; R7 is a halogen; t is 0, 1, 2, or 3, and m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0085] In another aspect, provided herein is a compound of formula (II-a): [ka] During the ceremony, R1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a is selected from the group consisting of R a is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, or phenyl, wherein C 3-8 Cycloalkyl or phenyl may contain one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R2 is hydrogen; R3 and R4 are hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, and C 1-6 are each independently selected from the group consisting of alkoxy; R5 is -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-OC 1-6 Alkyl, and C 3-8 cycloalkyl; R6 is C 1-6 Alkyl or C 1-6 is an alkoxy; R7 is a halogen; t is 0, 1, 2, or 3, and m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0086] In another aspect, provided herein is a compound of formula (II-b): [ka] During the ceremony, R1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a wherein C is selected from the group consisting of 1-6 Alkyl is C 1-6 optionally substituted with alkoxy; Ra is C 1-6 is alkyl, R2 is hydrogen; R3 and R4 are hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, and C 1-6 are each independently selected from the group consisting of alkoxy; R5 is halogen, cyano, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, and 4- to 8-membered heterocyclyl, 1-6 Alkyl, C 3-8 cycloalkyl 、 or 4-8 membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R6 is C 1-6 Alkyl or C 1-6 is an alkoxy; R7 is halogen, cyano, -NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C3-8 cycloalkyl, and 4- to 8-membered heterocyclyl, 1-6 Alkyl, C 3-8 cycloalkyl 、 or 4-8 membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R c and R d are each independently hydrogen or C 1-6 is alkyl, t is 0, 1, 2, or 3, and m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments of the compound of Formula (II), (II-a), or (II-b), R1 is 、 C 1-6 Alkyl or -NHR a In some embodiments of the compound of Formula (II), (II-a), or (II-b), R is C 1-6 In some embodiments of a compound of Formula (II), (II-a), or (II-b), R1 is methyl, ethyl, or isopropyl. In some embodiments of a compound of Formula (II), (II-a), or (II-b), R1 is methyl. In some embodiments of a compound of Formula (II), (II-a), or (II-b), R1 is 、 -NHR a In some embodiments of compounds of Formula (II), (II-a), or (II-b), R a is C 1-6 In some embodiments of compounds of Formula (II), (II-a), or (II-b), R a is methyl, ethyl, or isopropyl. In some embodiments of compounds of Formula (II), (II-a), or (II-b), R a In some embodiments of the compound of Formula (II), (II-a), or (II-b), R is C3-8 In some embodiments of a compound of Formula (II), (II-a), or (II-b), R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of a compound of Formula (II), (II-a), or (II-b), R is cyclopropyl. In some embodiments of a compound of Formula (II), (II-a), or (II-b), R is C 1-6 Alkoxy-substituted C 1-6 In some embodiments of the compound of Formula (II), (II-a), or (II-b), R is C substituted with —OCH 1-6 It is alkyl.

[0088] In some embodiments of the compounds of Formula (II), (II-a), or (II-b), R3 is hydrogen.

[0089] In some embodiments of a compound of Formula (II), (II-a), or (II-b), R4 is hydrogen or methyl. In some embodiments of a compound of Formula (II), (II-a), or (II-b), R4 is hydrogen. In some embodiments of a compound of Formula (II), (II-a), or (II-b), R4 is methyl. In some embodiments of a compound of Formula (II), (II-a), or (II-b), R3 and R4 are hydrogen.

[0090] In some embodiments of the compound of Formula (II), (II-a), or (II-b), R5 is halogen, cyano, —OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, and C 3-8 cycloalkyl, each independently selected from the group consisting of C 1-6 Alkyl or C 3-8 Cycloalkyl is halogen, cyano, or C 1-6In some embodiments of the compound of Formula (II), (II-a), or (II-b), R5 is chloro, fluoro, bromo, cyano, —OH, methyl, ethyl, isopropyl, tert-butyl, —CHCF 2、 -CF3, -OCH 3、 are each independently selected from the group consisting of -OCH2CH3, -OCH(CH3)2, -OCH2CF3, and cyclopropyl optionally substituted with -CF3.

[0091] In some embodiments of the compound of Formula (II), (II-a), or (II-b), R5 is halogen, —OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, and C 3-8 In some embodiments of the compound of Formula (II), (II-a), or (II-b), R5 is each independently selected from the group consisting of chloro, fluoro, bromo, —OH, methyl, —CF3, —OCH3, and cyclopropyl.

[0092] In some embodiments of the compound of Formula (II), (II-a), or (II-b), R7 is halogen, cyano, -NR c R d , C optionally substituted with cyano 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, and C 1-6 C optionally substituted with haloalkyl 3-8In some embodiments of a compound of Formula (II), (II-a), or (II-b), R7 is selected from the group consisting of chloro, bromo, cyano, methyl, ethyl, isopropyl, tert-butyl, —CHCF2, —CF3, —OCH2CH3, —OCH2CF3, and cyclopropyl optionally substituted with —CF3. In some embodiments of a compound of Formula (II), (II-a), or (II-b), R7 is 4-8 membered heterocyclyl. In some embodiments, the 4-8 membered heterocyclyl contains one nitrogen.

[0093] In some embodiments of a compound of Formula (II), (II-a), or (II-b), t is 1 or 2. In some embodiments of a compound of Formula (II), (II-a), or (II-b), t is 0. In some embodiments of a compound of Formula (II), (II-a), or (II-b), t is 1. In some embodiments of a compound of Formula (II), (II-a), or (II-b), t is 2.

[0094] In some embodiments of the compound of Formula (II), (II-a), or (II-b), m is 0.

[0095] In some embodiments of the compound of Formula (II) or (II-a), R1 is 、 C 1-6 Alkyl or -NHR a In some embodiments of the compound of Formula (II) or (II-a), R is C 1-6 In some embodiments of the compound of Formula (II) or (II-a), R is methyl. In some embodiments of the compound of Formula (II) or (II-a), R is 、 -NHR a is.

[0096] In some embodiments of compounds of Formula (II) or (II-a), R a is C 1-6 In some embodiments of the compound of Formula (II) or (II-a), Ra is methyl.

[0097] In some embodiments of the compound of Formula (II) or (II-a), R3 is hydrogen.

[0098] In some embodiments of the compound of Formula (II) or (II-a), R4 is hydrogen or methyl.

[0099] In some embodiments of the compound of Formula (II) or (II-a), R5 is selected from the group consisting of halogen, —OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, and C 3-8 In some embodiments of the compound of Formula (II) or (II-a), R5 is each independently selected from the group consisting of chloro, fluoro, bromo, —OH, methyl, —CF3, —OCH3, and cyclopropyl.

[0100] In some embodiments of the compound of Formula (II) or (II-a), t is 1 or 2.

[0101] In another aspect, provided herein is a compound of formula (III): [ka] During the ceremony, R1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a wherein C is selected from the group consisting of 1-6 Alkyl is C 1-6 optionally substituted with alkoxy; R a is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, or phenyl, wherein C 3-8 Cycloalkyl or phenyl may contain one or more halogens, C1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R2 is hydrogen; R3 and R4 are hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, and C 1-6 are each independently selected from the group consisting of alkoxy; R5 is halogen, cyano, -OH, -NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, and 4- to 8-membered heterocyclyl; C 1-6 Alkyl, C 3-8 The cycloalkyl or 4- to 8-membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R c and R d are each independently hydrogen or C 1-6 is alkyl, R6 is C 1-6 Alkyl or C 1-6 is an alkoxy; t is 0, 1, 2, or 3, and m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0102] In some embodiments of the compound of Formula (III), R is C 1-6In some embodiments of the compound of Formula (III), R is methyl, ethyl, or isopropyl. In some embodiments of the compound of Formula (III), R is methyl.

[0103] In some embodiments of the compound of Formula (III), R3 is hydrogen.

[0104] In some embodiments of the compound of Formula (III), R4 is hydrogen.

[0105] In some embodiments of the compound of Formula (III), R5 is halogen, cyano, —OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, and C 3-8 cycloalkyl, each independently selected from the group consisting of C 1-6 Alkyl or C 3-8 Cycloalkyl is halogen, cyano, or C 1-6 In some embodiments of the compound of Formula (III), R5 is -CF3, and R5 is optionally substituted with haloalkyl.

[0106] In some embodiments of the compound of Formula (III), t is 1. In some embodiments of the compound of Formula (III), t is 2. In some embodiments of the compound of Formula (III), t is 0.

[0107] In some embodiments of the compound of Formula (III), m is 0.

[0108] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0109] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (A-1), Formula (A-2), Formula (A-3), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0110] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0111] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of Formula (Ia) or Formula (Ib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0112] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0113] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula (II-a) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0114] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula (II-b) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0115] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula (III) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0116] In typical embodiments, the present invention is intended to encompass the compounds disclosed herein, as well as pharmaceutically acceptable salts, tautomeric forms, polymorphs, and prodrugs of such compounds. In some embodiments, the present invention includes pharmaceutically acceptable addition salts, pharmaceutically acceptable esters, solvates (e.g., hydrates) of addition salts, tautomeric forms, all polymorphs, including polymorphs of hydrates and solvates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, stereoisomers, or mixtures of stereoisomers (pure or as racemic or non-racemic mixtures) of the compounds described herein, such as, for example, compounds of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-b), or (III).

[0117] In this specification, [ka] TIFF0007824664000018.tif234170TIFF0007824664000019.tif232170TIFF0007824664000020.tif139170, or a pharmaceutically acceptable salt thereof.

[0118] General synthetic scheme Exemplary methods for preparing the compounds described herein are illustrated in the following synthetic schemes, which are provided for the purpose of illustrating the invention and should not be construed as limiting the scope or spirit of the invention in any way. [ka]

[0119] Scheme 1 The synthetic route illustrated in Scheme 1 shows an exemplary procedure for preparing compounds of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-b), or (III). Coupling of carboxylic acid aa and amine bb using standard peptide coupling procedures (e.g., DIPEA followed by HATU in DCM or DMF) provides compounds of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-b), or (III).

[0120] 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 neural excitability and / or gain-of-function mutations in genes (e.g., KCNT1). Exemplary diseases, disorders, or conditions include epilepsy and other encephalopathies (e.g., infantile epilepsy 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 epileptic encephalopathy (EIEE), generalized epilepsy, focal epilepsy, multifocal epilepsy, temporal lobe epilepsy, Ohtahara syndrome, early myoclonic encephalopathy and Lennox-Gastaut syndrome, drug-resistant epilepsy, seizures (e.g., frontal lobe seizures, generalized tonic-clonic seizures, asymmetric tonic seizures, focal seizures, leukodystrophies, myeloid leukemia, and leukodystrophies). These conditions include: phosphorylated leukodystrophies, leukoencephalopathy, and sudden unexpected death in epilepsy; cardiac dysfunction (e.g., cardiac arrhythmias, Brugada syndrome, myocardial infarction); pulmonary vascular disorders / hemorrhage; 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.

[0121] In some embodiments, the neurological disease or disorder, or disease or condition associated with excessive neural excitability and / or gain-of-function mutations in a gene (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 a gene (e.g., KCNT1), is selected from infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, and Lennox-Gastaut syndrome. In some embodiments, the neurological disease or disorder, or disease or condition associated with excessive neural excitability and / or gain-of-function mutations in a gene (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 a gene (e.g., KCNT1), is selected from cardiac arrhythmia, Brugada syndrome, and myocardial infarction.

[0122] In some embodiments, the neurological disease or disorder, or disease or condition associated with excessive neural 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, psychiatric disorders, and autism spectrum disorders.

[0123] Thus, the compounds and compositions thereof can be administered to subjects with neurological diseases or disorders, or diseases or conditions 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).

[0124] EIMFS is a rare and debilitating genetic condition characterized by early onset (before age 6 months) of nearly continuous, heterogeneous focal seizures that appear to migrate from one brain region and hemisphere to another. Patients with EIMFS typically have intellectual disability, speech disorders, and gait disorders. While several genes have been implicated, 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, and K1154Q (Barcia et al. (2012) Nat Genet. 44:1255-1260, Ishii et al. 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. 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. 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. 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 that alter the function of the encoded potassium channels when tested in Xenopus oocytes or mammalian expression systems, causing significant increases in whole-cell currents (see, e.g., Milligan et al. (2015) Ann Neurol. 75(4):581-590, Barcia et al. (2012) Nat Genet. 44(11):1255-1259, and Mikati et al. (2015) Ann Neurol. 78(6):995-999).

[0125] ADNFLE has a later onset than EIMFS, generally occurring in mid-childhood, and is generally a less severe condition. It is characterized by nocturnal frontal lobe seizures and can cause mental, behavioral, and cognitive impairment in patients with the condition. ADNFLE is associated with genes encoding several neuronal nicotinic acetylcholine receptor subunits, but mutations in the KCNT1 gene are associated with 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).

[0126] West syndrome is a severe form of epilepsy characterized by three distinct features: infantile spasms, an interictal electroencephalogram (EEG) pattern called hypsarrhythmia, and mental retardation. However, it can be diagnosed even if one of these features is absent. Mutations in KCNT1, including G652V and R474H, have been associated with West syndrome (Fukuoka et al. (2017) Brain Dev 39:80-83 and Ohba et al. (2015) Epilepsia 56:el21-el28). Therapeutics targeting the KCNT1 channel suggest that these mutations are gain-of-function mutations (Fukuoka et al. (2017) Brain Dev 39:80-83).

[0127] In one aspect, the present invention provides a method for treating diseases or conditions associated with excessive neural excitability and / or gain-of-function mutations in genes such as KCNT1 (e.g., epilepsy and other encephalopathies (e.g., migratory focal seizures in infancy (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies (DEE), and Rennock syndrome). Clinical features include: Cous-Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic seizures, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia, asymmetric tonic seizures), cardiac 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, neuromyopathy, etc.), and and autism spectrum disorders (e.g., otonia, 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 method comprises administering to a subject in need thereof a compound disclosed herein (e.g., a compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-a), (II-b), or (III), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-b), or (III), or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable excipient).

[0128] In some embodiments, subjects exhibiting a disease or condition that may be associated with a gain-of-function mutation in KCNT1 are genotyped to confirm the presence of a known gain-of-function mutation in KCNT1 before administering the compound and compositions thereof. 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 syndrome include, but are not limited to, R209C. Gain-of-function mutations associated with seizures include, but are not limited to, A259D, G288S, R474C, and 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 encephalopathies include, but are not limited to, F346L, R474H, and A934T. Gain-of-function mutations associated with epileptic encephalopathies include, but are not limited to, L437F, Y796H, P924L, and R961H.Gain-of-function mutations associated with early infantile epileptic encephalopathy (EIEE) include, but are not limited to, M896K. Gain-of-function mutations associated with drug-resistant epilepsy and generalized tonic-clonic seizures include, but are not limited to, F346L. Gain-of-function mutations associated with migratory partial seizures of infancy include, but are not limited to, R428Q. Gain-of-function mutations associated with leukoencephalopathy include, but are not limited to, F932I. Gain-of-function mutations associated with NFLE include, but are not limited to, A934T and R950Q. Gain-of-function mutations associated with Ohtahara syndrome include, but are not limited to, A966T. Gain-of-function mutations associated with infantile spasms include, but are not limited to, P924L. Gain-of-function mutations associated with Brugada syndrome include, but are not limited to, R1106Q. Gain-of-function mutations associated with Brugada syndrome include, but are not limited to, R474H.

[0129] In other examples, a subject is first genotyped to identify the presence of a mutation in KCNT1, and then the mutation is confirmed to be a gain-of-function mutation using a standard in vitro assay, such as the assay described in Milligan et al. (2015) Ann Neurol. 75(4):581-590. Typically, the presence of a gain-of-function mutation is confirmed when expression of a mutant KCNT1 allele results in an increase in whole-cell current compared to the whole-cell current resulting from expression of wild-type KCNT1, as assessed using whole-cell electrophysiological methods (e.g., 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). This increase in whole-cell current can be, for example, at least or about 50%, 100%, 150%, 200%, 250%, 300%, 350%, 400% or more. Thus, the subject can be identified as having a disease or condition associated with a gain-of-function mutation in KCNT1.

[0130] In certain examples, the subject is identified as having a KCNT1 allele containing a gain-of-function mutation (e.g., V271F, G288S, R398Q, R428Q, R474Q, R474H, R474C, G652V, I760M, Y796H, M896I, P924L, R928C, or A934T).

[0131] A compound disclosed herein (e.g., a compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-b), or (III), (II-j), (II-k), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-b), or (III), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient) may be used therapeutically for conditions associated with excessive neural excitability, where the excessive neural 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 can result in reduced neuronal excitability, thereby providing a therapeutic effect. For this reason, a compound disclosed herein (e.g., a compound of formula (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-b), or (III), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-b), or (III), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient) can be used. The compounds can be used to treat subjects having conditions associated with excessive neural excitability, 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 arrhythmias, Brugada syndrome, myocardial infarction), regardless of whether the disease or disorder is associated with a gain-of-function mutation in KCNT1.

[0132] Pharmaceutical Compositions and Routes of Administration The compounds provided by the present invention, e.g., compounds of Formula (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-b), or (III), or pharmaceutically acceptable salts thereof, are typically administered in the form of pharmaceutical compositions. Accordingly, the present invention provides pharmaceutical compositions containing, as an active ingredient, one or more of the compounds described, or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.)).

[0133] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration for drugs, for example, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, including rectal, buccal, intranasal, and transdermal routes, as an inhalant, or via an impregnated or coated device such as, for example, a stent or an arterially inserted cylindrical polymer, with utilities similar to those described in those patents and patent applications incorporated by reference.

[0134] One mode of administration is parenteral, particularly by injection. Forms into which the novel compositions of the present 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 saline are also conventionally used for injection, but are less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be provided by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0135] Sterile injectable solution is prepared by incorporating the compound of the present invention in the required amount in a suitable solvent containing various other ingredients as listed above, as needed, and then sterilizing by filtration.In general, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the other ingredients as listed above that are required.For the preparation of sterile powder for preparing sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains powder of active ingredient and any additional desired ingredients from the sterile solution that has been previously sterilized and filtered.

[0136] Oral administration is another route for administering the compounds according to the present invention. Administration may be via capsules or enteric-coated tablets, etc. In preparing pharmaceutical compositions containing at least one compound described herein, the active ingredient is usually diluted with an excipient and / or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it may be in the form of a solid, semi-solid, or liquid material (as described above) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0137] 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 include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl- and propylhydroxy-benzoates, sweeteners, and flavoring agents.

[0138] 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 transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for delivering pharmaceuticals is well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0139] The compositions are preferably formulated in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably 0.1 to 700 mg of a compound described herein. However, it will be understood that the amount of compound actually administered will typically be determined by a physician in light of relevant circumstances, including the condition being treated, the selected route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0140] To prepare solid compositions such as tablets, the principal active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present invention. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0141] The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablets or pills may comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope over the former. The two components may be separated by an enteric layer which serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be delayed in release. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0142] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0143] In some embodiments, a pharmaceutical composition comprising a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present invention includes aspects described in the following sections. [Section 1] A compound of formula A, JPEG0007824664000022.jpg24170 During the ceremony, A is phenyl or pyridyl; R 1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a wherein C is selected from the group consisting of 1-6 Alkyl is C 1-6 optionally substituted with alkoxy; R a is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, or phenyl, wherein C 3-8 Cycloalkyl or phenyl may contain one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R 2 is hydrogen or C 1-6 is alkyl, R 3 and R 4 is hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, and C 1-6 are each independently selected from the group consisting of alkoxy; R 5 is halogen, cyano, -OH, -NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, and 4- to 8-membered heterocyclyl, 1-6 Alkyl, C 3-8 The cycloalkyl or 4- to 8-membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R c and R d are each independently hydrogen or C 1-6 is alkyl, R 6 is C 1-6 Alkyl or C 1-6 is an alkoxy; t is 0, 1, 2, 3, or 4, and m is 0, 1, or 2; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [Section 2] A compound of formula A-1, formula A-2, or formula A-3, JPEG0007824664000023.jpg50169 During the ceremony, R 1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a wherein C is selected from the group consisting of 1-6 Alkyl is C 1-6 optionally substituted with alkoxy; R a is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, or phenyl, wherein C 3-8 Cycloalkyl or phenyl may contain one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, or C1-6 optionally substituted with alkoxy; R 5 is halogen, cyano, -OH, -NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, and 4- to 8-membered heterocyclyl, 1-6 Alkyl, C 3-8 The cycloalkyl or 4- to 8-membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R c and R d are each independently hydrogen or C 1-6 is alkyl, R 6 is C 1-6 Alkyl or C 1-6 is an alkoxy; t is 0, 1, 2, 3, or 4, and m is 0, 1, or 2; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [Section 3] R 1 But C 1-6 Alkyl or -NHR a Item 3. The pharmaceutical composition according to Item 1 or 2, [Section 4] R 1 But C 1-6 Item 4. The pharmaceutical composition according to any one of Items 1 to 3, wherein the aryl group is alkyl. [Section 5] R 1 Item 5. The pharmaceutical composition according to any one of Items 1 to 4, wherein is methyl, ethyl, or isopropyl. [Section 6] R 1 But, -NHR a Item 4. The pharmaceutical composition according to any one of Items 1 to 3, wherein [Section 7] R a But C 1-6 Item 7. The pharmaceutical composition according to Item 6, wherein the aryl group is alkyl. [Section 8] R a Item 8. The pharmaceutical composition according to Item 6 or 7, wherein is methyl. [Section 9] R 3 The pharmaceutical composition according to any one of Items 1 and 3 to 8, wherein is hydrogen. [Section 10] R 4 Item 10. The pharmaceutical composition according to any one of Items 1 and 3 to 9, wherein is hydrogen or methyl. [Section 11] R 5 But halogen, cyano, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, and C 3-8 cycloalkyl, wherein each C is independently selected from the group consisting of 1-6 Alkyl or C 3-8 Cycloalkyl is halogen, cyano, or C 1-6 Item 11. The pharmaceutical composition according to any one of items 1 to 10, which is optionally substituted with haloalkyl. [Section 12] R 5 Chloro, fluoro, bromo, cyano, -OH, methyl, ethyl, isopropyl, tert-butyl, -CHCF 2、 -CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH- 3 ) 2、 -OCH 2 CF 3、 and -CF 3 cyclopropyl, optionally substituted with 、 Item 12. The pharmaceutical composition according to any one of Items 1 to 11. [Section 13] Item 13. The pharmaceutical composition according to any one of Items 1 to 12, wherein t is 1 or 2. [Section 14] Item 14. The pharmaceutical composition according to any one of Items 1 to 13, wherein m is 0. [Section 15] A compound of formula II, JPEG0007824664000024.jpg25170 During the ceremony, R 1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a wherein C is selected from the group consisting of 1-6 Alkyl is C 1-6 optionally substituted with alkoxy; R a is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, or phenyl, wherein C 3-8 Cycloalkyl or phenyl may contain one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R 2 is hydrogen, R 3 and R 4 is hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, and C 1-6 are each independently selected from the group consisting of alkoxy; R 5 is halogen, cyano, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, and 4- to 8-membered heterocyclyl, 1-6 Alkyl, C3-8 cycloalkyl 、 or 4-8 membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R 6 is C 1-6 Alkyl or C 1-6 is an alkoxy; R 7 is halogen, cyano, -NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, and C 3-8 cycloalkyl, wherein C 1-6 Alkyl, C 3-8 cycloalkyl 、 or 4-8 membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R c and R d are each independently hydrogen or C 1-6 is alkyl, t is 0, 1, 2, or 3, and m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof. [Section 16] Compounds of formula II-b, JPEG0007824664000025.jpg24170 During the ceremony, R 1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a wherein C is selected from the group consisting of 1-6 Alkyl is C 1-6 optionally substituted with alkoxy; Ra is C 1-6 is alkyl, R 2 is hydrogen, R 3 and R 4 is hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, and C 1-6 are each independently selected from the group consisting of alkoxy; R 5 is halogen, cyano, -OH, -C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, and 4- to 8-membered heterocyclyl, 1-6 Alkyl, C 3-8 cycloalkyl 、 or 4-8 membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R 6 is C 1-6 Alkyl or C 1-6 is an alkoxy; R 7 is halogen, cyano, -NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 cycloalkyl, and 4- to 8-membered heterocyclyl, 1-6 Alkyl, C 3-8 cycloalkyl 、 or 4-8 membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R c and R d are each independently hydrogen or C 1-6 is alkyl, t is 0, 1, 2, or 3, and m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof. [Section 17] R 1 But C 1-6 Alkyl or -NHR a Item 17. The compound according to item 15 or 16, wherein [Section 18] R 1 But C 1-6 18. The compound according to any one of items 15 to 17, wherein the aryl group is alkyl. [Section 19] R 1 Item 19. The compound according to any one of items 15 to 18, wherein is methyl, ethyl, or isopropyl. [Section 20] R 1 20. The compound according to any one of items 15 to 19, wherein is methyl. [Section 21] R 1 But, -NHR a 18. The compound according to any one of items 15 to 17, wherein [Section 22] R a But C 1-6 22. The compound according to item 21, wherein the aryl group is alkyl. [Section 23] R a Item 23. The compound according to item 21 or 22, wherein is methyl. [Section 24] R 1 But C 3-8 Item 17. The compound according to item 15 or 16, wherein the compound is cycloalkyl. [Section 25] R 1 25. The compound according to any one of clauses 15, 16 and 24, wherein is cyclopropyl. [Section 26] R 3 26. The compound according to any one of items 15 to 25, wherein is hydrogen. [Section 27] R 4 27. The compound according to any one of items 15 to 26, wherein is hydrogen or methyl. [Section 28] R 3 and R 4 28. The compound according to any one of items 15 to 27, wherein is hydrogen. [Section 29] R 5 But halogen, cyano, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, and C 3-8 cycloalkyl, wherein each C is independently selected from the group consisting of 1-6 Alkyl or C 3-8 Cycloalkyl is halogen, cyano, or C 1-6 29. The compound according to any one of items 15 to 28, optionally substituted with haloalkyl. [Section 30] R 5 Chloro, fluoro, bromo, cyano, -OH, methyl, ethyl, isopropyl, tert-butyl, -CHCF 2、 -CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH- 3 ) 2、 -OCH 2 CF 3、 and -CF 3 cyclopropyl, optionally substituted with 、 Item 30. The compound according to any one of items 15 to 29. [Section 31] R 5 But halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, and C 3-8 29. The compound according to any one of items 15 to 28, wherein each independently is selected from the group consisting of cycloalkyl. [Section 32] R 5 Chloro, fluoro, bromo, -OH, methyl, -CF 3 , -OCH 3 32. The compound according to any one of items 15 to 28 and 31, wherein each independently is selected from the group consisting of cyclopropyl, cyclopropyl, and cyclopropyl. [Section 33] R 7 C optionally substituted with halogen, cyano, cyano 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, and C 1-6 C optionally substituted with haloalkyl 3-8 33. The compound according to any one of items 15 to 32, wherein the compound is selected from the group consisting of cycloalkyl. [Section 34] R 7 Chloro, bromo, cyano, methyl, ethyl, isopropyl, tert-butyl, -CHCF 2、 -CF 3 , -OCH 2 CH 3、 -OCH 2 CF 3、 and -CF 3 cyclopropyl optionally substituted with 、 34. The compound according to any one of items 15 to 33. [Section 35] R 7 Item 33. The compound according to any one of items 15 to 32, wherein is 4- to 8-membered heterocyclyl. [Section 36] Item 36. The compound according to item 35, wherein the 4- to 8-membered heterocyclyl contains one nitrogen atom. [Section 37] 37. The compound according to any one of items 15 to 36, wherein t is 1 or 2. [Section 38] 37. The compound according to any one of items 15 to 36, wherein t is 0. [Section 39] Item 38. The compound according to any one of items 15 to 37, wherein t is 1. [Section 40] Item 38. The compound according to any one of items 15 to 37, wherein t is 2. [Section 41] 41. The compound according to any one of items 15 to 40, wherein m is 0. [Section 42] The compound is JPEG0007824664000026.jpg140169JPEG0007824664000027.jpg236169JPEG0007824664000028.jpg231169JPEG0007824664000029.jpg89169 Item 16. The compound according to item 15, which is selected from the group consisting of: [Section 43] A compound of formula III, JPEG0007824664000030.jpg24170 During the ceremony, R 1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a wherein C is selected from the group consisting of 1-6 Alkyl is C 1-6 optionally substituted with alkoxy; R a is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, or phenyl, wherein C 3-8 Cycloalkyl or phenyl may contain one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R 2 is hydrogen, R 3 and R 4 is hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, and C 1-6 are each independently selected from the group consisting of alkoxy; R 5 is halogen, cyano, -OH, -NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, and 4- to 8-membered heterocyclyl, 1-6 Alkyl, C 3-8 The cycloalkyl or 4- to 8-membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R c and R d are each independently hydrogen or C 1-6 is alkyl, R 6 is C 1-6 Alkyl or C 1-6 is an alkoxy; t is 0, 1, 2, or 3, and m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof. [Section 44] R 1 But C 1-6 44. The compound according to item 43, wherein the aryl group is alkyl. [Section 45] R 1 Item 45. The compound according to item 43 or 44, wherein is methyl. [Section 46] R 3 46. ​​The compound according to any one of items 43 to 45, wherein is hydrogen. [Section 47] R 4 47. The compound according to any one of items 43 to 46, wherein is hydrogen. [Section 48] R 5 But halogen, cyano, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, and C 3-8 cycloalkyl, wherein each C is independently selected from the group consisting of 1-6 Alkyl or C 3-8 Cycloalkyl is halogen, cyano, or C 1-6 48. The compound according to any one of items 43 to 47, optionally substituted with haloalkyl. [Section 49] R 5 But -CF 3 Item 49. The compound according to any one of items 43 to 48, wherein [Section 50] 50. The compound according to any one of items 43 to 49, wherein t is 1. [Section 51] 51. The compound according to any one of items 43 to 50, wherein m is 0. [Section 52] The compound is JPEG0007824664000031.jpg43170 Item 44. The compound according to item 43, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. [Section 53] JPEG0007824664000032.jpg239169JPEG0007824664000033.jpg224170JPEG0007824664000034.jpg236169JPEG0007824664000035.jpg43170 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof. [Section 54] 54. A pharmaceutical composition comprising the compound according to any one of items 15 to 53 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [Section 55] 1. A method of treating a neurological disease or disorder, said method comprising administering to a subject a compound of formula A: JPEG0007824664000036.jpg26169 During the ceremony, A is phenyl or pyridyl; R 1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a wherein C is selected from the group consisting of 1-6 Alkyl is C 1-6 optionally substituted with alkoxy; R a is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, or phenyl, wherein C 3-8 Cycloalkyl or phenyl may contain one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R 2 is hydrogen or C 1-6 is alkyl, R 3 and R 4 is hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, and C 1-6 are each independently selected from the group consisting of alkoxy; R 5 is halogen, cyano, -OH, -NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, and 4- to 8-membered heterocyclyl, 1-6 Alkyl, C 3-8 The cycloalkyl or 4- to 8-membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R c and R d are each independently hydrogen or C 1-6 is alkyl, R 6 is C 1-6 Alkyl or C 1-6 is an alkoxy; t is 0, 1, 2, 3, or 4, and m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. [Section 56] 1. A method for treating a disease or condition associated with excessive neural excitability, said method comprising administering to a subject a compound of formula A: JPEG0007824664000037.jpg24167 During the ceremony, A is phenyl or pyridyl; R 1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a wherein C is selected from the group consisting of 1-6 Alkyl is C 1-6 optionally substituted with alkoxy; R a is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, or phenyl, wherein C 3-8 Cycloalkyl or phenyl may contain one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R 2 is hydrogen or C 1-6 is alkyl, R 3 and R 4 is hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, and C 1-6 are each independently selected from the group consisting of alkoxy; R 5 is halogen, cyano, -OH, -NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, and 4- to 8-membered heterocyclyl, 1-6 Alkyl, C 3-8 The cycloalkyl or 4- to 8-membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R c and R d are each independently hydrogen or C 1-6 is alkyl, R 6 is C 1-6 Alkyl or C 1-6 is an alkoxy; t is 0, 1, 2, 3, or 4, and m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. [Section 57] 1. A method of treating a disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1), said method comprising administering to a patient a compound of formula A: JPEG0007824664000038.jpg24169 During the ceremony, A is phenyl or pyridyl; R 1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, and -NHR a wherein C is selected from the group consisting of 1-6 Alkyl is C 1-6 optionally substituted with alkoxy; R a is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, or phenyl, wherein C 3-8 Cycloalkyl or phenyl may contain one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R 2 is hydrogen or C 1-6 is alkyl, R 3 and R 4 is hydrogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, and C 1-6 are each independently selected from the group consisting of alkoxy; R 5 is halogen, cyano, -OH, -NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-OC 1-6 Alkyl, C 3-8 cycloalkyl, and 4- to 8-membered heterocyclyl, 1-6 Alkyl, C 3-8 The cycloalkyl or 4- to 8-membered heterocyclyl may be one or more of halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with alkoxy; R c and R d are each independently hydrogen or C 1-6 is alkyl, R 6 is C 1-6 Alkyl or C 1-6 is an alkoxy; t is 0, 1, 2, 3, or 4, and m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. [Section 58] A method for treating a neurological disease or disorder, the method comprising administering the compound according to any one of items 15 to 53 or the pharmaceutical composition according to any one of items 1 to 14 and 54 to a subject in need thereof. [Section 59] A method for treating a disease or condition associated with excessive neural excitability, the method comprising administering to a subject in need thereof the compound according to any one of items 15 to 53 or the pharmaceutical composition according to any one of items 1 to 14 and 54. [Section 60] A method for treating a disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1), the method comprising administering to a subject in need thereof the compound according to any one of items 15 to 53 or the pharmaceutical composition according to any one of items 1 to 14 and 54. [Section 61] Item 61. The method according to any one of Items 55 to 60, 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 epilepsy, an epilepsy syndrome, or encephalopathy. [Section 62] Item 61. The method according to any one of Items 55 to 60, 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 hereditary or childhood epilepsy or a hereditary or childhood epilepsy syndrome. [Section 63] Item 61. The method according to any one of Items 55 to 60, 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 cardiac dysfunction. [Section 64] 61. The method of any one of paragraphs 55 to 60, 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 the group consisting of epilepsy and other encephalopathies (e.g., migratory focal seizures in infancy (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), leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, or cerebellar ataxia). [Section 65] Item 61. The method according to any one of Items 55 to 60, 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 the group consisting of cardiac arrhythmia, sudden unexpected death in epilepsy, Brugada syndrome, and myocardial infarction. [Section 66] Item 61. The method according to any one of Items 55 to 60, 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). [Section 67] Item 61. The method according to any one of Items 55 to 60, 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 a muscle disorder (e.g., myotonia, neuromyotonia, muscle spasms, spasticity). [Section 68] Item 61. The method according to any one of Items 55 to 60, 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 itch and pruritus, ataxia, and cerebellar ataxia. [Section 69] Item 61. The method according to any one of Items 55 to 60, 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 psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia). [Section 70] 61. The method of any one of paragraphs 55 to 60, wherein the neurological disease or disorder, or the disease or condition associated with excessive neural 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, neuroplasticity, and autism spectrum disorders. [Item 71] 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 epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutation, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, or benign familial neonatal-infantile seizures. 61. The method according to any one of items 55 to 60, wherein the epileptic encephalopathy is selected from the group consisting of SCN2A epileptic encephalopathy, focal epilepsy with an SCN3A mutation, cryptogenic childhood partial epilepsy with an SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy. [Example]

[0144] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed as in any way limiting the scope thereof.

[0145] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or suitable process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization.

[0146] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups and their introduction and removal are described in T.W. Greene and P.G.M. Buts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0147] 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). It should be noted 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.

[0148] List of Abbreviations TEA Triethylamine THF tetrahydrofuran ACN Acetonitrile DMF N,N-dimethylformamide DCM dichloromethane TFA trifluoroacetic acid HATU Azabenzotriazole tetramethyluranium hexafluorophosphate DIPEA N,N-Diisopropylethylamine DMSO dimethyl sulfoxide RT room temperature EtOAc ethyl acetate m-CPBA meta-chloroperoxybenzoic acid DAST Diethylaminosulfur trifluoride LAH Lithium aluminum hydride Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0)

[0149] Example 1. Synthesis of 5-(N-methylsulfamoyl)thiophene-2-carboxylic acid (a3) [ka] Synthesis of methyl 5-(chlorosulfonyl)thiophene-2-carboxylate (a1) Compound a1 was synthesized according to the procedure disclosed in US Patent Application Publication No. 20160200719.

[0150] Synthesis of methyl 5-(N-methylsulfamoyl)thiophene-2-carboxylate (a2) To a stirred solution of a1 (15 g, 62.32 mmol) in THF (150 mL) was added TEA (26.1 mL, 186.97 mmol) and methanamine (1 M in THF, 5.81 g, 186.97 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by column chromatography using 100-200 silica and DCM as the eluent to give a2 (10 g, 39.3 mmol, 63% yield) as a liquid.

[0151] Synthesis of 5-(N-methylsulfamoyl)thiophene-2-carboxylic acid (a3) To a stirred solution of a2 (1 g, 4.25 mmol) in THF was added an aqueous solution of LiOH (267.51 mg, 6.38 mmol) at 0 °C, and the reaction mixture was stirred at RT for 4 h. The volatile solvents were removed under reduced pressure. The residue was diluted with water and extracted with diethyl ether (3 × 5 mL). The aqueous layer was separated, cooled to 0 °C, and acidified with 2 N HCl. The precipitated solid was collected by filtration and dried under reduced pressure to give a3 (700 mg, 3.12 mmol, 74% yield).

[0152] Example 2. General procedure for amidation: [ka] To a stirred solution of acid a3 (1 equiv.) and the corresponding amine bb (1.1 equiv.) in DMF / DCM, DIPEA (2 equiv.) was added, followed by HATU (1.5 equiv.) at 0° C. The resulting reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography / preparative HPLC to give the desired compound (compound of formula (A), (A-1), (A-2), (A-3), (I), (Ia), (Ib), (II), (II-a), (II-b), or (III)).

[0153] Example 3. Synthesis of (R)-N-(1-(2,4-dichlorophenyl)ethyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 1) [ka] Compound 1 was synthesized according to the procedure described in Example 2. Yield: 58 mg, 0.145 mmol (from 200 mg of a3). HPLC: Rt 8.52 min, 98.1%, Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 393.10 (M + H), Rt 1.93 min, Column: X-select CSH C18 (3 * 50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H 9.24 (d, 1H), 7.94 (d, 1H), 7.86-7.80 (m, 1H), 7.64-7.58 (m, 2H), 7.54-7.48 (m, 1H), 7.48-7.42 (m, 1H), 5.36-5.30 (m, 1H), 1.44 (d, 3H), merged with the 3H solvent peak. Chiral HPLC: Rt 5.36 min, 100%; Method 84076, SFC column: DIACEL CHIRALPAK-IG (150 x 4.6 mm, 5 µm), mobile phase: A) CO₂, B) MeOH + 0.1% NH₃, gradient: 20-40% B in 5 min, hold 40% B until 9 min, 40-20% B in 10 min, hold 20% B until 12 min. Wavelength: 271nm, flow: 3mL / min.

[0154] Example 4. Synthesis of (S)—N-(1-(2,4-dichlorophenyl)ethyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 2) [ka] Compound 2 was synthesized according to the procedure described in Example 2. Yield: 53 mg, 0.135 mmol (from 200 mg of a3). HPLC: Rt 8.52 min, 99.9%, Column: X-Select CSH C18 (4.6x150) mm, 5 μm, Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 393.10 (M+H), Rt 1.95 min, Column: X-select CSH C18 (3*50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δH 9.25 (d, 1H), 7.94 (d, 1H), 7.84-7.80 (m, 1H), 7.64-7.58 (m, 2H), 7.54-7.48 (m, 1H), 7.48-7.42 (m, 1H), 5.36-5.30 (m, 1H), 1.45 (d, 3H), merged with the 3H solvent peak. Chiral HPLC: Rt 6.62 min, 99.67%; Method: 84076, SFC Column: DIACEL CHIRALPAK-IG (150 x 4.6 mm, 5 µm), Mobile Phase: A) CO₂, B) MeOH + 0.1% NH₃, Gradient: 20-40% B in 5 min, hold 40% B until 9 min, 40-20% B in 10 min, hold 20% B until 12 min. Wavelength: 271nm, flow: 3mL / min.

[0155] Example 5. Synthesis of N-(2,4-dichlorobenzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 3) [ka] Compound 3 was synthesized according to the procedure described in Example 2. Yield: 25 mg, 0.065 mmol (from 200 mg of a3). HPLC: Rt 8.46 min, 98.7%, Column: X-Select CSH C18 (4.6x150) mm, 5 μm, Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 379.00 (M+H), Rt 1.87 min, Column: X-select CSH C18 (3*50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H 9.38-9.32(m,1H),7.86-7.80(m,2H),7.64-7.60(m,1H),7.59(d,1H),7.44-7.36(m,2H),4.49(d,2H),2.51(s,3H).

[0156] Example 6. Synthesis of (R)-N-(1-(4-chlorophenyl)ethyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 4) [ka] Compound 4 was synthesized according to the procedure described in Example 2. Yield: 80 mg, 0.208 mmol (from 200 mg of a3). HPLC: Rt 8.22 min, 93.5% Column: X-Select CSH C18 (4.6 * 150) mm 5 μm; Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 359.05 (M + H), Rt 1.82 min, Column: X-select CSH C18 (3 * 50) mm, 2.5 μm. 1H NMR (400 MHz, DMSO-d6) δ H 9.12 (d, 1H), 7.90 (d, 1H), 7.85-7.78 (m, 1H), 7.58 (d, 1H), 7.42-7.38 (m, 4H), 5.12-5.08 (m, 1H), 1.47 (d, 3H), merged with the 3H solvent peak.

[0157] Example 7. Synthesis of (S)—N-(1-(4-chlorophenyl)ethyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 5) [ka] Compound 5 was synthesized according to the procedure described in Example 2. Yield: 92.8 mg, 0.257 mmol (from 200 mg of a3). HPLC: Rt 8.04 min, 99.7%, Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCM: 358.95 (M + H), Rt 1.83 min, Column: X-select CSH C18 (3 * 50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H 9.13(d,1H),7.90(d,1H),7.80-7.72(m,1H),7.59(d,1H),7.42-7.36(m,4H),5.12-5.06(m,1H),2.51(s,3H),1.47(d,3H).

[0158] Example 8. Synthesis of N-(2,4-dichlorobenzyl)-5-(methylsulfonyl)thiophene-2-carboxamide (Compound 6) [ka] 5-(Methylsulfonyl)thiophene-2-carboxylic acid (a4) was synthesized according to the protocol described in WO2000 / 058277. Following the general procedure of Example 2, compound 6 was obtained as a solid (57.5 mg, 0.157 mmol (from 60 mg of a4)). HPLC: Rt 8.48 min, 99.6%, Column: X-Select CSH C18 (4.6x150) mm, 5 μm, Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 364.00 (M+H), Rt 1.97 min, Column: X-Select CSH C18 (3*50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H 9.42(t,1H),7.90(d,1H),7.84(d,1H),7.64(s,1H),7.46-7.38(m,2H),4.52(d,2H),3.39(s,3H).

[0159] Example 9. Synthesis of N-(4-chlorobenzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 7) [ka] Compound 7 was synthesized according to the procedure described in Example 2. Yield: 97.1 mg, 0.275 mmol (from 200 mg of a3). HPLC: Rt 7.99 min, 98.0%, Column: X-Select CSH C18 (4.6x150) mm, 5 μm, Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 344.95 (M+H), Rt 1.95 min. Column: X-select CSH C18 (3*50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H9.37 (t, 1H), 7.84-7.80 (m, 2H), 7.59 (d, 1H), 7.40 (d, 2H), 7.33 (d, 2H), 4.45 (d, 2H), merged with the 3H solvent peak.

[0160] Example 10. Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 8) [ka] Compound 8 was synthesized according to the procedure described in Example 2. Yield: 60 mg, 0.143 mmol, 32% yield as a solid (from 100 mg of a3). HPLC: Rt 8.66 min, 98.1%, Column: X-Select CSH C18 (4.6x150) mm, 5 μm, Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 413.05 (M+H), Rt 2.02 min, Column: X-Select CSH C18 (3*50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H 9.48-9.40(m,1H),7.90-7.80(m,3H),7.76(d,1H),7.62(d,1H),7.56(d,1H),4.61(d,2H),2.53(s,3H).

[0161] Example 11. Synthesis of N-(4-chloro-2-methylbenzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 9) [ka] Compound 9 was synthesized according to the procedure described in Example 2. Yield: 40.0 mg, 0.110 mmol (from 100 mg of a3). HPLC: Rt 8.33 min, 98.5%, Column: X-Select CSH C18 (4.6x150) mm, 5 μm, Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 358.90 (M+H), Rt 1.91 min, Column: X-Select CSH C18 (3*50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H 9.23 (t, 1H), 7.86-7.82 (m, 2H), 7.59 (d, 1H), 7.28-7.20 (m, 3H), 4.40-4.30 (m, 2H), 2.45 (s, 3H), merged with the 3H solvent peak.

[0162] Example 12. Synthesis of N-(4-chloro-2-fluorobenzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 10) [ka] Compound 10 was synthesized according to the procedure described in Example 2. Yield: 35 mg, 0.095 mmol (from 100 mg of a3). HPLC: Rt 7.94 min, 98.4%. Column: X-Select CSH C18 (4.6x150) mm, 5 μm. Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 362.85 (M+H), Rt 1.89 min. Column: X-select CSH C18 (3*50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H = 9.35 (t, 1H), 7.85-7.80 (m, 2H), 7.60-7.58 (m, 1H), 7.46-7.36 (m, 2H), 7.28 (d, 1H), 4.47 (d, 2H), merged with the 3H solvent peak.

[0163] Example 13. Synthesis of N-(2-bromo-4-chlorobenzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 11) [ka] Compound 11 was synthesized according to the procedure described in Example 2. Yield: 35 mg, 0.082 mmol (from 100 mg of a3). HPLC: Rt 7.08 min, 97.4%, Column: X-Bridge C18 (4.6x150) mm, 5 μm; Mobile phase: A: 0.1% NH3 in water, B: ACN, Flow rate: 1.2 mL / min. LCMS: 424.95 (M+3), Rt 1.97 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),7.86(d,1H),7.84-7.76(m,2H),7.61(d,1H),7.50-7.45(m,1H),7.37(d,1H),4.47(d,2H),2.52-2.46(m,3H).

[0164] Example 14. Synthesis of N-(4-chloro-2-cyclopropylbenzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 12) [ka] Compound 12 was synthesized according to the procedure described in Example 2. Yield: 45 mg, 0.111 mmol (from 100 mg of a3). HPLC: Rt 8.54 min, 95.0%, Column: X-Select CSH C18 (4.6x150) mm, 5 μm, Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 384.7 (M+H), Rt 1.90 min, Column: X-select CSH C18 (3*50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d) δ H9.26(t,1H),7.85(d,1H),7.82-7.78(m,1H),7.59(d,1H),7.28-7.20(m,2H),7.04-7.00(m ,1H),4.61(d,2H),2.52(s,3H),2.06-2.00(m,1H),0.98-0.90(m,2H),0.72-0.067(m,2H).

[0165] Example 15. Synthesis of N-(4-chloro-2-methoxybenzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 13) [ka] Compound 13 was synthesized according to the procedure described in Example 2. Yield: 55 mg, 0.144 mmol (from 100 mg of a3). HPLC: Rt 8.10 min, 98.8%, Column: X-Select CSH C18 (4.6x150) mm, 5 μm, Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 375.10 (M+H), Rt 1.83 min, Column: X-select CSH C18 (3*50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H 9.19 (t, 1H), 7.86-7.80 (m, 2H), 7.59 (d, 1H), 7.19 (d, 1H), 7.08 (s, 1H), 6.98 (d, 1H), 4.38 (d, 2H), 3.85 (s, 3H), merged with the 3H solvent peak.

[0166] Example 16. Synthesis of N-(4-chloro-2-hydroxybenzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 14) [ka] To a stirred solution of compound 13 (100 mg, 0.2700 mmol) in DCM 、BBr3 (1 M in DCM, 0.8 mL, 0.8 mmol) was added. The reaction mixture was stirred at 0 °C for 30 min. The reaction was quenched with methanol (2 mL), and the organic layer was concentrated under reduced pressure. The crude compound was purified by column chromatography using 100-200 silica and 30-80% EtOAc / hexane as eluent to give 14 (40 mg, 0.108 mmol, 41% yield) as a solid. HPLC: Rt 7.79 min, 97%, Column: X-Select CSH C18 (4.6 × 150) mm, 5 μm, Mobile phase: A: 0.1% formic acid in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min. LCMS: 360.95 (M+H), Rt 1.95 min, Column: X-select CSH C18 (3*50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ H 10.13 (s, 1H), 9.25-9.15 (m, 1H), 7.86-7.80 (m, 2H), 7.59-7.56 (m, 1H), 7.14 (d, 1H), 6.86-6.80 (m, 2H), 4.37 (d, 2H), merged with the 3H solvent peak.

[0167] Example 17. Synthesis of 5-(cyclopropylsulfonyl)-N-(2,4-dichlorobenzyl)thiophene-2-carboxamide (Compound 15): [ka] Synthesis of methyl 5-(cyclopropylsulfonyl)thiophene-2-carboxylate (a6): To a stirred solution of a5 (1.5 g, 6.79 mmol) and sodium cyclopropanesulfinate (1.3 g, 10.18 mmol) in DMSO (20 mL) was added copper iodide (0.13 g, 0.68 mmol), L-proline (0.16 g, 1.36 mmol), and sodium hydroxide (0.054 g, 1.35 mmol) at RT. The reaction mixture was stirred at 95 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The organic layer was separated, dried over anhydrous NaSO, filtered, and evaporated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography using 20–40% EtOAc / hexane as the eluent to give a6 (0.4 g, 1.54 mmol, 23% yield) as a solid.

[0168] Synthesis of 5-(cyclopropylsulfonyl)thiophene-2-carboxylic acid (a7): To a stirred solution of a6 (0.4 g, 1.62 mmol) in THF:water (10 mL:3 mL) was added LiOH.HO (0.102 g, 2.44 mmol) at RT. The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The organic layer was separated and the aqueous layer was acidified with 1 N HCl. The precipitated solid was collected by filtration and dried under reduced pressure to give a7 (0.23 mg, 0.95 mmol, 58% yield) as a solid.

[0169] Synthesis of 5-(cyclopropylsulfonyl)-N-(2,4-dichlorobenzyl)thiophene-2-carboxamide (compound 15): To a stirred solution of a7 (105.45 mg, 0.45 mmol) and a8 (0.06 mg, 0.45 mmol) in DCM (10 mL) was added HATU (207.14 mg, 0.54 mmol) and DIPEA (0.16 mL, 0.91 mmol) at 0 °C, and the resulting reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2 × 50 mL). The combined organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography using 30–80% EtOAc / hexane as the eluent to give 15 (30 mg, 0.077 mmol, 17% yield). HPLC: Rt 8.64 min, 99.81%, Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 391.8 (M+2), Rt 1.967 min, Column: X-Select CSH C18 (3 × 50) mm, 2.5 μm. 1 H NMR (400MHz, DMSO-d6): δ9.42(t,1H),7.91(d,1H),7.81(d,1H),7.67-7.61( m,1H),7.48-7.37(m,2H),4.52(d,2H),3.05-2.98(m,1H),1.23-1.08(m,4H).

[0170] Example 18. Synthesis of N-(2,4-dichlorobenzyl)-5-(ethylsulfonyl)thiophene-2-carboxamide (Compound 16): [ka] Synthesis of methyl 5-(ethylsulfonyl)thiophene-2-carboxylate (a10): To a stirred solution of a5 (1 g, 4.52 mmol) in DMSO (10 mL) was added a9 (630.26 mg, 5.43 mmol), copper iodide (85.95 mg, 0.45 mmol), sodium hydroxide (36.19 mg, 0.90 mmol), and L-proline (104.16 mg, 0.90 mmol) at RT and stirred at 95 °C for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (5 × 25 mL). The combined organic layers thus obtained were dried over NaSO and evaporated to give the crude compound. The crude compound was purified by column chromatography on 100-200 silica with 8-10% EtOAc / hexane eluent to give a10 (300 mg, 1.21 mmol, 26% yield) as a solid.

[0171] Synthesis of 5-(ethylsulfonyl)thiophene-2-carboxylic acid (a11): To a stirred solution of a10 (300 mg, 1.28 mmol) in THF (5 mL) was added lithium hydroxide (46 mg, 1.92 mmol) in water (1 mL) at 0 °C and stirred at RT for 2 h. The reaction mixture was concentrated to give the crude product. The crude product thus obtained was diluted with cold water (10 mL), acidified to about pH 4 with 2 N aqueous HCl, and extracted with DCM (3 × 15 mL). The combined organic layers were separated and dried over NaSO to give a11 (220 mg, 0.60 mmol, 46% yield, 60% purity) as a solid.

[0172] Synthesis of N-(2,4-dichlorobenzyl)-5-(ethylsulfonyl)thiophene-2-carboxamide (compound 16): To a stirred solution of a11 (100 mg, 0.45 mmol) and a8 (0.06 mL, 0.45 mmol) in DCM (10 mL) was added HATU (207.14 mg, 0.54 mmol) and DIPEA (0.16 mL, 0.91 mmol) at RT. The reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 50 mL). The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude reaction was purified by silica gel column chromatography using 30–80% EtOAc / hexane as the eluent to give 16 (30 mg, 0.0791 mmol, 17% yield) as a solid. HPLC: Rt 8.48 min, 99.70%, Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 379.7 (M+2), Rt 1.936 min, Column: X-Select CSH C18 (3 × 50) mm, 2.5 μm. 1 H NMR (400MHz, DMSO-d6) δ9.42(t,1H),7.93(d,1H),7.81(d,1H),7.67-7.61(m,1H),7.48-7.37(m,2H),4.52(d,2H),3.44(q,2H),1.18(t,3H).

[0173] Example 19. Synthesis of N-(4-cyanobenzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 17) and N-(3-chlorobenzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 18): [ka] Compounds 17 and 18 were prepared according to the synthesis method described in Example 2. Compound 17: Yield: 20 mg, 0.0586 mmol, 13%. HPLC: Rt 7.33 min, 98.28%. Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm. Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 335.90 (M+H), Rt 1.909 min. Column: X-Select CSH C18 (3 * 50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ 9.44 (t, 1H), 7.84-7.79 (m, 4H), 7.60 (d, 1H), 7.51 (d, 2H), 4.55 (d, 2H), merged with 3H solvent peak. Chiral method: Rt: 9.329 min, 99.47%, Column: YMC CHIRAL ART CELLULOSE-SC (250 x 4.6 mm, 5 μL), Mobile phase: A) n-hexane + 0.1% TFA, B) DCM:MeOH (50:50), Isocratic: 35% B, Wavelength: 267 nm, Flow rate: 1.0 mL / min. Compound 18: Yield: 25 mg, 0.072 mmol, 16%. HPLC: Rt 8.075 min, 98.91%, Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 344.85 (M+H), Rt 2.088 min, Column: X-select CSH C18 (3 × 50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d6) δ 9.40-9.35 (m, 1H), 7.84-7.80 (m, 2H), 7.57 (d, 1H), 7.38-7.26 (m, 4H), 4.46 (d, 2H), merged with the 3H solvent peak. Chiral method: Rt 6.757 min, 99.69%; Column: YMC CHIRAL ART CELLULOSE-SC (250 x 4.6 mm, 5 μm); Mobile phase: A) n-hexane + 0.1% TFA, B) DCM:MeOH (50:50), isocratic: 35% B; Wavelength: 268 nm; Flow rate: 1.0 mL / min.

[0174] Example 20. Synthesis of N-(4-isopropylbenzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 19): [ka] To a stirred solution of (4-isopropylphenyl)methanamine (80.94 mg, 0.54 mmol) and a3 (100 mg, 0.45 mmol) in DCM (4 mL) was added DIPEA (0.24 mL, 1.36 mmol) and HATU (257.78 mg, 0.68 mmol). The reaction mixture was stirred at RT for 3 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 10 (15 mg, 0.04 mmol, 9% yield) as a solid. HPLC: Rt 8.321 min, 95.32%, Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 352.9 (M+H), Rt 1.985 min, Column: X-select CSH C18 (3 × 50) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d) δ 9.32-9.25 (m, 1H), 7.85-7.75 (m, 2H), 7.58-7.56 (m, 1H), 7.30-7.15 (m, 4H), 4.46 (d, 2H), 2.88-2.83 (m, 1H), 1.18 (d, 6H), 3H merged with solvent peak.

[0175] Example 21. Synthesis of N-(4-chloro-3-fluorobenzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 20): [ka] To a stirred solution of a3 (100 mg, 0.45 mmol) and the corresponding amine (86.56 mg, 0.54 mmol) in DCM (5 mL) was added DIPEA (0.16 mL, 0.90 mmol) followed by HATU (206.23 mg, 0.54 mmol) at 0 °C, and the resulting reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography using 30–80% EtOAc / hexane as the eluent to give 20 (48 mg, 0.13 mmol, 29% yield) as a solid. HPLC: Rt 8.065 min, 98.75%, Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 362.8 (M+H), Rt 1.923 min, Column: X-Select CSH C18 (4.6 × 150) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d): 9.42-9.35 (m, 1H), 7.824-7.80 (m, 2H), 7.62-7.51 (m, 2H), 7.35 (d, 1H), 7.19 (d, 1H), 4.47 (d, 2H), merged with 3H solvent peak.

[0176] Example 22. Synthesis of N-(4-bromobenzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 21): [ka] To a stirred solution of a3 (100 mg, 0.45 mmol) and the corresponding amine (100.91 mg, 0.54 mmol) in DCM (5 mL) was added DIPEA (0.16 mL, 0.90 mmol) followed by HATU (206.23 mg, 0.54 mmol) at 0 °C, and the resulting reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography using 30–80% EtOAc / hexane as the eluent to give 21 (20 mg, 0.05 mmol, 11% yield) as a solid. HPLC: Rt 7.822 min, 96.13%, Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 388.8 (M+H), Rt 2.079 min, Column: X-select CSH C18 (4.6 x 150) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d) δ 9.38-9.35 (m, 1H), 7.82-7.78 (m, 2H), 7.61-7.58 (m, 1H), 7.53 (d, 2H), 7.28 (d, 2H), 4.43 (d, 2H), merged with 3H solvent peak.

[0177] Example 23. Synthesis of N-(4-methylbenzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 22): [ka] To a stirred solution of a3 (100 mg, 0.45 mmol) and the corresponding amine (65.7 mg, 0.54 mmol) in DCM (5 mL) was added DIPEA (0.16 mL, 0.90 mmol) followed by HATU (206.2 mg, 0.54 mmol) at 0 °C, and the resulting reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography using 30–80% EtOAc / hexane as the eluent to give 22 (30 mg, 0.09 mmol, 20% yield) as a solid. HPLC: Rt 7.588 min, 99.01%, Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 324.9 (M+H), Rt 1.877 min, Column: X-Select CSH C18 (4.6 x 150) mm, 2.5 μm. 1 H NMR (400 MHz, DMSO-d) δ 9.33-9.25 (m, 1H), 7.81 (d, 2H), 7.57 (d, 1H), 7.23-7.11 (m, 4H), 4.41 (d, 2H), 2.28 (s, 3H), merged with 3H solvent peak.

[0178] Example 24. Synthesis of 5-(methylsulfonyl)-N-(4-(pyrrolidin-1-yl)benzyl)thiophene-2-carboxamide (Compound 23): [ka] To a stirred reaction mixture of 5-methylsulfonylthiophene-2-carboxylic acid (200 mg, 0.9697 mmol) and a12 (205.11 mg, 1.1637 mmol) in DCM (20 mL) was added HATU (553.09 g, 1.4546 mmol) followed by DIPEA (376.02 mg, 2.9092 mmol) at 0° C., and stirring was then continued for an additional 1 h at 0° C. The reaction mixture was concentrated under reduced pressure and then diluted by adding water (10.0 mL), and the reaction mixture was then extracted with EtOAc (2×25 mL), and the combined extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude residue (220 mg) as a viscous liquid. The crude material was purified by Combi-Flash column chromatography (100-200 silica gel) eluting with 0-40% EtOAc in hexanes to give 23 (75.4 mg, 0.2012 mmol, 20% yield) as a solid. LCMS: 365.1 (M+H), R t = 2.206 min, Column: X-Bridge BEH C-18 (3.0 x 50 mm, 2.5 μm); Mobile phase: A: 0.025% FA in water, B: ACN; T / B%: 0.01 / 2, 0.2 / 2, 2 / 98, 3 / 98, 3.2 / 2, 4 / 2, Flow rate: 1.2 ml / min (gradient); Column oven temperature: 50 °C. HPLC: R t = 6.138 min, 97.26%; Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 μ); Mobile phase-A: 0.05% TFA:acetonitrile (95:05); Mobile phase-B: acetonitrile:0.05% TFA (95:05); Program: T / B%: 0.01 / 10, 12 / 90, 16 / 90, Flow: 1.0 mL / min; Diluent: ACN:water. 1 H-NMR NMR(400MHz,DMSO-d6):δ9.23(t,1H),7.84(d,1H),7.79(d,1H),7.11(d,2 H),6.49(d,2H),4.33(d,2H),3.37(s,3H),3.18(t,4H),1.98-1.89(m,4H).

[0179] Example 25. Synthesis of N-(4-isopropylbenzyl)-5-(methylsulfonyl)thiophene-2-carboxamide (Compound 24): [ka] To a stirred reaction mixture of 5-methylsulfonylthiophene-2-carboxylic acid (200 mg, 0.9697 mmol) and a13 (217.07 mg, 1.4546 mmol) in DCM (25 mL) was added HATU (553.09 g, 1.4546 mmol) followed by DIPEA (376.02 mg, 2.9092 mmol) at 0° C., and stirring was then continued for an additional 1 h at 0° C. The reaction mixture was concentrated under reduced pressure and then diluted by adding water (10.0 mL), and the reaction mixture was then extracted with EtOAc (2×25 mL), and the combined extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude residue (220 mg) as a viscous liquid. The resulting crude product was purified by Combi-Flash column chromatography (100-200 silica gel) eluting with 0-40% EtOAc in hexane to give 24 (183.1 mg, 0.54 mmol, 55% yield) as a solid. LCMS: 338.1 (M+H), R t =2.335 min, Column: X-Bridge BEH C-18 (3.0 x 50 mm, 2.5 μm); Mobile phase: A: 0.025% FA in water, B: ACN; T / B%: 0.01 / 2, 0.2 / 2, 2 / 98, 3 / 98, 3.2 / 2, 4 / 2, Flow rate: 1.2 ml / min (gradient); Column oven temperature: 50 °C. HPLC: R t = 10.841 min, 99.22%. Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 0.05% TFA:acetonitrile (95:05); Mobile phase B: acetonitrile:0.05% TFA (95:05); Program: T / B%: 0.01 / 10, 12 / 90, 16 / 90, Flow rate: 1.0 mL / min; Diluent: ACN:water. 1 H NMR (400MHz, DMSO-d6) δ9.34(t,1H),7.86(d,1H),7.81(d,1H),7.27-7.18(m,4H),4.43(d,2H),3.38(s,3H),2.92-2.80(m,1H),1.18(d,6H).

[0180] Example 26. Synthesis of N-(4-isopropoxybenzyl)-5-(methylsulfonyl)thiophene-2-carboxamide (Compound 25): [ka] To a stirred reaction mixture of 5-methylsulfonylthiophene-2-carboxylic acid (200 mg, 0.9697 mmol) and a14 (240.35 mg, 1.4546 mmol) in DCM (5.00 mL) was added HATU (553.09 g, 1.4546 mmol) followed by DIPEA (376.02 mg, 2.9092 mmol) at 0° C., and stirring was continued for an additional 1 h at 0° C. The reaction mixture was concentrated under reduced pressure and then diluted by adding water (10.0 mL), and the reaction mixture was then extracted with EtOAc (2×25 mL), and the combined extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude residue (220 mg) as a viscous liquid. The resulting crude product was purified by Combi-Flash column chromatography (100-200 silica gel) eluting with 0-40% EtOAc in hexane to give 25 (161.19 mg, 0.4537 mmol, 46% yield) as a solid. LCMS: 354.1 (M+H), R t = 2.184 min, Column: X-Bridge BEH C-18 (3.0 × 50 mm, 2.5 μm); Mobile phase: A: 0.025% FA in water, B: ACN; T / B%: 0.01 / 2, 0.2 / 2, 2 / 98, 3 / 98, 3.2 / 2, 4 / 2, Flow rate: 1.2 ml / min (gradient); Column oven temperature: 50 °C. HPLC: R t = 10.56 min, 99.48%, Column: X SELECT CSH C18 (150 x 4.6 mm, 3.5 u); Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Program: T / B %; 0.01 / 20, 5 / 80, 12 / 90, 16 / 90; Flow: 1.0 mL / min; Diluent: ACN:water. 1H NMR (400MHz, DMSO-d6): δ9.31(t,1H),7.85(d,1H),7.80(d,1H),7.21(d,2 H),6.87(d,2H),4.61-4.52(m,1H),4.39(d,2H),3.37(s,3H),1.24(d,6H).

[0181] Example 27. Synthesis of N-(4-cyclopropylbenzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 26): [ka] To a stirred solution of a3 (200 mg, 0.9040 mmol) in DMF (10 mL) was added DIPEA (323 mg, 2.499 mmol), HATU (443 mg, 1.1651 mmol), followed by the corresponding amine (244 mg, 1.6574 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 0%-35%-90% EtOAc in heptane as the eluent to give 26 (52.2 mg, 0.1453 mmol, 16% yield). LCMS: 349.15 (MH), R t = 2.059 min, Column: X-SELECT CSH C18 (50*3) mm 2.5u; Mobile phase: A: 2.5 mM ammonium bicarbonate solution; B: acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Column oven temperature: 50 °C, Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, B concentration 0% from 3.2 min to 4.0 min. HPLC: R t = 9.09 min, 97.55%, Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Program: T / B%: 0.01 / 20, 12 / 90, 16 / 90. Flow rate: 1.0 mL / min; Diluent: water:ACN. 1H NMR (400MHz, DMSO-d6) δ9.27(t,1H),7.87-7.74(m,2H),7.62-7.53(m,1H),7.25-7.12(m,2H),7.10-6 .97(m,2H),4.45-4.31(m,2H),1.96-1.81(m,1H),0.97-0.81(m,2H),0.67-0.55(m,2H),Merge with 3H solvent peak

[0182] Example 28. Synthesis of N-(4-isopropoxybenzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 27): [ka] To a stirred solution of a3 (200 mg, 0.9040 mmol) in DMF (15 mL) was added DIPEA (323 mg, 2.499 mmol), HATU (443 mg, 1.1651 mmol), followed by the corresponding amine (234 mg, 1.4162 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 0%-35%-90% EtOAc in heptane as the eluent to give 27 (41 mg, 0.1112 mmol, 12% yield). LCMS: 366.8 (MH), R t = 3.214 min, Column: X-Bridge BEH C-18 (3.0 x 50 mm, 2.5 μm), Mobile phase: A: 2.5 mM ammonium bicarbonate, B: ACN, Gradient T / B%: 0.01 / 10, 3 / 90, 5 / 90, 5.5 / 10, 6 / 10, Flow rate: 0.8 ml / min. HPLC: R t = 9.17 min, 99.95%. Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Program: T / B%: 0.01 / 20, 12 / 90, 16 / 90. Flow rate: 1.0 mL / min; Diluent: water:ACN. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (t, 1H), 7.87-7.72 (m, 2H), 7.61-7.51 (m, 1H), 7.21 (d, 2H), 6.87 (d, 2H), 4.63-4.49 (m, 1H), 4.38 (d, 2H), 1.24 (d, 6H), 3H merged with solvent peak.

[0183] Example 29. Synthesis of N-(4-(tert-butyl)benzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 28): [ka] To a stirred solution of a3 (200 mg, 0.9040 mmol) in DMF (10 mL) was added HATU (443 mg, 1.1651 mmol) and DIPEA (323 mg, 2.499 mmol), followed by the corresponding amine (244 mg, 1.4945 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 0% to 35% to 90% EtOAc in heptane as the eluent to give 28 (50.3 mg, 0.13 mmol, 15% yield). LCMS: 365.25 (MH), Rt = 2.066 min. Column: X-select CSH C18 (3*50) mm, 2.5 μm. Mobile phase: A: 2.5 mM ammonium bicarbonate in water; B: acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Column oven temperature: 50 °C, Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, B concentration 0% from 3.2 min to 4.0 min. HPLC: R t = 10.160 min, 97.04%, Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 μ); Mobile phase-A: 0.05% TFA:acetonitrile (95:05); Mobile phase-B: acetonitrile:0.05% TFA (95:05); Program: T / B%: 0.01 / 10, 12 / 90, 16 / 90; Flow: 1.0 mL / min; Diluent: ACN:water. 1H NMR (400 MHz, DMSO-d) δ 9.28 (t, 1H), 7.87-7.74 (m, 2H), 7.62-7.53 (m, 1H), 7.36 (d, 2H), 7.24 (d, 2H), 4.46-4.34 (m, 2H), 1.26 (s, 9H), merged with 3H solvent peak.

[0184] Example 30. Synthesis of 5-(N-methylsulfamoyl)-N-(4-(trifluoromethyl)benzyl)thiophene-2-carboxamide (Compound 29): [ka] To a stirred solution of a3 (200 mg, 0.9040 mmol) in DMF (15 mL) was added HATU (443 mg, 1.1651 mmol) and DIPEA (323 mg, 2.499 mmol), followed by the corresponding amine (274 mg, 1.5644 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 0%-35%-90% EtOAc in heptane as the eluent to give the title compound 29 (31 mg, 0.0802 mmol, 9%). LCMS: 379.0 (M+H), R t = 2.066 min, Column: X-Bridge BEH C-18 (3.0 x 50 mm, 2.5 μm), Mobile phase: A: 0.025% FA in water, B: ACN; T / B%: 0.01 / 2, 0.2 / 2, 2 / 98, 3 / 98, 3.2 / 2, 4 / 2, Flow rate: 1.2 ml / min (gradient); Column oven temperature: 50 °C. HPLC: R t = 8.200 min, 97.94%. Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 0.05% TFA:acetonitrile (95:05); Mobile phase B: acetonitrile:0.05% TFA (95:05); Program: T / B%: 0.01 / 10, 12 / 90, 16 / 90; Flow rate: 1.0 mL / min; Diluent: ACN:water. 1H NMR (400 MHz, DMSO-d) δ 9.43 (t, 1H), 7.82 (s, 2H), 7.71 (d, 2H), 7.60 (s, 1H), 7.54 (d, 2H), 4.60-4.47 (m, 2H), merged with 3H solvent peak.

[0185] Example 31. Synthesis of 5-(N-methylsulfamoyl)-N-(4-(pyrrolidin-1-yl)benzyl)thiophene-2-carboxamide (Compound 30): [ka] To a stirred solution of a3 (200 mg, 0.9040 mmol) in DMF (10 mL) was added HATU (443 mg, 1.1651 mmol) and DIPEA (323 mg, 2.499 mmol), followed by the corresponding amine (244 mg, 1.3843 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The crude material was purified by flash column chromatography using 0%-35%-90% EtOAc in heptane as the eluent to give 30 (27.6 mg, 0.0802 mmol, 9% yield). LCMS: 380.2 (M+H), R t = 3.389 min, Column n: X-Bridge BEH C-18 (3.0 x 50 mm, 2.5 μm); Mobile phase: A: 2.5 mM ammonium bicarbonate, B: ACN, (gradient) T / B%: 0.01 / 10, 3 / 90, 5 / 90, 5.5 / 10, 6 / 10, Flow rate: 0.8 ml / min. HPLC: R t = 9.58 min, 97.12%. Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Program: T / B%: 0.01 / 20, 12 / 90, 16 / 90. Flow rate: 1.0 mL / min; Diluent: water:ACN. 1 H NMR (400 MHz, DMSO-d6): 9.16 (t, 1H), 7.79 (d, 2H), 7.56 (d, 1H), 7.11 (d, 2H), 6.49 (d, 2H), 4.32 (d, 2H), 3.14 (t, 4H), 1.93 (t, 4H), 3H merged with solvent peak.

[0186] Example 32. Synthesis of N-(4-cyclopropylbenzyl)-5-(methylsulfonyl)thiophene-2-carboxamide (Compound 31): [ka] To a stirred reaction mixture of 5-methylsulfonylthiophene-2-carboxylic acid (200 mg, 0.9697 mmol) and a15 (214.15 mg, 1.4546 mmol) in DCM (20 mL) was added HATU (553.09 mg, 1.4546 mmol) followed by DIPEA (376.02 mL, 2.9092 mmol) at 0° C., and stirring was then continued for an additional 1 h at 0° C. The reaction mixture was concentrated under reduced pressure and then diluted by adding water (10.0 mL), and the reaction mixture was then extracted with EtOAc (2×25 mL), and the combined extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude residue (220 mg) as a colorless viscous liquid. The resulting crude material was purified by Combi-Flash column chromatography (100-200 silica gel) eluting with 0-40% EtOAc in hexane to give 31 (102.3 mg, 0.3033 mmol, 31% yield) as a solid. LCMS: 336.1 (M+H), R t = 2.192 min, Column: X-Bridge BEH C-18 (3.0 × 50 mm, 2.5 μm); Mobile phase: A: 0.025% FA in water, B: ACN; T / B%: 0.01 / 2, 0.2 / 2, 2 / 98, 3 / 98, 3.2 / 2, 4 / 2, Flow rate: 1.2 ml / min (gradient); Column oven temperature: 50 °C. HPLC: R t = 10.164 min, 99.46%; Mobile phase-A: 0.05% TFA:acetonitrile (95:05); Mobile phase-B: acetonitrile:0.05% TFA (95:05); Program: T / B%: 0.01 / 10, 12 / 90, 16 / 90, Flow: 1.0 mL / min; Diluent: ACN:water. 1H NMR (400MHz, DMSO-d6) δ9.33(t,1H),7.85(d,1H),7.81(d,1H),7.18(d,2H),7.04(d,2) H),4.41(d,2H),3.38(s,3H),1.93-1.83(m,1H),0.96-0.88(m,2H),0.66-0.59(m,2H).

[0187] Example 33. Synthesis of N-(4-(tert-butyl)benzyl)-5-(N-methylsulfonyl)thiophene-2-carboxamide (Compound 32): [ka] To a stirred reaction mixture of 5-methylsulfonylthiophene-2-carboxylic acid (0.15 g, 0.7300 mmol) and a16 (0.18 g, 1.12 mmol) in DCM (5.00 mL) was added HATU (0.41 g, 1.09 mmol) followed by DIPEA (0.25 mL, 1.45 mmol) at 0° C., and stirring was then continued for an additional 1 h at 0° C. The reaction mixture was concentrated under reduced pressure and then diluted by adding water (10.0 mL), and the reaction mixture was then extracted with EtOAc (2×25 mL), and the combined extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude residue (220 mg) as a colorless viscous liquid. The resulting crude product was purified by Combi-Flash column chromatography (100-200 silica gel) eluting with 0-40% EtOAc in hexane to give 32 (114 mg, 0.32 mmol, 43% yield) as a solid. LCMS: 350.20 (M−H), R t = 2.004 min, Column: X-SELECT CSH C18 (50*3) mm 2.5u; Mobile phase: A: 2.5 mM ammonium bicarbonate solution; B: acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Column oven temperature: 50 °C, Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, B concentration is 0% from 3.2 min to 4.0 min. HPLC: R t= 10.56 min, 98.42%, Me. Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Program: T / B%: 0.01 / 20, 12 / 90, 16 / 90. Flow rate: 1.0 mL / min; Diluent: water:ACN. 1 H NMR (400MHz, DMSO-d6) δ9.34(t, 1H), 7.86(d, 1H), 7.81(d, 1H), 7.35(s, 1H), 7.24(m, 2H), 4.43(d, 2H), 3.37(s, 3H), 1.26(s9H).

[0188] Example 34. Synthesis of 5-(N-methylsulfonyl)-N-(4-(trifluoromethyl)benzyl)thiophene-2-carboxamide (Compound 33): [ka] To a stirred reaction mixture of 5-methylsulfonylthiophene-2-carboxylic acid (0.15 g, 0.7273 mmol) and a17 (0.18 g, 1.04 mmol) in DCM (5 mL) was added HATU (0.41 g, 1.09 mmol) followed by DIPEA (0.1880 mg, 1.45 mmol) at 0° C., and stirring was continued for an additional 1 h at 0° C. The reaction mixture was concentrated under reduced pressure and then diluted by adding water (10.0 mL), the reaction mixture was then extracted with EtOAc (2×25 mL), and the combined extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude residue (250 mg) as a colorless viscous liquid. The resulting crude product was purified by Combi-Flash column chromatography (100-200 silica gel) eluting with 0-40% EtOAc in hexane to give 33 (121 mg, 0.33 mmol, 45% yield) as a solid. LCMS: 362.10 (M−H), R t = 2.206 min, Column: X-SELECT CSH C18 (50*3) mm 2.5u; Mobile phase: A: 2.5 mM ammonium bicarbonate solution; B: acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Column oven temperature: 50 °C, Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, B concentration 0% from 3.2 min to 4.0 min. HPLC: R t= 10.211 min, 98.63%. Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 0.05% TFA:acetonitrile (95:05); Mobile phase B: acetonitrile:0.05% TFA (95:05); Program: T / B%: 0.01 / 10, 12 / 90, 16 / 90, Flow rate: 1.0 mL / min; Diluent: ACN:water. 1 H NMR (400MHz, DMSO-d6) δ9.50(t,1H),7.88(d,1H),7.83(d,1H),7.71(d,2H),7.54(d,2H),4.57(d,2H),3.39(s,3H).

[0189] Example 35. Synthesis of 5-(methylsulfonyl)-N-(4-(2,2,2-trifluoroethoxy)benzyl)thiophene-2-carboxamide (Compound 34): [ka] To a stirred reaction mixture of 5-methylsulfonylthiophene-2-carboxylic acid (0.15 g, 0.7273 mmol) and a18 (0.1829 g, 0.8914 mmol) in DCM (20 mL) was added HATU (0.41 g, 1.09 mmol) followed by DIPEA (0.1880 mg, 1.45 mmol) at 0 °C, and stirring was continued for an additional 1 h at 0 °C. The reaction mixture was concentrated under reduced pressure and then diluted by adding water (10.0 mL), and the reaction mixture was then extracted with EtOAc (2 × 25 mL). The combined extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude residue (270 mg) as a viscous liquid. The resulting crude product was purified by Combi-Flash column chromatography (100-200 silica gel) eluting with 0-40% EtOAc in hexane to give 34 (211 mg, 0.52 mmol, 72% yield) as a solid. LCMS: 392.15 (M−H), R t= 1.891 min, Column: X-SELECT CSH C18 (50*3) mm 2.5u; Mobile phase: A: 2.5 mM ammonium bicarbonate solution; B: acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Column oven temperature: 50 °C, Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, B concentration is 0% from 3.2 min to 4.0 min. HPLC: R t = 8.084 min, 97.87%. Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 i); Mobile phase A: 0.1% formic acid in water; Mobile phase B: acetonitrile; Program: T / B%: 0.01 / 5, 1.0 / 5, 8.0 / 100, 12.0 / 100, 14.0 / 5, 18.0 / 5; Flow rate: 1.0 mL / min; Diluent: ACN:water. 1 H NMR (400MHz, DMSO-d6) δ9.35(t,1H),7.85(d,1H),7.81(d,1H),7.28(d,2H),7.06-7.00(m,2H),4.73(q,H),4.42(d,2H),3.38(s,3H).

[0190] Example 36. Synthesis of 5-(N-methylsulfamoyl)-N-(4-(2,2,2-trifluoroethoxy)benzyl)thiophene-2-carboxamide (Compound 35): [ka] To a stirred solution of a3 (200 mg, 0.9040 mmol) in DMF (10 mL) was added DIPEA (323 mg, 2.499 mmol), HATU (443 mg, 1.1651 mmol), followed by the corresponding amine (244 mg, 1.1892 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 0%-35%-90% EtOAc in heptane as the eluent to give the title compound 35 (95 mg, 0.23 mmol, 25% yield). LCMS: 409.00 (M+H), R t= 2.066 min, Column: X-SELECT CSH C18 (50*3) mm 2.5u; Mobile phase: A: 2.5 mM ammonium bicarbonate solution; B: acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Column oven temperature: 50 °C, Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, B concentration 0% from 3.2 min to 4.0 min. HPLC: R t = 9.51 min, 97.73%, Column: X SELECT CSH C18 (150 x 4.6 mm, 3.5 u); Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Program: T / B %; 0.01 / 2, 2 / 2, 12 / 90, 16 / 90; Flow: 1.0 mL / min; Diluent: ACN:water. 1 H NMR (400 MHz, DMSO-d) δ 9.30 (t, 1H), 7.80 (d, 2H), 7.57 (d, 1H), 7.28 (d, 2H), 7.03 (d, 2H), 4.79-4.67 (m, 2H), 4.41 (d, 2H), merged with 3H solvent peak.

[0191] Example 37. Synthesis of 5-(N-methylsulfamoyl)-N-(4-(1-trifluoromethyl)cyclopropyl)benzyl)thiophene-2-carboxamide (Compound 36): [ka] Synthesis of 4-(1-(trifluoromethyl)cyclopropyl)benzonitrile (a20): To a stirred solution of a19 (3 ​​g, 11.32 mmol) in DMF (15 mL) under an argon atmosphere, zinc cyanide (0.9256 g, 7.9111 mmol) and Pd(PPh3)4 (0.78 g, 0.6800 mmol) were added. The reaction mixture was then stirred at 80 °C overnight. The reaction mixture was cooled to room temperature, followed by the addition of ZnCN2 (0.93 g, 7.91 mmol) and Pd(PPh3)4 (0.78 g, 0.6800 mmol). The reaction mixture was stirred at 120 °C for 5 h. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with DMF. The filtrate was concentrated under reduced pressure, ethyl acetate was added, washed twice with 2 M aqueous ammonia solution, then washed with saturated aqueous sodium chloride solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to give a20 (1 g, 4.69 mmol, yield 41%).

[0192] Synthesis of (4-(1-(trifluoromethyl)cyclopropyl)phenyl)methanamine (a21): To a stirred solution of a20 (800 mg, 3.79 mmol) in MeOH (16 mL), Raney Nickel (659 mg, 11.36 mmol) was added and hydrogenated (100 psi) at room temperature for 3 hours. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give a21 (244 mg, 1.13 mmol, 29% yield).

[0193] Synthesis of 5-(N-methylsulfamoyl)-N-(4-(1-trifluoromethyl)cyclopropyl)benzyl)thiophene-2-carboxamide (compound 36): To a stirred solution of a3 (160 mg, 0.72 mmol) in DCM (15 mL) was added DIPEA (0.44 mL, 2.5 mmol) and HATU (443 mg, 1.17 mmol) at 0 °C and stirred for 10 min, followed by the addition of a21 (244 mg, 1.13 mmol) at the same temperature. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography using 0% to 90% EtOAc in heptane as the eluent to give 36 (67.4 mg, 0.1567 mmol, 22% yield). HPLC: Rt 10.491 min, 97.29%; Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Program: T / B%: 0.01 / 20, 12 / 90, 16 / 90. Flow rate: 1.0 mL / min, Diluent: ACN:water. LCMS: 417.15 (MH), Rt 2.088 min, Column: X-SELECT CSH C18 (50*3) mm 2.5 u; Mobile phase: A: 2.5 mM ammonium bicarbonate in water; B: acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Column oven temperature: 50 °C, Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, B concentration 0% from 3.2 min to 4.0 min. 1 H NMR (400MHz, DMSO-d6) δ9.33(t,1H),7.85-7.78(m,2H),7.58(d,1H),7.43(d, 2H),7.33(d,2H),4.46(d,2H),2.58-2.52(m,3H),1.38-1.27(m,2H),1.09(br s,2H).

[0194] Example 38. Synthesis of 5-(methylsulfonyl)-N-(4-(1-trifluoromethyl)cyclopropyl)benzyl)thiophene-2-carboxamide (Compound 37): [ka] To a stirred solution of a4 (50 mg, 0.2400 mmol) in DCM (5 mL) was added DIPEA (0.08 mL, 0.48 mmol) and HATU (118 mg, 0.31 mmol) at 0 °C and stirred for 10 min, followed by the addition of a21 (52 mg, 0.24 mmol) at the same temperature. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel using 0% to 90% EtOAc in heptane as the eluent to give 37 (27.31 mg, 0.0647 mmol, 28% yield). HPLC: Rt 10.143 min, 95.60%; Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Program: T / B%: 0.01 / 20, 12 / 90, 16 / 90. Flow rate: 1.0 mL / min. Diluent: ACN:water. LCMS: 402.30 (MH), Rt 2.106 min. Column: X-SELECT CSH C18 (50*3) mm 2.5 u; Mobile phase: A: 2.5 mM ammonium bicarbonate in water; B: acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min. Column oven temperature: 50 °C. Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, B concentration 0% from 3.2 min to 4.0 min. 1 H NMR (400MHz, DMSO-d6) δ9.41(t,1H),7.88-7.80(m,2H),7.43(d,2H),7.27(d,2H),4.46(d,2H),3.38(s,3H),1.36-1.28(m,2H),1.08(br s,2H).

[0195] Example 39. Synthesis of N-(4-(2-cyanopropan-2-yl)benzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 38): [ka] Synthesis of 2-(4-(hydroxymethyl)benzyl)isoindoline-1,3-dione (a24): To a stirred solution of a22 (1 g, 6.39 mmol) in MeCN (80 mL) was added a23 (1.32 g, 8.94 mmol) and 18-crown-6 (0.24 g, 0.89 mmol). The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was filtered, the filter cake was washed with ethyl acetate (50 mL), and the organic layer of the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (100-200 silica) using 20-30% ethyl acetate in hexane as the eluent to give a24 (1 g, 3.704 mmol, 58% yield) as a solid.

[0196] Synthesis of 2-(4-(bromomethyl)benzyl)isoindoline-1,3-dione (a25): To a stirred solution of a24 (1 g, 3.74 mmol) in DCM (20 mL) was added PPh3 (1.963 g, 7.48 mmol) and CBr4 (1.58 mL, 7.48 mmol) at 0 °C, and the reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (100-200 silica) using 20-30% ethyl acetate in hexane as the eluent to give a25 (600 mg, 1.7627 mmol, 47% yield) as a solid.

[0197] Synthesis of 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)phenyl)acetonitrile (a26): To a stirred solution of a25 (500 mg, 1.51 mmol) in MeCN (10 mL) was added TMSCN (0.21 mL, 1.67 mmol) and CsCO (986.8 mg, 3.03 mmol) at room temperature, and stirring was continued at 80 °C for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The crude material was purified by column chromatography (100-200 silica) using 20-30% ethyl acetate in hexane as the eluent to give a26 (350 mg, 1.2034 mmol, 79% yield) as a solid.

[0198] Synthesis of 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)phenyl)-2-methylpropanenitrile (a27): To a stirred solution of a26 (200 mg, 0.72 mmol) in DMF (2 mL) at 0 °C, NaH (34.75 mg, 1.45 mmol) was added and stirred for 10 min, followed by the addition of iodomethane (0.09 mL, 1.45 mmol). The reaction mixture was then stirred at room temperature for 18 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (100-200 silica) using 30–40% ethyl acetate in hexane as the eluent to give a25 (70 mg, 0.1656 mmol, 23% yield) as a solid.

[0199] Synthesis of 2-(4-(aminomethyl)phenyl)-2-methylpropanenitrile (a28): To a stirred solution of a27 (70 mg, 0.23 mmol) in ethanol (0.2 mL) / DCM (1 mL) was added N2H4.HO (12.65 mg, 0.25 mmol), and stirring was continued overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The resulting crude product was diluted with aqueous NaOH (2 mL), extracted with diethyl ether (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a28 (20 mg, 0.07 mmol, 30% yield) as a liquid.

[0200] Synthesis of N-(4-(2-cyanopropan-2-yl)benzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (compound 38): To a stirred solution of a3 (190.47 mg, 0.86 mmol) in DCM (2 mL) was added DIPEA (0.2 mL, 1.15 mmol) and HATU (327 mg, 0.86 mmol) at 0 °C and stirred for 10 min, followed by the addition of a28 (100 mg, 0.57 mmol) at the same temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 5 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (100-200 silica) using 30–50% ethyl acetate in hexane as the eluent to give 38 (70 mg, 0.183 mmol, 32% yield). HPLC: Rt 7.693 min, 98.70%, Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 0.1% FA in water; Mobile phase B: acetonitrile; Program: T / B%: 0.01 / 5, 1 / 5, 8 / 100, 12 / 100, 14 / 5, 18 / 5, Flow rate: 1.2 mL / min. LCMS: Rt 378.90 (M+H), Rt 1.874 min, Column: X-SELECT C18 (50 × 3) mm, 2.5 μm. Mobile phase: A: 2.5 mM ammonium bicarbonate in water; B: acetonitrile; injection volume: 2 μL, flow rate: 1.2 mL / min; column oven temperature: 45 °C; gradient program: 0% B to 98% B in 2.0 min, held until 3.0 min, B concentration 0% from 3.2 min to 4.0 min. 1 H NMR (400MHz, DMSO-d) δ7.53(d,1H),7.50-7.45(m,2H),7.41(d,1H),7.40-7.36(m,2H),6.31(br s, 1H), 4.63 (d, 2H), 4.50-4.43 (m, 1H), 2.78 (d, 3H), 1.72 (s, 6H).

[0201] Example 40. Synthesis of N-(4-(2-cyanopropan-2-yl)benzyl)-5-(methylsulfonyl)thiophene-2-carboxamide (Compound 39): [ka] To a stirred solution of a4 (190.47 mg, 0.92 mmol) in DCM (2 mL) was added DIPEA (0.2 mL, 1.15 mmol) and HATU (327 mg, 0.86 mmol) at 0 °C and stirred for 10 min, followed by the addition of a28 (100 mg, 0.5700 mmol) at the same temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 5 mL). The combined organic phases were washed with water (10 mL), brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (100-200 silica) using 30–50% ethyl acetate in hexane as the eluent, followed by preparative HPLC to give 39 (60 mg, 0.1654 mmol, 29% yield). HPLC: Rt 7.660 min, 99.94%; Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase-A: 0.1% FA in water; Mobile phase-B: acetonitrile; Program: T / B%: 0.01 / 5, 1 / 5, 8 / 100, 12 / 100, 14 / 5, 18 / 5, Flow: 1.2 mL / min. LCMS: 363.1 (M+H), Rt 1.928 min. Column: X-Bridge BEH C-18 (3.0 × 50 mm, 2.5 μm); Mobile phase: A: 0.025% FA in water, B: ACN; T / B%: 0.01 / 2, 0.2 / 2, 2.2 / 98, 3 / 98, 3.2 / 2, 4 / 2; Flow rate: 1.2 ml / min (gradient); Column oven temperature: 50 °C. 1 H NMR (400MHz, CHLOROFORM-d) δ7.65(d,1H),7.52-7.42(m,3H),7.41-7.34(m,2H),6.35(br s,1H),4.63(d,2H),3.20(s,3H),1.72(s,6H).

[0202] Example 41. Synthesis of N-(4-isopropylamino)benzyl)-5-(N-methylsulfamoyl)thiophene-2-carboxamide (Compound 40): [ka] To a stirred solution of a3 (160 mg, 0.7200 mmol) in DCM (15 mL) was added DIPEA (0.44 mL, 2.5 mmol) and HATU (443 mg, 1.17 mmol) at 0 °C and stirred for 10 min, followed by the addition of the corresponding amine (244 mg, 1.49 mmol) at the same temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (15 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel using 0–90% EtOAc in heptane as the eluent, followed by preparative HPLC to give 40 (35 mg, 0.093 mmol, 13% yield). HPLC: Rt 8.43 min, 97.47%; Column: X SELECT CSH C18 (150 x 4.6 mm, 3.5 μm); Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Program: T / B%: 0.01 / 10, 12 / 90, 16 / 90; Flow rate: 1.0 mL / min; Diluent: water:ACN:DMSO. LCMS: 368.1 (M+H), Rt 1.505 min; Column: X-Bridge BEH C-18 (3.0 x 50 mm, 2.5 μm); Mobile phase: A: 0.025% FA in water, B: ACN; T / B%: 0.01 / 2, 0.2 / 2, 2.2 / 98, 3 / 98, 3.2 / 2, 4 / 2; Flow rate: 1.2 mL / min (gradient); Column oven temperature: 50 °C. 1 H NMR (400MHz, DMSO-d6) δ9.13(br t,1H),7.82-7.76(m,2H),7.56(d,1H),7.02(d,2H),6.51(d,2H),5.26(d,1H),4.28(d,2H),3.56-3.45(m,1H),2.52(br s,3H),1.10(d,6H).

[0203] Example 42. Synthesis of N-(4-isopropylamino)benzyl)-5-(N-methylsulfonyl)thiophene-2-carboxamide (Compound 41): [ka] To a stirred solution of a4 (160 mg, 0.7800 mmol) in DCM (15 mL) was added DIPEA (0.44 mL, 2.5 mmol) and HATU (443 mg, 1.17 mmol) at 0 °C and stirred for 10 min, followed by the addition of the corresponding amine (244 mg, 1.49 mmol) at the same temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 30 mL). The combined organic phases were washed with water (10 mL), brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel using 0% to 90% EtOAc in hexane as the eluent, followed by preparative HPLC to give 41 (60 mg, 0.16 mmol, 21% yield). HPLC: Rt 8.451 min, 96.42%; Column: X-SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Program: T / B%: 0.01 / 20, 12 / 90, 16 / 90; Flow rate: 1 mL / min; Diluent: water:ACN. LCMS: 353.0 (M+H), Rt 1.747 min; Column: X-SELECT CSH C18 (50 × 3) mm 2.5 μm; Mobile phase: A: 2.5 mM ammonium bicarbonate in water; B: acetonitrile; Injection volume: 2 μL; Flow rate: 1.2 mL / min; Column oven temperature: 45 °C; Gradient program: 0% B to 98% B in 2.0 min, hold to 3.0 min, B concentration 0% from 3.2 to 4.0 min. 1 H NMR (400MHz, DMSO-d6)δ9.20(br t,1H),7.85(d,1H),7.79(d,1H),7.02(d,2H),6.51(d,2H),5.27(d,1H),4.29(d,2H),3.56-3.45(m,1H),3.37(s,3H),1.10(d, 6H).

[0204] Example 43. Synthesis of N-(2-fluoro-4-(trifluoromethyl)benzyl)-5-(methylsulfonyl)thiophene-2-carboxamide (Compound 42): [ka] To a stirred solution of a4 (300 mg, 1.45 mmol) and a29 (337.13 mg, 1.75 mmol) in DCM (10 mL) was added DIPEA (0.38 mL, 2.18 mmol) and HATU (829.63 mg, 2.18 mmol) at 0 °C, and the reaction was stirred at 0 °C for 1 h. The reaction mixture was concentrated to dryness, and the resulting residue was diluted with EtOAc (30 mL), washed with water (10 mL), followed by saturated brine solution (10 mL), dried over MgSO, and concentrated under reduced pressure. The crude product was then purified by flash column chromatography eluting with 60% EtOAc / heptane to give 42 (208 mg, 0.54 mmol, 37% yield). HPLC: Rt 8.270 min, 99.99%; Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase-A: 0.1% FA in water; Mobile phase-B: acetonitrile; Program: T / B%: 0.01 / 5, 1 / 5, 8 / 100, 12 / 100, 14 / 5, 18 / 5; Flow: 1.2 mL / min. 1 H NMR (400 MHz, DMSO- d 6) δ9.47(t,1H),7.89(d,1H),7.83(d,1H),7.69(d,1H),7.64-7.55(m,2H),4.58(d,2H),3.38(s,3H).

[0205] Example 44. Synthesis of N-(2-fluoro-4-(trifluoromethyl)benzyl)-5-(methylsulfamoyl)thiophene-2-carboxamide (Compound 43): [ka] To a stirred solution of a3 (300 mg, 1.36 mmol) and a29 (314.26 mg, 1.63 mmol) in DCM (10 mL) was added DIPEA (0.35 mL, 2.03 mmol) and HATU (773.35 mg, 2.03 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated to dryness, and the resulting residue was diluted with EtOAc (30 mL), washed with water (10 mL), followed by saturated brine solution (10 mL), dried over MgSO, and concentrated under reduced pressure. The crude product was then purified by flash column chromatography eluting with 60% EtOAc / heptane to give 43 (139.34 mg, 0.3503 mmol, 25.8% yield). HPLC: Rt 8.266 min, 99.67%; Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase-A: 0.1% FA in water; Mobile phase-B: acetonitrile; Program: T / B%: 0.01 / 5, 1 / 5, 8 / 100, 12 / 100, 14 / 5, 18 / 5; Flow: 1.2 mL / min. 1 H NMR (400MHz, DMSO-d6) δ9.41(t,1H),7.86-7.79(m,2H),7.68(d,1H),7.64-7.56(m,3H),4.57(d,2H),2.52(br d,3H).

[0206] Example 45. Synthesis of N-(2-methyl-4-(trifluoromethyl)benzyl)-5-(methylsulfonyl)thiophene-2-carboxamide (Compound 44): [ka] To a stirred solution of a4 (245.29 mg, 1.19 mmol) and a30 (150 mg, 0.79 mmol) in DCM (5 mL) was added DIPEA (0.41 mL, 2.38 mmol) and HATU (452.22 mg, 1.19 mmol), and the reaction was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 25 mL). The combined organic layers were washed with water (50 mL), brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel using 30% to 50% EtOAc in hexanes as the eluent to give 44 (130 mg, 0.33 mmol, 41% yield). HPLC: Rt 7.799 min, 95.115%; Column: X Select CSH C18 (150 x 4.6) mm, 3.5 μm; Mobile phase A: 0.1% FA in water:ACN (95:05); Mobile phase B: acetonitrile; Gradient program: T / B%: 0.01 / 5, 1 / 5, 8 / 100, 12 / 100, 14 / 5, 18 / 5; Flow rate: 1.2 ml / min. LCMS: 378.0 (M+H), Rt 1.806 min, Column: X-Select CSH (3.0*50) mm 2.5u; Mobile phase: A: 0.05% formic acid in water:ACN (95:5); B: 0.05% formic acid in ACN; Injection volume: 2.0 μL, Flow rate: 1.2 mL / min; Column oven temperature: 50 °C, Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, B concentration 0% from 3.2 min to 4.0 min. 1 H NMR (400MHz, DMSO-d6) δ9.37(t,1H), 7.86-7.79(m,2H), 7.59-7.41(m,3H), 4.57(d,2H), 3.38(s,3H), 2.40(s,3H).

[0207] Example 46. Synthesis of N-(2-methyl-4-(trifluoromethyl)benzyl)-5-(methylsulfamoyl)thiophene-2-carboxamide (Compound 45): [ka] To a stirred solution of a30 (150 mg, 0.7900 mmol) and a3 (263.14 mg, 1.19 mmol) in DMF (5 mL) was added HATU (452.22 mg, 1.19 mmol) followed by DIPEA (0.41 mL, 2.38 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 25 mL). The combined organic layers were washed with water (50 mL), brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel using 50% to 90% EtOAc in hexane as the eluent to give 45 (90 mg, 0.22 mmol, 28% yield). HPLC: Rt 7.804 min, 96.260%; Column: X Select CSH C18 (150 × 4.6) mm, 3.5 μm; Mobile phase A: 0.1% FA in water:ACN (95:05); Mobile phase B: acetonitrile; Gradient program: T / B%: 0.01 / 5, 1 / 5, 8 / 100, 12 / 100, 14 / 5, 18 / 5; Flow rate: 1.2 mL / min. LCMS: 393.1 (M+H), Rt 2.559 min. Column: X-Bridge BEH C-18 (3.0 x 50 mm, 2.5 μm); Mobile phase: A: 0.025% FA in water, B: ACN; T / B%: 0.01 / 2, 0.2 / 2, 2.2 / 98, 3 / 98, 3.2 / 2, 4 / 2; Flow rate: 1.2 ml / min (gradient); Column oven temperature: 50°C. 1 H NMR (400MHz, METHANOL-d4) δ7.72(d,1H),7.56(d,1H),7.51-7.43(m,3H),4.62(s,2H),2.64(s,3H),2.45(s,3H).

[0208] Example 47. Synthesis of 5-(methylsulfonyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)thiophene-2-carboxamide (Compound 46): [ka] To a stirred solution of a4 (300 mg, 1.45 mmol) and a31 (307.46 mg, 1.75 mmol) in DCM (10 mL) was added DIPEA (0.51 mL, 2.91 mmol) and HATU (829.63 mg, 2.18 mmol) at 0 °C, followed by stirring at the same temperature for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting crude product was purified by combi-flash chromatography on silica gel using 0–40% EtOAc in hexane as the eluent to give 46 (253 mg, 0.69 mmol, 47% yield) as a solid. HPLC: Rt 6.612 min, 99.62%; Column: X Select CSH C18 (150 x 4.6) mm, 3.5 μm; Mobile phase A: 0.1% FA in water: ACN (95:05); Mobile phase B: acetonitrile; Gradient program: T / B%: 0.01 / 5, 1 / 5, 8 / 100, 12 / 100, 14 / 5, 18 / 5, Flow rate: 1.2 ml / min; LCMS: 365.0 (M+H), Rt 1.694 min, Mobile phase: A: 0.025% FA in water, B: ACN; T / B%: 0.01 / 2, 0.2 / 2, 2.2 / 98, 3 / 98, 3.2 / 2, 4 / 2, Flow rate: 1.2 ml / min (gradient); Column oven temperature: 50 °C. 1 H NMR (400MHz, DMSO-d6) δ9.52(t,1H),8.75(d,1H),8.01(dd,1H),7.92-7.81(m,3H),4.61(d,2H),3.38(s,3H).

[0209] Example 48. Synthesis of 5-(cyclopropylsulfonyl)-N-(4-(trifluoromethyl)benzyl)thiophene-2-carboxamide (Compound 47): [ka] To a stirred reaction mixture of a7 (250 mg, 1.08 mmol) and a32 (226.21 mg, 1.29 mmol) in DCM (10 mL) was added HATU (818.47 mg, 2.15 mmol) followed by DIPEA (0.56 mL, 3.23 mmol) at 0 °C, and then stirring was continued at the same temperature for another 2 h. The reaction mixture was quenched with water, and the aqueous layer was extracted with DCM (2 × 25 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (100-200 mesh) using 0–60% EtOAc in heptane as the eluent to give 47 (348 mg, 0.8803 mmol, 81% yield) as a solid. HPLC: Rt 7.264 min, 98.52%; Column: X-Select CSH C18 (4.6*150) mm, 3.5 μm; Mobile phase: A - 0.1% formic acid in water: acetonitrile (95:05); B - acetonitrile; Flow rate: 1.0 mL / min; Gradient program: Time (min) / B concentration: 0.01 / 10, 6.0 / 90, 10.0 / 100, 12.0 / 100, 14 / 10, 18.0 / 10. LCMS: 388.05 (MH), Rt 1.873 min, Column: X-Bridge BEH C18 (50*3) mm 2.5u, Mobile phase: A: 2.5 mM ammonium bicarbonate in water; B: acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Column oven temperature 50 °C, Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, B concentration 0% from 3.2 min to 4.0 min. 1 H NMR (400MHz, DMSO-d6) δ9.53(t,1H),7.90(d,1H),7.82(d,1H),7.72(d,2H),7.55(br d,2H),4.57(br d,2H),3.07-2.99(m,1H),1.22-1.09(m,4H).

[0210] Example 49. Synthesis of 5-(methylsulfonyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)thiophene-2-carboxamide (Compound 48): [ka] To a stirred reaction mixture of a4 (250 mg, 1.21 mmol) and a33 (255 mg, 1.45 mmol) in DCM (10 mL) was added HATU (921.81 mg, 2.42 mmol) followed by DIPEA (0.63 mL, 3.64 mmol) at 0 °C, and stirring was continued at the same temperature for another 2 h. The reaction mixture was quenched with water (20 mL), and the aqueous layer was extracted with DCM (2 × 25 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (100-200 mesh) using 0–80% EtOAc in heptane as the eluent to give 48 (437 mg, 1.19 mmol, 97% yield) as a solid. HPLC: Rt 6.106 min, 98.81%; Column: X-Select CSH C18 (4.6*150) mm, 3.5 μm; Mobile phase: A - 0.1% formic acid in water: acetonitrile (95:05); B - acetonitrile; Flow rate: 1.0 mL / min; Gradient program: Time (min) / B concentration: 0.01 / 10, 6.0 / 90, 10.0 / 100, 12.0 / 100, 14 / 10, 18.0 / 10. LCMS: 364.90 (M+H), Rt 1.713 min, Column: X-Bridge BEH C18 (50*3) mm 2.5u, Mobile phase: A: 2.5 mM ammonium bicarbonate in water; B: acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Column oven temperature 50 °C, Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, B concentration 0% from 3.2 min to 4.0 min. 1 H NMR (400 MHz, DMSO-d6) 1 H NMR1H (400MHz, DMSO-d6) δ=9.62(br t,1H),8.93(s,1H),8.20(dd,,1H),7.92(d,1H),7.85(d,1H),7.59(d,1H),4.67(br d,2H),3.40(s,3H).

[0211] Example 50. Synthesis of 5-(ethylsulfonyl)-N-(4-(trifluoromethyl)benzyl)thiophene-2-carboxamide (Compound 49) [ka] To a stirred solution of a11 (180 mg, 0.8200 mmol) in DCM (3 mL) was added a34 (143.13 mg, 0.82 mmol) and HATU (310.72 mg, 0.82 mmol), followed by DIPEA (0.28 mL, 1.63 mmol) at 0 °C, and stirring was continued for another 1 h at 0 °C. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 25 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting crude product was purified by Combi-Flash chromatography on silica gel using 0–40% EtOAc in hexane as the eluent to give 49 (70 mg, 0.18 mmol, 22% yield) as a solid. HPLC: Rt 7.879 min, 98.28%, Column: X-Select CSH C18 (4.6*150) mm 5u; Mobile phase: A - 0.1% TFA in water; B - acetonitrile; Injection volume: 5.0 μL, Flow rate: 1.2 mL / min; Gradient program: Time (min) / B concentration: 0.01 / 5, 1.0 / 5, 8.0 / 100, 12.0 / 100, 14.0 / 5, 18.0 / 5. LCMS: 376.2 (MH), Rt 2.037 min, Column: X-Bridge BEH C18 (50*3) mm 2.5u; Mobile phase: A: 2.5 mM ammonium bicarbonate in water; B: acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Column oven temperature 50 °C, Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, B concentration 0% from 3.2 min to 4.0 min. 1 H NMR (400MHz, DMSO-d6) δ9.50(t,1H),7.90(d,1H),7.81(d,1H),7.71(d,2H),7.54(d,2H),4.56(d,2H),3.44(q,2H),1.18(t,3H).

[0212] Example 51. Synthesis of 5-(isopropylsulfonyl)-N-(4-(trifluoromethyl)benzyl)thiophene-2-carboxamide (Compound 50) [ka] Synthesis of methyl 5-(isopropylsulfonyl)thiophene-2-carboxylate (a36): To a stirred solution of a5 (1 g, 4.52 mmol) in DMSO (30 mL), a35 (1 g, 7.8 mmol), L-proline (208.31 mg, 1.81 mmol), copper iodide (343.78 mg, 1.81 mmol), followed by CsCO (294.77 mg, 0.9000 mmol) were added at room temperature, and stirring was continued at 95 °C for an additional 16 h. The reaction mixture was cooled to room temperature and then diluted with water (30 mL) and EtOAc (30 mL), and the resulting crude product was filtered through a Celite pad. The filtrate was separated, the aqueous layer was washed with EtOAc (30 mL), and the combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a crude residue. The resulting crude product was purified by flash column chromatography eluting with 20% EtOAc in hexane to give a36 (100 mg, 0.40 mmol, 9% yield) as a solid.

[0213] Synthesis of 5-(isopropylsulfonyl)thiophene-2-carboxylic acid (a37): To a stirred solution of a36 (100 mg, 0.40 mmol) in THF (4 mL) and water (1 mL) was added LiOH (48 mg, 1.2 mmol) at room temperature, and stirring was continued at the same temperature for 2 h. The reaction mixture was acidified with 2 M HCl and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give a37 (75 mg, 0.32 mmol, 79% yield), which was used in the next step without further purification.

[0214] Synthesis of 5-(isopropylsulfonyl)-N-(4-(trifluoromethyl)benzyl)thiophene-2-carboxamide (compound 50): To a stirred reaction mixture of a37 (70 mg, 0.3 mmol) and a34 (62.8 mg, 0.36 mmol) in DCM (5 mL) was added HATU (227.2 mg, 0.6 mmol) followed by DIPEA (0.16 mL, 0.90 mmol) at 0 °C, and then stirring was continued for another 2 h at the same temperature. The reaction mixture was quenched with water (10 mL), and the aqueous layer was extracted with DCM (2 × 25 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (100–200 mesh) using 0–60% EtOAc in heptane as the eluent to give 50 (38 mg, 0.095 mmol, 31% yield) as a solid. HPLC: Rt 10.47 min, 98.21%, Column: X-SELECT; Program: T / B%: 0.01 / 20, 12 / 90, 16 / 90; Flow: 1.0 mL / min; Diluent: ACN:water (80:20). LCMS: 391.90 (MH), Rt 2.055 min, Column: X-Select CSH C18 (3.0*50) mm 2.5 μL; Mobile phase: A: 0.05% formic acid in water:ACN (95:05); B:ACN; Injection volume: 2.0 μL; Flow rate: 1.2 mL / min; Column oven temperature: 50 °C. Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, B concentration 0% from 3.2 min to 4.0 min. 1 H NMR (400MHz, DMSO-d6) δ9.51(t,1H),7.92(d, 1H),7.79(d,1H),7.71(d,2H),7.55(d, 2H),4.56(d,2H),3.53(quin,1H),1.23(d,6H).

[0215] Example 52. Synthesis of N-(4-difluoromethyl)benzyl)-5-(methylsulfonyl)thiophene-2-carboxamide (Compound 51): [ka] To a stirred solution of a4 (200 mg, 0.97 mmol) and a38 (167.65 mg, 1.07 mmol) in DCM (5 mL) was added HATU (553.09 mg, 1.45 mmol) followed by DIPEA (0.51 mL, 2.91 mmol) at 0 °C, and stirring was continued for another 1 h at the same temperature. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel using 30–40% EtOAc in heptane as the eluent to give 51 (180 mg, 0.52 mmol, 53% yield) as a solid. HPLC: Rt 7.047 min, 99.416%; Column: X-Select CSH C18 (150 x 4.6) mm, 3.5 μm; Mobile phase A: 0.1% FA in water:ACN (95:05); Mobile phase B: acetonitrile; Gradient program: T / B%: 0.01 / 5, 1 / 5, 8 / 100, 12 / 100, 14 / 5, 18 / 5, Flow rate: 1.2 ml / min. LCMS: 345.80 (M+H), Rt 1.692 min, Column: X-Select CSH (3.0*50) mm. 2.5 μL; Mobile phase: A: 0.05% formic acid in water: ACN (95:5); B: ACN; Injection volume: 2.0 μL; Flow rate: 1.2 mL / min; Column oven temperature: 50 °C; Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min; B concentration was 0% from 3.2 min to 4.0 min. 1 H NMR (400MHz, DMSO-d6) δ9.47(t,1H),7.89(d,1H),7.84(d,1H),7.56(d,2H),7.47(d,2H),7.03(t,1H),4.55(d,2H),3.40(s,3H).

[0216] Example 53. Synthesis of 5-((2-methoxyethyl)sulfonyl)-N-(4-(trifluoromethyl)benzyl)thiophene-2-carboxamide (Compound 52) [ka] Synthesis of 5-bromothiophene-2-carboxylic acid (a39) To a stirred solution of a5 (5 g, 22.62 mmol) in THF (45 mL) and water (20 mL) was added LiOH.HO (1.9 g, 45.23 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and diluted with water (20 mL). The aqueous layer was washed with DCM (20 mL) and acidified using 2 N HCl (20 mL). The resulting precipitate was filtered and dried to give a39 (4.9 g, 20.826 mmol, 92% yield) as a solid.

[0217] Synthesis of 5-bromo-N-(4-(trifluoromethyl)benzyl)thiophene-2-carboxamide (a41) To a stirred solution of a39 (1.5 g, 7.24 mmol) and a40 (1.52 g, 8.69 mmol) in DCM (50 mL) was added HATU (4.13 g, 10.87 mmol) followed by DIPEA (2.52 mL, 14.49 mmol) at 0 °C, and stirring was continued for an additional 1 h at 0 °C. The reaction mixture was quenched with water (20 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting crude product was purified by Combi-Flash column chromatography (100–200 silica gel) eluting with 0–40% EtOAc in hexane to give a41 (2.32 g, 6.37 mmol, 87% yield) as a solid.

[0218] Synthesis of 5-((2-methoxyethyl)thio)-N-(4-(trifluoromethyl)benzyl)thiophene-2-carboxamide (a43) To a stirred solution of a41 (600 mg, 1.65 mmol) in 1,4-dioxane (10 mL) was added a42 (303.67 mg, 3.3 mmol) and DIPEA (0.86 mL, 4.94 mmol). The reaction mixture was degassed under N2 atmosphere for 20 min, after which tris(dibenzylidene-acetone)dipalladium(0) (150.87 mg, 0.16 mmol) and 1,1'-ferrocenediyl-bis(diphenylphosphine) (182.67 mg, 0.33 mmol) were added. The reaction mixture was microwaved at 110 °C for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting crude product was then purified by combi-flash using 10-20% EtOAc / hexane as the eluent to give a43 (510 mg, 1.3584 mmol, 82% yield) as a solid.

[0219] Synthesis of 5-((2-methoxyethyl)sulfonyl)-N-(4-(trifluoromethyl)benzyl)thiophene-2-carboxamide (compound 52): To a stirred solution of a43 (400 mg, 1.07 mmol) in DCM (10 mL) was added a portion of m-CPBA (551.59 mg, 3.2 mmol) at 0 °C, followed by stirring at room temperature for 2 h. The reaction mixture was quenched with water (20 mL), and the aqueous layer was extracted with DCM (2 × 25 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude product was purified by Combi-Flash column chromatography (100-200 silica gel) eluting with 0–40% EtOAc in hexane to give 52 (303.33 mg, 0.7428 mmol, 69% yield) as a solid. HPLC: Rt 9.378 min, 99.77%; Column: X-Select CSH C18 (150x4.6mm, 3.5μm; Mobile phase A: 5mM NH4HCO 3、Mobile phase B: acetonitrile; gradient program: T / B%: 0.01 / 20, 12 / 90, 16 / 90, flow rate: 1 mL / min. Diluent: ACN:water (20:80). LCMS: 406.20 (MH), Rt: 2.242 min. Column: X-Bridge BEH C18 (50*3) mm 2.5 u; Mobile phase: A: 2.5 mM ammonium bicarbonate in water; B: acetonitrile; injection volume: 2 μL, flow rate: 1.2 mL / min. Column oven temperature: 45 °C. Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, B concentration 0% from 3.2 min to 4.0 min. 1 H NMR(400MHz,DMSO-d6):δ9.49(t,1H),7.87(d,1H),7.80(d,1H),7.71(d,2H), 7.54(d,2H),4.56(d,2H),3.78-3.71(m,2H),3.70-3.64(m,2H),3.15(s,3H).

[0220] Example 54. Synthesis of N-(4-(difluoromethyl)-2-methylbenzyl)-5-(methylsulfonyl)thiophene-2-carboxamide (Compound 53): [ka] Synthesis of 4-(difluoromethyl)-2-methylbenzonitrile (a45): To a stirred solution of a44 (400 mg, 2.76 mmol) in DCM (4 mL) was added DAST (1.84 mL, 13.78 mmol) at 0 °C and stirring was continued at room temperature for 16 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with NaHCO3 solution 、 The crude product was then purified by flash column chromatography eluting with 8% EtOAc in isohexane to give a45 (410 mg, 1.96 mmol, 71% yield) as a liquid.

[0221] Synthesis of (4-(difluoromethyl)-2-methylphenyl)methanamine (a46): To a stirred solution of a45 (380 mg, 1.82 mmol) in THF (5 mL) was added LAH (2.73 mL, 5.46 mmol) dropwise at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with 15% NaOH solution (5 mL) and filtered through Celite. The filtrate was extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure to give a46 (310 mg, 0.52 mmol, 29% yield) as a solid.

[0222] Synthesis of N-(4-(difluoromethyl)-2-methylbenzyl)-5-(methylsulfonyl)thiophene-2-carboxamide (compound 53): To a stirred solution of a46 (300 mg, 0.510 mmol) and a4 (83 mg, 0.41 mmol) in DCM (3 mL) was added DIPEA (0.27 mL, 1.52 mmol) and HATU (232 mg, 0.61 mmol) at 0 °C, and stirring was continued at the same temperature for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The resulting crude product was purified by combi-flash chromatography on silica gel using 30% EtOAc in hexane as the eluent to give 53 (75 mg, 0.20 mmol, 40% yield) as a solid. HPLC: Rt 6.672 min, 97.783%; Method file: HPLC-FORMIC ACID-XSELECT-10-90-100.1 cm; Column: X-Select CSH C18 (4.6*150) mm, 3.5 u; Mobile phase: A - 0.1% formic acid in water:acetonitrile (95:05); B - acetonitrile; Flow rate: 1.0 mL / min; Gradient program: Time (min) / B concentration: 0.01 / 10, 6.0 / 90, 10.0 / 100, 12.0 / 100, 14 / 10, 18.0 / 10. LCMS: 359.90 (M+H), Rt 1.716 min, Column: X-Select CSH (3.0*50) mm 2.5u; Mobile phase: A: 0.05% formic acid in water: ACN (95:5); B: ACN, Injection volume: 2.0 μL, Flow rate: 1.2 mL / min; Column oven temperature: 50 °C, Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, B concentration 0% from 3.2 min to 4.0 min. 1 H NMR (400MHz, DMSO-d6): δ9.33(t,1H),7.91(d,1H),7.83(d,1H),7.40-7.37(m,3H),7.13-6.83(m,1H),4.50(d,2H),3.39(s,3H),2.38(s,3H).

[0223] Example 55. Synthesis of N((4-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-5-(methylsulfonyl)thiophene-2-carboxamide (Compound 54): [ka] To a stirred solution of a4 (117.13 mg, 0.57 mmol) and a47 (90 mg, 0.47 mmol) in DCM (3 mL) was added DIPEA (0.25 mL, 1.42 mmol) and HATU (269.92 mg, 0.71 mmol) at 0 °C, and stirring was continued at the same temperature for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The resulting crude product was then purified by combi-flash chromatography on silica gel using 0–40% EtOAc in hexane as the eluent to give 54 (80 mg, 0.2067 mmol, 43% yield) as a solid. HPLC: Rt 6.959 min, 97.8%; Column: X Select CSH C18 (150 × 4.6) mm, 3.5 μm; Mobile phase A: 0.1% FA in water:ACN (95:05); Mobile phase B: acetonitrile; Gradient program: T / B%: 0.01 / 5, 1 / 5, 8 / 100, 12 / 100, 14 / 5, 18 / 5; Flow rate: 1.2 ml / min. LCMS: 378.75 (M+H), Rt 1.668 min; Column: X-Select CSH (3.0*50) mm 2.5 u; Mobile phase: A: 0.05% formic acid in water: ACN (95:5); B: ACN, Injection volume: 2.0 μL, Flow rate: 1.2 mL / min; Column oven temperature: 50 °C, Gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, increase B concentration to 0% in 3.2 min. 1 H NMR (400MHz, DMSO-d6): δ 9.35 (br t, 1H), 8.60 (s, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.78 (s, 1H), 4.58 (br d, 2H), 3.38 (s, 3H), 2.46 (s, 3H).

[0224] Example 55. Efficacy of exemplary compounds in inhibiting KCNT1 KCNT1-patch clamp assay Inhibition of KCNT1 (KNa1.1, Slack) was evaluated using a tetracycline-inducible cell line (HEK-TREX). Currents were recorded using a SyncroPatch384PE automated patch clamp system. Pulse generation and data collection were performed with PatchController384 V1.3.0 and DataController384 V1.2.1 (Nanion Technologies). Access resistance and apparent membrane capacitance were estimated using built-in protocols. Currents were recorded from a population of cells in perforated patch mode (10 μM escin). Cells were lifted, triturated, and resuspended at 800,000 cells / mL. Cells were allowed to recover in a cell hotel before the experiment. Currents were recorded at room temperature. The external solution contained the following (in mM): NaCl 105, NMDG 40, KCl 4, MgCl 2 1, CaCl 2 5, and HEPES 10 (pH = 7.4, osmolarity approximately 300 mOsm). The extracellular solution was used as the wash solution, reference solution, and compound delivery solution. The internal solution contained the following (in mM): NaCl 70, KF 70, KCl 10, EGTA 5, HEPES 5, and Escin 0.01 (pH = 7.2, osmolarity approximately 295 mOsm). Escin was made into a 5 mM aqueous stock, aliquoted, and stored at -20°C. Compound plates were made at 2x concentrations in the extracellular solution. Compounds were diluted 1:2 when added to recording wells. The amount of DMSO in the extracellular solution was kept constant at the level used for the highest test concentration. A holding potential of -80 mV to 0 mV in 100 ms steps was used. The mean current was measured during the step to 0 mV. 100 μM Bepridil was used to completely inhibit KCNT1 currents, allowing offline subtraction of non-KCNT1 currents. The average mean current from three sweeps was calculated, and the % inhibition for each compound was calculated. The % inhibition as a function of compound concentration was fit with the Hill equation to determine the IC 50 , slope, minimum and maximum parameters were derived. If KCNT1 inhibition was less than 50% at the highest tested concentration, or IC 50 If it is not possible to calculate IC 50 Percent inhibition was reported instead of the mean.

[0225] The results from this assay are summarized in Table 1 below. In this table, "A" denotes an IC of 1 μM or less. 50 "B" indicates inhibition between 1 μM and 20 μM, and "C" indicates inhibition above 20 μM. [Table 1] TIFF0007824664000095.tif54170

[0226] Equivalents and Scope In the claims, articles such as "a," "an," and "the" can mean one or more, unless otherwise indicated to the contrary or clear from the context. A claim or description including "or" between one or more elements of a group is considered to be satisfied if one, more than one, or all of the group elements are present in, employed in, or relevant to a given product or process, unless otherwise indicated to the contrary or clear from the context. The invention includes embodiments in which exactly one element of a group is present in, employed in, or relevant to a given product or process. The invention includes embodiments in which two or more, or all, group elements are present in, employed in, or relevant to a given product or process.

[0227] Furthermore, the present invention encompasses all variations, combinations, and permutations, including the introduction into another claim of one or more limitations, elements, clauses, and recited terms from one or more of the enumerated claims. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends from the same base claim. Where elements are presented as a list, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element may be removed from the group. Generally, when the invention, or inventive aspects, are described as including certain elements and / or features, it should be understood that certain embodiments of the invention or inventive aspects consist of, or consist essentially of, such elements and / or features. For purposes of brevity, those embodiments have not been specifically described verbatim herein. It should also be noted that the terms "comprising" and "containing" are intended to be open-ended and permit the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can be considered to be any specific value or subrange within the stated ranges of different embodiments of the invention, to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0228] This application references various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. In addition, any particular embodiment of the present invention within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be deemed known to those of ordinary skill in the art and therefore may be excluded even if the exclusion is not expressly set forth herein. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0229] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above detailed description, but rather is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description can be made without departing from the spirit or scope of the present invention, as defined in the following claims. *****************************

Claims

1. A compound of formula A, 【Chemistry 1】 During the ceremony, A is phenyl or pyridyl; R １ is C １－６ Alkyl, C ３－８ cycloalkyl, and —NHR ａ wherein C is selected from the group consisting of １－６ Alkyl is C １－６ optionally substituted with alkoxy; R ａ is C １－６ Alkyl, C １－６ Alkylene -O-C １－６ Alkyl, C ３－８ cycloalkyl, or phenyl, wherein C ３－８ The cycloalkyl or phenyl may be one or more halogens, C １－６ Alkyl, C １－６ haloalkyl, or C １－６ optionally substituted with alkoxy; R ２ is hydrogen, R ３ and R ４ is hydrogen, and C １－６ alkyl, R ５ is halogen, cyano, —OH, —NR ｃ R ｄ , C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Alkylene -O-C １－６ Alkyl, C ３－８ cycloalkyl, and 4- to 8-membered heterocyclyl; １－６ Alkyl, C ３－８ The cycloalkyl or 4- to 8-membered heterocyclyl may be one or more of halogen, cyano, C １－６ Alkyl, C １－６ haloalkyl, or C １－６ optionally substituted with alkoxy; R ｃ and R ｄ are each independently hydrogen or C １－６ is alkyl, R ６ is C １－６ Alkyl or C １－６ is an alkoxy, t is 0, 1, 2, 3, or 4; and m is 0, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

2. A compound of formula A-1, formula A-2, or formula A-3, 【Chemistry 2】 During the ceremony, R １ is C １－６ Alkyl, C ３－８ cycloalkyl, and —NHR ａ wherein C is selected from the group consisting of １－６ Alkyl is C １－６ optionally substituted with alkoxy; R ａ is C １－６ Alkyl, C １－６ Alkylene -O-C １－６ Alkyl, C ３－８ cycloalkyl, or phenyl, wherein C ３－８ The cycloalkyl or phenyl may be one or more halogens, C １－６ Alkyl, C １－６ haloalkyl, or C １－６ optionally substituted with alkoxy; R ５ is halogen, cyano, —OH, —NR ｃ R ｄ , C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Alkylene -O-C １－６ Alkyl, C ３－８ cycloalkyl, and 4- to 8-membered heterocyclyl; １－６ Alkyl, C ３－８ The cycloalkyl or 4- to 8-membered heterocyclyl may be one or more of halogen, cyano, C １－６ Alkyl, C １－６ haloalkyl, or C １－６ optionally substituted with alkoxy; R ｃ and R ｄ are each independently hydrogen or C １－６ is alkyl, R ６ is C １－６ Alkyl or C １－６ is an alkoxy, t is 0, 1, 2, 3, or 4; and m is 0, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. R １ The pharmaceutical composition of claim 1 or 2, wherein is methyl, ethyl, or isopropyl.

4. R ａ The pharmaceutical composition according to claim 1 or 2, wherein is methyl.

5. R ５ is chloro, fluoro, bromo, cyano, —OH, methyl, ethyl, isopropyl, tert-butyl, —CHCF ２、 -CF ３ , -OCH ３ , -OCH ２ CH ３ , —OCH(CH— ３ ) ２、 -OCH ２ CF ３、 and -CF ３ cyclopropyl, optionally substituted with 、 The pharmaceutical composition according to any one of claims 1 to 4.

6. A compound of formula II, 【Transformation 3】 During the ceremony, R １ is C １－６ Alkyl, C ３－８ cycloalkyl, and —NHR ａ wherein C is selected from the group consisting of １－６ Alkyl is C １－６ optionally substituted with alkoxy; R ａ is C １－６ Alkyl, C １－６ Alkylene -O-C １－６ Alkyl, C ３－８ cycloalkyl, or phenyl, wherein C ３－８ The cycloalkyl or phenyl may be one or more halogens, C １－６ Alkyl, C １－６ haloalkyl, or C １－６ optionally substituted with alkoxy; R ２ is hydrogen, R ３ and R ４ is hydrogen, and C １－６ alkyl, R ５ is halogen, cyano, -OH, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Alkylene -O-C １－６ Alkyl, C ３－８ cycloalkyl, and 4- to 8-membered heterocyclyl; １－６ Alkyl, C ３－８ cycloalkyl 、 or 4-8 membered heterocyclyl may be one or more of halogen, cyano, C １－６ Alkyl, C １－６ haloalkyl, or C １－６ optionally substituted with alkoxy; R ６ is C １－６ Alkyl or C １－６ is an alkoxy, R ７ is halogen, cyano, -NR ｃ R ｄ , C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ３－８ cycloalkyl, and 4- to 8-membered heterocyclyl, １－６ Alkyl, C ３－８ cycloalkyl 、 or 4-8 membered heterocyclyl may be one or more of halogen, cyano, C １－６ Alkyl, C １－６ haloalkyl, or C １－６ optionally substituted with alkoxy; R ｃ and R ｄ are each independently hydrogen or C １－６ is alkyl, t is 0, 1, 2, or 3; and m is 0, or a pharmaceutically acceptable salt thereof.

7. Compounds of formula II-b: 【Chemistry 4】 During the ceremony, R １ is C １－６ Alkyl, C ３－８ cycloalkyl, and —NHR ａ wherein C is selected from the group consisting of １－６ Alkyl is C １－６ optionally substituted with alkoxy; R ａ is C １－６ is alkyl, R ２ is hydrogen, R ３ and R ４ is hydrogen, and C １－６ alkyl, R ５ is halogen, cyano, -OH, -C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Alkylene -O-C １－６ Alkyl, C ３－８ cycloalkyl, and 4- to 8-membered heterocyclyl; １－６ Alkyl, C ３－８ cycloalkyl 、 or 4-8 membered heterocyclyl may be one or more of halogen, cyano, C １－６ Alkyl, C １－６ haloalkyl, or C １－６ optionally substituted with alkoxy; R ６ is C １－６ Alkyl or C １－６ is an alkoxy, R ７ is halogen, cyano, -NR ｃ R ｄ , C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ３－８ cycloalkyl, and 4- to 8-membered heterocyclyl, １－６ Alkyl, C ３－８ cycloalkyl 、 or 4-8 membered heterocyclyl may be one or more of halogen, cyano, C １－６ Alkyl, C １－６ haloalkyl, or C １－６ optionally substituted with alkoxy; R ｃ and R ｄ are each independently hydrogen or C １－６ is alkyl, t is 0, 1, 2, or 3; and m is 0, or a pharmaceutically acceptable salt thereof.

8. R １ 8. The compound of claim 6 or 7, wherein is methyl, ethyl, isopropyl, or cyclopropyl.

9. R ａ The compound according to claim 6 or 7, wherein is methyl.

10. R ５ is chloro, fluoro, bromo, cyano, —OH, methyl, ethyl, isopropyl, tert-butyl, —CHCF ２、 -CF ３ , -OCH ３ , -OCH ２ CH ３ , —OCH(CH— ３ ) ２、 -OCH ２ CF ３、 and -CF ３ cyclopropyl, optionally substituted with 、 The compound according to any one of claims 6 to 9.

11. R ７ is chloro, bromo, cyano, methyl, ethyl, isopropyl, tert-butyl, -CHCF ２、 -CF ３ , -OCH ２ CH ３、 -OCH ２ CF ３、 and -CF ３ cyclopropyl optionally substituted with 、 The compound according to any one of claims 6 to 10.

12. R ７ The compound of any one of claims 6 to 10, wherein is a 4-8 membered heterocyclyl, said 4-8 membered heterocyclyl containing one nitrogen.

13. The compound is 【Transformation 5】 【change】 【change】 【change】 7. The compound of claim 6, which is selected from the group consisting of:

14. A compound of formula III, 【Transformation 6】 During the ceremony, R １ is C １－６ Alkyl, C ３－８ cycloalkyl, and —NHR ａ wherein C is selected from the group consisting of １－６ Alkyl is C １－６ optionally substituted with alkoxy; R ａ is C １－６ Alkyl, C １－６ Alkylene -O-C １－６ Alkyl, C ３－８ cycloalkyl, or phenyl, wherein C ３－８ The cycloalkyl or phenyl may be one or more halogens, C １－６ Alkyl, C １－６ haloalkyl, or C １－６ optionally substituted with alkoxy; R ２ is hydrogen, R ３ and R ４ is hydrogen, and C １－６ alkyl, R ５ is halogen, cyano, —OH, —NR ｃ R ｄ , C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Alkylene -O-C １－６ Alkyl, C ３－８ cycloalkyl, and 4- to 8-membered heterocyclyl; １－６ Alkyl, C ３－８ The cycloalkyl or 4- to 8-membered heterocyclyl may be one or more of halogen, cyano, C １－６ Alkyl, C １－６ haloalkyl, or C １－６ optionally substituted with alkoxy; R ｃ and R ｄ are each independently hydrogen or C １－６ is alkyl, R ６ is C １－６ Alkyl or C １－６ is an alkoxy, t is 0, 1, 2, or 3; and m is 0, or a pharmaceutically acceptable salt thereof.

15. R １ The compound of claim 14, wherein is methyl.

16. R ５ But, -CF ３ 16. The compound of claim 14 or 15,

17. The compound is 【Transformation 7】 15. The compound of claim 14 selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 【Request Item 18】 【Chemistry 8】 【change】 【change】 【change】 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising the compound according to any one of claims 6 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. 20. The pharmaceutical composition of any one of claims 1 to 4 and 19 for use in a method for treating a neurological disease or disorder, a disease or condition associated with excessive neural excitability, or a disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1).

21. 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 epilepsy, epilepsy syndrome, encephalopathy, hereditary or childhood epilepsy, hereditary or childhood epilepsy syndrome, cardiac dysfunction, infantile epilepsy 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 encephalopathy, 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, 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), itching and pruritus, ataxia, psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia), learning disabilities, fragile X, neuroplasticity, autism spectrum disorders, epileptic encephalopathies with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, 21. The pharmaceutical composition of claim 20, wherein the therapeutic agent is selected from the group consisting of generalized epilepsy with febrile seizures, intractable 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's encephalitis, malignant migratory partial seizures of infancy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

22. 20. A compound according to any one of claims 6 to 18 for use in a method for treating a neurological disease or disorder, a disease or condition associated with excessive neural excitability, or a disease or condition associated with a gain-of-function mutation in a gene (e.g. KCNT1).

23. 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 epilepsy, epilepsy syndrome, encephalopathy, hereditary or childhood epilepsy, hereditary or childhood epilepsy syndrome, cardiac dysfunction, infantile epilepsy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms Cancer, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, 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, 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, psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia), learning disabilities, fragile X, neuroplasticity, autism spectrum disorders, epileptic encephalopathies with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, 23. The compound of claim 22, selected from the group consisting of 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's encephalitis, malignant migratory partial seizures of infancy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

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