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 for treating neurological diseases or disorders, diseases or conditions associated with excessive neural excitability and / or gain-of-function mutations in genes such as KCNT1 are also provided herein.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 842,855, filed May 3, 2019, U.S. Provisional Patent Application No. 62 / 842,858, filed May 3, 2019, U.S. Provisional Patent Application No. 62 / 842,861, filed May 3, 2019, and U.S. Provisional Patent Application No. 62 / 982,858, filed February 28, 2020, the contents of each 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 [Means for solving the problem]

[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 II: [ka] or a pharmaceutically acceptable salt thereof, wherein: X is selected from the group consisting of NH, O, and S, and the hydrogen of NH may be replaced by R3; Y is selected from N and CH, and the hydrogen of CH may be replaced by R3; Z is selected from N and CH, and the hydrogen of CH may be replaced by R3, or when Z is replaced by a -C(O)N(R2)- moiety, Z is C; R1 is -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F 1-6 is selected from the group consisting of alkyl, R2 is hydrogen; Each R3 is halogen, C 1-6 Alkyl, C 1-6 independently selected from the group consisting of heteroalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, -S(O)2NR4R5, -NR4S(O)R6, -C(O)NR4R5, -S(O)2R6, and -O-R6; C 1-6 the alkyl is optionally substituted with one or more substituents independently selected from halogen, —NR4R5, and —S(O)2R6; n is selected from the group consisting of 0, 1, 2, 3, and 4; R4 and R5 are each independently hydrogen or C 1-6 alkyl, C 1-6 The alkyl is optionally substituted with oxo, or R4 and R5, together with the nitrogen to which they are attached, are selected from halogen, -OH, C 1-6 Alkyl, and C 1-6 may form a 4- to 7-membered heterocyclyl optionally substituted with one or more substituents independently selected from heteroalkyl; Each R6 is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-7 independently selected from the group consisting of cycloalkyl, phenyl, and benzyl; a compound of formula II, or a pharmaceutically acceptable salt thereof, wherein s is 1 or 2; and a pharmaceutically acceptable excipient.

[0005] In some embodiments, the compound of formula II is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for formula II.

[0006] In some embodiments, the compound of Formula II is a compound of Formula I-Ia or Formula I-Ia1: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula II.

[0007] In some embodiments, the compound of Formula II is a compound of Formula I-Ib or Formula I-Ib1: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula II.

[0008] In some embodiments, the compound of Formula II is a compound of Formula I-Ic or Formula I-Ic1: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula II.

[0009] In some embodiments, the compound of Formula II is a compound of Formula Ia or Formula I-a1: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula II.

[0010] In some embodiments, the compound of Formula II is a compound of Formula Ib or Formula I-b1: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula II.

[0011] In some embodiments, the compound of Formula II is a compound of Formula Ic or Formula I-c1: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula II.

[0012] In some embodiments, the compound of Formula II is a compound of Formula Id or Formula I-d1: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula II.

[0013] In another aspect, the present disclosure provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein: R1 is -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F 1-6 is selected from the group consisting of alkyl, R2 is hydrogen; R3 is halogen, C 1-6 Alkoxy, C 1-6Alkylene-S(O)2-C 1-6 Alkyl, -C(O)NR5R6, -NR7S(O)2C 1-6 Alkyl, -NR7S(O)2C 3-7 Cycloalkyl, -NR7S(O)2NR5R6, -NR9R 10 , -S(O)2-C 3-6 Cycloalkyl, -S(O)2-NR5R6, -S(O)2-C 1-6 Alkoxy, and -S(O)2-C 1-6 alkyl, independently selected from the group consisting of C 1-6 The alkyl may contain one or more halogens or C 1-6 optionally substituted with alkoxy; Each R4 is C 1-6 independently selected from the group consisting of alkyl, halogen, and -OH, and when R4 is -OH, R4 is substituted on the carbon adjacent to R3; n is selected from the group consisting of 0, 1, 2, 3, and 4; R5, R6, R9, and R 10 are each independently hydrogen or C 1-6 is alkyl, Each R7 is hydrogen, C 1-6 independently selected from the group consisting of alkyl, and 3- to 7-membered heterocyclyl; 1-6 Alkyl is halogen, C 1-6 Alkoxy, C 1-6 optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxy, —OH, —NR5R6, and —C(O)NR5R6; a compound of formula II, or a pharmaceutically acceptable salt thereof, wherein s is 1 or 2; and a pharmaceutically acceptable excipient.

[0014] In some embodiments, the compound of Formula II is a compound of Formula II-a, Formula II-a1, or Formula II-a2: [ka] or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the compound is a compound of Formula II-b, Formula II-b1, or Formula II-b2: [ka] or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the compound of Formula II is a compound of Formula II-c, Formula II-c1, or Formula II-c2: [ka] or a pharmaceutically acceptable salt thereof.

[0017] In another aspect, the present disclosure provides a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein: R1 is -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F 1-6 is selected from the group consisting of alkyl, R2 is hydrogen; R3 is hydrogen; R4 is C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Haloalkyl, -NR7S(O)2C 1-6 Alkyl, and NRC(O)-C 1-6 alkyl, n is selected from the group consisting of 0, 1, 2, 3, and 4; R7 and R8 are each independently hydrogen or C 1-6 is alkyl, a compound of formula III or a pharmaceutically acceptable salt thereof, wherein s is 1 or 2; and a pharmaceutically acceptable excipient.

[0018] In some embodiments, the compound of Formula III is a compound of Formula III-a, Formula III-a1, or Formula III-a2: [ka] or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the compound of Formula III is a compound of Formula III-b, Formula III-b1, or Formula III-b2: [ka] or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the compound of Formula III is a compound of Formula III-c, Formula III-c1, or Formula III-c2: [ka] or a pharmaceutically acceptable salt thereof.

[0021] In one aspect, the disclosure provides a method of treating a neurological disease or disorder, the method comprising administering to a subject a compound disclosed herein (e.g., a compound of Formula (II) or (I) (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), a compound of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), or a compound of formula (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2))), or a pharmaceutical composition disclosed herein (e.g., For example, a compound of formula (II) or (I) (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), a compound of formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), or a pharmaceutical composition comprising a compound of formula (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2))), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient) to a subject in need of treatment.

[0022] In another aspect, the disclosure provides a method for treating a disease or condition associated with excessive neural excitability, the method comprising administering to a subject a compound disclosed herein (e.g., a compound of Formula (II) or (I) (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), a compound of Formula (II), a compound of formula (III) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), or a compound of formula (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), or a pharmaceutical composition disclosed herein a compound of formula (II) or (I) (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), a compound of formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c ), (II-c1), (II-c2)), or a pharmaceutical composition comprising a compound of formula (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2))), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient) to a subject in need of treatment.

[0023] In another aspect, the 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 a compound disclosed herein (e.g., a compound of Formula (II) or (I) (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1) ), a compound of formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), or a compound of formula (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III ... The indicated pharmaceutical compositions (e.g., a compound of formula (II) or (I) (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), a compound of formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (I and administering to a subject in need of treatment a pharmaceutical composition comprising a compound of formula (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)) or a compound of formula (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2))), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[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 epilepsy, an epilepsy syndrome, or an encephalopathy.

[0025] 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 genetic or childhood epilepsy, or a genetic or childhood epilepsy syndrome.

[0026] 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.

[0027] 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., epilepsy of infancy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic 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).

[0028] In some embodiments, the neurological disease or disorder, disease or condition associated with excessive neural excitability, or disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from the group consisting of cardiac arrhythmia, sudden unexpected death in epilepsy, Brugada syndrome, and myocardial infarction.

[0029] 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.).

[0030] 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).

[0031] 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.

[0032] 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).

[0033] 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.

[0034] 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-onset epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, and infantile spasms. The epileptic encephalopathy is selected from the group consisting of malignant migratory partial seizures of infancy, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, 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.

[0035] 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

[0036] As generally described herein, the present invention provides compounds and compositions useful for preventing and / or treating the diseases, disorders, or conditions described herein, for example, 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., epilepsy of infancy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, and Lennox syndrome. Gastaut syndrome, seizures, leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic seizures, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia, asymmetric tonic seizures), 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, and psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia).

[0037] 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.

[0038] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture 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 (E.L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). Additionally, the invention encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0039] As used herein, a pure enantiomer 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%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 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.

[0040] In the compositions provided herein, enantiomerically pure compounds 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.

[0041] The compounds described herein may also contain one or more isotopic substitutions. For example, H may be: 1 H, 2 H (D or deuterium), and3 H (T or tritium), and C can be in any isotopic form. 12 C. 13 C, and 14 C can be any isotopic form, including O 16 O and 18 O may be any isotopic form, including F. 18 F and 19 It can be any isotopic form containing F, etc.

[0042] 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 an invention that 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. Also, as described herein, it should be understood that any of the moieties defined below can 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 should further be understood that the terms "group" and "radical" can be considered interchangeable when used herein. The articles "a" and "an" can 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 analog" means one analog or more than one analog.

[0043] When a range of values ​​is listed, it is intended to encompass each value and sub-range 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 , C3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0044] 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.

[0045] The term "heteroalkyl," as used herein, refers to an "alkyl" group in which at least one carbon atom has been replaced with an O or S atom. Heteroalkyl includes, for example, -O-C-C 10The heteroalkyl group may be an alkyl group, a -C1-C6 alkylene-O-C1-C6 alkyl group, or a C1-C6 alkylene-OH group. In certain embodiments, "heteroalkyl" may be a 2- to 8-membered heteroalkyl, indicating that the heteroalkyl contains 2 to 8 atoms selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. In still other embodiments, the heteroalkyl may be a 2- to 6-membered, 4- to 8-membered, or 5- to 8-membered heteroalkyl group (which may contain, for example, one or two heteroatoms selected from oxygen and nitrogen groups). In certain embodiments, the heteroalkyl is an "alkyl" group in which one to three carbon atoms are replaced with oxygen atoms. One type of heteroalkyl group is an "alkoxy" group.

[0046] 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 ("C2-3 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 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc.

[0047] 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 ("C2-4 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 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 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.

[0048] 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.

[0049] As used herein, "aryl" refers to a radical of a 4n+2 aromatic ring system ("C6-14 aryl") that is monocyclic or polycyclic (e.g., bicyclic or tricyclic) (e.g., having 6, 10, or 14 π electrons shared in the cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system. In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C6 aryl", e.g., phenyl). 10aryl," 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. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0050] 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 can be at a carbon or nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring defined above is fused to one or more carbocyclyl or heterocyclyl groups, with the point of attachment being 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 the heteroaryl ring defined above is fused to one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring, and in such instances the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. 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 that does not contain a heteroatom (e.g., 5-indolyl).

[0051] 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.

[0052] 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, 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.

[0053] Representative examples of heteroaryls include: [ka] wherein each Z is a carbonyl, N, NR65 , 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.

[0054] As used herein, "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 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 Included are 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 (C10 ), 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"), and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a 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, and in such instances the number of carbons continues to designate the number of carbons in the carbocyclic ring system.

[0055] 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 Cycloalkyl groups are referred to as "cycloalkyl." Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane. 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.

[0056] 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 can be at a carbon or nitrogen atom, valence permitting. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can 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, where in such instances the number of ring members continues to designate the number of ring members in the heterocyclyl ring system.

[0057] 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, In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0058] 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.

[0059] "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 nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the above hydrocarbyl groups, such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; or aryl, e.g., heteroaryl, having 1 to 5, especially 1 to 3, heteroatoms.

[0060] As used herein, "cyano" refers to --CN.

[0061] 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.

[0062] As used herein, "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0063] As used herein, "nitro" refers to --NO.sub.2.

[0064] As used herein, "oxo" refers to -C=O.

[0065] In general, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen present on the 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.

[0066] 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- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc The groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc , and R dd is as defined above.

[0067] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The invention is not intended to be limited in any way by the above exemplary list of substituents.

[0068] Other definitions The term "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is 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. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxy-ethanesulfonate. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1-4Representative 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.

[0069] 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.

[0070] Disease, disorder, and condition are used interchangeably herein.

[0071] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is afflicted with the specified disease, disorder, or condition and that reduce the severity of the disease, disorder, or condition or slow or delay the progression of the disease, disorder, or condition (also "therapeutic treatment").

[0072] In general, 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.

[0073] 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 refers to the 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 efficacy of another therapeutic agent.

[0074] 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 prevention or enhances the prophylactic efficacy of another prophylactic agent.

[0075] 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.

[0076] 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 assay or electrophysiology (e.g., using whole-cell patch clamp technique). Typically, a gain-of-function mutation results in an increase of at least or about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400% or more compared to the activity of the potassium channel encoded by wild-type KCNT1.

[0077] Compounds and Compositions In one aspect, the present disclosure provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein: X is selected from the group consisting of NH, O, and S, and the hydrogen of NH may be replaced by R3; Y is selected from N and CH, and the hydrogen of CH may be replaced by R3; Z is selected from N and CH, and the hydrogen of CH may be replaced by R3, or when Z is replaced by a -C(O)N(R2)- moiety, Z is C; R1 is -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F 1-6 is selected from the group consisting of alkyl, R2 is hydrogen; Each R3 is halogen, C 1-6 Alkyl, C 1-6 independently selected from the group consisting of heteroalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, -S(O)2NR4R5, -NR4S(O)R6, -C(O)NR4R5, -S(O)2R6, and -O-R6; C 1-6 the alkyl is optionally substituted with one or more substituents independently selected from halogen, —NR4R5, and —S(O)2R6; n is selected from the group consisting of 0, 1, 2, 3, and 4; R4 and R5 are each independently hydrogen or C 1-6 alkyl, C 1-6 The alkyl is optionally substituted with oxo, or R4 and R5, together with the nitrogen to which they are attached, are selected from halogen, -OH, C 1-6 Alkyl, and C 1-6 may form a 4- to 7-membered heterocyclyl optionally substituted with one or more substituents independently selected from heteroalkyl; Each R6 is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 independently selected from the group consisting of cycloalkyl, phenyl, and benzyl; The present invention features a compound of Formula II, or a pharmaceutically acceptable salt thereof, wherein s is 1 or 2.

[0078] In some embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: X is selected from the group consisting of NH, O, and S, and the hydrogen of NH may be replaced by R3; Y is selected from N and CH, and the hydrogen of CH may be replaced by R3; R1 is -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F 1-6 is selected from the group consisting of alkyl, R2 is hydrogen; Each R3 is halogen, C 1-6 Alkyl, C 1-6 independently selected from the group consisting of heteroalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, -S(O)2NR4R5, -NR4S(O)R6, -C(O)NR4R5, -S(O)2R6, and -O-R6; C1-6 the alkyl is optionally substituted with one or more substituents independently selected from halogen, —NR4R5, and —S(O)2R6; n is selected from the group consisting of 0, 1, 2, 3, and 4; R4 and R5 are each independently hydrogen or C 1-6 alkyl, or R4 and R5 together with the nitrogen to which they are attached can form a 4- to 7-membered heterocyclyl optionally substituted with one or more halogens; Each R6 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 independently selected from the group consisting of cycloalkyl, phenyl, and benzyl; The present invention features a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein s is 1 or 2.

[0079] In another aspect, the present disclosure provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein: X is selected from the group consisting of NH, O, and S, and the hydrogen of NH may be replaced by R3; Y is selected from N and CH, and the hydrogen of CH may be replaced by R3; Z is selected from N and CH, and the hydrogen of CH may be replaced by R3, or when Z is replaced by a -C(O)N(R2)- moiety, Z is C; R1 is -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F 1-6 is selected from the group consisting of alkyl, R2 is hydrogen; Each R3 is halogen, C 1-6 Alkyl, C 1-6independently selected from the group consisting of heteroalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, -S(O)2NR4R5, -NR4S(O)R6, -C(O)NR4R5, -S(O)2R6, and -O-R6; C 1-6 the alkyl is optionally substituted with one or more substituents independently selected from halogen, —NR4R5, and —S(O)2R6; n is selected from the group consisting of 0, 1, 2, 3, and 4; R4 and R5 are each independently hydrogen or C 1-6 alkyl, C 1-6 The alkyl is optionally substituted with oxo, or R4 and R5, together with the nitrogen to which they are attached, are selected from halogen, -OH, C 1-6 Alkyl, and C 1-6 may form a 4- to 7-membered heterocyclyl optionally substituted with one or more substituents independently selected from heteroalkyl; Each R6 is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 independently selected from the group consisting of cycloalkyl, phenyl, and benzyl; a compound of formula II, or a pharmaceutically acceptable salt thereof, wherein s is 1 or 2; and a pharmaceutically acceptable excipient.

[0080] In some embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: X is selected from the group consisting of NH, O, and S, and the hydrogen of NH may be replaced by R3; Y is selected from N and CH, and the hydrogen of CH may be replaced by R3; R1 is -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F1-6 is selected from the group consisting of alkyl, R2 is hydrogen; Each R3 is halogen, C 1-6 Alkyl, C 1-6 independently selected from the group consisting of heteroalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, -S(O)2NR4R5, -NR4S(O)R6, -C(O)NR4R5, -S(O)2R6, and -O-R6; C 1-6 the alkyl is optionally substituted with one or more substituents independently selected from halogen, —NR4R5, and —S(O)2R6; n is selected from the group consisting of 0, 1, 2, 3, and 4; R4 and R5 are each independently hydrogen or C 1-6 alkyl, or R4 and R5 together with the nitrogen to which they are attached can form a 4- to 7-membered heterocyclyl optionally substituted with one or more halogens; Each R6 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 independently selected from the group consisting of cycloalkyl, phenyl, and benzyl; a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein s is 1 or 2; and a pharmaceutically acceptable excipient.

[0081] In some embodiments of Formula II, x is NH. In some embodiments of Formula II, x is O. In some embodiments of Formula II, x is S.

[0082] In some embodiments of Formula II, Y is N. In some embodiments of Formula II, Y is CH.

[0083] In some embodiments of Formula II, Z is N. In some embodiments of Formula II, Z is CH. In some embodiments of Formula II, Z is C when Z is substituted with a -C(O)N(R2)- moiety.

[0084] In some embodiments of Formula I, x is NH. In some embodiments of Formula I, x is O. In some embodiments of Formula I, x is S.

[0085] In some embodiments of Formula I, Y is N. In some embodiments of Formula I, Y is CH.

[0086] In some embodiments, the compound of formula II is a compound of formula I (e.g., Ia, I-a1, Ib, I-b1, Ic, I-c1, Id, or I-d1).

[0087] In some embodiments, the compound of Formula II is a compound of Formula I-Ia or Formula I-Ia1: [ka] or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the compound of Formula II is a compound of Formula I-Ib or Formula I-Ib1: [ka] or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the compound of Formula II is a compound of Formula I-Ic or Formula I-Ic1: [ka] or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the compound of Formula II or Formula I is a compound of Formula Ia or Formula I-a1: [ka] or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the compound of Formula II or Formula I is a compound of Formula Ib or Formula I-b1: [ka] or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the compound of Formula II or Formula I is a compound of Formula Ic or Formula I-c1: [ka] or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the compound of Formula II or Formula I is a compound of Formula Id or Formula I-d1: [ka] or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the compound of Formula II is a compound of Formula I-Ia1: [ka] or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the compound of Formula II is a compound of Formula I-Ib1: [ka] or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the compound of Formula II is a compound of Formula I-Ic1: [ka] or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the compound of Formula II or Formula I is a compound of Formula I-a1: [ka] or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the compound of Formula II or Formula I is a compound of Formula I-b1: [ka] or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the compound of Formula II or Formula I is a compound of Formula I-c1: [ka] or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the compound of Formula II or Formula I is a compound of Formula I-d1: [ka] or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), R1 is selected from the group consisting of -Cl, -F, and -CF3. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), R1 is -Cl. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), R1 is -F. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), R1 is -CF3.

[0102] In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), each R3 is selected from the group consisting of -Cl, methyl, methyl substituted with -NR4R5 or -S(O)2R6, methoxymethyl, trifluoromethyl, ethyl, cyclopropyl, cyclohexyl, -S(O)2R6, -C(O)NR4R5, and -S(O)2NR4R5. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), each R3 is selected from the group consisting of -Cl, methyl, methyl substituted with -NR4R5 or -S(O)2R6, methoxymethyl, trifluoromethyl, ethyl, cyclopropyl, -S(O)2R6, -C(O)NR4R5, and -S(O)2NR4R5. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), each R3 is selected from the group consisting of methyl, ethyl, cyclopropyl, cyclohexyl, and -S(O)2NR4R5. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), each R3 is selected from the group consisting of methyl, cyclopropyl, and -S(O)2NR4R5.

[0103] In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), each R3 is methyl. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), each R3 is cyclopropyl. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), each R3 is -S(O)2NR4R5. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), R3 is a C substituted with -NR4R5 or -S(O)2R6. 1-6 It is alkyl.

[0104] In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), n is 1 or 2. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), n is 2. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), n is 1.

[0105] In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), each of R4 and R5 is independently selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, and —C(O)CH3. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), each of R4 and R5 is independently hydrogen or methyl. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), each R4 and R5 is hydrogen. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), each R4 and R5 is methyl. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), R4 is H and R5 is methyl. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), R4 and R5, together with the nitrogen to which R4 and R5 are attached, form a 4- to 6-membered heterocyclyl optionally substituted with -OH, methyl, or -OCH3.

[0106] In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), R6 is selected from the group consisting of methyl, ethyl, methoxyethyl, and cyclopropyl.

[0107] In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), each R3 is selected from the group consisting of -Cl, methyl, methyl substituted with -NR4R5 or -S(O)2R6, methoxymethyl, trifluoromethyl, ethyl, cyclopropyl, -S(O)2R6, -C(O)NR4R5, and -S(O)2NR4R5, wherein each of R4 and R5 is independently selected from the group consisting of hydrogen, methyl, and -C(O)CH3, and R6 is selected from the group consisting of methyl, ethyl, methoxyethyl, and cyclopropyl.

[0108] In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), s is 2. In some embodiments of Formula II (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), s is 1.

[0109] In some embodiments of Formula I (e.g., (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), or a pharmaceutically acceptable salt thereof), R1 is selected from the group consisting of -Cl, -F, and -CF3.

[0110] In some embodiments of Formula I (e.g., (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), or a pharmaceutically acceptable salt thereof), R1 is -Cl. In some embodiments of Formula I (e.g., (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), or a pharmaceutically acceptable salt thereof), R1 is -F. In some embodiments of Formula I (e.g., (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), or a pharmaceutically acceptable salt thereof), R1 is -CF3.

[0111] In some embodiments of Formula I (e.g., (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), or a pharmaceutically acceptable salt thereof), R3 is selected from the group consisting of methyl, ethyl, cyclopropyl, cyclohexyl, and -S(O)2NR4R5. In some embodiments of Formula I (e.g., (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), or a pharmaceutically acceptable salt thereof), R3 is selected from the group consisting of methyl, cyclopropyl, and -S(O)2NR4R5. In some embodiments of Formula I (e.g., (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), or a pharmaceutically acceptable salt thereof), R3 is methyl. In some embodiments of Formula I (e.g., (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), or a pharmaceutically acceptable salt thereof), R3 is cyclopropyl. In some embodiments of Formula I (e.g., (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), or a pharmaceutically acceptable salt thereof), R3 is -S(O)2NR4R5.

[0112] In some embodiments of Formula I, n is 1 or 2. In some embodiments of Formula I, n is 2. In some embodiments of Formula I, n is 1.

[0113] In some embodiments of Formula I (e.g., (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), or a pharmaceutically acceptable salt thereof), each of R4 and R5 is independently hydrogen or methyl. In some embodiments of Formula I (e.g., (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), or a pharmaceutically acceptable salt thereof), each R4 and R5 is hydrogen. In some embodiments of Formula I (e.g., (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), or a pharmaceutically acceptable salt thereof), each R4 and R5 is methyl. In some embodiments of Formula I (e.g., (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), or a pharmaceutically acceptable salt thereof), R4 is H and R5 is methyl.

[0114] In some embodiments of Formula I (e.g., (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), or a pharmaceutically acceptable salt thereof), s is 2. In some embodiments of Formula I (e.g., (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), or a pharmaceutically acceptable salt thereof), s is 1.

[0115] In some embodiments, the compound of formula II is [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0116] In another aspect, the present invention provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein: R1 is -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F 1-6 is selected from the group consisting of alkyl, R2 is hydrogen; R3 is halogen, C 1-6 Alkoxy, C 1-6 Alkylene-S(O)2-C 1-6 Alkyl, -C(O)NR5R6, -NR7S(O)2C 1-6 Alkyl, -NR7S(O)2C 3-7 Cycloalkyl, -NR7S(O)2NR5R6, -NR9R 10 , -S(O)2-C 3-6 Cycloalkyl, -S(O)2-NR5R6, -S(O)2-C 1-6 Alkoxy, and -S(O)2-C 1-6 alkyl, independently selected from the group consisting of C 1-6 The alkyl may contain one or more halogens or C 1-6 optionally substituted with alkoxy; Each R4 is C 1-6 independently selected from the group consisting of alkyl, halogen, and -OH, and when R4 is -OH, R4 is substituted on the carbon adjacent to R3; n is selected from the group consisting of 0, 1, 2, 3, and 4; R5, R6, R9, and R 10 are each independently hydrogen or C 1-6 is alkyl, Each R7 is hydrogen, C 1-6 independently selected from the group consisting of alkyl, and 3- to 7-membered heterocyclyl; 1-6 Alkyl is halogen, C 1-6 Alkoxy, C 1-6 optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxy, —OH, —NR5R6, and —C(O)NR5R6; The present invention features a compound of Formula II, or a pharmaceutically acceptable salt thereof, wherein s is 1 or 2.

[0117] In another aspect, the present invention provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein: R1 is -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F 1-6 is selected from the group consisting of alkyl, R2 is hydrogen; R3 is halogen, C 1-6 Alkoxy, C 1-6 Alkylene-S(O)2-C 1-6 Alkyl, -C(O)NR5R6, -NR7S(O)2C 1-6 Alkyl, -NR7S(O)2C 3-7 Cycloalkyl, -NR7S(O)2NR5R6, -NR9R 10 , -S(O)2-C 3-6 Cycloalkyl, -S(O)2-NR5R6, -S(O)2-C 1-6 Alkoxy, and -S(O)2-C 1-6 alkyl, independently selected from the group consisting of C 1-6 The alkyl may contain one or more halogens or C 1-6 optionally substituted with alkoxy; Each R4 is C 1-6 independently selected from the group consisting of alkyl, halogen, and -OH, and when R4 is -OH, R4 is substituted on the carbon adjacent to R3; n is selected from the group consisting of 0, 1, 2, 3, and 4; R5, R6, R9, and R 10 are each independently hydrogen or C 1-6 is alkyl, Each R7 is hydrogen, C 1-6 independently selected from the group consisting of alkyl, and 3- to 7-membered heterocyclyl; 1-6 Alkyl is halogen, C 1-6 Alkoxy, C 1-6 optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxy, —OH, —NR5R6, and —C(O)NR5R6; a compound of formula II, or a pharmaceutically acceptable salt thereof, wherein s is 1 or 2; and a pharmaceutically acceptable excipient.

[0118] In some embodiments, the compound of Formula II is a compound of Formula II-a, Formula II-a1, or Formula II-a2: [ka] or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the compound of Formula II is a compound of Formula II-b, Formula II-b1, or Formula II-b2: [ka] or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, the compound of Formula II is a compound of Formula II-c, Formula II-c1, or Formula II-c2: [ka] or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the compound of Formula II is a compound of Formula II-a2: [ka] or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, the compound of Formula II is a compound of Formula II-b2: [ka] or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, the compound of Formula II is a compound of Formula II-c2: [ka] or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R1 is selected from the group consisting of -Cl, -F, and -CF3. In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R1 is -Cl. In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R1 is -F. In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R1 is -CF3.

[0125] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R3 is -F, methoxy, -NH2, [ka] [ka] is selected from the group consisting of:

[0126] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R3 is [ka] is selected from the group consisting of:

[0127] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R3 is [ka] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R3 is [ka] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R3 is [ka] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R3 is [ka] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R3 is [ka] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R3 is [ka] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R3 is [ka] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R3 is [ka] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R3 is [ka] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R3 is [ka] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R3 is [ka] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R3 is [ka] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R3 is [ka] is.

[0128] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R4 is -F or methyl. In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R4 is -F. In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R4 is methyl.

[0129] In some embodiments of Formula (II), n is 1.

[0130] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), each of R, R, R, and R 10 In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R5, R6, R9, and R 10 is methyl.

[0131] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R5 is H and R6 is methyl.

[0132] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R7 is hydrogen, methyl, ethyl, and [ka] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R7 is hydrogen. In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R7 is methyl. In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R7 is ethyl. In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), R7 is [ka] is.

[0133] In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), s is 1. In some embodiments of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), s is 2.

[0134] In some embodiments, the compound of formula II is [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0135] In another aspect, the present invention provides a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein: R1 is -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F 1-6 is selected from the group consisting of alkyl, R2 is hydrogen; R3 is hydrogen; R4 is C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Haloalkyl, -NR7S(O)2C 1-6 Alkyl, and NRC(O)-C 1-6 alkyl, n is selected from the group consisting of 0, 1, 2, 3, and 4; R7 and R8 are each independently hydrogen or C 1-6 is alkyl, The present invention features a compound of Formula III, or a pharmaceutically acceptable salt thereof, wherein s is 1 or 2.

[0136] In another aspect, the present invention provides a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein: R1 is -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F 1-6 is selected from the group consisting of alkyl, R2 is hydrogen; R3 is hydrogen; R4 is C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Haloalkyl, -NR7S(O)2C 1-6 Alkyl, and NRC(O)-C 1-6 alkyl, n is selected from the group consisting of 0, 1, 2, 3, and 4; R7 and R8 are each independently hydrogen or C 1-6 is alkyl, a compound of formula III or a pharmaceutically acceptable salt thereof, wherein s is 1 or 2; and a pharmaceutically acceptable excipient.

[0137] In some embodiments, the compound of Formula III is a compound of Formula III-a, Formula III-a1, or Formula III-a2: [ka] or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, the compound of Formula III is a compound of Formula III-b, Formula III-b1, or Formula III-b2: [ka] or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, the compound of Formula III is a compound of Formula III-c, Formula III-c1, or Formula III-c2: [ka] or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, the compound of Formula III is a compound of Formula III-a2: [ka] or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments, the compound of Formula III is a compound of Formula III-b2: [ka] or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, the compound of Formula III is a compound of Formula III-c2: [ka] or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments of Formula III (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), R1 is selected from the group consisting of -Cl, -F, and -CF3. In some embodiments of Formula III (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), R1 is -Cl. In some embodiments of Formula III (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), R1 is -F. In some embodiments of Formula III (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), R1 is -CF3.

[0144] In some embodiments of Formula III (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), R4 is methyl, methoxy, -F, -Cl, -CF3, methoxy, [ka] In some embodiments of Formula III (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), R4 is -F. In some embodiments of Formula III (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), R4 is Cl. In some embodiments of Formula III (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), R4 is -CF3. In some embodiments of Formula III (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), R4 is methoxy. In some embodiments of Formula III (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), R4 is [ka] In some embodiments of Formula III (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), R4 is [ka] is.

[0145] In some embodiments of Formula III, n is selected from the group consisting of 0, 1, and 2. In some embodiments of Formula III, n is 0 or 1. In some embodiments of Formula III, n is 1. In some embodiments of Formula III, n is 0.

[0146] In some embodiments of Formula III (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), each R7 and R8 is independently hydrogen.

[0147] In some embodiments of Formula III (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), s is 2. In some embodiments of Formula III (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), s is 1.

[0148] In some embodiments, the compound of formula III is [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0149] 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.

[0150] The synthetic route illustrated in Scheme I-1 shows an exemplary procedure for preparing carboxylic acid IC. In the first step, IA is carbonylated under standard carbonylation reaction conditions (e.g., CO, Pd(dppf)Cl, and EtN in ROH) to form ester IB. Ester IB is then hydrolyzed to provide carboxylic acid IC. [ka]

[0151] The synthetic route shown in Scheme I-2 illustrates an exemplary procedure for preparing IE (a compound of formula II), in which carboxylic acid IC is coupled with aminoindan ID under standard peptide coupling reaction conditions (e.g., HATU and base) to provide IE (a compound of formula II). [ka]

[0152] The synthetic route illustrated in Scheme 1 shows an exemplary procedure for preparing carboxylic acid C. In the first step, A is carbonylated under standard carbonylation reaction conditions (e.g., CO, Pd(dppf)Cl, and EtN in ethanol) to form ester B. Ester B is then hydrolyzed to provide carboxylic acid C. [ka]

[0153] The synthetic route illustrated in Scheme 2 shows an exemplary procedure for preparing E (a compound of formula I). ​​In this route, carboxylic acid C is coupled with aminoindan D under standard peptide coupling reaction conditions (e.g., HATU and EtN in acetonitrile) to provide E (a compound of formula I). [ka]

[0154] The synthetic route illustrated in Scheme II-1 shows an exemplary procedure for preparing aminoindan II-B, in which indanone II-A is reacted with ammonium acetate and sodium cyanoborohydride to form aminoindan II-B. [ka]

[0155] The synthetic route illustrated in Scheme II-2 shows an exemplary procedure for preparing carboxylic acid II-D, in which ester II-C is hydrolyzed to provide carboxylic acid II-D. [ka]

[0156] The synthetic route illustrated in Scheme II-3 shows an exemplary procedure for preparing II-E (a compound of Formula II), in which carboxylic acid II-D is coupled with aminoindan II-B under standard peptide coupling reaction conditions (e.g., HOBt and EDCI in dichloromethane in the presence of NEt) to provide II-E (a compound of Formula II). [ka]

[0157] The synthetic route illustrated in Scheme III-1 shows an exemplary procedure for preparing III-C (a compound of Formula III), in which carboxylic acid III-A is coupled with aminoindan III-B under standard peptide coupling reaction conditions (e.g., HOBt and EDCI in dichloromethane in the presence of DMAP) to provide III-C (a compound of Formula III). [ka]

[0158] Treatment methods 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., epilepsy of infancy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, developmental and epileptic encephalopathy (DEE), early infantile onset epileptic encephalopathy (EIEE), generalized epilepsy, focal epilepsy, multifocal epilepsy, temporal lobe epilepsy, Ohtahara syndrome, early myoclonic encephalopathy, and Lennox syndrome. Gastaut syndrome, drug-resistant epilepsy, seizures (e.g., frontal lobe seizures, generalized tonic-clonic seizures, asymmetric tonic seizures, focal seizures, leukodystrophies, myelinating leukodystrophies, leukoencephalopathy, and sudden unexpected death in epilepsy), cardiac dysfunction (e.g., cardiac arrhythmias, Brugada syndrome, myocardial infarction), pulmonary vascular disorders / 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.

[0159] 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.

[0160] 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, psychotic disorders, and autism spectrum disorders.

[0161] 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).

[0162] 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 de novo mutations in KCNT1 have been identified in patients with EIMFS, including V271F, G288S, R428Q, R474Q, R474H, R474C, I760M, A934T, P924L, G243S, H257D, A259D, R262Q, Q270E, L274I, F346L, C377S, R398Q, P409S, A477T, F502V, M516V, Q550del, K629E, K629N, I760F, E893K, M896K, R933G, R950Q, 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 a marked increase in whole-cell current (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).

[0163] ADNFLE has a later onset than EIMFS, typically occurring in mid-childhood, and is generally a less severe condition. It is characterized by nocturnal frontal lobe seizures and can result in 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 involved in more severe cases of the disease (Heron et al. (2012) Nat Genet. 44:1188-1190). Functional studies of the mutant KCNT1 gene associated with ADNFLE have shown that the underlying mutations (M896I, R398Q, Y796H, and R928C) are dominant gain-of-function mutations (Milligan et al. (2015) Ann Neurol. 75(4):581-590, Mikati et al. (2015) Ann Neurol. 78(6):995-999).

[0164] West syndrome is a severe form of epilepsy characterized by three features: infantile spasms, an interictal electroencephalogram (EEG) pattern called hypsarrhythmia, and mental retardation. However, it can be diagnosed if one of these features is absent. Mutations in KCNT1, including G652V and R474H, are associated with West syndrome (Fukuoka et al. (2017) Brain Dev 39:80-83 and Ohba et al. (2015) Epilepsia 56:el21-el28). Therapies targeting the KCNT1 channel suggest that these mutations are gain-of-function mutations (Fukuoka et al. (2017) Brain Dev 39:80-83).

[0165] In one aspect, the present invention provides a method for treating diseases or conditions associated with excessive neuronal excitation and / or gain-of-function mutations in genes such as KCNT1 (e.g., epilepsy and other encephalopathies (e.g., epilepsy of infancy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies (DEE), and Lennox syndrome). Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia, asymmetric tonic seizures), as well as cardiac dysfunction (e.g., cardiac arrhythmias, Brugada syndrome, sudden unexpected death in epilepsy, myocardial infarction), pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.), muscle disorders (e.g., myotonia, , neuromyotonia, muscle spasms, spasticity), itch and pruritus, ataxia and cerebellar ataxia, psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia), learning disabilities, fragile X, neuroplasticity, and autism spectrum disorders), comprising administering to a subject a compound disclosed herein (e.g., a compound of Formula (II) or (I) (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Id), (I-Ie), (I-If), (I-Ig), (I-Ih), (I-Ii), ( ... a compound of formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), or a compound of formula (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (I (II-b1), (III-b2), (III-c), (III-c1), (III-c2))), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a compound disclosed herein (e.g., a compound of formula (II) or (I) (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic),(I-c1), (Id), or (I-d1)), a compound of Formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), or a compound of Formula (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)))), or a pharmaceutically acceptable salt thereof), and a pharmaceutical composition comprising a pharmaceutically acceptable excipient to a subject in need of treatment.

[0166] In some embodiments, the subject who presents with disease or condition that may be related to KCNT1 gain-of-function mutation is genotyped to confirm the existence of known KCNT1 gain-of-function mutation before administering compound and its composition.For example, whole exome sequencing can be performed on the subject. Gain-of-function mutations associated with EIMFS can 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 encephalopathy include, but are not limited to, L437F, Y796H, P924L, and R961H. Gain-of-function mutations associated with early infantile-onset 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.

[0167] 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 that described in Milligan et al. (2015) Ann Neurol. 75(4):581-590. Typically, the presence of a gain-of-function mutation is confirmed if expression of the 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 electrophysiology (such as that 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. The subject can then be identified as having a disease or condition associated with a gain-of-function mutation in KCNT1.

[0168] 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).

[0169] The compounds disclosed herein (e.g., compounds of formula (II) or (I) (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), compounds of formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II- (III-c), (II-c1), (II-c2)), or a compound of formula (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)))), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a compound disclosed herein (e.g., a compound of formula (II) or (I) (e.g., ( I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), a compound of formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), or a compound of formula (III) (e.g., A pharmaceutical composition comprising (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)))) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient) can also be used therapeutically for conditions associated with excessive neural excitability when the excessive neural excitability is not necessarily the result of a gain-of-function mutation in KCNT1. Even when the disease is not the result of increased KCNT1 expression and / or activity, inhibition of KCNT1 expression and / or activity can still result in reduced neural excitability, thereby providing a therapeutic effect.Thus, compounds disclosed herein (e.g., compounds of formula (II) or (I) (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), compounds of formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), or compounds of formula a compound of formula (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2))), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a compound disclosed herein (e.g., a compound of formula (II) or (I) (e.g., (I-Ia), (I-Ia1), (I-Ib), (I-Ib1), (I-Ic), (I-Ic1), (Ia), (I-a1 ), (Ib), (I-b1), (Ic), (I-c1), (Id), or (I-d1)), a compound of formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), or a compound of formula (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2))), or and a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient) can be used to treat subjects with conditions associated with excessive neural excitability, such as epilepsy and other encephalopathies (e.g., infantile epilepsy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, and Lennox-Gastaut syndrome, seizures), or cardiac dysfunction (e.g., cardiac arrhythmia, Brugada syndrome, myocardial infarction), whether or not the disease or disorder is associated with a gain-of-function mutation in KCNT1.

[0170] Pharmaceutical Compositions and Routes of Administration The compounds provided by the present invention are usually administered in the form of pharmaceutical compositions. Thus, the present invention provides pharmaceutical compositions containing one or more of the compounds described above, or pharmaceutically acceptable salts or esters thereof, as an active ingredient, 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. Pharmaceutical compositions can be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical arts (see, for example, 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.)).

[0171] 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 a stent or an arterially inserted cylindrical polymer, having similar utilities as described in those patents and patent applications incorporated by reference.

[0172] One mode of administration is parenteral, particularly by injection. Forms in 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 brine are also conventionally used for injections, 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 can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0173] Sterile injectable solution can be prepared by incorporating the compound of the present invention in the amount required in a suitable solvent, which contains various other components as listed above, as needed, and then be filtered and sterilized.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains basic dispersion medium and other components as listed above.For the sterile powder used to prepare sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which can obtain the powder of active ingredient and any additional desired components from the sterile solution that has been previously sterilized and filtered.

[0174] Oral administration is another route for administering the compounds of the present invention. Administration can 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 in such a carrier, which can be in the form of a capsule, a sachet, paper, or other container. When an excipient functions as a diluent, the excipient can be in the form of a solid, semi-solid, or liquid material (as above) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can 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.

[0175] 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, sterilized water, syrup and methylcellulose.In addition, formulation can contain lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying agents and suspending agents; preservatives such as methyl and propylhydroxybenzoates; sweeteners; and flavoring agents.

[0176] The compositions of the 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 provided 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 invention employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the invention in controlled amounts. The construction and use of transdermal patches to deliver pharmaceutical agents 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.

[0177] 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.

[0178] To prepare solid compositions such as tablets, the primary 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.

[0179] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action or to protect against the acidic conditions of the stomach.For example, the tablets or pills can comprise an inner dosage component and an outer dosage component, the latter being in the form of a coating covering the former.The two components can be separated by an enteric layer that functions to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be delayed-released.A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0180] 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.

[0181] In some embodiments, a pharmaceutical composition comprising a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [Example]

[0182] 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.

[0183] 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. Optimal 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.

[0184] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing 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 the references cited therein.

[0185] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, trituration, high-pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). It should be noted that flash chromatography can be performed 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. List of abbreviations MeI methyl iodide Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) THF tetrahydrofuran TEA or Et3N Triethylamine TFA trifluoroacetic acid FA formic acid DMF N,N-dimethylformamide MeOH Methanol DCM dichloromethane MeCN or ACN Acetonitrile PE Petroleum Ether EtOAc or EA ethyl acetate EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HATU o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HOBt 1-Hydroxybenzotriazole Monohydrate DIPEA N,N-Diisopropylethylamine DEA Diethylamine NBS N-Bromosuccinimide NaOMe Sodium methoxide mCPBA meta-chloroperoxybenzoic acid PPh3 Triphenylphosphine DEA Diethylamine NH4OAc Ammonium Acetate DIAD Diisopropyl azodicarboxylate i-PrOH isopropanol Tf2O Trifluoromethanesulfonic anhydride DMAP 4-dimethylaminopyridine Oxone potassium peroxymonosulfate t-BuOH tert-butanol CSI Chlorosulfonyl Isocyanate ODS Octadecylsilane HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid DMSO dimethyl sulfoxide EGTA Ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid NMDG N-methyl-D-glucamine I C 50 Half maximal inhibitory concentration TLC thin layer chromatography LCMS Liquid Chromatography Mass Spectrometry HPLC High Performance Liquid Chromatography SFC Supercritical Fluid Chromatography MS mass spectrometry ESI electrospray ionization NMR nuclear magnetic resonance

[0186] Example 1. Synthesis of Compound I-1 [ka] A mixture of 5-cyclopropyl-1-methyl-pyrazole-3-carboxylic acid (100 mg, 0.60 mmol), HOBt (162.63 mg, 1.2 mmol), EDCI (173.04 mg, 0.90 mmol), and (1R)-5-chloroindan-1-amine (100.88 mg, 0.60 mmol) in DCM (20 mL) was stirred at 15° C. for 16 hours. The mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Xtimate C18 150 × 25 mm, 5 μm) A = HO (0.05% NH4OH) and B = CH3CN; 46–76% B over 8.5 min) to give the product (89.1 mg, 0.28 mmol, 47% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ H =8.23(d,1H),7.30(s,1H),7.24-7.17(m,1H),7.16-7.11(m,1H),6.31(s,1H),5.42(q,1H),3.86(s,3H),3.01-2.92(m ,1H),2.86-2.75(m,1H),2.42-2.31(m,1H),2.11-1.99(m,1H),1.94-1.86(m,1H),1.00-0.92(m,2H),0.68-0.61(m,2H) LCMS R t = 1.28 min in 2.0 min chromatography, 10-80AB, C 17 H 19 ClNO[M+H] + MS ESI calculated value 316.1, found value 316.0.

[0187] Example 2. Synthesis of Compound I-2 [ka] A mixture of 5-cyclopropyl-2-methyl-pyrazole-3-carboxylic acid (100 mg, 0.60 mmol), HOBt (162.63 mg, 1.2 mmol), EDCI (173.04 mg, 0.90 mmol), and (1R)-5-chloroindan-1-amine (100.88 mg, 0.60 mmol) in DCM (10 mL) was stirred at 15° C. for 16 hours. The mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime C18 150 mm × 30 mm, 5 μm) A = HO (0.05% NH4OH) and B = CH3CN; 52–82% B over 8 min) to give the product (77.7 mg, 0.25 mmol, 41% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ H =8.63(d,1H),7.33(s,1H),7.26-7.18(m,2H),6.57(s,1H),5.43(q,1H),3.99(s,3H),3.04-2.93(m,1H),2.91 -2.77(m,1H),2.47-2.39(m,1H),2.02-1.91(m,1H),1.87-1.79(m,1H),0.88-0.82(m,2H),0.61-0.55(m,2H). LCMS R t = 1.26 min in 2.0 min chromatography, 10-80AB, C 17 H 19 ClNO[M+H] + MS ESI calculated value 316.1, found value 316.0.

[0188] Example 3. Synthesis of Compound I-3 [ka] A mixture of 5-sulfamoylfuran-2-carboxylic acid (100 mg, 0.52 mmol), (1R)-5-chloroindan-1-amine (131.54 mg, 0.78 mmol), EtN (0.14 mL, 1.05 mmol), and HATU (198.91 mg, 0.52 mmol) in CHCN (5 mL) was stirred at 25 °C for 3 h. The mixture was diluted with HO (20 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative TLC (silica gel, PE:EtOAc = 1:1) to give the product (22.9 mg, 67.3 μmol, 23% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =8.90(d,1H),7.91(s,2H),7.35(s,1H),7.29(d,1H),7.26-7.21(m,2H),7.06(d,1H),5 .47(q,1H),3.05-2.95(m,1H),2.91-2.79(m,1H),2.48-2.41(m,1H),2.05-1.94(m,1H). LCMS R t = 2.0 min chromatography at 1.12 min, 10-80AB, C 14 H 14 ClN2O4S[M+H] + MS ESI calculated value 341.0, found value 340.9.

[0189] Example 4. Synthesis of Compound I-4 [ka] Synthesis of IA-5b: A mixture of 5-bromothiophene-2-sulfonamide (2 g, 8.26 mmol), Pd(dppf)Cl (906.65 mg, 1.24 mmol), and EtN (3.43 mL, 24.78 mmol) in ethanol (20 mL) was stirred at 80 °C for 16 h under CO (50 psi). The mixture was filtered through Celite, and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel (0% to 30% to 50% EtOAc in PE) to give the product (1 g, 4.25 mmol, 51% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =7.95(s,2H),7.77(d,1H),7.58(d,1H),4.32(q,2H),1.30(t,3H).

[0190] Synthesis of IA-5c: A mixture of ethyl 5-sulfamoylthiophene-2-carboxylate (900 mg, 3.83 mmol) and LiOH·HO (481.52 mg, 11.48 mmol) in THF (10 mL) and water (10 mL) was stirred at 20 °C for 1 h. 1N HCl was added to adjust the pH to 1. The mixture was extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (450 mg, 2.17 mmol) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =7.91(s,2H),7.70(d,1H),7.56(d,1H).

[0191] Synthesis of I-4: A mixture of 5-sulfamoylthiophene-2-carboxylic acid (230 mg, 1.11 mmol), (1R)-5-chloroindan-1-amine (372.12 mg, 2.22 mmol), EtN (0.31 mL, 2.22 mmol), and HATU (422.02 mg, 1.11 mmol) in MeCN (5 mL) was stirred at 20 °C for 1 h. Water (15 mL) was added, and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 35% to 70%) to give the product (64 mg, 174.7 μmol, 15% yield) as a solid. The product was blended with another batch (36 mg, prepared from 200 mg of 5-sulfamoylthiophene-2-carboxylic acid). The combined solid (100 mg) was triturated from MeOH (3 mL) to give the product (82.9 mg, 232.3 μmol, 85% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =9.08(d,1H),7.84(s,2H),7.77(d,1H),7.53(d,1H),7.36(s,1H),7.24(s,2H),5.46 (q,1H),3.05-2.95(m,1H),2.92-2.81(m,1H),2.48-2.42(m,1H),2.05-1.94(m,1H). LCMS R t = 2.0 min chromatography, 1.20 min, 10-80AB, C 14 H 14 ClN2O3S2[M+H] + MS ESI calculated value 357.0, found value 356.8.

[0192] Example 5. Synthesis of Compound I-5 [ka] A mixture of 4-sulfamoylthiophene-2-carboxylic acid (150 mg, 0.72 mmol), (1R)-5-chloroindan-1-amine (182.02 mg, 1.09 mmol), EtN (0.2 mL, 1.45 mmol), and HATU (275.23 mg, 0.72 mmol) in MeCN (5 mL) was stirred at 25 °C for 2 h. Water (15 mL) was added, and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0% to 35% to 70% EtOAc in PE) followed by preparative HPLC (Xtime C18 150 × 25 mm, 5 μm, A = HO (10 mM NH4HCO3) and B = CH3CN; 30 to 60% B over 10 min) to give the product (53.3 mg, 149.5 μmol, 20% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =9.11(d,1H),8.23(d,1H),8.09(d,1H),7.44(s,2H),7.35(s,1H),7.24(s,2H),5.44 (q,1H),3.06-2.95(m,1H),2.91-2.80(m,1H),2.47-2.41(m,1H),2.05-1.93(m,1H). LCMS R t = 2.0 min chromatography at 1.11 min, 10-80AB, C 14 H 14 ClN2O3S2[M+H] + MS ESI calculated value 357.0, found value 356.9.

[0193] Example 6. Synthesis of Compound I-6 [ka] A mixture of (1R)-5-chloroindan-1-amine (182.02 mg, 1.09 mmol), 5-sulfamoylthiophene-3-carboxylic acid (150 mg, 0.72 mmol), EtN (0.2 mL, 1.45 mmol), and HATU (275.23 mg, 0.72 mmol) in MeCN (0.50 mL) was stirred at 25 °C for 2 h. Water (15 mL) was added, and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0% to 35% to 70% EtOAc in PE) to give the product (73.09 mg, 204.8 μmol, 28% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =8.85(d,1H),8.41(s,1H),8.01(s,1H),7.74(s,2H),7.34(s,1H),7.23(s,2H),5.46 (q,1H),3.04-2.94(m,1H),2.91-2.80(m,1H),2.45-2.40(m,1H),2.04-1.93(m,1H). LCMS R t = 1.09 min in 2.0 min chromatography, 10-80AB, C 14 H 14 ClN2O3S2[M+H] + MS ESI calculated value 357.0, found value 356.9.

[0194] Example 7. Synthesis of Compound I-7 [ka] A mixture of 1-methyl-4-sulfamoyl-pyrrole-2-carboxylic acid (150 mg, 0.73 mmol), (1R)-5-chloroindan-1-amine (184.72 mg, 1.1 mmol), EtN (0.2 mL, 1.47 mmol), and HATU (279.31 mg, 0.73 mmol) in MeCN (5 mL) was stirred at 25 °C for 2 h. Water (15 mL) was added, and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0% to 35% to 70% EtOAc in PE) to give the product (78.9 mg, 222.9 μmol, 30% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =8.62(d,1H),7.41(d,1H),7.32(s,1H),7.26-7.17(m,2H),7.14(d,1H),7.03(s,2H),5.43(q, 1H),3.90(s,3H),3.03-2.93(m,1H),2.88-2.77(m,1H),2.45-2.37(m,1H),2.05-1.92(m,1H). LCMS R t = 2.0 min chromatography, 1.10 min, 10-80AB, C 15 H 17 MS ESI calculated for ClN3O3S [M+H]+ 354.1, found 353.9.

[0195] Example 8. Synthesis of Compound I-8 [ka] A mixture of 5-methyl-4-sulfamoyl-thiophene-2-carboxylic acid (150 mg, 0.68 mmol), (1R)-5-chloroindan-1-amine (170.48 mg, 1.02 mmol), EtN (0.19 mL, 1.36 mmol), and HATU (257.79 mg, 0.68 mmol) in MeCN (5 mL) was stirred at 25 °C for 2 h. Water (15 mL) was added, and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0% to 35% to 70% EtOAc in PE) followed by preparative HPLC (Xtime C18 150 × 25 mm, 5 μm, A = HO (10 mM NH4HCO3) and B = CH3CN; 30 to 60% B over 10 min) to give the product (120.4 mg, 324.6 μmol, 47% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =9.03(d,1H),8.01(s,1H),7.38(s,2H),7.34(s,1H),7.26-7.19(m,2H),5.42(q,1H),3 .04-2.95(m,1H),2.89-2.79(m,1H),2.64(s,3H),2.46-2.39(m,1H),2.03-1.92(m,1H). LCMS R t = 1.13 min in 2.0 min chromatography, 10-80AB, C 15 H 16 ClN2O3S2[M+H] + MS ESI calculated value 371.0, found value 370.9.

[0196] Example 9. Synthesis of Compound I-9 [ka] A mixture of 5-methyl-4-sulfamoyl-furan-2-carboxylic acid (150 mg, 0.73 mmol), (1R)-5-chloroindan-1-amine (183.82 mg, 1.1 mmol), EtN (0.2 mL, 1.46 mmol), and HATU (277.97 mg, 0.73 mmol) in MeCN (5 mL) was stirred at 25 °C for 2 h. Water (15 mL) was added, and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0% to 35% to 70% EtOAc in PE) followed by preparative HPLC (Xtime C18 150 × 25 mm, 5 μm, A = HO (10 mM NH4HCO3) and B = CH3CN; 30 to 60% B over 10 min) to give the product (48.2 mg, 135.8 μmol, 18% yield) as a solid. 1 H NMR (400 MHz, CD3OD) δ H =8.84(d,1H),7.47(s,2H),7.36-7.29(m,2H),7.26-7.14(m,2H),5.43(q,1H),3.04 -2.93(m,1H),2.89-2.78(m,1H),2.52(s,3H),2.45-2.38(m,1H),2.05-1.93(m,1H). LCMS R t = 2.0 min chromatography, 1.10 min, 10-80AB, C 15 H 16 ClN2O4S[M+H] + MS ESI calculated value 355.0, found value 354.9.

[0197] Example 10. Synthesis of Compound I-10 [ka] A mixture of 3-methyl-5-sulfamoyl-thiophene-2-carboxylic acid (100 mg, 0.45 mmol), (1R)-5-chloroindan-1-amine (113.65 mg, 0.68 mmol), EtN (0.13 mL, 0.90 mmol), and HATU (171.86 mg, 0.45 mmol) in MeCN (5 mL) was stirred at 25 °C for 2 h. The mixture was diluted with HO (20 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative TLC (silica gel, PE:EtOAc = 1:1) followed by preparative HPLC (Waters Xbridge 150 × 25 mm, 5 μm), A = H2O (10 mM NH4HCO3) and B = CH3CN; 35–65% B over 10 min) to give the product (22.8 mg, 61.6 μmol, 76% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =8.71(d,1H),8.13(s,1H),7.52(s,2H),7.33(s,1H),7.29-7.23(m,2H),5.43(q,1H),3 .02-2.93(m,1H),2.90-2.79(m,1H),2.52(s,3H),2.46-2.41(m,1H),2.04-1.93(m,1H). LCMS R t = 1.13 min in 2.0 min chromatography, 10-80AB, C 15 H 16 ClN2O3S2[M+H] + MS ESI calculated value 371.0, found value 370.9.

[0198] Example 11. Synthesis of Compound I-11 [ka] A mixture of 2-methyl-5-sulfamoyl-furan-3-carboxylic acid (150 mg, 0.73 mmol), (1R)-5-chloroindan-1-amine (183.82 mg, 1.1 mmol), EtN (0.2 mL, 1.46 mmol), and HATU (277.97 mg, 0.73 mmol) in MeCN (5 mL) was stirred at 25 °C for 2 h. Water (15 mL) was added, and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30%) to give the product (23.7 mg, 0.07 mmol, 24% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =8.54(d,1H),7.76(s,2H),7.51(s,1H),7.34(s,1H),7.27-7.18(m,2H),5.45(q,1H),3 .02-2.95(m,1H),2.89-2.80(m,1H),2.64(s,3H),2.44-2.39(m,1H),2.00-1.91(m,1H). LCMS R t = 1.13 min in 2.0 min chromatography, 10-80AB, C 15 H 16 ClN2O4S[M+H] + MS ESI calculated value 355.0, found value 355.1.

[0199] Example 12. Synthesis of Compound I-12 [ka] A mixture of 3-methyl-5-sulfamoyl-furan-2-carboxylic acid (150 mg, 0.73 mmol), HATU (277.97 mg, 0.73 mmol), EtN (0.2 mL, 1.46 mmol), and (1R)-5-chloroindan-1-amine (183.82 mg, 1.1 mmol) in MeCN (5 mL) was stirred at 15 °C for 16 h. Water (15 mL) was added, and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0% to 30% EtOAc in PE) to give the product (19.3 mg, 0.05 mmol, 19% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =8.53(d,1H),7.76(s,2H),7.35(s,1H),7.29-7.19(m,2H),6.98(s,1H),5.48(q,1H),3 .07-2.94(m,1H),2.90-2.81(m,1H),2.47-2.40(m,1H),2.33(s,3H),2.09-1.97(m,1H). LCMS R t = 1.14 min in 2.0 min chromatography, 10-80AB, C 15 H 16 ClN2O4S[M+H] + MS ESI calculated value 355.0, found value 354.9.

[0200] Example 13. Synthesis of Compound I-13 [ka] A mixture of 1-methyl-5-sulfamoyl-pyrrole-2-carboxylic acid (150 mg, 0.73 mmol), HOBt (198.53 mg, 1.47 mmol), EDCI (281.64 mg, 1.47 mmol), DIPEA (0.22 mL, 2.2 mmol), and (1R)-5-chloroindan-1-amine (184.72 mg, 1.1 mmol) in DMF (5 mL) was stirred at 20 °C for 2 h. Water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Waters Xbridge 150 × 25 mm, 5 μm, A = H2O (10 mM NH4HCO3) and B = CH3CN; 35-65% B over 10 min) to give the product (79.66 mg, 225.1 μmol, 66% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =8.62(d,1H),7.41(d,1H),7.32(s,1H),7.24-7.18(m,2H),7.14(d,1H),7.03(s,2H),5.43(q, 1H),3.90(s,3H),3.02-2.93(m,1H),2.88-2.78(m,1H),2.43-2.36(m,1H),2.04-1.93(m,1H). LCMS R t = 1.16 min in 2.0 min chromatography, 10-80AB, C 15 H 17 ClN3O3S[M+H] + MS ESI calculated value 354.1, found value 353.8.

[0201] Example 14. Synthesis of Compound I-14 [ka] A mixture of 4-sulfamoyl-1H-pyrrole-2-carboxylic acid (150 mg, 0.79 mmol), EDCI (302.4 mg, 1.58 mmol), HOBt (213.16 mg, 1.58 mmol), DIPEA (0.24 mL, 2.37 mmol), and (1R)-5-chloroindan-1-amine (198.33 mg, 1.18 mmol) in DMF (5 mL) was stirred at 20 °C for 2 h. Water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Xtimate C18 150 × 25 mm, 5 μm, A = H2O (10 mM NH4HCO3) and B = CH3CN; 0 to 60% B over 10 min) to give the product (17.0 mg, 50.0 μmol, 14% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =12.03(s,1H),8.62(d,1H),7.34(s,1H),7.24-7.18(m,3H),7.15(d,1H),7.02(s,2H),5 .46(q,1H),3.02-2.94(m,1H),2.89-2.79(m,1H),2.46-2.39(m,1H),2.02-1.92(m,1H). LCMS R t = 2.0 min chromatography at 1.11 min, 10-80AB, C 14 H 15 ClN3O3S[M+H] + MS ESI calculated value 340.0, found value 339.8.

[0202] Example 15. Synthesis of Compound I-15 [ka] Synthesis of IA-5b: A mixture of 5-bromothiophene-2-sulfonamide (2 g, 8.26 mmol), Pd(dppf)Cl (906.65 mg, 1.24 mmol), and EtN (3.43 mL, 24.78 mmol) in ethanol (20 mL) was stirred at 80 °C for 16 h under CO (50 psi). The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (0% to 30% to 50% EtOAc in PE) to give the product (1 g, 4.25 mmol, 51% yield) as a solid. 1 H NMR (400 MHz, DMSO-d6) δ H =7.95(s,1H),7.77(d,1H),7.58(d,1H),4.32(q,2H),1.30(t,3H).

[0203] Synthesis of IA-16a: To a mixture of ethyl 5-sulfamoylthiophene-2-carboxylate (100 mg, 0.43 mmol) in DMF (5 mL) was added NaH (51 mg, 1.28 mmol, 60% in oil). Then, to the above mixture was added iodomethane (960 mg, 6.76 mmol). The mixture was stirred at 20 °C for 12 h. Saturated NH Cl solution (20 mL) was added, and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na SO , filtered, and concentrated to give the crude product (100 mg, 379.8 μmol) as a solid. LCMS R t = 0.82 min in 1.5 min chromatography, 5-95AB, C9H 14 NO4S2[M+H] + MS ESI calculated value 264.0, found value 263.8.

[0204] Synthesis of IA-16b: A mixture of ethyl 5-(dimethylsulfamoyl)thiophene-2-carboxylate (100 mg, 0.38 mmol) and LiOH·HO (47.8 mg, 1.14 mmol) in THF (2 mL) and water (2 mL) was stirred at 20 °C for 1 h. 1 N HCl (10 mL) was added to adjust the pH to 2. The aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (85 mg, 361.3 μmol) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =13.92(s,1H),7.81(d,1H),7.65(d,1H),2.69(s,6H).

[0205] Synthesis of I-15: A mixture of 5-(dimethylsulfamoyl)thiophene-2-carboxylic acid (120 mg, 0.51 mmol), (1R)-5-chloroindan-1-amine (102.6 mg, 0.61 mmol), DIPEA (0.15 mL, 1.53 mmol), and HATU (232.72 mg, 0.61 mmol) in DMF (5 mL) was stirred at 20 °C for 1 h. Water (15 mL) was added, and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 35% to 50%) to give the product (71.6 mg, 186.0 μmol, 36% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =9.16(d,1H),7.93(d,1H),7.65(d,1H),7.36(s,1H),7.26(s,2H),5.46(q,1H),3.06 -2.96(m,1H),2.92-2.81(m,1H),2.69(s,6H),2.48-2.43(m,1H),2.05-1.92(m,1H). LCMS R t= 1.26 min in 2.0 min chromatography, 10-80AB, C 16 H 18 ClN2O3S2[M+H] + MS ESI calculated value 385.0, found value 384.9.

[0206] Example 16. Synthesis of Compound I-16 [ka] Synthesis of IA-17b: A mixture of 5-bromothiophene-2-sulfonyl chloride (3 g, 11.47 mmol), methanamine hydrochloride (929.39 mg, 13.76 mmol), and EtN (4.76 mL, 34.41 mmol) in DCM (30 mL) was stirred at 20 °C for 12 h. Water (30 mL) was added, and the aqueous layer was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (2.9 g, 11.3 mmol) as an oil.

[0207] Synthesis of IA-17c: A mixture of 5-bromo-N-methyl-thiophene-2-sulfonamide (2.9 g, 11.32 mmol), Pd(dppf)Cl (1.24 g, 1.7 mmol), and EtN (4.7 mL, 33.97 mmol) in ethanol (20 mL) was stirred at 80 °C for 16 h under CO (50 psi). The mixture was filtered through Celite, and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel (0% to 30% to 50% EtOAc in PE) to give the product (2.2 g, 8.82 mmol, 77% yield) as a solid. 1 H NMR (400 MHz, CDCl3) δ H =7.73(d,1H),7.55(d,1H),4.87-4.79(m,1H),4.38(q,2H),2.78(d,3H),1.39(t,3H).

[0208] Synthesis of IA-17d: A mixture of ethyl 5-(methylsulfamoyl)thiophene-2-carboxylate (1 g, 4.01 mmol) and LiOH·HO (504.91 mg, 12.03 mmol) in THF (10 mL) and water (10 mL) was stirred at 20 °C for 1 h. 1 N HCl (30 mL) was added to adjust the pH to 2. The aqueous layer was extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (880 mg, 3.97 mmol) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =13.78(brs,1H),7.91(dd,1H),7.74(d,1H),7.58(d,1H),2.53(d,3H).

[0209] Synthesis of I-16: A mixture of 5-(methylsulfamoyl)thiophene-2-carboxylic acid (200 mg, 0.90 mmol), (1R)-5-chloroindan-1-amine (181.85 mg, 1.08 mmol), DIPEA (0.27 mL, 2.71 mmol), and HATU (412.46 mg, 1.08 mmol) in DMF (10 mL) was stirred at 20 °C for 1 h. Water (15 mL) was added, and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0% to 35% to 50% EtOAc in PE) to give the product (201.1 mg, 542.3 μmol, 59% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =9.12(d,1H),7.89-7.79(m,2H),7.58(d,1H),7.37(s,1H),7.26(d,2H),5.47(q,1H),3.07 -2.97(m,1H),2.93-2.82(m,1H),2.54-2.52(m,3H),2.49-2.44(m,1H),2.06-1.94(m,1H). LCMS R t = 1.24 min in 2.0 min chromatography, 10-80AB, C 15 H 16 ClN2O3S2[M+H] + MS ESI calculated value 371.0, found value 371.0.

[0210] Example 17. Synthesis of Compound I-17 [ka] Synthesis of IA-18a: To a stirred solution of IA-17a (1 g, 3.82 mmol) in DCM (30 mL) were added pyrrolidine (0.41 g, 5.74 mmol), K2CO3 (1.59 g, 11.47 mmol), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (20 mL) and water (15 mL). The organic layer was separated and washed with 2 × 10 mL of water and 1 × 10 mL of saturated brine solution. The organic layer was dried over MgSO4 and evaporated to give a crude mixture. The crude mixture was purified by flash column chromatography eluting with 50% EtOAc in hexane to give the desired IA-18a (1 g, 3.33 mmol, 87% yield) as a solid, which was used in the next step without further purification.

[0211] Synthesis of IA-18b: In an autoclave, a stirred solution of IA-18a (1 g, 3.38 mmol) in methanol (20 mL) and DMF (2 mL) was added with TEA (0.34 g, 3.38 mmol), Pd(dppf)Cl . DCM (0.28 g, 0.34 mmol) was added. The reaction mass was then heated to 80 °C at 100 psi atmospheric CO pressure for 6 h. Upon completion, the reaction mass was cooled to room temperature, filtered through a bed of Celite, and concentrated to dryness. The crude material was purified by flash column chromatography eluting with 40% EtOAc in hexanes to afford the desired IA-18b (0.90 g, 2.57 mmol, 76% yield) as a solid.

[0212] Synthesis of IA-18c: To a stirred solution of IA-18b (0.9 g, 3.27 mmol) in THF (6 mL) was added lithium hydroxide (0.12 g, 4.9 mmol) in water (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was concentrated, and the residue was diluted with water and ether. The organic layer was separated. The aqueous layer was acidified with dilute HCl. The solid that formed was filtered to give the desired IA-18c (0.60 g, 2.26 mmol, 69% yield) as a solid, which was used in the next step without further purification.

[0213] Synthesis of I-17: To a stirred solution of IA-18c (0.1 g, 0.38 mmol) in DCM (5 mL), IA-2 (0.06 g, 0.380 mmol), HATU (0.17 g, 0.46 mmol), and DIPEA (0.13 mL, 0.77 mmol) were added and stirred at room temperature for 6 h. The reaction was diluted with water (10 mL) and DCM (10 mL). The organic layer was separated and washed with 1×20 mL of saturated brine solution. The organic layer was separated, dried over MgSO4, and concentrated. The crude material was purified by flash column chromatography eluting with 50% EtOAc in hexane to afford I-17 (55 mg, 0.13 mmol, 34% yield) as a solid. HPLC: Rt 9.26 min, 97.6%; Column: X-select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 411.15 (M+H), Rt 2.05 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d): δ H =9.13(d,1H),7.90(d,1H),7.69(d,1H),7.36(s,1H),7.25(s,2H),5.5-5.4(m,1H),3. 32-3.17(m,5H),3.06-2.95(m,1H),2.87(dt,1H),2.06-1.92(m,1H),1.8-1.60(m,4H).

[0214] Example 18. Synthesis of Compound I-18 [ka] Synthesis of IA-19b: To a stirred solution of IA-19a (1 g, 4.52 mmol) and sodium methanesulfinate (553.67 mg, 5.43 mmol) in DMSO (20 mL), copper iodide (85.95 mg, 0.45 mmol) and L-proline (104.16 mg, 0.90 mmol) were added at room temperature, followed by the addition of sodium hydroxide. The reaction mixture was then stirred at 95 °C for 16 h. The reaction was quenched with water (50 mL) to which EtOAc (50 mL × 2) was added. The organic layer was separated, dried over Na2SO4, and concentrated to give a crude mixture. The crude mixture was purified by column chromatography using 100-200 silica and 20-40% EtOAc / hexane to give the desired IA-19b (270 mg, 1.16 mmol, 26% yield) as a solid, which was used in the next step without further purification.

[0215] Synthesis of IA-19c: To a stirred solution of IA-19b (0.25 g, 1.13 mmol) in THF:water (8:2 mL) was added LiOH.HO (57.15 mg, 1.36 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 2 h. The reaction was quenched with water (100 mL) and diluted with EtOAc (50 mL × 2). The organic layer was separated, and the aqueous layer was acidified with 1 N HCl. The formed precipitate was filtered, separated, and dried under high vacuum to give the desired IA-19c (0.15 g, 0.69 mmol, 61%) as a solid. IA-19c was used in the next step without further purification.

[0216] Synthesis of I-18: To a stirred solution of IA-19c (0.1 g, 0.48 mmol) and IA-2 (97.54 mg, 0.58 mmol) in DCM (10 mL) was added DIPEA (0.17 mL, 0.97 mmol) and HATU (276.54 mg, 0.73 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 2 h. The reaction was quenched using water (100 mL) and DCM (2 × 100 mL). The organic layer was separated and dried over NaSO, then filtered and concentrated. The crude product was purified by column chromatography on 100-200 silica with 30-80% EtOAc / hexane elution to afford I-18 (80 mg, 0.22 mmol, 46% yield) as a solid. HPLC: Rt 8.31 min, 99.7%; Column: X-select CSH C18 (4.6 x 150) mm, 3.5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 355.95 (M+H), Rt 1.88 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d): δ H =9.17(d,1H),7.88(d,1H),7.81(d,1H),7.36(s,1H),7.25(bs,2H),5.47(q,1H),3.3 8(s,3H),3.04-2.98(m,1H),2.91-2.83(m,1H),2.47-2.44(m,1H),2.00-1.95(m,1H).

[0217] Example 19. Synthesis of Compound I-19 [ka] Synthesis of IA-20b: To a stirred solution of IA-17a (1 g, 3.82 mmol) in DCM (20 mL), IA-20a (436.57 mg, 7.65 mmol) was added and stirred at room temperature for 30 min. The reaction was quenched with water (50 mL) and diluted with DCM (50 mL × 2). The organic layer was separated, dried over NaSO, and concentrated to give a crude mixture. The crude mixture was then purified by column chromatography using 100-200 silica and 5-10% EtOAc / hexane as the eluent to give IA-20b (900 mg, 3.16 mmol, 83% yield) as a solid.

[0218] Synthesis of IA-20c: To a stirred solution of IA-20b (0.5 g, 1.77 mmol) in methanol:DMF (20:2 mL) was added TEA (179.08 mg, 1.77 mmol) at room temperature. The reaction mixture was degassed using argon gas at room temperature for 30 min and treated with Pd(dppf)Cl₂·DCM (144.68 mg, 0.180 mmol). CO₂ gas was purged (100 psi) into the reaction mixture, and the reaction mixture was heated at 80 °C for 16 h. The reaction mixture was evaporated under reduced pressure. The crude product was purified by column chromatography using 100-200 silica with 10-20% EtOAc / hexane as eluent to afford the desired IA-20c (250 mg, 0.90 mmol, 51.25% yield) as a solid, which was used in the next step without further purification.

[0219] Synthesis of IA-20d: To a stirred solution of IA-20c (0.25 g, 0.95 mmol) in THF:water (8:2 mL) was added lithium hydroxide (0.06 mg, 0.0014 mmol) at room temperature and stirred for 2 h. The reaction was quenched with water (100 mL) and diluted with EtOAc (50 mL × 2). The organic layer was separated, and the aqueous layer was acidified with 1 N HCl, resulting in precipitation. The formed precipitate was filtered, isolated, and dried under high vacuum to afford the desired IA-20d (120 mg, 0.47 mmol, 49% yield) as a solid, which was used in the next step without further purification.

[0220] Synthesis of I-19: To a stirred solution of IA-20d (0.1 g, 0.40 mmol) and IA-2 (81.35 mg, 0.49 mmol) in DCM (10 mL) was added DIPEA (0.14 mL, 0.81 mmol) and HATU (230.64 mg, 0.610 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (100 mL) and diluted with DCM (100 mL × 2). The organic layer was separated, dried over NaSO, and concentrated to give the crude product. The crude was purified by column chromatography using 100-200 silica with 30-80% EtOAc / hexane as the eluent to give I-19 (60 mg, 0.14 mmol, 37% yield) as a solid. HPLC: Rt 8.99 min, 99.6%; Column: X-select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 397 (M+H), Rt 2.01 min, Column: X-select CSH C18 (3.0 × 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =9.19(d,1H),7.99(d,1H),7.74(d,1H),7.37(s,1H),7.29-7.24(m,2H),5.48(q,1H) ),3.77(t,4H),3.02(ddd,1H),2.88(dt,1H),2.51-2.41(m,1H),2.12-1.93(m,3H).

[0221] Example 20. Synthesis of Compound I-20 [ka] Synthesis of IA-21a: A stirred solution of IA-19a (1 g, 4.52 mmol) and copper(I) cyanide (0.61 g, 6.79 mmol) in DMF (10 mL) was heated at 120 °C for 12 h. After completion, ice-cold water was added to the reaction mixture. The solid was filtered and purified by column chromatography using silica gel (100-200) and 20% ethyl acetate in hexane as the eluent to give IA-21a (500 mg, 2.66 mmol, 59% yield) as a solid.

[0222] Synthesis of IA-21b: To a stirred solution of IA-21a (0.5 g, 2.99 mmol) in THF (5 mL) was added NaOH (0.36 g, 8.97 mmol) in water (5 mL), and the reaction was then heated at 90° C. for 12 h. The solvent was removed, and the aqueous layer was cooled to 0° C. and acidified with 2 N HCl. The solid was filtered and dried to afford IA-21b (0.35 g, 1.02 mmol, 34% yield) as a solid, which was used in the next step without further purification.

[0223] Synthesis of I-20: To a stirred solution of IA-21b (0.1 g, 0.58 mmol) in DCM (3 mL) was added DIPEA (0.2 mL, 1.17 mmol) and HATU (0.3 g, 0.88 mmol) at 0 °C and stirred for 10 min. The resulting reaction mixture was added to IA-2 (0.11 g, 0.64 mmol), and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was quenched with water and extracted with DCM (10 mL × 3), and the organic layer was separated. The combined organic layers were dried over sodium sulfate, and the solvent was removed under reduced pressure to give the crude product, which was purified by preparative HPLC to give I-20 (20.61 mg, 11% yield) as a solid. HPLC: Rt 7.64 min, 97.8%; Column: X-select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 321.05 (M+H), Rt 1.74 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1H NMR (400 MHz, DMSO-d6) δ H =8.92(d,1H),8.07(bs,1H),7.76(d,1H),7.68(d,1H),7.57(bs,1H),7.35(s,1H),7.24(d,2H), 5.48-5.41(m,1H),3.02-2.96(m,1H),2.90-2.84(m,1H),2.50-2.42(m,1H),2.01-1.96(m,1H).

[0224] Example 21. Synthesis of Compound I-21 [ka] Synthesis of IA-22b: To a stirred solution of IA-19a (1.5 g, 6.79 mmol) and IA-22a (1.3 g, 10.18 mmol) in DMSO (20 mL), copper iodide (0.13 g, 0.68 mmol), L-proline (0.16 g, 1.36 mmol), and sodium hydroxide (0.05 g, 1.35 mmol) were added at room temperature. The reaction mixture was stirred at 95 °C for 16 h. The reaction was quenched using water (50 mL) and diluted with EtOAc (50 mL × 2). The organic layer was separated and diluted with NaSO. 4, The mixture was dried over ice, filtered, and evaporated under reduced pressure to give the crude product, which was purified by column chromatography using 100-200 silica and 20-40% EtOAc / hexane eluent to give IA-22b (0.4 g, 1.54 mmol, 23% yield) as a solid, which was used in the next step without further purification.

[0225] Synthesis of IA-22c: To a stirred solution of IA-22b (0.4 g, 1.62 mmol) in THF:water (10:3 mL) was added LiOH.HO (0.1 g, 2.44 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched using water (100 mL) and diluted with EtOAc (50 mL × 2). The organic layer was separated, and the resulting aqueous layer was acidified with 1 N HCl, resulting in precipitation. The formed solid was filtered, separated, and dried to afford IA-22c (0.23 g, 0.95 mmol, 58% yield) as a solid, which was used in the next step without further purification.

[0226] Synthesis of I-21: To a stirred solution of IA-22c (0.1 g, 0.43 mmol) and IA-2 (86.61 mg, 0.52 mmol) in DCM (10 mL) was added HATU (245.54 mg, 0.65 mmol) and DIPEA (0.15 mL, 0.86 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (100 mL) and diluted with DCM (100 mL × 2). The organic layer was then separated, dried over NaSO, filtered, and evaporated under reduced pressure to give the crude product. The crude mixture was purified by column chromatography using 100-200 silica and 30-80% EtOAc / hexane elution to give I-21 (0.092 g, 0.24 mmol, 56% yield) as a solid. HPLC: Rt 8.90 min, 99.9%; Column: X-select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 382.00 (M+H), Rt 2.00 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H=9.18(d,1H),7.89(d,1H),7.79(d,1H),7.36(s,1H),7.25(s,2H),5.47(q,1H),3.04-2 .97(m,2H),2.91-2.83(m,1H),2.46-2.44(m,1H),2.04-1.92(m,1H),1.28-1.08(m,4H).

[0227] Example 22. Synthesis of Compound I-22 and Compound I-23 [ka] To a stirred solution of IA-23a (160 mg, 0.90 mmol) and 5-(methylsulfamoyl)thiophene-2-carboxylic acid (210 mg, 0.90 mmol) in DCM (20 mL) was added DIPEA (0.31 mL, 1.81 mmol) and HATU (380 mg, 0.99 mmol) at 0 °C and stirred at room temperature for 6 h. The reaction mixture was quenched with water (10 mL) and diluted with DCM (10 mL). The organic layer was washed with brine solution (10 mL), dried over MgSO4, and evaporated to give the crude product. The crude product IA-23b was purified by chiral SFC chromatography using a mobile phase: (A) CO₂, (B) MeOH + NH₃, gradient: 25–50% B in 5 min, hold 50% B at 9 min, 50–25% B at 10 min, hold 25% B until 12 min, column: DAICEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm), wavelength: 263 nm, flow rate: 3 mL / min to give I-22 (53 mg, 0.13 mmol, 15% yield) and I-23 (53 mg, 0.13 mmol, 15% yield) as solids. Stereochemistry was randomly assigned. I-22: HPLC: Rt 7.25 min, 98.5%; Column: X-Bridge C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% NH3 in water, B: ACN; Flow rate: 1.2 mL / min LCMS: 384.98 (M+H), Rt 1.98 min; Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H=9.11(d,1H),7.88-7.80(m,2H),7.56(d,1H),7.26-7.16(m,3H),5.16-5.12(m, 1H), 2.80-2.70 (m, 2H), 2.52-2.48 (m, 3H), 2.00-1.90 (m, 2H), 1.86-1.68 (m, 2H). Chiral HPLC: Rt: 3.62 min, 100%, Column: DIACEL CHIRALPAK-1G (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂ B) MeOH + 0.1% NH₃, Gradient: 35–50% B in 5 min, hold 50% B until 9 min, 50–35% B in 10 min, hold 35% B until 12 min, Wavelength: 265 nm, Flow rate: 3 mL / min I-23: HPLC: Rt 7.25 min, 99.4%; Column: X-Bridge C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% NH3 in water, B: ACN; Flow rate: 1.2 mL / min LCMS: 384.91 (M+H), Rt 1.97 min; Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =9.11(d,1H),7.86-7.78(m,2H),7.56(d,1H),7.26-7.12(m,3H),5.16-5.10(m, 1H), 2.82-2.72 (m, 2H), 2.52-2.44 (m, 3H), 2.00-1.90 (m, 2H), 1.85-1.74 (m, 2H). Chiral HPLC: Rt: 4.68 min, 100%, Column: DIACEL CHIRALPAK-1G (250 x 4.6 mm, 5 μm), Mobile phase: A) CO₂, B) MeOH + 0.1% NH₃, Gradient: 35-50% B in 5 min, hold 50% B until 9 min, 50-35% B in 10 min, hold 35% B until 12 min, Wavelength: 265 nm, Flow rate: 3 mL / min

[0228] Example 23. Synthesis of Compound I-24 and Compound I-25 [ka] Synthesis of IA-24b: To a stirred solution of IA-24a (2.3 g, 12.73 mmol) in water:THF (1:5, 60 mL) was added NHOH (8.85 g, 127.33 mmol), sodium acetate (10.45 g, 127.33 mmol) and heated at 70 °C for 4 h. The reaction mixture was cooled, concentrated, and then washed with water. The organic layer was dried over MgSO and evaporated to give IA-24b (2.4 g, 11.81 mmol, 92% yield) as a solid.

[0229] Synthesis of IA-23a: To a stirred solution of IA-24b (2.4 g, 12.27 mmol) in acetic acid (50 mL), ammonium chloride (6.56 g, 122.67 mmol), zinc powder (8.02 g, 122.67 mmol) were added and stirred at room temperature for 24 h. The reaction mixture was evaporated to dryness, and the residue was washed with EtOAc (100 mL) and saturated NaHCO. The organic layer was washed with water (2 × 30 mL), then saturated brine solution (30 mL), and dried over MgSO to give IA-23a (1.4 g, 3.94 mmol, 32% yield) as a liquid.

[0230] Synthesis of I-24 and I-25: To a stirred solution of IA-23a (132.12 mg, 0.73 mmol) and 5-(methylsulfonyl)thiophene-2-carboxylic acid (150 mg, 0.73 mmol) in DCM (10 mL), DIPEA (0.25 mL, 1.45 mmol) and HATU (414.82 mg, 1.09 mmol) were added at room temperature and stirred for 2 h. The reaction was quenched with water (100 mL) and diluted with DCM (100 mL × 2). The combined organic layers were dried over sodium sulfate and evaporated to give the crude product, which was purified by column chromatography on 100-200 ml silica gel with 30-80% EtOAc in hexanes to give the racemic mixture IA-24c. This was then purified by chiral SFC chromatography using the following mobile phase: (A) CO₂, (B) MeOH + NH₃, gradient: 25-50% B in 5 min, hold 50% B at 9 min, 50-25% B at 10 min, hold 25% B until 12 min, column: DAICEL CHIRALPAK-IG (250 x 4.6 mm, 5 µm), wavelength: 263 nm, flow rate: 3 mL / min to give I-24 (56.1 mg, 0.15 mmol, 21% yield) and I-25 (62.5 mg, 0.16 mmol, 23% yield) as solids. Stereochemistry was randomly assigned. I-24: HPLC: Rt 8.79 min, 99.2%; Column: X-Select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 369.95 (M+H), Rt 2.07 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =9.18(d,1H),7.89(d,1H),7.80(d,1H),7.26-7.16(m,3H),5.16-5.12(m,1H) ,3.38-3.30(m,3H),2.84-2.70(m,2H),2.01-1.92(m,2H),1.90-1.76(m,2H). I-25: HPLC: Rt 8.52 min, 98.2%; Column: X-Select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 369.95 (M+H), Rt 2.05 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =9.15(d,1H),7.88(d,1H),7.78(d,1H),7.24-7.14(m,3H),5.16-5.10(m, 1H),3.36(d,3H),2.78-2.72(m,2H),1.96-1.88(m,2H),1.84-1.55(m,2H).

[0231] Example 24. Synthesis of Compound I-26 [ka] To a stirred solution of IA-25a (115.8 mg, 0.6 mmol) and IA-2 (100 mg, 0.6 mmol) in DCM (2 mL) was added DIPEA (0.26 mL, 1.49 mmol) and HATU (340.2 mg, 0.89 mmol) at room temperature and stirred for 5 hours. The reaction mixture was quenched with water (10 mL) and diluted with DCM (10 mL). The organic layer was washed with brine solution (15 mL), dried over (NaSO), and evaporated to give the crude product. The crude product was purified by preparative HPLC to give I-26 (75 mg, 0.25 mmol, 36% yield) as a solid. HPLC: Rt 9.40 min, 98.4%; Column: X-Select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 344 (M+H), Rt 2.17 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H=8.97(d,1H),7.36(d,2H),7.32-7.21(m,2H),5.46(q,1H),4.18(s,3H),3 .04-2.96(m,1H),2.92-2.82(m,1H),2.51-2.41(m,1H),2.02-1.92(m,1H). Chiral method: Rt3.20 min, 95%; SFC column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂, B) MeOH + 0.1% NH₃; Gradient: 10–40% B in 5 min, hold 40% B until 9 min, hold 40–10% B in 10 min, hold 10% B until 12 min; Wavelength: 280 nm; Flow rate: 3 mL / min

[0232] Example 25. Synthesis of Compound I-27 [ka] Synthesis of IA-26b: To IA-26a (2 g, 9.01 mmol) was added sodium methanethiolate (1.26 g, 18.01 mmol) in DMF (10 mL) at room temperature, and the reaction mixture was stirred at 60 °C for 2 h. The reaction was quenched using water (100 mL) and diluted with EtOAc (100 mL × 2). The organic layer was separated, dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by column chromatography using 100-200 silica and 10-40% EtOAc / hexane as the eluent to give IA-26b (0.70 g, 3.66 mmol, 40% yield) as a solid.

[0233] Synthesis of IA-26c: To a stirred solution of IA-26b (0.5 g, 2.7 mmol) and sodium tungstate dihydrate (0.09 g, 0.0003 mmol) in acetic acid (10 mL) was added 30% HO in water (0.6 mL, 0.01 mmol) at room temperature, and the reaction mixture was stirred for 10 min. The reaction was quenched using water (100 mL) and diluted with EtOAc (100 mL × 2). The organic layer was separated, dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by column chromatography using 100-200 silica and 10-40% EtOAc / hexane as the eluent to give IA-26c (0.50 g, 2.24 mmol, 84% yield) as a solid.

[0234] Synthesis of IA-26d: To a stirred solution of IA-26c (0.5 g, 2.27 mmol) in THF:water (10:5 mL), LiOH.HO (114.3 mg, 2.72 mmol) was added at room temperature and stirred for 2 h. The reaction mixture was quenched with water (100 mL) and diluted with EtOAc (50 mL × 2). The aqueous layer was separated. The aqueous layer was acidified with 1 N HCl. The precipitate thus formed was filtered and dried using high vacuum to give IA-26d (0.30 g, 1.36 mmol, 60% yield) as a solid.

[0235] Synthesis of I-27: To a stirred solution of IA-26d (0.1 g, 0.48 mmol) and IA-2 (97.07 mg, 0.58 mmol) in DCM (10 mL) was added HATU (275.22 mg, 0.72 mmol) followed by DIPEA (0.17 mL, 0.97 mmol) at 0 °C and stirred at room temperature for 2 h. The reaction mixture was diluted with water (100 mL) and DCM (100 mL × 2). The organic layer was separated, dried over NaSO, filtered, and concentrated to give the crude product. The crude product was then purified by column chromatography using 100-200 silica and 30-80% EtOAc in hexane as the eluent to give I-27 (85.1 g, 0.23 mmol, 49% yield) as a solid. HPLC: Rt 8.34 min, 99.7%; Column: X-select CSH C18 (4.6 x 150) mm, 3.5 μm; Mobile phase: A - 0.1% FA in water:acetonitrile (95:05), B - acetonitrile; Flow rate: 1.0 mL / min LCMS: 356.85 (M+H), Rt 2.01 min, Column: X-select CSH C18 (3.0 × 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d): δ H = 9.35 (d, 1H), 8.68 (d, 1H), 7.37 (s, 1H), 7.33-7.22 (m, 2H), 5.52-5.42 (m, 1H), 3.50 (d, 3H), 3.05-2.98 (m, 1H), 2.93-2.84 (m, 1H), 2.06-1.92 (m, 1H). Note: 1H was not observed.

[0236] Example 26. Synthesis of Compound I-28 and Compound I-29 [ka] Synthesis of IA-27b: To a stirred solution of IA-27a (400 mg, 2.15 mmol) and IA-2 (432.18 mg, 2.58 mmol) in DCM (10 mL) was added HATU (1225.3 mg, 3.22 mmol) and DIPEA (0.75 mL, 4.3 mmol) at room temperature. The reaction was then stirred at room temperature for 2 h. The reaction was quenched using water (100 mL) and diluted with DCM (100 mL × 2). The combined organic layers were separated, dried over NaSO, filtered, and evaporated to give the crude product, which was purified by column chromatography using 100-200 silica and 30-80% EtOAc / hexane elution to give IA-27b (600 mg, 1.71 mmol, 80% yield) as a solid.

[0237] Synthesis of IA-27c: To a solution of IA-27b (500 mg, 1.49 mmol) in THF:water (10:5 mL), LiOH.HO (74.97 mg, 1.79 mmol) was added at room temperature and stirred for 2 h. The reaction was quenched with water (100 mL) and diluted with EtOAc (50 mL × 2). The combined organic layer was separated and acidified with 1 N HCl to give a precipitate, which was filtered, separated, and dried to give IA-27c (0.40 g, 1.21 mmol, 81% yield) as a solid.

[0238] Synthesis of I-28: To a stirred solution of IA-27c (100 mg, 0.31 mmol) in DCM (10 mL) and methylamine (0.2 mL, 0.37 mmol) in THF (2 M), HATU (177.25 mg, 0.47 mmol) and DIPEA (0.11 mL, 0.62 mmol) were added at room temperature and stirred for 2 h. The reaction was quenched with water (100 mL) and diluted with DCM (100 mL × 2). The combined organic layers were separated, dried over NaSO, filtered, and evaporated under reduced pressure to give the crude product, which was purified by column chromatography using 100-200 silica gel and 30-80% EtOAc / hexane elution to give I-28 (44.1 mg, 0.13 mmol, 42% yield) as a solid. HPLC: Rt 7.84 min, 99.5%; Column: X-select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 335.15 (M+H), Rt 1.95 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =8.92(d,1H),8.57(d,1H),7.76(d,1H),7.64(d,1H),7.35(s,1H),7.24(s,2H),5.50-5 .40(m,1H),3.02-2.97(m,1H),2.92-2.73(m,4H),2.48-2.42(m,1H),2.03-1.96(m,1H). Chiral method: Rt 7.28 min, 98.7%; SFC column: DIACEL CHIRALPAK-IG (250 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, hold 20% B until 12 min; Wavelength: 280 nm; Flow rate: 3 mL / min

[0239] Synthesis of I-29: To a stirred solution of IA-27c (100 mg, 0.31 mmol) and dimethylamine (0.2 mL, 0.37 mmol) in THF (2 M) in DCM (10 mL), HATU (177.25 mg, 0.47 mmol) and DIPEA (0.11 mL, 0.62 mmol) were added at room temperature and stirred for 2 h. The reaction was quenched with water (100 mL) and diluted with DCM (100 mL × 2). The combined organic layer was separated, dried over NaSO, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography using 100-200 silica and 30-80% EtOAc / hexane elution to give I-29 (65.2 mg, 0.18 mmol, 59% yield) as a solid. HPLC: Rt 7.98 min, 98.7%; Column: X-select CSH C18 (4.6 x 150) mm, 3.5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 348.95 (M+H), Rt 2.01 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =8.94(d,1H),7.76(d,1H),7.45(d,1H),7.35(s,1H),7.24(s,2H),5.52 -5.41(m,1H),3.18-2.82(m,8H),2.51-2.41(m,1H),2.02-1.96(m,1H). Chiral method: Rt 6.35 min, 98.4%; SFC column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂, B) MeOH + 0.1% NH₃; Gradient: 35-50% B in 5 min, hold 50% B until 9 min, 50-10% B in 10 min, hold 35% B until 12 min; Wavelength: 280 nm; Flow rate: 3 mL / min

[0240] Example 27. Synthesis of Compound I-30 and Compound I-31 [ka] To a stirred solution of IA-23a (151.95 mg, 0.84 mmol) and 5-carbamoylthiophene-2-carboxylic acid (119.31 mg, 0.70 mmol) in DCM (10 mL) was added DIPEA (0.24 mL, 1.39 mmol) and HATU (318.04 mg, 0.84 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction was quenched using water (15 mL) and diluted with DCM (30 mL). The aqueous layer was washed with DCM (2 × 30 mL). The organic layer was washed with brine solution (20 mL), dried over NaSO, and evaporated to give the crude product. The crude product was purified by flash column chromatography using 100-200 silica and 25% EtOAc in hexanes as the eluent. The desired fractions were evaporated, and racemic compound IA-28a was purified by chiral SFC chromatography using a mobile phase: (A) CO₂, (B) MeOH + NH₃, gradient: 25–50% B in 5 min, hold 50% B at 9 min, 50–25% B at 10 min, hold 25% B until 12 min, column: DAICEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm), wavelength: 263 nm, flow rate: 3 mL / min to give I-30 (4.85 mg, 0.01 mmol, 2% yield) and I-31 (2.03 mg, 0.0061 mmol, 1% yield) as solids. Stereochemistry was randomly assigned. I-30: HPLC: Rt 7.74 min, 99.5% Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm; Mobile phase: A: 0.1% FA in water:acetonitrile (95:05), B: ACN; Flow rate: 1.0 mL / min LCMS: 335.10 (M+H), Rt 1.95 min, Column: X-select CSH (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d): δ H =8.91(d,1H),8.08-8.03(m,1H),7.75(d,1H),7.66(d,1H),7.55(s,1H),7.24-7.14 (m,3H),5.16-5.08(m,1H),2.85-2.68(m,2H),1.98-1.88(m,2H),1.84-1.70(m,2H). I-31: HPLC: Rt 7.75 min, 99.8% Column: X-select CSH C18 (4.6 x 150) mm, 3.5 μm; Mobile phase: A: 0.1% FA in water:acetonitrile (95:05), B: ACN; Flow rate: 1.0 mL / min LCMS: 335.10 (M+H), Rt 1.97 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =8.91(d,1H),8.05(s,1H),7.76(d,1H),7.66(d,1H),7.55(s,1H),7.24-7.14(m, 3H), 5.16-5.08(m, 1H), 2.84-2.69(m, 2H), 2.00-1.88(m, 2H), 1.85-1.66(m, 2H).

[0241] Example 28. Synthesis of Compound I-32 and Compound I-33 [ka] To a stirred solution of IA-23a (260 mg, 1.45 mmol) and 5-sulfamoylthiophene-2-carboxylic acid (300 mg, 1.45 mmol) in DCM (20 mL) was added DIPEA (0.5 mL, 2.9 mmol) and HATU (660 mg, 1.74 mmol) at room temperature and stirred for 6 h. The reaction mixture was quenched with water (10 mL) and diluted with DCM (10 mL). The organic layer was washed with brine solution (15 mL), dried over MgSO4, and evaporated to give the crude product. The crude product was purified by flash column chromatography using 100-200 silica and 50% EtOAc in hexanes as the eluent. The desired fractions were evaporated, and racemic compound IA-29a was purified by chiral SFC chromatography using the following mobile phase: (A) CO₂, (B) MeOH + NH₃, gradient: 25–50% B in 5 min, hold 50% B at 9 min, 50–25% B at 10 min, hold 25% B until 12 min, column: DAICEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm), wavelength: 263 nm, flow rate: 3 mL / min to give I-32 (18 mg, 0.04 mmol, 3% yield) and I-33 (23 mg, 0.06 mmol, 4% yield) as solids. Stereochemistry was randomly assigned. I-32: HPLC: Rt 8.15 min, 96.3%; Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm; Mobile phase: A: 0.1% FA in water:acetonitrile (95:05), B: ACN; Flow rate: 1.0 mL / min LCMS: 371.05 (M+H), Rt 2.05 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =9.07(d,1H),7.84-7.75(m,3H),7.52(d,1H),7.25-7.10(m,3H),5.16 -5.08(m,1H),2.85-2.68(m,2H),2.00-1.92(m,2H),1.86-1.70(m,2H). Chiral method: Rt 9.36 min, 100%; SFC column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂ B) MeOH + 0.1% NH₃; Gradient: 35-50% B in 5 min, hold 50% B until 9 min, 50-35% B in 10 min, hold 35% B until 12 min; Wavelength: 270 nm; Flow rate: 3 mL / min I-33: HPLC: Rt 8.27 min, 99.6%; Column: X-select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:acetonitrile (95:05), B: ACN; Flow rate: 1.0 mL / min LCMS: 371.05 (M+H), Rt 2.05 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d): δ H =9.07(d,1H),7.86-7.70(m,2H),7.54-7.50(m,1H),7.25-7.15(m,3H),5. 16-5.09(m,1H),2.84-2.65(m,2H),2.00-1.90(m,2H),1.86-1.68(m,2H). Chiral method: Rt 10.64 min, 99.5%; SFC column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂ B) MeOH + 0.1% NH₃; Gradient: 35-50% B in 5 min, hold 50% B until 9 min, 50-35% B in 10 min, hold 35% B until 12 min; Wavelength: 270 nm; Flow rate: 3 mL / min

[0242] Example 29. Synthesis of Compound I-34 [ka] Synthesis of IA-30b: To a stirred solution of IA-19a (1 g, 4.52 mmol) in DMSO (10 mL), IA-30a (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) were added at room temperature 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 were dried over NaSO and evaporated to give the crude compound. The crude was purified by column chromatography on 100-200 silica with 8–10% EtOAc / hexane elution to give IA-30b (300 mg, 1.21 mmol, 26% yield) as a solid.

[0243] Synthesis of IA-30c: To a stirred solution of IA-30b (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 room temperature for 2 h. The reaction mixture was concentrated to give the crude product. The crude product was diluted with cold water (10 mL), acidified with 2 N aqueous HCl to a maximum pH of 4, and extracted with DCM (3 × 15 mL). The combined organic layers were separated and dried over NaSO to give IA-30c (220 mg, 0.60 mmol, 46% yield) as a solid.

[0244] Synthesis of I-34: To a stirred solution of IA-30c (100 mg, 0.45 mmol) and IA-2 (76.11 mg, 0.45 mmol) in DCM (10 mL) was added HATU (207.14 mg, 0.54 mmol) followed by DIPEA (0.16 mL, 0.91 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (5 × 25 mL). The combined organic layers were separated, dried over NaSO, and evaporated to give the crude product. The crude product was purified by column chromatography using 100–200 mesh silica and 20–22% EtOAc in hexane as the eluent to give I-34 (130 mg, 0.34 mmol, 77% yield) as a solid. HPLC: Rt 9.01 min, 99.5%; Column: X-select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 10 mM ammonium bicarbonate in water, B: ACN; Flow rate: 1.0 mL / min LCMS: 369.80 (M+H), Rt 1.97 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d): δ H =9.17(d,1H),7.91(d,1H),7.78(d,1H),7.36(s,1H),7.25(s,2H),5.52-5.41(m,1H),3.49-3 .35(m,2H),3.29(d,1H),2.98-2.82(m,1H),2.5-2.45(m,1H),2.02-1.96(m,1H),1.18(t,3H).

[0245] Chiral method: Rt 6.00 min, 98.9%; SFC column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂ B) MeOH + 0.1% NH₃; Gradient: 35-50% B in 5 min, hold 50% B until 9 min, 50-35% B in 10 min, hold 35% B until 12 min; Wavelength: 261 nm; Flow rate: 3 mL / min

[0246] Example 30. Synthesis of Compound I-35 [ka] Synthesis of IA-31b: To a stirred solution of IA-31a (1 g, 6.4 mmol) in chloroform (10 mL) was added NBS (1.25 g, 7.04 mmol) and benzyl peroxide (0.16 g, 0.64 mmol) at room temperature and stirred at 70 °C for 7 h. The reaction mixture was then cooled to room temperature, diluted with DCM (20 mL), and washed with water (2 × 20 mL) and brine solution (20 mL). The organic layer was dried over NaSO and evaporated to give the crude product. The crude product was purified by column chromatography using 100-200 silica and 1-2% EtOAc / hexane eluent to give IA-31b (0.50 g, 1.94 mmol, 30% yield) as a solid.

[0247] Synthesis of IA-31c: To a stirred solution of IA-31b (300 mg, 1.28 mmol) in DMF (10 mL), sodium methanesulfinate (156.33 mg, 1.53 mmol) and tetrabutylammonium iodide (94.27 mg, 0.26 mmol) were added at room temperature and stirred for 16 h. After completion, the reaction was quenched using ice-cold water and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with ice-cold water (20 mL × 2), dried over NaSO, and evaporated to give the crude product. The crude product was purified by column chromatography using 100-200 silica and 4-5% EtOAc / hexane eluent to give IA-31c (250 mg, 1.06 mmol, 83% yield) as a solid.

[0248] Synthesis of IA-31d: To a stirred solution of IA-31c (300 mg, 1.28 mmol) in THF (9 mL) was added LiOH.HO (161.18 mg, 3.84 mmol) in water (1 mL) at room temperature and stirred for 16 h at room temperature. The reaction mixture was diluted with water (1 mL), washed with ether (2 × 5 mL), and separated. The aqueous layer was cooled to 0-5 °C and acidified using 6 M HCl, then stirred at room temperature for 30 min, resulting in precipitation. The resulting solid was filtered and dried to afford IA-31d (250 mg, 1.06 mmol, 82% yield) as a solid.

[0249] Synthesis of I-35: To a stirred solution of IA-31d (100 mg, 0.45 mmol) in DCM (2 mL), IA-2 (91.33 mg, 0.54 mmol), HATU (258.93 mg, 0.68 mmol), and DIPEA (0.16 mL, 0.91 mmol) were added at room temperature and stirred for 2 h. The reaction mixture was diluted with DCM and washed with water (10 mL × 2). The organic layer was separated, dried over NaSO, and evaporated to give the crude product. The crude product was purified by column chromatography using 100-200 silica and 25% EtOAc / hexane eluent to give I-35 (55 mg, 0.14 mmol, 31% yield) as a solid. HPLC: Rt 8.07 min, 99.7%; Column: X-select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 370.05 (M+H), Rt 1.87 min, Column: X-select CSH C18 (3.0 × 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =8.86(d,1H),7.74(dd,1H),7.35(d,1H),7.28-7.17(m,2H),7.15(dd,1H),5.48-5.42(m,1H),4.8 0(s,2H),3.05-2.94(m,3H),2.89-2.82(m,1H),2.69(d,1H),2.51-2.46(m,1H),2.01-1.94(m,1H). Chiral method: Rt 5.19 min, 97.3%; SFC column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂ B) MeOH + 0.1% NH₃; Gradient: 35-50% B in 5 min, hold 50% B until 9 min, 50-35% B in 10 min, hold 35% B until 12 min; Wavelength: 272 nm; Flow rate: 3 mL / min

[0250] Example 31. Synthesis of Compound I-36 [ka] Synthesis of IA-32a: To a stirred solution of IA-31b (400 mg, 1.7 mmol) in methanol (5 mL) was added NaOMe (183.82 mg, 3.4 mmol) at room temperature and stirred for 16 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2 × 10 mL) and brine (10 mL). The organic layer was dried over NaSO and evaporated to give the crude product. The crude product was purified by column chromatography using 100-200 silica and 2-3% EtOAc / hexane eluent to give IA-32a (120 mg, 0.59 mmol, 35% yield) as a liquid.

[0251] Synthesis of IA-32b: To a stirred solution of IA-32a (120 mg, 0.64 mmol) in THF (5 mL) was added LiOH.HO (81.11 mg, 1.93 mmol) in water (0.50 mL) at room temperature and stirred for 16 h. The reaction mixture was evaporated and diluted with water (0.5 mL). The aqueous layer was cooled to 0-5 °C, acidified with 6 M HCl, and stirred at room temperature for 30 min. The solid was filtered and dried to give IA-32b (65 mg, 0.36 mmol, 57% yield).

[0252] Synthesis of I-36: To a stirred solution of IA-32b (60 mg, 0.35 mmol) in DCM (2 mL), IA-2 (70.09 mg, 0.42 mmol), HATU (198.73 mg, 0.52 mmol), and DIPEA (0.12 mL, 0.70 mmol) were added at room temperature and stirred for 2 h. The reaction mixture was diluted with DCM and washed with water (10 mL × 2). The organic layer was separated, dried using NaSO, and evaporated to give the crude product. The crude product was purified by column chromatography using 100-200 silica and 25% EtOAc / hexane eluent to give I-36 (30 mg, 0.09 mmol, 25% yield) as a solid. HPLC: Rt 8.85 min, 96.0%; Column: X-select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 321.9 (M+H), Rt 1.94 min, Column: X-select CSH C18 (3.0 × 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =8.79(d,1H),7.70(d,1H),7.36(s,1H),7.27-7.22(m,2H),7.06(d,1H),5.51-5.41(m,1H),4.59 (s,2H),3.31(d,3H),3.04-2.98(m,1H),2.91-2.82(m,1H),2.49-2.43(m,1H),2.05-1.95(m,1H). Chiral method: Rt 7.03 min, 96.1%; SFC column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂ B) MeOH + 0.1% NH₃; Gradient: 10–40% B in 5 min, hold 40% B until 9 min, 40–10% B in 10 min, hold 10% B until 12 min; Wavelength: 264 nm; Flow rate: 3 mL / min

[0253] Example 32. Synthesis of Compound I-37 [ka] Synthesis of IA-33b: To a cooled solution of IA-33a (500 mg, 2.4 mmol) in DCM (10 mL), DIPEA (0.84 mL, 4.81 mmol), HATU (1.37 g, 3.61 mmol), and (1R)-5-chloroindan-1-amine (443.21 mg, 2.64 mmol) were added, and the reaction was stirred at room temperature for 3 h. The reaction was diluted with water and extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated to give the crude product, which was purified by column chromatography using silica gel (100-200) and MeOH:DCM (1:99) as the eluent to give IA-33b (380 mg, 1.06 mmol, 44% yield) as a solid.

[0254] Synthesis of IA-33c: To a solution of IA-33b (380 mg, 1.06 mmol) in DMF (5 mL), KCO (440.45 mg, 3.19 mmol) and (4-methoxyphenyl)methanethiol (163.87 mg, 1.06 mmol) were added at room temperature and stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with water and brine. The organic layer was dried over sodium sulfate and evaporated to give the crude product, which was purified by Combiflash chromatography using ethyl acetate:hexane as the eluent to give IA-33c (210 mg, 0.45 mmol, 43% yield) as a solid.

[0255] Synthesis of IA-33e: To a cooled solution of IA-33c (210 mg, 0.4900 mmol) in MeCN (2 mL), water (0.5 mL), and acetic acid (0.5 mL), 1,3-dichloro-5,5-dimethylhydantoin (191.99 mg, 0.97 mmol) was added at 0 °C and stirred at 0 °C for 2 h. The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated to give the crude product, which was purified by Combiflash chromatography using ethyl acetate:hexane as the eluent to give IA-33e (150 mg, 0.39 mmol, 81% yield) as a solid.

[0256] Synthesis of I-37: To a solution of IA-33e (200 mg, 0.530 mmol) in DCM (10 mL) was added saturated ammonia in DCM at 0 °C, and the reaction was stirred at the same temperature for 30 min, followed by stirring for 2 h. The reaction mixture was diluted with water and extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated to give the crude product, which was purified by Combiflash chromatography to give I-37 (65.1 mg, 0.21 mmol, 39% yield) as a solid. HPLC: Rt 9.26 min, 99.3%; Column: X-Select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 312.95 (M+H), Rt 2.08 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =9.12(d,1H),8.28(s,1H),7.36(s,1H),7.28-7.24(m,2H),5.43(q,1H),3 .03-2.96(m,1H),2.90-2.82(m,1H),2.52-2.41(m,1H),2.02-1.92(m,1H). Chiral method: Rt 6.90 min, 98.0%; SFC column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂, B) MeOH + 0.1% NH₃; Gradient: 10–40% B in 5 min, hold 40% B until 9 min, 40–10% B in 10 min, hold 10% B until 12 min; Wavelength: 263 nm; Flow rate: 3 mL / min

[0257] Example 33. Synthesis of Compound I-38 [ka] Synthesis of IA-34a: To a stirred solution of IA-31b (0.5 g, 2.13 mmol) and dimethylamine (0.16 mL, 3.19 mmol) in DMF (10 mL) was added KCO (587.75 mg, 4.25 mmol) at room temperature and stirred for 2 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were separated, dried over NaSO, filtered, and evaporated under reduced pressure to give the crude product, which was purified by column chromatography using 100-200 silica and 30-80% EtOAc / hexane as the eluent to give IA-34a (0.3 g, 1.2 mmol, 57% yield) as a solid.

[0258] Synthesis of IA-34b: To a stirred solution of IA-34a (0.3 g, 1.5 mmol) in THF:water (10:5 mL) was added LIOH.HO (63.17 mg, 1.51 mmol) at room temperature and stirred for 2 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (50 mL × 2). The organic layer was separated, and the remaining aqueous layer was acidified with 1 N HCl, resulting in precipitation. The precipitated solid was filtered and dried to give IA-34b (0.1 g, 0.48 mmol, 32% yield).

[0259] Synthesis of I-38: To a stirred solution of IA-34b (0.2 g, 1.08 mmol) and (1R)-5-chloroindan-1-amine (217.2 mg, 1.3 mmol) in DCM (10 mL) was added HATU (615.79 mg, 1.62 mmol) and DIPEA (0.38 mL, 2.16 mmol) at room temperature and stirred for 2 h. The reaction was quenched with water (100 mL) and extracted with DCM (100 mL × 2). The combined organic layers were separated, dried over NaSO, filtered, and evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography using 100-200 silica and 30-80% EtOAc / hexane as the eluent to give I-38 (20 mg, 0.06 mmol, 5% yield). HPLC: Rt 5.79 min, 99.7%; Column: X-Select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 334.95 (M+H), Rt 1.46 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =8.70(d,1H),7.63(d,1H),7.33(s,1H),7.27-7.17(m,2H),6.94(d,1H),5.43(q,1H),3.58(s, 2H), 3.00-2.94 (m, 1H), 2.88-2.78 (m, 1H), 2.46-2.40 (m, 1H), 2.17 (s, 6H), 2.02-1.92 (m, 1H). Chiral method: Rt 5.98 min, 100%; SFC column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂ B) MeOH + 0.1% NH₃; Gradient: 10–40% B in 5 min, hold 40% B until 9 min, 40–10% B in 10 min, hold 10% B until 12 min; Wavelength: 280 nm; Flow rate: 3 mL / min

[0260] Example 34. Synthesis of Compound I-39 [ka] Synthesis of IA-35a: To a stirred solution of IA-31b (0.5 g, 2.13 mmol) in DMF (10 mL), 1 M methanamine in THF (132.11 mg, 4.25 mmol) and K2CO3 (587.75 mg, 4.25 mmol) were added at room temperature and stirred for 2 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 2). The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography using 100-200 silica and 30-80% EtOAc / hexane elution to give IA-35a (0.2 g, 0.86 mmol, 40% yield).

[0261] Synthesis of IA-35b: To a stirred solution of IA-35a (0.2 g, 1.08 mmol) in acetic anhydride (10 mL) was added sodium acetate (177.13 mg, 2.16 mmol) at room temperature and stirred at 50 °C for 12 h. The reaction was quenched with water (100 mL) diluted with EtOAc (50 mL × 2). The organic layer was separated and dried over sodium sulfate rather than evaporated. The crude material was purified by column chromatography using 100-200 silica and 30-50% EtOAc / hexane as the eluent to give IA-35b (0.15 g, 0.35 mmol, 33% yield) as a solid.

[0262] Synthesis of IA-35c: To a stirred solution of IA-35b (0.3 g, 1.51 mmol) in THF:water (10:5 mL), LiOH.HO (63.17 mg, 1.51 mmol) was added at room temperature and stirred for 2 h. The reaction mixture was quenched with water (100 mL), and EtOAc (50 mL × 2) was added. The organic layer was separated, and the aqueous layer was acidified with 1 N HCl, resulting in precipitation. The precipitate thus formed was then filtered. The solid was isolated and dried under high vacuum to give IA-35c (0.1 g, 0.48 mmol, 32% yield).

[0263] Synthesis of I-39: To a stirred solution of IA-35c (0.1 g, 0.48 mmol) and (1R)-5-chloroindan-1-amine (96.13 mg, 0.57 mmol) in DCM (10 mL), HATU (272.54 mg, 0.72 mmol) and DIPEA (0.17 mL, 0.96 mmol) were added at room temperature and stirred for 2 h. The reaction was quenched with water (100 mL) and DCM (100 mL × 2). The organic layer was separated, dried over NaSO, and then filtered. The organic layer was evaporated, and the crude product was purified by column chromatography using 100-200 silica and 30-80% EtOAc / hexane as the eluent to give I-39 (75 mg, 0.2 mmol, 43% yield) as a solid. HPLC: Rt 8.14 min, 99.5%; Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 362.95 (M+H), Rt 1.87 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) (VT at 80 °C): δ H =8.48(d,1H),7.63(s,1H),7.30(s,1H),7.29-7.17(m,2H),6.98(d,1H),5.44(q, 1H), 4.80-4.60 (m, 2H), 3.08-2.76 (m, 5H), 2.49-2.44 (m, 1H), 2.05-2.00 (m, 4H). Chiral method: Rt 5.08 min, 99.7%; SFC column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂ B) MeOH + 0.1% NH₃; Gradient: 10–40% B in 5 min, hold 40% B until 9 min, 40–10% B in 10 min, hold 10% B until 12 min; Wavelength: 265 nm; Flow rate: 3 mL / min

[0264] Example 35. Synthesis of Compound I-40 [ka] Synthesis of IA-36b: To a stirred solution of IA-36a (0.5 g, 2.08 mmol) in DCM (5 mL), DIPEA (1.08 g, 6.23 mmol) and R-(+)-3-pyrrolidinol (0.34 mL, 4.15 mmol) were added at room temperature and stirred for 1 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over NaSO, filtered, and evaporated to give IA-36b (250 mg, 0.86 mmol, 41% yield) as a liquid.

[0265] Synthesis of IA-36c: To a stirred solution of IA-36b (0.4 g, 1.32 mmol) in THF:water (1:1, 3 mL), NaOH (158 mg, 3.96 mmol) was added at room temperature and stirred for 2 h. The reaction mixture was then evaporated, diluted with water (10 mL), and extracted with ethyl acetate (15 mL). The separated aqueous layer was acidified with 3 N HCl, resulting in a precipitate. The precipitate was filtered, washed with water, and dried to give IA-36c (220 mg, 0.64 mmol, 49% yield) as a solid.

[0266] Synthesis of I-40: To a stirred solution of IA-36c (200 mg, 0.72 mmol) and IA-2 (145 mg, 0.87 mmol) in DCM (5 mL) was added DIPEA (0.38 mL, 2.16 mmol) and HATU (411.3 mg, 1.08 mmol) at room temperature and stirred for 16 h. The reaction mixture was quenched with water (10 mL) and diluted with EtOAc (20 mL). The organic layer was washed with brine solution (15 mL), dried over (NaSO), and evaporated to give the crude product. The crude product was purified by preparative HPLC to give I-40 (40 mg, 0.09 mmol, 13% yield) as a solid. HPLC: Rt 8.30 min, 96.6%; Column: X-Select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 427.15 (M+H), Rt 1.89 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =9.12(d,1H),7.89(d,1H),7.66(d,1H),7.36(s,1H),7.26-7.24(m,2H),5.46(q,1H),4.20-4.18(m,1H),3.38 -3.22(m,4H),3.12-2.95(m,2H),2.90-2.84(m,1H),2.49-2.46(m,1H),2.02-1.96(m,1H),1.86-1.63(m,2H). Chiral method: Rt 5.80 min, 99.5%; SFC column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂, B) MeOH + 0.1% NH₃; Gradient: 35-50% B in 5 min, hold 50% B until 9 min, 50-35% B in 10 min, hold 35% B until 12 min; Wavelength: 273 nm; Flow rate: 3 mL / min

[0267] Example 36. Synthesis of Compound I-41 [ka] Synthesis of IA-37a: To a stirred solution of IA-36a (0.5 g, 2.08 mmol) in DCM (10 mL), DIPEA (1.08 g, 6.23 mmol) and S-(+)-3-pyrrolidinol (0.34 mL, 4.15 mmol) were added at room temperature and stirred for 1 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over NaSO, filtered, and evaporated to give IA-37a (300 mg, 1.03 mmol, 49% yield) as a liquid.

[0268] Synthesis of IA-37b: To a stirred solution of IA-37a (0.3 g, 1.05 mmol) in THF:water (1:1, 6 mL), NaOH (126 mg, 3.15 mmol) was added at room temperature and stirred for 2 h. The reaction mixture was then evaporated, diluted with water (10 mL), and extracted with ethyl acetate (15 mL). The separated aqueous layer was acidified with 3 N HCl, resulting in a precipitate. The precipitate was filtered, washed with water, and dried to give IA-37b (200 mg, 0.52 mmol, 49% yield) as a solid.

[0269] Synthesis of I-41: To a stirred solution of IA-37b (200 mg, 0.72 mmol) and IA-2 (181.3 mg, 1.08 mmol) in DCM (5 mL) was added DIPEA (0.38 mL, 2.16 mmol) and HATU (411.3 mg, 1.08 mmol) at room temperature and stirred for 16 h. The reaction mixture was quenched with water (10 mL) and diluted with EtOAc (20 mL). The organic layer was washed with brine solution (15 mL), dried over (NaSO), and evaporated to give the crude product. The crude product was purified by preparative HPLC to give I-41 (32 mg, 0.07 mmol, 10% yield) as a solid. HPLC: Rt 8.29 min, 98.7%; Column: X-Select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 427 (M+H), Rt 1.89 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =9.12(d,1H),7.89(d,1H),7.66(d,1H),7.36(s,1H),7.26-7.18(m,2H),5.46(q,1H),4.96-4.94(m,1H),4.20-4.18(m, 1H),3.38-3.24(m,3H),3.10-2.96(m,2H),2.88-2.84(m,1H),2.49-2.46(m,1H),2.10-1.92(m,1H),1.86-1.68(m,2H). Chiral method: Rt 5.86 min, 99.6%; SFC column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂ B) MeOH + 0.1% NH₃; Gradient: 35-50% B in 5 min, hold 50% B until 9 min, 50-35% B in 10 min, hold 35% B until 12 min; Wavelength: 273 nm; Flow rate: 3 mL / min

[0270] Example 37. Synthesis of Compound I-42 [ka] Synthesis of IA-36a: To a stirred solution of IA-38a (10 g, 70.3 mmol) in chloroform (100 mL), chlorosulfonic acid (12.24 g, 105.5 mmol) was added dropwise at −10° C., and the reaction mixture was heated at 70° C. for 16 h. The reaction mixture was cooled to −10° C. and treated dropwise with pyridine (18.73 mL, 232.1 mmol), followed by the portionwise addition of phosphorus pentachloride (17.58 g, 84.4 mmol) over 30 min. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured onto ice-cold water (300 mL) and stirred for 1 h. The reaction was extracted with DCM (3×250 mL). The combined organic phase was washed with brine (3×200 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography (100-200 mesh silica, 2-5% EtOAc in hexanes as eluent) to afford IA-36a (12 g, 48.86 mmol, 69% yield) as an oil.

[0271] Synthesis of IA-38c: To a stirred solution of IA-36a (0.5 g, 2.08 mmol) in DCM (5 mL), DIPEA (0.72 mL, 4.15 mmol) and 1-methylpiperazine (0.28 mL, 2.49 mmol) were added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated to give the crude product, which was purified by Combiflash chromatography using ethyl acetate:hexane as the eluent to give IA-38c (300 mg, 0.88 mmol, 42% yield) as an oil.

[0272] Synthesis of IA-38d: To a stirred solution of IA-38c (300 mg, 0.99 mmol) in THF (5 mL) was added a solution of LiOH.HO (82.71 mg, 1.97 mmol) in water (1 mL) at 0 °C and stirred at room temperature for 2 h. The reaction mixture was evaporated, and the residue was diluted with water and acidified with 2 N HCl. The aqueous layer was then evaporated to give IA-38d (180 mg, 0.57 mmol, 58% yield) as a solid, which was used directly in the next step.

[0273] Synthesis of I-42: To a stirred solution of IA-38d (100 mg, 0.6 mmol) and IA-2 (207.8 mg, 0.72 mmol) in DCM (10 mL) was added DIPEA (0.21 mL, 1.19 mmol) and HATU (272.8 mg, 0.72 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction mixture was quenched with water (10 mL) and diluted with DCM (20 mL). The separated aqueous layer was washed with DCM (20 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, and evaporated to give the crude product. The crude product was purified by column chromatography using 30% EA in hexane as the eluent to give I-42 (10 mg, 0.02 mmol, 3.6% yield) as a solid. HPLC: Rt 6.27 min, 95.9%; Column: X-Select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 440 (M+H), Rt 1.43 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =9.16(d,1H),7.92(d,1H),7.64(d,1H),7.36(s,1H),7.26-7.24(m,2H),5.46 (q,1H),3.07-2.80(m,6H),2.50-2.36(m,5H),2.16(s,3H),2.05-1.95(m,1H). Chiral method: Rt 7.87 min, 97.5%; SFC column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂ B) MeOH + 0.1% NH₃; Gradient: 35-50% B in 5 min, hold 50% B until 9 min, 50-35% B in 10 min, hold 35% B until 12 min; Wavelength: 272 nm; Flow rate: 3 mL / min

[0274] Example 38. Synthesis of Compound I-43 [ka] Synthesis of IA-39a: To a stirred solution of IA-36a (0.5 g, 2.08 mmol) in DCM (5 mL) was added DIPEA (0.72 mL, 4.15 mmol) and (3S)-3-methoxypyrrolidine (0.25 g, 2.49 mmol) at 0 °C and stirred at room temperature for 10 h. The reaction mixture was diluted with water and extracted with DCM (10 mL × 3). The combined organic layers were dried over NaSO, filtered, and evaporated to give the crude product, which was purified by Combiflash chromatography using ethyl acetate:hexane as eluent to give IA-39a (300 mg, 1.88 mmol, 42% yield).

[0275] Synthesis of I-A39b: To a stirred solution of IA-39a (0.3 g, 0.98 mmol) in THF (3 mL) was added LiOH.HO (82.44 mg, 1.96 mmol) in water (1 mL) at 0 °C and stirred at room temperature for 3 h. The reaction mixture was then evaporated to give a residue, which was dissolved in water and acidified with 2 N HCl. The resulting solid was filtered and dried to give IA-39b (250 mg, 0.7870 mmol, 80% yield) as a solid, which was used in the next step.

[0276] Synthesis of I-43: To a stirred solution of IA-39b (208 mg, 0.72 mmol) and IA-2 (100 mg, 0.6 mmol) in DCM (10 mL) was added DIPEA (0.21 mL, 1.19 mmol) and HATU (272 mg, 0.72 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction mixture was quenched with water (20 mL) and diluted with DCM (20 mL). The organic layer was washed with brine solution, dried over NaSO, and evaporated to give the crude product. The crude product was purified by column chromatography using silica gel 100-200 mesh and 40% EA in hexane as the eluent to give I-43 (66 mg, 0.15 mmol, 25% yield) as a solid. HPLC: Rt 8.95 min, 99.8%; Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 441.05 (M+H), Rt 2.01 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =9.12(d,1H),7.89(d,1H),7.69(d,1H),7.36(s,1H),7.26-7.24(m,2H),5.46(q,1H),3.90-3.84(m,1H),3.30-3.16 (m,4H),3.07(s,3H),3.04-2.98(m,1H),2.90-2.84(m,1H),2.49-2.44(m,1H),2.04-1.94(m,1H),1.90-1.80(m,2H). Chiral method: Rt 5.82 min, 98.6%; SFC column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂ B) MeOH + 0.1% NH₃; Gradient: 35-50% B in 5 min, hold 50% B until 9 min, 50-35% B in 10 min, hold 35% B until 12 min; Wavelength: 273 nm; Flow rate: 3 mL / min

[0277] Example 39. Synthesis of Compound I-44 [ka] Synthesis of IA-40a: To a stirred solution of IA-31b (1 g, 4.25 mmol) in ACN (10 mL) was added NaN (0.55 g, 8.51 mmol) at room temperature, and the reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was evaporated, treated portionwise with acetic acid (5 mL), Zn dust (556.27 mg, 8.51 mmol), and stirred at room temperature for 3 h. The reaction mixture was filtered over Celite and diluted with an aqueous layer treated with 1 N HCl and ethyl acetate (30 mL). The aqueous layer was basified with NaHCO and extracted with ethyl acetate. The organic layer was dried over NaSO, filtered, and evaporated to give IA-40a (400 mg, 2.3 mmol, 54% yield) as an oil.

[0278] Synthesis of IA-40b: To a stirred solution of IA-40a (0.5 g, 2.41 mmol) in DCM (10 mL), acetyl chloride (0.25 mL, 3.5 mmol), DIPEA (0.92 mL, 5.26 mmol) were added and stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over NaSO, filtered, and concentrated to give IA-40b (300 mg, 1.4 mmol, 80% yield) as a solid.

[0279] Synthesis of IA-40c: To a stirred solution of IA-40b (0.3 g, 1.41 mmol) in THF:water (1:1), NaOH (56.3 g, 1.41 mmol) was added and stirred at room temperature for 1 h. The reaction mixture was evaporated, and the crude product was diluted with water and treated with ethyl acetate. The aqueous layer was acidified with 2 N HCl to pH = 2, which was extracted with ethyl acetate, dried over Na2SO4, filtered, and evaporated to give IA-40c (160 mg, 0.8 mmol, 57% yield) as a solid.

[0280] Synthesis of I-44: To a stirred solution of IA-2 (100 mg, 0.6 mmol) and IA-40c (119 mg, 0.6 mmol) in DCM (5 mL), DIPEA (0.31 mL, 1.79 mmol) and HATU (340.22 mg, 0.89 mmol) were added at room temperature and stirred for 16 h. The mixture was diluted with water, extracted with DCM, and the organic layer was dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography using 5% MeOH / DCM as the eluent to give I-44 (44 mg, 0.12 mmol, 20.5% yield) as a solid. HPLC: Rt 7.49 min, 97%; Column: X-Select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 349 (M+H), Rt 1.82 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =8.72(d,1H),8.51(t,1H),7.62(d,1H),7.34(s,1H),7.26-7.18(m,2H),6.94(d,1H),5.44(q,1H),4 .39(d,2H),3.04-2.92(m,1H),2.88-2.82(m,1H),2.46-2.40(m,1H),2.00-1.94(m,1H),1.85(s,3H). Chiral method: Rt 6.84 min, 99.3%; SFC column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂, B) MeOH + 0.1% NH₃; Gradient: 10–40% B in 5 min, hold 40% B until 9 min, 40–20% B in 10 min, hold 10% B until 12 min; Wavelength: 272 nm; Flow rate: 3 mL / min

[0281] Example 40. Synthesis of Compound I-45 [ka] Synthesis of IA-41a: To a stirred solution of IA-36a (0.5 g, 2.08 mmol) in DCM (5 mL) was added DIPEA (0.72 mL, 4.15 mmol) and morpholine (217.2 mg, 2.49 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with water (15 mL) and extracted with DCM (20 mL). The combined organic layers were dried over sodium sulfate and evaporated to give the crude product, which was purified by Combiflash chromatography using ethyl acetate:hexane as eluent to give IA-41a (400 mg, 1.15 mmol, 55% yield).

[0282] Synthesis of IA-41b: To a stirred solution of IA-41a (300 mg, 0.99 mmol) in THF:water (1:1, 10 mL) was added a solution of LiOH.HO (144 mg, 3.43 mmol) at 0 °C and gradually warmed to room temperature. The reaction was concentrated to dryness, the residue was taken up in EtOAc, and the organic layer was washed with 2 mL of water followed by 1 mL of saturated brine solution. The organics were then separated, dried over MgSO, and then concentrated to dryness. The crude product was then purified by flash column chromatography using EtOAc in isohexane as the eluent. The desired fractions were concentrated to dryness in vacuo to afford IA-41b (320 mg, 67%) as an oil.

[0283] Synthesis of I-45: To a stirred solution of IA-41b (90 mg, 0.32 mmol) and IA-2 (90 mg, 0.32 mmol) in DCM (10 mL) was added DIPEA (0.11 mL, 0.65 mmol) and HATU (148 mg, 0.39 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction mixture was quenched with water (10 mL) and diluted with DCM (25 mL). The organic layer was washed with brine solution, dried over NaSO, and evaporated to give the crude product. The crude product was purified by column chromatography using 35% EA in hexane as the eluent to give I-45 (10 mg, 0.023 mmol, 7.13% yield) as a solid. HPLC: Rt 8.93 min, 98.8%; Column: X-Select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 427.20 (M+H), Rt 2.18 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H =9.16(d,1H),7.94(d,1H),7.66(d,1H),7.36(s,1H),7.26-7.24(m,2H),5.46(q,1H),3.67(t,4H),3.07-2.80(m,7H),2.07-1.92(m,1H). Chiral method: Rt 9.00 min, 100%; SFC column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) CO₂ B) MeOH + 0.1% NH₃; Gradient: 35-50% B in 5 min, hold 50% B until 9 min, 50-35% B in 10 min, hold 35% B until 12 min; Wavelength: 272 nm; Flow rate: 3 mL / min

[0284] Example 41. Synthesis of Compound I-46 [ka] Synthesis of IA-42a: To a stirred solution of IA-36a (0.5 g, 2.25 mmol) in DCM (10 mL), DIPEA (0.78 mL, 4.49 mmol) and (3R)-3-methoxypyrrolidine (0.27 g, 2.69 mmol) were added at 0 °C and stirred at room temperature for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL). The organic layer was washed with brine, dried over NaSO, filtered, and evaporated to give IA-42a (500 mg, 1.64 mmol, 50% yield) as an oil.

[0285] Synthesis of IA-42b: To a stirred solution of IA-42a (0.5 g, 1.64 mmol) in THF:water (1:1, 10 mL) was added lithium hydroxide (78.43 mg, 3.27 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction mixture was then evaporated to give a residue, which was dissolved in water (5 mL) and acidified with 5 N HCl (4 mL) to give a precipitate, which was filtered and dried to give IA-42b (300 mg, 1.0 mmol, 61% yield) as a solid, which was used in the next step without further purification.

[0286] Synthesis of I-46: To a stirred solution of IA-42b (100 mg, 0.34 mmol) and IA-2 (69.5 mg, 0.41 mmol) in DCM (5 mL) was added DIPEA (0.12 mL, 0.69 mmol) and HATU (157 mg, 0.41 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction mixture was quenched with water (10 mL) and diluted with DCM (15 mL × 2). The combined organic layers were washed with brine solution (10 mL), dried over NaSO, and evaporated to give the crude product. The crude product was purified by column chromatography using silica gel 100-200 mesh and 40% EA in hexane as the eluent to give I-46 (30.3 mg, 0.69 mmol, 20% yield) as a solid. HPLC: Rt 8.99 min, 99.9%; Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 441.09 (M+H), Rt 2.02 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H=9.13(d,1H),7.89(d,1H),7.69(d,1H),7.36(s,1H),7.26-7.24(m,2H),5.46(q,1H),3.90-3.85(m,1H),3.33-3.18 (m,3H),3.07(s,3H),3.00-2.96(m,1H),2.89-2.84(m,1H),2.49-2.44(m,2H),2.02-1.96(m,1H),1.90-1.78(m,2H). Chiral method: Rt 5.33 min, 100%; Column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) n-hexane + 0.1% isopropylamine; B) DCM:MeOH (1:1), isocratic: 50% B; Wavelength: 273 nm; Flow rate: 1.0 mL / min

[0287] Example 42. Synthesis of Compound I-47 [ka] Synthesis of IA-43b: To a stirred solution of IA-43a (0.5 g, 2.41 mmol) in DCM (5 mL), TEA (1.01 g, 7.24 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was then treated with (1R)-5-chloroindan-1-amine (404.8 mg, 2.4 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over NaSO, filtered, and evaporated to give the crude product, which was purified using flash column chromatography with 10% EtOAc / hexane as the eluent to give IA-43b (310 mg, 0.78 mmol, 33% yield) as a solid.

[0288] Synthesis of IA-43c: To a stirred solution of IA-43b (0.3 g, 0.84 mmol) in 1,4-dioxane (4 mL), 2-methoxyethanethiol (155.03 mg, 1.68 mmol) and DIPEA (0.44 mL, 2.52 mmol) were added. The reaction mixture was purged with N gas for 20 min and charged with Pd(dba) (77.05 mg, 0.08 mmol) and DPPF (46.63 mg, 0.08 mmol) at room temperature and stirred at 100 °C for 6 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude product, which was purified by CombiFlash and 7% EtOAc / hexane as eluent to give IA-43c (210 mg, 0.55 mmol, 66% yield) as an oil.

[0289] Synthesis of I-47: To a stirred solution of IA-2 (150 mg, 0.41 mmol) in DCM (5 mL) was added mCPBA (211 mg, 1.22 mmol) portionwise at room temperature and stirred for 2 h at room temperature. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL). The organic layer was washed with NaHCO (15 mL), dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by preparative HPLC to give I-47 (11 mg, 0.03 mmol, 7% yield) as a solid. HPLC: Rt 8.49 min, 98.2%; Column: X-Select CSH C18 (4.6 x 150) mm, 5 μm; Mobile phase: A: 0.1% FA in water:ACN (95:05), B:ACN; Flow rate: 1.0 mL / min LCMS: 399.8 (M+H), Rt 2.06 min, Column: X-select CSH C18 (3 x 50) mm, 2.5 μm 1 H NMR (400 MHz, DMSO-d6) δ H= 9.17 (d, 1H), 7.87 (d, 1H), 7.77 (d, 1H), 7.36 (s, 1H), 7.26-7.24 (m, 2H), 5.46 (q, 1H), 3.79-3.60 (m, 4H), 3.16 (s, 3H), 3.05-2.80 (m, 2H), 2.10-1.95 (m, 1H), merged with 1H solvent peak Chiral method: Rt 5.29 min, 99%; Column: DIACEL CHIRALPAK-IG (250 x 4.6 mm, 5 μm); Mobile phase: A) n-hexane + 0.1% isopropylamine; B) DCM:MeOH (1:1), isocratic: 50% B; Wavelength: 265 nm; Flow rate: 1.0 mL / min

[0290] Example 43. Synthesis of Compounds II-1 and II-2 [ka] Synthesis of II-A-1b: To a mixture of 4-(methanesulfonamido)benzoic acid (300 mg, 1.39 mmol), HATU (795 mg, 2.09 mmol), and DIPEA (0.73 mL, 4.18 mmol) in DMF (10 mL) was added 5-chloroindan-1-amine (280 mg, 1.67 mmol). The resulting mixture was stirred at 20 °C for 2 h. Saturated NH Cl solution (50 mL) was added to the solution, and the aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic phase was washed with water (50 mL × 2) and brine (50 mL × 2), dried over anhydrous Na SO , filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%) to give the product (400 mg, 1.10 mmol, 79% yield) as a solid. LCMS R t = 0.78 min in 1.5 min chromatography, 5-95AB, C 17 H 18 ClN2O3S[M+H] + MS ESI calculated value 365.1, found value 365.0.

[0291] Synthesis of II-A-1c: To a mixture of N-(5-chloroindan-1-yl)-4-(methanesulfonamido)benzamide (150 mg, 0.41 mmol) and K2CO3 (170.47 mg, 1.23 mmol) in DMF (7 mL) was added MeI (116.71 mg, 0.82 mmol). The resulting mixture was stirred at 20 °C for 2 hours. Saturated NH4Cl solution (20 mL) was added, and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with water (20 mL × 2) and brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to give the product (128 mg, 0.34 mmol, 82% yield) as a solid. 1 H NMR (400 MHz, CDCl3) δ H =7.89-7.76(m,2H),7.51-7.40(m,2H),7.27-7.24(m,2H),7.23-7.17(m,1H),6.29(d,1H),5.66(q,1H) ,3.36(s,3H),3.08-2.98(m,1H),2.97-2.88(m,1H),2.85(s,3H),2.76-2.66(m,1H),2.02-1.88(m,1H). LCMS R t = 0.80 min in 1.5 min chromatography, 5-95AB, C 18 H 20 ClN2O3S[M+H] + MS ESI calculated value 379.1, found value 379.0. Analytical SFC: Chiralcel OJ-3 100mm x 4.6mm i.d., 3µm, Mobile phase: A:CO2, B:Ethanol (0.05% DEA), Gradient: 5% to 40% B in 5 min, 40% B for 2.5 min, then hold at 5% B for 2.5 min, Flow rate: 2.8mL / min, Column temperature: 35°C) showed two peaks at 1.12 min (50%) and 3.02 min (50%).

[0292] Synthesis of Compounds II-1 and II-2: N-(5-chloroindan-1-yl)-4-[methyl(methylsulfonyl)amino]benzamide (100 mg, 0.26 mmol) was purified by SFC (YMC CHIRAL Amylose-C (250 mm x 30 mm, 10 μm i.d.); A = CO and B = EtOH (0.1% NHHO); 38 °C; 80 mL / min; 55% B; 8 min run; 7 injections) to give enantiomer 1 (Rt of peak 1 = 1.12 min), randomly assigned as compound II-1 (38.4 mg, 0.1 mmol), as a solid, and enantiomer 2 (Rt of peak 2 = 3.02 min), randomly assigned as compound II-2 (53.3 mg, 0.14 mmol), as a solid. Compound II-1 1 H NMR (400 MHz, CDCN) δ H =7.91-7.78(m,2H),7.46(d,2H),7.35-7.25(m,3H),7.23-7.15(m,1H),5.56(q,1H),3. 29(s,3H),3.09-2.97(m,1H),2.95-2.81(m,4H),2.62-2.50(m,1H),2.07-1.97(m,1H). LCMS R t = 1.08 min in 2 min chromatography, 10-80AB, C 18 H 20 ClN2O3S[M+H] + MS ESI calculated value 379.1, found value 379.0. Compound II-2 1 H NMR (400 MHz, CDCN) δ H =7.89-7.80(m,2H),7.46(d,2H),7.35-7.25(m,3H),7.24-7.17(m,1H),5.56(q,1H),3. 30(s,3H),3.09-2.97(m,1H),2.94-2.84(m,4H),2.62-2.50(m,1H),2.08-1.98(m,1H). LCMS R t = 1.06 min in 2 min chromatography, 10-80AB, C 18 H 20ClN2O3S[M+H] + MS ESI calculated value 379.1, found value 379.0.

[0293] Example 44. Synthesis of Compound II-3 [ka] To a mixture of 4-(methanesulfonamido)benzoic acid (128.39 mg, 0.60 mmol), EDCI (171.53 mg, 0.89 mmol), and HOBt (161.21 mg, 1.19 mmol) in DCM (5 mL) was added EtN (0.25 mL, 1.79 mmol) and (1S)-5-chloroindan-1-amine (100 mg, 0.60 mmol). The resulting mixture was stirred at 20 °C for 16 h. The mixture was diluted with HO (10 mL), and the mixture was extracted with EtOAc (30 mL × 2). The combined organic phase was washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (220 mg) as a solid. The crude product (40 mg) was purified by preparative TLC (silica gel, PE: EtOAc = 1:2) to give the product (12.2 mg, 33.5 μmol, 31% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.89-7.77(m,3H),7.33-7.17(m,6H),5.56(q,1H),3.09-2.96(m,4H),2.95-2.83(m,1H),2.61-2.49(m,1H),2.05-1.97(m,1H). LCMS R t = 2.0 min chromatography at 1.11 min, 10-80AB, C 17 H 18 ClN2O3S[M+H] + MS ESI calculated value 365.1, found value 364.9.

[0294] Example 45. Synthesis of Compound II-4 [ka] To a mixture of 4-(methanesulfonamido)benzoic acid (89.87 mg, 0.42 mmol), EDCI (120.07 mg, 0.63 mmol), and HOBt (112.85 mg, 0.84 mmol) in DCM (5 mL) was added EtN (0.17 mL, 1.25 mmol) and (1R)-5-chloroindan-1-amine (70 mg, 0.42 mmol). The resulting mixture was stirred at 20 °C for 16 h. The mixture was diluted with HO (10 mL), and the mixture was extracted with EtOAc (30 mL × 2). The combined organic phase was washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 50% to 100%) to give the product (109.6 mg, 297.3 μmol, 71% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.90-7.79(m,3H),7.37-7.19(m,6H),5.59(q,1H),3.11-2.99(m,4H),2.98-2.86(m,1H),2.64-2.52(m,1H),2.08-2.01(m,1H). LCMS R t = 2.0 min chromatography, 1.10 min, 10-80AB, C 17 H 18 ClN2O3S[M+H] + MS ESI calculated value 365.1, found value 364.9.

[0295] Example 46. Synthesis of Compounds II-5 and II-6 [ka] Synthesis of II-A-2b: A mixture of methyl 4-(methylsulfonylmethyl)benzoate (300 mg, 1.31 mmol) and NaOH (105.14 mg, 2.63 mmol) in water (4 mL) and ethanol (4 mL) was stirred at 20 °C for 16 h. The ethanol was concentrated, and the mixture was quenched with 1 N HCl and adjusted to pH 2. The mixture was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (270 mg, 1.26 mmol) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =13.03(br s,1H),7.96(d,2H),7.53(d,2H),4.59(s,2H),2.93(s,3H).

[0296] Synthesis of II-A-2c: A mixture of 4-(methylsulfonylmethyl)benzoic acid (138.02 mg, 0.64 mmol), HOBt (193.46 mg, 1.43 mmol), EDCI (205.83 mg, 1.07 mmol), EtN (0.3 mL, 2.15 mmol), and 5-chloroindan-1-amine (120 mg, 0.72 mmol) in DCM (5 mL) was stirred at 20 °C for 16 h under N. The reaction was quenched with saturated NH Cl (10 mL), and the mixture was extracted with DCM (20 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na SO , filtered, and concentrated to give the product (150 mg, 0.41 mmol) as a solid. LCMS R t = 0.79 min in 1.5 min chromatography, 5-95AB, C 18 H 19 ClNO3S[M+H] + MS ESI calculated value 364.1, found value 363.9. Analytical SFC: (Chiralpak OJ-3 150 mm x 4.6 mm, id, 3 μm, mobile phase: A:CO2, B:ethanol (0.05% DEA), gradient: 5% to 40% B in 5 min, 40% B for 2.5 min, then hold at 5% B for 2.5 min, flow rate: 2.8 mL / min, column temperature: 35°C) showed two peaks at 1.23 and 1.92 min.

[0297] Synthesis of Compounds II-5 and II-6: N-(5-chloroindan-1-yl)-4-(methylsulfonylmethyl)benzamide (150 mg, 0.41 mmol) was purified by SFC [DAICEL CHIRALCEL OJ-H (250 mm × 30 mm, i.d., 5 μm); A = CO and B = EtOH (0.1% NH H O); 38 °C; 60 mL / min; 35% B; 8 min run; 12 injections] to yield the randomly assigned enantiomer 1 (R peak 1) as compound 5 (22.26 mg, 61.2 μmol). t =1.23 min) as a solid and compound 6 (27.97 mg, 76.9 μmol) as the randomly assigned enantiomer 2 (R t = 1.92 min) as a solid. Compound II-5 1 H NMR (400 MHz, CDCN) δ H =7.85(d,2H),7.49(d,2H),7.37-7.24(m,3H),7.23-7.14(m,1H),5.61-5.51(m,1H),4.37(s, 2H), 3.09-2.97 (m, 1H), 2.95-2.85 (m, 1H), 2.82 (s, 3H), 2.61-2.50 (m, 1H), 2.08-1.98 (m, 1H). LCMS R t = 1.03 min in 2 min chromatography, 10-80AB, C 18 H 19 ClNO3S[M+H] + MS ESI calculated value 364.1, found value 364.0. Compound II-6 1 H NMR (400 MHz, CDCN) δ H=7.85(d,2H),7.49(d,2H),7.37-7.23(m,3H),7.23-7.16(m,1H),5.61-5.51(m,1H),4.37(s, 2H), 3.09-2.98 (m, 1H), 2.96-2.84 (m, 1H), 2.82 (s, 3H), 2.61-2.51 (m, 1H), 2.07-1.98 (m, 1H). LCMS R t = 1.01 min in 2 min chromatography, 10-80AB, C 18 H 19 ClNO3S[M+H] + MS ESI calculated value 364.1, found value 364.0.

[0298] Example 47. Synthesis of Compounds II-7 and II-8 [ka] Synthesis of II-A-3b: To a mixture of 4-methoxybenzoic acid (150 mg, 0.99 mmol), HATU (562.29 mg, 1.48 mmol), and DIPEA (0.34 mL, 1.97 mmol) in DMF (5 mL), 5-chloroindan-1-amine (198.33 mg, 1.18 mmol) was added. The resulting mixture was stirred at 20 °C for 2 h. Saturated aqueous NH Cl (30 mL) was added, and the aqueous layer was extracted with EtOAc (30 mL × 2). The combined organic phase was washed with water (20 mL × 2) and brine (20 mL × 2), dried over anhydrous Na SO , filtered, and concentrated. The crude product was purified by preparative HPLC [Xtimate C18 (150 mm × 25 mm, 5 μm) A = HO (0.04% NH3H2O ​​+ 10 mM NH4HCO3) and B = CH3CN; 47–77% B over 7 min] to give the product (250 mg, 819.3 μmol, 83% yield) as a solid. LCMS R t = 0.84 min in 1.5 min chromatography, 5-95AB, C 17 H 17 ClNO2[M+H] + MS ESI calculated value 302.1, found value 301.9. Analytical SFC: Chiralcel OJ-3 100 mm x 4.6 mm ID, 3 μm column, Mobile phase: A: CO2, B: 40% ethanol (0.05% DEA), Gradient: 5% to 40% B in 5 min, 40% B for 2.5 min, then hold at 5% B for 2.5 min, Flow rate: 2.8 mL / min, Column temperature: 40 °C) showed two peaks at 0.94 and 2.18 min.

[0299] Synthesis of Compounds II-7 and II-8: N-(5-chloroindan-1-yl)-4-methoxy-benzamide (250 mg, 819.3 μmol) was purified by SFC [DAICEL CHIRALPAK OJ-H (250 mm × 30 mm, 5 μm); A = CO and B = EtOH (0.1% NH.HO); 35 °C; 60 mL / min; 40% B; 13 min run; 9 injections] to give enantiomer 1 (Rt = 0.94 min, peak 1), randomly assigned as compound II-7 (92.5 mg, 306.4 μmol), as a solid, and enantiomer 2 (Rt = 2.18 min, peak 2), randomly assigned as compound II-8 (87.4 mg, 289.6 μmol), as a solid. Compound II-7 1 H NMR (400 MHz, CD3OD) δ H =7.84(dd,2H),7.29-7.21(m,2H),7.21-7.16(m,1H),7.02-6.96(m,2H),5.60(t,1H),3 .85(s,3H),3.10-3.01(m,1H),2.96-2.85(m,1H),2.64-2.54(m,1H),2.09-1.98(m,1H). LCMS R t = 1.13 min in 2.0 min chromatography, 10-80AB, C 17 H 17 ClNO2[M+H] + MS ESI calculated value 302.1, found value 301.9. Compound II-8 1 H NMR (400 MHz, CD3OD) δ H=7.84(d,2H),7.28-7.22(m,2H),7.21-7.17(m,1H),6.98(d,2H),5.60(t,1H),3.87 (s,3H),3.10-3.00(m,1H),2.96-2.85(m,1H),2.64-2.54(m,1H),2.10-1.97(m,1H). LCMS R t = 2.0 min chromatography at 1.11 min, 10-80AB, C 17 H 17 ClNO2[M+H] + MS ESI calculated value 302.1, found value 301.9.

[0300] Example 48. Synthesis of Compounds II-9 and II-16 [ka] Synthesis of II-A-4b: A mixture of 4-nitrobenzoic acid (3.99 g, 23.86 mmol), HOBt (6.45 g, 47.72 mmol), EtN (9.9 mL, 71.58 mmol), EDCI (6.86 g, 35.79 mmol), and 5-chloroindan-1-amine (4 g, 23.86 mmol) in DCM (50 mL) was stirred at 20 °C for 16 h under N. The reaction was quenched with saturated NHCl (50 mL), and the mixture was extracted with DCM (50 mL × 2). The combined organic phase was washed with brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated to give the product (6941 mg, 19.45 mmol) as a solid. LCMS R t = 0.84 min in 1.5 min chromatography, 5-95AB, C 16 H 14 ClN2O3[M+H] + MS ESI calculated value 317.1, found value 316.9.

[0301] Synthesis of II-A-4c: A mixture of N-(5-chloroindan-1-yl)-4-nitro-benzamide (3 g, 9.47 mmol), NH4Cl (5.07 g, 94.71 mmol), and Fe (5.29 g, 94.71 mmol) in ethanol (30 mL) and water (30 mL) was stirred at 70 °C for 6 h under N2. The mixture was filtered through Celite, and the filter cake was eluted with EtOAc (50 mL × 2). The filtrate was concentrated under reduced pressure. The crude product was diluted with HO (50 mL), and the aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product (1260 mg, 4.3 mmol) as a solid. LCMS R t = 0.98 min in 2.0 min chromatography, 10-80AB, C 16 H 16 ClNO[M+H] + MS ESI calculated value 287.1, found value 286.9. Analytical SFC: (Chiralcel OJ-3 150mm x 4.6mm ID, 3µm, Mobile phase: A:CO2 B:Ethanol (0.05% DEA), Gradient: 5% to 40% B in 5 min, 40% B for 2.5 min, then hold at 5% B for 2.5 min, Flow rate: 2.5mL / min, Column temperature: 35°C) showed two peaks at 2.24 and 4.83 min.

[0302] Synthesis of compounds II-16 and II-9: 4-amino-N-(5-chloroindan-1-yl)benzamide (4 g, 13.95 mmol) was purified by SFC (DAICEL CHIRALCEL OJ (250 mm × 30 mm, i.d., 5 μm); A = CO and B = EtOH (0.1% NH H O); 38 °C; 50 mL / min; 45% B; 13 min run; 10 injections) to give enantiomer 1 assigned as compound II-16 (Rt of peak 1 = 2.26 min, 46.6 mg) as a solid and enantiomer 2 assigned as compound II-9 (Rt of peak 2 = 2.26 min, 46.6 mg) as a solid. t = 4.83 min) was obtained as a solid. Stereochemistry was randomly assigned. Compound II-16 1 H NMR (400 MHz, DMSO-d 6 )δ H =8.26(d,1H),7.62(d,2H),7.31(s,1H),7.24-7.14(m,2H),6.53(d,2H),5.61(s,2H),5 .47(q,1H),3.03-2.91(m,1H),2.90-2.75(m,1H),2.52-2.48(m,1H)2.06-1.92(m,1H). LCMS R t = 1.04 min in 2.0 min chromatography, 10-80AB, C 16 H 16 ClNO[M+H] + MS ESI calculated value 287.1, found value 286.9.

[0303] 4-amino-N-[(1R)-5-chloroindan-1-yl]benzamide (50 mg, 0.17 mmol) (peak 2 t = 4.83 min) was triturated from CHCl / n-hexane (5 mL, 1:5) to give the product (45.4 mg, 0.16 mmol) as a solid. The absolute stereochemistry of compound II-9 was confirmed by X-ray crystallography. 1 H NMR (400 MHz, DMSO-d 6 )δ H =8.27(d,1H),7.62(d,2H),7.32(s,1H),7.23-7.16(m,2H),6.53(d,2H),5.62(s,2H),5 .47(q,1H),3.01-2.93(m,1H),2.87-2.78(m,1H),2.45-2.37(m,1H),2.04-1.93(m,1H). LCMS R t = 1.03 min in 2.0 min chromatography, 10-80AB, C 16 H 16 ClNO[M+H] + MS ESI calculated value 287.1, found value 286.9.

[0304] Example 49. Synthesis of Compound II-10 [ka] A mixture of 4-amino-N-[(1R)-5-chloroindan-1-yl]benzamide (100 mg, 0.35 mmol) and ethanesulfonyl chloride (58.29 mg, 0.45 mmol) in pyridine (4 mL) was stirred at 15 °C for 2 h. The reaction was quenched with 1 N HCl (5 mL), and the mixture was extracted with EtOAc (5 mL × 2). The combined organic phases were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm) A = HO (10 mM NHHCO) and B = CHCN; 32–62% B over 6 min) to give the product (64.8 mg, 0.17 mmol, 49% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =10.13(br s,1H),8.67(d,1H),7.86(d,2H),7.33(s,1H),7.27-7.18(m,4H),5.50(q,1H),3.15(q,2H) ,3.03-2.94(m,1H),2.90-2.80(m,1H),2.47-2.40(m,1H),2.06-1.95(m,1H),1.18(t,3H). LCMS R t = 2.0 min chromatography at 1.12 min, 10-80AB, C 18 H 20 ClN2O3S[M+H] + MS ESI calculated value 379.1, found value 378.9.

[0305] Example 50. Synthesis of Compound II-11 [ka] A mixture of 4-amino-N-[(1R)-5-chloroindan-1-yl]benzamide (100 mg, 0.35 mmol) and cyclopropanesulfonyl chloride (63.74 mg, 0.45 mmol) in pyridine (4 mL) was stirred at 15 °C for 2 h. The reaction was quenched with 1 M HCl (5 mL), and the mixture was extracted with EtOAc (5 mL × 2). The combined organic phases were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm) A = HO (10 mM NHHCO) and B = CHCN; 32–62% B over 6.5 min) to give the product (71.4 mg, 0.18 mmol, 52% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =10.08(s,1H),8.68(d,1H),7.87(d,2H),7.34(s,1H),7.27(d,2H),7.25-7.19(m,2H),5.50(q,1H),3.03-2 .95(m,1H),2.90-2.80(m,1H),2.73-2.66(m,1H),2.48-2.40(m,1H),2.06-1.95(m,1H),1.00-0.91(m,4H). LCMS R t = 1.14 min in 2.0 min chromatography, 10-80AB, C 19 H 20 ClN2O3S[M+H] + MS ESI calculated value 391.1, found value 390.9.

[0306] Example 51. Synthesis of Compound II-12 [ka] A mixture of trifluoromethylsulfonyl trifluoromethanesulfonate (177.1 mg, 0.63 mmol), EtN (0.11 mL, 0.78 mmol), and 4-amino-N-[(1R)-5-chloroindan-1-yl]benzamide (150 mg, 0.52 mmol) in CHCl (10 mL) was stirred at 15° C. for 16 hours. The reaction was quenched with saturated NHCl solution (10 mL). The mixture was extracted with CHCl (10 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Xbridge BEH C18 (250 mm × 50 mm, 10 μm) A = HO (10 mM NH4HCO3) and B = CH3CN; 25–45% B over 9 min) to give the product (17.9 mg, 42.7 μmol, 8% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.82(d,2H),7.36-7.23(m,5H),7.21-7.18(m,1H),5.56(q,1H),3.06 -2.98(m,1H),2.93-2.84(m,1H),2.59-2.50(m,1H),2.06-1.97(m,1H). LCMS R t = 1.21 min in 2.0 min chromatography, 10-80AB, C 17 H 15 ClF3N2O3S[M+H] + MS ESI calculated value 419.0, found value 418.8.

[0307] Example 52. Synthesis of Compound II-13 [ka] A mixture of N-[(1R)-5-chloroindan-1-yl]-4-(ethylsulfonylamino)benzamide (120 mg, 0.32 mmol), K2CO3 (87.55 mg, 0.63 mmol), and MeI (134.87 mg, 0.95 mmol) in DMF (5 mL) was stirred at 15 °C for 3 h. The mixture was diluted with HO (5 mL), and the aqueous layer was extracted with EtOAc (5 mL × 2). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm) A = HO (10 mM NHHCO) and B = CHCN; 38–68% B over 6 min) to give the product (86.8 mg, 0.22 mmol, 70% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =8.79(d,1H),7.91(d,2H),7.50(d,2H),7.34(s,1H),7.25-7.19(m,2H),5.51(q,1H),3.30(s,3H),3 .19(q,2H),3.03-2.95(m,1H),2.90-2.80(m,1H),2.47-2.41(m,1H),2.07-1.96(m,1H),1.17(t,3H). LCMS R t = 1.18 min in 2.0 min chromatography, 10-80AB, C 19 H 22 ClN2O3S[M+H] + MS ESI calculated value 393.1, found value 392.9.

[0308] Example 53. Synthesis of Compound II-14 [ka] A mixture of N-[(1R)-5-chloroindan-1-yl]-4-(cyclopropylsulfonylamino)benzamide (140 mg, 0.36 mmol), K2CO3 (99 mg, 0.72 mmol), and MeI (152.51 mg, 1.07 mmol) in DMF (5 mL) was stirred at 15 °C for 3 h. The mixture was diluted with HO (5 mL), and the aqueous layer was extracted with EtOAc (5 mL × 2). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm) A = HO (10 mM NH4HCO3) and B = CH3CN; 40–70% B over 6 min) to give the product (83.3 mg, 0.21 mmol, 57% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.83(dd,2H),7.50(dd,2H),7.32-7.24(m,3H),7.22-7.18(m,1H),5.57(q,1H),3.33(s,3H), 3.07-2.99(m,1H),2.94-2.85(m,1H),2.61-2.45(m,2H),2.07-1.98(m,1H),0.98-0.87(m,4H). LCMS R t = 1.18 min in 2.0 min chromatography, 10-80AB, C 20 H 22 ClN2O3S[M+H] + MS ESI calculated value 405.1, found value 404.9.

[0309] Example 54. Synthesis of Compound II-15 [ka] A mixture of N-[(1S)-5-chloroindan-1-yl]-4-(trifluoromethylsulfonylamino)benzamide (250 mg, 0.60 mmol), K2CO3 (165 mg, 1.19 mmol), and MeI (254.18 mg, 1.79 mmol) in DMF (10 mL) was stirred at 20 °C for 3 h. The mixture was diluted with HO (15 mL), and the aqueous layer was extracted with EtOAc (15 mL × 2). The combined organic phases were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN; 55–85% B over 8 min) to give the product (65.9 mg, 0.15 mmol, 25% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.89(d,2H),7.52(d,2H),7.38-7.26(m,3H),7.23-7.18(m,1H),5.56(q,1H),3.48 (s,3H),3.09-2.97(m,1H),2.96-2.83(m,1H),2.62-2.50(m,1H),2.07-1.98(m,1H). LCMS R t = 1.27 min in 2 min chromatography, 10-80AB, C 18 H 17 ClF3N2O3S[M+H] + MS ESI calculated value 433.1, found value 432.8.

[0310] Example 55. Synthesis of Compound II-17 [ka] A mixture of 4-amino-N-[(1S)-5-chloroindan-1-yl]benzamide (200 mg, 0.7 mmol) and ethanesulfonyl chloride (448.39 mg, 3.49 mmol) in pyridine (20 mL) was stirred at 20 °C for 72 h under N2. The reaction was concentrated and quenched with saturated NH4Cl (15 mL). The mixture was extracted with EtOAc (15 mL × 2). The combined organic phases were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm) A = HO (0.05% NH4OH) and B = CH3CN; 37–67% B over 8 min) to give the product (35.3 mg, 0.09 mmol, 13% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.89-7.74(m,3H),7.32-7.14(m,6H),5.56(q,1H),3.13(q,2H),3.07-2.96( m,1H),2.95-2.83(m,1H),2.61-2.49(m,1H),2.06-1.97(m,1H),1.25(t,3H). LCMS R t = 1.02 min in 2 min chromatography, 10-80AB, C 18 H 20 ClN2O3S[M+H] + MS ESI calculated value 379.1, found value 379.0.

[0311] Example 56. Synthesis of Compound II-18 [ka] A mixture of 4-amino-N-[(1S)-5-chloroindan-1-yl]benzamide (200 mg, 0.7 mmol) and cyclopropanesulfonyl chloride (127.47 mg, 0.91 mmol) in pyridine (15 mL) was heated at 20 °C for 72 h under N 2The mixture was stirred under reduced pressure. The reaction was concentrated and quenched with saturated NH4Cl (15 mL). The mixture was extracted with EtOAc (15 mL x 2). The combined organic phase was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was triturated from hexane and DCM (5:1, 5 mL) to give the product (49.5 mg, 0.13 mmol, 18% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =10.08(s,1H),8.68(d,1H),7.87(d,2H),7.43-7.14(m,5H),5.50(q,1H),3.07-2.93(m,1H),2 .92-2.79(m,1H),2.74-2.65(m,1H),2.46-2.40(m,1H),2.10-1.91(m,1H),1.04-0.91(m,4H). LCMS R t = 1.05 min with 2 min chromatography, 10-80AB, C 19 H 20 ClN2O3S[M+H] + MS ESI calculated value 391.1, found value 391.0.

[0312] Example 57. Synthesis of Compound II-19 [ka] A mixture of N-[(1S)-5-chloroindan-1-yl]-4-(ethylsulfonylamino)benzamide (220 mg, 0.58 mmol), KK2CO3 (160.51 mg, 1.16 mmol), and MeI (247.26 mg, 1.74 mmol) in DMF (5 mL) was stirred at 20 °C for 3 h. The mixture was diluted with HO (5 mL), and the aqueous layer was extracted with EtOAc (15 mL × 2). The combined organic phases were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN; 48–78% B over 8 min) to give the product (119.2 mg, 0.31 mmol, 52% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.83(dd,2H),7.47(dd,2H),7.33-7.23(m,3H),7.22-7.16(m,1H),5.56(q,1H),3.32(s,3H),3.1 0(q,2H),3.07-2.97(m,1H),2.95-2.84(m,1H),2.61-2.51(m,1H),2.07-1.97(m,1H),1.25(t,3H). LCMS R t = 1.04 min in 2 min chromatography, 10-80AB, C 19 H 22 ClN2O3S[M+H] + MS ESI calculated value 393.1, found value 393.0.

[0313] Example 58. Synthesis of Compound II-20 [ka] A mixture of N-[(1S)-5-chloroindan-1-yl]-4-(cyclopropylsulfonylamino)benzamide (150 mg, 0.38 mmol), K2CO3 (106.08 mg, 0.77 mmol), and MeI (163.41 mg, 1.15 mmol) in DMF (5 mL) was stirred at 20 °C for 3 h. The mixture was diluted with HO (15 mL) and extracted with EtOAc (15 mL × 2). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was triturated from hexane and DCM (5:1, 5 mL) to give the product (146.5 mg, 0.36 mmol, 94% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.83(d,2H),7.50(d,2H),7.34-7.23(m,3H),7.23-7.17(m,1H),5.57(q,1H),3.33(s,3H),3 .09-2.98(m,1H),2.95-2.83(m,1H),2.62-2.43(m,2H),2.07-1.97(m,1H),1.00-0.83(m,4H). LCMS R t = 1.05 min with 2 min chromatography, 10-80AB, C 20 H 22 ClN2O3S[M+H] + MS ESI calculated value 405.1, found value 405.0.

[0314] Example 59. Synthesis of Compound II-21 [ka] A mixture of N-[(1S)-5-chloroindan-1-yl]-4-(trifluoromethylsulfonylamino)benzamide (250 mg, 0.60 mmol), K2CO3 (165 mg, 1.19 mmol), and MeI (254.18 mg, 1.79 mmol) in DMF (10 mL) was stirred at 20 °C for 3 h. The mixture was diluted with HO (15 mL), and the aqueous layer was extracted with EtOAc (15 mL × 2). The combined organic phases were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN; 55–85% B over 8 min) to give the product (65.9 mg, 0.15 mmol, 25% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.89(d,2H),7.52(d,2H),7.38-7.26(m,3H),7.23-7.18(m,1H),5.56(q,1H),3.48 (s,3H),3.09-2.97(m,1H),2.96-2.83(m,1H),2.62-2.50(m,1H),2.07-1.98(m,1H). LCMS R t = 1.27 min in 2 min chromatography, 10-80AB, C 18 H 17 ClF3N2O3S[M+H] + MS ESI calculated value 433.1, found value 432.8.

[0315] Example 60. Synthesis of Compound II-22 [ka] To a mixture of (1R)-5-chloroindan-1-amine (50 mg, 0.30 mmol), HOBt (80.61 mg, 0.60 mmol), and EtN (0.21 mL, 1.49 mmol) in CHCl (5 mL) was added EDCI (114.35 mg, 0.60 mmol) and 4-methylsulfonylbenzoic acid (71.66 mg, 0.36 mmol). The reaction mixture was stirred at 15 °C for 16 h. The mixture was diluted with saturated NHCl solution (5 mL), and the aqueous layer was extracted with CHCl (5 mL × 2). The combined organic phase was washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm) A = HO (10 mM NHHCO) and B = CHCN; 32–62% B over 7 min) to give the product (13.7 mg, 0.04 mmol, 13% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =8.03-7.97(m,4H),7.49-7.39(m,1H),7.32-7.29(m,2H),7.23-7.19(m,1H),5.58(q,1H) ,3.08(s,3H),3.07-3.00(m,1H),2.96-2.86(m,1H),2.62-2.53(m,1H),2.07-1.99(m,1H). LCMS R t = 2.0 min chromatography at 1.12 min, 10-80AB, C 17 H 17 ClNO3S[M+H] + MS ESI calculated value 350.1, found value 349.9.

[0316] Example 61. Synthesis of Compound II-23 [ka] Synthesis of II-A-6b: A mixture of N-methylmethanamine hydrochloride (500 mg, 6.13 mmol), EtN (2.55 mL, 18.4 mmol), and methyl 4-chlorocarbonylbenzoate (1826.71 mg, 9.2 mmol) in DCM (10 mL) was stirred at 15 °C for 16 h. The mixture was diluted with saturated NH Cl (10 mL), and the aqueous layer was extracted with DCM (10 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na SO , filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (30% to 60% EtOAc in PE) to give the product (1100 mg, 4.70 mmol, 77% yield) as a solid. LCMS R t = 0.65 min in 1.5 min chromatography, 5-95AB, C 11 H 13 NO3[M+H] + MS ESI calculated value 208.1, found value 207.9.

[0317] Synthesis of II-A-7a: A mixture of methyl 4-(dimethylcarbamoyl)benzoate (500 mg, 2.41 mmol) and LiOH.HO (202.48 mg, 4.83 mmol) in THF (8 mL) and water (4 mL) was stirred at 15 °C for 3 h. The mixture was acidified with 1 N HCl to pH 2. The mixture was diluted with HO (10 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were concentrated to give the crude product (518 mg, 2.45 mmol) as a solid. LCMS R t = 0.87 min in 2 min chromatography, 0-60AB, C 10 H 12 NO3[M+H] + MS ESI calculated value 194.1, found value 193.8.

[0318] Synthesis of Compound II-23: To a mixture of 4-(dimethylcarbamoyl)benzoic acid (80.67 mg, 0.42 mmol), HOBt (112.85 mg, 0.84 mmol), and EtN (0.29 mL, 2.09 mmol) in DCM (5 mL) was added EDCI (120.07 mg, 0.63 mmol) and (1R)-5-chloroindan-1-amine (70 mg, 0.42 mmol). The reaction mixture was stirred at 15 °C for 16 h. The reaction was quenched with saturated NH Cl (20 mL), and the mixture was extracted with DCM (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na SO , filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN; 39–69% B over 8 min) to give the product (13.7 mg, 0.04 mmol, 10% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.85(d,2H),7.44(d,2H),7.37-7.26(m,3H),7.24-7.17(m,1H),5.58(q,1H) ,3.11-2.96(m,4H),2.96-2.81(m,4H),2.64-2.50(m,1H),2.06-1.99(m,1H). LCMS R t = 1.15 min with 2 min chromatography, 10-80AB, C 19 H 20 ClN2O2[M+H] + MS ESI calculated value 343.1, found value 343.0.

[0319] Example 62. Synthesis of Compound II-24 [ka] Synthesis of II-A-8a: A mixture of methanamine hydrochloride (500 mg, 7.41 mmol), EtN (3.07 mL, 22.22 mmol), and methyl 4-chlorocarbonylbenzoate (2.21 g, 11.11 mmol) in DCM (15 mL) was stirred at 15 °C for 16 h. The mixture was diluted with saturated NH Cl (15 mL), and the aqueous layer was extracted with DCM (15 mL × 2). The combined organic phases were washed with brine (15 mL), dried over anhydrous Na SO , filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (30% to 60% EtOAc in PE) to give the product (712 mg, 3.69 mmol, 50% yield) as a solid. LCMS R t = 0.60 min in 1.5 min chromatography, 5-95AB, C 10 H 12 NO3[M+H] + MS ESI calculated value 194.1, found value 193.9.

[0320] Synthesis of II-A-9a: Methyl 4-(methylcarbamoyl)benzoate (500 mg, 2.59 mmol) and LiOH in THF (4 mL) and water (2 mL) . A mixture of HO (217.18 mg, 5.18 mmol) was stirred at 15° C. for 3 h. The mixture was acidified with 1 N HCl (5 mL) and diluted with HO (10 mL). The aqueous layer was extracted with EtOAc (20 mL×2). The combined organic phases were concentrated to give the crude product (606 mg, 3.38 mmol) as a solid. LCMS R t = 0.81 min in 2 min chromatography, 0-60AB, C9H9NO3 [M+H] + MS ESI calculated value 180.1, found value 179.9.

[0321] Synthesis of II-24: To a mixture of (1R)-5-chloroindan-1-amine (100 mg, 0.6 mmol), HOBt (161.21 mg, 1.19 mmol), and EtN (0.41 mL, 2.98 mmol) in DCM (5 mL), EDCI (171.53 mg, 0.89 mmol) and 4-(methylcarbamoyl)benzoic acid (106.88 mg, 0.6 mmol) were added. The reaction mixture was stirred at 15 °C for 16 h. The reaction was quenched with saturated NH Cl (20 mL), and the mixture was extracted with DCM (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na SO , filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN; 35–65% B over 8 min) to give the product (8.8 mg, 0.03 mmol, 4% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =8.89(d,1H),8.56(d,1H),8.03-7.80(m,4H),7.34(s,1H),7.24(s,2H),5.52(q,1H),3 .07-2.94(m,1H),2.92-2.83(m,1H),2.79(d,3H),2.47-2.42(m,1H),2.09-1.95(m,1H). LCMS R t = 1.09 min in 2 min chromatography, 10-80AB, C 18 H 18 ClN2O2[M+H] + MS ESI calculated value 329.1, found value 329.1.

[0322] Example 63. Synthesis of Compound II-25 [ka] To a mixture of 4-sulfamoylbenzoic acid (72.01 mg, 0.36 mmol), HOBt (80.61 mg, 0.60 mmol), and EtN (0.21 mL, 1.49 mmol) in CHCl (3 mL) was added EDCI (114.35 mg, 0.60 mmol) and (1R)-5-chloroindan-1-amine (50 mg, 0.30 mmol). The reaction mixture was stirred at 35 °C for 16 h. The mixture was diluted with saturated NHCl (5 mL) and extracted with EtOAc (5 mL × 2). The combined organic phase was washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Xtime C18 (150 mm × 25 mm, 5 μm) A = HO (10 mM NH4HCO3) and B = CH3CN; 40-50% B over 9 min) to give the product (20.6 mg, 58.6 μmol, 20% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.98-7.91(m,4H),7.43-7.35(m,1H),7.32-7.29(m,2H),7.23-7.19(m,1H),5.74(s,2H) ,5.58(q,1H),3.09-3.00(m,1H),2.95-2.86(m,1H),2.62-2.53(m,1H),2.06-2.00(m,1H). LCMS R t = 2.0 min chromatography at 1.11 min, 10-80AB, C 16 H 16 ClN2O3S[M+H] + MS ESI calculated value 351.0, found value 351.1.

[0323] Example 64. Synthesis of Compound II-26 [ka] To a mixture of 4-carbamoylbenzoic acid (75.86 mg, 0.46 mmol), DIPEA (0.22 mL, 1.25 mmol), and HATU (317.54 mg, 0.84 mmol) in DMF (3 mL) was added (1R)-5-chloroindan-1-amine (70 mg, 0.42 mmol). The reaction mixture was stirred at 35 °C for 16 h. The mixture was diluted with saturated NH Cl (5 mL), and the aqueous layer was extracted with EtOAc (5 mL × 2). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na SO , filtered, and concentrated. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm) A = HO (10 mM NHHCO) and B = CHCN; 33–53% B over 7 min) to give the product (7.6 mg, 24.0 μmol, 6% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =8.95-8.82(m,1H),8.07(br s,1H),8.02-7.88(m,4H),7.48(br s,1H),7.34(s,1H),7.32-7.22(m,2H),5.52(q,1H),3.06-2.96(m,1H),2.92-2.82(m,1H),2.46-2.42(m,1H),2.08-1.98(m,1H). LCMS R t = 1.07 min in 2.0 min chromatography, 10-80AB, C 17 H 16 ClN2O2[M+H] + MS ESI calculated value 315.1, found value 314.9.

[0324] Example 65. Synthesis of Compound II-27 [ka] Synthesis of II-A-12b: A mixture of methanamine hydrochloride (500 mg, 7.41 mmol) and methyl 4-chlorosulfonylbenzoate (2606.56 mg, 11.11 mmol) in pyridine (10 mL) was stirred at 15 °C for 16 h. The reaction was concentrated and acidified with 1 M HCl to pH 7, and the mixture was extracted with CHCl (80 mL × 2). The combined organic phase was washed with water (80 mL) and brine (80 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (1600 mg, 6.35 mmol) as a solid. LCMS R t = 0.65 min in 1.5 min chromatography, 5-95AB, C9H 12 NO4S[M+H] + MS ESI calculated value 230.0, found value 229.9.

[0325] Synthesis of II-A-13a: A mixture of methyl 4-(methylsulfamoyl)benzoate (500 mg, 2.18 mmol) and LiOH.H (183.03 mg, 4.36 mmol) in THF (8 mL) and water (4 mL) was stirred for 3 h at 15° C. The mixture was concentrated to give the crude product (488 mg, 2.08 mmol) as a solid, which was used directly in the next step without further purification. LCMS R t = 0.87 min in 1.5 min chromatography, 5-95AB, C8H 10 NO4S[M+H] + MS ESI calculated value 216.0, found value 215.8.

[0326] Synthesis of II-27: To a mixture of (1R)-5-chloroindan-1-amine (100 mg, 0.60 mmol), DIPEA (0.31 mL, 1.79 mmol), and HATU (453.63 mg, 1.19 mmol) in DMF (5 mL), lithium 4-(methylsulfamoyl)benzoate (141.23 mg, 0.66 mmol) was added. The reaction mixture was stirred at 60 °C for 16 h. The mixture was diluted with saturated NH Cl (5 mL), and the aqueous layer was extracted with EtOAc (15 mL × 2). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na SO , filtered, and concentrated. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm) A = HO (10 mM NHHCO) and B = CHCN; 35–55% B over 8 min) to give the product (26.6 mg, 73.0 μmol, 12% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.98(dd,2H),7.88(dd,2H),7.45-7.37(m,1H),7.33-7.28(m,2H),7.23-7.19(m,1H),5.58(q,1H),5.5 3-5.47(m,1H),3.09-3.00(m,1H),2.95-2.86(m,1H),2.62-2.54(m,1H),2.51(d,3H),2.08-1.98(m,1H). LCMS R t = 2.0 min chromatography, 1.20 min, 10-80AB, C 17 H 18 ClN2O3S[M+H] + MS ESI calculated value 365.1, found value 364.9.

[0327] Example 66. Synthesis of Compound II-28 [ka] Synthesis of II-A-14a: A mixture of N-methylmethanamine hydrochloride (500 mg, 6.13 mmol), EtN (2.55 mL, 18.4 mmol), and methyl 4-chlorosulfonylbenzoate (2158.39 mg, 9.2 mmol) in CHCl (10 mL) was stirred at 15 °C for 16 h. The mixture was quenched with saturated NHCl (10 mL), and the mixture was extracted with CHCl (10 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (1700 mg, 5.7 mmol). LCMS R t = 0.73 min in 1.5 min chromatography, 5-95AB, C 10 H 14 NO4S[M+H] + MS ESI calculated value 244.1, found value 243.9.

[0328] Synthesis of II-A-14b: A mixture of methyl 4-(dimethylsulfamoyl)benzoate (500 mg, 2.06 mmol) and LiOH.HO (172.48 mg, 4.11 mmol) in THF (8 mL) and water (4 mL). The mixture was stirred at 15 °C for 3 hours. The mixture was concentrated to give the crude product (510 mg, 2.05 mmol) as a solid.

[0329] Synthesis of II-28: To a mixture of (1R)-5-chloroindan-1-amine (100 mg, 0.60 mmol), DIPEA (0.31 mL, 1.79 mmol), and HATU (453.63 mg, 1.19 mmol) in DMF (5 mL), lithium 4-(methylsulfamoyl)benzoate (150.43 mg, 0.66 mmol) was added. The reaction mixture was stirred at 35 °C for 16 h. The mixture was diluted with saturated NH Cl solution (5 mL), and the aqueous layer was extracted with EtOAc (5 mL × 2). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na SO , filtered, and concentrated. The crude product was purified by preparative HPLC (Xtime C18 (150 mm × 25 mm, 5 μm) A = HO (10 mM NH4HCO3) and B = CH3CN; 35–65% B over 9 min) to give the product (74.0 mg, 0.19 mmol, 33% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =8.01(d,2H),7.83(d,2H),7.49-7.38(m,1H),7.33-7.28(m,2H),7.23-7.19(m,1H),5.58(q, 1H),3.09-3.00(m,1H),2.96-2.86(m,1H),2.66(s,6H),2.62-2.53(m,1H),2.09-2.00(m,1H). LCMS R t = 2.0 min chromatography, 1.25 min, 10-80AB, C 18 H 20 ClN2O3S[M+H] + MS ESI calculated value 379.1, found value 379.0.

[0330] Example 67. Synthesis of Compound II-29 [ka] A mixture of 4-amino-N-[(1S)-5-chloroindan-1-yl]benzamide (140 mg, 0.49 mmol), EtN (0.1 mL, 0.73 mmol), and TfO (165.29 mg, 0.59 mmol) in DCM (8 mL) was stirred at −30° C. for 1 h under N. The mixture was then stirred at 20° C. for 16 h. The reaction was concentrated and quenched with saturated NH Cl (25 mL). The mixture was extracted with DCM (25 mL × 2). The combined organic phase was washed with brine (25 mL), dried over anhydrous Na SO , filtered, and concentrated. The crude product was purified by preparative HPLC (Xtime (150 mm × 25 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN; 33–63% B over 8 min) to give the product (17.2 mg, 0.04 mmol, 8% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.83(dd,2H),7.40-7.23(m,5H),7.23-7.16(m,1H),5.56(q,1H),3.06 -2.98(m,1H),2.94-2.83(m,1H),2.59-2.50(m,1H),2.05-1.99(m,1H). LCMS R t = 1.26 min in 2 min chromatography, 10-80AB, C 17 H 15 ClF3N2O3S[M+H] + MS ESI calculated value 419.0, found value 418.9.

[0331] Example 68. Synthesis of Compound II-30 [ka] Synthesis of II-A-16b: To a mixture of 4-ethylsulfanylbenzoic acid (100 mg, 0.55 mmol) in methanol (3 mL) was added oxone (673.44 mg, 1.1 mmol) in water (3 mL) at 0 °C. The mixture was stirred at 20 °C for 15 hours. Methanol was evaporated under vacuum, and the reaction mixture was diluted with water (20 mL). The aqueous layer was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give the product (90 mg, 0.42 mmol) as a solid. 1 H NMR (400 MHz, CDCl3) δ H =8.31(d,2H),8.05(d,2H),3.18(q,2H),1.31(t,3H).

[0332] Synthesis of II-30: To a mixture of (1R)-5-chloroindan-1-amine (75.12 mg, 0.45 mmol), HOBt (75.69 mg, 0.56 mmol), and EDCI (85.9 mg, 0.45 mmol) in DCM (3 mL), DIPEA (0.2 mL, 1.12 mmol) and 4-ethylsulfonylbenzoic acid (80 mg, 0.37 mmol) were added. The mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (20 mL), and the aqueous layer was extracted with DCM (30 mL × 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Waters Xbridge 150 mm × 25 mm, 5 μm, A = water (0.05% NHOH v / v) and B = CHCN; 31–61% B over 8 min) to give the product (25.0 mg, 68.8 μmol, 18% yield) as a solid. 1 H NMR (400 MHz, CDCl3) δ H=8.03-7.82(m,4H),7.32-7.27(m,2H),7.24-7.20(m,1H),6.36(d,1H),5.68(q,1H),3.14(q, 2H),3.10-3.10(m,1H),3.01-2.89(m,1H),2.76-2.70(m,1H),2.04-1.94(m,1H),1.28(t,3H). LCMS R t = 1.19 min in 2.0 min chromatography, 10-80AB, C 18 H 19 ClNO3S[M+H] + MS ESI calculated value 364.1, found value 364.0.

[0333] Example 69. Synthesis of Compound II-31 [ka] A mixture of (1R)-5-chloroindan-1-amine (200 mg, 1.19 mmol), 4-fluorobenzoic acid (167.16 mg, 1.19 mmol), HOBt (322.43 mg, 2.39 mmol), EDCI (343.06 mg, 1.79 mmol), and TEA (603.61 mg, 5.97 mmol) in DCM (20 mL) was stirred at 20 °C for 16 h. The mixture was diluted with HO (10 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Kromasil (150 mm × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN; 53–83% B over 8 min) to give the product (160.6 mg, 0.55 mmol, 46% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.91-7.83(m,2H),7.35-7.24(m,3H),7.23-7.13(m,3H),5.55(q,1H),3 .08-2.98(m,1H),2.94-2.84(m,1H),2.60-2.50(m,1H),2.07-1.96(m,1H) LCMS R t = 1.28 min in 2.0 min chromatography, 10-80AB, C 16 H 14 MS ESI calculated for ClFNO[M+H]+ 290.1, found 289.9.

[0334] Example 70. Synthesis of Compound II-32 [ka] Synthesis of II-A-18b: To a mixture of ethyl 4-aminobenzoate (1 g, 6.05 mmol) and DMAP (1.11 g, 9.08 mmol) in pyridine (20 mL) was added N-methylsulfamoyl chloride (1.18 g, 9.08 mmol) at 0 °C. The mixture was stirred at 20 °C for 16 h under N. The mixture was concentrated and diluted with HO (10 mL). The aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was triturated from EtOAc (5 mL) to give the product (1100 mg, 4.12 mmol, 68% yield) as a solid. LCMS R t = 0.69 min in 1.5 min chromatography, 5-95AB, C 10 H 15 N2O4S[M+H] + MS ESI calculated value 259.1, found value 259.0.

[0335] Synthesis of II-A-18c: To a solution of ethyl 4-(methylsulfamoylamino)benzoate (400 mg, 1.55 mmol) in methanol (10 mL) was slowly added a solution of NaOH (247.78 mg, 6.19 mmol) in water (10 mL). The resulting mixture was stirred at 50° C. for 12 hours. The mixture was concentrated to remove MeOH under reduced pressure. 1N HCl (30 mL) was added to adjust the pH to 2. The mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (320 mg, 1.39 mmol) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =12.65(s,1H),10.19(s,1H),7.85(d,2H),7.62-7.48(m,1H),7.21(d,2H),2.44(d,3H)

[0336] Synthesis of II-32: A mixture of 4-(methylsulfamoylamino)benzoic acid (123.61 mg, 0.54 mmol), HOBt (161.21 mg, 1.19 mmol), EtN (0.25 mL, 1.79 mmol), EDCI (171.53 mg, 0.89 mmol), and (1R)-5-chloroindan-1-amine (100 mg, 0.6 mmol) in DCM (10 mL) was heated at 20 °C for 16 h under N 2 The mixture was stirred under reduced pressure. The mixture was quenched with saturated NH4Cl (20 mL), and the mixture was extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm) A = HO (0.05% NH4OH) and B = CH3CN; 40-70% B over 8 min) to give the product (11.4 mg, 0.03 mmol, 5% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H=7.94(br s,1H),7.82(d,2H),7.30(d,2H),7.27-7.18(m,4H),5.65-5.52(m,2H),3. 11-2.99(m,1H),2.98-2.85(m,1H),2.63-2.50(m,4H),2.08-2.00(m,1H). LCMS R t = 1.14 min in 2.0 min chromatography, 10-80AB, C 17 H 19 ClN3O3S[M+H] + MS ESI calculated value 380.1, found value 380.0.

[0337] Example 71. Synthesis of Compound II-33 [ka] A mixture of (1R)-5-chloroindan-1-amine (78.25 mg, 0.47 mmol), 2-methyl-4-methylsulfonyl-benzoic acid (100 mg, 0.47 mmol), HOBt (126.15 mg, 0.93 mmol), EDCI (134.22 mg, 0.70 mmol), and TEA (236.16 mg, 2.33 mmol) in DCM (20 mL) was stirred at 20 °C for 16 h. The mixture was diluted with HO (10 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Kromasil (150 mm × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN; 45–75% B over 8 min) to give the product (73.0 mg, 0.20 mmol, 43% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H=8.88(d,1H),7.83(s,1H),7.79(d,1H),7.58(d,1H),7.33(d,2H),7.29-7.25(m,1H),5.47(q, 1H),3.22(s,3H),3.03-2.92(m,1H),2.90-2.79(m,1H),2.50-2.40(m,4H),2.01-1.89(m,1H). LCMS R t = 1.17 min in 2.0 min chromatography, 10-80AB, C 18 H 19 ClNO3S[M+H] + MS ESI calculated value 364.1, found value 363.9.

[0338] Example 72. Synthesis of Compound II-34 [ka] Synthesis of II-A-20b: To a mixture of ethyl 4-aminobenzoate (500 mg, 3.03 mmol) in pyridine (20 mL) was added N,N-dimethylsulfamoyl chloride (1303.86 mg, 9.08 mmol) at 0 °C for 1 h. The mixture was then stirred at 90 °C for 16 h under N. The mixture was concentrated and diluted with H0 (10 mL). The aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN; 35–65% B over 8 min) to give the product (500 mg, 1.84 mmol, 61% yield) as a solid. LCMS R t = 0.75 min with 1.5 min chromatography, 5-95AB, C 11 H 17 N2O4S[M+H] + MS ESI calculated value 273.1, found value 273.2.

[0339] Synthesis of II-A-20c: To NaOH (88.13 mg, 2.2 mmol) in water (10 mL) was added ethyl 4-(dimethylsulfamoylamino)benzoate (150 mg, 0.55 mmol) in MeOH (10 mL) at 20° C. The resulting mixture was stirred at 20° C. for 16 hours. The mixture was concentrated, and water (20 mL) was added. The aqueous layer was extracted with EtOAc (20 mL×2). The combined organic phases were washed with 1 N HCl (20 mL×4), water (20 mL×2), and brine (20 mL×2), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (105 mg, 0.41 mmol) as a solid, which was used directly in the next step without further purification. LCMS R t = 0.55 min in 1.5 min chromatography, 5-95AB, C9H 13 MS ESI calculated for N2O4S[M+H]+ 245.1, found 244.9.

[0340] Synthesis of compound II-34: A mixture of 4-(dimethylsulfamoylamino)benzoic acid (118.03 mg, 0.48 mmol), HOBt (145.09 mg, 1.07 mmol), EtN (0.22 mL, 1.61 mmol), EDCI (154.38 mg, 0.81 mmol), and (1R)-5-chloroindan-1-amine (90 mg, 0.54 mmol) in DCM (10 mL) was heated at 20 °C for 16 h under N 2 The mixture was stirred under reduced pressure. The reaction was quenched with saturated NH4Cl (20 mL), and the mixture was extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm) A = HO (0.05% NH4OH) and B = CH3CN; 40–70% B over 8 min) to give the product (86.5 mg, 0.22 mmol, 41% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H=7.91(br s,1H),7.77(d,2H),7.32-7.23(m,4H),7.23-7.12(m,2H),5.55(q,1H),3.08-2. 97(m,1H),2.95-2.83(m,1H),2.77(s,6H),2.61-2.48(m,1H),2.05-1.97(m,1H). LCMS R t = 1.19 min in 2.0 min chromatography, 10-80AB, C 18 H 21 ClN3O3S[M+H] + MS ESI calculated value 394.1, found value 394.0.

[0341] Example 73. Synthesis of Compound II-35 [ka] A mixture of (1R)-5-chloroindan-1-amine (76.83 mg, 0.46 mmol), 3-fluoro-4-methylsulfonyl-benzoic acid (100 mg, 0.46 mmol), HOBt (123.86 mg, 0.92 mmol), EDCI (131.78 mg, 0.69 mmol), and TEA (231.87 mg, 2.29 mmol) in DCM (20 mL) was stirred at 20 °C for 16 h. The mixture was concentrated and diluted with HO (10 mL). The aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Kromasil (150 mm × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN; 46–76% B over 8 min) to give the product (60.0 mg, 0.16 mmol, 36% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H=9.11(d,1H),8.05-7.89(m,3H),7.36(s,1H),7.29-7.22(m,2H),5.51(q,1H),3.37 (s,3H),3.05-2.96(m,1H),2.92-2.82(m,1H),2.49-2.44(m,1H),2.08-1.95(m,1H). LCMS R t = 1.19 min in 2.0 min chromatography, 10-80AB, C 17 H 16 ClFNO3S[M+H] + MS ESI calculated value 368.0, found value 368.0.

[0342] Example 74. Synthesis of Compound II-36 [ka] A mixture of (1R)-5-chloroindan-1-amine (76.83 mg, 0.46 mmol), 2-fluoro-4-methylsulfonyl-benzoic acid (100 mg, 0.46 mmol), HOBt (123.86 mg, 0.92 mmol), EDCI (131.78 mg, 0.69 mmol), and TEA (231.87 mg, 2.29 mmol) in DCM (20 mL) was stirred at 20 °C for 16 h. The mixture was diluted with HO (10 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Kromasil (150 mm × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN; 45–75% B over 8 min) to give the product (56.2 mg, 0.15 mmol, 33% yield) as a solid. 1 H NMR (400 MHz, CD3OD) δ H =7.94-7.78(m,3H),7.34-7.27(m,2H),7.24-7.20(m,1H),5.59(t,1H),3.18(s, 3H), 3.10-3.01 (m, 1H), 2.97-2.88 (m, 1H), 2.67-2.58 (m, 1H), 2.08-1.98 (m, 1H). LCMS R t = 1.18 min in 2.0 min chromatography, 10-80AB, C 17 H 16 ClFNO3S[M+H] + MS ESI calculated value 368.0, found value 368.0.

[0343] Example 75. Synthesis of Compound II-37 [ka] Synthesis of II-A-23b: To a solution of CSI (500 mg, 3.53 mmol) and t-BuOH (261.85 mg, 3.53 mmol) in DCM (20 mL) was added methyl 4-aminobenzoate (534.01 mg, 3.53 mmol). The mixture was stirred at 20 °C for 16 h. The reaction was quenched with saturated NH Cl solution (15 mL). The mixture was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na SO , filtered, and concentrated to give the crude product (780 mg, 1.39 mmol) as a solid. LCMS R t = 2.04 min in 4 min chromatography, 10-80AB, C 13 H 18 N2O6SNa[M+Na] + MS ESI calculated value 353.1, found value 352.9.

[0344] Synthesis of II-A-23c: To a solution of methyl 4-(tert-butoxysulfamoylamino)benzoate (550 mg, 1.82 mmol) in methanol (10 mL) and water (10 mL), NaOH (218.29 mg, 5.46 mmol) was added. The mixture was stirred at 50 °C for 8 hours. The mixture was diluted with saturated NH Cl solution (15 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na SO , filtered, and concentrated. The aqueous phase was concentrated, and then the mixture was extracted with EtOAc (20 mL × 2) to give the crude product (400 mg, 1.38 mmol) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =12.65(br s,1H),11.52(s,1H),10.83(s,1H),7.88(d,2H),7.23(d,2H),1.31(s,9H).

[0345] Synthesis of II-A-23d: A mixture of 4-(tert-butoxycarbonylsulfamoylamino)benzoic acid (400 mg, 1.26 mmol), HOBt (341.74 mg, 2.53 mmol), EtN (0.52 mL, 3.79 mmol), EDCI (363.61 mg, 1.9 mmol), and (1R)-5-chloroindan-1-amine (211.98 mg, 1.26 mmol) in DCM (30 mL) was stirred at 20 °C for 16 h under N. The reaction was quenched with saturated NH Cl (20 mL), and the mixture was extracted with DCM (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na SO , filtered, and concentrated. The crude product was triturated from DCM (1 mL) to give the product (180 mg, 0.39 mmol, 31% yield) as a solid. LCMS R t = 0.88 min in 1.5 min chromatography, 5-95AB, C 21 H 25 MS ESI calculated for ClN3O5S [M+H]+ 466.1, found 466.2.

[0346] Synthesis of II-37: To a solution of tert-butyl N-[[4-[[(1R)-5-chloroindan-1-yl]carbamoyl]phenyl]sulfamoyl]carbamate (60 mg, 0.13 mmol) in DCM (15 mL) was added TFA (5 mL, 20 mmol). The mixture was stirred at 20 °C for 3 h. The reaction was quenched with saturated Na2CO3 solution (15 mL) and concentrated. The mixture was extracted with DCM (15 mL × 2), and the organic layer was concentrated. The crude product was triturated with DCM (1 mL) to give the product (36.4 mg, 0.1 mmol, 77% yield) as a solid. 1H NMR (400 MHz, CDCN) δ H =7.97(s,1H),7.80(d,2H),7.31-7.17(m,6H),5.63(s,2H),5.56(q,1H),3 .09-2.96(m,1H),2.95-2.82(m,1H),2.61-2.49(m,1H),2.05-1.97(m,1H). LCMS R t = 1.07 min in 2.0 min chromatography, 10-80AB, C 16 H 17 ClN3O3S[M+H] + MS ESI calculated value 366.1, found value 366.0.

[0347] Example 76. Synthesis of Compound II-38 [ka] Synthesis of II-A-24b: A mixture of KMnO (2000 mg, 12.66 mmol) and 4-(trifluoromethylsulfanyl)benzoic acid (500 mg, 2.25 mmol) in acetic acid (15 mL) and water (5 mL) was stirred at 20 °C for 12 hours. The mixture was diluted with water (20 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give the product (500 mg, 1.97 mmol) as a solid. 1 H NMR (400 MHz, CD3OD) δ H =8.37(d,2H),8.20(d,2H).

[0348] Synthesis of II-38: To a mixture of DIPEA (0.31 mL, 1.79 mmol), 4-(trifluoromethylsulfonyl)benzoic acid (151.62 mg, 0.60 mmol), and HOBt (161.21 mg, 1.19 mmol) in DCM (3 mL), EDCI (171.53 mg, 0.89 mmol) and (1R)-5-chloroindan-1-amine (100 mg, 0.60 mmol) were added. The mixture was stirred at 20 °C for 2 hours. The mixture was diluted with water (20 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 30%) to give the product (59.9 mg, 145.6 μmol, 24% yield) as a solid. 1 H NMR (400 MHz, CDCl3) δ H =8.16-8.10(m,2H),8.09-8.03(m,2H),7.29-7.27(m,2H),7.24-7.20(m,1H),6.40(d,1H) ,5.67(q,1H),3.11-3.01(m,1H),3.00-2.90(m,1H),2.78-2.72(m,1H),2.02-1.93(m,1H). LCMS R t = 1.32 min in 2.0 min chromatography, 10-80AB, C 17 H 14 ClF3NO3S[M+H] + MS ESI calculated value 404.0, found value 404.0.

[0349] Example 77. Synthesis of Compound II-39 [ka] Synthesis of II-A-25b: A mixture of methyl 4-iodobenzoate (750 mg, 2.86 mmol), cyclopropylsulfinyloxysodium (440.07 mg, 3.43 mmol), copper(I) trifluoromethanesulfonate benzene complex (144.06 mg, 0.57 mmol), and N,N-dimethylethane-1,2-diamine (100.92 mg, 1.14 mmol) in DMSO (5 mL) was stirred at 120 °C for 16 h under N. After cooling to room temperature, the mixture was diluted with HO (30 mL) and EtOAc (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (30 mL). The combined organic phase was washed with brine (20 × 2 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 15% to 30%) to give the product (480 mg, 1.99 mmol, 70% yield) as a solid. 1 H NMR (400 MHz, CDCl3) δ H =8.22(dd,2H),7.98(dd,2H),3.98(s,3H),2.56-2.43(m,1H),1.43-1.35(m,2H),1.12-1.03(m,2H).

[0350] Synthesis of II-A-25c: To a solution of methyl 4-cyclopropylsulfonylbenzoate (80 mg, 0.33 mmol) in methanol (2 mL) and water (2 mL), LiOH.HO (41.91 mg, 1 mmol) was added. The resulting mixture was stirred at 20 °C for 2 hours. 1N aqueous HCl solution (10 mL) was added, and the aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (75 mg, 331.5 μmol) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =13.50(br s,1H),8.17(d,2H),8.02(d,2H),2.98-2.88(m,1H),1.19-1.03(m,4H).

[0351] Synthesis of Compound II-39: A mixture of 4-cyclopropylsulfonylbenzoic acid (75 mg, 0.33 mmol), HATU (252.09 mg, 0.66 mmol), DIPEA (0.17 mL, 0.99 mmol), and (1R)-5-chloroindan-1-amine (55.57 mg, 0.33 mmol) in DMF (5 mL) was stirred at 20 °C for 1 h. Water (20 mL) was added, and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (20 mL × 2), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 10% to 30%) to give the product (72.0 mg, 191.4 μmol, 58% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =8.02-7.98(m,2H),7.98-7.93(m,2H),7.45(d,1H),7.33-7.27(m,2H),7.23-7.18(m,1H),5.57(q,1H),3.10 -2.99(m,1H),2.96-2.85(m,1H),2.64-2.52(m,2H),2.09-1.98(m,1H),1.24-1.18(m,2H),1.08-1.01(m,2H). LCMS R t = 1.22 min in 2.0 min chromatography, 10-80AB, C 19 H 19 ClNO3S[M+H] + MS ESI calculated value 376.1, found value 376.0.

[0352] Example 78. Synthesis of Compound II-40 [ka] Synthesis of II-A-26b: To a mixture of 4-sulfanylbenzoic acid (140 mg, 0.91 mmol) in methanol (3 mL) was added NaOH (108.96 mg, 2.72 mmol) and 1-chloro-2-methoxyethane (171.68 mg, 1.82 mmol) at 20 °C. The reaction mixture was stirred at 70 °C for 4 hours. After cooling to room temperature, the mixture was quenched by adding 1 M HCl (20 mL). The mixture was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give the product (140 mg, 659.5 μmol) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =12.88(br s,1H),7.84(d,2H),7.40(d,2H),3.56(t,2H),3.29-3.21(m,5H).

[0353] Synthesis of II-A-26c: A mixture of oxone (2081.41 mg, 3.39 mmol) and 4-(2-methoxyethylsulfanyl)benzoic acid (120 mg, 0.57 mmol) in water (4 mL) and methanol (6 mL) was stirred at 20 °C for 12 hours. The mixture was diluted with water (20 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with 1 M HCl (20 mL), water (20 mL × 2), and brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give the product (140 mg, 573.2 μmol) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H =13.55(br s,1H),8.15(d,2H),8.01(d,2H),3.70-3.60(m,4H),3.06(s,3H).

[0354] Synthesis of II-40: To a mixture of HOBt (14.51 mg, 0.11 mmol), EDCI (18.87 mg, 0.10 mmol), and 4-(2-methoxyethylsulfonyl)benzoic acid (24.04 mg, 0.10 mmol) in DCM (6 mL) was added DIPEA (0.05 mL, 0.27 mmol) and (1R)-5-chloroindan-1-amine (15 mg, 0.09 mmol). The mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (20 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with 1 M HCl (10 mL), water (20 mL × 2), and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Waters Xbridge 150 mm × 25 mm, 5 μm), A = H2O (10 mM NH4HCO3)-ACN) and B = CH3CN; 36–66% B over 7 min) to give the product (78.6 mg, 197.5 μmol) as a solid. 1 H NMR (400 MHz, CDCN) δ H =8.02-7.92(m,4H),7.54-7.40(m,1H),7.34-7.28(m,2H),7.23-7.15(m,1H),5.58(q,1H),3.67(t,2H) ,3.44(t,2H),3.13(s,3H),3.08-3.00(m,1H),2.96-2.86(m,1H),2.63-2.50(m,1H),2.08-2.00(m,1H). LCMS R t = 1.18 min in 2.0 min chromatography, 10-80AB, C 19 H 21 ClNO4S[M+H] + MS ESI calculated value 394.1, found value 393.9.

[0355] Example 79. Synthesis of Compounds II-41 and II-31 [ka] Synthesis of II-A-27b: A mixture of 4-fluorobenzoic acid (83.58 mg, 0.60 mmol), HOBt (161.21 mg, 1.19 mmol), EDCI (171.53 mg, 0.89 mmol), TEA (301.81 mg, 2.98 mmol), and 5-chloroindan-1-amine (100 mg, 0.60 mmol) in DCM (20 mL) was stirred at 20 °C for 16 h. The mixture was diluted with HO (10 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (110 mg, 0.37 mmol, 62% yield) as a solid. LCMS R t = 0.88 min in 2.0 min chromatography, 10-80AB, C 16 H 14 MS ESI calculated for ClFNO[M+H]+ 290.1, found 290.0. Analytical SFC: (Chiralcel OD-3 150mm x 4.6mm i.d., 3µm, Mobile phase: A:CO2 B:Ethanol (0.05% DEA), Gradient: 5% to 40% B in 5 min, 40% to 5% B in 0.5 min, hold at 5% B for 1.5 min, Flow rate: 2.5mL / min, Column temperature: 35°C) showed two peaks at 3.18 and 3.81 min.

[0356] Synthesis of compounds II-41 and II-31: The product (110 mg, 0.37 mmol) was purified by SFC [DAICEL CHIRALCEL OD-H (250 mm × 30 mm, 5 μm); A = CO and B = EtOH (0.1% NHHO); 38 °C; 50 mL / min; 30% B; 9 min run; 7 injections] to give enantiomer 1 (R peak 1), assigned as compound II-31 (32 mg, 0.11 mmol). t =3.18 min) as a solid and enantiomer 2 (R peak 2) assigned as compound II-41 (28.0 mg, 0.10 mmol) t = 3.81 min) was obtained as a solid. Stereochemistry was randomly assigned. Compound II-31: 1 H NMR (400 MHz, CDCN) δ H =7.91-7.82(m,2H),7.35-7.22(m,3H),7.22-7.14(m,3H),5.55(q,1H),3 .07-2.98(m,1H),2.94-2.84(m,1H),2.60-2.50(m,1H),2.06-1.97(m,1H) LCMS R t = 1.28 min in 2.0 min chromatography, 10-80AB, C 16 H 14 MS ESI calculated for ClFNO[M+H]+ 290.1, found 289.9. Compound II-41: 1 H NMR (400 MHz, CDCN) δ H =7.91-7.82(m,2H),7.35-7.22(m,3H),7.22-7.14(m,3H),5.55(q,1H),3 .07-2.98(m,1H),2.94-2.84(m,1H),2.60-2.50(m,1H),2.06-1.97(m,1H) LCMS R t = 1.28 min in 2.0 min chromatography, 10-80AB, C 16 H 14 MS ESI calculated for ClFNO[M+H]+ 290.1, found 289.9.

[0357] Example 80. Synthesis of Compound II-42 [ka] To a mixture of HOBt (58.04 mg, 0.43 mmol), EDCI (75.47 mg, 0.39 mmol), and 4-(difluoromethylsulfonyl)benzoic acid (92.99 mg, 0.39 mmol) in DMF (3 mL) was added DIPEA (0.19 mL, 1.07 mmol) and (1R)-5-chloroindan-1-amine (60 mg, 0.36 mmol). The mixture was stirred at 20 °C for 2 hours. The mixture was diluted with water (20 mL), and the aqueous layer was extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm) A = HO (10 mM NHHCO) and B = CHCN; 45–75% B over 7 min) to give the product (56.3 mg, 146.0 μmol, 41% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =8.11-8.01(m,4H),7.58-7.43(m,1H),7.35-7.26(m,2H),7.24-7.18(m,1H),6.57(t,1H) ,5.58(q,1H),3.09-3.00(m,1H),2.96-2.85(m,1H),2.62-2.52(m,1H),2.09-1.99(m,1H). LCMS R t = 1.24 min in 2.0 min chromatography, 10-80AB, C 17 H 15 ClF2NO3S[M+H] + MS ESI calculated value 386.0, found value 385.9.

[0358] Example 81. Synthesis of Compound II-43 [ka] To a mixture of N-[(1R)-5-chloroindan-1-yl]-4-(methanesulfonamido)benzamide (100 mg, 0.27 mmol), 1-chloro-2-methoxyethane (116.6 mg, 1.23 mmol), and KI (13.65 mg, 0.08 mmol) in DMF (6 mL) was added K2CO3 (113.64 mg, 0.82 mmol) at 20 °C. The mixture was stirred at 80 °C for 16 h under N2. After cooling to room temperature, the mixture was concentrated to give a residue. The residue was diluted with HO (30 mL), and the mixture was extracted with EtOAc (10 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN; 39–69% B over 9 min) to give the product (65.5 mg, 0.16 mmol, 57% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.84(dd,2H),7.43(dd,2H),7.35-7.25(m,3H),7.22-7.17(m,1H),5.56(q,1H),3.83(t,2H),3.37(t,2H) ),3.23(s,3H),3.07-2.98(m,1H),2.96(s,3H),2.93-2.84(m,1H),2.60-2.50(m,1H),2.07-1.97(m,1H). LCMS R t = 1.19 min in 2.0 min chromatography, 10-80AB, C 20 H 24 ClN2O4S[M+H] + MS ESI calculated value 423.1, found value 423.0.

[0359] Example 82. Synthesis of Compound II-44 [ka] To a mixture of N-[(1R)-5-chloroindan-1-yl]-4-(methanesulfonamido)benzamide (100 mg, 0.27 mmol), 2-(dimethylamino)ethanol (73.3 mg, 0.82 mmol), and Ph3P (143.79 mg, 0.55 mmol) in THF (10 mL) was added DIAD (110.85 mg, 0.55 mmol) at 0 °C. The mixture was stirred at 20 °C for 16 h under N2. The mixture was concentrated to dryness and diluted with HO (10 mL). The mixture was extracted with EtOAc (10 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm × 10 μm) A = HO (0.05% aqueous ammonia) and B = CH3CN; 45-55% B over 9 min) to give the product (23.7 mg, 0.05 mmol, 20% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.86(dd,2H),7.45(dd,2H),7.35-7.25(m,3H),7.24-7.16(m,1H),5.57(q,1H),3.76(t,2H),3.09-2.99 (m,1H),2.97(s,3H),2.94-2.84(m,1H),2.62-2.50(m,1H),2.29(t,2H),2.14(s,6H),2.07-1.98(m,1H). LCMS R t = 0.96 min in 2.0 min chromatography, 10-80AB, C 21 H 27 ClN3O3S[M+H] + MS ESI calculated value 436.1, found value 436.1.

[0360] Example 83. Synthesis of Compound II-45 [ka] To a mixture of N-[(1R)-5-chloroindan-1-yl]-4-(methanesulfonamido)benzamide (100 mg, 0.27 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (318.08 mg, 1.37 mmol), and KI (22.75 mg, 0.14 mmol) in DMF (6 mL) was added KCO (113.64 mg, 0.82 mmol) at 20 °C. The mixture was stirred at 80 °C for 16 h under N. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with HO (30 mL), and the mixture was extracted with EtOAc (10 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was triturated from i-Pr2O (10 mL) to give the product (96.3 mg, 0.22 mmol, 79% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.89(d,2H),7.52(d,2H),7.38-7.25(m,3H),7.23-7.17(m,1H),5.56(q,1H),4.40 (q,2H),3.15-2.96(m,4H),2.94-2.84(m,1H),2.61-2.50(m,1H),2.07-1.97(m,1H). LCMS R t = 1.26 min in 2.0 min chromatography, 10-80AB, C 19 H 19 ClF3N2O3S[M+H] + MS ESI calculated value 447.1, found value 447.1.

[0361] Example 84. Synthesis of Compound II-46 [ka] To a mixture of N-[(1R)-5-chloroindan-1-yl]-4-(methanesulfonamido)benzamide (60 mg, 0.16 mmol), 1-chloro-2-(trifluoromethoxy)ethane (109.9 mg, 0.74 mmol), and KI (13.65 mg, 0.08 mmol) in DMF (6 mL) was added K2CO3 (68.19 mg, 0.49 mmol) at 20 °C. The mixture was stirred at 100 °C for 16 h under N2. The mixture was diluted with HO (10 mL), and the mixture was extracted with EtOAc (10 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm × 5 μm) A = HO (0.05% aqueous ammonia) and B = CH3CN; 51–71% B over 9 min) to give the product (35.71 mg, 0.07 mmol, 46% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.88(dd,2H),7.46(dd,2H),7.38-7.25(m,3H),7.23-7.16(m,1H),5.57(q,1H),4.10-4.03(m,2H),4.0 3-3.95(m,2H),3.09-2.98(m,1H),2.95(s,3H),2.94-2.84(m,1H),2.62-2.51(m,1H),2.07-1.98(m,1H). LCMS R t = 1.23 min in 2.0 min chromatography, 10-80AB, C 20 H 21 ClF3N2O4S[M+H] + MS ESI calculated value 477.1, found value 477.0.

[0362] Example 85. Synthesis of Compound II-47 [ka] To a mixture of N-[(1R)-5-chloroindan-1-yl]-4-(methanesulfonamido)benzamide (120 mg, 0.33 mmol), 2-bromoethanol (184.95 mg, 1.48 mmol), and KI (16.38 mg, 0.1 mmol) in DMF (6 mL) was added K2CO3 (136.37 mg, 0.99 mmol) at 20 °C. The mixture was stirred at 100 °C for 16 h under N2. The mixture was quenched with saturated NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN; 30–60% B over 9 min) to give the product (36.3 mg, 0.09 mmol, 27% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.85(d,2H),7.46(dd,2H),7.36-7.26(m,3H),7.23-7.16(m,1H),5.57(q,1H),3.77(t,2H),3.50 (q,2H),3.08-2.98(m,1H),2.97(s,3H),2.94-2.84(m,2H),2.63-2.49(m,1H),2.05-1.97(m,1H). LCMS R t = 2.0 min chromatography at 1.11 min, 10-80AB, C 19 H 22 ClN2O4S[M+H] + MS ESI calculated value 409.1, found value 409.0.

[0363] Example 86: Synthesis of Compound II-48 [ka] A mixture of 3-methyl-4-methylsulfonyl-benzoic acid (100 mg, 0.47 mmol), HOBt (126.15 mg, 0.93 mmol), EDCI (134.22 mg, 0.7 mmol), TEA (0.32 mL, 2.33 mmol), and (1R)-5-chloroindan-1-amine (78.25 mg, 0.47 mmol) in DCM (10 mL) was stirred at 20 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was diluted with HO (20 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with water (20 mL) and brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN; 46–76% B over 9 min) to give the product (56.1 mg, 0.15 mmol, 33% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =8.01(d,1H),7.87-7.75(m,2H),7.54-7.40(m,1H),7.35-7.25(m,2H),7.24-7.17(m,1H),5.56( q,1H),3.14-2.99(m,4H),2.96-2.84(m,1H),2.70(s,3H),2.62-2.50(m,1H),2.07-1.99(m,1H). LCMS R t = 1.19 min in 2 min chromatography, 10-80AB, C 18 H 19 ClNO3S[M+H] + MS ESI calculated value 364.1, found value 364.0.

[0364] Example 87. Synthesis of Compound II-49 [ka] To a mixture of N-[(1R)-5-chloroindan-1-yl]-4-(methanesulfonamido)benzamide (100 mg, 0.27 mmol), 2-chloro-N,N-dimethyl-acetamide (166.6 mg, 1.37 mmol), and KI (13.65 mg, 0.08 mmol) in THF (10 mL) was added K2CO3 (113.64 mg, 0.82 mmol) at 0 °C. The mixture was stirred at 20 °C for 16 h under N2. The mixture was concentrated to dryness and diluted with HO (10 mL). The mixture was extracted with EtOAc (10 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 25 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN; 40–60% B over 9 min) to give the product (37.5 mg, 0.08 mmol, 30% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.85(d,2H),7.56(d,2H),7.37-7.28(m,3H),7.27-7.20(m,1H),5.59(q,1H),4.62(s,2H),3.15 (s,3H),3.10-3.01(m,1H),2.97(s,3H),2.95-2.80(m,4H),2.63-2.54(m,1H),2.09-2.00(m,1H). LCMS R t = 2.0 min chromatography, 1.15 min, 10-80AB, C 21 H 25 ClN3O4S[M+H] + MS ESI calculated value 450.1, found value 450.1.

[0365] Example 88. Synthesis of Compound II-50 [ka] To a mixture of N-[(1R)-5-chloroindan-1-yl]-4-(methanesulfonamido)benzamide (180 mg, 0.49 mmol), oxetan-3-yl methyl 4-benzenesulfonate (1.13 g, 4.93 mmol), and CsCO (642.94 mg, 1.97 mmol) in DMF (10 mL) was added KI (409.48 mg, 2.47 mmol) at 0 °C, and the mixture was stirred at 120 °C for 16 h under N. After cooling to room temperature, the reaction was quenched with saturated NHCl (20 mL). The mixture was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Green ODS (150 mm × 30 mm, 5 μm) A = water (0.075% TFA) and B = CHCN; 42-62% B over 9 min) to give the product, which was then neutralized with saturated NaHCO (10 mL) and the mixture was extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to give the product (19.8 mg, 0.05 mmol, 9% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =7.94-7.79(m,2H),7.40-7.25(m,5H),7.24-7.16(m,1H),5.57(q,1H),5.27-5.13(m,1H),4.61(t,2H) ,4.45(t,2H),3.10-2.97(m,1H),2.95-2.85(m,1H),2.82(s,3H),2.62-2.49(m,1H),2.07-1.98(m,1H). LCMS R t = 2.0 min chromatography, 1.15 min, 10-80AB, C 20 H 22 ClN2O4S[M+H] + MS ESI calculated value 421.1, found value 421.2.

[0366] Example 89. Synthesis of Compound II-51 [ka] Synthesis of II-A-26b: A mixture of 4-sulfanylbenzoic acid (500 mg, 3.24 mmol) and NaOH (389.13 mg, 9.73 mmol) in methanol (15 mL) was stirred at 45 °C for 20 minutes. 2-Bromo-1,1-difluoroethane (940.07 mg, 6.49 mmol) was then added. The reaction mixture was stirred at 45 °C for 48 hours. After cooling to room temperature, the mixture was diluted with HO (20 mL) and concentrated to remove MeOH. The solution was then acidified to pH 3 with 1 M HCl. The solid was collected by filtration, and the filter cake was dried in an oven to give the product (400 mg, 1.83 mmol). 1 H NMR (400 MHz, DMSO-d 6 )δ H =7.86(d,2H),7.51(d,2H),6.25(tt,1H),3.64(dt,2H).

[0367] Synthesis of II-A-26c: A mixture of 4-(2,2-difluoroethylsulfanyl)benzoic acid (300 mg, 1.37 mmol), HOBt (371.54 mg, 2.75 mmol), EDCI (527.08 mg, 2.75 mmol), DIPEA (0.76 mL, 5.5 mmol), and (1R)-5-chloroindan-1-amine (230.46 mg, 1.37 mmol) in DCM (15 mL) was stirred at 25 °C for 16 h. The reaction was concentrated and diluted with HO (20 mL), and the aqueous layer was extracted with DCM (20 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified using flash chromatography on silica gel (DCM) to give the product (300 mg, 0.8071 mmol, 59% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 )δ H=7.75(d,2H),7.46(d,2H),7.28-7.25(m,2H),7.25-7.18(m,1H),6.34-6.22(m,1H),5.92(t t,1H),5.67(q,1H),3.34(dt,2H),3.15-2.90(m,2H),2.80-2.63(m,1H),2.05-1.92(m,1H). LCMS R t = 2.0 min chromatography, 1.25 min, 10-80AB, C 18 H 17 ClF2NOS[M+H] + MS ESI calculated value 368.1, found value 367.9.

[0368] Synthesis of Compound II-51: To a solution of N-[(1R)-5-chloroindan-1-yl]-4-(2,2-difluoroethylsulfanyl)benzamide (80 mg, 0.22 mmol) in methanol (15 mL) and water (10 mL) was added oxone (800.75 mg, 1.3 mmol). The mixture was stirred at 25 °C for 24 hours. The suspension was filtered, and the filtrate was concentrated under reduced pressure. The crude product was washed with HO (10 mL) and triturated from MeOH (5 mL) to give the product (30.7 mg, 0.07 mmol, 34% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H =8.08-7.96(m,4H),7.55-7.45(m 1H),7.36-7.26(m,2H),7.25-7.17(m,1H),6.24(tt,1H),5.58(q,1H),3.90(dt, 2H), 3.13-2.99 (m, 1H), 2.97-2.83 (m, 1H), 2.66-2.51 (m, 1H), 2.10-1.98 (m, 1H). LCMS R t = 2.0 min of chromatography at 1.22 min, 10-80AB, C 18 H 17 ClF2NO3S[M+H] + MS ESI calculated value 400.1, observed value 400.0.

[0369] Example 90. Synthesis of Compounds II-52 and II-53 [ka] Synthesis of II-A-5: A mixture of 6-chlorotetralin-1-one (500 mg, 2.77 mmol) and NHOAc (2134.2 mg, 27.68 mmol) in I-PrOH (14 mL) was stirred at 20 °C for 1 h. NaBHCN (608.81 mg, 9.69 mmol) was then added, and the resulting mixture was heated to 85 °C. The mixture was stirred at 85 °C for 3 h. 5 N NaOH solution (50 mL) was added, and the aqueous layer was extracted with EtOAc (30 mL). The organic phase was separated, washed with brine (20 mL × 2), dried over anhydrous NaSO, filtered, and concentrated. The residue was redissolved in DCM (30 mL) and extracted with 1 N aqueous HCl (30 mL × 2). Saturated Na2CO3 solution (30 mL) was added to adjust the pH to 9, and the aqueous layer was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with water (30 mL × 2) and brine (30 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product (270 mg, 1.49 mmol) as an oil. 1 H NMR (400 MHz, CDCl3) δ H =7.35(d,1H),7.15(dd,1H),7.08(s,1H),3.99-3.89(m,1H),2.85-2.63(m,2H),2.06-1.87(m,2H),1.82-1.62(m,2H).

[0370] Synthesis of II-A-27a: A mixture of 4-(methanesulfonamido)benzoic acid (170.61 mg, 0.79 mmol), HOBt (238.04 mg, 1.76 mmol), EtN (0.37 mL, 2.64 mmol), EDCI (253.26 mg, 1.32 mmol), and 6-chlorotetralin-1-amine (160 mg, 0.88 mmol) in DCM (15 mL) was heated at 20 °C for 16 h under N 2The mixture was stirred under reduced pressure. The reaction was quenched with saturated NH4Cl (20 mL), and the mixture was extracted with DCM (30 mL x 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the product (301 mg, 0.79 mmol) as a solid. LCMS R t = 1.06 min in 1.5 min chromatography, 5-95AB, C 18 H 20 ClN2O3S[M+H] + MS ESI calculated value 379.1, found value 379.0. Analytical SFC: (Chiralpak OJ-3 150 mm x 4.6 mm i.d., 3 μm, mobile phase: A:CO2, B:ethanol (0.05% DEA), gradient: 5% to 40% B in 5 min, 40% B for 2.5 min, then hold at 5% B for 2.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C) t = 5.08 min and R t = 5.67 min showed two peaks.

[0371] Synthesis of compounds II-52 and II-53: N-(6-chlorotetralin-1-yl)-4-(methanesulfonamido)benzamide (300 mg, 0.79 mmol) was purified by SFC [DAICEL CHIRALCEL OJ-H (250 mm × 30 mm, i.d., 5 μm); A = CO and B = EtOH (0.1% NH H O); 38 °C; 60 mL / min; 35% B; 12 min run; 9 injections] to yield randomly assigned enantiomer 1 (R peak 1) as compound II-52 (95.6 mg, 0.25 mmol). t = 5.08 min) as a solid and randomly assigned enantiomer 2 (R peak 2) as compound II-53 (62.12 mg, 0.16 mmol). t = 5.67 min) was obtained as a solid. Stereochemistry was randomly assigned. Compound II-52 1 H NMR (400 MHz, DMSO-d 6 )δ H=10.08(s,1H),8.66(d,1H),7.89(d,2H),7.32-7.11(m,5H),5.28-5.10(m, 1H),3.05(s,3H),2.84-2.73(m,2H),2.04-1.87(m,2H),1.85-1.65(m,2H). LCMS R t = 1.09 min in 2 min chromatography, 10-80AB, C 18 H 20 ClN2O3S[M+H] + MS ESI calculated value 379.1, found value 379.0. Compound II-53 1 H NMR (400 MHz, DMSO-d 6 )δ H =10.08(s,1H),8.66(d,1H),7.88(d,2H),7.28-7.13(m,5H),5.25-5.12(m, 1H), 3.05 (s, 3H), 2.84-2.74 (m, 2H), 2.03-1.87 (m, 2H), 1.85-1.66 (m, 2H). LCMS R t = 1.07 min in 2 min chromatography, 10-80AB, C 18 H 20 ClN2O3S[M+H] + MS ESI calculated value 379.1, found value 379.0.

[0372] Example 91. Synthesis of Compounds II-54 and II-55 [ka] To a mixture of 6-chlorotetralin-1-amine (110 mg, 0.61 mmol), HOBt (163.65 mg, 1.21 mmol), and EDCI (174.12 mg, 0.91 mmol) in DCM (3 mL) was added DIPEA (0.32 mL, 1.82 mmol) and 4-methylsulfonylbenzoic acid (145.48 mg, 0.73 mmol). The mixture was stirred at 20 °C for 2 hours. The mixture was diluted with water (20 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with 1 M HCl (20 mL), water (20 mL × 2), and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. Analytical SFC: (Chiralcel OJ-3 150x4.6mm i.d., 3µm, Mobile phase: A:CO2 B:Ethanol (0.05% DEA), Gradient: 5% to 40% B in 5 min, 40% B for 2.5 min, then hold at 5% B for 2.5 min, Flow rate: 2.5mL / min, Column temperature: 35°C) showed two peaks at 1.84 and 5.65 min.

[0373] The product was purified by SFC [DAICEL CHIRALPAK AS (250 mm × 30 mm, 10 μm); A = CO and B = MeOH (0.1% NH HO); 38 °C; 70 mL / min; 50% B; 13 min run; 6 injections] to give the randomly assigned enantiomer 1 (R peak 1) as compound II-54 (38.1 mg, 103.2 μmol). t =1.84 min) as a solid and randomly assigned enantiomer 2 (R of peak 2) as compound II-55 (47.5 mg, 130.5 μmol). t = 5.65 min) was obtained as a solid. Stereochemistry was randomly assigned. Compound II-54 1 H NMR (400 MHz, CDCl3) δ H=8.05-8.00(m,2H),7.99-7.93(m,2H),7.25(s,1H),7.20-7.12(m,2H),6.37(d,1H),5. 43-5.34(m,1H),3.07(s,3H),2.91-2.76(m,2H),2.21-2.11(m,1H),2.00-1.84(m,3H). LCMS R t = 2.0 min chromatography, 1.20 min, 10-80AB, C 18 H 19 ClNO3S[M+H] + MS ESI calculated value 364.1, found value 364.0. Compound II-55 1 H NMR (400 MHz, CDCl3) δ H =8.08-8.00(m,2H),8.00-7.94(m,2H),7.25(s,1H),7.20-7.13(m,2H),6.35(d,1H),5. 46-5.31(m,1H),3.07(s,3H),2.90-2.74(m,2H),2.22-2.09(m,1H),2.01-1.84(m,3H). LCMS R t = 1.19 min in 2.0 min chromatography, 10-80AB, C 18 H 19 ClNO3S[M+H] + MS ESI calculated value 364.1, found value 364.0.

[0374] Example 92. Synthesis of Compounds II-56 and II-58 [ka] Synthesis of II-A-7: A mixture of 5-(trifluoromethyl)indan-1-one (400 mg, 2 mmol) and NHOAc (1.54 g, 19.98 mmol) in I-PrOH (10 mL) was stirred at 20 °C for 1 h, and then NaBHCN (439.53 mg, 6.99 mmol) was added. The mixture was heated to 85 °C and stirred for 3 h. 5 N aqueous NaOH solution (150 mL) was added, and the aqueous layer was extracted with EtOAc (100 mL). The organic phase was separated, washed with brine (100 mL × 2), dried over anhydrous NaSO, filtered, and concentrated. The residue was redissolved in DCM (100 mL) and extracted with 1 N aqueous HCl solution (100 mL × 2). Saturated aqueous NaCO solution (100 mL) was added to adjust the pH to 9, and the aqueous layer was extracted with EtOAc (100 mL × 2). The combined organic phase was washed with water (100 mL × 2) and brine (100 mL × 2), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (210 mg, 0.94 mmol) as an oil, which was used directly in the next step without further purification. LCMS R t = 0.74 min in 1.5 min chromatography, 5-95AB, C 10 H 10 F3N2[M-NH3+H] + MS ESI calculated value 185.1, found value 184.8.

[0375] Synthesis of II-A-29a: A mixture of 4-(methanesulfonamido)benzoic acid (192.56 mg, 0.89 mmol), HOBt (268.66 mg, 1.99 mmol), EtN (0.41 mL, 2.98 mmol), EDCI (285.85 mg, 1.49 mmol), and 5-(trifluoromethyl)indan-1-amine (200 mg, 0.99 mmol) in DCM (15 mL) was heated at 20 °C for 16 h under N 2The mixture was stirred under reduced pressure. The reaction was quenched with saturated NH4Cl (30 mL), and the mixture was extracted with DCM (30 mL x 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was triturated from DCM / n-hexane (2 mL / 8 mL) to give the product (310 mg, 0.77 mmol, 78% yield) as a solid. LCMS R t = 0.94 min in 1.5 min chromatography, 5-95AB, C 18 H 18 F3N2O3S[M+H] + MS ESI calculated value 399.1, found value 398.9. Analytical SFC: (Chiralpak AD-3 150x4.6 mm, id, 3 μm, mobile phase: A:CO2 B:ethanol (0.05% DEA), gradient: 5% to 40% B in 5 min, 40% B for 2.5 min, then hold at 5% B for 2.5 min, flow rate: 2.5 mL / min, column temperature: 35°C) showed two peaks at 4.16 and 4.36 min.

[0376] Synthesis of compounds II-58 and II-56: 4-(methanesulfonamido)-N-[5-(trifluoromethyl)indan-1-yl]benzamide (310 mg, 0.77 mmol) was purified by SFC (DAICEL CHIRALPAK AD-H (250 mm × 30 mm, i.d., 5 μm); A = CO and B = EtOH (0.1% NH H O); 38 °C; 50 mL / min; 35% B; 8 min run; 24 injections) to yield randomly assigned enantiomer 1 (R peak 1) as compound II-58 (41.9 mg, 104.7 μmol). t = 4.16 min) as a solid and randomly assigned enantiomer 2 (R of peak 2) as compound II-56 (43.4 mg, 109.0 μmol). t = 4.36 min) was obtained as a solid. Stereochemistry was randomly assigned. Compound II-58 1 H NMR (400 MHz, CDCN) δ H=7.91-7.73(m,3H),7.59(s,1H),7.54-7.43(m,2H),7.37-7.18(m,3H),5.65(q, 1H),3.16-3.05(m,1H),3.03-2.91(m,4H),2.65-2.54(m,1H),2.09-2.01(m,1H). LCMS R t = 1.18 min in 2.0 min chromatography, 10-80AB, C 18 H 18 F3N2O3S[M+H] + MS ESI calculated value 399.1, found value 399.0. Compound II-56 1 H NMR (400 MHz, CDCN) δ H =7.89-7.64(m,3H),7.59(s,1H),7.54-7.43(m,2H),7.37-7.21(m,3H),5.65(q, 1H),3.15-3.05(m,1H),3.02-2.91(m,4H),2.65-2.55(m,1H),2.09-2.01(m,1H). LCMS R t = 1.17 min in 2.0 min chromatography, 10-80AB, C 18 H 18 F3N2O3S[M+H] + MS ESI calculated value 399.1, found value 399.0.

[0377] Example 93. Synthesis of compounds II-57 and II-59 [ka] Synthesis of II-A-9: A mixture of 5-fluoroindan-1-one (2 g, 13.32 mmol) and NHOAc (10.27 g, 133.2 mmol) in I-PrOH (250 mL) was stirred at 20 °C for 1 h, and then NaBHCN (2.93 g, 46.62 mmol) was added. The mixture was heated to 85 °C and stirred for 3 h. 5 N aqueous NaOH (100 mL) was added, and the mixture was extracted with EtOAc (100 mL). The organic phase was separated, washed with brine (100 mL × 2), dried over anhydrous NaSO, filtered, and concentrated. The residue was redissolved in DCM (100 mL), and the organic layer was extracted with 1 M HCl (100 mL × 2). Saturated NaCO solution (100 mL) was added to adjust the pH to 9, and the aqueous layer was extracted with EtOAc (100 mL × 2). The combined organic phase was washed with water (100 mL x 2) and brine (100 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product (900 mg, 4.99 mmol) as an oil. LCMS R t = 0.27 min in 1.5 min chromatography, 5-95AB, C9H 10 FN2[M-NH2] + MS ESI calculated value 135.1, found value 134.9.

[0378] Synthesis of II-A-30a: A mixture of 4-(methanesulfonamido)benzoic acid (384.39 mg, 1.79 mmol), HOBt (536.3 mg, 3.97 mmol), EtN (0.82 mL, 5.95 mmol), EDCI (570.61 mg, 2.98 mmol), and 5-fluoroindan-1-amine (300 mg, 1.98 mmol) in DCM (15 mL) was heated at 20 °C for 16 h under N 2 The mixture was stirred under reduced pressure. The reaction was quenched with saturated NH4Cl (30 mL), and the mixture was extracted with DCM (30 mL x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the product (350 mg, 1.0 mmol, 51% yield) as a solid. LCMS R t = 1.08 min in 2 min chromatography, 10-80AB, C17 H 18 FN2O3S[M+H] + MS ESI calculated value 349.1, found value 348.9. Analytical SFC: (Chiralcel OJ-3 100 mm x 4.6 mm ID, 3 μm, Mobile phase: A:CO2 B:Ethanol (0.05% DEA), Gradient: 5% to 40% B in 5 min, 40% B for 2.5 min, then hold at 5% B for 2.5 min, Flow rate: 2.5 mL / min, Column temperature: 35 °C) showed two peaks at 3.32 and 3.67 min.

[0379] Synthesis of II-A-9: N-[5-fluoroindan-1-yl]-4-(methanesulfonamido)benzamide (200 mg, 0.57 mmol) was purified by SFC (DAICEL CHIRALCEL OJ-H (250 mm × 30 mm, i.d., 5 μm); A = CO and B = EtOH (0.1% NH H O); 38 °C; 50 mL / min; 35% B; 9 min run; 14 injections) to yield randomly assigned enantiomer 1 (R peak 1) as compound 59 (89.7 mg, 0.26 mmol). t = 3.32 min) as a solid and randomly assigned enantiomer 2 (R of peak 2) as compound 57 (81.4 mg, 0.23 mmol). t = 3.67 min) was obtained as a solid. Stereochemistry was randomly assigned. Compound II-59 1 H NMR (400 MHz, CDCN) δ H =7.88-7.72(m,3H),7.33-7.15(m,4H),7.05-6.97(m,1H),6.97-6.87(m,1H),5.55( q,1H),3.08-2.95(m,4H),2.94-2.82(m,1H),2.63-2.49(m,1H),2.08-1.97(m,1H). LCMS R t = 1.09 min in 2.0 min chromatography, 10-80AB, C 17 H 18 FN2O3S[M+H] + MS ESI calculated value 349.1, found value 348.9. Compound II-57 1 H NMR (400 MHz, CDCN) δ H =7.86-7.77(m,3H),7.32-7.17(m,4H),7.05-6.98(m,1H),6.97-6.88(m,1H),5.55( q,1H),3.09-2.95(m,4H),2.94-2.83(m,1H),2.63-2.50(m,1H),2.07-1.96(m,1H). LCMS R t = 1.08 min in 2.0 min chromatography, 10-80AB, C 17 H 18 FN2O3S[M+H] + MS ESI calculated value 349.1, found value 348.9.

[0380] Example 94. Synthesis of Compounds III-1 and III-2 [ka] Synthesis of III-A-1b A mixture of 2-hydroxy-4-methoxy-benzoic acid (135.41 mg, 0.81 mmol), HOBt (241.82 mg, 1.79 mmol), EDCI (257.29 mg, 1.34 mmol), EtN (0.37 mL, 2.68 mmol), and 5-chloroindan-1-amine (150 mg, 0.89 mmol) in DCM (10 mL) was stirred at 20 °C for 16 h under N. The reaction was quenched with saturated NHCl (15 mL), and the mixture was extracted with DCM (20 mL × 2). The combined organic phase was washed with brine (15 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0-15%-25%-40%) to give the product (101 mg, 0.32 mmol, 35% yield) as a solid. LCMS R t = 0.89 min in 1.5 min chromatography, 5-95AB, C 17 H 17 ClNO3[M+H] +MS ESI calculated value 318.1, found value 317.9. Analytical SFC: (Chiralcel OJ-3 100 mm x 4.6 mm ID, 3 μm, Mobile phase: A:CO2 B:Ethanol (0.05% DEA), Gradient: 5% to 40% B in 5 min, 40% B for 2.5 min, then hold at 5% B for 2.5 min, Flow rate: 2.5 mL / min, Column temperature: 35 °C) showed two peaks at 1.97 min (50%) and 7.57 min (50%).

[0381] Synthesis of compounds III-1 and III-2 N-(5-chloroindan-1-yl)-2-hydroxy-4-methoxy-benzamide (100 mg, 0.31 mmol) was purified by SFC [DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); A = CO and B = EtOH (0.1% NH H O); 38 °C; 80 mL / min; 55% B; 11 min run; 8 injections] to yield enantiomer 1 (R peak 1), randomly assigned as compound 1 (55.80 mg, 0.18 mmol). t =1.98 min) as a solid and compound 2 (70.50 mg, 0.22 mmol) as randomly assigned enantiomer 2 (R t = 7.56 min) was obtained as a solid. Stereochemistry was randomly assigned. Compound III-1 1 H NMR (400 MHz, CDCN) δ H =12.94(s,1H),7.51(d,1H),7.41-7.25(m,3H),7.24-7.17(m,1H),6.48-6.38(m,2H),5.59(q, 1H),3.80(s,3H),3.11-2.98(m,1H),2.97-2.83(m,1H),2.61-2.50(m,1H),2.10-1.99(m,1H). LCMS R t = 1.21 min in 2 min chromatography, 10-80AB, C 17 H 17 ClNO3[M+H] + MS ESI calculated value 318.1, found value 317.9. Compound III-2 1 H NMR (400 MHz, CDCN) δ H =12.94(s,1H),7.51(d,1H),7.44-7.25(m,3H),7.24-7.16(m,1H),6.49-6.37(m,2H),5.59(q, 1H),3.80(s,3H),3.10-3.00(m,1H),2.97-2.84(m,1H),2.61-2.50(m,1H),2.08-2.00(m,1H). LCMS R t = 1.21 min in 2 min chromatography, 10-80AB, C 17 H 17 ClNO3[M+H] + MS ESI calculated value 318.1, found value 317.9.

[0382] Example 95. Synthesis of Compound III-3 [ka] To a mixture of 2-hydroxybenzoic acid (63.44 mg, 0.46 mmol), HOBt (112.85 mg, 0.84 mmol), and EtN (0.29 mL, 2.09 mmol) in CHCl (3 mL) was added EDCI (160.09 mg, 0.84 mmol) and (1R)-5-chloroindan-1-amine (70 mg, 0.42 mmol). The reaction mixture was stirred at 35 °C for 16 h. The mixture was diluted with saturated NHCl (5 mL), and the aqueous layer was extracted with CHCl (5 mL × 2). The combined organic phase was washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Xtime C18 (150 mm × 25 mm, 5 μm) A = HO (10 mM NH4HCO3) and B = CH3CN; 56–76% B over 9 min) to give the product (29.1 mg, 0.10 mmol, 24% yield) as a solid. 1 H NMR (400 MHz, CDCN) δ H=12.66-12.46(m,1H),7.62-7.48(m,2H),7.44-7.39(m,1H),7.32-7.28(m,2H),7.23-7.19(m,1H),6.93(dd,1H) ),6.89-6.84(m,1H),5.61(q,1H),3.10-3.01(m,1H),2.96-2.87(m,1H),2.62-2.53(m,1H),2.11-2.02(m,1H). LCMS R t = 1.36 min in 2.0 min chromatography, 10-80AB, C 16 H 15 ClNO2[M+H] + MS ESI calculated value 288.1, found value 287.9.

[0383] Example 96. Synthesis of Compound III-4 [ka] A mixture of 4-fluoro-2-hydroxybenzoic acid (93.12 mg, 0.60 mmol), HOBt (161.21 mg, 1.19 mmol), EDCI (171.53 mg, 0.89 mmol), TEA (301.81 mg, 2.98 mmol), and (1R)-5-chloroindan-1-amine (100 mg, 0.60 mmol) in DCM (20 mL) was stirred at 20 °C for 16 h. The mixture was diluted with HO (10 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm) A = HO (0.05% NH4OH) and B = CH3CN; 55–85% B over 8 min) to give impure product. The impure product was purified by preparative HPLC (Boston Green ODS (150 mm × 30 mm, 5 μm) A = HO (0.1% TFA) and B = CH3CN; 65–95% B over 9 min) to give the product (12.1 mg, 0.04 mmol, 7% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ H =12.66(d,1H),7.34-7.20(m,4H),6.71(dd,1H),6.62-6.54(m,1H),6.29(d,1H),5.6 4(q,1H),3.11-3.00(m,1H),2.99-2.88(m,1H),2.77-2.66(m,1H),2.03-1.94(m,1H) LCMS R t = 1.36 min in 2.0 min chromatography, 10-80AB, C 16 H 14 ClNO2[M+H] + MS ESI calculated value 306.1, found value 305.9.

[0384] Example 97. Synthesis of Compound III-5 [ka] To a mixture of DIPEA (0.5 mL, 2.84 mmol), 2-hydroxy-4-(methanesulfonamido)benzoic acid (218.98 mg, 0.95 mmol), and HOBt (255.94 mg, 1.89 mmol) in DCM (3 mL) was added EDCI (272.32 mg, 1.42 mmol) and (1R)-5-chloroindan-1-amine (158.76 mg, 0.95 mmol). The mixture was stirred at 20 °C for 2 hours. The mixture was diluted with 1 M HCl (10 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with 1 M HCl (20 mL), water (20 mL × 2), and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm) A = HO (10 mM NHHCO) and B = CHCN; 38–58% B over 8 min) to give the product (23.0 mg, 6% yield) as a solid. 1 H NMR (400 MHz, CDCl3) δ H=12.63(s,1H),7.32-7.20(m,4H),6.77(d,1H),6.69(dd,1H),6.55(br s,1H),6.30(d,1H),5.64(q,1H),3.10(s,3H),3.08-3.01(m,1H...

Claims

1. Compound of formula I-I: 【Chemistry 193】 or a pharma- ceutically acceptable salt thereof, X is selected from the group consisting of NH, O, and S, and the hydrogen of NH is R ３ may be substituted with Y is selected from N and CH, and the hydrogen of CH is R ３ may be substituted with Z is selected from N and CH, and the hydrogen of CH is R ３ or Z may be substituted with -C(O)N(R ２ )-moiety, Z is C; R １ is substituted with one or more substituents independently selected from -Cl, -F, and -Cl and -F; １－６ is selected from the group consisting of alkyl, R ２ is hydrogen, Each R ３ But halogen, C １－６ Alkyl, C １－６ Heteroalkyl, C ３ - ７ Cycloalkyl, 3- to 7-membered heterocyclyl, -S(O) ２ N.R. ４ R ５ , -NR ４ S(O)R ６ , -C(O)NR ４ R ５ , -S(O) ２ R ６ and -O-R ６ C is independently selected from the group consisting of １－６ Alkyl is halogen, —NR ４ R ５ , and -S(O) ２ R ６ and optionally substituted with one or more substituents independently selected from n is selected from the group consisting of 0, 1, 2, 3, and 4; R ４ and R ５ are each independently hydrogen or C １－６ alkyl, C １－６ Alkyl is optionally substituted with oxo or R ４ and R ５ But, R ４ and R ５ Together with the nitrogen to which it is attached, it forms halogens, -OH, C １－６ Alkyl, and C １－６ a 4- to 7-membered heterocyclyl optionally substituted with one or more substituents independently selected from heteroalkyl; Each R ６ But, C １－６ Alkyl, C １－６ Heteroalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ independently selected from the group consisting of cycloalkyl, phenyl, and benzyl; a compound of formula II or a pharma- ceutically acceptable salt thereof, wherein s is 1 or 2; and a pharma- ceutically acceptable excipient.

2. 2. The pharmaceutical composition of claim 1, wherein X is S.

3. Y is CH, and the hydrogen of CH is R ３ The pharmaceutical composition of claim 1 , wherein the compound is substituted with

4. The pharmaceutical composition of claim 1 , wherein Z is CH.

5. The compound is a compound of formula I-Ia, I-Ia1, I-Ib, I-Ib1, I-a, I-a1, I-Ic, I-Ic1, I-c, I-c1, I-d, or I-d1: 【Chemistry 250】 or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

6. R １ is -Cl, -F, and -CF ３ The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition is selected from the group consisting of:

7. Each R ３ is -Cl, methyl, -NR ４ R ５ Or -S(O) ２ R ６ Methyl, methoxymethyl, trifluoromethyl, ethyl, cyclopropyl, cyclohexyl, -S(O) ２ R ６ , -C(O)NR ４ R ５ , -S(O) ２ N.R. ４ R ５ and -NR ４ R ５ Or -S(O) ２ R ６ C substituted with １－６ The pharmaceutical composition of any one of claims 1 to 5, wherein said alkyl is selected from the group consisting of:

8. The pharmaceutical composition according to any one of claims 1 to 5, wherein n is 1 or 2.

9. R ４ and R ５ each of which is hydrogen, methyl, ethyl, cyclopropyl, and -C(O)CH ３ The pharmaceutical composition of any one of claims 1 to 5, independently selected from the group consisting of:

10. R ６ The pharmaceutical composition of any one of claims 1 to 5, wherein is selected from the group consisting of methyl, ethyl, methoxyethyl, and cyclopropyl.

11. The pharmaceutical composition according to any one of claims 1 to 5, wherein s is 1 or 2.

12. The compound is 【Chemistry 200】 【Chemistry 201】 【Chemistry 202】 【Chemistry 203】 or a pharma- ceutically acceptable salt thereof.

13. A pharmaceutical composition for treating a disease or condition associated with a gain-of-function mutation in KCNT1 in a subject in need of such treatment, the pharmaceutical composition comprising a compound of formula II: 【Chemistry 204】 or a pharma- ceutically acceptable salt thereof, X is selected from the group consisting of NH, O, and S, and the hydrogen of NH is R ３ may be substituted with Y is selected from N and CH, and the hydrogen of CH is R ３ may be substituted with Z is selected from N and CH, and the hydrogen of CH is R ３ or Z may be substituted with -C(O)N(R ２ )-moiety, Z is C; R １ is substituted with one or more substituents independently selected from -Cl, -F, and -Cl and -F; １－６ is selected from the group consisting of alkyl, R ２ is hydrogen, Each R ３ But halogen, C １－６ Alkyl, C １－６ Heteroalkyl, C ３ - ７ Cycloalkyl, 3- to 7-membered heterocyclyl, -S(O) ２ N.R. ４ R ５ , -NR ４ S(O)R ６ , -C(O)NR ４ R ５ , -S(O) ２ R ６ and -O-R ６ C is independently selected from the group consisting of １－６ Alkyl is halogen, —NR ４ R ５ , and -S(O) ２ R ６ and optionally substituted with one or more substituents independently selected from n is selected from the group consisting of 0, 1, 2, 3, and 4; R ４ and R ５ are each independently hydrogen or C １－６ alkyl, C １－６ Alkyl is optionally substituted with oxo or R ４ and R ５ But, R ４ and R ５ Together with the nitrogen to which it is attached, it forms halogens, -OH, C １－６ Alkyl, and C １－６ a 4- to 7-membered heterocyclyl optionally substituted with one or more substituents independently selected from heteroalkyl; Each R ６ But, C １－６ Alkyl, C １－６ Heteroalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ independently selected from the group consisting of cycloalkyl, phenyl, and benzyl; Compounds of formula II, or pharma- ceutically acceptable salts thereof, include those of formula II, or pharma- ceutically acceptable salts thereof, wherein s is 1 or 2; Here, the disease or condition associated with the gain-of-function mutation of KCNT1 is epilepsy, epilepsy syndrome, encephalopathy (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 encephalopathy, Lennox syndrome, Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, or cerebellar ataxia), genetic or childhood epilepsy or genetic or childhood epilepsy syndromes, cardiac dysfunction, cardiac arrhythmias, sudden unexpected death in epilepsy (SUDEP), Brugada syndrome, myocardial infarction, pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine), itch and pruritus, ataxia, and cerebellar ataxia, SCN. epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile onset epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy. Pharmaceutical compositions.

14. Compound of Formula II: 【Chemistry 207】 or a pharma- ceutically acceptable salt thereof, R １ is substituted with one or more substituents independently selected from -Cl, -F, and -Cl and -F; １－６ is selected from the group consisting of alkyl, R ２ is hydrogen, R ３ But halogen, C １－６ Alkoxy, C １－６ Alkylene-S(O) ２ -C １－６ Alkyl, —C(O)NR ５ R ６ , -NR ７ S (O) ２ C １－６ Alkyl, -NR ７ S (O) ２ C ３－７ Cycloalkyl, -NR ７ S (O) ２ N.R. ５ R ６ , -NR ９ R １０ , -S(O) ２ -C ３－６ Cycloalkyl, -S(O) ２ -NR ５ R ６ , -S(O) ２ -C １－６ Alkoxy, and -S(O) ２ -C １－６ alkyl; １－６ The alkyl is selected from the group consisting of one or more halogens or C １－６ optionally substituted with alkoxy; Each R ４ But, C １－６ independently selected from the group consisting of alkyl, halogen, and -OH; R ４ When is —OH, R ４ But, R ３ is substituted at the carbon adjacent to n is selected from the group consisting of 0, 1, 2, 3, and 4; R ５ , R ６ , R ９ , and R １０ are each independently hydrogen or C １－６ is alkyl, Each R ７ is hydrogen, C １－６ independently selected from the group consisting of alkyl, and 3- to 7-membered heterocyclyl; １－６ Alkyl is halogen, C １－６ Alkoxy, C １－６ Haloalkoxy, -OH, -NR ５ R ６ and -C(O)NR ５ R ６ and optionally substituted with one or more substituents independently selected from the group consisting of: a compound of formula II, or a pharma- ceutically acceptable salt thereof, wherein s is 1 or 2; and a pharma- ceutically acceptable excipient.

15. The compound is a compound of formula II-a, II-a1, II-a2, II-b, II-b1, II-b2, II-c1 or II-c2: 【Chemistry 251】 or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined in claim 14.

16. R １ is -Cl, -F, and -CF ３ 16. The pharmaceutical composition of claim 14 or 15, wherein the pharmaceutical composition is selected from the group consisting of:

17. R ３ is -F, methoxy, -NH ２ , 【Chemistry 211】 16. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is selected from the group consisting of:

18. R ４ The pharmaceutical composition of claim 14 or 15, wherein is -F or methyl.

19. The compound is 【Chemical 228】 【Chemical 229】 【Chemistry 230】 【Chemistry 231】 【Chemical 232】 【Chemistry 233】 【Chemical 234】 or a pharma- ceutically acceptable salt thereof.

20. A pharmaceutical composition for treating a disease or condition associated with a gain-of-function mutation in KCNT1 in a subject in need of such treatment, the pharmaceutical composition comprising a compound of formula II: 【Chemistry 235】 or a pharma- ceutically acceptable salt thereof, R １ is substituted with one or more substituents independently selected from -Cl, -F, and -Cl and -F; １－６ is selected from the group consisting of alkyl, R ２ is hydrogen, R ３ But halogen, C １－６ Alkoxy, C １－６ Alkylene-S(O) ２ -C １－６ Alkyl, —C(O)NR ５ R ６ , -NR ７ S (O) ２ C １－６ Alkyl, -NR ７ S (O) ２ C ３－７ Cycloalkyl, -NR ７ S (O) ２ N.R. ５ R ６ , -NR ９ R １０ , -S(O) ２ -C ３－６ Cycloalkyl, -S(O) ２ -NR ５ R ６ , -S(O) ２ -C １－６ Alkoxy, and -S(O) ２ -C １－６ alkyl; １－６ The alkyl is selected from the group consisting of one or more halogens or C １－６ optionally substituted with alkoxy; Each R ４ But, C １－６ independently selected from the group consisting of alkyl, halogen, and -OH; R ４ When is —OH, R ４ But, R ３ is substituted at the carbon adjacent to n is selected from the group consisting of 0, 1, 2, 3, and 4; R ５ , R ６ , R ９ , and R １０ are each independently hydrogen or C １－６ is alkyl, Each R ７ is hydrogen, C １－６ independently selected from the group consisting of alkyl, and 3- to 7-membered heterocyclyl; １－６ Alkyl is halogen, C １－６ Alkoxy, C １－６ Haloalkoxy, -OH, -NR ５ R ６ and -C(O)NR ５ R ６ and optionally substituted with one or more substituents independently selected from the group consisting of: Compounds of formula II, or pharma- ceutically acceptable salts thereof, include those compounds of formula II, or pharma- ceutically acceptable salts thereof, wherein s is 1 or 2; Here, the disease or condition associated with the gain-of-function mutation of KCNT1 is epilepsy, epilepsy syndrome, encephalopathy (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 encephalopathy, Lennox syndrome, Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, or cerebellar ataxia), genetic or childhood epilepsy, genetic or childhood epilepsy syndromes, cardiac dysfunction, cardiac arrhythmias, sudden unexpected death in epilepsy (SUDEP), Brugada syndrome, myocardial infarction, pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine), itch and pruritus, ataxia, and cerebellar ataxia, SCN1 A, epileptic encephalopathy with SCN2A, SCN8A mutations, early infantile onset epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy. Pharmaceutical compositions.

21. Compound of Formula III: 【Chemical 238】 or a pharma- ceutically acceptable salt thereof, R １ is substituted with one or more substituents independently selected from -Cl, -F, and -Cl and -F; １－６ is selected from the group consisting of alkyl, R ２ is hydrogen, R ３ is hydrogen, R ４ But, C １－６ Alkyl, C １－６ Alkoxy, halogen, C １－６ Haloalkyl, -NR ７ S (O) ２ C １－６ Alkyl, and NR ８ C(O)-C １－６ alkyl, n is selected from the group consisting of 0, 1, 2, 3, and 4; R ７ and R ８ are each independently hydrogen or C １－６ is alkyl, a compound of formula III, or a pharma- ceutically acceptable salt thereof, wherein s is 1 or 2; and a pharma- ceutically acceptable excipient.

22. The compound is a compound of formula III-a, III-a1, III-a2, III-b, III-b1, III-b2, III-c, III-c1, or III-c2: 【Chemistry 252】 or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined in claim 21.

23. R １ is -Cl, -F, and -CF ３ 23. The pharmaceutical composition of claim 21 or 22, wherein the pharmaceutical composition is selected from the group consisting of:

24. R ４ Methyl, methoxy, -F, -Cl, -CF ３ , methoxy, 【Chemical 242】 23. The pharmaceutical composition of claim 21 or 22, wherein the pharmaceutical composition is selected from the group consisting of:

25. The compound is 【Chemistry 245】 【Chemical 246】 or a pharma- ceutically acceptable salt thereof.

26. A pharmaceutical composition for treating a disease or condition associated with a gain-of-function mutation in KCNT1 in a subject in need of such treatment, the pharmaceutical composition comprising a compound of formula III: 【Chemical 247】 or a pharma- ceutically acceptable salt thereof, R １ is substituted with one or more substituents independently selected from -Cl, -F, and -Cl and -F; １－６ is selected from the group consisting of alkyl, R ２ is hydrogen, R ３ is hydrogen, R ４ But, C １－６ Alkyl, C １－６ Alkoxy, halogen, C １－６ Haloalkyl, -NR ７ S (O) ２ C １－６ Alkyl, and NR ８ C(O)-C １－６ alkyl, n is selected from the group consisting of 0, 1, 2, 3, and 4; R ７ and R ８ are each independently hydrogen or C １－６ is alkyl, and m is 0, 1 or 2; or a pharma- ceutically acceptable salt thereof; Here, the disease or condition associated with the gain-of-function mutation of KCNT1 is epilepsy, epilepsy syndrome, encephalopathy (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 encephalopathy, Lennox syndrome, Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, or cerebellar ataxia), genetic or childhood epilepsy, genetic or childhood epilepsy syndromes, cardiac dysfunction, cardiac arrhythmias, sudden unexpected death in epilepsy (SUDEP), Brugada syndrome, myocardial infarction, pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine), itch and pruritus, ataxia, and cerebellar ataxia, SCN1 A, epileptic encephalopathy with SCN2A, SCN8A mutations, early infantile onset epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy. Pharmaceutical compositions.

27. The compound is a compound of formula I-d1, wherein R １ is Cl, s is 1, R ２ is H, X is S, R ３ Ga-S (O) ２ N.R. ４ R ５ , R ４ H, R ５ The pharmaceutical composition of claim 5, wherein is methyl.

28. Compound of formula I-I: 【Chemistry 253】 or a pharma- ceutically acceptable salt thereof, X is selected from the group consisting of NH, O, and S, and the hydrogen of NH is R ３ may be substituted with Y is selected from N and CH, and the hydrogen of CH is R ３ may be substituted with Z is selected from N and CH, and the hydrogen of CH is R ３ or Z may be substituted with -C(O)N(R ２ )-moiety, Z is C; R １ is substituted with one or more substituents independently selected from -Cl, -F, and -Cl and -F; １－６ is selected from the group consisting of alkyl, R ２ is hydrogen, Each R ３ But halogen, C １－６ Alkyl, C １－６ Heteroalkyl, C ３ - ７ Cycloalkyl, 3- to 7-membered heterocyclyl, -S(O) ２ N.R. ４ R ５ , -NR ４ S(O)R ６ , -C(O)NR ４ R ５ , -S(O) ２ R ６ and -O-R ６ C is independently selected from the group consisting of １－６ Alkyl is halogen, —NR ４ R ５ , and -S(O) ２ R ６ and optionally substituted with one or more substituents independently selected from n is selected from the group consisting of 0, 1, 2, 3, and 4; R ４ and R ５ are each independently hydrogen or C １－６ alkyl, C １－６ Alkyl is optionally substituted with oxo or R ４ and R ５ But, R ４ and R ５ Together with the nitrogen to which it is attached, it forms halogens, -OH, C １－６ Alkyl, and C １－６ a 4- to 7-membered heterocyclyl optionally substituted with one or more substituents independently selected from heteroalkyl; Each R ６ But, C １－６ Alkyl, C １－６ Heteroalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ independently selected from the group consisting of cycloalkyl, phenyl, and benzyl; s is 1 or 2; A compound or a pharma- ceutically acceptable salt thereof.

29. The compound is 【Chemical 254】 【255】 【256】 【Chemistry 257】 or a pharma- ceutically acceptable salt thereof.

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