KCNT1 inhibitors and methods of use

Abstract

This invention relates in part to compounds and compositions that can be used to prevent and / or treat neurological diseases or conditions, diseases or conditions associated with excessive neuronal excitability and / or gain-of-function mutations in genes (e.g., KCNT1). Methods for treating neurological diseases or conditions, diseases or conditions associated with excessive neuronal excitability and / or gain-of-function mutations in genes (e.g., KCNT1) are also provided herein.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to 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 which are incorporated herein by reference in their entirety. Technical Field Background Technology

[0003] KCNT1 encoding is called Slack (sequence such as calcium activation K). + Sodium-activated potassium channels (channels). These channels are found in neurons throughout the brain and can mediate sodium-activated potassium currents (I0). KNa This delayed outward current can modulate neuronal excitability and the rate of adaptation in response to maintaining stimuli. Abnormal Slack activity has been associated with the development of early-onset epilepsy and intellectual disability. Therefore, selective modulation of sodium-activated potassium channels (e.g., abnormal KCNT1, abnormal I) can also modulate this activity. KNa The drug compounds are indicated for the treatment of neurological disorders or conditions or diseases or conditions associated with excessive neuronal excitability and / or KCNT1 gain-of-function mutations. Summary of the Invention

[0004] This article describes compounds and compositions, such as KCNT1, that can be used to prevent and / or treat diseases, conditions, or symptoms, such as neurological diseases or symptoms, diseases, conditions, or symptoms associated with excessive neuronal excitability and / or gain-of-function mutations.

[0005] Therefore, in one aspect, this disclosure is characterized by pharmaceutical compositions comprising compounds of formula II:

[0006]

[0007] Or its pharmaceutically acceptable salt, wherein

[0008] X is selected from the group consisting of NH, O and S, where the hydrogen in NH can be substituted by R3;

[0009] Y is selected from N and CH, where the hydrogen in CH can be substituted by R3;

[0010] Z is selected from N and CH, where the hydrogen in CH can be substituted by R3, or Z is C when Z is partially substituted by -C(O)N(R2)-.

[0011] R1 is selected from the group consisting of: -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F. 1-6 alkyl;

[0012] R2 is hydrogen;

[0013] Each R3 is independently selected from the following groups: halogens, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -S(O)2NR4R5, -NR4S(O)R6, -C(O)NR4R5, -S(O)2R6 and -O-R6, wherein C 1-6 The alkyl group may be optionally substituted by one or more substituents independently selected from the following: halogen, -NR4R5 and -S(O)2R6;

[0014] n can be freely chosen from groups consisting of 0, 1, 2, 3, and 4;

[0015] R4 and R5 are each independently hydrogen or C. 1-6 Alkyl, wherein C 1-6 The alkyl group may be optionally substituted with an oxo group; or R4 and R5 may together with the nitrogen attached to R4 and R5 to form a 4-7 membered heterocyclic group, which may be optionally substituted with one or more substituents independently selected from: halogen, -OH, C 1-6 Alkyl and C 1-6 Heteroalkyl;

[0016] Each R6 is independently selected from the following groups: C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, phenyl and benzyl; and

[0017] s is 1 or 2;

[0018] And pharmaceutically acceptable excipients.

[0019] In some embodiments, the compound of formula II is a compound of formula I:

[0020]

[0021] Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in Formula II.

[0022] In some embodiments, the compound of formula II is a compound of formula I-Ia or formula I-Ia1:

[0023] Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in Formula II.

[0024] In some embodiments, the compound of formula II is a compound of formula I-Ib or formula I-Ib1:

[0025]

[0026] Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in Formula II.

[0027] In some embodiments, the compound of formula II is a compound of formula I-Ic or formula I-Ic1:

[0028]

[0029] Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in Formula II.

[0030] In some embodiments, the compound of formula II is a compound of formula Ia or formula I-a1:

[0031]

[0032] Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in Formula II.

[0033] In some embodiments, the compound of formula II is a compound of formula Ib or formula I-b1:

[0034]

[0035] Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in Formula II.

[0036] In some embodiments, the compound of formula II is a compound of formula Ic or formula I-c1:

[0037]

[0038] Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in Formula II.

[0039] In some embodiments, the compound of formula II is a compound of formula Id or formula I-d1:

[0040]

[0041] Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in Formula II.

[0042] In another aspect, this disclosure is characterized by a pharmaceutical composition comprising a compound of formula II:

[0043]

[0044] Or its pharmaceutically acceptable salt, wherein

[0045] R1 is selected from the group consisting of: -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F. 1-6 alkyl;

[0046] R2 is hydrogen;

[0047] R3 is independently selected from the following groups: halogens, C 1-6 Alkoxy, C 1-6 Alkylene-S(O)2-C 1-6 Alkyl groups, -C(O)NR5R6, -NR7S(O)2C 1-6 Alkyl group, -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 groups and -S(O)2-C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be oxidized by one or more halogens or C 1-6 Alkyl substitution;

[0048] Each R4 is independently selected from the following groups: C 1-6 Alkyl, halogen, and -OH; wherein when R4 is -OH, R4 is substituted at a carbon adjacent to R3;

[0049] n can be freely chosen from groups consisting of 0, 1, 2, 3, and 4;

[0050] R5, R6, R9 and R 10 Each is independently hydrogen or C 1-6 alkyl;

[0051] Each R7 is independently selected from the following groups: hydrogen, C 1-6 Alkyl groups and 3-7 membered heterocyclic groups, wherein the C 1-6 Alkyl groups may be optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, -OH, -NR5R6, and -C(O)NR5R6; and

[0052] s is 1 or 2;

[0053] And pharmaceutically acceptable excipients.

[0054] In some embodiments, the compound of formula II is a compound of formula II-a, formula II-a1, or formula II-a2:

[0055]

[0056] Or its pharmaceutically acceptable salt.

[0057] In some embodiments, the compound is a compound of formula II-b, formula II-b1, or formula II-b2:

[0058] Or its pharmaceutically acceptable salt.

[0059] In some embodiments, the compound of formula II is a compound of formula II-c, formula II-c1, or formula II-c2:

[0060]

[0061] Or its pharmaceutically acceptable salt.

[0062] In another aspect, this disclosure is characterized by a pharmaceutical composition comprising a compound of formula III:

[0063]

[0064] Or its pharmaceutically acceptable salt, wherein

[0065] R1 is selected from the group consisting of: -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F. 1-6 alkyl;

[0066] R2 is hydrogen;

[0067] R3 is hydrogen;

[0068] R4 members are independently selected from the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl group, -NR7S(O)2C 1-6 Alkyl groups and -NR8C(O)-C 1-6 alkyl;

[0069] n can be freely chosen from groups consisting of 0, 1, 2, 3, and 4;

[0070] R7 and R8 are each independently hydrogen or C. 1-6 Alkyl groups; and

[0071] s is 1 or 2;

[0072] And pharmaceutically acceptable excipients.

[0073] In some embodiments, the compound of formula III is a compound of formula III-a, formula III-a1, or formula III-a2:

[0074]

[0075] Or its pharmaceutically acceptable salt.

[0076] In some embodiments, the compound of formula III is a compound of formula III-b, formula III-b1, or formula III-b2:

[0077]

[0078] Or its pharmaceutically acceptable salt.

[0079] In some embodiments, the compound of formula III is a compound of formula III-c, formula III-c1, or formula III-c2:

[0080]

[0081] Or its pharmaceutically acceptable salt.

[0082] In one aspect, this disclosure provides a method for treating a neurological disease or condition, said method comprising administering to a subject in need 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)). 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)), or 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 (III) (e.g., compounds of (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients).

[0083] In another aspect, this disclosure provides a method for treating a disease or symptom associated with excessive neuronal excitability, said method comprising administering to a subject in need 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 ... 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), (I-c1), (I-c1), (I-d1)), (I-c1 ... Compounds of formula (I-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), or compounds of formula (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), or pharmaceutically acceptable salts and pharmaceutically acceptable excipients thereof.

[0084] In another aspect, this disclosure provides a method for treating a disease or symptom associated with a gain-of-function mutation in a gene (e.g., KCNT1), wherein the method comprises administering to a subject in need a compound disclosed herein (e.g., 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), (I... Compounds of formula (d) 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 (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1) Compounds of formula (II) or (III-c2)) or pharmaceutical compositions disclosed herein (e.g., including 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)) Compounds of formula (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)), or compounds of formula (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), or pharmaceutically acceptable salts and pharmaceutically acceptable excipients thereof.

[0085] In some embodiments, the neurological disease or condition, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with gain-of-function mutations in a gene (e.g., KCNT1) is epilepsy, epilepsy syndrome, or encephalopathy.

[0086] In some implementations, the neurological disease or condition, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with gain-of-function mutations in a gene (e.g., KCNT1) is hereditary or pediatric epilepsy or hereditary or pediatric epilepsy syndrome.

[0087] In some implementations, a neurological disease or condition, a disease or condition associated with excessive neuronal excitability, or a disease or condition associated with gain-of-function mutations in a gene (e.g., KCNT1) is a cardiac dysfunction.

[0088] In some implementations, the neurological disease or condition, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with gain-of-function mutations in a gene (e.g., KCNT1) is selected from epilepsy and other encephalopathy (e.g., infantile epilepsy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia).

[0089] In some implementations, neurological diseases or conditions, diseases or conditions associated with excessive neuronal excitability, or diseases or conditions associated with gain-of-function mutations in genes (e.g., KCNT1) are selected from the group consisting of: arrhythmias, sudden epileptic death, Brugada syndrome, and myocardial infarction.

[0090] In some implementations, neurological diseases or conditions, diseases or conditions associated with excessive neuronal excitability, or diseases or conditions associated with gain-of-function mutations in genes (e.g., KCNT1) are selected from pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.).

[0091] In some implementations, neurological diseases or conditions, diseases or conditions associated with excessive neuronal excitability, or diseases or conditions associated with gain-of-function mutations in genes (such as KCNT1) are muscle diseases (such as myotonia, neuromyotonia, cramp muscle spasm, spasticity).

[0092] In some implementations, the neurological disease or condition, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with gain-of-function mutations in a gene (e.g., KCNT1) is selected from pruritus and itching, ataxia, and cerebellar ataxia.

[0093] In some implementations, the neurological disease or condition, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with gain-of-function mutations in a gene (e.g., KCNT1) is selected from mental disorders (e.g., major depressive disorder, anxiety disorder, bipolar disorder, schizophrenia).

[0094] In some implementations, the neurological disease or condition or disease or condition associated with excessive neuronal excitability and / or gain-of-function mutations in genes (e.g., KCNT1) is selected from the group consisting of: learning disabilities, Fragile X syndrome, neuronal plasticity, and autism spectrum disorders.

[0095] In some implementations, neurological diseases or conditions, diseases or conditions associated with excessive neuronal excitability, or diseases or conditions associated with gain-of-function mutations in genes (e.g., KCNT1) are selected from the group consisting of: epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations; early infantile epileptic encephalopathy; Dravet syndrome; Dravet syndrome with SCN1A mutations; generalized epilepsy with febrile seizures; intractable childhood epilepsy with generalized tonic-clonic seizures; infantile spasms; and benign familial neonatal-infantile seizures. Seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic partial epilepsy of children with SCN3A mutation, SCN8A epileptic encephalopathy, sudden death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0096] Other objectives and advantages will become apparent to those skilled in the art upon consideration of the following detailed descriptions, embodiments, and claims. Attached Figure Description Detailed Implementation

[0097] As generally described herein, the present invention provides compounds and compositions suitable for the prevention and / or treatment of diseases, conditions, or symptoms described herein, such as diseases, conditions, or symptoms associated with excessive neuronal excitability, and / or diseases, conditions, or symptoms associated with gain-of-function mutations in KCNT1. Exemplary diseases, conditions, or symptoms include epilepsy and other encephalopathy (e.g., infantile epilepsy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Wester syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ōtahara syndrome, developmental and epileptic encephalopathy, and Lennox). Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic seizures, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia, asymmetric tonic seizures, and cardiac dysfunction (e.g., arrhythmia, Brugada syndrome, sudden epileptic death, myocardial infarction), pain and related symptoms (e.g., neuropathic pain, acute / chronic pain, migraine, etc.), myopathic disorders (e.g., myotonia, neuromuscular myotonia, convulsive muscle spasms, tetany), pruritus and pruritus, ataxia and cerebellar ataxia, and mental disorders (e.g., major depressive disorder, anxiety disorder, bipolar disorder, schizophrenia).

[0098] definition

[0099] Chemical definition

[0100] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the periodic table, CAS edition, the 75th edition of the Handbook of Chemistry and Physics, and the inner cover, and specific functional groups are generally defined as described herein. Additionally, general principles of organic chemistry, as well as specific functional groups and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0101] The compounds described herein may include one or more asymmetric centers and thus may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in individual enantiomers, diastereomers, or geometric isomers, or may be in mixtures of stereoisomers (including racemic mixtures and mixtures rich in one or more stereoisomers). Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferably, 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 (McGrawHill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (Ell. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, 1972). This invention further covers compounds described herein in their individual isomer forms, substantially free of other isomers, and alternatively in mixtures of various isomers.

[0102] As used herein, a pure enantiomer is substantially free of other enantiomers or stereoisomers of the compound (i.e., exhibiting an enantiomeric excess). In other words, the “S” form of the compound is substantially free of the “R” form of the compound, and therefore exhibits an enantiomeric excess of the “R” form. The terms “enantiomerically pure” or “pure enantiomer” indicate that the compound includes greater than 75 wt%, greater than 80 wt%, greater than 85 wt%, greater than 90 wt%, greater than 91 wt%, greater than 92 wt%, greater than 93 wt%, greater than 94 wt%, greater than 95 wt%, greater than 96 wt%, greater than 97 wt%, greater than 98 wt%, greater than 98.5 wt%, greater than 99 wt%, greater than 99.2 wt%, greater than 99.5 wt%, greater than 99.6 wt%, greater than 99.7 wt%, greater than 99.8 wt%, or greater than 99.9 wt% of enantiomers. In some implementations, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0103] In the compositions provided herein, enantiomerically pure compounds may be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound may include, for example, about 90% excipients and about 10% enantiomerically pure R-compound. In some embodiments, the enantiomerically pure R-compound in such compositions may, for example, comprise 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 compounds. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound may include, for example, about 90% excipients and about 10% enantiomerically pure S-compound. In some embodiments, the enantiomerically pure S-compound in such compositions may, for example, comprise 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 compounds. In some embodiments, the active ingredient may be formulated with minimal or no excipients or carriers.

[0104] The compounds described herein may also include one or more isotopic substitutions. For example, H can be in any isotopic form, including 1 H, 2 H (D or deuterium) and 3 H (T or tritium); C can exist in any isotopic form, including 12 C 13 C and 14 C and O can exist in any isotopic form, including 16 O and 18 O; F can exist in any isotopic form, including 18 F and 19 F; etc.

[0105] The following terms are intended to have the meanings presented below and are used to understand the description and intended scope of the invention. When describing the invention, it may include compounds and pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, and unless otherwise specified, the following terms, if present, will have the following meanings. It should also be understood that, as described herein, any portion defined below may be substituted with various substituents, and the corresponding definitions are intended to include such substituted portions within the scope set forth below. Unless otherwise stated, the term “substituted” will be defined as set forth below. It should also be understood that, when used herein, the terms “group” and “radical” are considered interchangeable. The article “a / an” may be used herein to refer to one or more (i.e., at least one) grammatical object of the article. As an example, “analogue” means one or more analogues.

[0106] When listing a range of values, it is expected to cover every value within that range and its subranges. For example, "C1-6 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0107] As used herein, "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1-20 Alkyl group). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1-10 Alkyl group). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1”). 1-9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has one carbon atom (“C1 alkyl”). 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc.

[0108] As used herein, the term "heteroalkyl" refers to an alkyl group in which at least one carbon atom has been replaced by an O or S atom. Heteroalkyl groups can be, for example, -O-C1-C 10Alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, or C1-C6 alkylene-OH groups. In some embodiments, "heterocyclic alkyl" can be a 2-8 membered heterocyclic alkyl group, indicating that the heterocyclic alkyl contains 2 to 8 atoms selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. In other embodiments, heteroalkyl can be a 2-6 membered, 4-8 membered, or 5-8 membered heteroalkyl group (which may contain, for example, 1 or 2 heteroatoms selected from the group consisting of oxygen and nitrogen). In some embodiments, heteroalkyl is an "alkyl" group in which 1 to 3 carbon atoms have been replaced by oxygen atoms. One type of heterocyclic group is an "alkoxy" group.

[0109] As used herein, “alkenyl” refers to 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). 2-20 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C”). 2-10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2-9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2-8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2-7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3 Alkenyl (“C2-alkenyl”). In some embodiments, the alkenyl group has two carbon atoms (“C2-alkenyl”). One or more carbon-carbon double bonds may be internal (as in 2-butenyl) or terminal (as in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the aforementioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octtrienyl (C8), etc.

[0110] As used herein, “alkynyl” refers to 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). 2-20 The alkynyl group (“Alynyl”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 10 carbon atoms (“C”). 2-10 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 9 carbon atoms (“C”). 2-9 The alkynyl group (“acetylenic”) has 2 to 8 carbon atoms in some embodiments. 2-8 The alkynyl group (“C”) has 2 to 7 carbon atoms in some embodiments. 2-7 The alkynyl group (“C”) has 2 to 6 carbon atoms in some embodiments. 2-6 The alkynyl group (“H”) has 2 to 5 carbon atoms in some embodiments. 2-5 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C”). 2-4 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkynyl group (“C2-alkynyl”) is present in some embodiments. One or more carbon-carbon triple bonds may be internal (as in 2-butynyl) or terminal (as in 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 Examples of alkenyl groups include the aforementioned C 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), etc. Other examples of alkynyl groups include heptynyl (C7), octynyl (C8), etc.

[0111] As used herein, “alkylene,” “alkenylene,” and “ynylene” refer to the divalent groups of alkyl, alkenyl, and ynyl groups, respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” or “ynylene,” it should be understood that the range or number refers to the range or number of carbons in a linear divalent carbon chain. “alkylene,” “alkenylene,” and “ynylene” may be substituted with one or more substituents as described herein or may not be substituted.

[0112] As used herein, “aryl” refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) having 6 to 14 ring carbon atoms and zero heteroatoms provided by the aromatic ring system (“C”). 6-14Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms (“C14”). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclic or heterocyclic groups, wherein said group or connecting point is on the aryl ring, and in such cases, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from: aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, chamomile, benzene, chrysene, hexabenzobenzene, fluoranthene, fluorene, hexabenzobenzene, hexanthene, hexalene, and asymmetric benzodiinden. e) Symmetrical benzodiindacene, indene, indene, naphthalene, octaphene, octalene, ovalene, pentadiene, pentaphene, cyclopentadiene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Aromatic groups especially include phenyl, naphthyl, indene, and tetrahydronaphthyl.

[0113] As used herein, “heteroaryl” refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 shared electrons in a ring array) having a ring carbon atom and 1 to 4 heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In heteroaryls containing one or more nitrogen atoms, the bonding point may be a carbon or nitrogen atom, where the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or two rings. “Heteroaryl” includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the bonding point is on the heteroaryl ring, and in such cases, the number of ring members continues to represent the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, wherein the linking point is on either the aryl or heteroaryl ring, and in such cases, the number of ring members specifies the number of ring members in the fused (aryl / heteroaryl) ring system. A bicyclic heteroaryl group (e.g., indolyl, quinolinyl, carbazolyl, etc.) in which one ring does not contain a heteroatom can have its linking point on either ring, i.e., a ring carrying a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0114] In some embodiments, the heteroaryl group is a 5-10-membered aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8-membered aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6-membered aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6-membered heteroaryl”). In some embodiments, the 5-6-membered heteroaryl group has 1 to 3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6-membered heteroaryl group has 1 to 2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6-membered heteroaryl group has 1 cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0115] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroleyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl, 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, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolazinyl, and purinel. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridinyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0116] Representative examples of heteroaryl groups include the following:

[0117]

[0118] Each Z is selected from carbonyl, N, NR 65 O and S; and R 65 Independently hydrogen, C1-C8 alkyl, C3-C 10 Carbocyclic group, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 heteroaryl compounds.

[0119] As used herein, "carbocyclic group" or "carbocyclic ring" refers to a non-aromatic cyclic hydrocarbon group ("C") having 3 to 10 ring carbon atoms and zero heteroatoms in a non-aromatic ring system. 3-10 (Carbocyclic group). In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms (“C”). 3-8 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C”). 3-6 (Carbocyclic group). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C”). 5-10 (Carbocyclic group). Example C 3-6Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). Example C 3-8 Carbocyclic groups include, but are not limited to, the aforementioned C 3-6 Carbocyclic groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Example C 3-10 Carbocyclic groups include, but are not limited to, the aforementioned C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl (C 10 As illustrated in the foregoing examples, in some embodiments, the carbocyclic group is a monocyclic (“monocyclic carbocyclic”) or contains a fused, bridged, or spirocyclic system, such as a bicyclic system (“bicyclic carbocyclic”), and may be saturated or partially unsaturated. “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the carbocyclic ring, and in such cases, the number of carbons continues to represent the number of carbons in the carbocyclic system.

[0120] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group having 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbons, such as the "C" group derived from cycloalkanes. 4-8 "Cycloalkyl". Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane. Unless otherwise specified, the cycloalkyl group may optionally be substituted at one or more ring positions with the following: for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amide, amidyl, amino, aryl, aralkyl, azide, carbamate, carbonate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclic, hydroxyl, imino, ketone, nitro, phosphate ester, phosphonic acid, phosphonite, sulfate ester, sulfate, sulfonylamino, sulfonyl, or thiocarbonyl. The cycloalkyl group may be fused with other cycloalkyl, aryl, or heterocyclic groups. In some embodiments, the cycloalkyl group is unsubstituted, i.e., it is unsubstituted.

[0121] As used herein, "heterocyclic group" or "heterocycle" refers to a group having a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the connecting point may be a carbon or nitrogen atom, where the valence allows. Heterocyclic groups may be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and may be saturated or partially unsaturated. A bicyclic heterocyclic system may include one or more heteroatoms in one or both rings. "Heterocyclic group" also includes a ring system in which a heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic or heterocyclic ring; or a ring system in which a heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocyclic ring, and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system.

[0122] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1 to 3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1 to 2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0123] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indololinyl, isoindololinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused with an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0124] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group have been replaced by nitrogen, oxygen, or sulfur atoms. Hetero can be applied to any of the above-mentioned hydrocarbon groups, such as alkyl groups (e.g., heterocyclic alkyl); carbocyclic groups (e.g., heterocyclic); aryl groups (e.g., heteroaryl); and similar groups having 1 to 5, particularly 1 to 3, heteroatoms.

[0125] As used in this article, "cyano" refers to -CN.

[0126] As used herein, "halogenated" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogenated group is fluorine or chlorine.

[0127] As used in this article, “haloalkyl” refers to an alkyl group that has been substituted with one or more halogen atoms.

[0128] As used in this article, "nitro" refers to -NO2.

[0129] As used in this article, "oxo" refers to -C=O.

[0130] Generally, whether or not preceded by the term "optionally," the term "substituted" refers to the permissible substitution of at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) with a substituent, such as a substituent that yields a stable compound, for example, a compound that does not spontaneously transform as by rearrangement, cyclization, elimination, or other reactions. Unless otherwise specified, a "substituted" group has a substituent at one or more substituted positions of the group, and when substituted at more than one position in any given structure, the substituent may be the same or different at each position.

[0131] Where the valence allows, the nitrogen atom may be substituted or unsubstituted, and includes primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen-substituted derivatives include, but are not limited to: hydrogen, -OH, and -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 1-10Alkyl, C 1-10 All-haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, or two R groups attached to a nitrogen atom cc The groups combine to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently defined by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, and wherein R aa R bb R cc and R dd It is as defined above.

[0132] These and other exemplary substituents are described in more detail in the detailed description, embodiments, and claims. The invention is not intended to be limited in any way by the exemplary list of substituents provided above.

[0133] Other definitions

[0134] The term "pharmaceutically acceptable salt" refers to those salts that, within reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. described pharmaceutically acceptable salts in detail in Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by using other methods (such as ion exchange) used in the art. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, p-valerate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using balancing ions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, low-carbon alkyl sulfonate, and aryl sulfonate.

[0135] As used herein, the term "subject" considered for administration includes, but is not limited to, humans (i.e., men or women of any age group, such as child subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, like primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0136] Disease, symptom, and illness are used interchangeably in this article.

[0137] As used herein, and unless otherwise stated, the term “treat / treating / treatment” encompasses actions that occur when a subject suffers from a specified disease, symptom, or condition, which reduce the severity of the disease, symptom, or condition, or delay or slow its progression (also referred to as “therapeutic treatment”).

[0138] Generally, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As those skilled in the art will understand, the effective amount of the compounds of the present invention can vary depending on factors such as the intended biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the individual’s age, weight, health, and condition.

[0139] As used herein and unless otherwise specified, a "therapeuticly effective amount" of a compound is an amount sufficient to provide therapeutic benefit in the treatment of a disease, condition, or symptom, or sufficient to delay or minimize one or more symptoms associated with a disease, condition, or symptom. A therapeutically effective amount of a compound means the amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, condition, or symptom. The term "therapeuticly effective amount" may also encompass amounts that improve overall therapy, reduce or prevent symptoms or causes of a disease or symptom, or enhance the efficacy of another therapeutic agent.

[0140] In alternative embodiments, this invention covers the administration as a preventative agent of the compound of the invention or a pharmaceutically acceptable salt or composition thereof before a subject begins to suffer from a specified disease, condition, or symptom. As used herein, “preventative treatment” covers actions that occur before a subject begins to suffer from a specified disease, condition, or symptom. As used herein and unless otherwise specified, a “preventatively effective amount” of a compound is an amount sufficient to prevent a disease, condition, or symptom or one or more symptoms associated with said disease, condition, or symptom, or to prevent its recurrence. A preventatively effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a preventative benefit in preventing a disease, condition, or symptom. The term “preventatively effective amount” may also cover an amount that improves overall prevention or enhances the preventative efficacy of another preventative agent.

[0141] As used herein, “disease or symptom associated with gain-of-function mutations in KCNT1” refers to a disease or symptom associated with, partially or entirely caused by, a mutation in KCNT1, or having one or more symptoms partially or entirely caused by a mutation in KCNT1, which results in a gain-of-function phenotype, namely, increased activity of potassium channels encoded by KCNT1, leading to increased whole-cell currents.

[0142] As used herein, a “gain-of-function mutation” is a mutation in KCNT1 that results in increased activity of the potassium channel encoded by KCNT1. Activity can be assessed, for example, by ion flux analysis or electrophysiology (e.g., using whole-cell patch-clamp technique). Typically, gain-of-function mutations result 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 potassium channels encoded by wild-type KCNT1.

[0143] Compounds and Compositions

[0144] In one aspect, this disclosure is characterized by compounds of formula II:

[0145]

[0146] Or its pharmaceutically acceptable salt, wherein

[0147] X is selected from the group consisting of NH, O and S, where the hydrogen in NH can be substituted by R3;

[0148] Y is selected from N and CH, where the hydrogen in CH can be substituted by R3;

[0149] Z is selected from N and CH, where the hydrogen in CH can be substituted by R3, or Z is C when Z is partially substituted by -C(O)N(R2)-.

[0150] R1 is selected from the group consisting of: -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F. 1-6 alkyl;

[0151] R2 is hydrogen;

[0152] Each R3 is independently selected from the following groups: halogens, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -S(O)2NR4R5, -NR4S(O)R6, -C(O)NR4R5, -S(O)2R6 and -O-R6, wherein C 1-6 The alkyl group may be optionally substituted by one or more substituents independently selected from the following: halogen, -NR4R5 and -S(O)2R6;

[0153] n can be freely chosen from groups consisting of 0, 1, 2, 3, and 4;

[0154] R4 and R5 are each independently hydrogen or C. 1-6 Alkyl, wherein C 1-6 The alkyl group may be optionally substituted with an oxo group; or R4 and R5 may together with the nitrogen attached to R4 and R5 to form a 4-7 membered heterocyclic group, which may be optionally substituted with one or more substituents independently selected from: halogen, -OH, C 1-6 Alkyl and C 1-6 Heteroalkyl;

[0155] Each R6 is independently selected from the following groups: C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, phenyl and benzyl; and

[0156] s is 1 or 2.

[0157] In some embodiments, the invention is characterized by compounds of formula I:

[0158]

[0159] Or its pharmaceutically acceptable salt, wherein

[0160] X is selected from the group consisting of NH, O and S, where the hydrogen in NH can be substituted by R3;

[0161] Y is selected from N and CH, where the hydrogen in CH can be substituted by R3;

[0162] R1 is selected from the group consisting of: -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F. 1-6 alkyl;

[0163] R2 is hydrogen;

[0164] Each R3 is independently selected from the following groups: halogens, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -S(O)2NR4R5, -NR4S(O)R6, -C(O)NR4R5, -S(O)2R6 and -O-R6, wherein C 1-6 The alkyl group may be optionally substituted by one or more substituents independently selected from the following: halogen, -NR4R5 and -S(O)2R6;

[0165] n can be freely chosen from groups consisting of 0, 1, 2, 3, and 4;

[0166] R4 and R5 are each independently hydrogen or C. 1-6 Alkyl groups, or R4 and R5, can form 4-7-membered heterocyclic groups together with the nitrogen attached to R4 and R5, which may optionally be substituted with one or more halogens;

[0167] Each R6 is independently selected from the following groups: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, phenyl and benzyl; and

[0168] s is 1 or 2.

[0169] In another aspect, this disclosure is characterized by a pharmaceutical composition comprising a compound of formula II:

[0170]

[0171] Or its pharmaceutically acceptable salt, wherein

[0172] X is selected from the group consisting of NH, O and S, where the hydrogen in NH can be substituted by R3;

[0173] Y is selected from N and CH, where the hydrogen in CH can be substituted by R3;

[0174] Z is selected from N and CH, where the hydrogen in CH can be substituted by R3, or Z is C when Z is partially substituted by -C(O)N(R2)-.

[0175] R1 is selected from the group consisting of: -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F. 1-6 alkyl;

[0176] R2 is hydrogen;

[0177] Each R3 is independently selected from the following groups: halogens, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -S(O)2NR4R5, -NR4S(O)R6, -C(O)NR4R5, -S(O)2R6 and -O-R6, wherein C 1-6 The alkyl group may be optionally substituted by one or more substituents independently selected from the following: halogen, -NR4R5 and -S(O)2R6;

[0178] n can be freely chosen from groups consisting of 0, 1, 2, 3, and 4;

[0179] R4 and R5 are each independently hydrogen or C. 1-6 Alkyl, wherein C 1-6 The alkyl group may be optionally substituted with an oxo group; or R4 and R5 may together with the nitrogen attached to R4 and R5 to form a 4-7 membered heterocyclic group, which may be optionally substituted with one or more substituents independently selected from: halogen, -OH, C 1-6 Alkyl and C 1-6 Heteroalkyl;

[0180] Each R6 is independently selected from the following groups: C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, phenyl and benzyl; and

[0181] s is 1 or 2;

[0182] And pharmaceutically acceptable excipients.

[0183] In some embodiments, the present invention is characterized by pharmaceutical compositions of compounds of formula I:

[0184]

[0185] Or its pharmaceutically acceptable salt, wherein

[0186] X is selected from the group consisting of NH, O and S, where the hydrogen in NH can be substituted by R3;

[0187] Y is selected from N and CH, where the hydrogen in CH can be substituted by R3;

[0188] R1 is selected from the group consisting of: -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F. 1-6 alkyl;

[0189] R2 is hydrogen;

[0190] Each R3 is independently selected from the following groups: halogens, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -S(O)2NR4R5, -NR4S(O)R6, -C(O)NR4R5, -S(O)2R6 and -O-R6, wherein C 1-6 The alkyl group may be optionally substituted by one or more substituents independently selected from the following: halogen, -NR4R5 and -S(O)2R6;

[0191] n can be freely chosen from groups consisting of 0, 1, 2, 3, and 4;

[0192] R4 and R5 are each independently hydrogen or C. 1-6 Alkyl groups, or R4 and R5, can form 4-7-membered heterocyclic groups together with the nitrogen attached to R4 and R5, which may optionally be substituted with one or more halogens;

[0193] Each R6 is independently selected from the following groups: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, phenyl and benzyl; and

[0194] s is 1 or 2;

[0195] And pharmaceutically acceptable excipients.

[0196] 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.

[0197] In some embodiments of Formula II, Y is N. In some embodiments of Formula II, Y is CH.

[0198] 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 partially substituted with -C(O)N(R2)-.

[0199] 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.

[0200] In some embodiments of Formula I, Y is N. In some embodiments of Formula I, Y is CH.

[0201] 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).

[0202] In some embodiments, the compound of formula II is a compound of formula I-Ia or formula I-Ia1:

[0203] Or its pharmaceutically acceptable salt.

[0204] In some embodiments, the compound of formula II is a compound of formula I-Ib or formula I-Ib1:

[0205]

[0206] Or its pharmaceutically acceptable salt.

[0207] In some embodiments, the compound of formula II is a compound of formula I-Ic or formula I-Ic1:

[0208]

[0209] Or its pharmaceutically acceptable salt.

[0210] In some embodiments, the compound of formula II or formula I is a compound of formula Ia or formula I-a1:

[0211]

[0212] Or its pharmaceutically acceptable salt.

[0213] In some embodiments, the compound of formula II or formula I is a compound of formula Ib or formula I-b1:

[0214]

[0215] Or its pharmaceutically acceptable salt.

[0216] In some embodiments, the compound of formula II or formula I is a compound of formula Ic or formula I-c1:

[0217]

[0218] Or its pharmaceutically acceptable salt.

[0219] In some embodiments, the compound of formula II or formula I is a compound of formula Id or formula I-d1:

[0220]

[0221] Or its pharmaceutically acceptable salt.

[0222] In some embodiments, the compound of formula II is a compound of formula I-Ia1:

[0223]

[0224] Or its pharmaceutically acceptable salt.

[0225] In some embodiments, the compound of formula II is a compound of formulas I-Ib1:

[0226]

[0227] Or its pharmaceutically acceptable salt.

[0228] In some embodiments, the compound of formula II is a compound of formulas I-Ic1:

[0229]

[0230] Or its pharmaceutically acceptable salt.

[0231] In some embodiments, the compound of formula II or formula I is a compound of formula I-a1:

[0232]

[0233] Or its pharmaceutically acceptable salt.

[0234] In some embodiments, the compound of formula II or formula I is a compound of formula I-b1:

[0235]

[0236] Or its pharmaceutically acceptable salt.

[0237] In some embodiments, the compound of formula II or formula I is a compound of formula I-c1:

[0238]

[0239] Or its pharmaceutically acceptable salt.

[0240] In some embodiments, the compound of formula II or formula I is the compound of formula I-d1:

[0241]

[0242] Or its pharmaceutically acceptable salt.

[0243] 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.

[0244] 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.

[0245] 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 a methyl group. 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 a cyclopropyl group. 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 C substituted with -NR4R5 or -S(O)2R6. 1-6 alkyl.

[0246] 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.

[0247] 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 are each 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)), R4 and R5 are each 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)), R4 and R5 are each 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)), R4 and R5 are each 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 4-6 membered heterocyclic group, which is optionally substituted with -OH, methyl, or -OCH3.

[0248] 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.

[0249] 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 R4 and R5 are each independently selected from the group consisting of: hydrogen, methyl and -C(O)CH3; wherein R6 is selected from the group consisting of: methyl, ethyl, methoxyethyl and cyclopropyl.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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 and R5 are each 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), R4 is H and R5 is methyl.

[0256] 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.

[0257] In some embodiments, the compounds of Formula II are selected from the group consisting of:

[0258]

[0259]

[0260] Or its pharmaceutically acceptable salt.

[0261] In another aspect, the invention is characterized by compounds of formula II:

[0262]

[0263] Or its pharmaceutically acceptable salt, wherein

[0264] R1 is selected from the group consisting of: -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F. 1-6 alkyl;

[0265] R2 is hydrogen;

[0266] R3 is independently selected from the following groups: halogens, C 1-6 Alkoxy, C 1-6 Alkylene-S(O)2-C 1-6 Alkyl groups, -C(O)NR5R6, -NR7S(O)2C 1-6 Alkyl group, -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 groups and -S(O)2-C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be oxidized by one or more halogens or C 1-6 Alkyl substitution;

[0267] Each R4 is independently selected from the following groups: C 1-6Alkyl, halogen, and -OH; wherein when R4 is -OH, R4 is substituted at a carbon adjacent to R3;

[0268] n can be freely chosen from groups consisting of 0, 1, 2, 3, and 4;

[0269] R5, R6, R9 and R 10 Each is independently hydrogen or C 1-6 alkyl;

[0270] Each R7 is independently selected from the following groups: hydrogen, C 1-6 Alkyl groups and 3-7 membered heterocyclic groups, wherein the C 1-6 Alkyl groups are optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, -OH, -NR5R6, and -C(O)NR5R6; and

[0271] s is 1 or 2.

[0272] In another aspect, the present invention is characterized by a pharmaceutical composition comprising compounds of formula II:

[0273]

[0274] Or its pharmaceutically acceptable salt, wherein

[0275] R1 is selected from the group consisting of: -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F. 1-6 alkyl;

[0276] R2 is hydrogen;

[0277] R3 is independently selected from the following groups: halogens, C 1-6 Alkoxy, C 1-6 Alkylene-S(O)2-C 1-6 Alkyl groups, -C(O)NR5R6, -NR7S(O)2C 1-6 Alkyl group, -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 groups and -S(O)2-C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be oxidized by one or more halogens or C 1-6 Alkyl substitution;

[0278] Each R4 is independently selected from the following groups: C 1-6 Alkyl, halogen, and -OH; wherein when R4 is -OH, R4 is substituted at a carbon adjacent to R3;

[0279] n can be freely chosen from groups consisting of 0, 1, 2, 3, and 4;

[0280] R5, R6, R9 and R 10 Each is independently hydrogen or C 1-6 alkyl;

[0281] Each R7 is independently selected from the following groups: hydrogen, C 1-6 Alkyl groups and 3-7 membered heterocyclic groups, wherein the C 1-6 Alkyl groups may be optionally substituted by one or more substituents independently selected from the group consisting of: halogens, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, -OH, -NR5R6, and -C(O)NR5R6; and

[0282] s is 1 or 2;

[0283] And pharmaceutically acceptable excipients.

[0284] In some embodiments, the compound of formula II is a compound of formula II-a, formula II-a1, or formula II-a2:

[0285]

[0286] Or its pharmaceutically acceptable salt.

[0287] In some embodiments, the compound of formula II is a compound of formula II-b, formula II-b1, or formula II-b2:

[0288]

[0289] Or its pharmaceutically acceptable salt.

[0290] In some embodiments, the compound of formula II is a compound of formula II-c, formula II-c1, or formula II-c2:

[0291]

[0292] Or its pharmaceutically acceptable salt.

[0293] In some embodiments, the compound of formula II is the compound of formula II-a2:

[0294]

[0295] Or its pharmaceutically acceptable salt.

[0296] In some embodiments, the compound of formula II is a compound of formula II-b2:

[0297]

[0298] Or its pharmaceutically acceptable salt.

[0299] In some embodiments, the compound of formula II is the compound of formula II-c2:

[0300]

[0301] Or its pharmaceutically acceptable salt.

[0302] 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.

[0303] 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 selected from the group consisting of: -F, methoxy, -NH2,

[0304] 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 selected from the group consisting of the following

[0305] 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 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 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 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 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 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 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 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 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 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 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 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 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

[0306] 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.

[0307] In some embodiments of equation (II), n is 1.

[0308] 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 10Each 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)), R5, R6, R9 and R 10 It is a methyl group.

[0309] 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.

[0310] 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 selected from the group consisting of hydrogen, methyl, ethyl, and 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 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

[0311] 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.

[0312] In some embodiments, the compound of formula II is selected from the group consisting of:

[0313]

[0314]

[0315]

[0316]

[0317]

[0318] Or its pharmaceutically acceptable salt.

[0319] In another aspect, the present invention is characterized by compounds of formula III:

[0320]

[0321] Or its pharmaceutically acceptable salt, wherein

[0322] R1 is selected from the group consisting of: -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F. 1-6 alkyl;

[0323] R2 is hydrogen;

[0324] R3 is hydrogen;

[0325] R4 members are independently selected from the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl group, -NR7S(O)2C 1-6 Alkyl groups and -NR8C(O)-C 1-6 alkyl;

[0326] n can be freely chosen from groups consisting of 0, 1, 2, 3, and 4;

[0327] R7 and R8 are each independently hydrogen or C. 1-6 Alkyl groups; and

[0328] s is 1 or 2.

[0329] In another aspect, the present invention is characterized by a pharmaceutical composition comprising compounds of formula III:

[0330]

[0331] Or its pharmaceutically acceptable salt, wherein

[0332] R1 is selected from the group consisting of: -Cl, -F, and C substituted with one or more substituents independently selected from -Cl and -F. 1-6 alkyl;

[0333] R2 is hydrogen;

[0334] R3 is hydrogen;

[0335] R4 members are independently selected from the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl group, -NR7S(O)2C 1-6 Alkyl groups and -NR8C(O)-C 1-6 alkyl;

[0336] n can be freely chosen from groups consisting of 0, 1, 2, 3, and 4;

[0337] R7 and R8 are each independently hydrogen or C. 1-6 Alkyl groups; and

[0338] s is 1 or 2;

[0339] And pharmaceutically acceptable excipients.

[0340] In some embodiments, the compound of formula III is a compound of formula III-a, formula III-a1, or formula III-a2:

[0341]

[0342] Or its pharmaceutically acceptable salt.

[0343] In some embodiments, the compound of formula III is a compound of formula III-b, formula III-b1, or formula III-b2:

[0344]

[0345] Or its pharmaceutically acceptable salt.

[0346] In some embodiments, the compound of formula III is a compound of formula III-c, formula III-c1, or formula III-c2:

[0347]

[0348] Or its pharmaceutically acceptable salt.

[0349] In some embodiments, the compound of formula III is a compound of formula III-a2:

[0350]

[0351] Or its pharmaceutically acceptable salt.

[0352] In some embodiments, the compound of formula III is a compound of formula III-b2:

[0353]

[0354] Or its pharmaceutically acceptable salt.

[0355] In some embodiments, the compound of formula III is a compound of formula III-c2:

[0356]

[0357] Or its pharmaceutically acceptable salt.

[0358] 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.

[0359] 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 selected from the group consisting of: methyl, methoxy, -F, -Cl, -CF3, 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 -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 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

[0360] In some embodiments of Equation III, n is selected from the group consisting of 0, 1, and 2. In some embodiments of Equation III, n is 0 or 1. In some embodiments of Equation III, n is 1. In some embodiments of Equation III, n is 0.

[0361] 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)), R7 and R8 are each independently hydrogen.

[0362] 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.

[0363] In some implementations, the compound of formula III is selected from the group consisting of:

[0364]

[0365] Or its pharmaceutically acceptable salt.

[0366] General synthesis scheme

[0367] Exemplary methods for preparing the compounds described herein are illustrated in the following synthetic schemes. These schemes are given for illustrative purposes and should not be construed in any way as limiting the scope or spirit of the invention.

[0368] The synthetic route shown in Scheme I-1 depicts an exemplary procedure for the preparation of carboxylic acid IC. In a first step, IA is carbonylated under standard carbonylation reaction conditions (e.g., CO, Pd(dppf)Cl2, and Et3N in ROH) to form ester IB. Then, ester IB is hydrolyzed to obtain carboxylic acid IC.

[0369] Plan I-1

[0370]

[0371] The synthetic route shown in Scheme I-2 depicts an exemplary procedure for the preparation of IE (the compound of Formula II). In this route, carboxylic acid IC is coupled with aminoindene ID under standard peptide coupling reaction conditions (e.g., HATU and base) to give IE (the compound of Formula II).

[0372] Plan I-2

[0373]

[0374] The synthetic route shown in Scheme 1 depicts an exemplary procedure for the preparation of carboxylic acid C. In a first step, A is carbonylated under standard carbonylation reaction conditions (e.g., CO, Pd(dppf)Cl2, and Et3N in ethanol) to form ester B. Ester B is then hydrolyzed to give carboxylic acid C.

[0375] Option 1

[0376]

[0377] The synthetic route shown in Scheme 2 describes an exemplary procedure for preparing E (the compound of Formula I). ​​In this route, carboxylic acid C is coupled with aminoindene D under standard peptide coupling reaction conditions (e.g., HATU and Et3N in acetonitrile) to obtain E (the compound of Formula I).

[0378] Option 2

[0379]

[0380] The synthetic route shown in Scheme II-1 depicts an exemplary procedure for the preparation of aminoindanone II-B. In this route, indanone II-A is reacted with ammonium acetate and sodium cyanoborohydride to form aminoindanone II-B.

[0381] Option II-1

[0382]

[0383] The synthetic route shown in Scheme II-2 depicts an exemplary procedure for the preparation of carboxylic acid II-D. In this route, ester II-C is hydrolyzed to obtain carboxylic acid II-D.

[0384] Plan II-2

[0385]

[0386] The synthetic route shown in Scheme II-3 describes an exemplary procedure for the preparation of II-E (the compound of formula II). In this route, carboxylic acid II-D is coupled with aminoindene II-B under standard peptide coupling reaction conditions (e.g., HOBt and EDCI in dichloromethane in the presence of NEt3) to give II-E (the compound of formula II).

[0387] Option II-3

[0388]

[0389] The synthetic route shown in Scheme III-1 describes an exemplary procedure for the preparation of III-C (the compound of formula III). In this route, carboxylic acid III-A is coupled with aminoindene III-B under standard peptide coupling reaction conditions (e.g., in the presence of DMAP, HOBt in dichloromethane, and EDCI) to give III-C (the compound of formula III).

[0390] Option III-1

[0391]

[0392] Treatment

[0393] The compounds and compositions described above and herein may be used to treat neurological disorders or conditions associated with excessive neuronal excitability and / or gain-of-function mutations in genes (e.g., KCNT1). Exemplary disorders, conditions, or symptoms include epilepsy and other encephalopathy (e.g., infantile epilepsy 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 epileptic encephalopathy in infancy (EIEE), generalized epilepsy, focal epilepsy, multifocal epilepsy, temporal lobe epilepsy, Ōtahara syndrome, early myoclonic encephalopathy, and Lennox). Gastaut syndrome, drug-resistant epilepsy, seizures (e.g., frontotemporal seizures, generalized tonic-clonic seizures, asymmetric tonic seizures, focal seizures), leukodystrophy, myelodysplastic leukodystrophy, leukoencephalopathy and sudden death in epilepsy, cardiac dysfunction (e.g., arrhythmias, Brugada syndrome and myocardial infarction), pulmonary vascular disease / hemorrhagic disease, pain and related symptoms (e.g., neuropathic pain, acute / chronic pain, migraine, etc.), muscle disorders (e.g., myotonia, neuromuscular myotonia, convulsive muscle spasms, convulsions), pruritus and pruritus, movement disorders (e.g., ataxia and cerebellar ataxia), mental disorders (e.g., major depressive disorder, anxiety disorder, bipolar disorder, schizophrenia, attention deficit hyperactivity disorder), neurodevelopmental disorders, learning disabilities, intellectual disability, Fragile X syndrome, neuronal plasticity and autism spectrum disorders.

[0394] In some embodiments, the neurological disease or condition, or the disease or condition associated with excessive neuronal excitability and / or gain-of-function mutations in genes (e.g., KCNT1), is selected from EIMFS, ADNFLE, and Wester syndrome. In some embodiments, the neurological disease or condition, or the disease or condition associated with excessive neuronal excitability and / or gain-of-function mutations in genes (e.g., KCNT1), is selected from infantile spasms, epileptic encephalopathy, focal epilepsy, Ōtahara syndrome, developmental and epileptic encephalopathy, and Lennox-Gastaut syndrome. In some embodiments, the neurological disease or condition, or the disease or condition associated with excessive neuronal excitability and / or gain-of-function mutations in genes (e.g., KCNT1), is epileptic seizures. In some embodiments, the neurological disease or condition, or the disease or condition associated with excessive neuronal excitability and / or gain-of-function mutations in genes (e.g., KCNT1), is selected from arrhythmias, Brugada syndrome, and myocardial infarction.

[0395] In some implementations, the neurological disease or condition or disease or condition associated with excessive neuronal excitability and / or gain-of-function mutations in genes (e.g., KCNT1) is selected from the group consisting of: learning disabilities, Fragile X syndrome, intellectual function, neuronal plasticity, mental disorders, and autism spectrum disorders.

[0396] Therefore, the compounds and their compositions may be administered to subjects suffering from neurological diseases or conditions or diseases or conditions associated with excessive neuronal excitability and / or gain-of-function mutations in genes (such as KCNT1) (e.g., EIMFS, ADNFLE, Wester syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ōtahara syndrome, developmental and epileptic encephalopathy and Lennox-Gastaut syndrome, seizures, arrhythmias, Brugada syndrome and myocardial infarction).

[0397] EIMFS is a rare, exhaustive genetic disorder characterized by early onset (before 6 months of age) of almost consecutive, heterogeneous, focal seizures, in which seizures appear to migrate from one brain region and hemisphere to another. Individuals with EIMFS are generally intellectually impaired, nonverbal, and nonmotorized. While several genes have been investigated to date, KCNT1 is the most commonly associated gene with EIMFS. Several new mutations in KCNT1 were 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, and M. 896K, R933G, R950Q, K1154Q (Barcia et al. (2012) *Nature Genetics* 44:1255-1260; Ishii et al. (2013) *Gene* 531:467-471; McTague et al. (2013) *Brain* 136:1578-1591; Epi4K Consortium & Epipsis Phenome / Genome) Project. (2013) Nature 501:217-221; Lim et al. (2016) Neurogenetics; Ohba et al. (2015) Epilepsy 56:el21-el28; Zhou et al. (2018) Genes, Brain, and Behavior e12456; Moller et al. (2015) Epilepsy e114-20; Numis et al. (2018) Epilepsy 1889-1898; Madaan et al., Brain Behavior Dev.) 40(3):229-232; McTague et al. (2018) Neurology. 90(1):e55-e66; Kawasaki et al. (2017) Journal of Pediatrics. 191:270-274; Kim et al. (2014) Cell Reports. 9(5):1661-1672; Ohba et al. (2015) Epilepsy 56(9):e121-8; Rizzo et al. (2016) Molecular and Cellular Neuroscience.)72:54-63; Zhang et al. (2017) Clinical Genetics (Clin Genet.) 91(5):717-724; Mikati et al. (2015) Ann Neurol. 78(6):995-9; Baumer et al. (2017) Neurology 89(21):2212; Dilena et al. (2018) Neurotherapeutics (Neurotherapeutics.) 15(4):1112-1126). These mutations are gain-of-function missense mutations, which are dominant (i.e., present in only one allele) and result in altered function of the potassium channel encoding a phalloidea, causing a significant increase in whole-cell currents when tested in toad oocytes or mammalian expression systems (see, for example, Milligan et al. (2015) Annals of Neurology 75(4):581-590; Barcia et al. (2012) Nature Genetics 44(11):1255-1259; and Mikati et al. (2015) Annals of Neurology 78(6):995-999).

[0398] ADNFLE develops later than EIMFS, typically in middle age, and is generally a less severe condition. It is characterized by nocturnal frontal lobe seizures and can lead to mental, behavioral, and cognitive impairments in patients with the condition. While ADNFLE is associated with genes encoding several neuronal nicotinic acetylcholine receptor subunits, mutations in the KCNT1 gene have been linked to more severe cases of the disease (Heron et al. (2012) Nature Genetics 44:1188-1190). Functional studies of mutant KCNT1 genes associated with ADNFLE have shown that the basic mutations (M896I, R398Q, Y796H, and R928C) are dominant, gain-of-function mutations (Milligan et al. (2015) Annals of Neurology 75(4):581-590; Mikati et al. (2015) Annals of Neurology 78(6):995-999).

[0399] Wester syndrome is a severe form of epilepsy characterized by a triad of infantile spasms, an episodic EEG pattern known as hyperhypsarrhythmia, and mental retardation, but a diagnosis can be made if one of these elements is absent. Mutations in KCNT1, including G652V and R474H, have been associated with Wester syndrome (Fukuoka et al. (2017) Brain Development 39:80-83 and Ohba et al. (2015) Epilepsy 56:el21-el28). Therapies targeting the KCNT1 pathway have shown these mutations to be gain-of-function mutations (Fukuoka et al. (2017) Brain Development 39:80-83).

[0400] In one aspect, the invention is characterized by a treatment for diseases or conditions associated with excessive neuronal excitability and / or gain-of-function mutations in genes such as KCNT1 (e.g., epilepsy and other encephalopathy, such as infantile epilepsy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ōtahara syndrome, developmental and epileptic encephalopathy (DEE), and Lennox). Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic seizures, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia, asymmetric tonic seizures) and cardiac dysfunction (e.g., arrhythmia, Brugada syndrome, sudden epileptic death, myocardial infarction), pain and related symptoms (e.g., neuropathic pain, acute / chronic pain, migraine, etc.), myopathies (e.g., myotonia, neurogenic myotonia, convulsive muscle spasms, spastic states), pruritus and pruritus, ataxia and cerebellar ataxia, mental disorders (e.g., major depressive disorder, anxiety disorder, bipolar disorder, schizophrenia), learning disabilities, Fragile X syndrome, neuronal plasticity and autism spectrum disorder), said method comprising administering to a subject in need the compounds disclosed herein (e.g., formula (II) or (I) (e.g., (I-Ia), (I-Ia) 1) compounds of formula (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 (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), or pharmaceutically acceptable salts thereof) or pharmaceutical compositions disclosed herein (e.g., comprising the following pharmaceutical compositions: 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 (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)) or pharmaceutically acceptable salts thereof) and pharmaceutically acceptable excipients.

[0401] In some examples, prior to administration of the compound and its composition, subjects presenting with diseases or symptoms that may be associated with gain-of-function mutations in KCNT1 are genotyped to confirm the presence of known gain-of-function mutations in KCNT1. For example, whole-exome sequencing may be performed on the subjects. Gaining-function mutations associated with EIMFS may include, but are not limited to, V271F, G288S, R428Q, R474Q, R474H, R474C, I760M, A934T, P924L, G243S, H257D, A259D, R262Q, Q270E, L274I, F346L, C377S, R398Q, P409S, A477T, F502V, M516V, Q550del, K629E, K629N, I760F, E893K, M896K, R933G, R950Q, and K1154Q. Gaining-function mutations associated with ADNFLE may include, but are not limited to, M896I, R398Q, Y796H, R928C, and G288S. Gain-of-function mutations associated with Wester syndrome may include, but are not limited to, G652V and R474H. Gain-of-function mutations associated with temporal lobe epilepsy may include, but are not limited to, R133H and R565H. Gain-of-function mutations associated with Lennox-Gastaut may include, but are not limited to, R209C. Gain-of-function mutations associated with seizures may include, but are not limited to, A259D, G288S, R474C, and R474H. Gain-of-function mutations associated with leukodystrophy may include, but are not limited to, G288S and Q906H. Gain-of-function mutations associated with multifocal epilepsy may include, but are not limited to, V340M. Gain-of-function mutations associated with EOE may include, but are not limited to, F346L and A934T. Gain-of-function mutations associated with early-onset epileptic encephalopathy (EOEE) may include, but are not limited to, R428Q. Gain-of-function mutations associated with developmental and epileptic encephalopathy may include, but are not limited to, F346L, R474H, and A934T. Gain-of-function mutations associated with epileptic encephalopathy may include, but are not limited to, L437F, Y796H, P924L, and R961H. Gain-of-function mutations associated with early infantile epileptic encephalopathy (EIEE) may include, but are not limited to, M896K. Gain-of-function mutations associated with drug-resistant epilepsy and generalized tonic-clonic seizures may include, but are not limited to, F346L. Gain-of-function mutations associated with infantile transitional partial seizures may include, but are not limited to, R428Q. Gain-of-function mutations associated with leukoencephalopathy may include, but are not limited to, F932I. Gain-of-function mutations associated with non-fibrotic encephalopathy (NFLE) may include, but are not limited to, A934T and R950Q. Gain-of-function mutations associated with Ōtahara syndrome may include, but are not limited to, A966T.Gain-of-function mutations associated with infantile spasms may include, but are not limited to, P924L. Gain-of-function mutations associated with Brugada syndrome may include, but are not limited to, R1106Q. Gain-of-function mutations associated with Brugada syndrome may include, but are not limited to, R474H.

[0402] In other examples, subjects were first subjected to genotypic analysis to identify the presence of mutations in KCNT1, followed by standard in vitro assays, such as Milligan et al. (2015) Annals of Neurology 75(4):581-590. Typically, the presence of gain-of-function mutations is confirmed when expression of the mutant KCNT1 allele results in an increase in whole-cell currents compared to those produced by expression of wild-type KCNT1, as assessed using whole-cell electrophysiology (such as described in Milligan et al. (2015) Annals of Neurology 75(4):581-590; Barcia et al. (2012) Nature Genetics 44(11):1255-1259; Mikati et al. (2015) Annals of Neurology 78(6):995-999; or Rizzo et al. Molecular and Cellular Neuroscience (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 confirmed to have a disease or condition associated with a gain-of-function mutation in KCNT1.

[0403] In specific cases, subjects were confirmed to have KCNT1 alleles with gain-of-function mutations (e.g., V271F, G288S, R398Q, R428Q, R474Q, R474H, R474C, G652V, I760M, Y796H, M896I, P924L, R928C, or A934T).

[0404] 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)) Compounds of formula (II-c), (II-c1), (II-c2)), or compounds of formula (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), or pharmaceutically acceptable salts thereof) or pharmaceutical compositions disclosed herein (e.g., pharmaceutical compositions comprising compounds disclosed herein (e.g., formula (II) or (I)). (e.g., compounds of formula (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)), and compounds of formula (II) (e.g., (II-a), (II-a1), (II-a2), (II-b), (II-b1), (II-b2), (II-c), (II-c1), (II-c2)) Compounds of formula (III) or compounds of formula (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)) or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients may also be therapeutically used for symptoms associated with excessive neuronal resectableness, wherein excessive neuronal resectableness is not necessarily caused by gain-of-function mutations in KCNT1. Even in cases where the disease is not caused by increased KCNT1 expression and / or activity, inhibition of KCNT1 expression and / or activity can still lead to decreased neuronal excitability, thereby providing a therapeutic effect.Therefore, 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-c), (II-c1), (II-c2)), or compounds of formula (III) (e.g.) Compounds of formula (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein (e.g., comprising the following pharmaceutical compositions: compounds disclosed herein (e.g., 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)). Compounds of formula (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 (III) (e.g., (III-a), (III-a1), (III-a2), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)) or pharmaceutically acceptable salts thereof) and pharmaceutically acceptable The excipient may be used to treat subjects with symptoms associated with excessive neuronal excitability, such as epilepsy and other encephalopathy (e.g., infantile epilepsy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ōtahara syndrome, developmental and epileptic encephalopathy and Lennox-Gastaut syndrome, seizures) or cardiac dysfunction (e.g., arrhythmia, Brugada syndrome, myocardial infarction), regardless of whether the disease or symptom is associated with gain-of-function mutations in KCNT1.

[0405] Pharmaceutical Compositions and Routes of Administration

[0406] The compounds according to the invention are typically administered in the form of pharmaceutical compositions. Therefore, the invention provides pharmaceutical compositions comprising, as active ingredients, one or more of the described compounds or their pharmaceutically acceptable salts or esters, and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers, and adjuvants. The pharmaceutical compositions can be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical field (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (edited by G.S. Banker and T. Rhodes).

[0407] The pharmaceutical composition can be administered in single or multiple doses via any acceptable administration modality having similar efficacy, such administration modalities as described in, for example, those patents and patent applications incorporated herein by reference, including transrectal, buccal, intranasal, and percutaneous routes, via intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, local administration, as an inhalant, or, for example, via an impregnation or coating device such as a stent, or via arterial insertion of a cylindrical polymer.

[0408] One mode of administration is parenteral, particularly by injection. The novel compositions of the present invention can be incorporated into forms for injection including aqueous or oil 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 mediators. Saline solutions are also commonly used for injection, but are not preferred in the context of this invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Appropriate flowability can be maintained, for example, by using a coating (such as lecithin), by maintaining the desired particle size in the case of a dispersion, and by using surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).

[0409] The sterile injectable solution is prepared by incorporating the required amount of the compound according to the invention, as needed, together with various other components listed above, into a suitable solvent, followed by filtration and sterilization. Generally, a dispersion is prepared by incorporating various sterilized active ingredients into a sterile medium containing an alkaline dispersion medium and other desired components from those listed above. When sterile powder is used to prepare the sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any other desired components from a previously sterile filtered solution.

[0410] Oral administration is another route of administration of the compounds according to the invention. Administration can be via capsules or enteric-coated tablets or the like. In the manufacture of pharmaceutical compositions comprising at least one of the compounds described herein, the active ingredient is typically diluted with excipients and / or encapsulated within a carrier, which may be in the form of capsules, pouches, paper, or other containers. When the excipient is used as a diluent, it may be in the form of a solid, semi-solid, or liquid material (as described above), acting as a mordant, carrier, or medium for the active ingredient. Therefore, the composition can be in the following forms: tablets, pills, powders, lozenges, pouches, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0411] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. Formulas may also include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners; and flavoring agents.

[0412] The compositions of the present invention can be formulated to provide a rapid, sustained, or delayed release of an active ingredient after administration to a patient 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 given in U.S. Patents 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs a transdermal delivery device (“patch”). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. Such patches can be constructed to deliver medications continuously, in pulses, or on demand.

[0413] The composition is preferably formulated in unit dosage forms. The term "unit dosage form" refers to a physically discrete unit suitable for use as a unit dose in human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, combined with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compound is generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dose unit contains 1 mg to 2 g of the compound described herein, and for parenteral administration, preferably 0.1 to 700 mg of the compound described herein. However, it should be understood that the actual amount of the compound administered will generally be determined by the physician based on relevant circumstances, including the condition to be treated; the chosen route of administration; the actual compound administered and its relative activity; the individual patient's age, weight, and response; and the severity of the patient's symptoms.

[0414] To prepare solid compositions (such as tablets), the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformed composition containing a homogeneous mixture of the compounds of the present invention. When it is mentioned that these preformed compositions are homogeneous, it means that the active ingredient is generally uniformly dispersed throughout the composition so that the composition can be easily further divided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0415] The tablets or pills of the present invention can be coated or otherwise formulated to provide a dosage form that has the advantage of a long duration of action or protection against the acidic conditions of the stomach. For example, the tablets or pills may comprise an internal dose component and an external dose component, the latter being coated over the former. The two components may be separated by an enteric coating layer, which resists disintegration in the stomach and allows the internal component to be delivered intact into the duodenum or to be released with a delay. A variety of materials can be used for such an enteric coating or coating, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, hexadecyl alcohol, and cellulose acetate.

[0416] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered via the oral or nasal respiratory route for local or systemic effects. Compositions in preferably pharmaceutically acceptable solvents can be nebulized using an inert gas. The nebulized solution can be inhaled directly from a nebulizer or the nebulizer can be connected to a mask holder or an intermittent positive pressure ventilator. The solution, suspension, or powder composition can preferably be administered orally or nasally from a device for delivering the preparation in a suitable manner.

[0417] In some embodiments, the pharmaceutical composition comprises the disclosed compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0418] Example

[0419] To provide a more complete understanding of the invention described herein, the following embodiments are set forth. The synthetic and biological embodiments described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed as limiting their scope in any way.

[0420] The compounds described herein can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that, unless otherwise specified, other process conditions may be used, provided that typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through routine optimization.

[0421] Furthermore, it will be apparent to those skilled in the art that conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The selection of suitable protecting groups for specific functional groups, and the appropriate conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups and their introduction and removal are described in TW Greene and PGM Uts, Protecting Groups in Organic Synthesis, 2nd Edition, Wiley, New York, 1991, and the references listed therein.

[0422] The compounds described herein can be separated and purified using known standard procedures. These procedures include recrystallization, filtration, rapid chromatography, wet milling, high-performance liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). Note that rapid chromatography can be performed manually or by an automated system. The compounds described herein can be characterized using 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 generated using methods well-known to those skilled in the art.

[0423] List of abbreviations

[0424] MeI iodomethane

[0425] Pd(dppf)Cl2 [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloro

[0426] Pd2(dba)3 tris(diphenylmethyleneacetone)dipalladium(0)

[0427] THF Tetrahydrofuran

[0428] TEA or Et3N triethylamine

[0429] TFA (trifluoroacetic acid)

[0430] FA Formic acid

[0431] DMF N,N-dimethylformamide

[0432] MeOH (methanol)

[0433] DCM dichloromethane

[0434] MeCN or ACN acetonitrile

[0435] PE petroleum ether

[0436] EtOAc or EA (ethyl acetate)

[0437] EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0438] HATU o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate

[0439] HOBt 1-hydroxybenzotriazole monohydrate

[0440] DIPEA N,N,-Diisopropylethylamine

[0441] DEA diethylamine

[0442] NBS N-bromosuccinimide

[0443] NaOMe (sodium methoxide)

[0444] mCPBA (m-chloroperoxybenzoic acid)

[0445] PPPh3 triphenylphosphine

[0446] DEA diethylamine

[0447] NH4OAc ammonium acetate

[0448] DIAD (Diisopropyl Azodicarbonate)

[0449] i-PrOH isopropanol

[0450] Tf2O trifluoromethanesulfonic anhydride

[0451] DMAP 4-Dimethylaminopyridine

[0452] Potassium peroxymonosulfate

[0453] t-BuOH tert-butanol

[0454] CSI Chlorosulfonyl isocyanate

[0455] ODS Octadecylsilane

[0456] HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid

[0457] DMSO (dimethyl sulfoxide)

[0458] EGTA (ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid)

[0459] NMDG N-methyl-D-glucosamine

[0460] IC 50 Maximum Inhibitory Concentration

[0461] TLC (Thin Layer Chromatography)

[0462] LCMS (Liquid Chromatography-Mass Spectrometry)

[0463] HPLC (High Performance Liquid Chromatography)

[0464] SFC Supercritical Fluid Chromatography

[0465] MS mass spectrometry

[0466] ESI Electrospray Ionization

[0467] NMR (Nuclear Magnetic Resonance)

[0468] Example 1. Synthesis of compound I-1

[0469]

[0470] A mixture of 5-cyclopropyl-1-methylpyrazole-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 h. The mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Xtimate C18 150 × 25 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 46-76% B in 8.5 min, to give the product (89.1 mg, 0.28 mmol, 47% yield).

[0471] 1 H NMR (400MHz, 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)

[0472] LCMS R t = 1.28 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 17H 19 ClN3O[M+H] + The calculated MS ESI value is 316.1, and the experimental value is 316.0.

[0473] Example 2. Synthesis of compound I-2

[0474]

[0475] A mixture of 5-cyclopropyl-2-methylpyrazole-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 h. The mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were 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 = H2O (0.05% NH4OH) and B = CH3CN; 52-82% B over 8 min to give the product (77.7 mg, 0.25 mmol, 41% yield).

[0476] 1 H NMR (400MHz, 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).

[0477] LCMS R t = 1.26 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 17 H 19 ClN3O[M+H] + The calculated MS ESI value is 316.1, and the experimental value is 316.0.

[0478] Example 3. Synthesis of compound I-3

[0479]

[0480] A mixture of 5-aminosulfonylfuran-2-carboxylic acid (100 mg, 0.52 mmol), (1R)-5-chloroindan-1-amine (131.54 mg, 0.78 mmol), Et3N (0.14 mL, 1.05 mmol), and HATU (198.91 mg, 0.52 mmol) in CH3CN (5 mL) was stirred at 25 °C for 3 hours. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative TLC (silica gel, PE:EtOAc = 1:1) to give a solid product (22.9 mg, 67.3 μmol, 23% yield).

[0481] 1 H NMR (400MHz, 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).

[0482] LCMS R t = 1.12 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 14 H 14 ClN2O4S[M+H] + The calculated MS ESI value is 341.0, and the experimental value is 340.9.

[0483] Example 4. Synthesis of compound I-4

[0484]

[0485] Synthesis of IA-5b: A mixture of 5-bromothiophene-2-sulfonamide (2 g, 8.26 mmol), Pd(dppf)Cl2 (906.65 mg, 1.24 mmol), and Et3N (3.43 mL, 24.78 mmol) in ethanol (20 mL) was stirred at 80 °C for 16 h under CO2 (50 psi). The mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0% to 30% to 50%) to give a solid product (1 g, 4.25 mmol, 51% yield).

[0486] 1 H NMR (400MHz, 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).

[0487] Synthesis of IA-5c: A mixture of ethyl 5-aminosulfonylthiophene-2-carboxylate (900 mg, 3.83 mmol) and LiOH·H₂O (481.52 mg, 11.48 mmol) in THF (10 mL) and water (10 mL) was stirred at 20 °C for 1 hour. 1 N HCl was added to adjust the pH to 1. The mixture was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product as a solid (450 mg, 2.17 mmol).

[0488] 1 H NMR (400MHz, DMSO-d) 6 )δ H =7.91(s,2H),7.70(d,1H),7.56(d,1H).

[0489] Synthesis of I-4: A mixture of 5-aminosulfonylthiophene-2-carboxylic acid (230 mg, 1.11 mmol), (1R)-5-chloroindan-1-amine (372.12 mg, 2.22 mmol), Et3N (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 Na2SO4, filtered, and concentrated. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0% to 35% to 70%) to give a solid product (64 mg, 174.7 μmol, 15% yield). The product was mixed with another batch (36 mg, prepared with 200 mg of 5-aminosulfonylthiophene-2-carboxylic acid). The combined solid (100 mg) was moistened with MeOH (3 mL) to give the product as a solid (82.9 mg, 232.3 μmol, 85% yield).

[0490] 1 H NMR (400MHz, 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).

[0491] LCMS R t =1.20 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 14 H 14 ClN2O3S2[M+H] + The calculated MS ESI value is 357.0, and the experimental value is 356.8.

[0492] Example 5. Synthesis of compound I-5

[0493]

[0494] A mixture of 4-aminosulfonylthiophene-2-carboxylic acid (150 mg, 0.72 mmol), (1R)-5-chloroindan-1-amine (182.02 mg, 1.09 mmol), Et3N (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 hours. 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 Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (EtOAc / PE = 0% to 35% to 70%), followed by preparative HPLC (Xtimate C18 150×25mm, 5μm, A = H2O (10mMNH4HCO3) and B = CH3CN; 30-60% B within 10 minutes) to obtain a solid product (53.3 mg, 149.5 μmol, 20% yield).

[0495] 1 H NMR (400MHz, 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).

[0496] LCMS R t = 1.11 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 14 H 14 ClN2O3S2[M+H] + The calculated MS ESI value is 357.0, and the experimental value is 356.9.

[0497] Example 6. Synthesis of compound I-6

[0498]

[0499] A mixture of (1R)-5-chloroindan-1-amine (182.02 mg, 1.09 mmol), 5-aminosulfonylthiophene-3-carboxylic acid (150 mg, 0.72 mmol), Et3N (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 hours. 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 Na2SO4, filtered, and concentrated. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0% to 35% to 70%) to give a solid product (73.09 mg, 204.8 μmol, 28% yield).

[0500] 1 H NMR (400MHz, 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).

[0501] LCMS R t = 1.09 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 14 H 14 ClN2O3S2[M+H] + The calculated MS ESI value is 357.0, and the experimental value is 356.9.

[0502] Example 7. Synthesis of compound I-7

[0503]

[0504] A mixture of 1-methyl-4-aminosulfonyl-pyrrole-2-carboxylic acid (150 mg, 0.73 mmol), (1R)-5-chloroindan-1-amine (184.72 mg, 1.1 mmol), Et3N (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 hours. 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 Na2SO4, filtered, and concentrated. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0% to 35% to 70%) to give a product as a solid (78.9 mg, 222.9 μmol, 30% yield).

[0505] 1 H NMR (400MHz, 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).

[0506] LCMS R t =1.10 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 15 H 17 The MS ESI calculated value of ClN3O3S[M+H]+ is 354.1, and the measured value is 353.9.

[0507] Example 8. Synthesis of compound I-8

[0508]

[0509] A mixture of 5-methyl-4-aminosulfonyl-thiophene-2-carboxylic acid (150 mg, 0.68 mmol), (1R)-5-chloroindan-1-amine (170.48 mg, 1.02 mmol), Et3N (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 hours. 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 Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (EtOAc / PE = 0% to 35% to 70%), followed by preparative HPLC (Xtimate C18 150×25mm, 5μm, A = H2O (10mM NH4HCO3) and B = CH3CN; 30-60% B over 10 minutes) to give a solid product (120.4 mg, 324.6 μmol, 47% yield).

[0510] 1 H NMR (400MHz, 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).

[0511] LCMS R t = 1.13 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 15 H 16 ClN2O3S2[M+H] + The calculated MS ESI value is 371.0, and the experimental value is 370.9.

[0512] Example 9. Synthesis of compound I-9

[0513]

[0514] A mixture of 5-methyl-4-aminosulfonyl-furan-2-carboxylic acid (150 mg, 0.73 mmol), (1R)-5-chloroindan-1-amine (183.82 mg, 1.1 mmol), Et3N (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 hours. 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 Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (EtOAc / PE = 0% to 35% to 70%), followed by preparative HPLC (Xtimate C18 150×25mm, 5μm, A = H2O (10mM NH4HCO3) and B = CH3CN; 30-60% B over 10 minutes) to give a solid product (48.2 mg, 135.8 μmol, 18% yield).

[0515] 1 H NMR (400MHz, 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).

[0516] LCMS R t =1.10 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 15 H 16 ClN2O4S[M+H] + The calculated MS ESI value is 355.0, and the experimental value is 354.9.

[0517] Example 10. Synthesis of compound I-10

[0518]

[0519] A mixture of 3-methyl-5-aminosulfonyl-thiophene-2-carboxylic acid (100 mg, 0.45 mmol), (1R)-5-chloroindan-1-amine (113.65 mg, 0.68 mmol), Et3N (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 hours. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative TLC (silica gel, PE:EtOAc = 1:1), followed by preparative HPLC (Waters Xbridge 150×25mm, 5μm), A = H2O (10mM NH4HCO3) and B = CH3CN; 35-65% B over 10 minutes, to obtain a solid product (22.8 mg, 61.6 μmol, 76% yield).

[0520] 1 H NMR (400MHz, 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).

[0521] LCMS R t = 1.13 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 15 H 16 ClN2O3S2[M+H] + The calculated MS ESI value is 371.0, and the experimental value is 370.9.

[0522] Example 11. Synthesis of compound I-11

[0523]

[0524] A mixture of 2-methyl-5-aminosulfonyl-furan-3-carboxylic acid (150 mg, 0.73 mmol), (1R)-5-chloroindan-1-amine (183.82 mg, 1.1 mmol), Et3N (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 hours. 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 Na2SO4, filtered, and concentrated. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0% to 30%) to give a solid product (23.7 mg, 0.07 mmol, 24% yield).

[0525] 1 H NMR (400MHz, 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).

[0526] LCMS R t = 1.13 min (at 2.0 min chromatogram), 10-80 AB, C 15 H 16 ClN2O4S[M+H] + The calculated MS ESI value is 355.0, and the experimental value is 355.1.

[0527] Example 12. Synthesis of compound I-12

[0528]

[0529] A mixture of 3-methyl-5-aminosulfonyl-furan-2-carboxylic acid (150 mg, 0.73 mmol), HATU (277.97 mg, 0.73 mmol), Et3N (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 hours. 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 Na2SO4, filtered, and concentrated. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0% to 30%) to give a solid product (19.3 mg, 0.05 mmol, 19% yield).

[0530] 1 H NMR (400MHz, 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).

[0531] LCMS R t = 1.14 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 15 H 16 ClN2O4S[M+H] + The calculated MS ESI value is 355.0, and the experimental value is 354.9.

[0532] Example 13. Synthesis of compound I-13

[0533]

[0534] A mixture of 1-methyl-5-aminosulfonyl-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 hours. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by preparative HPLC (Waters Xbridge 150x 25mm, 5μm, A=H2O (10mM NH4HCO3) and B=CH3CN; 35-65% B over 10 minutes) to obtain a solid product (79.66 mg, 225.1 μmol, 66% yield).

[0535] 1 H NMR (400MHz, 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).

[0536] LCMS R t = 1.16 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 15 H 17 ClN3O3S[M+H] + The calculated MS ESI value is 354.1, and the experimental value is 353.8.

[0537] Example 14. Synthesis of compound I-14

[0538]

[0539] A mixture of 4-aminosulfonyl-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 hours. Water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by preparative HPLC (Xtimate C18 150×25mm, 5μm, A=H2O(10mM NH4HCO3) and B=CH3CN; 0-60% B over 10 minutes) to obtain a solid product (17.0 mg, 50.0 μmol, 14% yield).

[0540] 1 H NMR (400MHz, 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).

[0541] LCMS R t = 1.11 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 14 H 15 ClN3O3S[M+H] + The calculated MS ESI value is 340.0, and the experimental value is 339.8.

[0542] Example 15. Synthesis of compound I-15

[0543]

[0544] Synthesis of IA-5b: A mixture of 5-bromothiophene-2-sulfonamide (2 g, 8.26 mmol), Pd(dppf)Cl2 (906.65 mg, 1.24 mmol), and Et3N (3.43 mL, 24.78 mmol) in ethanol (20 mL) was stirred at 80 °C for 16 hours under CO2 (50 psi). The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0% to 30% to 50%) to give a solid product (1 g, 4.25 mmol, 51% yield).

[0545] 1 H NMR (400MHz, DMSO-d6)δ H =7.95(s,1H),7.77(d,1H),7.58(d,1H),4.32(q,2H),1.30(t,3H).

[0546] Synthesis of IA-16a: NaH (51 mg, 1.28 mmol, 60% in oil) was added to a mixture of ethyl 5-aminosulfonylthiophene-2-carboxylate (100 mg, 0.43 mmol) in DMF (5 mL). Iodomethane (960 mg, 6.76 mmol) was then added to the mixture. The mixture was stirred at 20 °C for 12 hours. A saturated NH4Cl solution (20 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 Na2SO4, filtered, and concentrated to give a crude product as a solid (100 mg, 379.8 μmol).

[0547] LCMS R t =0.82 min (in 1.5 min chromatogram), 5-95AB, C9H 14 NO4S2[M+H] + The calculated MS ESI value is 264.0, and the experimental value is 263.8.

[0548] Synthesis of IA-16b: Ethyl 5-(dimethylaminosulfonyl)thiophene-2-carboxylate (100 mg, 0.38 mmol) and LiOH·H₂O (47.8 mg, 1.14 mmol) were stirred at 20 °C for 1 hour in a mixture of THF (2 mL) and water (2 mL). 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 Na₂SO₄, filtered, and concentrated to give a crude product as a solid (85 mg, 361.3 μmol).

[0549] 1 H NMR (400MHz, DMSO-d) 6 )δ H =13.92(s,1H),7.81(d,1H),7.65(d,1H),2.69(s,6H).

[0550] Synthesis of I-15: A mixture of 5-(dimethylaminosulfonyl)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 phases were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0% to 35% to 50%) to give a product as a solid (71.6 mg, 186.0 μmol, 36% yield).

[0551] 1 H NMR (400MHz, 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).

[0552] LCMS R t = 1.26 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 16 H 18 ClN2O3S2[M+H] + The calculated MS ESI value is 385.0, and the experimental value is 384.9.

[0553] Example 16. Synthesis of compound I-16

[0554]

[0555] Synthesis of IA-17b: A mixture of 5-bromothiophene-2-sulfonyl chloride (3 g, 11.47 mmol), methylamine hydrochloride (929.39 mg, 13.76 mmol), and Et3N (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 x 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product (2.9 g, 11.3 mmol) as an oil.

[0556] Synthesis of IA-17c: A mixture of 5-bromo-N-methylthiophene-2-sulfonamide (2.9 g, 11.32 mmol), Pd(dppf)Cl2 (1.24 g, 1.7 mmol), and Et3N (4.7 mL, 33.97 mmol) in ethanol (20 mL) was stirred at 80 °C for 16 hours under CO2 (50 psi). The mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0% to 30% to 50%) to give a solid product (2.2 g, 8.82 mmol, 77% yield).

[0557] 1 H NMR (400MHz, 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).

[0558] Synthesis of IA-17d: Ethyl 5-(methylaminosulfonyl)thiophene-2-carboxylate (1 g, 4.01 mmol) and LiOH·H₂O (504.91 mg, 12.03 mmol) were stirred at 20 °C for 1 hour in a mixture of THF (10 mL) and water (10 mL). 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 phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product as a solid (880 mg, 3.97 mmol).

[0559] 1 H NMR (400MHz, 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).

[0560] Synthesis of I-16: A mixture of 5-(methylaminosulfonyl)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 Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0% to 35% to 50%) to give a solid product (201.1 mg, 542.3 μmol, 59% yield).

[0561] 1 H NMR (400MHz, 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).

[0562] LCMS R t = 1.24 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 15 H 16 ClN2O3S2[M+H] + The calculated MS ESI value is 371.0, and the experimental value is also 371.0.

[0563] Example 17. Synthesis of compound I-17

[0564]

[0565] Synthesis of IA-18a: Pyrrolidine (0.41 g, 5.74 mmol) and K₂CO₃ (1.59 g, 11.47 mmol) were added to a stirred solution of IA-17a (1 g, 3.82 mmol) in DCM (30 mL), and the reaction mixture was stirred at room temperature for 1 hour. 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 salt solution. The organic layer was dried over MgSO₄ and evaporated to give a crude mixture. The crude mixture was purified by rapid column chromatography with elution of 50% EtOAc / hexane to give the desired solid IA-18a (1 g, 3.33 mmol, 87% yield), which was used in the next step without further purification.

[0566] Synthesis of IA-18b: In an autoclave, TEA (0.34 g, 3.38 mmol) and PPd(dppf)Cl2 were added to a stirred solution of IA-18a (1 g, 3.38 mmol) in methanol (20 mL) and DMF (2 mL). . DCM (0.28 g, 0.34 mmol). The reactants were then heated to 80 °C at 100 psi CO atm for 6 hours. After completion, the reactants were cooled to room temperature, filtered through a diatomaceous earth bed, and concentrated to dryness. The crude material was purified by rapid column chromatography with 40% EtOAc / hexane elution to give the desired solid IA-18b (0.90 g, 2.57 mmol, 76% yield).

[0567] Synthesis of IA-18c: At 0 °C, 2 mL of water containing lithium hydroxide (0.12 g, 4.9 mmol) was added to a stirred solution of IA-18b (0.9 g, 3.27 mmol) in THF (6 mL). The reaction mixture was stirred at room temperature for 6 hours. 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 diluted HCl. The solid formed was filtered to give IA-18c (0.60 g, 2.26 mmol, 69% yield) as desired, which was used in the next step without further purification.

[0568] Synthesis of I-17: 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 to a stirred solution of IA-18c (0.1 g, 0.38 mmol) in DCM (5 mL), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with water (10 mL) and DCM (10 mL). The organic layer was separated and washed with 1 × 20 mL of saturated salt solution. The organic layer was then dried over MgSO4 and concentrated. The crude material was purified by rapid column chromatography with elution of 50% EtOAc / hexane to give I-17 as a solid (55 mg, 0.13 mmol, 34% yield).

[0569] HPLC: Rt 9.26 min, 97.6%; Column: X-select CSH C18 (4.6×150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min.

[0570] LCMS: 411.15(M+H), Rt 2.05min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0571] 1 H NMR (400MHz, DMSO-d6): 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).

[0572] Example 18. Synthesis of compound I-18

[0573]

[0574] Synthesis of IA-19b: At room temperature, copper iodide (85.95 mg, 0.45 mmol) and L-proline (104.16 mg, 0.90 mmol) were added to a stirred solution of IA-19a (1 g, 4.52 mmol) and sodium methanesulfonate (553.67 mg, 5.43 mmol) in DMSO (20 mL), followed by the addition of sodium hydroxide. The reaction mixture was then stirred at 95 °C for 16 hours. The reaction mixture was quenched with water (50 mL) and EtOAc (50 mL × 2) was added. The organic layers were separated, dried over Na₂SO₄, and concentrated to give a crude mixture. The crude mixture was purified by column chromatography using 100–200 silica gel and 20–40% EtOAc / hexane to give the desired solid IA-19b (270 mg, 1.16 mmol, 26% yield), which was used in the next step without further purification.

[0575] Synthesis of IA-19c: L LiOH·H₂O (57.15 mg, 1.36 mmol) was added to a stirred solution of IA-19b (0.25 g, 1.13 mmol) in THF:water (8:2 mL) at room temperature. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture 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 solid IA-19c (0.15 g, 0.69 mmol, 61%). IA-19c was used in the next step without further purification.

[0576] Synthesis of I-18: At room temperature, DIPEA (0.17 mL, 0.97 mmol) and HATU (276.54 mg, 0.73 mmol) were added 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). The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was quenched with water (100 mL) and DCM (2 × 100 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The crude material was purified by column chromatography with 100-200 silica gel and 30-80% EtOAc / hexane as eluent to give I-18 as a solid (80 mg, 0.22 mmol, 46% yield).

[0577] HPLC: Rt 8.31 min, 99.7%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0578] LCMS: 355.95(M+H), Rt 1.88min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0579] 1 H NMR (400MHz, DMSO-d6): 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).

[0580] Example 19. Synthesis of compound I-19

[0581]

[0582] Synthesis of IA-20b: IA-20a (436.57 mg, 7.65 mmol) was added to a stirred solution of IA-17a (1 g, 3.82 mmol) in DCM (20 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with water (50 mL) and diluted with DCM (50 mL × 2). The organic layer was separated, dried over Na2SO4, and concentrated to give a crude mixture. The crude mixture was then purified by column chromatography using 100-200 silica gel and 5-10% EtOAc / hexane as eluent to give IA-20b as a solid (900 mg, 3.16 mmol, 83% yield).

[0583] Synthesis of IA-20c: TEA (179.08 mg, 1.77 mmol) was added to a stirred solution of IA-20b (0.5 g, 1.77 mmol) in methanol:DMF (20:2 mL) at room temperature. The reaction mixture was degassed with argon for 30 min at room temperature and treated with Pd(dppf)Cl2·DCM (144.68 mg, 0.180 mmol). CO gas was purged into the reaction mixture (100 psi), and the reaction mixture was heated at 80 °C for 16 h. The reaction mixture was evaporated under reduced pressure. The crude substance was purified by column chromatography using 100-200 silica gel and 10-20% EtOAc / hexane as eluent to give the desired solid IA-20c (250 mg, 0.90 mmol, 51.25% yield), which was used in the next step without further purification.

[0584] Synthesis of IA-20d: Lithium hydroxide (0.06 mg, 0.0014 mmol) was added to a stirred solution of IA-20c (0.25 g, 0.95 mmol) in THF:water (8:2 mL) at room temperature, and the mixture was stirred for 2 hours. The reaction mixture 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 precipitate was filtered, separated, and dried under high vacuum to obtain the desired solid IA-20d (120 mg, 0.47 mmol, 49% yield), which was used in the next step without further purification.

[0585] Synthesis of I-19: At room temperature, DIPEA (0.14 mL, 0.81 mmol) and HATU (230.64 mg, 0.610 mmol) were added 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). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (100 mL) and diluted with DCM (100 mL × 2). The organic layer was separated, dried over Na2SO4, and concentrated to obtain the crude product. The crude product was purified by column chromatography using 100-200 silica gel with 30-80% EtOAc / hexane as eluent to give I-19 as a solid (60 mg, 0.14 mmol, 37% yield).

[0586] HPLC: Rt 8.99 min, 99.6%; Column: X-select CSH C18 (4.6 × 150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0587] LCMS: 397 (M+H), Rt 2.01min, column: X-select CSH C18 (3.0 x 50)mm, 2.5μm

[0588] 1 H NMR (400MHz, 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).

[0589] Example 20. Synthesis of compound I-20

[0590]

[0591] Synthesis of IA-21a: A stirred solution of IA-19a (1 g, 4.52 mmol) and copper cyanide (I) (0.61 g, 6.79 mmol) in DMF (10 mL) was heated at 120 °C for 12 hours. 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 / hexane as eluent to give IA-21a as a solid (500 mg, 2.66 mmol, 59% yield).

[0592] Synthesis of IA-21b: A stirred solution of IA-21a (0.5 g, 2.99 mmol) in THF (5 mL) was added to water (5 mL) containing NaOH (0.36 g, 8.97 mmol), and the reaction mixture was heated at 90 °C for 12 hours. The solvent was removed, and the aqueous layer was cooled to 0 °C and acidified with 2N HCl. The solid was filtered and dried to give IA-21b as a solid (0.35 g, 1.02 mmol, 34% yield), which was used in the next step without further purification.

[0593] Synthesis of I-20: DIPEA (0.2 mL, 1.17 mmol) and HATU (0.3 g, 0.88 mmol) were added to a stirred solution of IA-21b (0.1 g, 0.58 mmol) in DCM (3 mL) at 0 °C, and the mixture was stirred for 10 min. The resulting reaction mixture IA-2 (0.11 g, 0.64 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 6 h. The reaction mixture was quenched with water, extracted with DCM (10 mL × 3), and the organic layers were separated. The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure to give a crude product, which was purified by preparative HPLC to give I-20 as a solid (20.61 mg, 11% yield).

[0594] HPLC: Rt 7.64 min, 97.8%; Column: X-select CSH C18 (4.6 × 150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0595] LCMS: 321.05 (M+H), Rt 1.74min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0596] 1 H NMR (400MHz, 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).

[0597] Example 21. Synthesis of compound I-21

[0598]

[0599] Synthesis of IA-22b: At room temperature, 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 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). The reaction mixture was stirred at 95 °C for 16 h. The reaction mixture was quenched with water (50 mL) and diluted with EtOAc (50 mL × 2). The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography using 100-200 silica gel and 20-40% EtOAc / hexane as eluent to give IA-22b as a solid (0.4 g, 1.54 mmol, 23% yield), which was used in the next step without further purification.

[0600] Synthesis of IA-22c: LiOH·H₂O (0.1 g, 2.44 mmol) was added to a stirred solution of IA-22b (0.4 g, 1.62 mmol) in THF:water (10:3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 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 solid formed was filtered, separated, and dried to give IA-22c as a solid (0.23 g, 0.95 mmol, 58% yield), which was used in the next step without further purification.

[0601] Synthesis of I-21: IA-22c (0.1 g, 0.43 mmol) and IA-2 (86.61 mg, 0.52 mmol) were added to a stirred solution in DCM (10 mL). HATU (245.54 mg, 0.65 mmol) and DIPEA (0.15 mL, 0.86 mmol) were added to the resulting reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (100 mL) and diluted with DCM (100 mL × 2). The organic layers were then separated, dried over Na₂SO₄, filtered, and evaporated under reduced pressure to give the crude product. The crude mixture was purified by column chromatography using 100–200 silica gel and 30–80% EtOAc / hexane as eluent to give I-21 as a solid (0.092 g, 0.24 mmol, 56% yield).

[0602] HPLC: Rt 8.90 min, 99.9%; Column: X-select CSH C18 (4.6 × 150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0603] LCMS: 382.00 (M+H), Rt 2.00min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0604] 1 H NMR (400MHz, 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).

[0605] Example 22. Synthesis of compounds I-22 and I-23

[0606]

[0607] DIPEA (0.31 mL, 1.81 mmol) and HATU (380 mg, 0.99 mmol) were added to a stirred solution of IA-23a (160 mg, 0.90 mmol) and 5-(methylaminosulfonyl)thiophene-2-carboxylic acid (210 mg, 0.90 mmol) in DCM (20 mL) at 0 °C, and the mixture was 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 (10 mL), dried over MgSO4, and evaporated to give the crude product. The crude product IA-23b was subjected to chiral SFC chromatography (where the mobile phase was: A) CO2, B) MeOH + NH3, with the gradient: 25-50% B for 5 min, holding at 50% B for 9 min, and 50-25% B for 10 min, holding at 25% B for 12 min. Column: DAIEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm). Wavelength: 263 nm. Flow rate: 3 mL / min. Purification yielded 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.

[0608] I-22: HPLC: Rt 7.25 min, 98.5%; Column: X-Bridge C18 (4.6×150) mm, 5 μm; Mobile phase: A: 0.1% NH3 aqueous solution, B: ACN; Flow rate: 1.2 mL / min.

[0609] LCMS: 384.98 (M+H), Rt 1.98min; column: X-select CSH C18 (3×50)mm, 2.5μm.

[0610] 1 H NMR (400MHz, 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).

[0611] Chiral HPLC: Rt: 3.62 min, 100%; Column: DIACEL CHIRALPAK-1G (250 × 4.6 mm, 5 μm); Mobile phase: A) CO2, B) MeOH + 0.1% NH3; Gradient: 35-50% B for 5 min, hold at 50% B for 9 min, 50-35% B for 10 min, hold at 35% B for 12 min. Wavelength: 265 nm; Flow rate: 3 mL / min.

[0612] I-23: HPLC: Rt 7.25 min, 99.4%; Column: X-Bridge C18 (4.6×150) mm, 5 μm; Mobile phase: A: 0.1% NH3 aqueous solution, B: ACN; Flow rate: 1.2 mL / min.

[0613] LCMS: 384.91 (M+H), Rt 1.97min; column: X-select CSH C18 (3×50)mm, 2.5μm.

[0614] 1 H NMR (400MHz, 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).

[0615] Chiral HPLC: Rt: 4.68 min, 100%, column: DIACEL CHIRALPAK-1G (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1%. NH 3. Gradient: 35-50% B for 5 min, maintain 50% B for 9 min; 50-35% B for 10 min, maintain 35% B for 12 min. Wavelength: 265 nm; Flow rate: 3 mL / min.

[0616] Example 23. Synthesis of compounds I-24 and I-25

[0617]

[0618] Synthesis of IA-24b: NH₂OH (8.85 g, 127.33 mmol) and sodium acetate (10.45 g, 127.33 mmol) were added to a stirred solution of IA-24a (2.3 g, 12.73 mmol) in water:THF (1:5, 60 mL), and the mixture was heated at 70 °C for 4 hours. The reaction mixture was cooled, concentrated, and then washed with water. The organic layer was dried over MgSO₄ and evaporated to give IA-24b as a solid (2.4 g, 11.81 mmol, 92% yield).

[0619] Synthesis of IA-23a: Ammonium chloride (6.56 g, 122.67 mmol) and zinc powder (8.02 g, 122.67 mmol) were added to a stirred solution of IA-24b (2.4 g, 12.27 mmol) in acetic acid (50 mL), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was evaporated to dryness; the residue was then washed with EtOAc (100 mL) and saturated NaHCO3. The organic layer was washed with (2 × 30 mL) water, then with a saturated brine solution (30 mL), and dried over MgSO4 to give IA-23a as a liquid (1.4 g, 3.94 mmol, 32% yield).

[0620] Synthesis of I-24 and I-25: DIPEA (0.25 mL, 1.45 mmol) and HATU (414.82 mg, 1.09 mmol) were added 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) at room temperature, and the mixture was stirred for 2 hours at room temperature. The reactants were 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 a crude product, which was purified by column chromatography with 100-200 silica gel in 30% to 80% EtOAc / hexane to give a racemic mixture IA-24c. This racemic mixture was then purified by chiral SFC chromatography (where the mobile phase was: A) CO2, B) MeOH + NH3, with a gradient of 25-50% B for 5 min, holding at 50% B for 9 min, and 50-25% B for 10 min, holding at 25% B for 12 min. Column: DAICELCHIRALPAK-IG (250 × 4.6 mm, 5 μm). Wavelength: 263 nm. Flow rate: 3 mL / min. The purification yielded I-24 (56.1 mg, 0.15 mmol, 21% yield) and I-25 (62.5 mg, 0.16 mmol, 23% yield) as solids. The stereochemistry was randomly assigned.

[0621] I-24: HPLC: Rt 8.79 min, 99.2%; Column: X-Select CSH C18 (4.6×150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min.

[0622] LCMS: 369.95 (M+H), Rt 2.07min, column: X-select CSH C18 (3×50)mm, 2.5μm.

[0623] 1 H NMR (400MHz, 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).

[0624] I-25: HPLC: Rt 8.52 min, 98.2%; Column: X-Select CSH C18 (4.6×150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min.

[0625] LCMS: 369.95 (M+H), Rt 2.05min, column: X-select CSH C18 (3×50)mm, 2.5μm.

[0626] 1 H NMR (400MHz, 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).

[0627] Example 24. Synthesis of compound I-26

[0628]

[0629] DIPEA (0.26 mL, 1.49 mmol) and HATU (340.2 mg, 0.89 mmol) were added 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) at room temperature, and the mixture was stirred for 5 hours at room temperature. The reaction mixture was quenched with water (10 mL) and diluted with DCM (10 mL). The organic layer was washed with a brine solution (15 mL), dried over (Na2SO4) and evaporated to give the crude product. The crude product was purified by preparative HPLC to give I-26 as a solid (75 mg, 0.25 mmol, 36% yield).

[0630] HPLC: Rt 9.40 mi, 98.4%; Column: X-Select CSH C18 (4.6 × 150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min.

[0631] LCMS: 344 (M+H), Rt 2.17min, column: X-select CSH C18 (3×50)mm, 2.5μm.

[0632] 1H NMR (400MHz, 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).

[0633] Chiral method: Rt 3.20 min, 95%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH 3. Gradient: 10-40% B for 5 min, maintain 40% B for 9 min; 40-10% B for 10 min, maintain 10% B for 12 min. Wavelength: 280 nm; Flow rate: 3 mL / min.

[0634] Example 25. Synthesis of compound I-27

[0635]

[0636] Synthesis of IA-26b: At room temperature, 10 mL of DMF containing sodium methanethiol (1.26 g, 18.01 mmol) was added to IA-26a (2 g, 9.01 mmol), and the reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was quenched with water (100 mL) and diluted with EtOAc (100 mL × 2). The organic layer was separated, dried over Na₂SO₄, filtered, and evaporated to obtain the crude product. The crude product was purified by column chromatography using 100–200 silica gel and 10–40% EtOAc / hexane as eluent to give IA-26b as a solid (0.70 g, 3.66 mmol, 40% yield).

[0637] Synthesis of IA-26c: At room temperature, 30% aqueous H₂O₂ (0.6 mL, 0.01 mmol) was added 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), and the reaction mixture was stirred for 10 min. The reaction mixture was quenched with water (100 mL) and diluted with EtOAc (100 mL × 2). The organic layer was separated, dried over Na₂SO₄, filtered, and evaporated to give the crude product. The crude product was purified by column chromatography using 100–200 silica gel and 10–40% EtOAc / hexane as eluent to give IA-26c as a solid (0.50 g, 2.24 mmol, 84% yield).

[0638] Synthesis of IA-26d: LiOH·H₂O (114.3 mg, 2.72 mmol) was added to a stirred solution of IA-26c (0.5 g, 2.27 mmol) in THF:water (10:5 mL) at room temperature, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched with water (50 mL) and diluted with EtOAc (100 mL × 2). The aqueous layer was separated. The aqueous layer was acidified with 1 N HCl. The resulting precipitate was filtered and dried under high vacuum to give IA-26d as a solid (0.30 g, 1.36 mmol, 60% yield).

[0639] Synthesis of I-27: HATU (275.22 mg, 0.72 mmol) was added 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), followed by the addition of DIPEA (0.17 mL, 0.97 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL) and DCM (100 mL × 2). The organic layers were separated, dried over Na₂SO₄, filtered, and concentrated to give the crude product. The crude product was then purified by column chromatography using 100–200 silica gel and 30–80% EtOAc / hexane as eluent to give I-27 as a solid (85.1 mg, 0.23 mmol, 49% yield).

[0640] HPLC: Rt 8.34 min, 99.7%; Column: X-Select CSH C18 (4.6×150) mm, 3.5 μm; Mobile phase: A-0.1% FA aqueous solution: acetonitrile (95:05), B: acetonitrile; Flow rate: 1.0 mL / min.

[0641] LCMS: 356.85 (M+H), Rt 2.01min, column: X-select CSH C18 (3.0×50)mm, 2.5μm.

[0642] 1 H NMR (400MHz, DMSO-d6): 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.

[0643] Example 26. Synthesis of compounds I-28 and I-29

[0644]

[0645] Synthesis of IA-27b: HATU (1225.3 mg, 3.22 mmol) and DIPEA (0.75 mL, 4.3 mmol) were added 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) at room temperature. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was quenched with water (100 mL) and diluted with DCM (100 mL × 2). The combined organic layers were separated, dried over Na₂SO₄, filtered, and evaporated to give a crude product, which was purified by column chromatography using 100-200 silica gel and 30-80% EtOAc / hexane eluent to give IA-27b as a solid (600 mg, 1.71 mmol, 80% yield).

[0646] Synthesis of IA-27c: LiOH·H₂O (74.97 mg, 1.79 mmol) was added to a solution of IA-27b (500 mg, 1.49 mmol) in THF:water (10:5 mL) at room temperature and stirred for 2 hours. The reaction mixture was quenched with water (100 mL) and diluted with EtOAc (50 mL × 2). The combined organic layers were separated and acidified with 1N HCl, resulting in a precipitation. The precipitate was filtered, separated, and dried to give IA-27c as a solid (0.40 g, 1.21 mmol, 81% yield).

[0647] Synthesis of I-28: HATU (177.25 mg, 0.47 mmol) and DIPEA (0.11 mL, 0.62 mmol) were added to a stirred solution of IA-27c (100 mg, 0.31 mmol) in DCM (10 mL) and methylamine in THF (2 M) (0.2 mL, 0.37 mmol) at room temperature and stirred for 2 hours. The reaction mixture was quenched with water (100 mL) and diluted with DCM (100 mL × 2). The combined organic layers were separated, dried over Na₂SO₄, filtered, and evaporated under reduced pressure to give a crude product, which was purified by column chromatography using 100-200 silica gel and 30-80% EtOAc / hexane eluent to give I-28 as a solid (44.1 mg, 0.13 mmol, 42% yield).

[0648] HPLC: Rt 7.84 min, 99.5%; Column: X-select CSH C18 (4.6 × 150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0649] LCMS: 335.15(M+H), Rt 1.95min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0650] 1 H NMR (400MHz, 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).

[0651] Chiral method: Rt 7.28 μm, 98.7%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH 3. Gradient: 20-40% B for 5 min, maintain 40% B for 9 min, maintain 20% B for 12 min. Wavelength: 280 nm, Flow rate: 3 mL / min.

[0652] Synthesis of I-29: HATU (177.25 mg, 0.47 mmol) and DIPEA (0.11 mL, 0.62 mmol) were added to a stirred solution of IA-27c (100 mg, 0.31 mmol) and dimethylamine in THF (2 M) (0.2 mL, 0.37 mmol) and DCM (10 mL) at room temperature, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched with water (100 mL) and diluted with DCM (100 mL × 2). The combined organic layers were separated, dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography using 100–200 silica gel and 30–80% EtOAc / hexane eluent to give I-29 as a solid (65.2 mg, 0.18 mmol, 59% yield).

[0653] HPLC: Rt 7.98 min, 98.7%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0654] LCMS: 348.95 (M+H), Rt 2.01min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0655] 1 H NMR (400MHz, 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).

[0656] Chiral method: Rt 6.35 min, 98.4%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH3, gradient: 35-50% B for 5 min, hold at 50% B for 9 min, 50-35% B for 10 min, hold at 10% B for 12 min. Wavelength: 280 nm, flow rate: 3 mL / min.

[0657] Example 27. Synthesis of compounds I-30 and I-31

[0658]

[0659] DIPEA (0.24 mL, 1.39 mmol) and HATU (318.04 mg, 0.84 mmol) were added 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) at 0 °C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (15 mL) and diluted with DCM (30 mL). The aqueous layer was washed with (2 × 30 mL) DCM. The organic layer was washed with a saline solution (20 mL), dried over Na2SO4, and evaporated to give the crude product. The crude product was purified by rapid column chromatography using 100-200 silica gel and 25% EtOAc / hexane as eluent. The desired fractions were evaporated, and the racemic compound IA-28a was purified by chiral SFC chromatography (where the mobile phase was (A) CO2, B) MeOH + NH3, gradient: 25-50% B for 5 min, hold at 50% B for 9 min, 50-25% B for 10 min, hold at 25% B for 12 min. Column: DAIEL CHIRALPAK-IG (250 × 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.

[0660] I-30: HPLC: Rt 7.74 min, 99.5%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% FA aqueous solution: acetonitrile (95:05), B: ACN; Flow rate: 1.0 mL / min

[0661] LCMS: 335.10(M+H), Rt 1.95min, column: X-select CSH (3×50)mm, 2.5μm

[0662] 1 H NMR (400MHz, DMSO-d6): 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).

[0663] 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 aqueous solution: acetonitrile (95:05), B: ACN; Flow rate: 1.0 mL / min

[0664] LCMS: 335.10 (M+H), Rt 1.97min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0665] 1 H NMR (400MHz, 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).

[0666] Example 28. Synthesis of compounds I-32 and I-33

[0667]

[0668] DIPEA (0.5 mL, 2.9 mmol) and HATU (660 mg, 1.74 mmol) were added to a stirred solution of IA-23a (260 mg, 1.45 mmol) and 5-aminosulfonylthiophene-2-carboxylic acid (300 mg, 1.45 mmol) in DCM (20 mL) at room temperature, and the mixture was stirred for 6 hours at room temperature. The reaction mixture was quenched with water (10 mL) and diluted with DCM (10 mL). The organic layer was washed with a saline solution (15 mL), dried over MgSO4, and evaporated to give the crude product. The crude product was purified by rapid column chromatography using 100-200 silica gel and 50% EtOAc / hexane as eluent. The desired fractions were evaporated, and the racemic compound IA-29a was purified by chiral SFC chromatography (with mobile phases: A) CO2, B) MeOH + NH3, gradient: 25-50% B for 5 min, hold at 50% B for 9 min, 50-25% B for 10 min, hold at 25% B for 12 min. Column: DAIEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm). Wavelength: 263 nm. Flow rate: 3 mL / min. The purification yielded 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.

[0669] I-32: HPLC: Rt 8.15 min, 96.3%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% FA aqueous solution: acetonitrile (95:05), B: ACN; Flow rate: 1.0 mL / min

[0670] LCMS: 371.05 (M+H), Rt 2.05min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0671] 1 H NMR (400MHz, 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).

[0672] Chiral method: Rt 9.36 min, 100%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH3, gradient: 35-50% B for 5 min, hold at 50% B for 9 min, 50-35% B for 10 min, hold at 35% B for 12 min. Wavelength: 270 nm, flow rate: 3 mL / min.

[0673] I-33: HPLC: Rt 8.27 min, 99.6%; Column: X-select CSH C18 (4.6 × 150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: acetonitrile (95:05), B: ACN; Flow rate: 1.0 mL / min

[0674] LCMS: 371.05 (M+H), Rt 2.05min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0675] 1 H NMR (400MHz, DMSO-d6): 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).

[0676] Chiral method: Rt 10.64 min, 99.5%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH3, gradient: 35-50% B for 5 min, hold at 50% B for 9 min, 50-35% B for 10 min, hold at 35% B for 12 min. Wavelength: 270 nm, flow rate: 3 mL / min.

[0677] Example 29. Synthesis of compound I-34

[0678]

[0679] Synthesis of IA-30b: 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 to a stirred solution of IA-19a (1 g, 4.52 mmol) in DMSO (10 mL) at room temperature, and the mixture was 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 Na₂SO₄ and evaporated to obtain the crude compound. The crude compound was purified by column chromatography in 100–200 silica gel with 8–10% EtOAc / hexane eluent to give IA-30b as a solid (300 mg, 1.21 mmol, 26% yield).

[0680] Synthesis of IA-30c: At 0 °C, 1 mL of water containing sodium hydroxide (46 mg, 1.92 mmol) was added to a stirred solution of IA-30b (300 mg, 1.28 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give a crude product. The crude product was diluted with cold water (10 mL), acidified to pH 4 with 2N HCl aqueous solution, and extracted with DCM (3 × 15 mL). The combined organic layers were separated and dried over Na2SO4 to give IA-30c as a solid (220 mg, 0.60 mmol, 46% yield).

[0681] Synthesis of I-34: HATU (207.14 mg, 0.54 mmol) was added 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), followed by the addition of DIPEA (0.16 mL, 0.91 mmol) at 0 °C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (5 × 25 mL). The combined organic layers were separated, dried over Na₂SO₄, and evaporated to give the crude product. The crude product was purified by column chromatography using 100-200 mesh silica gel and 20-22% EtOAc / hexane as eluent to give I-34 as a solid (130 mg, 0.34 mmol, 77% yield).

[0682] HPLC: Rt 9.01 min, 99.5%; Column: X-select CSH C18 (4.6 × 150) mm, 5 μm; Mobile phase: A: 10 mM ammonium bicarbonate aqueous solution, B: ACN; Flow rate: 1.0 mL / min

[0683] LCMS: 369.80 (M+H), Rt 1.97min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0684] 1 H NMR (400MHz, DMSO-d6): 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).

[0685] Chiral method: Rt 6.00 min, 98.9%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH3, gradient: 35-50% B for 5 min, hold at 50% B for 9 min, 50-35% B for 10 min, hold at 35% B for 12 min. Wavelength: 261 nm, flow rate: 3 mL / min.

[0686] Example 30. Synthesis of compound I-35

[0687]

[0688] Synthesis of IA-31b: NBS (1.25 g, 7.04 mmol) and methyl peroxide (0.16 g, 0.64 mmol) were added to a stirred solution of IA-31a (1 g, 6.4 mmol) in chloroform (10 mL) at room temperature, and the mixture was stirred at 70 °C for 7 h. The reaction mixture was then cooled to room temperature and diluted with DCM (20 mL), and washed with water (2 × 20 mL) and brine (20 mL). The organic layer was dried over Na₂SO₄ and evaporated to give the crude product. The crude product was purified by column chromatography using 100-200 silica gel and 1-2% EtOAc / hexane as eluent to give IA-31b as a solid (0.50 g, 1.94 mmol, 30% yield).

[0689] Synthesis of IA-31c: Sodium methanesulfinate (156.33 mg, 1.53 mmol) and tetrabutylammonium iodide (94.27 mg, 0.26 mmol) were added to a stirred solution of IA-31b (300 mg, 1.28 mmol) in DMF (10 mL) at room temperature, and the mixture was stirred for 16 hours. After completion, the reaction mixture was quenched with 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 Na₂SO₄ and evaporated to give the crude product. The crude product was purified by column chromatography using 100-200 silica gel and 4-5% EtOAc / hexane as eluent to give IA-31c as a solid (250 mg, 1.06 mmol, 83% yield).

[0690] Synthesis of IA-31d: Water (1 mL) containing LiOH·H₂O (161.18 mg, 3.84 mmol) was added to a stirred solution of IA-31c (300 mg, 1.28 mmol) in THF (9 mL) at room temperature, and the mixture was stirred for 16 hours 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 with 6 M HCl, then stirred at room temperature for 30 minutes, resulting in precipitation. The obtained solid was filtered and dried to give IA-31d as a solid (250 mg, 1.06 mmol, 82% yield).

[0691] Synthesis of I-35: 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 to a stirred solution of IA-31d (100 mg, 0.45 mmol) in DCM (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM and washed with water (10 mL × 2). The organic layer was separated, dried over Na₂SO₄, and evaporated to obtain the crude product. The crude product was purified by column chromatography using 100-200 silica gel and 25% EtOAc / hexane as eluent to give I-35 as a solid (55 mg, 0.14 mmol, 31% yield).

[0692] HPLC: Rt 8.07 min, 99.7%; Column: X-select CSH C18 (4.6 × 150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0693] LCMS: 370.05 (M+H), Rt 1.87min, column: X-select CSH C18 (3.0×50)mm, 2.5μm

[0694] 1 H NMR (400MHz, 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).

[0695] Chiral method: Rt 5.19 min, 97.3%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH3, gradient: 35-50% B for 5 min, hold at 50% B for 9 min, 50-35% B for 10 min, hold at 35% B for 12 min. Wavelength: 272 nm, flow rate: 3 mL / min.

[0696] Example 31. Synthesis of compound I-36

[0697]

[0698] Synthesis of IA-32a: NaOMe (183.82 mg, 3.4 mmol) was added to a stirred solution of IA-31b (400 mg, 1.7 mmol) in methanol (5 mL) at room temperature, and the mixture was stirred for 16 hours. 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 subjected to Na₂SO₄... 4干燥 The crude product was obtained by evaporation. The crude product was purified by column chromatography using 100-200 silica gel and 2-3% EtOAc / hexane eluent to give IA-32a in liquid form (120 mg, 0.59 mmol, 35% yield).

[0699] Synthesis of IA-32b: Water (0.50 mL) containing LiOH·H₂O (81.11 mg, 1.93 mmol) was added to a stirred solution of IA-32a (120 mg, 0.64 mmol) in THF (5 mL), and the mixture was stirred for 16 hours. 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 minutes. The solid was filtered and dried to give IA-32b (65 mg, 0.36 mmol, 57% yield).

[0700] Synthesis of I-36: 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 to a stirred solution of IA-32b (60 mg, 0.35 mmol) in DCM (2 mL) at room temperature, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with DCM and washed with water (10 mL × 2). The organic layer was separated, dried over Na₂SO₄, and evaporated to obtain the crude product. The crude product was purified by column chromatography using 100-200 silica gel and 25% EtOAc / hexane as eluent to give I-36 as a solid (30 mg, 0.09 mmol, 25% yield).

[0701] HPLC: Rt 8.85 min, 96.0%; Column: X-select CSH C18 (4.6×150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0702] LCMS: 321.9(M+H), Rt 1.94min, column: X-select CSH C18 (3.0×50)mm, 2.5μm

[0703] 1 H NMR (400MHz, 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).

[0704] Chiral method: Rt 7.03 min, 96.1%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH3, gradient: 10-40% B within 5 min, hold at 40% B for 9 min, 40%-10% B at 10 min, hold at 10% B for 12 min. Wavelength: 264 nm, flow rate: 3 mL / min.

[0705] Example 32. Synthesis of compound I-37

[0706]

[0707] Synthesis of IA-33b: 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 to a cooled solution of IA-33a (500 mg, 2.4 mmol) in DCM (10 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with DCM (10 mL, × 3 times), and the combined organic layers were dried over sodium sulfate and evaporated to give a crude product. The crude product was purified by column chromatography using silica gel (100-200) and MeOH:DCM (1:99) as eluent to give IA-33b as a solid (380 mg, 1.06 mmol, 44% yield).

[0708] Synthesis of IA-33c: K₂CO₃ (440.45 mg, 3.19 mmol) and (4-methoxyphenyl)methanethiol (163.87 mg, 1.06 mmol) were added to a solution of IA-33b (380 mg, 1.06 mmol) in DMF (5 mL) at room temperature, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with water and brine. The organic layers were dried over sodium sulfate and evaporated to give a crude product, which was purified by Ombi-flash chromatography using ethyl acetate:hexane as eluent to give IA-33c as a solid (210 mg, 0.45 mmol, 43% yield).

[0709] Synthesis of IA-33e: 1,3-dichloro-5,5-dimethylhydantoin (191.99 mg, 0.97 mmol) was added 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) at 0 °C, and the mixture was stirred at 0 °C for 2 hours. The reaction mixture was then stirred at room temperature for 2 hours. 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 a crude product, which was purified by combi-flash chromatography using ethyl acetate:hexane as eluent to give IA-33e as a solid (150 mg, 0.39 mmol, 81% yield).

[0710] Synthesis of I-37: At 0 °C, saturated ammonia-containing DCM was added to a solution of IA-33e (200 mg, 0.530 mmol) in DCM (10 mL). The reaction mixture was then stirred at the same temperature for 30 minutes, followed by stirring for 2 hours. 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 a crude product, which was purified by combi-flash chromatography to give I-37 as a solid (65.1 mg, 0.21 mmol, 39% yield).

[0711] HPLC: Rt 9.26 min, 99.3%; Column: X-Select CSH C18 (4.6 × 150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0712] LCMS: 312.95 (M+H), Rt 2.08min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0713] 1 H NMR (400MHz, 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).

[0714] Chiral method: Rt 6.90 min, 98.0%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH3, gradient: 10-40% B within 5 min, hold 40% B to 9 min, 40%-10% B within 10 min, hold 10% B to 12 min. Wavelength: 263 nm, flow rate: 3 mL / min.

[0715] Example 33. Synthesis of compound I-38

[0716]

[0717] Synthesis of IA-34a: K₂CO₃ (587.75 mg, 4.25 mmol) was added 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) at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were separated, dried over Na₂SO₄, filtered, and evaporated under reduced pressure to give a crude product, which was purified by column chromatography using 100-200 silica gel and 30-80% EtOAc / hexane as eluent to give IA-34a as a solid (0.3 g, 1.2 mmol, 57% yield).

[0718] Synthesis of IA-34b: LIOH·H₂O (63.17 mg, 1.51 mmol) was added to a stirred solution of IA-34a (0.3 g, 1.5 mmol) in THF:water (10:5 mL) at room temperature, and the mixture was stirred for 2 hours. The reaction mixture 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 precipitate was filtered and dried to give IA-34b (0.1 g, 0.48 mmol, 32% yield).

[0719] Synthesis of I-38: HATU (615.79 mg, 1.62 mmol) and DIPEA (0.38 mL, 2.16 mmol) were added 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) at room temperature, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched with water (100 mL) and extracted with DCM (100 mL × 2). The combined organic layers were separated, dried over Na₂SO₄, filtered, and evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography using 100-200 silica gel and 30-80% EtOAc / hexane as eluent to give I-38 (20 mg, 0.06 mmol, 5% yield).

[0720] HPLC: Rt 5.79 min, 99.7%; Column: X-Select CSH C18 (4.6 × 150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0721] LCMS: 334.95 (M+H), Rt 1.46min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0722] 1 H NMR (400MHz, 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).

[0723] Chiral method: Rt 5.98 min, 100%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH3, gradient: 10-40% B within 5 min, hold 40% B to 9 min, 40%-10% B within 10 min, hold 10% B to 12 min. Wavelength: 280 nm, flow rate: 3 mL / min.

[0724] Example 34. Synthesis of compound I-39

[0725]

[0726] Synthesis of IA-35a: At room temperature, a stirred solution of IA-31b (0.5 g, 2.13 mmol) in DMF (10 mL) was added to THF (132.11 mg, 4.25 mmol) containing 1 M methylamine and K₂CO₃ (587.75 mg, 4.25 mmol), and the mixture was stirred for 2 hours. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 2). The organic layers were separated, dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography using 100–200 silica gel and 30–80% EtOAc / hexane eluent to give IA-35a (0.2 g, 0.86 mmol, 40% yield).

[0727] Synthesis of IA-35b: Sodium acetate (177.13 mg, 2.16 mmol) was added to a stirred solution of IA-35a (0.2 g, 1.08 mmol) in acetic anhydride (10 mL) at room temperature, and the mixture was stirred at 50 °C for 12 h. The reaction mixture was quenched with water (100 mL) and diluted with EtOAc (50 mL × 2). The organic layer was separated and dried over sodium sulfate instead of evaporation. The crude substance was purified by column chromatography using 100-200 silica gel and 30-50% EtOAc / hexane as eluent to give IA-35b as a solid (0.15 g, 0.35 mmol, 33% yield).

[0728] Synthesis of IA-35c: LiOH·H₂O (63.17 mg, 1.51 mmol) was added to a stirred solution of IA-35b (0.3 g, 1.51 mmol) in THF:water (10:5 mL) at room temperature, and the mixture was stirred for 2 hours. 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 was then filtered. The solid was separated and dried under high vacuum to give IA-35c (0.1 g, 0.48 mmol, 32% yield).

[0729] Synthesis of I-39: HATU (272.54 mg, 0.72 mmol) and DIPEA (0.17 mL, 0.96 mmol) were added 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) at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was quenched with water (100 mL) and DCM (100 mL × 2). The organic layer was separated, dried over Na₂SO₄, and then filtered. The organic layer was evaporated, and the crude product was purified by column chromatography using 100-200 silica gel and 30-80% EtOAc / hexane as eluent to give I-39 as a solid (75 mg, 0.2 mmol, 43% yield).

[0730] HPLC: Rt 8.14 min, 99.5%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0731] LCMS: 362.95 (M+H), Rt 1.87min, column: X-select CSH C18 (3×50mm, 2.5μm

[0732] 1 H NMR(400MHz,DMSO-d6)(VT at 80℃):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).

[0733] Chiral method: Rt 5.08 min, 99.7%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH3, gradient: 10-40% B within 5 min, hold 40% B to 9 min, 40%-10% B within 10 min, hold 10% B to 12 min. Wavelength: 265 nm, flow rate: 3 mL / min.

[0734] Example 35. Synthesis of compound I-40

[0735]

[0736] Synthesis of IA-36b: DIPEA (1.08 g, 6.23 mmol) and R-(+)-3-pyrrolidone (0.34 mL, 4.15 mmol) were added to a stirred solution of IA-36a (0.5 g, 2.08 mmol) in DCM (5 mL) at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and evaporated to give IA-36b as a liquid (250 mg, 0.86 mmol, 41% yield).

[0737] Synthesis of IA-36c: NaOH (158 mg, 3.96 mmol) was added to a stirred solution of IA-36b (0.4 g, 1.32 mmol) in THF:water (1:1, 3 mL) at room temperature, and the mixture was stirred for 2 hours at room temperature. 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 3N HCl, resulting in a precipitation. The precipitate was filtered, washed with water, and dried to give IA-36c as a solid (220 mg, 0.64 mmol, 49% yield).

[0738] Synthesis of I-40: DIPEA (0.38 mL, 2.16 mmol) and HATU (411.3 mg, 1.08 mmol) were added to a stirred solution of IA-36c (200 mg, 0.72 mmol) and IA-2 (145 mg, 0.87 mmol) in DCM (5 mL) at room temperature, and the mixture was stirred for 16 hours. The reaction mixture was quenched with water (10 mL) and diluted with EtOAc (20 mL). The organic layer was washed with a brine solution (15 mL), dried over (Na2SO4) and evaporated to give the crude product. The crude product was purified by preparative HPLC to give I-40 as a solid (40 mg, 0.09 mmol, 13% yield).

[0739] HPLC: Rt 8.30 min, 96.6%; Column: X-Select CSH C18 (4.6 × 150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0740] LCMS: 427.15 (M+H), Rt 1.89min, column: X-select CSH C18 (3×50mm, 2.5μm

[0741] 1 H NMR (400MHz, 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).

[0742] Chiral method: Rt 5.80 min, 99.5%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH3, gradient: 35-50% B for 5 min, hold at 50% B for 9 min, 50-35% B for 10 min, hold at 35% B for 12 min. Wavelength: 273 nm, flow rate: 3 mL / min.

[0743] Example 36. Synthesis of compound I-41

[0744]

[0745] Synthesis of IA-37a: DIPEA (1.08 g, 6.23 mmol) and S-(+)-3-pyrrolidone (0.34 mL, 4.15 mmol) were added to a stirred solution of IA-36a (0.5 g, 2.08 mmol) in DCM (10 mL) at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and evaporated to give IA-37a as a liquid (300 mg, 1.03 mmol, 49% yield).

[0746] Synthesis of IA-37b: NaOH (126 mg, 3.15 mmol) was added to a stirred solution of IA-37a (0.3 g, 1.05 mmol) in THF:water (1:1, 6 mL) at room temperature, and the mixture was stirred for 2 hours. 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 3N HCl, resulting in a precipitation. The precipitate was filtered, washed with water, and dried to give IA-37b as a solid (200 mg, 0.52 mmol, 49% yield).

[0747] Synthesis of I-41: DIPEA (0.38 mL, 2.16 mmol) and HATU (411.3 mg, 1.08 mmol) were added 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) at room temperature, and the mixture was stirred for 16 hours. The reaction mixture was quenched with water (10 mL) and diluted with EtOAc (20 mL). The organic layer was washed with a brine solution (15 mL), dried over (Na2SO4) and evaporated to give the crude product. The crude product was purified by preparative HPLC to give I-41 as a solid (32 mg, 0.07 mmol, yield 10%).

[0748] HPLC: Rt 8.29 min, 98.7%; Column: X-Select CSH C18 (4.6 × 150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0749] LCMS: 427(M+H), Rt 1.89min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0750] 1 H NMR (400MHz, 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).

[0751] Chiral method: Rt 5.86 min, 99.6%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH3, gradient: 35-50% B for 5 min, hold at 50% B for 9 min, 50-35% B for 10 min, hold at 35% B for 12 min. Wavelength: 273 nm, flow rate: 3 mL / min.

[0752] Example 37. Synthesis of compound I-42

[0753]

[0754] Synthesis of IA-36a: Chlorothiosulfonic acid (12.24 g, 105.5 mmol) was added dropwise to a stirred solution of IA-38a (10 g, 70.3 mmol) in chloroform (100 mL) 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 fractional 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 mixture was extracted with DCM (3 × 250 mL). The combined organic phases were 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 gel, 2-5% EtOAc / hexane as eluent) to obtain IA-36a (12 g, 48.86 mmol, 69% yield) as an oil.

[0755] Synthesis of IA-38c: DIPEA (0.72 mL, 4.15 mmol) and 1-methylpiperazine (0.28 mL, 2.49 mmol) were added to a stirred solution of IA-36a (0.5 g, 2.08 mmol) in DCM (5 mL), and the reaction mixture was stirred at room temperature for 16 hours. 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 a crude product, which was purified by combi-flash chromatography using ethyl acetate:hexane as eluent to give IA-38c (300 mg, 0.88 mmol, 42% yield) as an oil.

[0756] Synthesis of IA-38d: A solution of LiOH·H₂O (82.71 mg, 1.97 mmol) in water (1 mL) was added to a stirred solution of IA-38c (300 mg, 0.99 mmol) in THF (5 mL) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated, and the residue was diluted with water and acidified with 2N HCl. The aqueous layer was then evaporated to give IA-38d as a solid (180 mg, 0.57 mmol, 58% yield), which was used directly in the next step.

[0757] Synthesis of I-42: DIPEA (0.21 mL, 1.19 mmol) and HATU (272.8 mg, 0.72 mmol) were added 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) at 0 °C, and the mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (10 mL) and diluted with DCM (20 mL). The aqueous layer was washed with DCM (20 mL). The combined organic layers were washed with a brine solution, dried over Na2SO4 and evaporated to give the crude product. The crude product was purified by column chromatography using 30% EA / hexane as eluent to give I-42 as a solid (10 mg, 0.02 mmol, 3.6% yield).

[0758] HPLC: Rt 6.27 min, 95.9%; Column: X-Select CSH C18 (4.6 × 150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0759] LCMS: 440 (M+H), Rt 1.43min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0760] 1 H NMR (400MHz, 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).

[0761] Chiral method: Rt 7.87 min, 97.5%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH3, gradient: 35-50% B for 5 min, hold at 50% B for 9 min, 50-35% B for 10 min, hold at 35% B for 12 min. Wavelength: 272 nm, flow rate: 3 mL / min.

[0762] Example 38. Synthesis of compound I-43

[0763]

[0764] Synthesis of IA-39a: DIPEA (0.72 mL, 4.15 mmol) and (3S)-3-methoxypyrrolidine (0.25 g, 2.49 mmol) were added to a stirred solution of IA-36a (0.5 g, 2.08 mmol) in DCM (5 mL) at 0 °C, and the mixture was 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 Na2SO4, filtered, and evaporated to give a crude product, which was purified by combi-flash chromatography using ethyl acetate:hexane as eluent to give IA-39a (300 mg, 1.88 mmol, 42% yield).

[0765] Synthesis of I-A39b: Water (1 mL) containing LiOH·H2O (82.44 mg, 1.96 mmol) was added to a stirred solution of IA-39a (0.3 g, 0.98 mmol) in THF (3 mL) at 0 °C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then evaporated to give a residue, which was dissolved in water and acidified with 2N HCl. The obtained solid was filtered and dried to give IA-39b as a solid (250 mg, 0.7870 mmol, 80% yield), which was used in the next step.

[0766] Synthesis of I-43: DIPEA (0.21 mL, 1.19 mmol) and HATU (272 mg, 0.72 mmol) were added to a stirred solution of IA-39b (208 mg, 0.72 mmol) and IA-2 (100 mg, 0.6 mmol) in DCM (10 mL) at 0 °C, and the mixture was 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 a brine solution, dried over Na2SO4, and evaporated to give the crude product. The crude product was purified by column chromatography using 100-200 mesh silica gel and 40% EA / hexane as eluent to give I-43 as a solid (66 mg, 0.15 mmol, 25% yield).

[0767] HPLC: Rt 8.95 min, 99.8%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0768] LCMS: 441.05 (M+H), Rt 2.01min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0769] 1 H NMR (400MHz, 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).

[0770] Chiral method: Rt 5.82 min, 98.6%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH3, gradient: 35-50% B for 5 min, hold at 50% B for 9 min, 50-35% B for 10 min, hold at 35% B for 12 min. Wavelength: 273 nm, flow rate: 3 mL / min.

[0771] Example 39. Synthesis of compound I-44

[0772]

[0773] Synthesis of IA-40a: NaN3 (0.55 g, 8.51 mmol) was added to a stirred solution of IA-31b (1 g, 4.25 mmol) in ACN (10 mL) at room temperature, and the reaction mixture was stirred at 90 °C for 1 hour. The reaction mixture was evaporated, treated in portions with acetic acid (5 mL) and Zn dust (556.27 mg, 8.51 mmol), and stirred at room temperature for 3 hours. The reaction mixture was filtered through diatomaceous earth, diluted with 1 N HCl, and the aqueous layer was treated with ethyl acetate (30 mL). The aqueous layer was alkalized with NaHCO3 and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and evaporated to give IA-40a as an oil (400 mg, 2.3 mmol, 54% yield).

[0774] Synthesis of IA-40b: Acetyl chloride (0.25 mL, 3.5 mmol) and DIPEA (0.92 mL, 5.26 mmol) were added to a stirred solution of IA-40a (0.5 g, 2.41 mmol) in DCM (10 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated to give IA-40b as a solid (300 mg, 1.4 mmol, 80% yield).

[0775] Synthesis of IA-40c: NaOH (56.3 g, 1.41 mmol) was added to a stirred solution of IA-40b (0.3 g, 1.41 mmol) in THF:water (1:1), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated, and the crude product was diluted with water and treated with ethyl acetate. The aqueous layer was acidified with 2N HCl until pH = 2, and the product was extracted with ethyl acetate, dried over Na2SO4, filtered, and evaporated to give IA-40c as a solid (160 mg, 0.8 mmol, 57% yield).

[0776] Synthesis of I-44: DIPEA (0.31 mL, 1.79 mmol) and HATU (340.22 mg, 0.89 mmol) were added to a stirred solution of IA-2 (100 mg, 0.6 mmol) and IA-40c (119 mg, 0.6 mmol) in DCM (5 mL) at room temperature, and the mixture was stirred for 16 hours at room temperature. The mixture was diluted with water and extracted with DCM. The organic layer was dried over Na2SO4, filtered off, and concentrated to give the crude product. The crude product was purified by column chromatography using 5% MeOH / DCM as eluent to give I-44 as a solid (44 mg, 0.12 mmol, 20.5% yield).

[0777] HPLC: Rt 7.49 min, 97%; Column: X-Select CSH C18 (4.6 × 150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0778] LCMS: 349(M+H), Rt 1.82min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0779] 1 H NMR (400MHz, 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).

[0780] Chiral method: Rt 6.84 min, 99.3%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH3, gradient: 10-40% B within 5 min, hold 40% B to 9 min, 40%-10% B within 10 min, hold 20% B to 12 min. Wavelength: 272 nm, flow rate: 3 mL / min.

[0781] Example 40. Synthesis of compound I-45

[0782]

[0783] Synthesis of IA-41a: DIPEA (0.72 mL, 4.15 mmol) and morpholine (217.2 mg, 2.49 mmol) were added to a stirred solution of IA-36a (0.5 g, 2.08 mmol) in DCM (5 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 6 hours. 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 a crude product, which was purified by combi-flash chromatography using ethyl acetate:hexane as eluent to give IA-41a (400 mg, 1.15 mmol, 55% yield).

[0784] Synthesis of IA-41b: A solution of LiOH·H₂O (144 mg, 3.43 mmol) was added to a stirred solution of IA-41a (300 mg, 0.99 mmol) in THF:water (1:1, 10 mL) at 0 °C, and the temperature was gradually increased to room temperature. The reactants were concentrated to dryness, and the residue was dissolved in EtOAc. The organic layer was washed with 2 × mL of water, followed by washing with 1 × mL of saturated salt solution. The organic matter was then separated and dried over MgSO₄, followed by concentration to dryness. The crude product was then purified by rapid column chromatography using EtOAc / isohexane as the eluent. The desired fraction was concentrated to dryness under vacuum to give IA-41b (320 mg, 67%) as an oil.

[0785] Synthesis of I-45: DIPEA (0.11 mL, 0.65 mmol) and HATU (148 mg, 0.39 mmol) were added to a stirred solution of IA-41b (90 mg, 0.32 mmol) and IA-2 (90 mg, 0.32 mmol) in DCM (10 mL) at 0 °C, and the mixture was 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 a brine solution, dried over Na2SO4, and evaporated to give the crude product. The crude product was purified by column chromatography using 35% EA / hexane as eluent to give I-45 as a solid (10 mg, 0.023 mmol, 7.13% yield).

[0786] HPLC: Rt 8.93 min, 98.8%; Column: X-Select CSH C18 (4.6 × 150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0787] LCMS: 427.20 (M+H), Rt 2.18min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0788] 1 H NMR (400MHz, 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).

[0789] Chiral method: Rt 9.00 min, 100%; SFC column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) CO2, B) MeOH + 0.1% NH3, gradient: 35-50% B for 5 min, hold at 50% B for 9 min, 50-35% B for 10 min, hold at 35% B for 12 min. Wavelength: 272 nm, flow rate: 3 mL / min.

[0790] Example 41. Synthesis of compound I-46

[0791]

[0792] Synthesis of IA-42a: DIPEA (0.78 mL, 4.49 mmol) and (3R)-3-methoxypyrrolidine (0.27 g, 2.69 mmol) were added to a stirred solution of IA-36a (0.5 g, 2.25 mmol) in DCM (10 mL) at 0 °C, and the mixture was 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 Na2SO4, filtered, and evaporated to give IA-42a as an oil (500 mg, 1.64 mmol, 50% yield).

[0793] Synthesis of IA-42b: Lithium hydroxide (78.43 mg, 3.27 mmol) was added to a stirred solution of IA-42a (0.5 g, 1.64 mmol) in THF:water (1:1, 10 mL) at 0 °C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then evaporated to give a residue, which was dissolved in water (5 mL) and acidified with 5N HCl (4 mL) to cause precipitation. The precipitate was filtered and dried to give IA-42b as a solid (300 mg, 1.0 mmol, 61% yield), which was used in the next step without further purification.

[0794] Synthesis of I-46: DIPEA (0.12 mL, 0.69 mmol) and HATU (157 mg, 0.41 mmol) were added 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) at 0 °C, and the mixture was 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 a brine solution (10 mL), dried over Na2SO4, and evaporated to give the crude product. The crude product was purified by column chromatography using 100-200 mesh silica gel and 40% EA / hexane as eluent to give I-46 as a solid (30.3 mg, 0.69 mmol, 20% yield).

[0795] HPLC: Rt 8.99 min, 99.9%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0796] LCMS: 441.09 (M+H), Rt 2.02min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0797] 1 H NMR (400MHz, 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).

[0798] Chiral method: Rt 5.33 min, 100%; Column: DIACEL CHIRALPAK-IG (250×4.6 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.

[0799] Example 42. Synthesis of compound I-47

[0800]

[0801] Synthesis of IA-43b: TEA (1.01 g, 7.24 mmol) was added to a stirred solution of IA-43a (0.5 g, 2.41 mmol) in DCM (5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 10 min. 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 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and evaporated to give a crude product, which was purified by rapid column chromatography with 10% EtOAc / hexane as eluent to give IA-43b as a solid (310 mg, 0.78 mmol, 33% yield).

[0802] Synthesis of IA-43c: 2-Methoxyethanethiol (155.03 mg, 1.68 mmol) and DIPEA (0.44 mL, 2.52 mmol) were added to a stirred solution of IA-43b (0.3 g, 0.84 mmol) in 1,4-dioxane (4 mL). The reaction mixture was purged with N2 gas for 20 min, and Pd2(dba)3 (77.05 mg, 0.08 mmol) and DPPF (46.63 mg, 0.08 mmol) were added 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 Na2SO4, filtered, and evaporated to give a crude product, which was purified by ombi-flash and 7% EtOAc / hexane as eluent to give IA-43c as an oil (210 mg, 0.55 mmol, 66% yield).

[0803] Synthesis of I-47: mCPBA (211 mg, 1.22 mmol) was added fractionally to a stirred solution of IA-2 (150 mg, 0.41 mmol) in DCM (5 mL) at room temperature, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL). The organic layer was washed with NaHCO3 (15 mL), dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by preparative HPLC to give I-47 as a solid (11 mg, 0.03 mmol, 7% yield).

[0804] HPLC: Rt 8.49 min, 98.2%; Column: X-Select CSH C18 (4.6 × 150) mm, 5 μm; Mobile phase: A: 0.1% FA aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min

[0805] LCMS: 399.8(M+H), Rt 2.06min, column: X-select CSH C18 (3×50)mm, 2.5μm

[0806] 1 H NMR (400MHz, 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), 1H is merged into the solvent peak.

[0807] Chiral method: Rt 5.29 min, 99%; Column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5 μm), mobile phase: A) n-hexane + 0.1% isopropylamine, B) DCM: MeOH (1:1), isocratic properties: 50% B; wavelength: 265 nm, flow rate: 1.0 mL / min

[0808] Example 43. Synthesis of compounds II-1 and II-2

[0809]

[0810] Synthesis of II-A-1b: 5-Chloroindan-1-amine (280 mg, 1.67 mmol) was added to a mixture of 4-(methanesulfonylamino)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). The resulting mixture was stirred at 20 °C for 2 hours. A saturated NH4Cl solution (50 mL) was added to the solution, and the aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with water (50 mL × 2) and brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0% to 30% to 50%) to give a solid product (400 mg, 1.10 mmol, 79% yield).

[0811] LCMS Rt =0.78 min (in a 1.5 min chromatogram), 5-95AB, C 17 H 18 ClN2O3S[M+H] + The calculated MS ESI value is 365.1, and the experimental value is 365.0.

[0812] Synthesis of II-A-1c: MeI (116.71 mg, 0.82 mmol) was added to a mixture of N-(5-chloroindan-1-yl)-4-(methanesulfonylamino)benzamide (150 mg, 0.41 mmol) and K₂CO₃ (170.47 mg, 1.23 mmol) in DMF (7 mL). The resulting mixture was stirred at 20 °C for 2 hours. A saturated NH₄Cl solution (20 mL) was added, and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (20 mL × 2) and brine (20 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to give the product as a solid (128 mg, 0.34 mmol, 82% yield).

[0813] 1 H NMR (400MHz, 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).

[0814] LCMS R t =0.80 min (in a 1.5 min chromatogram), 5-95AB, C 18 H 20 ClN2O3S[M+H] + The calculated MS ESI value is 379.1, and the experimental value is 379.0.

[0815] Analytical SFC: Chiralcel OJ-3, 100mm × 4.6mm inner diameter, 3μm; mobile phase: A: CO2, B: ethanol (0.05% DEA); gradient: 5% to 40% B over 5 min, holding at 40% B for 2.5 min, followed by 5% B for 2.5 min. Flow rate: 2.8 mL / min; column temperature: 35℃. Peaks were observed at 1.12 min (50%) and 3.02 min (50%).

[0816] Synthesized 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 × 30 mm inner diameter, 10 μm); A = CO2, B = EtOH (0.1% NH3H2O); 38 °C; 80 mL / min; 55% B; 8 min run; 7 injections) to give a solid enantiomer 1 (Rt = 1.12 min) randomly designated as compound II-1 (38.4 mg, 0.1 mmol) and a solid enantiomer 2 (Rt = 3.02 min) randomly designated as compound II-2 (53.3 mg, 0.14 mmol).

[0817] Compound II-1

[0818] 1 H NMR (400MHz, CD3CN)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).

[0819] LCMS R t = 1.08 min (in a 2 min chromatogram), 10⁻⁸ AB, C 18 H 20 ClN2O3S[M+H] + The calculated MS ESI value is 379.1, and the experimental value is 379.0.

[0820] Compound II-2

[0821] 1 H NMR (400MHz, CD3CN)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).

[0822] LCMS R t= 1.06 min (in a 2 min chromatogram), 10⁻⁸ AB, C 18 H 20 ClN2O3S[M+H] + The calculated MS ESI value is 379.1, and the experimental value is 379.0.

[0823] Example 44. Synthesis of compound II-3

[0824]

[0825] Et3N (0.25 mL, 1.79 mmol) and (1S)-5-chloroindan-1-amine (100 mg, 0.60 mmol) were added to a mixture of 4-(methanesulfonylamino)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). The resulting mixture was stirred at 20 °C for 16 hours. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product as a solid (220 mg). The crude product (40 mg) was purified by preparative TLC (silica gel, PE:EtOAc = 1:2) to obtain a solid product (12.2 mg, 33.5 μmol, 31% yield).

[0826] 1 H NMR (400MHz, CD3CN)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).

[0827] LCMS R t = 1.11 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 17 H 18 ClN2O3S[M+H] + The calculated MS ESI value is 365.1, and the experimental value is 364.9.

[0828] Example 45. Synthesis of compound II-4

[0829]

[0830] Et3N (0.17 mL, 1.25 mmol) and (1R)-5-chloroindan-1-amine (70 mg, 0.42 mmol) were added to a mixture of 4-(methanesulfonylamino)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). The resulting mixture was stirred at 20 °C for 16 hours. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0% to 50% to 100%) to give a solid product (109.6 mg, 297.3 μmmol, 71% yield).

[0831] 1 H NMR (400MHz, CD3CN)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).

[0832] LCMS R t =1.10 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 17 H 18 ClN2O3S[M+H] + The calculated MS ESI value is 365.1, and the experimental value is 364.9.

[0833] Example 46. Synthesis of compounds II-5 and II-6

[0834]

[0835] 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 to adjust the pH to 2. The mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product as a solid (270 mg, 1.26 mmol).

[0836] 1 H NMR (400MHz, 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).

[0837] Synthesis of II-A-2c: A mixture of 4-(methylsulfonylmethyl)benzoic acid (138.02 mg, 0.64 mmol) and HOBt (193.46 mg, 1.43 mmol), EDCI (205.83 mg, 1.07 mmol), Et3N (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 under N2 for 16 h. The reactants were quenched with saturated NH4Cl (10 mL) and the mixture was extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a solid product (150 mg, 0.41 mmol).

[0838] LCMS R t =0.79 min (in a 1.5 min chromatogram), 5-95AB, C 18 H 19 ClNO3S[M+H] + The calculated MS ESI value is 364.1, and the experimental value is 363.9.

[0839] Analytical SFC (Chiralpak OJ-3, 150mm × 4.6mm inner diameter, 3μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B over 5 min, holding 40% B for 2.5 min, then 5% B for 2.5 min. Flow rate: 2.8 mL / min, column temperature: 35℃) showed two peaks at 1.23 min and 1.92 min.

[0840] 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 inner diameter, 5 μm); A = CO2 and B = EtOH (0.1% NH3H2O); 38 °C; 60 mL / min; 35% B; 8 min run; 12 injections] to give a solid enantiomer 1 (peak 1 of which was randomly designated as compound 5 (22.26 mg, 61.2 μmol) t=1.23 min) and the enantiomer 2 (peak 2 of R) of compound 6 (27.97 mg, 76.9 μmol) in solid form, randomly designated as compound 6 (27.97 mg, 76.9 μmol). t =1.92min).

[0841] Compound II-5

[0842] 1 H NMR (400MHz, CD3CN)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).

[0843] LCMS R t = 1.03 min (in a 2 min chromatogram), 10⁻⁸ AB, C 18 H 19 ClNO3S[M+H] + The calculated MS ESI value is 364.1, and the experimental value is 364.0.

[0844] Compound II-6

[0845] 1 H NMR (400MHz, CD3CN)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).

[0846] LCMS R t = 1.01 min (in a 2 min chromatogram), 10⁻⁸ AB, C 18 H 19 ClNO3S[M+H] + The calculated MS ESI value is 364.1, and the experimental value is 364.0.

[0847] Example 47. Synthesis of compounds II-7 and II-8

[0848]

[0849] Synthesis of II-A-3b: 5-Chloroindan-1-amine (198.33 mg, 1.18 mmol) was added 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). The resulting mixture was stirred at 20 °C for 2 hours. A saturated aqueous solution of NH4Cl (30 mL) was added, and the aqueous layer was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with water (20 mL × 2) and brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC [Xtimate C18 (150 mm × 25 mm, 5 μm), A = H2O (0.04% NH3H2O ​​+ 10 mM NH4HCO3) and B = CH3CN; 47-77% B over 7 minutes] to obtain a solid product (250 mg, 819.3 μmol, 83% yield).

[0850] LCMS R t =0.84 min (in a 1.5 min chromatogram), 5-95AB, C 17 H 17 ClNO2[M+H] + The calculated MS ESI value is 302.1, and the experimental value is 301.9.

[0851] Analytical SFC: Chiralpak OJ-3, 100mm × 4.6mm inner diameter, 3μm; mobile phase: A: CO2, B: 40% ethanol (0.05% DEA); gradient: 5% to 40% B over 5 min, holding 40% B for 2.5 min, followed by 5% B for 2.5 min. Flow rate: 2.8 mL / min; column temperature: 40℃. Peaks were observed at 0.94 min and 2.18 min.

[0852] Synthesizing 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 = CO2 and B = EtOH (0.1% NH3·H2O); 35 °C; 60 mL / min; 40% B; 13 min run; 9 injections] to give a solid enantiomer 1 (Rt = 0.94 min) randomly designated as compound II-7 (92.5 mg, 306.4 μmol) and a solid enantiomer 2 (Rt = 2.18 min) randomly designated as compound II-8 (87.4 mg, 289.6 μmol).

[0853] Compound II-7

[0854] 1 H NMR (400MHz, 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).

[0855] LCMS R t = 1.13 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 17 H 17 ClNO2[M+H] + The calculated MS ESI value is 302.1, and the experimental value is 301.9.

[0856] Compound II-8

[0857] 1 H NMR (400MHz, 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).

[0858] LCMS R t = 1.11 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C17 H 17 ClNO2[M+H] + The calculated MS ESI value is 302.1, and the experimental value is 301.9.

[0859] Example 48. Synthesis of compounds II-9 and II-16

[0860]

[0861] Synthesis of II-A-4b: A mixture of 4-nitrobenzoic acid (3.99 g, 23.86 mmol) and HOBt (6.45 g, 47.72 mmol), along with Et3N (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 under N2 for 16 h. The reactants were quenched with saturated NH4Cl (50 mL) and the mixture was extracted with DCM (50 mL × 2). The combined organic phases were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a solid product (6941 mg, 19.45 mmol).

[0862] LCMS R t =0.84 min (in a 1.5 min chromatogram), 5-95AB, C 16 H 14 ClN2O3[M+H] + The calculated MS ESI value is 317.1, and the experimental value is 316.9.

[0863] 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 under N2 for 6 hours. The mixture was filtered through diatomaceous earth, and the filter cake was eluted with EtOAc (50 mL × 2). The filtrate was concentrated under reduced pressure. The crude product was diluted with H2O (50 mL), and the aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product as a solid (1260 mg, 4.3 mmol).

[0864] LCMS R t =0.98 min (in a 2 min chromatogram), 10⁻⁸ AB, C 16 H 16 ClN2O[M+H]+ The calculated MS ESI value is 287.1, and the experimental value is 286.9.

[0865] Analytical SFC (Chiralcel OJ-3, 150mm × 4.6mm inner diameter, 3μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B over 5 min, holding 40% B for 2.5 min, then 5% B for 2.5 min. Flow rate: 2.5 mL / min, column temperature: 35℃) showed two peaks at 2.24 min and 4.83 min.

[0866] 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 inner diameter, 5 μm); A = CO2 and B = EtOH (0.1% NH3H2O); 38 °C; 50 mL / min; 45% B; 13 min run, 10 injections) to give solid enantiomer 1 randomly designated as compound II-16 (Rt = 2.26 min, 46.6 mg) and solid enantiomer 2 randomly designated as compound II-9 (Rt = 2.26 min, 46.6 mg) t =4.83 min). Stereochemistry was randomly assigned.

[0867] Compound II-16

[0868] 1 H NMR (400MHz, 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).

[0869] LCMS R t = 1.04 min (in a 2 min chromatogram), 10⁻⁸ AB, C 16 H 16 ClN2O[M+H] + The calculated MS ESI value is 287.1, and the experimental value is 286.9.

[0870] 4-Amino-N-[(1R)-5-chloroindan-1-yl]benzamide (50 mg, 0.17 mmol) (peak 2 of R)t =4.83 min) wet milled from CH2Cl2 / n-hexane (5 mL, 1:5) to give a solid product (45.4 mg, 0.16 mmol). The absolute stereochemistry of compound II-9 was confirmed by X-ray crystallography.

[0871] 1 H NMR (400MHz, 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).

[0872] LCMS R t = 1.03 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 16 H 16 ClN2O[M+H] + The calculated MS ESI value is 287.1, and the experimental value is 286.9.

[0873] Example 49. Synthesis of compound II-10

[0874]

[0875] 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 mixture was quenched with 1N HCl (5 mL) and 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 = H₂O (10 mM NH₄HCO₃) and B = CH₃CN; 32-62% B over 6 min) to give a solid product (64.8 mg, 0.17 mmol, 49% yield).

[0876] 1 H NMR (400MHz, 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).

[0877] LCMS R t = 1.12 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 18 H 20 ClN2O3S[M+H] + The calculated MS ESI value is 379.1, and the experimental value is 378.9.

[0878] Example 50. Synthesis of compound II-11

[0879]

[0880] 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 mixture was quenched with 1 M HCl (5 mL) and 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 = H₂O (10 mM NH₄HCO₃) and B = CH₃CN; 32-62% B over 6.5 min) to give a solid product (71.4 mg, 0.18 mmol, 52% yield).

[0881] 1 H NMR (400MHz, 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).

[0882] LCMS R t = 1.14 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 19 H 20 ClN2O3S[M+H] + The calculated MS ESI value is 391.1, and the experimental value is 390.9.

[0883] Example 51. Synthesis of compound II-12

[0884]

[0885] A mixture of trifluoromethanesulfonyl trifluoromethanesulfonate (177.1 mg, 0.63 mmol), Et3N (0.11 mL, 0.78 mmol), and 4-amino-N-[(1R)-5-chloroindan-1-yl]benzamide (150 mg, 0.52 mmol) in CH2Cl2 (10 mL) was stirred at 15 °C for 16 hours. The reaction mixture was quenched with saturated NH4Cl solution (10 mL). The mixture was extracted with CH2Cl2 (10 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Xbridge BECC18 (250 mm × 50 mm, 10 μm), A = H2O (10 mM NH4HCO3) and B = CH3CN; 25-45% B over 9 min) to give a solid product (17.9 mg, 42.7 μmol, 8% yield).

[0886] 1 H NMR (400MHz, CD3CN)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).

[0887] LCMS R t = 1.21 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 17 H 15 ClF3N2O3S[M+H] + The calculated MS ESI value is 419.0, and the experimental value is 418.8.

[0888] Example 52. Synthesis of compound II-13

[0889]

[0890] A mixture of N-[(1R)-5-chloroindan-1-yl]-4-(ethylsulfonylamino)benzamide (120 mg, 0.32 mmol) and 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 H₂O (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 = H₂O (10 mM NH₄HCO₃) and B = CH₃CN; 38-68% B over 6 min) to give a solid product (86.8 mg, 0.22 mmol, 70% yield).

[0891] 1 H NMR (400MHz, 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).

[0892] LCMS R t = 1.18 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 19 H 22 ClN2O3S[M+H] + The calculated MS ESI value is 393.1, and the experimental value is 392.9.

[0893] Example 53. Synthesis of compound II-14

[0894]

[0895] 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 H₂O (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 = H₂O (10 mM NH₄HCO₃) and B = CH₃CN; 40–70% B over 6 min) to give a solid product (83.3 mg, 0.21 mmol, 57% yield).

[0896] 1 H NMR (400MHz, CD3CN)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).

[0897] LCMS R t = 1.18 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 20 H 22 ClN2O3S[M+H] + The calculated MS ESI value is 405.1, and the experimental value is 404.9.

[0898] Example 54. Synthesis of compound II-15

[0899]

[0900] 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 H₂O (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 = H₂O (0.05% NH₄OH) and B = CH₃CN; 55-85% B over 8 min) to give a solid product (65.9 mg, 0.15 mmol, 25% yield).

[0901] 1 H NMR (400MHz, CD3CN)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).

[0902] LCMS R t = 1.27 min (in a 2 min chromatogram), 10⁻⁸ AB, C 18 H 17 ClF3N2O3S[M+H] + The calculated MS ESI value is 433.1, and the experimental value is 432.8.

[0903] Example 55. Synthesis of compound II-17

[0904]

[0905] 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 under N2 for 72 h. The reaction mixture 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 = H2O (0.05% NH4OH) and B = CH3CN; 37-67% B over 8 min) to give a solid product (35.3 mg, 0.09 mmol, 13% yield).

[0906] 1 H NMR (400MHz, CD3CN)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).

[0907] LCMS R t = 1.02 min (in a 2 min chromatogram), 10⁻⁸ AB, C 18 H 20 ClN2O3S[M+H] + The calculated MS ESI value is 379.1, and the experimental value is 379.0.

[0908] Example 56. Synthesis of compound II-18

[0909]

[0910] 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 stirred at 20 °C under N2 for 72 hours. The reaction mixture 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 wet-milled from hexane and DCM (5:1, 5 mL) to give a product as a solid (49.5 mg, 0.13 mmol, 18% yield).

[0911] 1 H NMR (400MHz, 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).

[0912] LCMS R t = 1.05 min (in a 2 min chromatogram), 10⁻⁸ AB, C 19 H 20 ClN2O3S[M+H] + The calculated MS ESI value is 391.1, and the experimental value is 391.0.

[0913] Example 57. Synthesis of compound II-19

[0914]

[0915] A mixture of N-[(1S)-5-chloroindan-1-yl]-4-(ethylsulfonylamino)benzamide (220 mg, 0.58 mmol), K₂CO₃ (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 H₂O (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 = H₂O (0.05% NH₄OH) and B = CH₃CN; 48-78% B over 8 min) to give a solid product (119.2 mg, 0.31 mmol, 52% yield).

[0916] 1 H NMR (400MHz, CD3CN)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).

[0917] LCMS R t = 1.04 min (in a 2 min chromatogram), 10⁻⁸ AB, C 19 H 22 ClN2O3S[M+H] + The calculated MS ESI value is 393.1, and the experimental value is 393.0.

[0918] Example 58. Synthesis of compound II-20

[0919]

[0920] 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 hours. The mixture was diluted with H₂O (15 mL) and extracted with EtOAc (15 m × 2). The combined organic phases were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated to give a crude product. The crude product was wet-milled from hexane and DCM (5:1, 5 mL) to give a solid product (146.5 mg, 0.36 mmol, 94% yield).

[0921] 1 H NMR (400MHz, CD3CN)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).

[0922] LCMS R t = 1.05 min (in a 2 min chromatogram), 10⁻⁸ AB, C 20 H22 ClN2O3S[M+H] + The calculated MS ESI value is 405.1, and the experimental value is 405.0.

[0923] Example 59. Synthesis of compound II-21

[0924]

[0925] 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 H₂O (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 = H₂O (0.05% NH₄OH) and B = CH₃CN; 55-85% B over 8 min) to give a solid product (65.9 mg, 0.15 mmol, 25% yield).

[0926] 1 H NMR (400MHz, CD3CN)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).

[0927] LCMS R t = 1.27 min (in a 2 min chromatogram), 10⁻⁸ AB, C 18 H 17 ClF3N2O3S[M+H] + The calculated MS ESI value is 433.1, and the experimental value is 432.8.

[0928] Example 60. Synthesis of compound II-22

[0929]

[0930] Add EDCI (114.35 mg, 0.60 mmol) and 4-methylsulfonylbenzoic acid (71.66 mg, 0.36 mmol) to a mixture of (1R)-5-chloroindan-1-amine (50 mg, 0.30 mmol), HOBt (80.61 mg, 0.60 mmol), and Et3N (0.21 mL, 1.49 mmol) in CH2Cl2 (5 mL). Stir the reaction mixture at 15 °C for 16 hours. Dilute the mixture with saturated NH4C solution (5 mL) and extract the aqueous layer with CH2Cl2 (5 mL × 2). Wash the combined organic phases with brine (5 mL), dry to anhydrous Na2SO4, filter, and concentrate. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm) A = H₂O (10 mM NH₄HCO₃) and B = CH₃CN; 32-62% B over 7 min) to give a solid product (13.7 mg, 0.04 mmol, 13% yield).

[0931] 1 H NMR (400MHz, CD3CN)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).

[0932] LCMS R t = 1.12 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 17 H 17 ClNO3S

[0933] [M+H] + The calculated MS ESI value is 350.1, and the experimental value is 349.9.

[0934] Example 61. Synthesis of compound II-23

[0935]

[0936] Synthesis of II-A-6b: A mixture of N-methylmethylamine hydrochloride (500 mg, 6.13 mmol), Et3N (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 NH4Cl (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 Na2SO4, filtered, and concentrated. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 30% to 60%) to give a solid product (1100 mg, 4.70 mmol, 77% yield).

[0937] LCMS R t =0.65 min (in a 1.5 min chromatogram), 5-95AB, C 11 H 13 NO3[M+H] + The calculated MS ESI value is 208.1, and the experimental value is 207.9.

[0938] Synthesis of II-A-7a: A mixture of methyl 4-(dimethylcarbamoyl)benzoate (500 mg, 2.41 mmol) and LiOH·H₂O (202.48 mg, 4.83 mmol) in THF (8 mL) and water (4 mL) was stirred at 15 °C for 3 hours. The mixture was acidified to pH 2 with 1 N HCl. The mixture was diluted with H₂O (10 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were concentrated to give a crude product as a solid (518 mg, 2.45 mmol).

[0939] LCMS R t =0.87 min (in a 2 min chromatogram), 0-60 AB, C 10 H 12 NO3[M+H] + The calculated MS ESI value is 194.1, and the experimental value is 193.8.

[0940] Synthesizing compound II-23: EDCI (120.07 mg, 0.63 mmol) and (1R)-5-chloroindan-1-amine (70 mg, 0.42 mmol) were added to a mixture of 4-(dimethylcarbamoyl)benzoic acid (80.67 mg, 0.42 mmol), HOBt (112.85 mg, 0.84 mmol), and Et3N (0.29 mL, 2.09 mmol) in DCM (5 mL). The reaction mixture was stirred at 15 °C for 16 hours. The reaction mixture was quenched with saturated NH4Cl (20 mL) and 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 = H₂O (0.05% NH₄OH) and B = CH₃CN; 39-69% B over 8 min) to give a solid product (13.7 mg, 0.04 mmol, 10% yield).

[0941] 1 H NMR (400MHz, CD3CN)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).

[0942] LCMS R t = 1.15 min (in a 2 min chromatogram), 10⁻⁸ AB, C 19 H 20 ClN2O2[M+H] + The calculated MS ESI value is 343.1, and the experimental value is 343.0.

[0943] Example 62. Synthesis of compound II-24

[0944]

[0945] Synthesis of II-A-8a: A mixture of methylamine hydrochloride (500 mg, 7.41 mmol), Et3N (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 NH4Cl (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 Na2SO4, filtered, and concentrated. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 30% to 60%) to give a solid product (712 mg, 3.69 mmol, 50% yield).

[0946] LCMS R t =0.60 min (in a 1.5 min chromatogram), 5-95AB, C 10 H 12 NO3[M+H] + The calculated MS ESI value is 194.1, and the experimental value is 193.9.

[0947] Synthesis of II-A-9a: A mixture of methyl 4-(methylcarbamoyl)benzoate (500 mg, 2.59 mmol) and LiOH·H₂O (217.18 mg, 5.18 mmol) in THF (4 mL) and water (2 mL) was stirred at 15 °C for 3 h. The mixture was acidified with 1 N HCl (5 mL) and diluted with H₂O (10 mL). The aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were concentrated to give a crude product as a solid (606 mg, 3.38 mmol).

[0948] LCMS R t = 0.81 min (in a 2 min chromatogram), 0-60AB, C9H9NO3[M+H + The calculated MS ESI value is 180.1, and the experimental value is 179.9.

[0949] Synthesis II-24: EDCI (171.53 mg, 0.89 mmol) and 4-(methylcarbamoyl)benzoic acid (106.88 mg, 0.6 mmol) were added to a mixture of (1R)-5-chloroindan-1-amine (100 mg, 0.6 mmol), HOBt (161.21 mg, 1.19 mmol), and Et3N (0.41 mL, 2.98 mmol) in DCM (5 mL). The reaction mixture was stirred at 15 °C for 16 h. The reaction mixture was quenched with saturated NH4Cl (20 mL) and 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 = H₂O (0.05% NH₄OH) and B = CH₃CN; 35-65% B over 8 min) to give a solid product (8.8 mg, 0.03 mmol, 4% yield).

[0950] 1 H NMR (400MHz, 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).

[0951] LCMS R t = 1.09 min (in a 2 min chromatogram), 10⁻⁸ AB, C 18 H 18 ClN2O2[M+H] + The calculated MS ESI value is 329.1, and the experimental value is also 329.1.

[0952] Example 63. Synthesis of compound II-25

[0953]

[0954] EDCI (114.35 mg, 0.60 mmol) and (1R)-5-chloroindan-1-amine (50 mg, 0.30 mmol) were added to a mixture of 4-aminosulfonylbenzoic acid (72.01 mg, 0.36 mmol), HOBt (80.61 mg, 0.60 mmol), and Et3N (0.21 mL, 1.49 mmol) in CH2Cl2 (3 mL). The reaction mixture was stirred at 35 °C for 16 hours. The mixture was diluted with saturated NH4Cl (5 mL) and 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 (Xtimate C18 (150 mm × 25 mm, 5 μm), A = H2O (10 mM NH4HCO3) and B = CH3CN; 40-50% B over 9 minutes) to give a solid product (20.6 mg, 58.6 μmol, 20% yield).

[0955] 1 H NMR (400MHz, CD3CN)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).

[0956] LCMS R t = 1.11 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 16 H 16 ClN2O3S[M+H] + The calculated MS ESI value is 351.0, and the experimental value is 351.1.

[0957] Example 64. Synthesis of compound II-26

[0958]

[0959] (1R)-5-chloroindan-1-amine (70 mg, 0.42 mmol) was added 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). The reaction mixture was stirred at 35 °C for 16 hours. The mixture was diluted with saturated NH4Cl (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 = H₂O (10 mM NH₄HCO₃) and B = CH₃CN; 33-53% B over 7 min) to give a solid product (7.6 mg, 24.0 μmol, 6% yield).

[0960] 1 H NMR (400MHz, 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).

[0961] LCMS R t = 1.07 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 17 H 16 ClN2O2[M+H] + The calculated MS ESI value is 315.1, and the experimental value is 314.9.

[0962] Example 65. Synthesis of compound II-27

[0963]

[0964] Synthesis of II-A-12b: A mixture of methylamine 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 mixture was concentrated and acidified to pH 7 with 1 M HCl, and extracted with CH2Cl2 (80 mL × 2). The combined organic phases were washed with water (80 mL) and brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product as a solid (1600 mg, 6.35 mmol).

[0965] LCMS R t =0.65 min (in a 1.5 min chromatogram), 5-95AB, C9H 12 NO4S[M+H] + The calculated MS ESI value is 230.0, and the experimental value is 229.9.

[0966] Synthesis of II-A-13a: A mixture of methyl 4-(methylaminosulfonyl)benzoate (500 mg, 2.18 mmol) and LiOH·H₂O (183.03 mg, 4.36 mmol) in THF (8 mL) and water (4 mL) was stirred at 15 °C for 3 hours. The mixture was concentrated to give a crude product as a solid (488 mg, 2.08 mmol), which was used directly in the next step without further purification.

[0967] LCMS R t =0.87 min (in a 1.5 min chromatogram), 5-95AB, C8H 10 NO4S[M+H] + The calculated MS ESI value is 216.0, and the experimental value is 215.8.

[0968] Synthesis II-27: Lithium 4-(methylaminosulfonyl)benzoate (141.23 mg, 0.66 mmol) was added 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). The reaction mixture was stirred at 60 °C for 16 hours. The mixture was diluted with saturated NH4Cl (5 mL) and the aqueous layer was extracted with EtOAc (15 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 = H₂O (10 mM NH₄HCO₃) and B = CH₃CN; 35-55% B over 8 min) to give a solid product (26.6 mg, 73.0 μmol, 12% yield).

[0969] 1 H NMR (400MHz, CD3CN)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).

[0970] LCMS R t =1.20 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 17 H 18 ClN2O3S[M+H] + The calculated MS ESI value is 365.1, and the experimental value is 364.9.

[0971] Example 66. Synthesis of compound II-28

[0972]

[0973] Synthesis of II-A-14a: A mixture of N-methylmethylamine hydrochloride (500 mg, 6.13 mmol), Et3N (2.55 mL, 18.4 mmol), and methyl 4-chlorosulfonylbenzoate (2158.39 mg, 9.2 mmol) in CH2Cl2 (10 mL) was stirred at 15 °C for 16 h. The mixture was quenched with saturated NH4Cl (10 mL) and extracted with CH2Cl2 (10 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product (1700 mg, 5.7 mmol).

[0974] LCMS R t =0.73 min (in a 1.5 min chromatogram), 5-95AB, C 10 H 14 NO4S[M+H] + The calculated MS ESI value is 244.1, and the experimental value is 243.9.

[0975] Synthesize a mixture of II-A-14b: methyl 4-(dimethylaminosulfonyl)benzoate (500 mg, 2.06 mmol) and LiOH·H₂O (172.48 mg, 4.11 mmol) in THF (8 mL) and water (4 mL). Stir the mixture at 15 °C for 3 hours. Concentrate the mixture to give a crude product as a solid (510 mg, 2.05 mmol).

[0976] Synthesis II-28: Lithium 4-(dimethylaminosulfonyl)benzoate (150.43 mg, 0.66 mmol) was added 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). The reaction mixture was stirred at 35 °C for 16 h. The mixture was diluted with saturated NH4Cl solution (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 (Xtimate C18 (150 mm × 25 mm, 5 μm), A = H2O (10 mM NH4HCO3) and B = CH3CN; 35-65% B over 9 min) to give a solid product (74.0 mg, 0.19 mmol, 33% yield).

[0977] 1 H NMR (400MHz, CD3CN)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).

[0978] LCMS R t = 1.25 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 18 H 20 ClN2O3S[M+H] + The calculated MS ESI value is 379.1, and the experimental value is 379.0.

[0979] Example 67. Synthesis of compound II-29

[0980]

[0981] A mixture of 4-amino-N-[(1S)-5-chloroindan-1-yl]benzamide (140 mg, 0.49 mmol), Et3N (0.1 mL, 0.73 mmol), and Tf2O (165.29 mg, 0.59 mmol) in DCM (8 mL) was stirred at -30 °C under N2 for 1 h. The mixture was then stirred at 20 °C for 16 h. The reactants were concentrated and quenched with saturated NH4Cl (25 mL). The mixture was extracted with DCM (25 mL × 2). The combined organic phases were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Xtimate (150 mm × 25 mm, 5 μm), A = H₂O (0.05% NH₄OH) and B = CH₃CN; 33-63% B over 8 minutes) to give a solid product (17.2 mg, 0.04 mmol, 8% yield).

[0982] 1 H NMR (400MHz, CD3CN)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).

[0983] LCMS R t= 1.26 min (in a 2 min chromatogram), 10⁻⁸ AB, C 17 H 15 ClF3N2O3S[M+H] + The calculated MS ESI value is 419.0, and the experimental value is 418.9.

[0984] Example 68. Synthesis of compound II-30

[0985]

[0986] Synthesis of II-A-16b: At 0 °C, water (3 mL) containing potassium persulfate (673.44 mg, 1.1 mmol) was added to a mixture of 4-ethylthiobenzoic acid (100 mg, 0.55 mmol) in methanol (3 mL). The mixture was stirred at 20 °C for 15 hours. The 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 Na₂SO₄, filtered, and concentrated to give the product as a solid (90 mg, 0.42 mmol).

[0987] 1 H NMR (400MHz, CDCl3)δ H =8.31(d,2H),8.05(d,2H),3.18(q,2H),1.31(t,3H).

[0988] Synthesis II-30: DIPEA (0.2 mL, 1.12 mmol) and 4-ethylsulfonylbenzoic acid (80 mg, 0.37 mmol) were added 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). 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 DCM (30 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 (Waters Xbridge 150 mm × 25 mm, 5 μm, A = water (0.05% NH4OH v / v) and B = CH3CN; 31-61% B over 8 minutes) to obtain a solid product (25.0 mg, 68.8 μmol, 18% yield).

[0989] 1 H NMR (400MHz, 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).

[0990] LCMS R t = 1.19 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 18 H 19 ClNO3S[M+H] + The calculated MS ESI value is 364.1, and the experimental value is 364.0.

[0991] Example 69. Synthesis of compound II-31

[0992]

[0993] 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 hours. The mixture was diluted with H2O (10 mL) and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Kromasil (150 mm × 30 mm, 5 μm) A = H2O (0.05% NH4OH) and B = CH3CN; 53-83% B over 8 min) to give a solid product (160.6 mg, 0.55 mmol, 46% yield).

[0994] 1 H NMR (400MHz, CD3CN)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)

[0995] LCMS R t= 1.28 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 16 H 14 ClFNO[M+H] + The calculated MS ESI value is 290.1, and the experimental value is 289.9.

[0996] Example 70. Synthesis of compound II-32

[0997]

[0998] Synthesis of II-A-18b: N-methylaminosulfonyl chloride (1.18 g, 9.08 mmol) was added to a mixture of ethyl 4-aminobenzoate (1 g, 6.05 mmol) and DMAP (1.11 g, 9.08 mmol) in pyridine (20 mL) at 0 °C. The mixture was stirred at 20 °C under N2 for 16 h. The mixture was concentrated and diluted with H2O (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 Na2SO4, filtered, and concentrated. The crude product was moistened with EtOAc (5 mL) to give a product as a solid (1100 mg, 4.12 mmol, 68% yield).

[0999] LCMS R t =0.69 min (in a 1.5 min chromatogram), 5-95AB, C 10 H 15 N₂O₄S[M+H] + The calculated MS ESI value is 259.1, and the experimental value is 259.0.

[1000] Synthesis of II-A-18c: A solution of NaOH (247.78 mg, 6.19 mmol) in water (10 mL) was slowly added to a solution of ethyl 4-(methylaminosulfonylamino)benzoate (400 mg, 1.55 mmol) in methanol (10 mL). The resulting mixture was stirred at 50 °C for 12 hours. The mixture was concentrated to remove MeOH under reduced pressure. 1 N HCl (30 mL) was added to adjust the pH to 2. The mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product as a solid (320 mg, 1.39 mmol).

[1001] 1 H NMR (400MHz, 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)

[1002] Synthesis II-32: A mixture of 4-(methylaminosulfonylamino)benzoic acid (123.61 mg, 0.54 mmol), HOBt (161.21 mg, 1.19 mmol), Et3N (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 stirred at 20 °C under N2 for 16 h. The mixture was quenched with saturated NH4Cl (20 mL) and 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 = H₂O (0.05% NH₄OH) and B = CH₃CN; 40-70% B over 8 minutes) to give a solid product (11.4 mg, 0.03 mmol, 5% yield).

[1003] 1 H NMR (400MHz, CD3CN)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).

[1004] LCMS R t = 1.14 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 17 H 19 ClN3O3S[M+H] + The calculated MS ESI value is 380.1, and the experimental value is 380.0.

[1005] Example 71. Synthesis of compound II-33

[1006]

[1007] A mixture of (1R)-5-chloroindan-1-amine (78.25 mg, 0.47 mmol), 2-methyl-4-methylsulfonylbenzoic 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 hours. The mixture was diluted with H2O (10 mL) and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Kromasil (150 mm × 30 mm, 5 μm), A = H₂O (0.05% NH₄OH) and B = CH₃CN; 45-75% B over 8 min) to give a solid product (73.0 mg, 0.20 mmol, 43% yield).

[1008] 1 H NMR (400MHz, 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).

[1009] LCMS R t = 1.17 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 18 H 19 ClNO3S[M+H] + The calculated MS ESI value is 364.1, and the experimental value is 363.9.

[1010] Example 72. Synthesis of compound II-34

[1011]

[1012] Synthesis of II-A-20b: N,N-dimethylaminosulfonyl chloride (1303.86 mg, 9.08 mmol) was added to a mixture of ethyl 4-aminobenzoate (500 mg, 3.03 mmol) and pyridine (20 mL) at 0 °C for 1 h. The mixture was then stirred at 90 °C under N2 for 16 h. The mixture was concentrated and diluted with H2O (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 Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 35-65% B over 8 min) to give a solid product (500 mg, 1.84 mmol, 61% yield).

[1013] LCMS R t =0.75 min (in a 1.5 min chromatogram), 5-95AB, C 11 H 17 N₂O₄S[M+H] + The calculated MS ESI value is 273.1, and the experimental value is 273.2.

[1014] Synthesis of II-A-20c: MeOH (10 mL) containing ethyl 4-(dimethylaminosulfonylamino)benzoate (150 mg, 0.55 mmol) was added to a solution of NaOH (88.13 mg, 2.2 mmol) in water (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 1N HCl (20 mL × 4), water (20 mL × 2), and brine (20 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product as a solid (105 mg, 0.41 mmol), which was used directly in the next step without further purification.

[1015] LCMS R t =0.55 min (in a 1.5 min chromatogram), 5-95AB, C9H 13 The MS ESI calculated value for N2O4S[M+H]+ is 245.1, and the experimental value is 244.9.

[1016] Synthesis of compound II-34: A mixture of 4-(dimethylaminosulfonylamino)benzoic acid (118.03 mg, 0.48 mmol) and HOBt (145.09 mg, 1.07 mmol), along with Et3N (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 stirred at 20 °C under N2 for 16 h. The reactants were 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 = H₂O (0.05% NH₄OH) and B = CH₃CN; 40-70% B over 8 minutes) to give a solid product (86.5 mg, 0.22 mmol, 41% yield).

[1017] 1 H NMR (400MHz, CD3CN)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).

[1018] LCMS R t = 1.19 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 18 H 21 ClN3O3S[M+H] + The calculated MS ESI value is 394.1, and the measured value is 394.0.

[1019] Example 73. Synthesis of compound II-35

[1020]

[1021] A mixture of (1R)-5-chloroindan-1-amine (76.83 mg, 0.46 mmol), 3-fluoro-4-methylsulfonylbenzoic 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 hours. The mixture was concentrated and diluted with H2O (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 Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Kromasil (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 46-76% B over 8 min) to give a solid product (60.0 mg, 0.16 mmol, 36% yield).

[1022] 1 H NMR (400MHz, 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).

[1023] LCMS R t = 1.19 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 17 H 16 ClFNO3S[M+H] + The calculated MS ESI value is 368.0, and the experimental value is also 368.0.

[1024] Example 74. Synthesis of compound II-36

[1025]

[1026] A mixture of (1R)-5-chloroindan-1-amine (76.83 mg, 0.46 mmol), 2-fluoro-4-methylsulfonylbenzoic 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 hours. The mixture was diluted with H2O (10 mL) and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Kromasil (150 mm × 30 mm, 5 μm), A = H₂O (0.05% NH₄OH) and B = CH₃CN; 45-75% B over 8 minutes) to give a solid product (56.2 mg, 0.15 mmol, 33% yield).

[1027] 1 H NMR (400MHz, 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).

[1028] LCMS R t = 1.18 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 17 H 16 ClFNO3S[M+H] + The calculated MS ESI value is 368.0, and the experimental value is also 368.0.

[1029] Example 75. Synthesis of compound II-37

[1030]

[1031] Synthesis of II-A-23b: Methyl 4-aminobenzoate (534.01 mg, 3.53 mmol) was added to a solution of CSI (500 mg, 3.53 mmol) and t-BuOH (261.85 mg, 3.53 mmol) in DCM (20 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with saturated NH4Cl solution (15 mL). The mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product as a solid (780 mg, 1.39 mmol).

[1032] LCMS R t = 2.04 min (in a 4 min chromatogram), 10⁻⁸ AB, C 13 H 18 N₂O₆SNa[M+Na] + The calculated MS ESI value is 353.1, and the experimental value is 352.9.

[1033] Synthesis of II-A-23c: NaOH (218.29 mg, 5.46 mmol) was added to a solution of methyl 4-(tert-butoxyaminosulfonylamino)benzoate (550 mg, 1.82 mmol) in methanol (10 mL) and water (10 mL). The mixture was stirred at 50 °C for 8 hours. The mixture was diluted with saturated NH4Cl solution (15 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The aqueous phase was concentrated, and the mixture was then extracted with EtOAc (20 mL × 2) to give a crude product as a solid (400 mg, 1.38 mmol).

[1034] 1 H NMR (400MHz, 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).

[1035] Synthesis of II-A-23d: A mixture of 4-(tert-butoxycarbonylaminosulfonylamino)benzoic acid (400 mg, 1.26 mmol) and HOBt (341.74 mg, 2.53 mmol), along with Et3N (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 under N2 for 16 h. The reactants were 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 wet-milled from DCM (1 mL) to give a solid product (180 mg, 0.39 mmol, 31% yield).

[1036] LCMS R t =0.88 min (in a 1.5 min chromatogram), 5-95AB, C 21 H 25 The MS ESI calculated value of ClN3O5S[M+H]+ is 466.1, and the experimental value is 466.2.

[1037] Synthesis II-37: TFA (5 mL, 20 mmol) was added to a solution of N-[[4-[[(1R)-5-chloroindan-1-yl]carbamoyl]phenyl]aminosulfonyl]carbamate tert-butyl ester (60 mg, 0.13 mmol) in DCM (15 mL). The mixture was stirred at 20 °C for 3 h. The reaction mixture 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 wet-milled through DCM (1 mL) to give a solid product (36.4 mg, 0.1 mmol, 77% yield).

[1038] 1 H NMR (400MHz, CD3CN)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).

[1039] LCMS R t = 1.07 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 16 H 17 ClN3O3S[M+H]+ The calculated MS ESI value is 366.1, and the experimental value is 366.0.

[1040] Example 76. Synthesis of compound II-38

[1041]

[1042] Synthesis of II-A-24b: A mixture of KMnO4 (2000 mg, 12.66 mmol) and 4-(trifluoromethylthio)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 phases were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a solid product (500 mg, 1.97 mmol).

[1043] 1 H NMR (400MHz, CD3OD)δ H =8.37(d,2H),8.20(d,2H).

[1044] Synthesis II-38: EDCI (171.53 mg, 0.89 mmol) and (1R)-5-chloroindan-1-amine (100 mg, 0.60 mmol) were added to a mixture of DIPEA (0.31 mL, 1.79 mmol) and 4-(trifluoromethanesulfonyl)benzoic acid (151.62 mg, 0.60 mmol) and HOBt (161.21 mg, 1.19 mmol) in DCM (3 mL). 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 phases were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0% to 30%) to give a solid product (59.9 mg, 145.6 μmol, 24% yield).

[1045] 1 H NMR (400MHz, 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).

[1046] LCMS R t = 1.32 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 17 H 14 ClF3NO3S[M+H] + The calculated MS ESI value is 404.0, and the experimental value is also 404.0.

[1047] Example 77. Synthesis of compound II-39

[1048]

[1049] Synthesis of II-A-25b: A mixture of methyl 4-iodobenzoate (750 mg, 2.86 mmol) and sodium cyclopropylsulfinyloxy (440.07 mg, 3.43 mmol), a complex of trifluoromethanesulfonate (I) with benzene (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 under N2 for 16 h. After cooling to room temperature, the mixture was diluted with H2O (30 mL) and EtOAc (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (30 mL). The combined organic phases were washed with brine (20 x 2 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0% to 15% to 30%) to give a solid product (480 mg, 1.99 mmol, 70% yield).

[1050] 1 H NMR (400MHz, 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).

[1051] Synthesis of II-A-25c: LiOH·H₂O (41.91 mg, 1 mmol) was added to a solution of methyl 4-cyclopropylsulfonylbenzoate (80 mg, 0.33 mmol) in methanol (2 mL) and water (2 mL). The resulting mixture was stirred at 20 °C for 2 hours. 1 N HCl aqueous 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 Na₂SO₄, filtered, and concentrated to give a crude product as a solid (75 mg, 331.5 μmol).

[1052] 1 H NMR (400MHz, 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).

[1053] Synthesis of compound II-39: A mixture of 4-cyclopropylsulfonylbenzoic acid (75 mg, 0.33 mmol) and HATU (252.09 mg, 0.66 mmol), along with 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 phases were washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0% to 10% to 30%) to give a solid product (72.0 mg, 191.4 μmmol, 58% yield).

[1054] 1 H NMR (400MHz, CD3CN)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).

[1055] LCMS R t = 1.22 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C19 H 19 ClNO3S[M+H] + The calculated MS ESI value is 376.1, and the experimental value is 376.0.

[1056] Example 78. Synthesis of compound II-40

[1057]

[1058] Synthesis of II-A-26b: NaOH (108.96 mg, 2.72 mmol) and 1-chloro-2-methoxy-ethane (171.68 mg, 1.82 mmol) were added to a mixture of 4-thiobenzoic acid (140 mg, 0.91 mmol) in methanol (3 mL) at 20 °C. The reaction mixture was stirred at 70 °C for 4 h. 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 phases were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give the product as a solid (140 mg, 659.5 μmol).

[1059] 1 H NMR (400MHz, 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).

[1060] Synthesis of II-A-26c: A mixture of potassium persulfate (2081.41 mg, 3.39 mmol) and 4-(2-methoxyethylthio)benzoic acid (120 mg, 0.57 mmol) in water (4 mL) and methanol (6 mL) was stirred at 20 °C for 12 h. The mixture was diluted with water (20 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with 1 M HCl (20 mL), water (20 mL × 2), and brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give a solid product (140 mg, 573.2 μmol).

[1061] 1 H NMR (400MHz, 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).

[1062] Synthesis II-40: DIPEA (0.05 mL, 0.27 mmol) and (1R)-5-chloroindan-1-amine (15 mg, 0.09 mmol) were added to a mixture of HOBt (14.51 mg, 0.11 mmol) and EDCI (18.87 mg, 0.10 mmol) in DCM (6 mL). 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 phases were 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 150mm×25mm, 5μm) using A=H2O(10mM NH4HCO3)-ACN and B=CH3CN; the crude product was purified in 7 minutes at 36-66% B to obtain a solid product (78.6mg, 197.5μmol).

[1063] 1 H NMR (400MHz, CD3CN)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).

[1064] LCMS R t = 1.18 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 19 H 21 ClNO4S[M+H] + The calculated MS ESI value is 394.1, and the experimental value is 393.9.

[1065] Example 79. Synthesis of compounds II-41 and II-31

[1066]

[1067] Synthesis of II-A-27b: A mixture of 4-fluorobenzoic acid (83.58 mg, 0.60 mmol) and 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 H2O (10 mL), and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product as a solid (110 mg, 0.37 mmol, 62% yield).

[1068] LCMS R t =0.88 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 16 H 14 ClFNO[M+H] + The calculated MS ESI value is 290.1, and the experimental value is 290.0.

[1069] Analytical SFC (Chiralcel OD-3, 150mm × 4.6mm inner diameter, 3μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B over 5 min, then 40% to 5% B over 0.5 min, maintaining 5% B for 1.5 min. Flow rate: 2.5 mL / min, column temperature: 35℃) showed two peaks at 3.18 min and 3.81 min.

[1070] Synthesis of compounds II-41 and II-31: The products (110 mg, 0.37 mmol) were passed through an SFC (DAICEL CHIRALCELOD-H (250 mm × 30 mm, 5 μm); A = CO2 and B = EtOH (0.1%). NH Purification was performed using 3H₂O; 38℃; 50 mL / min; 30% B; 9 min run, 7 injections) to obtain a solid enantiomer 1 (peak 1 of R) randomly designated as compound II-31 (32 mg, 0.11 mmol). t =3.18 min) and the enantiomer 2 (peak 2 of R) of compound II-41 (28.0 mg, 0.10 mmol) in solid form, randomly designated as compound II-41 (28.0 mg, 0.10 mmol). t =3.81 min). Stereochemistry was randomly assigned.

[1071] Compound II-31:

[1072] 1H NMR (400MHz, CD3CN)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)

[1073] LCMS R t = 1.28 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 16 H 14 ClFNO[M+H] + The calculated MS ESI value is 290.1, and the experimental value is 289.9.

[1074] Compound II-41:

[1075] 1 H NMR (400MHz, CD3CN)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)

[1076] LCMS R t = 1.28 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 16 H 14 ClFNO[M+H] + The calculated MS ESI value is 290.1, and the experimental value is 289.9.

[1077] Example 80. Synthesis of compound II-42

[1078]

[1079] DIPEA (0.19 mL, 1.07 mmol) and (1R)-5-chloroindan-1-amine (60 mg, 0.36 mmol) were added to a mixture of HOBt (58.04 mg, 0.43 mmol) and EDCI (75.47 mg, 0.39 mmol) and 4-(difluoromethylsulfonyl)benzoic acid (92.99 mg, 0.39 mmol) in DMF (3 mL). 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 phases were 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 = H₂O (10 mM NH₄HCO₃) and B = CH₃CN; 45-75% B over 7 min) to give a solid product (56.3 mg, 146.0 μmol, 41% yield).

[1080] 1 H NMR (400MHz, CD3CN)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).

[1081] LCMS R t = 1.24 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 17 H 15 ClF2NO3S[M+H] + The calculated MS ESI value is 386.0, and the experimental value is 385.9.

[1082] Example 81. Synthesis of compound II-43

[1083]

[1084] At 20 °C, K₂CO₃ (113.64 mg, 0.82 mmol) was added to a mixture of N-[(1R)-5-chloroindan-1-yl]-4-(methanesulfonylamino)benzamide (100 mg, 0.27 mmol), 1-chloro-2-methoxy-ethane (116.6 mg, 1.23 mmol), and KI (13.65 mg, 0.08 mmol) in DMF (6 mL). The mixture was stirred at 80 °C under N₂ for 16 hours. After cooling to room temperature, the mixture was concentrated to obtain a residue. The residue was diluted with H₂O (30 mL) and the mixture was extracted with EtOAc (10 mL × 2). The combined organic phases were 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 = H₂O (0.05% NH₄OH) and B = CH₃CN; 39-69% B over 9 minutes) to give a solid product (65.5 mg, 0.16 mmol, 57% yield).

[1085] 1 H NMR (400MHz, CD3CN)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).

[1086] LCMS R t = 1.19 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 20 H 24 ClN2O4S[M+H] + The calculated MS ESI value is 423.1, and the experimental value is 423.0.

[1087] Example 82. Synthesis of compound II-44

[1088]

[1089] DIAD (110.85 mg, 0.55 mmol) was added to a mixture of N-[(1R)-5-chloroindan-1-yl]-4-(methanesulfonylamino)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) at 0 °C. The mixture was stirred at 20 °C under N2 for 16 hours. The mixture was concentrated to dryness and diluted with H2O (10 mL). The mixture was extracted with EtOAc (10 mL × 2). The combined organic phases were 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 = H2O (0.05% ammonium hydroxide aqueous solution) and B = CH3CN; 45-55% B over 9 minutes) to give a solid product (23.7 mg, 0.05 mmol, 20% yield).

[1090] 1 H NMR (400MHz, CD3CN)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).

[1091] LCMS R t =0.96 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 21 H 27 ClN3O3S[M+H] + The calculated MS ESI value is 436.1, and the experimental value is also 436.1.

[1092] Example 83. Synthesis of compound II-45

[1093]

[1094] At 20 °C, K₂CO₃ (113.64 mg, 0.82 mmol) was added to a mixture of N-[(1R)-5-chloroindan-1-yl]-4-(methanesulfonylamino)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). The mixture was stirred at 80 °C under N₂ for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with H₂O (30 mL) and the mixture was extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was wet-milled from i-Pr2O (10 mL) to give a solid product (96.3 mg, 0.22 mmol, 79% yield).

[1095] 1 H NMR (400MHz, CD3CN)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).

[1096] LCMS R t = 1.26 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 19 H 19 ClF3N2O3S[M+H] + The calculated MS ESI value is 447.1, and the experimental value is also 447.1.

[1097] Example 84. Synthesis of compound II-46

[1098]

[1099] At 20 °C, K₂CO₃ (68.19 mg, 0.49 mmol) was added to a mixture of N-[(1R)-5-chloroindan-1-yl]-4-(methanesulfonylamino)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). The mixture was stirred at 100 °C under N₂ for 16 hours. The mixture was diluted with H₂O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phases were 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 = H2O (0.05% ammonium hydroxide solution) and B = CH3CN; 51-71% B over 9 minutes) to give a solid product (35.71 mg, 0.07 mmol, 46% yield).

[1100] 1 H NMR (400MHz, CD3CN)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).

[1101] LCMS R t = 1.23 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 20 H 21 ClF3N2O4S[M+H] + The calculated MS ESI value is 477.1, and the experimental value is 477.0.

[1102] Example 85. Synthesis of compound II-47

[1103]

[1104] K₂CO₃ (136.37 mg, 0.99 mmol) was added to a mixture of N-[(1R)-5-chloroindan-1-yl]-4-(methanesulfonylamino)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) at 20 °C. The mixture was stirred at 100 °C under N₂ for 16 h. The mixture was quenched with saturated NH₄Cl (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phases were 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 = H₂O (0.05% NH₄OH) and B = CH₃CN; 30-60% B over 9 minutes) to give a solid product (36.3 mg, 0.09 mmol, 27% yield).

[1105] 1 H NMR (400MHz, CD3CN)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).

[1106] LCMS R t = 1.11 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 19 H 22 ClN2O4S[M+H] + The calculated MS ESI value is 409.1, and the experimental value is 409.0.

[1107] Example 86. Synthesis of compound II-48

[1108]

[1109] A mixture of 3-methyl-4-methylsulfonylbenzoic acid (100 mg, 0.47 mmol) and 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 hours. The mixture was concentrated under reduced pressure. The residue was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (20 mL) and 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 = H₂O (0.05% NH₄OH) and B = CH₃CN; 46-76% B over 9 min) to give a solid product (56.1 mg, 0.15 mmol, 33% yield).

[1110] 1 H NMR (400MHz, CD3CN)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).

[1111] LCMS R t = 1.19 min (in a 2 min chromatogram), 10⁻⁸ AB, C 18 H 19 ClNO3S[M+H] + The calculated MS ESI value is 364.1, and the experimental value is 364.0.

[1112] Example 87. Synthesis of compound II-49

[1113]

[1114] K₂CO₃ (113.64 mg, 0.82 mmol) was added to a mixture of N-[(1R)-5-chloroindan-1-yl]-4-(methanesulfonylamino)benzamide (100 mg, 0.27 mmol), 2-chloro-N,N-dimethylacetamide (166.6 mg, 1.37 mmol), and KI (13.65 mg, 0.08 mmol) in THF (10 mL) at 0 °C. The mixture was stirred at 20 °C under N₂ for 16 hours. The mixture was concentrated to dryness and diluted with H₂O (10 mL). The mixture was extracted with EtOAc (10 mL × 2). The combined organic phases were 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 = H₂O (0.05% NH₄OH) and B = CH₃CN; 40-60% B over 9 minutes) to give a solid product (37.5 mg, 0.08 mmol, 30% yield).

[1115] 1 H NMR (400MHz, CD3CN)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).

[1116] LCMS R t = 1.15 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 21 H 25 ClN3O4S[M+H] + The calculated MS ESI value is 450.1, and the experimental value is also 450.1.

[1117] Example 88. Synthesis of compound II-50

[1118]

[1119] KI (409.48 mg, 2.47 mmol) was added to a mixture of N-[(1R)-5-chloroindan-1-yl]-4-(methanesulfonylamino)benzamide (180 mg, 0.49 mmol), 4-methylbenzenesulfonic acid oxetane-3-yl ester (1.13 g, 4.93 mmol), and Cs₂CO₃ (642.94 mg, 1.97 mmol) in DMF (10 mL) at 0 °C, and the mixture was stirred at 120 °C under N₂ for 16 h. After cooling to room temperature, the reactants were quenched with saturated NH₄Cl (20 mL). The mixture was extracted with EtOAc (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 Green ODS (150 mm × 30 mm, 5 μm), A = water (0.075% TFA) and B = CH3CN; 42-62% B over 9 min) to obtain the product. The product was then neutralized with saturated NaHCO3 (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 Na2SO4, filtered, and concentrated to give the product as a solid (19.8 mg, 0.05 mmol, 9% yield).

[1120] 1 H NMR (400MHz, CD3CN)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).

[1121] LCMS R t = 1.15 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 20 H 22 ClN2O4S[M+H] + The calculated MS ESI value is 421.1, and the experimental value is 421.2.

[1122] Example 89. Synthesis of compound II-51

[1123]

[1124] Synthesis of II-A-26b: A mixture of 4-thiobenzoic 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 min. Then, 2-bromo-1,1-difluoroethane (940.07 mg, 6.49 mmol) was added. The reaction mixture was stirred at 45 °C for 48 h. After cooling to room temperature, the mixture was diluted with H₂O (20 mL) and concentrated to remove MeOH. The solution was then acidified to pH approximately 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).

[1125] 1 H NMR (400MHz, DMSO-d) 6 )δ H =7.86(d,2H),7.51(d,2H),6.25(tt,1H),3.64(dt,2H).

[1126] Synthesis of II-A-26c: A mixture of 4-(2,2-difluoroethylthio)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 mixture was concentrated and diluted with H2O (20 mL), and the aqueous layer was extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid chromatography on silica gel (DCM) to give a solid product (300 mg, 0.8071 mmol, 59% yield).

[1127] 1 H NMR (400MHz, 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).

[1128] LCMS R t= 1.25 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 18 H 17 ClF2NOS[M+H] + The calculated MS ESI value is 368.1, and the experimental value is 367.9.

[1129] Synthesis of compound II-51: Potassium persulfate (800.75 mg, 1.3 mmol) was added to a solution of N-[(1R)-5-chloroindan-1-yl]-4-(2,2-difluoroethylthio)benzamide (80 mg, 0.22 mmol) in methanol (15 mL) and water (10 mL). 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 H₂O (10 mL) and wet-milled in MeOH (5 mL) to give a solid product (30.7 mg, 0.07 mmol, 34% yield).

[1130] 1 H NMR (400MHz, CD3CN)δ H =8.08-7.96(m,4H),7.55-7.45(m1H),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).

[1131] LCMS R t = 1.22 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 18 H 17 ClF2NO3S[M+H] + The calculated MS ESI value is 400.1, and the experimental value is 400.0.

[1132] Example 90. Synthesis of compounds II-52 and II-53

[1133]

[1134] Synthesis of II-A-5: A mixture of 6-chlorotetrahydronaphthyl-1-one (500 mg, 2.77 mmol) and NH4OAc (2134.2 mg, 27.68 mmol) in i-PrOH (14 mL) was stirred at 20 °C for 1 hour. Then, NaBH3CN (608.81 mg, 9.69 mmol) was added, and the resulting mixture was heated to 85 °C. The mixture was stirred at 85 °C for 3 hours. 5N NaOH solution (50 mL) was added, and the aqueous layer was extracted with EtOAc (30 mL). The organic phase was separated and washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was redissolved in DCM (30 mL) and extracted with 1N HCl aqueous solution (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 obtain a crude product in the form of an oil (270 mg, 1.49 mmol).

[1135] 1 H NMR (400MHz, 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).

[1136] Synthesis of II-A-27a: A mixture of 4-(methanesulfonylamino)benzoic acid (170.61 mg, 0.79 mmol) and HOBt (238.04 mg, 1.76 mmol), along with Et3N (0.37 mL, 2.64 mmol), EDCI (253.26 mg, 1.32 mmol), and 6-chlorotetrahydronaphthyl-1-amine (160 mg, 0.88 mmol) in DCM (15 mL) was stirred at 20 °C under N2 for 16 h. The reactants were quenched with saturated NH4Cl (20 mL) and the mixture was extracted with DCM (30 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a solid product (301 mg, 0.79 mmol).

[1137] LCMS R t = 1.06 min (in a 1.5 min chromatogram), 5-95AB, C 18 H 20 ClN2O3S[M+H] +The calculated MS ESI value is 379.1, and the experimental value is 379.0.

[1138] Analytical SFC: (Chiralpak OJ-3 150mm × 4.6mm inner diameter, 3×, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B over 5 min, followed by 40% B for 2.5 min, then 5% B for 2.5 min. Flow rate: 2.5 mL / min, column temperature: 35℃) Displayed on R t =5.08min and R t = Two peaks at 5.67 min.

[1139] Synthesis of compounds II-52 and II-53: N-(6-chlorotetrahydronaphth-1-yl)-4-(methanesulfonylamino)benzamide (300 mg, 0.79 mmol) was purified by SFC [DAICEL CHIRALCEL OJ-H (250 mm × 30 mm inner diameter, 5 μm); A = CO2 and B = EtOH (0.1% NH3H2O); 38 °C; 60 mL / min; 35% B; 12 min run; 9 injections] to give a solid enantiomer 1 (peak 1 of which was randomly designated as compound II-52 (95.6 mg, 0.25 mmol) t =5.08 min) and the enantiomer 2 (peak 2 of R) of compound II-53 (62.12 mg, 0.16 mmol) in solid form, randomly designated as compound II-53. t =5.67min). Stereochemistry was randomly assigned.

[1140] Compound II-52

[1141] 1 H NMR (400MHz, 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).

[1142] LCMS R t = 1.09 min (in a 2 min chromatogram), 10⁻⁸ AB, C 18 H 20 ClN2O3S[M+H] + The calculated MS ESI value is 379.1, and the experimental value is 379.0.

[1143] Compound II-53

[1144] 1 H NMR (400MHz, 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).

[1145] LCMS R t = 1.07 min (in a 2 min chromatogram), 10⁻⁸ AB, C 18 H 20 ClN2O3S[M+H] + The calculated MS ESI value is 379.1, and the experimental value is 379.0.

[1146] Example 91. Synthesis of compounds II-54 and II-55

[1147]

[1148] DIPEA (0.32 mL, 1.82 mmol) and 4-methylsulfonylbenzoic acid (145.48 mg, 0.73 mmol) were added to a mixture of 6-chlorotetrahydronaphthyl-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). 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 phases were washed with 1 M HCl (20 mL), water (20 mL × 2), and brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated.

[1149] Analytical SFC (Chiralcel OJ-3, 150mm × 4.6mm inner diameter, 3μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B over 5 min, followed by 40% B for 2.5 min, then 5% B for 2.5 min. Flow rate: 2.5 mL / min, column temperature: 35℃) showed two peaks at 1.84 min and 5.65 min.

[1150] The product was purified by SFC (DAICEL CHIRALPAK AS (250 mm × 30 mm, 10 μm); A = CO2 and B = MeOH (0.1% NH3H2O); 38 °C; 70 mL / min; 50% B; 13 min run; 6 injections) to give a solid enantiomer 1 (peak 1 of R) randomly designated as compound II-54 (38.1 mg, 103.2 μmol). t =1.84 min) and the enantiomer 2 (peak 2 of R) of compound II-55 (47.5 mg, 130.5 μmol) in solid form, randomly designated as compound II-55. t =5.65min). Stereochemistry was randomly assigned.

[1151] Compound II-54

[1152] 1 H NMR (400MHz, 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).

[1153] LCMS R t =1.20 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 18 H 19 ClNO3S[M+H] + The calculated MS ESI value is 364.1, and the experimental value is 364.0.

[1154] Compound II-55

[1155] 1 H NMR (400MHz, 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).

[1156] LCMS R t = 1.19 min (in a 2.0 min chromatogram), 10⁻⁸ AB, C 18 H19 ClNO3S[M+H] + The calculated MS ESI value is 364.1, and the experimental value is 364.0.

[1157] Example 92. Synthesis of compounds II-56 and II-58

[1158]

[1159] Synthesis of II-A-7: A mixture of 5-(trifluoromethyl)indan-1-one (400 mg, 2 mmol) and NH4OAc (1.54 g, 19.98 mmol) in i-PrOH (10 mL) was stirred at 20 °C for 1 hour, followed by the addition of NaBH3CN (439.53 mg, 6.99 mmol). The mixture was heated to 85 °C and stirred for 3 hours. 150 mL of 5N NaOH aqueous solution was added, and the aqueous layer was extracted with EtOAc (100 mL). The organic phase was separated and washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was redissolved in DCM (100 mL) and extracted with 1N HCl aqueous solution (100 mL × 2). 100 mL of saturated Na2CO3 aqueous solution was added to adjust the pH to 9, and the aqueous layer was extracted with EtOAc (100 mL × 2). The combined organic phases were washed with water (100 mL × 2) and brine (100 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product in an oily state (210 mg, 0.94 mmol), which was used directly in the next step without further purification.

[1160] LCMS R t =0.74 min (in a 1.5 min chromatogram), 5-95AB, C 10 H 10 F3N2[M-NH3+H] + The calculated MS ESI value is 185.1, and the experimental value is 184.8.

[1161] Synthesis of II-A-29a: A mixture of 4-(methanesulfonylamino)benzoic acid (192.56 mg, 0.89 mmol) and HOBt (268.66 mg, 1.99 mmol), along with Et3N (0.41 mL, 2.98 mmol), EDCI (285.85 mg, 1.49 mmol), and 5-(trifluoromethyl)indane-1-amine (200 mg, 0.99 mmol) in DCM (15 mL) was stirred at 20 °C under N2 for 16 h. The reactants were quenched with saturated NH4Cl (30 mL) and the mixture was extracted with DCM (30 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was wet-milled from DCM / n-hexane (2 mL / 8 mL) to give a solid product (310 mg, 0.77 mmol, 78% yield).

[1162] LCMS R t =0.94 min (in a 1.5 min chromatogram), 5-95AB, C 18 H 18 F3N2O3S[M+H] + The calculated MS ESI value is 399.1, and the experimental value is 398.9.

[1163] Analytical SFC (Chiralpak AD-3, 150mm × 4.6mm inner diameter, 3μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B over 5 min, followed by 40% B for 2.5 min, then 5% B for 2.5 min. Flow rate: 2.5 mL / min, column temperature: 35℃) showed two peaks at 4.16 min and 4.36 min.

[1164] Compounds II-58 and II-56 were synthesized: 4-(methanesulfonylamino)-N-[5-(trifluoromethyl)indan-1-yl]benzamide (310 mg, 0.77 mmol) was purified by SFC (DAICEL CHIRALPAK AD-H (250 mm × 30 mm inner diameter, 5 μm); A = CO2 and B = EtOH (0.1% NH3H2O); 38 °C; 50 mL / min; 35% B; 8 min run; 24 injections) to give a solid enantiomer 1 (peak 1 of which was randomly designated as compound II-58 (41.9 mg, 104.7 μmol)) as enantiomer 1 (peak 1 of which is R). t =4.16 min) and the en...

Claims

1. A pharmaceutical composition comprising a compound of formula II: or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

2. Use of a compound of formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pediatric epilepsy or pediatric epilepsy syndrome: Wherein the compound is selected from:

3. Use of the pharmaceutical composition according to claim 1 in the preparation of a medicament for treating pediatric epilepsy or pediatric epilepsy syndrome.

4. The use according to claim 2 or 3, wherein the pediatric epilepsy or pediatric epilepsy syndrome comprises: Other encephalopathy, epilepsy in 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, epileptic seizures, generalized tonic-clonic seizures, asymmetric tonic seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), or cerebellar ataxia.

5. The use according to claim 2 or 3, wherein the pediatric epilepsy or pediatric epilepsy syndrome comprises: Epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy of childhood with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

6. A pharmaceutical composition comprising a compound of formula II: or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

7. Use of a compound of formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pediatric epilepsy or pediatric epilepsy syndrome: Wherein the compound is selected from:

8. Use of the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating pediatric epilepsy or pediatric epilepsy syndrome.

9. The use according to claim 7 or 8, wherein the pediatric epilepsy or pediatric epilepsy syndrome comprises: Other encephalopathy, epilepsy in 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, epileptic seizures, generalized tonic-clonic seizures, asymmetric tonic seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), or cerebellar ataxia.

10. The use according to claim 7 or 8, wherein the pediatric epilepsy or pediatric epilepsy syndrome comprises: Epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy of childhood with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

11. A pharmaceutical composition comprising a compound of formula III: or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

12. Use of a compound of formula III or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pediatric epilepsy or pediatric epilepsy syndrome: Wherein the compound is selected from:

13. Use of the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating pediatric epilepsy or pediatric epilepsy syndrome.

14. The use according to claim 12 or 13, wherein the pediatric epilepsy or pediatric epilepsy syndrome comprises: Other encephalopathy, epilepsy in 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, epileptic seizures, generalized tonic-clonic seizures, asymmetric tonic seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), or cerebellar ataxia.

15. The use according to claim 12 or 13, wherein the pediatric epilepsy or pediatric epilepsy syndrome comprises: Epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy of childhood with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

16. Compound of formula II: or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

17. Compound of formula II: or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

18. Compound of formula III: or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

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