KCNT1 inhibitor and method of use

Abstract

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

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and interest to U.S. Provisional Patent Application No. 62 / 993,359, filed March 23, 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

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

[0003] Compounds and compositions useful for preventing and / or treating diseases, disorders, or conditions, such as neurological disorders or disorders, excessive neuronal excitability, and / or diseases, disorders, or conditions related to gain-of-function mutations in genes, such as KCNT1, are described herein.

[0004] Therefore, in one embodiment, the compound is of formula A, [ka] X is CR7 or N, and Y is S, or X is CR7, and Y is O. Ring A is selected from the group consisting of phenyl, 6-member heteroaryl, and 5-7-member heterocyclyl, R1 is selected from the group consisting of phenyl, 5-6-member heteroaryl, -CH2-phenyl, 5-8-member carbocyclyl, and 5-10-member heterocyclyl, and phenyl, 5-6-member heteroaryl, -CH2-phenyl, 5-8-member carbocyclyl, and 5-10-member heterocyclyl are optionally substituted with one or more R6, R2 is hydrogen or C 1-6 alkyl, R3 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-8 cycloalkyl, and is selected from the group consisting of C 1-6 alkyl is optionally substituted with C 1-6 alkoxy, or C 1-6 haloalkoxy, and R4 is hydrogen or R3 and R4 together with the carbon to which they are attached can form C 3-8 cycloalkylene or 3-7-member heterocycloalkylene, R5 and R6 are each independently halogen, C 1-6 alkyl, C 1-6 alkylene-O-C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S(O)2R8, -S(O)2-N(R9)2, and C 3-8 cycloalkyl, and are selected from the group consisting of R7 is hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl, and is selected from the group consisting of R8 is hydrogen or C 1-6 alkyl, each R9 is hydrogen, C 1-6 alkyl, and -(C 1-6Either independently selected from the group consisting of alkylene)-OH, or two R9s together with the nitrogen atoms bonded to the two R9s may form a heterocycle in which one or more substituents independently selected from halogens and -OH groups are optionally substituted. n is selected from the group consisting of 0, 1, 2, and 3. However, provided that R3 is hydrogen and ring A is a 6-membered heterocyclyl or 6-membered heteroaryl, R1 is not thiophene. However, provided that R3 is hydrogen and ring A is a 6-membered heteroaryl or 5-membered heterocycline, R1 is not phenyl, the compound, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising a pharmaceutically acceptable carrier is provided herein.

[0005] In another embodiment, the compound of formula A-1, [ka] X is CR7 or N, and Y is S, or X is CR7, and Y is O. Ring A is a 6-membered heteroaryl, R1 is selected from the group consisting of phenyl, 5-6 member heteroaryl, -CH2-phenyl, 5-8 member carbocyclyl, and 5-10 member heterocyclyl, and phenyl, 5-6 member heteroaryl, -CH2-phenyl, 5-8 member carbocyclyl, and 5-10 member heterocyclyl are optionally substituted with one or more R6s. R2 is hydrogen or C 1-6 It is alkyl, R3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, C 1-6 Alkyl is C 1-6 Alkoxy, or C 1-6It is optionally substituted with a haloalkoxy, and R4 is either hydrogen or R3 and R4, together with the carbons bonded to R3 and R4, C 3-8 It may form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R5 and R6 are each independently halogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2R8, -S(O)2-N(R9)2, and C 3-8 Selected from the group consisting of cycloalkyl groups, R7 uses hydrogen, C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R8 is hydrogen or C 1-6 It is alkyl, Each R9 is hydrogen, C 1-6 Alkyl, and -(C 1-6 Either independently selected from the group consisting of alkylene)-OH, or two R9s together with the nitrogen atoms bonded to the two R9s may form a heterocycle in which one or more substituents independently selected from halogens and -OH groups are optionally substituted. n is selected from the group consisting of 0, 1, 2, and 3. However, when R3 is hydrogen and ring A is a 6-membered heteroaryl, R1 is neither thiophene nor phenyl. A compound, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising a pharmaceutically acceptable carrier is provided herein.

[0006] In another embodiment, the compound of formula A-2, [ka] X is CR7 or N, and Y is S, or X is CR7, and Y is O. Ring A is a 5-7 member heterocyclyl, R1 is selected from the group consisting of phenyl, 5-6 member heteroaryl, -CH2-phenyl, 5-8 member carbocyclyl, and 5-10 member heterocyclyl, and phenyl, 5-6 member heteroaryl, -CH2-phenyl, 5-8 member carbocyclyl, and 5-10 member heterocyclyl are optionally substituted with one or more R6s. R2 is hydrogen or C 1-6 It is alkyl, R3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, C 1-6 Alkyl is C 1-6 Alkoxy, or C 1-6 It is optionally substituted with a haloalkoxy, and R4 is either hydrogen or R3 and R4, together with the carbons bonded to R3 and R4, C 3-8 It may form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R5 and R6 are each independently halogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2R8, -S(O)2-N(R9)2, and C 3-8 Selected from the group consisting of cycloalkyl groups, R7 uses hydrogen, C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R8 is hydrogen or C 1-6 It is alkyl, Each R9 is hydrogen, C 1-6 Alkyl, and -(C 1-6Either independently selected from the group consisting of alkylene)-OH, or two R9s together with the nitrogen atoms bonded to the two R9s may form a heterocycle in which one or more substituents independently selected from halogens and -OH groups are optionally substituted. n is selected from the group consisting of 0, 1, 2, and 3. However, when R3 is hydrogen and ring A is a 5-6 member heterocycline, R1 is neither thiophene nor phenyl, the compound or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising a pharmaceutically acceptable carrier is provided herein.

[0007] In one embodiment, a compound having formula I, [ka] Or a pharmaceutically acceptable salt thereof is provided herein, in the formula, X is CR7 or N, and Y is S, or X is CR7, and Y is O. Ring A is selected from the group consisting of phenyl, 6-membered heteroaryl, and 5- to 7-membered heterocyclyl. R1 is selected from the group consisting of phenyl, 5-6 member heteroaryl, -CH2-phenyl, 5-8 member carbocyclyl, and 5-10 member heterocyclyl, and phenyl, 5-6 member heteroaryl, -CH2-phenyl, 5-8 member carbocyclyl, and 5-10 member heterocyclyl are optionally substituted with one or more R6s. R2 is hydrogen or C 1-6 It is alkyl, R3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, C 1-6 Alkyl is C 1-6 Alkoxy or C 1-6 It is optionally substituted with a haloalkoxy, and R4 is either hydrogen or R3 and R4, together with the carbon to which they are attached, form a C 3-8 cycloalkylene or 3- to 7-membered hetero cycloalkylene, R5 and R6 are each independently halogen, C 1-6 alkyl, C 1-6 alkylene-O-C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S(O)2R8, -S(O)2-N(R9)2, and C 3-8 cycloalkyl selected from the group consisting of, R7 is hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl selected from the group consisting of, R8 is hydrogen or C 1-6 alkyl, each R9 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, and -(C 1-6 alkylene)-OH, or two R9s, together with the nitrogen atom to which they are attached, form a heterocyclic ring optionally substituted with one or more substituents independently selected from halogen and -OH, n is selected from the group consisting of 0, 1, 2, and 3.

[0008] In one embodiment, a compound having formula I-A,

Chemical formula

[0009] In one embodiment, a compound having formula IB, [ka] Or a pharmaceutically acceptable salt thereof is provided herein, in the formula, X is CR7 or N, and Y is S, or X is CR7, and Y is O. Ring A is phenyl or a 6-membered heteroaryl, R1 is a phenyl or 5-6 member heteroaryl, and the phenyl or 5-6 member heteroaryl is optionally substituted with one or more R6s. R2 is hydrogen or C 1-6 It is alkyl, R3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, C 1-6 Alkyl is C 1-6 Alkoxy or C 1-6 It is optionally substituted with a haloalkoxy, and R4 is either hydrogen or R3 and R4, together with the carbons bonded to R3 and R4, C 3-8 It may form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R5 and R6 are each independently halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2R8, -S(O)2-N(R9)2, and C 3-8 Selected from the group consisting of cycloalkyl groups, R7 uses hydrogen, C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R8 is hydrogen or C1-6 It is alkyl, Each R9 is hydrogen, C 1-6 Alkyl, and -(C 1-6 Either independently selected from the group consisting of alkylene)-OH, or two R9s together with the nitrogen atoms bonded to the two R9s may form a heterocycle in which one or more substituents independently selected from halogens and -OH groups are optionally substituted. n is selected from the group consisting of 0, 1, 2, and 3.

[0010] In one embodiment, the present disclosure relates to a method for treating a neurological disorder or condition, wherein the subject requiring the treatment is a compound disclosed herein (e.g., a compound of formula (A), (A-1), (A-1A), (A-1B), (A-2), (A-2A), (I), (IA), (I-IA), (I-IA2), (I-IA3), (I-IA4), (IB), (I-IB), (I-IB2), (I-IB3), (I-IB4), (I-IC), (I-IC2), (I-IC3), (I-IC4), (II), (II-A), or (II-B), or otherwise disclosed herein. The present invention provides a method comprising administering a pharmaceutical composition (for example, a pharmaceutical composition comprising a compound of formula (A), (A-1), (A-1A), (A-1B), (A-2), (A-2A), (I), (IA), (I-IA), (I-IA2), (I-IA3), (I-IA4), (IB), (I-IB), (I-IB2), (I-IB3), (I-IB4), (I-IC), (I-IC2), (I-IC3), (I-IC4), (II), (II-A), or (II-B), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient).

[0011] In another aspect, the present disclosure relates to a method for treating a disease or condition associated with excessive neuronal excitability, wherein the subject in need is a compound disclosed herein (e.g., a compound of formula (A), (A-1), (A-1A), (A-1B), (A-2), (A-2A), (I), (IA), (I-IA), (I-IA2), (I-IA3), (I-IA4), (IB), (I-IB), (I-IB2), (I-IB3), (I-IB4), (I-IC), (I-IC2), (I-IC3), (I-IC4), (II), (II-A), or (II-B), or the present invention The present invention provides a method comprising administering a pharmaceutical composition disclosed in the details (for example, a pharmaceutical composition comprising a compound of formula (A), (A-1), (A-1A), (A-1B), (A-2), (A-2A), (I), (IA), (I-IA), (I-IA2), (I-IA3), (I-IA4), (IB), (I-IB), (I-IB2), (I-IB3), (I-IB4), (I-IC), (I-IC2), (I-IC3), (I-IC4), (II), (II-A), or (II-B), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient).

[0012] In another aspect, the present disclosure relates to a method for treating a disease or condition associated with a gain-of-function mutation of a gene (e.g., KCNT1), wherein the treatment involves applying a compound disclosed herein (e.g., formula (A), (A-1), (A-1A), (A-1B), (A-2), (A-2A), (I), (IA), (I-IA), (I-IA2), (I-IA3), (I-IA4), (IB), (I-IB), (I-IB2), (I-IB3), (I-IB4), (I-IC), (I-IC2), (I-IC3), (I-IC4), (II), (II-A), or (II-B) to a subject requiring such treatment. The present invention provides a method comprising administering a substance or a pharmaceutical composition disclosed herein (for example, a pharmaceutical composition comprising a compound of formula (A), (A-1), (A-1A), (A-1B), (A-2), (A-2A), (I), (IA), (I-IA), (I-IA2), (I-IA3), (I-IA4), (IB), (I-IB), (I-IB2), (I-IB3), (I-IB4), (I-IC), (I-IC2), (I-IC3), (I-IC4), (II), (II-A), or (II-B), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient).

[0013] In some embodiments, neurological disorders or conditions, diseases or conditions related to excessive neuronal excitability, or diseases or conditions related to gain-of-function mutations in a gene (e.g., KCNT1) are epilepsy, epileptic syndromes, or encephalopathy.

[0014] In some embodiments, neurological disorders or conditions, disorders or conditions related to excessive neuronal excitability, or disorders or conditions related to gain-of-function mutations in a gene (e.g., KCNT1) are hereditary or childhood epilepsy, or hereditary or childhood epileptic syndromes.

[0015] In some embodiments, cardiac dysfunction is a neurological disorder or impairment, a disorder or condition related to excessive neuronal excitability, or a disorder or condition related to a gain-of-function mutation in a gene (e.g., KCNT1).

[0016] In some embodiments, neurological disorders or conditions, disorders or conditions associated with excessive neuronal excitability, or disorders or conditions associated with gain-of-function mutations in a gene (e.g., KCNT1) are selected from epilepsy and other encephalopathy (e.g., infantile epilepsy with migratory focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic 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).

[0017] In some embodiments, neurological disorders or conditions, diseases or conditions related to excessive neuronal excitability, or diseases or conditions related to gain-of-function mutations in a gene (e.g., KCNT1) are selected from the group consisting of cardiac arrhythmias, sudden unexpected death in epilepsy, Brugada syndrome, and myocardial infarction.

[0018] In some embodiments, neurological disorders or conditions, diseases or conditions related to excessive neuronal excitability, or diseases or conditions related to gain-of-function mutations in a gene (e.g., KCNT1) are selected from pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.).

[0019] In some embodiments, neurological disorders or conditions, disorders or conditions related to excessive neuronal excitability, or disorders or conditions related to gain-of-function mutations in a gene (e.g., KCNT1) are muscle disorders (e.g., myotonia, neuromyotonia, muscle spasms, spasticity).

[0020] In some embodiments, neurological disorders or conditions, disorders or conditions related to excessive neuronal excitability, or disorders or conditions related to gain-of-function mutations in a gene (e.g., KCNT1) are selected from itching and pruritus, ataxia, and cerebellar ataxia.

[0021] In some embodiments, the neurological disorder or condition, the disorder or condition related to excessive neuronal excitability, or the disorder or condition related to a gain-of-function mutation in a gene (e.g., KCNT1) is selected from mental disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia).

[0022] In some embodiments, neurological disorders or conditions, or disorders or conditions associated with excessive neuronal excitability and / or gain-of-function mutations in genes (e.g., KCNT1), are selected from the group consisting of learning disabilities, fragile X, neuroplasticity, and autism spectrum disorders.

[0023] In some embodiments, neurological disorders or conditions, diseases or conditions related to excessive neuronal excitability, or diseases or conditions related to gain-of-function mutations in a gene (e.g., KCNT1) include epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations, early-onset epileptic encephalopathy of infants, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, and infantile spasms. The group consists of benign familial neonatal-infant seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic childhood partial epilepsy with SCN3A mutation, SCNA8 epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures in infants, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0024] Other purposes and advantages will become apparent to those skilled in the art by considering the modes, examples, and claims for carrying out the invention. [Modes for carrying out the invention]

[0025] As generally described herein, the present invention provides compounds and compositions useful for preventing and / or treating diseases, disorders, or conditions described herein, such as diseases, disorders, or conditions related to excessive neuronal excitability and / or diseases, disorders, or conditions related to gain-of-function mutations in KCNT1. Exemplary diseases, disorders, or conditions include epilepsy and other encephalopathy (e.g., infantile epilepsy with migratory focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, and Lennox These include Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic seizures, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia, asymmetric tonic seizures), as well as cardiac dysfunction (e.g., cardiac arrhythmias, Brugada syndrome, sudden unexpected death in epilepsy, myocardial infarction), pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine), muscle disorders (e.g., myotonia, neuromyotonia, muscle spasms, spasticity), itching and pruritus, ataxia and cerebellar ataxia, and mental disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia).

[0026] definition chemical definition The definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th Identification follows the inside cover of the ed., and specific functional groups are generally defined as described in the book. Furthermore, general principles of organic chemistry, as well as specific functional parts and reactivity, are referenced in Thomas Sorrell, *Organic Chemistry*, University Science Books, Sausalito, 1999, and Smith and March, *March's Advanced Organic Chemistry*, 5 thEdition, John Wiley&Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3. rd This information is found in Edition, Cambridge University Press, Cambridge, 1987.

[0027] The compounds described herein may contain one or more chiral centers and therefore may exist in various isomers, such as enantiomers and / or diastereomers. For example, the compounds described herein may exist as individual enantiomers, diastereomers, or geometric isomers, or as a mixture of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be isolated from the mixture by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention also encompasses the compounds described herein as individual isomers substantially free from other isomers, or as mixtures of various isomers.

[0028] As used herein, a pure enantiomerized compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomerized). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is therefore enantiomerized in the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight of an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0029] In the compositions provided herein, enantiomerically pure compounds may be present together with other active or inactive components. For example, a pharmaceutical composition containing an enantiomerically pure R compound may, for example, comprise about 90% excipients and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may comprise, for example, at least about 95% by weight of the R compound and at most about 5% by weight of the S compound, by the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S compound may, for example, comprise about 90% excipients and about 10% enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may comprise, for example, at least about 95% by weight of the S compound and at most about 5% by weight of the R compound, by the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipients or carriers.

[0030] The compounds described herein may also include one or more isotopic substitutions. For example, H is 1 H, 2 H (D or deuterium), and 3It may be any isotopic form containing H (T or tritium), and C is 12 C, 13 C, and 14 It may be any isotopic form containing C, and O is, 16 O and 18 It may be any isotopic form containing O, and F is 18 F and 19 This may include any isotopic form, including F.

[0031] The following terms are intended to have the meanings presented below and are useful for understanding the description and intended scope of the invention. When describing an invention that may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms have the meanings below unless otherwise indicated, where present. It should also be understood that, where described herein, any of the parts defined below may be substituted with various substituents, and that each definition is intended to include the substituted parts within the scope of those described below. Unless otherwise specified, the term “substituted” is defined as described below. It should also be understood that the terms “group” and “radical” may be considered interchangeable where used herein. The articles “a” and “an” may be used herein to refer to one or more (i.e., at least one) of the grammatical objects of the articles. For example, “an analogue” means one analogue or two or more analogues.

[0032] When a range of values ​​is listed, it is intended to include each value and subrange within that range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3, C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 It is intended to include alkyl groups.

[0033] As used herein, "alkyl" refers to, for example, a radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1-20 This refers to an alkyl group having 1 to 10 carbon atoms ("C"). In some embodiments, an alkyl group has 1 to 10 carbon atoms. 1-10 (alkyl). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C"). 1-9 (alkyl). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C"). 1-8 Alkyl). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C"). 1-7 ("alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C"). 1-6 (alkyl). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C"). 1-5 (alkyl). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C"). 1-4 (alkyl). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C"). 1-3 Alkyl). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C"). 1-2 Alkyl). In some embodiments, the alkyl group has one carbon atom (C1 alkyl). 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl.

[0034] As used herein, the term "heteroalkyl" refers to an "alkyl" group in which at least one carbon atom is replaced by an O or S atom. A heteroalkyl is, for example, -O-C1-C 10The group may be an alkyl group, a -C1-C6 alkylene-O-C1-C6 alkyl group, or a C1-C6 alkylene-OH group. In certain embodiments, the "heteroalkyl" may be a 2- to 8-membered heteroalkyl group, indicating that the heteroalkyl group contains 2 to 8 atoms selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. In other embodiments, the heteroalkyl group may be a 2- to 6-membered, 4- to 8-membered, or 5- to 8-membered heteroalkyl group (which may contain 1 or 2 heteroatoms selected from, for example, oxygen and nitrogen groups). In certain embodiments, the heteroalkyl group is an "alkyl" group in which 1 to 3 carbon atoms are replaced by oxygen atoms. One type of heteroalkyl group is an "alkoxy" group.

[0035] As used herein, "alkenyl" refers to a radical of a linear 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 This refers to an alkenyl group. In certain embodiments, the alkenyl group does not contain a triple bond. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C"). 2-10 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C"). 2-9 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C"). 2-8 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C"). 2-7 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C"). 2-6 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C"). 2-5 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C"). 2-4 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C").2-3 "Alkenyl"). In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl (C4). 2-6 An example of an alkenyl group is the aforementioned C 2-4 Examples of alkenyl groups include pentenyl (C5), pentadienyl (C5), and hexenyl (C6). Additional examples of alkenyl groups include heptenyl (C7), octenyl (C8), and octatrienyl (C8).

[0036] As used herein, "alkynyl" refers to a radical of a linear 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 This refers to an alkynyl group. In certain embodiments, the alkynyl group does not contain a double bond. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C"). 2-10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C"). 2-9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C"). 2-8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C"). 2-7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C"). 2-6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C"). 2-5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C").2-4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C"). 2-3 "Alkynyl"). In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). 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 An example of an alkenyl group is the aforementioned C 2-4 Examples include alkynyl groups, as well as pentynyl (C5) and hexynyl (C6). Additional examples of alkynyl groups include heptynyl (C7) and octinyl (C8).

[0037] As used herein, “alkylene,” “alkenylene,” and “alkynylene” refer to the divalent radicals of alkyl, alkenyl, and alkynyl groups, respectively. When a range or number of carbon atoms is provided for a particular “alkylene,” “alkenylene,” or “alkynylene” group, the range or number is understood to refer to the range or number of carbon atoms in a linear divalent carbon chain. The “alkylene,” “alkenylene,” and “alkynylene” groups may be substituted with one or more substituents as described herein, or they may be unsubstituted.

[0038] As used herein, "aryl" refers to a radical of a 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided to the aromatic ring system, whether monocyclic or polycyclic (e.g., bicyclic or tricyclic). 6-14 This refers to an aryl group ("C6 aryl," e.g., phenyl). In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"). 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 14 ring carbon atoms ("C"). 14 "Aryl" (e.g., anthracyl). "Aryl" also refers to ring systems in which the aryl ring defined above is condensed with one or more carbocyrillic or heterocyclyl groups, and the radical or bond site is on the aryl ring, in such examples the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indan, indene, naphthalene, octacene, octafen, octaene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0039] As used herein, “heteroaryl” refers to a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (for example, having 6 or 10 electrons shared in the cyclic arrangement) radical ("5- to 10-membered heteroaryl") having a ring carbon atom provided to the aromatic ring system, and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom, as long as the valence allows. A heteroaryl bicyclic ring system may contain one or more heteroatoms in one or both rings. Examples of “heteroaryl” include ring systems in which the heteroaryl ring defined above is fused with one or more carbocykyl or heterocyclyl groups, and the bond site is on the heteroaryl ring, in such examples the number of ring members still specifies the number of ring members in the heteroaryl ring system. "Hyperaryl" also refers to ring systems in which the heteroaryl ring defined above is fused with one or more aryl groups, and the bond site is on either an aryl or heteroaryl ring, in which case the number of ring members specifies the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups where one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl), the bond site can be on either a ring, i.e., a ring supporting a heteroatom (e.g., 2-indolyl) or a ring not containing a heteroatom (e.g., 5-indolyl).

[0040] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system ("5-10 membered heteroaryl") having a ring carbon atom provided to the aromatic ring system, and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system ("5-8 membered heteroaryl") having a ring carbon atom provided to the aromatic ring system, and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system ("5-6 membered heteroaryl") having a ring carbon atom provided to the aromatic ring system, and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms, each selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms, each selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0041] Examples of five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Examples of seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolidinyl, and prinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolinyl, isoquinolinyl, sinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0042] Typical examples of heteroaryl compounds include the following: [ka] In the formula, each Z is a carbonyl, N, or NR. 65Selected from O and S, R 65 These are independently hydrogen, C1-C8 alkyl, and C3-C 10 Carbocyclyl, 4-10 member heterocyclyl, C6-C 10 They are aryl and 5- to 10-membered heteroaryl groups.

[0043] As used herein, "carbocykrill" or "carbocyclic" refers to a non-aromatic ring system with 3 to 10 ring carbon atoms ("C"). 3-10 This refers to a radical of a non-aromatic cyclic hydrocarbon group having 0 heteroatoms ("carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C"). 3-8 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C"). 5-10 Carbocyclyl). Exemplary C 3-6 Examples of carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3-8 The carbocyclyl group is not limited to the aforementioned C 3-6 Examples include the carbocyclyl group, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), and bicyclo[2.2.2]octanyl (C8). Exemplary C 3-10 The carbocyclyl group is not limited to the aforementioned C 3-8 Carbocyclyl group, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10), spiro[4.5]decanil(C 10 Examples include the above. As illustrated by the examples above, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contains condensed, cross-linked, or spirocyclic systems such as bicyclic carbocyclyl, and may be saturated or partially unsaturated. "Carbocyclyl" also includes cyclic systems in which the above-defined carbocyclyl ring is condensed with one or more aryl or heteroaryl groups, and the bond site is on the carbocyclyl ring, in which case the number of carbons continues to specify the number of carbons in the carbocyclic system.

[0044] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridging cyclic (e.g., adamantyl) hydrocarbon group with 3-12, 3-8, 4-8, or 4-6 carbon atoms, and in this specification, for example, "C" derived from cycloalkanes. 4-8 These are referred to as "cycloalkyl" groups. Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane. Unless otherwise specified, cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amide, amidino, amino, aryl, arylalkyl, azide, carbamic acid, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamide, sulfonyl, or thiocarbonyl groups. Cycloalkyl groups can be condensed with other cycloalkyl, aryl, or heterocyclyl groups. In certain embodiments, the cycloalkyl group is unsubstituted, i.e., unsubstituted.

[0045] As used herein, “heterocyclyl” or “heterocyclic” refers to a 3- to 10-membered non-aromatic ring radical ("3- to 10-membered heterocyclyl") having a ring carbon atom and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the bond sites can be carbon or nitrogen atoms, as long as the valence allows. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or bicyclic ("bicyclic heterocyclyl") systems, or condensed, bridged, or spirocyclic systems, and may be saturated or partially unsaturated. A heterocyclyl bicyclic ring system may contain one or more heteroatoms in one or both rings. Other examples of "heterocyclyls" include ring systems in which a heterocyclyl ring, as defined above, is fused with one or more carbocykyl groups, with the bond site located on either a carbocykyl or heterocyclyl ring or ring system, and in which case the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, with the bond site located on the heterocyclyl ring, in which case the number of ring members continues to specify the number of ring members in the heterocyclyl ring system.

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

[0047] Examples of three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azilidinyl, oxylanil, and thiorenyl. Examples of four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanil, and thietanil. Examples of five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanil, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Examples of five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinil, dithianil, and dioxanil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanil, oxepanil, and thiepanil. Examples of eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanil, oxecanil, and thiokanil. Examples of five-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl. Examples of six-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0048] When "hetero" is used to describe a compound or a group present in a compound, it means that one or more carbon atoms in the compound or group are replaced by a heteroatom of nitrogen, oxygen, or sulfur. Hetero may apply to any of the above-mentioned hydrocarbyl groups, such as alkyl, e.g., heteroalkyl; carbocyryl, e.g., heterocyclyl; aryl, e.g., heteroaryl; and similar groups having 1 to 5, particularly 1 to 3, heteroatoms.

[0049] As used herein, "cyano" refers to -CN.

[0050] As used herein, "halo" or "halogen" refers to fluoro(F), chloro(Cl), bromo(Br), and iodine(I). In certain embodiments, the halo group is either fluoro or chloro.

[0051] As used herein, "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0052] As used herein, "nitro" refers to -NO2.

[0053] As used herein, "oxo" refers to -C=O.

[0054] In general, the term “substituted” means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced by an acceptable substituent, such as one that, upon substitution, produces a stable compound, such as one that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reactions. Unless otherwise indicated, a “substituted” group has substituents at one or more of its substituted positions, and if two or more positions of any given structure are substituted, the substituents are either the same or different at each position.

[0055] Nitrogen atoms can be substituted or unsubstituted, as long as their valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents 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 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Examples include aryls and 5- to 14-membered heteroaryls, or two Rs bonded to a nitrogen atom. cc The groups join to form a 3-14 membered heterocyclyl or a 5-14 membered heteroaryl ring, where each of alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with R aa , R bb , R cc , and R dd This is as defined above.

[0056] These and other exemplary substituents are described in more detail in the modes, examples, and claims for carrying out the invention. The present invention is not intended to be limited in any way by the exemplary enumeration of substituents above.

[0057] Other definitions The term "pharmaceutically acceptable salt" refers to a salt that, within reasonable medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and that balances a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Examples of pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or using organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfonate. Examples include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Pharmaceutically acceptable salts derived from appropriate bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4Examples include alkyl)4 salts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons, where appropriate.

[0058] As used herein, the “subject” to which administration is intended includes, but is not limited to, human beings (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents), or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, such as mammals including primates (e.g., cynomolgus macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0059] Diseases, disorders, and conditions are used interchangeably in this specification.

[0060] As used herein, unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” refer to an effect that occurs while the subject is suffering from the specified disease, disorder, or condition, and that reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition (the “therapeutic treatment” also applies).

[0061] Generally, the “effective amount” of a compound refers to the amount sufficient to induce the desired biological response. As will be understood by those skilled in the art, the effective amount of a compound in an invention may vary depending on the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and factors such as the age, weight, health, and condition of the subject.

[0062] As used herein, and unless otherwise specified, “therapeutic dose” of a compound means an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. The therapeutic dose of a compound means the amount of the therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term “therapeutic dose” may include an amount that improves the overall therapy, reduces or avoids the symptoms or causes of the disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0063] In alternative embodiments, the present invention intends to administer the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, as a prophylactic agent before a subject begins to develop a specified disease, disorder, or condition. As used herein, “prophylactic treatment” intends an effect that occurs before a subject begins to develop a specified disease, disorder, or condition. As used herein, and unless otherwise specified, “prophylactic effective dose” of a compound is an amount sufficient to prevent or prevent the recurrence of one or more symptoms of a disease, disorder, or condition, or a disease, disorder, or condition. The prophylactic effective dose of a compound means the amount of a therapeutic agent, either alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term “prophylactic effective dose” may include an amount that improves overall prevention or enhances the prophylactic efficacy of another prophylactic agent.

[0064] As used herein, “disease or condition associated with a gain-of-function mutation in KCNT1” means a disease or condition having one or more symptoms that are associated with, partially or completely caused by, or partially or completely caused by, a mutation in KCNT1 that results in a gain-of-function phenotype, i.e., an increase in the activity of a potassium channel encoded by KCNT1 that results in an increase in total cellular current.

[0065] As used herein, “gain-of-function mutation” is a mutation in KCNT1 that results in an increase in the activity of the potassium channel encoded by KCNT1. The activity can be assessed, for example, by an ion flux assay or by electrophysiological methods (e.g., using the 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%, or 400% or more compared to the potassium channel activity encoded by wild-type KCNT1.

[0066] Compounds and compositions In one embodiment, a compound having formula A is used herein, [ka] X is CR7 or N, and Y is S, or X is CR7, and Y is O. Ring A is selected from the group consisting of phenyl, 6-membered heteroaryl, and 5- to 7-membered heterocyclyl. R1 is selected from the group consisting of phenyl, 5-6 member heteroaryl, -CH2-phenyl, 5-8 member carbocyclyl, and 5-10 member heterocyclyl, and phenyl, 5-6 member heteroaryl, -CH2-phenyl, 5-8 member carbocyclyl, and 5-10 member heterocyclyl are optionally substituted with one or more R6s. R2 is hydrogen or C 1-6 It is alkyl, R3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, C 1-6 Alkyl is C 1-6 Alkoxy, or C 1-6 It is optionally substituted with a haloalkoxy, and R4 is either hydrogen or R3 and R4, together with the carbons bonded to R3 and R4, C 3-8 It may form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R5 and R6 are each independently halogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2R8, -S(O)2-N(R9)2, and C 3-8 Selected from the group consisting of cycloalkyl groups, R7 uses hydrogen, C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R8 is hydrogen or C 1-6 It is alkyl, Each R9 is hydrogen, C 1-6 Alkyl, and -(C 1-6 Either independently selected from the group consisting of alkylene)-OH, or two R9s together with the nitrogen atoms bonded to the two R9s may form a heterocycle in which one or more substituents independently selected from halogens and -OH groups are optionally substituted. n is selected from the group consisting of 0, 1, 2, and 3. However, provided that R3 is hydrogen and ring A is a 6-membered heterocyclyl or 6-membered heteroaryl, R1 is not thiophene. A compound, or a pharmaceutically acceptable salt thereof, is provided, provided that R3 is hydrogen and ring A is a 6-membered heteroaryl or 5-membered heterocycline, and R1 is not phenyl.

[0067] In another embodiment, a compound having formula A-1 is used herein. [ka] X is CR7 or N, and Y is S, or X is CR7, and Y is O. Ring A is a 6-membered heteroaryl, R1 is selected from the group consisting of phenyl, 5-6 member heteroaryl, -CH2-phenyl, 5-8 member carbocyclyl, and 5-10 member heterocyclyl, and phenyl, 5-6 member heteroaryl, -CH2-phenyl, 5-8 member carbocyclyl, and 5-10 member heterocyclyl are optionally substituted with one or more R6s. R2 is hydrogen or C 1-6 It is alkyl, R3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, C 1-6 Alkyl is C 1-6 Alkoxy, or C 1-6 It is optionally substituted with a haloalkoxy, and R4 is either hydrogen or R3 and R4, together with the carbons bonded to R3 and R4, C 3-8 It may form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R5 and R6 are each independently halogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2R8, -S(O)2-N(R9)2, and C 3-8 Selected from the group consisting of cycloalkyl groups, R7 uses hydrogen, C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R8 is hydrogen or C 1-6 It is alkyl, Each R9 is hydrogen, C 1-6 Alkyl, and -(C 1-6Either independently selected from the group consisting of alkylene)-OH, or two R9s together with the nitrogen atoms bonded to the two R9s may form a heterocycle in which one or more substituents independently selected from halogens and -OH groups are optionally substituted. n is selected from the group consisting of 0, 1, 2, and 3. A compound, or a pharmaceutically acceptable salt thereof, is provided, provided that when R3 is hydrogen and ring A is a 6-membered heteroaryl, R1 is neither thiophene nor phenyl.

[0068] In some embodiments of formula A or A-1, ring A is pyridyl.

[0069] In some embodiments of formula A or A-1, the compound is the compound of formula A-1A or formula A-1B. [ka] or a pharmaceutically acceptable salt thereof.

[0070] In another embodiment, a compound having formula A-2 is used herein, [ka] X is CR7 or N, and Y is S, or X is CR7, and Y is O. Ring A is a 5-7 member heterocyclyl, R1 is selected from the group consisting of phenyl, 5-6 member heteroaryl, -CH2-phenyl, 5-8 member carbocyclyl, and 5-10 member heterocyclyl, and phenyl, 5-6 member heteroaryl, -CH2-phenyl, 5-8 member carbocyclyl, and 5-10 member heterocyclyl are optionally substituted with one or more R6s. R2 is hydrogen or C 1-6 It is alkyl, R3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, C 1-6 Alkyl is C 1-6 Alkoxy, or C 1-6 It is optionally substituted with a haloalkoxy, and R4 is either hydrogen or R3 and R4, together with the carbons bonded to R3 and R4, C 3-8 It may form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R5 and R6 are each independently halogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2R8, -S(O)2-N(R9)2, and C 3-8 Selected from the group consisting of cycloalkyl groups, R7 uses hydrogen, C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R8 is hydrogen or C 1-6 It is alkyl, Each R9 is hydrogen, C 1-6 Alkyl, and -(C 1-6 Either independently selected from the group consisting of alkylene)-OH, or two R9s together with the nitrogen atoms bonded to the two R9s may form a heterocycle in which one or more substituents independently selected from halogens and -OH groups are optionally substituted. n is selected from the group consisting of 0, 1, 2, and 3. A compound or a pharmaceutically acceptable salt thereof is provided, provided that R3 is hydrogen and ring A is a 5-6 member heterocycline, and R1 is neither thiophene nor phenyl.

[0071] In some embodiments of formula A or A-2, the compound is a compound of formula A-2A, [ka] Compounds in which q is 1 or 2, or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments of formula A, A-1, or A-2, X is N and Y is S. In other embodiments of formula A, A-1, or A-2, X is CH and Y is O.

[0073] In some embodiments of formula A, A-1, or A-2, R3 is C- 1-6 It is alkyl. For example, R3 is methyl.

[0074] In some embodiments of formulas A, A-1, or A-2, R3 is hydrogen.

[0075] In some embodiments of formulas A, A-1, or A-2, R2 is hydrogen.

[0076] In some embodiments of formula A, A-1, or A-2, R5 is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or C 3-8 It is a cycloalkyl group. For example, R5 is cyclopropyl, -CF3, methyl, -OCH3, or -CH2OCH 3である .

[0077] In some embodiments of formulas A, A-1, or A-2, R1 is a 5- to 6-membered heteroaryl compound optionally substituted with one or more R6s. In some embodiments, the heteroaryl compound is pyrazolyl.

[0078] In some embodiments of formula A, A-1, or A-2, R1 is a phenyl compound optionally substituted with one or more R6s.

[0079] In some embodiments of formulas A, A-1, or A-2, R1 is a -CH2-phenyl optionally substituted with one or more R6s. In some embodiments, the 10-membered heterocyclyl is a bicyclic heterocyclyl.

[0080] In some embodiments of formula A, A-1, or A-2, R1 is selected from the group consisting of the following: [ka] In the formula, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0081] In some embodiments of formulas A, A-1, or A-2, R6 is a halogen, C 1-6 Alkyl, or C 1-6 It is a haloalkyl group.

[0082] In another embodiment, a compound having formula I is used herein. [ka] Or a pharmaceutically acceptable salt thereof is provided, in the formula, X is CR7 or N, and Y is S, or X is CR7, and Y is O. Ring A is selected from the group consisting of phenyl, 6-membered heteroaryl, and 5- to 7-membered heterocyclyl. R1 is selected from the group consisting of phenyl, 5-6 member heteroaryl, -CH2-phenyl, 5-8 member carbocyclyl, and 5-10 member heterocyclyl, and phenyl, 5-6 member heteroaryl, -CH2-phenyl, 5-8 member carbocyclyl, and 5-10 member heterocyclyl are optionally substituted with one or more R6s. R2 is hydrogen or C 1-6 It is alkyl, R3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, C 1-6 Alkyl is C 1-6 Alkoxy or C 1-6 It is optionally substituted with a haloalkoxy, and R4 is either hydrogen or R3 and R4, together with the carbons bonded to R3 and R4, C 3-8 It may form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R5 and R6 are each independently halogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2R8, -S(O)2-N(R9)2, and C 3-8 Selected from the group consisting of cycloalkyl groups, R7 uses hydrogen, C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R8 is hydrogen or C 1-6 It is alkyl, Each R9 is hydrogen, C 1-6 Alkyl, and -(C 1-6 Either independently selected from the group consisting of alkylene)-OH, or two R9s together with the nitrogen atoms bonded to the two R9s may form a heterocycle in which one or more substituents independently selected from halogens and -OH groups are optionally substituted. n is selected from the group consisting of 0, 1, 2, and 3.

[0083] In one embodiment, in this specification, formula IA [ka] Or a pharmaceutically acceptable salt thereof is provided, in the formula, X is CR7 or N, and Y is S, or X is CR7, and Y is O. Ring A is a 6-membered heteroaryl or a 5-7 membered heterocyclyl. R1 is selected from the group consisting of phenyl, 5-6 member heteroaryl, -CH2-phenyl, 5-8 member carbocyclyl, and 5-10 member heterocyclyl, and phenyl, 5-6 member heteroaryl, -CH2-phenyl, 5-10 member carbocyclyl, and 5-10 member heterocyclyl are optionally substituted with one or more R6s. R2 is hydrogen or C 1-6 It is alkyl, R3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, C 1-6 Alkyl is C 1-6 Alkoxy or C 1-6 It is optionally substituted with a haloalkoxy, and R4 is either hydrogen or R3 and R4, together with the carbons bonded to R3 and R4, C 3-8 It may form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R5 and R6 are each independently halogen, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2R8, -S(O)2-N(R9)2, and C 3-8 Selected from the group consisting of cycloalkyl groups, R7 uses hydrogen, C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R8 is hydrogen or C 1-6 It is alkyl, Each R9 is hydrogen, C 1-6 Alkyl, and -(C 1-6Either independently selected from the group consisting of alkylene)-OH, or two R9s together with the nitrogen atoms bonded to the two R9s may form a heterocycle in which one or more substituents independently selected from halogens and -OH groups are optionally substituted. n is selected from the group consisting of 0, 1, 2, and 3.

[0084] In another embodiment, a compound having formula IB is used herein. [ka] Or a pharmaceutically acceptable salt thereof is provided, in the formula, X is CR7 or N, and Y is S, or X is CR7, and Y is O. Ring A is phenyl or a 6-membered heteroaryl, R1 is a phenyl or 5-6 member heteroaryl, and the phenyl or 5-6 member heteroaryl is optionally substituted with one or more R6s. R2 is hydrogen or C 1-6 It is alkyl, R3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, C 1-6 Alkyl is C 1-6 Alkoxy or C 1-6 It is optionally substituted with a haloalkoxy, and R4 is either hydrogen or R3 and R4, together with the carbons bonded to R3 and R4, C 3-8 It may form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R5 and R6 are each independently halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2R8, -S(O)2-N(R9)2, and C 3-8Selected from the group consisting of cycloalkyl groups, R7 uses hydrogen, C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R8 is hydrogen or C 1-6 It is alkyl, Each R9 is hydrogen, C 1-6 Alkyl, and -(C 1-6 Either independently selected from the group consisting of alkylene)-OH, or two R9s together with the nitrogen atoms bonded to the two R9s may form a heterocycle in which one or more substituents independently selected from halogens and -OH groups are optionally substituted. n is selected from the group consisting of 0, 1, 2, and 3.

[0085] In some embodiments of formulas I, IA, or IB, ring A is a six-membered heteroaryl. In some embodiments of formulas I, IA, or IB, ring A is a pyridyl.

[0086] In some embodiments of formulas I, IA, or IB, X is N and Y is S.

[0087] In some embodiments of formulas I, IA, or IB, X is CH and Y is O.

[0088] In some embodiments of formula I, IA, or IB, R3 is C 1-6 It is alkyl. For example, R3 is methyl.

[0089] In some embodiments of formulas I, IA, or IB, R2 is hydrogen.

[0090] In some embodiments of formula I or IA, R5 is C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or C 3-8It is a cycloalkyl group. For example, R5 is cyclopropyl, -CF3, methyl, -OCH3, or -CH2OCH3.

[0091] In some embodiments of formula I, IA, or IB, R5 is C 3-8 Cycloalkyl or C 1-6 It is a haloalkyl group. In some embodiments of formula I, IA, or IB, R5 is cyclopropyl or -CF3.

[0092] In some embodiments of formula I, IA, or IB, n is 0 or 1. In some embodiments of formula I, IA, or IB, n is 1. In some embodiments of formula I, IA, or IB, n is 0.

[0093] In some embodiments of formulas I, IA, or IB, R1 is a 5- to 6-membered heteroaryl compound optionally substituted with one or more R6s. In some embodiments, the heteroaryl compound is pyrazolyl.

[0094] In some embodiments of formulas I, IA, or IB, R1 is a phenyl molecule optionally substituted with one or more R6 molecules.

[0095] In some embodiments of formula I or IA, R1 is a -CH2-phenyl which is optionally substituted with one or more R6s.

[0096] In some embodiments of formula I or IA, R1 is a 10-membered heterocycline optionally substituted with one or more R6s. In some embodiments, the 10-membered heterocycline is a bicyclic heterocycline.

[0097] In some embodiments of formula I, IA, or IB, R6 is a halogen, C 1-6 Alkyl, or C 1-6 It is a haloalkyl group.

[0098] In some embodiments of formula I, IA, or IB, R6 is C1-6 Alkyl or C 1-6 It is a haloalkyl group.

[0099] In some embodiments of formula I, IA, or IB, the compound is a compound of formula I-IA or formula I-IB. [ka] or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments of formula I, IA, or IB, the compound is a compound of formula I-IA2 or formula I-IB2. [ka] or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments of formula I, IA, or IB, the compound is a compound of formula I-IA3, formula I-IA4, formula I-IB3, or formula I-IB4. [ka] or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments of formula I or IA, the compound is a compound of formula I-IC, [ka] Compounds in which q is 1 or 2 or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments of formula I or IA, the compound is a compound of formula I-IC2, [ka] Compounds in which q is 1 or 2 or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments of formula I or IA, the compound is a compound of formula I-IC3 or formula I-IC4. [ka] or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments of formula I, IA, or IB, R1 is selected from the group consisting of: [ka] In the formula, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0106] In some embodiments of formulas I, IA, or IB, R1 is pyrazolyl or phenyl, optionally substituted with one or more R6s.

[0107] In one embodiment, the present invention relates to a compound of formula (II), [ka] or characterized by a pharmaceutically acceptable salt thereof, in the formula, X is CR7 or N, and Y is S, or X is CR7, and Y is O. Ring A is phenyl or a 6-membered heteroaryl, R1 is a phenyl or 5-6 member heteroaryl, and the phenyl or 5-6 member heteroaryl is optionally substituted with one or more R6s. R2 is hydrogen or C 1-6 It is alkyl, R3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, C1-6 Alkyl is C 1-6 Alkoxy or C 1-6 It is optionally substituted with a haloalkoxy, and R4 is either hydrogen or R3 and R4, together with the carbons bonded to R3 and R4, C 3-8 It may form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R5 and R6 are each independently halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2R8, -S(O)2-N(R9)2, and C 3-8 Selected from the group consisting of cycloalkyl groups, R7 uses hydrogen, C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R8 is hydrogen or C 1-6 It is alkyl, Each R9 is hydrogen, C 1-6 Alkyl, and -(C 1-6 Either independently selected from the group consisting of alkylene)-OH, or two R9s together with the nitrogen atoms bonded to the two R9s may form a heterocycle in which one or more substituents independently selected from halogens and -OH groups are optionally substituted. n is selected from the group consisting of 0, 1, 2, and 3.

[0108] In some embodiments, ring A is a six-membered heteroaryl (e.g., pyridyl).

[0109] In some embodiments, X is N and Y is S. In some embodiments, X is CH and Y is O.

[0110] In some embodiments of Formula II, the compound is a compound of Formula II-A or Formula II-B. [ka] or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments of Equation II, R3 is C 1-6 It is an alkyl group (for example, methyl).

[0112] In some embodiments of formula II, R2 is hydrogen.

[0113] In some embodiments of Equation II, n is 0 or 1.

[0114] In some embodiments of Equation II, R5 is C 3-8 Cycloalkyl (e.g., cyclopropyl) or C 1-6 It is a haloalkyl group (for example, CF3).

[0115] In some embodiments of Formula II, R1 is a 5-6 member heteroaryl (e.g., pyrazolyl) optionally substituted with one or more R6s. In some embodiments of Formula II, R1 is a phenyl optionally substituted with one or more R6s. In some embodiments of Formula II, R6 is C 1-6 Alkyl or C 1-6 It is a haloalkyl group.

[0116] In some embodiments, the compound is [ka] Selected from the group consisting of TIFF0007838820000027.tif227170, TIFF0007838820000028.tif233170, or pharmaceutically acceptable salts thereof.

[0117] In another embodiment, the Specified herein provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (A), (A-1), (A-1A), (A-1B), (A-2), (A-2A), (I), (IA), (I-IA), (I-IA2), (I-IA3), (I-IA4), (IB), (I-IB), (I-IB2), (I-IB3), (I-IB4), (I-IC), (I-IC2), (I-IC3), (I-IC4), (II), (II-A), or (II-B), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient.

[0118] General synthesis scheme Exemplary methods for preparing the compounds described herein are illustrated in the following synthesis schemes. These schemes are provided for illustrative purposes only and should not be considered to limit the scope or spirit of the invention in any way.

[0119] [ka] The synthetic route illustrated in Scheme 1 shows exemplary steps for preparing intermediates D4 and E7. In the first step, compound D1 is reacted with (COCl)2 and ammonia to form amide D2. Next, amide D2 is reacted with chlorocarbonyl sulfenyl chloride to form D3, which is then reacted with an R3-containing cyanide to form D4. To form intermediate E7, carboxylic acid E1 is reacted with borane to form E2, which is then reacted with des-martin periodinane to form E3. Next, E3 is reacted with hydroxylamine to form E4, which is then reacted with N-chlorosuccinimide to form E5. Next, E5 is reacted with an R3-containing alcohol to form E6, which is then reacted with des-martin periodinane to form intermediate E7.

[0120] [ka] The synthetic route illustrated in Scheme 2 represents an exemplary procedure for preparing the compound of formula I from intermediate D4 or E7 described in Scheme 1. Intermediate D4 or E7 is reacted with a sulfinamide to form F, which is subsequently reduced to form G. Next, G is reacted with an acid to form H, which is reacted with an R1-containing carboxylic acid to form the compound of formula I.

[0121] [ka] The synthetic route illustrated in Scheme 3 shows exemplary steps for preparing the compounds J8 and J12 of formula I. In the first step, compound J1 is reacted with 1-ethoxyvinyltri-n-butyltin to form J2. Next, J2 is reacted with A-containing dioxaborolane to form J3, which is then reacted with an acid to form J4. Next, J4 is reacted with either (R)-2-methylpropane-2-sulfinamide or (S)-2-methylpropane-2-sulfinamide to form J5 or J9, which is then reacted with L-selectride to form J6 or J10. Next, J6 or J10 is reacted independently with an acid to form amine J7 or J11, which is then reacted with an R1-containing carboxylic acid to form J8 or J12.

[0122] [ka] The synthetic route illustrated in Scheme 4 shows an exemplary procedure for preparing compounds K7 and K12 of formula I. In the first step, compound K1 or K8 is reacted with phthalimide to form K2 or K9, respectively. Next, K2 or K9 is reacted with an A-containing carboxyimidoyl chloride to form K4 or K10, which is then reacted with hydrazine to form K6 or K11. Next, K6 or K11 is reacted with an R1-containing carboxylic acid to form K7 or K12.

[0123] Treatment method The compounds and compositions described above and in this specification can be used to treat neurological disorders or conditions, or diseases or conditions associated with excessive neuronal excitability and / or gain-of-function mutations in genes (e.g., KCNT1). Exemplary diseases, disorders, or conditions include epilepsy and other encephalopathy (e.g., infantile epilepsy with migratory focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, developmental and epileptic encephalopathy (DEE), early-onset infantile epileptic encephalopathy (EIEE), generalized epilepsy, focal epilepsy, multifocal epilepsy, temporal lobe epilepsy, Ohtahara syndrome, early myoclonic encephalopathy, and Lennox This includes Gastaut syndrome, drug-resistant epilepsy, seizures (e.g., frontal lobe seizures, generalized tonic-clonic seizures, asymmetric tonic seizures, focal seizures, leukodystrophy, myelinogenic leukodystrophy, leukoencephalopathy, and sudden unexpected death in epilepsy), cardiac dysfunction (e.g., cardiac arrhythmias, Brugada syndrome, myocardial infarction), pulmonary vascular disorders / hemorrhages, pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraines, etc.), muscle disorders (e.g., myotonia, neuromyotonia, muscle spasms, spasticity), itching and pruritus, motor disorders (e.g., ataxia and cerebellar ataxia), psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia, attention deficit hyperactivity disorder), neurodevelopmental disorders, learning disabilities, intellectual disabilities, fragility X, neuroplasticity, and autism spectrum disorder.

[0124] In some embodiments, the neurological disorder or condition, or the disorder or condition associated with excessive neuronal excitability and / or a gain-of-function mutation in a gene (e.g., KCNT1), is selected from EIMFS, ADNFLE, and West syndrome. In some embodiments, the neurological disorder or condition, or the disorder or condition associated with excessive neuronal excitability and / or a gain-of-function mutation in a gene (e.g., KCNT1), is selected from infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, and Lennox-Gastaut syndrome. In some embodiments, the neurological disorder or condition, or the disorder or condition associated with excessive neuronal excitability and / or a gain-of-function mutation in a gene (e.g., KCNT1), is seizure. In some embodiments, the neurological disorder or condition, or the disorder or condition associated with excessive neuronal excitability and / or a gain-of-function mutation in a gene (e.g., KCNT1), is selected from cardiac arrhythmias, Brugada syndrome, and myocardial infarction.

[0125] In some embodiments, neurological disorders or conditions, or disorders or conditions associated with excessive neuronal excitability and / or gain-of-function mutations in genes (e.g., KCNT1), are selected from the group consisting of learning disabilities, fragile X, intellectual disability, neuroplasticity, psychotic disorders, and autism spectrum disorders.

[0126] Therefore, the compound and its composition can be administered to subjects with neurological disorders 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, West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, as well as Lennox-Gastaut syndrome, seizures, cardiac arrhythmias, Brugada syndrome, and myocardial infarction).

[0127] EIMFS is a rare and debilitating genetic condition characterized by early onset (before 6 months of age) of nearly continuous, heterogeneous focal seizures, where the seizures appear to migrate from one brain region and hemisphere to another. Individuals with EIMFS generally have intellectual disability, speech impairment, and gait disturbances. Several genes have been linked to EIMFS, but the gene most commonly associated with EIMFS is KCNT1. Several new mutations in KCNT1 have been identified in patients with EIMFS, including V271F, G288S, R428Q, R474Q, R474H, R474C, I760M, A934T, P924L, G243S, H257D, A259D, R262Q, Q270E, L274I, F346L, C377S, R398Q, P409S, A477T, F502V, M516V, Q550del, K629E, K629N, I760F, E893K, M896K, R933G, R950Q, and K1154Q (Barcia et al. (2012) Nat Genet. 44:1255-1260, Ishii et al. al. (2013) Gene531:467-471, McTague et al. (2013) Brain.136:1578-1591, Epi4K Consortium&Epilepsy Phenome / Genome Project. (2013) Nature501:217-221, Lim et al. (2016) Neurogenetics, Ohba et al. al.(2015)Epilepsia56:el21-el28, Zhou et al.(2018)Genes Brain Behav.e12456, Moller et al.(2015)Epilepsia.e114-20, Numis et al.(2018)Epilepsia.1889-1898, Madaan et al.Brain Dev.40(3):229-232, McTague et al. al. (2018) Neurology.90(1):e55-e66, Kawasaki et al. (2017) J Pediatr.191:270-274, Kim et al. (2014) Cell Rep.9(5):1661-1672, Ohba et al. (2015) Epilepsia.56(9):e121-8, Rizzo et al. (2016) Mol Cell Neurosci.72:54-63, Zhang et al. (2017) Clin Genet.91(5):717-724, Mikati et al. (2015) Ann Neurol.78(6):995-9, Baumer et al. al.(2017) Neurology.89(21):2212, Dilena et al.(2018) Neurotherapeutics.15(4):1112-1126). These mutations are dominant (i.e., present in only one allele) gain-of-function missense mutations, and when tested in African clawed frog oocytes or mammalian expression systems, they alter the function of the encoded potassium channel, leading to a significant increase in total cell current (see, e.g., Milligan et al. (2015) Ann Neurol. 75(4):581-590, Barcia et al. (2012) Nat Genet. 44(11):1255-1259, and Mikati et al. (2015) Ann Neurol. 78(6):995-999).

[0128] ADNFLE has a later onset than EIMFS, generally occurring in mid-childhood, and is generally not severe. It is characterized by nocturnal frontal lobe seizures and can cause mental, behavioral, and cognitive impairments in patients with the condition. ADNFLE is associated with several genes encoding neuronicotinic acetylcholine receptor subunits, but mutations in the KCNT1 gene are associated with more severe cases of the disease (Heron et al. (2012) Nat Genet. 44:1188-1190). Functional studies of ADNFLE-associated mutant KCNT1 genes have shown that the underlying mutations (M896I, R398Q, Y796H, and R928C) are dominant gain-of-function mutations (Milligan et al. (2015) Ann Neurol. 75(4):581-590, Mikati et al. (2015) Ann Neurol. 78(6):995-999).

[0129] West syndrome is a severe form of epilepsy characterized by three features: infantile spasms, interictal electroencephalogram (EEG) patterns known as hypsarrhythmia, and intellectual disability. However, it can be diagnosed even if one of these features is absent. Mutations in KCNT1, including G652V and R474H, have been associated with West syndrome (Fukuoka et al. (2017) Brain Dev39:80-83 and Ohba et al. (2015) Epilepsia56:el21-el28). Therapies targeting the KCNT1 channel suggest that these mutations are gain-of-function mutations (Fukuoka et al. (2017) Brain Dev39:80-83).

[0130] In one embodiment, the present invention relates to 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 (e.g., infantile epilepsy with migratory focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy (DEE), and LennoxGastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic seizures, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia, asymmetric tonic seizures), as well as cardiac dysfunction (e.g., cardiac arrhythmias, Brugada syndrome, sudden unexpected death in epilepsy, myocardial infarction), pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.), muscle disorders (e.g., myotonia, neuromyotomy). The present invention relates to a therapeutic method for treating (muscle spasms, spasticity), itching and pruritus, ataxia and cerebellar ataxia, mental disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia), learning disabilities, fragility X, neuroplasticity, and autism spectrum disorder), wherein the present invention relates to a subject requiring the treatment of the compounds disclosed herein (e.g., formulas (A), (A-1), (A-1A), (A-1B), (A-2), (A-2A), (I), (IA), (I-IA), ( Compounds of formulas I-IA2), (I-IA3), (I-IA4), (IB), (I-IB), (I-IB2), (I-IB3), (I-IB4), (I-IC), (I-IC2), (I-IC3), (I-IC4), (II), (II-A), or (II-B), or their pharmaceutically acceptable salts), or pharmaceutical compositions disclosed herein (for example, compounds disclosed herein (for example, formulas (A), (A-1), (A-1A), (A-1B)) The treatment involves administering a pharmaceutical composition comprising (A-2), (A-2A), (I), (IA), (I-IA), (I-IA2), (I-IA3), (I-IA4), (IB), (I-IB), (I-IB2), (I-IB3), (I-IB4), (I-IC), (I-IC2), (I-IC3), (I-IC4), (II), (II-A), or (II-B) compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0131] In some embodiments, subjects presenting a disease or condition potentially associated with gain-of-function mutations in KCNT1 are genotyped to confirm the presence of known gain-of-function mutations in KCNT1 before administration of the compound and its composition. For example, whole-exome sequencing may be performed on the subjects. Gain-of-function mutations associated with EIMFS include, but are not limited to, V271F, G288S, R428Q, R474Q, R474H, R474C, I760M, A934T, P924L, G243S, H257D, A259D, R262Q, Q270E, L274I, F346L, C377S, R398Q, P409S, A477T, F502V, M516V, Q550del, K629E, K629N, I760F, E893K, M896K, R933G, R950Q, and K1154Q. Gain-of-function variants (GVs) associated with ADNFLE include, but are not limited to, M896I, R398Q, Y796H, R928C, and G288S. Gain-of-function variants associated with West syndrome include, but are not limited to, G652V and R474H. Gain-of-function variants associated with temporal lobe epilepsy include, but are not limited to, R133H and R565H. Gain-of-function variants associated with Lennox-Gastaut include, but are not limited to, R209C. Gain-of-function variants associated with seizures include, but are not limited to, A259D, G288S, R474C, and R474H. Gain-of-function variants associated with leukodystrophy include, but are not limited to, G288S and Q906H. Gain-of-function variants associated with multifocal epilepsy include, but are not limited to, V340M. Gain-of-function mutations associated with EOE include, but are not limited to, F346L and A934T. Gain-of-function mutations associated with early-onset epileptic encephalopathy (EOEE) include, but are not limited to, R428Q. Gain-of-function mutations associated with developmental and epileptic encephalopathy include, but are not limited to, F346L, R474H, and A934T. Gain-of-function mutations associated with epileptic encephalopathy include, but are not limited to, L437F, Y796H, P924L, and R961H.Gain-of-function mutations (GMOs) associated with early-onset epileptic encephalopathy of infants (EIEE) include, but are not limited to, M896K. Gain-of-function mutations associated with drug-resistant epilepsy and generalized tonic-clonic seizures include, but are not limited to, F346L. Gain-of-function mutations associated with migratory partial seizures in infants include, but are not limited to, R428Q. Gain-of-function mutations associated with leukoencephalopathy include, but are not limited to, F932I. Gain-of-function mutations associated with NFLE include, but are not limited to, A934T and R950Q. Gain-of-function mutations associated with Ohtahara syndrome include, but are not limited to, A966T. Gain-of-function mutations associated with infantile spasms include, but are not limited to, P924L. Gain-of-function mutations associated with Brugada syndrome include, but are not limited to, R1106Q. Gain-of-function mutations associated with Brugada syndrome include, but are not limited to, R474H.

[0132] In other examples, the subject is first genotyped to identify the presence of a mutation in KCNT1, and then, a standard in vitro assay, such as the assay described in Milligan et al. (2015) Ann Neurol. 75(4):581-590, is used to confirm that this mutation is a gain-of-function mutation. Typically, when evaluated using whole-cell electrophysiological methods (e.g., the methods described in Milligan et al. (2015) Ann Neurol. 75(4):581-590, Barcia et al. (2012) Nat Genet. 44(11):1255-1259, Mikati et al. (2015) Ann Neurol. 78(6):995-999, or Rizzo et al. Mol Cell Neurosci. (2016) 72:54-63), the presence of a gain-of-function mutation is confirmed when the expression of the mutant KCNT1 allele results in an increase in whole-cell current compared to the whole-cell current resulting from the expression of wild-type KCNT1. This increase in whole-cell current can be, for example, at least or about 50%, 100%, 150%, 200%, 250%, 300%, 350%, or 400% or more. In this way, it can be confirmed that the subject has a disease or condition related to gain-of-function mutations in KCNT1.

[0133] In certain embodiments, the subject is identified as having a KCNT1 allele containing a gain-of-function mutation (e.g., V271F, G288S, R398Q, R428Q, R474Q, R474H, R474C, G652V, I760M, Y796H, M896I, P924L, R928C, or A934T).

[0134] Compounds disclosed herein (e.g., compounds of formulas (A), (A-1), (A-1A), (A-1B), (A-2), (A-2A), (I), (IA), (I-IA), (I-IA2), (I-IA3), (I-IA4), (IB), (I-IB), (I-IB2), (I-IB3), (I-IB4), (I-IC), (I-IC2), (I-IC3), (I-IC4), (II), (II-A), or (II-B)), or pharmaceutically acceptable salts thereof), or pharmaceutical compositions disclosed herein (e.g., compounds disclosed herein (e.g., compounds of formulas (A), (A-1), (A-1A), ( A pharmaceutical composition comprising a compound of (A-1B), (A-2), (A-2A), (I), (IA), (I-IA), (I-IA2), (I-IA3), (I-IA4), (IB), (I-IB), (I-IB2), (I-IB3), (I-IB4), (I-IC), (I-IC2), (I-IC3), (I-IC4), (II), (II-A), or (II-B), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient may be used therapeutically for conditions associated with excessive neuronal excitability, which is not necessarily the result of a gain-of-function mutation in KCNT1. Even if the disease is not the result of increased KCNT1 expression and / or activity, inhibition of KCNT1 expression and / or activity can result in a reduction of neuronal excitability, thereby providing a therapeutic effect.Therefore, the compounds disclosed herein (for example, formulas (A), (A-1), (A-1A), (A-1B), (A-2), (A-2A), (I), (IA), (I-IA), (I-IA2), (I-IA3), (I-IA4), (IB), (I-IB), (I-IB2), (I-IB3), (I-IB4), (I-IC), (I-IC2), (I-IC3), Compounds of formula (I-IC4), (II), (II-A), or (II-B), or their pharmaceutically acceptable salts), or pharmaceutical compositions disclosed herein (for example, compounds disclosed herein (for example, formulas (A), (A-1), (A-1A), (A-1B), (A-2), (A-2A), (I), (IA), (I-IA), (I-IA2), (I-I A pharmaceutical composition comprising a compound of A3), (I-IA4), (IB), (I-IB), (I-IB2), (I-IB3), (I-IB4), (I-IC), (I-IC2), (I-IC3), (I-IC4), (II), (II-A), or (II-B) (or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable excipient, regardless of whether the disease or disorder is related to a gain-of-function mutation in KCNT1, for example, epilepsy and other encephalopathy (e.g., infantile epilepsy with migratory focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ANDFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, and Lennox It can be used to treat subjects with conditions associated with excessive neuronal excitability, such as Gastaut syndrome (seizures), or cardiac insufficiency (e.g., cardiac arrhythmias, Brugada syndrome, myocardial infarction).

[0135] Pharmaceutical composition and route of administration The compounds provided in accordance with the present invention are typically administered in the form of pharmaceutical compositions. Accordingly, the present invention provides pharmaceutical compositions containing, as active ingredients, one or more of the compounds described, or pharmaceutically acceptable salts or esters thereof, and a carrier comprising one or more pharmaceutically acceptable excipients, an inert solid diluent and a packing agent, a diluent comprising a sterile aqueous solution and various organic solvents, an osmotic enhancer, a solubilizer, and an adjuvant. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in ways well known in the pharmaceutical art (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & C.T. Rhodes, Eds.)).

[0136] The pharmaceutical composition may be administered in single or multiple doses by any of the acceptable modes of administration of the drug having similar utility to those described in the patents and patent applications incorporated by reference, for example, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, or topical, as an inhalant, or via an impregnated or coated device such as a stent or an arterial insertion cylindrical polymer.

[0137] One mode of administration is parenteral, particularly by injection. Forms into which the novel compositions of the present invention can be incorporated for injection include aqueous or oily suspensions, emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in physiological saline have also been conventionally used for injection, but are less preferred in relation to the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial activity can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0138] Sterile injectable solutions are prepared by incorporating the required amount of the compound according to the present invention into a suitable solvent containing, if necessary, various other components listed above, and then sterilizing by filtration. Generally, dispersions are prepared by incorporating various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other required components from those listed above. In the case of sterile powders for preparing sterile injectable solutions, preferred preparation methods are vacuum drying and freeze-drying techniques to obtain powders of the active ingredients and any additional desired components from the sterile solution that has been pre-sterilized and filtered.

[0139] Oral administration is another route for administering the compounds according to the present invention. Administration may be via capsules or enteric-coated tablets, etc. In the preparation of a pharmaceutical composition comprising at least one compound described herein, the active ingredient is usually diluted with an excipient and / or encapsulated in a carrier, which may be in the form of a capsule, pouch, paper, or other container. When the excipient functions as a diluent, the excipient may be in the form of a solid, semi-solid, or liquid material (as described above) acting as a vehicle, carrier, or medium for the active ingredient. For this reason, the composition may be in the form of tablets, pills, powders, licks, pouches, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), for example, ointments, soft and hard gelatin capsules, sterile injection solutions, and sterile packaging powders containing up to 10% by weight of the active compound.

[0140] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may further contain lubricants, wetting agents, emulsifiers and suspending agents such as talc, magnesium stearate, and mineral oil, as well as preservatives, sweeteners and flavoring agents such as methyl and propyl hydroxybenzoates.

[0141] The compositions of the present invention can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug polymer matrix formulations. Examples of controlled-release systems are described in U.S. Patents 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the method of the present invention utilizes a transdermal delivery device ("patch"). Such a transdermal patch may be used to provide continuous or discontinuous infusion of the compound of the present invention in a controlled amount. The configuration and use of transdermal patches for delivering pharmaceuticals 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 for continuous, pulsed, or on-demand delivery of pharmaceuticals.

[0142] The composition is preferably formulated in unit dosage forms. The term “unit dosage form” refers to a physically distinct unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect in relation to a suitable pharmaceutically effective excipient (e.g., tablet, capsule, ampoule). The compound is generally administered in a pharmaceutically effective dose. 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 will be understood that the actual amount of compound administered will usually be determined by a physician in consideration of relevant circumstances, including the condition being treated, the route of administration selected, the actual compound administered and its relative activity, the individual patient’s age, weight, and response, and the severity of the patient’s symptoms.

[0143] To prepare solid compositions such as tablets, the main active ingredients are mixed with pharmaceutical excipients to form a solid preliminary formulation composition containing a homogeneous mixture of the compounds of the present invention. When these preliminary formulation compositions are referred to as homogeneous, it means that the active ingredients are uniformly dispersed throughout the composition, thereby allowing the composition to be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0144] The tablets or pills of the present invention may be coated or otherwise formulated to provide a dosage form that offers the advantage of long-term action or to protect from the acidic conditions of the stomach. For example, the tablets or pills may contain an inner dosage component and an outer dosage component, the latter in the form of a coating covering the former. The two components may be separated by an enteric coating that functions to withstand disintegration in the stomach and allow the inner component to pass through the duodenum intact or be released with delayed release. A variety of materials can be used for such enteric coatings or coatings, including a number of polymer acids, as well as mixtures of polymer acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0145] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous solvents or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, compositions are administered orally or via nasal respiratory routes for topical or systemic effects. Preferably, compositions in pharmaceutically acceptable solvents may be sprayed using an inert gas. The sprayed solution may be inhaled directly from a spraying device, or the spraying device may be attached to a face mask tent or an intermittent positive pressure respirator. The solution, suspension, or powder composition may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0146] In some embodiments, a pharmaceutical composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. This disclosure includes the aspects described in the following sections. [Section 1] A compound having formula A, TIFF0007838820000033.tif25129 X, CR 7 Or N is S, or X, CR 7 And Y is O, Ring A is selected from the group consisting of phenyl, 6-membered heteroaryl, and 5- to 7-membered heterocyclyl. R 1 However, phenyl, 5-6 member heteroaryl, -CH 2 - Selected from the group consisting of phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl, and the phenyl, 5-6 membered heteroaryl, -CH 2 - Phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl are present in one or more R 6 It is optionally replaced by, R 2 However, hydrogen or C 1-6 It is alkyl, R 3 However, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, the C 1-6 Alkyl is C 1-6 Alkoxy, or C 1-6 Optionally substituted with a haloalkoxy, R 4 However, is it hydrogen, or R 3 and R 4 However, R 3 and R 4 Together with the carbon that is bonded to it, C 3-8 It may form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R 5 and R 6 However, each is independent of halogen and C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) 2 R 8 , -S(O) 2 -N(R 9 ) 2 , and C3-8 Selected from the group consisting of cycloalkyl groups, R 7 However, hydrogen, C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R 8 However, hydrogen or C 1-6 It is alkyl, Each R 9 However, hydrogen, C 1-6 Alkyl, and -(C 1-6 Independently selected from the group consisting of alkylene)-OH, or two R 9 However, the two Rs mentioned above 9 Together with the nitrogen atom bonded to it, it can form a heterocycle which is optionally substituted with one or more substituents independently selected from halogens and -OH groups. n is selected from the group consisting of 0, 1, 2, and 3. However, R 3 When is hydrogen and ring A is a 6-membered heterocyclyl or 6-membered heteroaryl, R 1 Provided that it is not thiophene, However, R 3 When is hydrogen and ring A is a 6-membered heteroaryl or 5-membered heterocycline, R 1 A compound, or a pharmaceutically acceptable salt thereof, provided that it is not phenyl, A pharmaceutical composition comprising a pharmaceutically acceptable carrier. [Section 2] A compound having formula A-1, TIFF0007838820000034.tif25129 X, CR 7 Or N is S, or X, CR 7 And Y is O, Ring A is a 6-membered heteroaryl, R 1 However, phenyl, 5-6 member heteroaryl, -CH 2 - Selected from the group consisting of phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl, and the phenyl, 5-6 membered heteroaryl, -CH 2 - Phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl are present in one or more R 6 It is optionally replaced by, R 2 However, hydrogen or C 1-6 It is alkyl, R 3 However, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, the C 1-6 Alkyl is C1-6 Alkoxy, or C 1-6 Optionally substituted with a haloalkoxy, R 4 However, is it hydrogen, or R 3 and R 4 However, R 3 and R 4 Together with the carbon that is bonded to it, C 3-8 It may form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R 5 and R 6 However, each is independent of halogen and C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) 2 R 8 , -S(O) 2 -N(R 9 ) 2 , and C 3-8 Selected from the group consisting of cycloalkyl groups, R 7 However, hydrogen, C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R 8 However, hydrogen or C 1-6 It is alkyl, Each R 9 However, hydrogen, C 1-6 Alkyl, and -(C 1-6 Independently selected from the group consisting of alkylene)-OH, or two R 9 However, the two Rs mentioned above 9 Together with the nitrogen atom bonded to it, it can form a heterocycle which is optionally substituted with one or more substituents independently selected from halogens and -OH groups. n is selected from the group consisting of 0, 1, 2, and 3. However, R 3 When is hydrogen and ring A is a 6-membered heteroaryl, R 1 A compound, or a pharmaceutically acceptable salt thereof, provided that it is neither thiophene nor phenyl, A pharmaceutical composition comprising a pharmaceutically acceptable carrier. [Section 3] The pharmaceutical composition according to item 1 or 2, wherein ring A is pyridyl. [Section 4] The aforementioned compound is a compound of formula A-1A or formula A-1B. TIFF0007838820000035.tif25169 A pharmaceutical composition according to any one of items 1 to 3, or a pharmaceutically acceptable salt thereof. [Section 5] A compound having formula A-2, TIFF0007838820000036.tif25129 X, CR 7 Or N is S, or X, CR 7 And Y is O, Ring A is a 5-7 member heterocyclyl, R 1 However, phenyl, 5-6 member heteroaryl, -CH 2 - Selected from the group consisting of phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl, and the phenyl, 5-6 membered heteroaryl, -CH 2 - Phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl are present in one or more R 6 It is optionally replaced by, R 2 However, hydrogen or C 1-6 It is alkyl, R 3 However, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, the C 1-6 Alkyl is C 1-6 Alkoxy, or C 1-6 Optionally substituted with a haloalkoxy, R 4 However, is it hydrogen, or R 3 and R 4 However, R 3 and R 4 Together with the carbon that is bonded to it, C 3-8 It may form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R 5 and R 6 However, each is independent of halogen and C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) 2 R 8 , -S(O) 2 -N(R 9) 2 , and C 3-8 Selected from the group consisting of cycloalkyl groups, R 7 However, hydrogen, C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R 8 However, hydrogen or C 1-6 It is alkyl, Each R 9 However, hydrogen, C 1-6 Alkyl, and -(C 1-6 Independently selected from the group consisting of alkylene)-OH, or two R 9 However, the two Rs mentioned above 9 Together with the nitrogen atom bonded to it, it can form a heterocycle which is optionally substituted with one or more substituents independently selected from halogens and -OH groups. n is selected from the group consisting of 0, 1, 2, and 3. However, R 3 When is hydrogen and ring A is a 5-6 member heterocycline, R 1 The compound or a pharmaceutically acceptable salt thereof is provided that it is neither thiophene nor phenyl. A pharmaceutical composition comprising a pharmaceutically acceptable carrier. [Section 6] The aforementioned compound is a compound of formula A-2A, TIFF0007838820000037.tif26128 Compounds in which q is 1 or 2, A pharmaceutical composition according to item 1 or 5, or a pharmaceutically acceptable salt thereof. [Section 7] A pharmaceutical composition according to any one of claims 1 to 6, wherein X is N and Y is S. [Section 8] A pharmaceutical composition according to any one of claims 1 to 6, wherein X is CH and Y is O. [Section 9] R 3 However, C 1-6 A pharmaceutical composition according to any one of items 1 to 8, wherein the composition is alkyl. [Section 10] R 3 A pharmaceutical composition according to any one of items 1 to 8, wherein the hydrogen is hydrogen. [Section 11] R 2 A pharmaceutical composition according to any one of items 1 to 10, wherein the hydrogen is hydrogen. [Section 12] R 5 However, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or C 3-8 A cycloalkyl pharmaceutically active composition as described in any one of items 1 to 11. [Section 13] R 1 However, one or more R 6 A pharmaceutical composition according to any one of claims 1 to 12, wherein the 5-6 member heteroaryl is optionally substituted. [Section 14] The pharmaceutical composition according to item 13, wherein the heteroaryl is pyrazolyl. [Section 15] R 1 However, one or more R 6 A pharmaceutical composition according to any one of claims 1 to 12, wherein the phenyl is optionally substituted with phenyl. [Section 16] R 1 However, one or more R 6 -CH is optionally substituted with 2 - A pharmaceutical composition according to any one of items 1 to 12, wherein the composition is phenyl. [Section 17] R 1 However, one or more R 6 A pharmaceutical composition according to any one of claims 1 to 12, wherein the 10-membered heterocycline is optionally substituted with . [Section 18] The pharmaceutical composition according to item 17, wherein the 10-membered heterocyclyl is a bicyclic heterocyclyl. [Section 19] R 6 However, halogen, C 1-6 Alkyl, or C 1-6 A pharmaceutical composition according to any one of items 1 to 18, which is a haloalkyl. [Section 20] Compounds having formula I, TIFF0007838820000038.tif26128 or a pharmaceutically acceptable salt thereof, in the formula, X, CR 7 Or N is S, or X, CR 7 And Y is O, Ring A is selected from the group consisting of phenyl, 6-membered heteroaryl, and 5- to 7-membered heterocyclyl. R 1 However, phenyl, 5-6 member heteroaryl, -CH 2 - Selected from the group consisting of phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl, and the phenyl, 5-6 membered heteroaryl, -CH 2 - Phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl are present in one or more R 6 It is optionally replaced by, R 2 However, hydrogen or C 1-6 It is alkyl, R 3 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, the C 1-6 Alkyl is C 1-6 Alkoxy or C 1-6 Optionally substituted with a haloalkoxy, R 4 However, is it hydrogen, or R 3 and R 4 However, R 3 and R 4 Together with the carbon that is bonded to it, C 3-8 It may form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R 5 and R 6 However, each is independent of halogen and C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) 2 R 8 , -S(O) 2 -N(R 9 ) 2 , and C 3-8 Selected from the group consisting of cycloalkyl groups, R 7 However, hydrogen, C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R 8 However, hydrogen or C 1-6 It is alkyl, Each R 9 However, hydrogen, C 1-6 Alkyl, and -(C 1-6 Independently selected from the group consisting of alkylene)-OH, or two R 9 However, the two Rs mentioned above 9 Together with the nitrogen atom bonded to it, it can form a heterocycle which is optionally substituted with one or more substituents independently selected from halogens and -OH groups. A compound or a pharmaceutically acceptable salt thereof, wherein n is selected from the group consisting of 0, 1, 2, and 3. [Section 21] Compounds having formula IA, TIFF0007838820000039.tif24128 or a pharmaceutically acceptable salt thereof, in the formula, X, CR 7 Or N is S, or X, CR 7 And Y is O, Ring A is a 6-membered heteroaryl or a 5-7 membered heterocyclyl. R 1 However, phenyl, 5-6 member heteroaryl, -CH 2 - Selected from the group consisting of phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl, and the phenyl, 5-6 membered heteroaryl, -CH 2 - Phenyl, 5-10 membered carbocyclyl, and 5-10 membered heterocyclyl are present in one or more R 6 It is optionally replaced by, R 2 However, hydrogen or C 1-6 It is alkyl, R 3 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, the C 1-6 Alkyl is C 1-6 Alkoxy or C 1-6 Optionally substituted with a haloalkoxy, R 4 However, is it hydrogen, or R 3 and R 4 However, R 3 and R 4 Together with the carbon that is bonded to it, C 3-8 It may form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R 5 and R 6 However, each is independent of halogen and C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) 2 R 8 , -S(O) 2 -N(R 9 ) 2 , and C 3-8 Selected from the group consisting of cycloalkyl groups, R 7 However, hydrogen, C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R 8 However, hydrogen or C 1-6 It is alkyl, Each R 9 However, hydrogen, C 1-6 Alkyl, and -(C 1-6 Independently selected from the group consisting of alkylene)-OH, or two R 9 However, the two Rs mentioned above 9 Together with the nitrogen atom bonded to it, it can form a heterocycle which is optionally substituted with one or more substituents independently selected from halogens and -OH groups. A compound or a pharmaceutically acceptable salt thereof, wherein n is selected from the group consisting of 0, 1, 2, and 3. [Section 22] Compounds having formula IB, TIFF0007838820000040.tif23128 or a pharmaceutically acceptable salt thereof, in the formula, X, CR 7 Or N is S, or X, CR 7 And Y is O, Ring A is phenyl or a 6-membered heteroaryl, R 1 However, the compound is phenyl or a 5-6 member heteroaryl, and the phenyl or 5-6 member heteroaryl is one or more R 6 It is optionally replaced by, R 2 However, hydrogen or C 1-6 It is alkyl, R 3 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 Selected from the group consisting of cycloalkyls, the C 1-6 Alkyl is C 1-6 Alkoxy or C 1-6 Optionally substituted with a haloalkoxy, R 4 However, is it hydrogen, or R 3 and R 4 However, R 3 and R 4 Together with the carbon that is bonded to it, C 3-8 It may form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R 5 and R 6 However, each is independent of halogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O) 2 R 8 , -S(O) 2 -N(R 9 ) 2 , and C 3-8 Selected from the group consisting of cycloalkyl groups, R 7 However, hydrogen, C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R 8 However, hydrogen or C 1-6 It is alkyl, Each R 9 However, hydrogen, C 1-6 Alkyl, and -(C 1-6 Independently selected from the group consisting of alkylene)-OH, or two R 9 However, the two Rs mentioned above 9 Together with the nitrogen atom bonded to it, it can form a heterocycle which is optionally substituted with one or more substituents independently selected from halogens and -OH groups. A compound or a pharmaceutically acceptable salt thereof, wherein n is selected from the group consisting of 0, 1, 2, and 3. [Section 23] A compound according to any one of items 20 to 22, wherein ring A is a 6-membered heteroaryl. [Section 24] A compound according to any one of items 20 to 23, wherein ring A is pyridyl. [Section 25] A compound according to any one of items 20 to 23, wherein X is N and Y is S. [Section 26] A compound according to any one of items 20 to 23, wherein X is CH and Y is O. [Section 27] R 3 However, C 1-6 A compound that is alkyl, as described in any one of items 20 to 26. [Section 28] R 3 A compound according to any one of items 20 to 27, wherein the compound is methyl. [Section 29] R 2 A compound described in any one of items 20 to 28, wherein the compound is hydrogen. [Section 30] R 5 However, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or C 3-8 A compound that is cycloalkyl, as described in any one of items 20-21 and 23-29. [Section 31] R 5 However, cyclopropyl, -CF 3 methyl, -OCH 3 , or -CH 2 OCH 3 The compound described in any one of items 20-21 and 23-30. [Section 32] R 5 However, C 3-8 Cycloalkyl or C 1-6 A compound that is a haloalkyl, as described in any one of items 20 to 30. [Section 33] R 5 However, cyclopropyl or -CF 3 The compound described in any one of items 20 to 32. [Section 34] A compound according to any one of items 20 to 33, wherein n is 0 or 1. [Section 35] The compound described in item 34, wherein n is 1. [Section 36] The compound described in item 34, wherein n is 0. [Section 37] R 1 However, one or more R 6 A compound according to any one of claims 20 to 36, wherein the compound is a 5-6 member heteroaryl that is optionally substituted with . [Section 38] The compound according to item 37, wherein the heteroaryl is pyrazolyl. [Section 39] R 1 However, one or more R 6 A compound according to any one of items 20 to 23, wherein the compound is a phenyl optionally substituted with phenyl. [Section 40] R 1 However, one or more R 6 -CH is optionally substituted with 2 - A compound that is phenyl, as described in any one of items 20-21 and 23-39. [Section 41] R 1 However, one or more R 6 A compound according to any one of items 20-21 and 23-39, which is a 10-membered heterocycline optionally substituted with . [Section 42] The compound according to item 41, wherein the 10-membered heterocyclyl is a bicyclic heterocyclyl. [Section 43] R 6 However, halogen, C 1-6 Alkyl, or C 1-6 A compound that is a haloalkyl, as described in any one of items 20 to 42. [Section 44] R 6 However, C 1-6 Alkyl or C 1-6 A compound that is a haloalkyl, as described in any one of items 20 to 43. [Section 45] The aforementioned compound is a compound of formula I-IA or formula I-IB, TIFF0007838820000041.tif24158 A compound according to any one of items 20 to 22, or a pharmaceutically acceptable salt thereof. [Section 46] The aforementioned compound is a compound of formula I-IA2 or formula I-IB2. TIFF0007838820000042.tif24165 A compound according to any one of items 20-22 and 45, or a pharmaceutically acceptable salt thereof. [Section 47] The aforementioned compound is a compound of formula I-IA3, formula I-IA4, formula I-IB3, or formula I-IB4. TIFF0007838820000043.tif47170 A compound described in any one of sections 20-22 and 45-46, or a pharmaceutically acceptable salt thereof. [Section 48] The aforementioned compound is a compound of formula I-IC, TIFF0007838820000044.tif25128 Compounds in which q is 1 or 2 The compounds described in item 20 or 21, or their pharmaceutically acceptable salts. [Section 49] The compound is an I-IC2 compound, TIFF0007838820000045.tif27128 Compounds in which q is 1 or 2 The compounds described in any one of the items 20, 21, and 48, or their pharmaceutically acceptable salts. [Section 50] The aforementioned compound is a compound of formula I-IC3 or formula I-IC4. TIFF0007838820000046.tif59142 The compounds described in item 49, or their pharmaceutically acceptable salts. [Section 51] R 1 but, TIFF0007838820000047.tif28166 A compound selected from the group consisting of the following, wherein m is 0, 1, or 2, as described in any one of items 20 to 50. [Section 52] The aforementioned compound, TIFF0007838820000048.tif250127TIFF0007838820000049.tif230132TIFF0007838820000050.tif234137 A compound selected from the group consisting of or pharmaceutically acceptable salts thereof, as described in item 1. [Section 53] A pharmaceutical composition comprising a compound described in any one of items 20 to 52, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [Section 54] A method for treating a neurological disorder or condition, the method comprising administering to a subject in need of such treatment an effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of items 20 to 52, or a pharmaceutically acceptable composition described in any one of items 1 to 19 and 53. [Section 55] A method for treating a disease or condition associated with excessive neuronal excitability, the method comprising administering to a subject in need of such treatment an effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of items 20 to 52, or a pharmaceutically acceptable composition described in any one of items 1 to 19 and 53. [Section 56] A method for treating a disease or condition associated with a gain-of-function mutation of a gene (e.g., KCNT1), the method comprising administering to a subject in need an effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of items 20 to 52, or a pharmaceutically acceptable composition described in any one of items 1 to 19 and 53. [Section 57] The method according to any one of claims 54 to 56, wherein the neurological disorder or impairment, the disorder or condition associated with excessive neuronal excitability, or the disorder or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is epilepsy, epileptic syndrome, or encephalopathy. [Section 58] The method according to any one of claims 54 to 56, wherein the neurological disorder or impairment, the disorder or condition associated with excessive neuronal excitability, or the disorder or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is hereditary or childhood epilepsy, or hereditary or childhood epileptic syndrome. [Section 59] The method according to any one of claims 54 to 56, wherein the neurological disorder or impairment, the disorder or condition related to excessive neuronal excitability, or the disorder or condition related to a gain-of-function mutation in the gene (e.g., KCNT1) is cardiac dysfunction. [Section 60] The method according to any one of claims 54 to 56, wherein the neurological disorder or impairment, the disorder or condition associated with excessive neuronal excitability, or the disorder or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is selected from the group consisting of epilepsy and other encephalopathy (e.g., infantile epilepsy with migratory focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic 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, or cerebellar ataxia). [Section 61] The method according to any one of claims 54 to 56, wherein the neurological disorder or impairment, the disorder or condition associated with excessive neuronal excitability, or the disorder or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is selected from the group consisting of cardiac arrhythmias, sudden unexpected death in epilepsy, Brugada syndrome, and myocardial infarction. [Section 62] The method according to any one of claims 54 to 56, wherein the neurological disorder or impairment, the disorder or condition associated with excessive neuronal excitability, or the disorder or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is selected from pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine). [Section 63] The method according to any one of claims 54 to 56, wherein the neurological disorder or impairment, the disorder or condition associated with excessive neuronal excitability, or the disorder or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is a muscle disorder (e.g., myotonia, neuromyotonia, muscle spasms, spasticity). [Section 64] The method according to any one of claims 54 to 56, wherein the neurological disorder or impairment, the disorder or condition associated with excessive neuronal excitability, or the disorder or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is selected from itching and pruritus, ataxia, and cerebellar ataxia. [Section 65] The method according to any one of claims 54 to 56, wherein the neurological disorder or impairment, the disorder or condition associated with excessive neuronal excitability, or the disorder or condition associated with a gain-of-function mutation in the gene (e.g., KCNT1) is selected from mental disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia). [Section 66] The method according to any one of claims 54 to 56, wherein the neurological disorder or condition, or a disorder or condition associated with excessive neuronal excitability and / or a gain-of-function mutation in a gene (e.g., KCNT1), is selected from the group consisting of learning disabilities, fragile X, neuroplasticity, and autism spectrum disorder. [Section 67] The neurological disorders or conditions, the diseases or conditions related to the excessive neuronal excitability, or the diseases or conditions related to the gain-of-function mutations of the gene (e.g., KCNT1) include epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations, early-onset epileptic encephalopathy of infants, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, and benign familial neonatal-infant epilepsy. The method according to any one of items 54 to 56, selected from the group consisting of seizures, SCN2A epileptic encephalopathy, focal epilepsy with an SCN3A mutation, cryptogenic partial epilepsy in children with an SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures in infants, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy. [Examples]

[0147] To allow for a more complete understanding of the inventions described herein, the following examples are provided. The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed as limiting their scope in any way.

[0148] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be determined by those skilled in the art through routine optimization.

[0149] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The selection of suitable protecting groups for specific functional groups, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups, as well as their introduction and removal, are described in TW Greene and PGMWuts, *Protecting Groups in Organic Synthesis*, Second Edition, Wiley, New York, 1991, and the references cited therein.

[0150] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, polishing, high-pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). It should be noted that flash chromatography can be performed manually or via an automated system. The compounds provided herein can be characterized by known standard procedures such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography-mass spectrometry (LCMS). NMR chemical shifts are reported in parts per million (ppm) and are generated using methods well known to those skilled in the art.

[0151] List of Abbreviations THF (Tetrahydrofuran) TFA (Trifluoroacetic Acid) DMF (N,N-dimethylformamide) MeOH methanol EtOH Ethanol DCM Dichloromethane MeCN or ACN acetonitrile HCl ethyl acetate DIPEA N,N,-Diisopyruethylamine HATU o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate Ti(OEt)4 Titanium(IV) Ethoxide Ti(OiPr)4 Titanium(IV) Isopropoxide T3P Propanephosphonic Acid Anhydride L-selectride lithium tri-s-butylborate K-Selectride potassium tri-sec-butylborate DIEA N,N-diisopropylethylamine Pd(dppf)Cl2[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)2Cl2 Dichlorobis(triphenylphosphine)palladium(II) DMSO (Dimethyl Sulfoxide) DMS (Dimethyl Sulfide) EGTA Ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid NMDG (N-methyl-D-glucamine) HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid I C 50 Median inhibitory concentration TLC (Thin-Layer Chromatography) LC-MS (Liquid Chromatography-Mass Spectrometry) HPLC (High-Performance Liquid Chromatography) SFC Supercritical Fluid Chromatography MS mass spectrometry NMR nuclear magnetic resonance

[0152] Example 1. Synthesis of 1-methyl-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (1) [ka]

[0153] Synthesis of 2-(trifluoromethyl)pyridine-4-carboxamide (A-2) To a stirred solution of A-1 (10 g, 52.33 mmol) in DCM (10 mL) at 0°C, DMF (1 mL) and oxalyl chloride (4.71 mL, 54.94 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain the residue, which was dissolved in MeCN (100 mL) and charged with aqueous ammonia (150 mL, 52.33 mmol). The mixture was quenched with water (100 mL) and diluted with siRNA (200 mL x 2). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by column chromatography using 100-200 silica and 30-80% siRNA / hexane as an eluent to obtain A-2 (7 g, 33.13 mmol, yield 63%).

[0154] Synthesis of 5-[2-(trifluoromethyl)-4-pyridyl]-1,3,4-oxathiazol-2-one (A-3) A solution of A-2 (1.5 g, 7.89 mmol) and chlorocarbonyl sulfenyl chloride (1.2 g, 9.47 mmol) in toluene (20 mL) was stirred at 120 °C for 16 hours. The reaction mixture was quenched with water (100 mL), diluted with siRNA (100 mL x 2), and the organic layer was separated. The organic layer was dried over Na₂SO₄, filtered, and concentrated to obtain the residue, which was purified by column chromatography using 100-200 silica and 5-50% siRNA / hexane as an eluent to obtain A-3 (1.5 g, 5.43 mmol, yield 69%).

[0155] Synthesis of 1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]etanone (A-4) A mixture of A-3 (1 g, 4.03 mmol) and acetyl cyanide (278.27 mg, 4.03 mmol) in 1,2-dichlorobenzene (10 mL) was stirred at 160°C for 24 hours. The reaction mixture was quenched with water (100 mL), diluted with siRNA (100 mL x 2), the organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by column chromatography using 100-200 silica and 10-50% siRNA / hexane as an eluent to obtain A-4 (0.4 g, 1.39 mmol, yield 34%).

[0156] Synthesis of (E)-2-methyl-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethylidene]propan-2-sulfinamide (A-5) To a stirred solution of A-4 (100 mg, 0.37 mmol) and 2-methylpropane-2-sulfinamide (66.54 mg, 0.55 mmol) in toluene (10 mL), titanium(IV) ethoxide (0.12 mL, 0.55 mmol) was added, and the mixture was stirred at 80°C for 16 hours. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated to obtain a residue, which was purified by column chromatography using 100-200 silica and 10-30% Â / hexane as an eluent to obtain A-5 (100 mg, 0.13 mmol, yield 36%) in liquid form.

[0157] Synthesis of 2-methyl-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]propan-2-sulfinamide (A-6) To a stirred solution of A-5 (100 mg, 0.27 mmol) in methanol (10 mL) at 0°C, sodium borohydride (15.07 mg, 0.4 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain A-6 (80 mg, 0.10 mmol, 40% yield).

[0158] Synthesis of 1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethanamine hydrochloride (A-7) To a stirred solution of A-6 (80 mg, 0.21 mmol) in 1,4-dioxane (5 mL) at 0°C, 4M HCl (5 mL, 0.21 mmol) in 1,4-dioxane was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue, which was washed with diethyl ether to obtain A-7 (65 mg, 0.15 mmol, 69% yield).

[0159] Synthesis of 1-methyl-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (1) To a stirred solution of A-7 (70 mg, 0.18 mmol) and A-8 (41.98 mg, 0.22 mmol) in DCM (10 mL), HATU (102.79 mg, 0.27 mmol) and DIPEA (0.06 mL, 0.36 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then quenched with rewater (100 mL) and diluted with DCM (100 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography using 100-200 silica and 30-80% siRNA / hexane eluate as an eluent to obtain 1 (10 mg, 0.022 mmol, yield 12%). HPLC: Rt 9.346 min, 97.6%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 450.9 (M+H), Rt 2.32 min; Column: X-select CSH C18 (3 × 50) mm, 2.5 μm. 1 1H NMR (400MHz, DMSO-d6)δ H=9.55(d,1H), 8.97(d,1H), 8.44(s,1H), 8.40(d,1H), 7.46(s,1H), 5.62-5.58(m,1H), 4.13(s,3H), 1.71(d,3H).

[0160] Examples 2 and 3. Synthesis of (S)-1-methyl-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (2) and (R)-1-methyl-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (3). Note that the stereochemistry was assigned randomly.

[0161] [ka]

[0162] Synthesis of (2-(trifluoromethyl)pyridine-4-yl)methanol (A-9) To a stirred solution of A-1 (7 g, 36.63 mmol) in THF (30 mL), borane DMS (2 M in THF) (36.6 mL, 73.26 mmol) was added at 0°C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then heated to 50°C for 12 hours and then cooled to room temperature. The reaction mixture was slowly quenched using MeOH (30 mL) at 0°C and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was cooled to 0°C. The residue was made alkaline with 1N sodium hydroxide (30 mL), diluted with Depositphotos (100 mL), and the phases were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain A-9 (2.8 g, 11.2 mmol, yield 31%) as oil.

[0163] Synthesis of 2-(trifluoromethyl)pyridine-4-carbaldehyde (A-10) To a stirred solution of A-9 (2.8 g, 15.81 mmol) in DCM (20 mL), desmartin periodinane (13.41 g, 31.62 mmol) was added at 0°C and stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (20 mL), saturated sodium thiosulfate (30 mL), and saturated sodium bicarbonate (30 mL), and the layers were separated. The organic layer was washed with water (2 × 30 mL) and then with saturated brine solution (30 mL). The organic layer was then separated, dried over MgSO4, and concentrated under reduced pressure to obtain A-10 (2.5 g, 7.56 mmol, yield 48%) as oil.

[0164] Synthesis of (4Z)-2-(trifluoromethyl)pyridine-4-carbaldehyde (A-11) To a stirred solution of A-10 (2.5 g, 14.28 mmol) in ethanol (10 mL) and water (20 mL), Na2CO3 (1.82 g, 17.13 mmol) and hydroxylamine hydrochloride (1.19 g, 17.13 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated, and the residue was diluted with SiO2 (20 mL) and water (10 mL) and separated. The organic layer was washed with water (2 × 10 mL) and saturated brine solution (10 mL), separated, dried over MgSO4, and concentrated under reduced pressure. The residue was then purified by flash column chromatography using 30% SiO2 in hexane as an eluent to obtain A-11 (1.9 g, 9.36 mmol, yield 65%) as a solid.

[0165] Synthesis of (4E)-N-hydroxy-2-(trifluoromethyl)pyridine-4-carboxyimidoyl chloride (A-12) To a solution of A-11 (1.9 g, 9.99 mmol) in DMF (5 mL), N-chlorosuccinate (2.67 g, 19.99 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with siRNA (50 mL) and water (20 mL), and the phases were separated. The organic layer was washed with water (2 × 20 mL), then with saturated brine solution (20 mL), the organic layer was separated, dried over MgSO4, and then concentrated. The residue was purified by flash column chromatography eluting 30% siRNA in hexane. The desired fraction was concentrated under reduced pressure to obtain A-12 (1.3 g, 4.39 mmol, yield 44%) as a solid.

[0166] Synthesis of 1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethanol (A-13) To a stirred solution of A-12 (0.4 g, 1.78 mmol) in toluene (10 mL), buta-3-in-2-ol (0.25 g, 3.56 mmol) and triethylamine (0.18 g, 1.78 mmol) at 0°C were added and the mixture was stirred at room temperature for 1 hour, then heated at 60°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with toluene (20 mL) and water (10 mL). The organic layer was separated and washed with water (2 × 10 mL), then saturated brine solution (10 mL). The organic layer was separated, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with 80% toluene in hexane. The desired fraction was concentrated under reduced pressure to obtain A-13 (0.45 g, 1.69 mmol, 95% yield) as oil.

[0167] Synthesis of 1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethanone (A-14) Desmartin periodinane (1.48 g, 3.49 mmol) was added to a stirred solution of A-13 (0.45 g, 1.74 mmol) in DCM (10 mL), and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM (30 mL) and 10 mL of saturated sodium thiosulfate, and washed with saturated bicarbonate (10 mL). The organic layer was then separated, dried over MgSO4, and evaporated to dryness to obtain the residue, which was purified by flash column chromatography using 80% toluene in hexane as the eluent to obtain A-14 (0.2 g, 0.73 mmol, yield 42%) as a solid.

[0168] Synthesis of (NE)-2-methyl-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethylidene]propan-2-sulfinamide (A-15) To a stirred solution of A-14 (0.15 g, 0.59 mmol) in toluene (10 mL), 2-methyl-2-propanesulfinamide (0.11 g, 0.88 mmol) and titanium(IV) ethoxide (0.2 g, 0.88 mmol) were added at room temperature. The reaction mixture was heated at 80°C for 12 hours. The reaction mixture was diluted with water and toluene (30 mL) and separated. The organic layer was dried over MgSO4 and evaporated to dryness. The residue was then purified by flash column chromatography using 80% toluene in hexane as an eluent to obtain A-15 (0.14 g, 0.32 mmol, yield 54%) as oil.

[0169] Synthesis of 2-methyl-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]propan-2-sulfinamide (A-16) To a stirred solution of A-15 (0.46 g, 1.28 mmol) in methanol (5 mL) at 0°C, sodium borohydride (0.048 g, 1.28 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with water, diluted with ethyl acetate, and the organic layer was separated. The organic layer was dried over MgSO4 and concentrated under reduced pressure to obtain the residue, which was purified by flash column chromatography using 80% siRNA in hexane as the eluent to obtain A-16 (450 mg, 1.24 mmol, 97% yield).

[0170] Synthesis of 1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethanamine hydrochloride (A-17) To a stirred solution of A-16 (430 mg, 1.19 mmol) in 1,4-dioxane (2 mL) at 0°C, 4M HCl in 1,4-dioxane (8.6 mL, 61.6 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to obtain A-17 (310 mg, 1.05 mmol, yield 89%).

[0171] Synthesis of (S)-1-methyl-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (2) and (R)-1-methyl-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (3). Note that the stereochemistry is randomly assigned.

[0172] To a stirred solution of A-17 (0.07 g, 0.24 mmol) in DCM (10 mL), 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (0.05 g, 0.24 mmol), HATU (90.63 mg, 0.24 mmol), and DIPEA (0.08 mL, 0.48 mmol) were added at 0°C, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with DCM (20 mL) and water (10 mL), and the organic layer was separated. The organic layer was washed with water (2 × 10 mL) and saturated brine solution (10 mL), separated, dried over MgSO4, concentrated to dryness, and the residue was then purified by flash column chromatography eluted with 80% siRNA in hexane. The desired fraction was concentrated to dryness to obtain A-18 as oil, which was purified by chiral preparative HPLC to obtain 2 (10 mg, 0.023 mmol, 9% yield) and 3 (8 mg, 0.018 mmol, 8% yield). Note: Absolute stereochemistry was randomly assigned. Separation was performed using preparative HPLC conditions SFC with the following conditions: DIACEL CHIRALPAK-IG (250 mm × 4.6 mm, 5 μm), mobile phase: A) n-hexane + 0.1% isopropylamine B) EtOH:MeOH (50:50), isocratic: 20% B; wavelength: 293 nm, flow rate: 1.0 mL / min.

[0173] 2:HPLC: Rt 9.172 min, 99.7%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 434.25 (M + H), Rt 2.018 min, Column: X-select CSH (3 × 50) mm, 2.5 μm. 1 1H NMR (400MHz, DMSO-d6)δ H=9.28(d,1H), 8.93(d,1H), 8.33(s,1H), 8.21(d,1H), 7.45(s,1H), 7.37(s,1H), 5.40(quintuplet,1H), 4.15(s,3H), 1.60(d,3H). Chiral method: Rt 5.392 min, 100%: DIACEL CHIRALPAK-IG (250 mm × 4.6 mm, 5 u), mobile phase: A) n-hexane + 0.1% isopropylamine B) EtOH:MeOH (50:50), isocratic: 20% B; wavelength: 293 nm, flow rate: 1.0 mL / min.

[0174] 3: HPLC: Rt 9.146 min, 99.8%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 433.95 (M + H), Rt 2.012 min, Column: X-select CSH (3 × 50) mm, 2.5 μm. 1 1H NMR (400MHz, DMSO-d6)δ H =9.29(d,1H), 8.93(d,1H), 8.33(s,1H), 8.21(d,1H), 7.45(s,1H), 7.38(s,1H), 5.40(quintuplet,1H), 4.15(s,3H), 1.61(d,3H). Chiral method: Rt 4.989 min, 98%: DIACEL CHIRALPAK-IG (250 mm × 4.6 mm, 5 u), Mobile phase: A) n-hexane + 0.1% isopropylamine B) EtOH:MeOH (50:50), Isocratic: 20% B; Wavelength: 254 nm, Flow rate: 1.0 mL / min.

[0175] Example 2-1. Synthesis of (S)-1-methyl-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (2-1) [ka]

[0176] Synthesis of (R,Z)-2-methyl-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethylidene)propan-2-sulfinamide (A-31): To a stirred solution of A-14 (1.2 g, 4.68 mmol) and (R)-2-methylpropane-2-sulfinamide (850.18 mg, 7.01 mmol) in THF (20 mL), titanium ethoxide (2.97 mL, 14.05 mmol) was added, and the mixture was stirred at 65°C for 6 hours. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain A-31 (1.4 g, 1.17 mmol, yield 25%).

[0177] Synthesis of (R)-2-methyl-N-((S)-1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)propan-2-sulfinamide (A-32): To a stirred solution of A-31 (700 mg, 1.95 mmol) in THF (10 mL), L-selectride (221.76 mg, 5.84 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, treated with water, and extracted with DCM (20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated to obtain the residue, which was purified by column chromatography using 100-200 silica gel particles and 50-60% siRNA / hexane as an eluent to obtain A-32 (250 mg, 0.64 mmol, 32% yield) in liquid form.

[0178] Synthesis of (S)-1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethane-1-amine (A-33): To a stirred solution of A-32 (250 mg, 0.69 mmol) in 1 mL of 1,4-dioxane, 4 M HCl in dioxane (0.5 mL, 0.69 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and polished with diethyl ether to obtain A-33 (150 mg, 0.566 mmol, yield 81%) as a solid.

[0179] Synthesis of (S)-1-methyl-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (2-1): To a stirred solution of A-33 (180 mg, 0.7000 mmol) in DCM (10 mL), 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (203.76 mg, 1.05 mmol), HATU (399.14 mg, 1.05 mmol), and DIPEA (0.37 mL, 2.1 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (20 mL) and water (10 mL), and the organic layer was separated. The organic layer was washed with water (2 × 10 mL) and saturated brine solution (10 mL), separated, dried over MgSO4, and concentrated under reduced pressure. The residue was then purified by flash column chromatography eluting with 30-50% Â in hexane, followed by preparative HPLC, to obtain 2-1 (95 mg, 0.218 mmol, yield 31%). HPLC: Rt 8.484 min, 99.58%; Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 0.1% TFA aqueous solution; Mobile phase B: Acetonitrile; LCMS: 434.1 (M + H), Rt 2.381 min, Column: X-Bridge BEH C-18 (3.0 × 50 mm, 2.5 μm); Mobile phase A: 0.025% FA aqueous solution, B: ACN; Flow rate: 1.2 ml / min; Chiral HPLC: Rt 4.869 min, 98.80%; Column: CHIRAL PAK (250 × 4.6 mm × 5 μm); Mobile phase A: 0.1% IP amine n-hexane solution; Mobile phase B: ETOH:MEOH (1:1); AB: 80:20; Flow rate: 1.0 mL / min 11H NMR (400MHz, DMSO-d6)δ H =9.27(d,1H), 8.93(d,1H), 8.33(s,1H), 8.23-8.19(m,1H), 7.45(s,1H), 7.39-7.36(m,1H), 5.40(quintet,1H), 4.15(s,3H), 1.61(d,3H).

[0180] Example 3-1. Synthesis of (R)-1-methyl-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (3-1): [ka]

[0181] Synthesis of (S,E)-2-methyl-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethylidene)propan-2-sulfinamide (A-34) Titanium ethoxide (1.48 mL, 7.03 mmol) was added to a stirred solution of A-14 (600 mg, 2.34 mmol) and (S)-2-methylpropane-2-sulfinamide (425.09 mg, 3.51 mmol) in toluene (20 mL), and the mixture was stirred at 90°C for 6 hours. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain A-34 (500 mg, 0.64 mmol, yield 27%).

[0182] Synthesis of (S)-2-methyl-N-((R)-1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)propan-2-sulfinamide (A-35) To a stirred solution of A-34 (500 mg, 1.39 mmol) in methanol (10 mL), sodium borohydride (105.6 mg, 2.78 mmol) was added at -40°C, and the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with water (25 mL) and diluted with siRNA (2 × 50 mL). The organic layer was separated, dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain the residue, which was purified by column chromatography using 100-200 silica and 30-80% siRNA / hexane as an eluent to obtain A-35 (270 mg, 0.7322 mmol, yield 52%).

[0183] (R)-1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethane-1-amine(A-36) To a stirred solution of A-35 (270 mg, 0.7500 mmol) in 1 mL of 1,4-dioxane, 4 M HCl in dioxane (0.5 mL, 0.7500 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was washed with diethyl ether to obtain A-36 (180 mg, 0.6578 mmol, yield 88%).

[0184] Synthesis of (R)-1-methyl-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (3-1): To a stirred solution of A-36 (180 mg, 0.7000 mmol) in DCM (10 mL), 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (203.76 mg, 1.05 mmol), HATU (399.14 mg, 1.05 mmol), and DIPEA (0.37 mL, 2.1 mmol) were added at 0°C, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with DCM (20 mL) and water (10 mL), and the organic layer was separated. The organic layer was washed with water (2 × 10 mL) and saturated brine solution (10 mL), separated, dried over MgSO4, and then concentrated to dryness. The residue was then purified by flash column chromatography eluting with 30-50% Â in hexane, followed by preparative HPLC, to obtain 3-1 (70 mg, 0.1596 mmol, yield 23%). HPLC: Rt 7.85 min, 98.78%; Column: X SELECT CSH C18 (150 × 4.6 mm, 3.5 u); Mobile phase A: 0.05% TFA aqueous solution; ACN (95:05); Mobile phase B: 0.05% FA aqueous solution: ACN (05:95); Flow rate: 1.0 mL / min; LCMS: 434.1 (M+H); Rt 2.342 min; Column: X-Bridge BEH C-18 (3.0 × 50 mm, 2.5 μm); Mobile phase A: 0.025% FA aqueous solution, B: ACN; Flow rate: 1.2 mL / min Chiral method: Rt 4.919 min, 100% Column: Chiral pak-IG (250*4.6 mm) 5 μm; Mobile phase A: 0.1% IP amine n-hexane Mobile phase B: ETOH:MEOH (50:50); PROGRAM-AB 80:20; Flow rate: 1.0 ML / min 1 1H NMR (400MHz, DMSO-d6)δ H =9.27(d,1H), 8.93(d,1H), 8.33(s,1H), 8.21(d,1H), 7.45(s,1H), 7.37(d,1H), 5.40(quintet,1H), 4.15(s,3H), 1.61(d,3H).

[0185] Note that the synthetic stereochemistry of Examples 2-2 and 3-2.2-methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide and 2-methyl-N-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide was randomly assigned.

[0186] [ka]

[0187] (4E)-2-bromopyridine-4-carbaldehyde oxime (B-2): To a mixture of 2-bromopyridine-4-carboaldehyde (20.0 g, 107 mmol) in water (120 mL) and MeOH (120 mL), NH2OH.HCl (33.2 g, 161 mmol) was added. The mixture was stirred under N2 at 60°C for 12 hours. After cooling to 30°C, the mixture was filtered, washed with water (50 mL), and concentrated to obtain the product (22.0 g, 76.6 mmol, yield 71%) as a solid. 1 1H NMR (DMSO-d6, 400MHz) δ H =12.14-11.93(m,1H), 8.43-8.32(m,1H), 8.20-8.13(m,1H), 7.80-7.73(m,1H), 7.66-7.57(m,1H).

[0188] (4Z)-2-bromo-N-hydroxypyridine-4-carboxyimidoyl chloride (B-3): A mixture of (4E)-2-bromopyridine-4-carboaldehyde oxime (22.0 g, 76.6 mmol) in DMF (60 mL) was mixed with NCS (12.3 g, 91.9 mmol) at 0°C. The mixture was stirred at 20°C for 3 days. The mixture was poured into water (100 mL) and stirred for 20 minutes. The aqueous phase was extracted with ELISA (3 × 50 mL). The combined organic phases were washed with saturated brine (2 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The mixture was polished with PE (50 mL) to obtain the product (15.0 g, 63.7 mmol, yield 83%) as a solid. LCMS R t = Chromatography for 1.5 minutes, 0.849 minutes, 5-95AB, C6H5BrClN2O[M+H] + MS ESI calculated value: 234.9, measured value: 236.7

[0189] 2-[1-[3-(2-bromo-4-pyridyl)isoxazole-5-yl]ethyl]isoindoline-1,3-dione(B-4): To a mixture of 2-(1-methylprop-2-inyl)isoindoline-1,3-dione (2.28 g, 11.5 mmol) in toluene (50.0 mL), Et3N (3.53 mL, 25.5 mmol) and (4Z)-2-bromo-N-hydroxypyridine-4-carboximidoyl chloride (3.0 g, 12.7 mmol) were added. The mixture was stirred at 120°C for 16 hours. The mixture was poured into water (100 mL) and stirred for 20 minutes. The aqueous phase was extracted with ethyl acetate (3 × 100 mL). The combined organic phase was washed with saturated brine (2 × 100 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / ethyl acetate = 5 / 1 to 3 / 1) to obtain the product (1.30 g, 3.26 mmol, yield 26%) as oil. 1 1H NMR (CDCl3, 400MHz) δ H =8.47(d,1H), 7.92-7.84(m,3H), 7.80-7.74(m,2H), 7.68-7.64(m,1H), 6.66(s,1H), 5.79-5.67(m,1H), 1.94(d,3H).

[0190] 2-[1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]isoindoline-1,3-dione(B-5): To a mixture of Cu (479 mg, 7.5 mmol) and 2,8-difluoro-5-(trifluoromethyl)-5H-dibenzo[b,d]thiophene-5-iumtrifluoromethanesulfonate (2.20 g, 5.0 mmol), 2-[1-[3-(2-bromo-4-pyridyl)isoxazole-5-yl]ethyl]isoindorin-1,3-dione (1.0 g, 2.5 mmol) in DMF (15 mL) was added under N2 conditions. The mixture was stirred at 0°C for 1 hour, then stirred at 80°C for 3 hours. The mixture was poured into water (50 mL) and extracted with RINKAN (3 × 50 mL). The combined organic phase was washed with brine (3 × 30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The mixture was purified by silica gel chromatography (PE / siRNA = 5 / 1 to 3 / 1) to obtain the product (720 mg, 1.90 mmol, yield 74%) as a solid. 1 1H NMR (CDCl3, 400MHz) δ H =8.84(d,1H), 8.08-7.99(m,1H), 7.93-7.84(m,3H), 7.82-7.68(m,2H), 6.74(d,1H), 5.80-5.67(m,1H), 1.96(d,3H).

[0191] 1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethanamine-[4,3-a]pyrazine(B-6): To a solution of 2-[1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]isoindoline-1,3-dione (300 mg, 0.77 mmol) in DCM (10 mL) and EtOH (2.0 mL), N2H4.H2O (0.23 mL, 4.70 mmol) was added dropwise at 25°C. After stirring at 25°C for 16 hours, the mixture was filtered, and the filtrate cake was washed with DCM (3 × 10 mL). The filtrate was concentrated to obtain the product (200 mg, 0.78 mmol, 100% yield) as a solid, which was used directly in the next step.

[0192] 2-methyl-5-(trifluoromethyl)-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]pyrazole-3-carboxamide (B-7): To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (125 mg, 0.64 mmol), DIEA (0.30 mL, 1.8 mmol), and HATU (443 mg, 1.2 mmol) in DMF (2.0 mL), 1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethanamine (150 mg, 0.58 mmol) was added at 20°C. After stirring for 1 hour, the mixture was poured into water (15 mL) and extracted with  (2 × 20 mL). The combined organic phase was washed with brine (2 × 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (PE /  = 5 / 1 to 3 / 1) to obtain the product (150 mg, 0.35 mmol, yield 59%) as a solid. 1 1H NMR (CDCl3, 400MHz) δ H =8.86(d,1H), 8.11-8.03(m,1H), 7.88(d,1H), 6.89-6.81(m,1H), 6.68-6. 61(m,1H), 6.42-6.31(m,1H), 5.59-5.45(m,1H), 4.23(s,3H), 1.75(d,3H).

[0193] 2-Methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide & 2-Methyl-N-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide A mixture of 2-methyl-5-(trifluoromethyl)-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]pyrazole-3-carboxamide (200 mg, 0.46 mmol) is processed using SFC (DAICEL CHIRALCEL column). The mixture was purified using OJ-H (250mm*30mm, 5μm), under conditions: 0.1%NH3H2O-EtOH, start B: 15%, end B: 15%, flow rate (ML / min): 60) to obtain 2-methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (60.4 mg, 0.14 mmol, yield 30%, peak 1) as a solid, and 2-methyl-N-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (69.1 mg, 0.16 mmol, yield 34%) as a solid.

[0194] 2-2: 1 1H NMR (CDCl3, 400MHz) δ H =8.85(d,1H), 8.05(s,1H), 7.88(d,1H), 6.86(s,1H), 6.64(s,1H), 6.41(d,1H), 5.59-5.50(m,1H), 4.22(s,3H), 1.74(d,3H). 19 F NMR (376.5 MHz, CDCl3) δ F =-62.214,-68.145. LCMS R t = 1.251 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 17 H 14 F6N5O2[M+H] + The MS ESI calculated value is 434.1, and the measured value is 434.1.

[0195] 3-2: 1 1H NMR (CDCl3, 400MHz) δ H=8.85(d,1H), 8.06(s,1H), 7.90-7.85(m,1H), 6.86(s,1H), 6.64(s,1H), 6.41(d,1H), 5.59-5.49(m,1H), 4.28-4.16(m,3H), 1.74(d,3H). 19 F NMR (376.5 MHz, CDCl3) δ F = -62.214, -68.145. LCMS R t = 1.229 minutes by chromatography at 2.0 minutes, 10⁻⁸ AB, C 17 H 14 F6N5O2[M+H] + The MS ESI calculated value is 434.2, and the measured value is 434.2.

[0196] Example 2-3. Synthesis of 2-methyl-5-(trifluoromethyl)-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]pyrazole-3-carboxamide (2-3) [ka]

[0197] 2-[(1S)-1-methylprop-2-inyl]isoindoline-1,3-dione(C-2): A mixture of (2R)-buta-3-in-2-ol (2.0 g, 29 mmol), phthalimide (4.2 g, 29 mmol), and PPh3 (11 g, 43 mmol) in THF (25 mL) was mixed with DEAD (6.8 mL, 43 mmol) at 25 °C. After stirring at 25 °C for 16 hours, the mixture was poured into water (100 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layer was washed with brine (2 × 50 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated. The residue was purified by flash column (0-20% ethyl acetate in PE) to obtain the product as a solid. 1 1H NMR (CDCl3, 400MHz) δ H =7.96-7.81(m,2H), 7.78-7.65(m,2H), 5.28-5.13(m,1H), 2.34(d,1H), 1.71(d,3H).

[0198] 2-[(1S)-1-[3-(2-bromo-4-pyridyl)isoxazole-5-yl]ethyl]isoindoline-1,3-dione(C-4): To a mixture of 2-[(1S)-1-methylprop-2-inyl]isoindoline-1,3-dione (1.1 g, 5.7 mmol) in toluene (13 mL), K2CO3 (2.6 g, 19 mmol) and (4Z)-2-bromo-N-hydroxypyridine-4-carboximidoyl chloride (1.5 g, 6.4 mmol) were added. After stirring at 120 °C for 12 hours, the mixture was poured into water (50 mL) and stirred for 20 minutes. The aqueous phase was extracted with ELISA (3 × 30 mL). The combined organic phase was washed with saturated brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / ELISA = 5 / 1 to 3 / 1) to obtain the product (1.1 g, 2.8 mmol, yield 43%) as a solid. 1 1H NMR (CDCl 3400MHz) δ H =8.47(d,1H), 7.92-7.84(m,3H), 7.78-7.74(m,2H), 7.68-7.61(m,1H), 6.66(d,1H), 5.77-5.69(m,1H), 1.94(d,3H).

[0199] 2-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]isoindoline-1,3 dione(C-5): To a mixture of Cu (287.3 mg, 4.52 mmol) and 2,8-difluoro-5-(trifluoromethyl)-5H-dibenzo[b,d]thiophene-5-iumtrifluoromethanesulfonate (1.33 g, 3.01 mmol) in DMF (15 mL), 2-[(1S)-1-[3-(2-bromo-4-pyridyl)isoxazole-5-yl]ethyl]isoindorin-1,3-dione (600 mg, 1.51 mmol) was added under N2 conditions, and the mixture was stirred at 0°C for 1 hour. After stirring at 80°C for 3 hours, the mixture was poured into water (30 mL) and extracted with RINKAN (3 × 10 mL). The combined organic phase was washed with saturated brine (3 × 30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The mixture was purified by silica gel chromatography (PE / siRNA = 5 / 1 to 3 / 1) to obtain the product (520 mg, 1.34 mmol, yield 89%) as oil. The product (100 mg, 0.26 mmol) was purified by SFC (column DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm), conditions Neu-ETOH, start B 40, end B 40, gradient time (min) 100% B) to obtain the product (17.0 mg, 0.0437 mmol, yield 24%) as solid. 1 1H NMR (CDCl3, 400MHz) δ H =8.83(d,1H), 8.06(s,1H), 7.92-7.85(m,3H), 7.80-7.73(m,2H), 6.73(s,1H), 5.85-5.67(m,1H), 1.96(d,3H). 19 F NMR (376.5 MHz, CDCl3) δ F = -68.155. LCMS R t = 1.029 minutes of chromatography in 1.5 minutes, 5-95AB, C 19 H 13 F3N3O3[M+H] + The MS ESI calculated value is 387.8, and the measured value is 387.8.

[0200] (1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethanamine(C-6): To a solution of 2-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]isoindoline-1,3-dione (250 mg, 0.65 mmol) in DCM (10 mL) and EtOH (2 mL), N2H4.H2O (0.19 mL, 3.87 mmol) was added dropwise at 25°C. After stirring at 25°C for 16 hours, the mixture was filtered, and the filtered cake was washed with DCM (3 × 10 mL). The mixture was concentrated to obtain the product (160 mg, 0.311 mmol, yield 48%) as a solid.

[0201] 2-methyl-5-(trifluoromethyl)-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]pyrazole-3-carboxamide(2-3) To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (132.8 mg, 0.68 mmol) and HATU (473 mg, 1.24 mmol) in DMF (10 mL), Et3N (0.26 mL, 1.87 mmol) and (1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethanamine (160 mg, 0.62 mmol) were added. After stirring at 20°C for 12 hours, the reaction mixture was diluted with water (30 mL), extracted with  (3 × 20 mL), the organic layer was washed with water (3 × 30 mL) and brine (3 × 30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel ( in PE = 0%~40%) to obtain the product (200 mg, 0.323 mmol, yield 52%) as oil. The product was purified by SFC (DAICEL CHIRALPAK AD column (250 mm*30 mm, 10 μm), under the conditions 0.1% NH3H2O ​​ETOH, start B 25, end B 25, gradient time (min) 100% B) to obtain the product (72.2 mg, 0.166 mmol, yield 36%) as a solid. 1 1H NMR (CDCl3, 400MHz) δ H=8.88(d,1H), 8.08(s,1H), 7.90(d,1H), 6.87(s,1H), 6.66(s,1H), 6.40-6.30(m,1H), 5.65-5.48(m,1H), 4.25(s,3H), 1.77(d,3H). 19 F NMR (376.5 MHz, CDCl3) δ F = -62.232, -68.164. LCMS R t = 1.022 minutes of chromatography in 1.5 minutes, 5-95AB, C 17 H 14 F6N5O2[M+H] + The MS ESI calculated value is 434.0, and the measured value is 434.0.

[0202] Example 3-3. Synthesis of 2-methyl-N-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (3-3): [ka]

[0203] 2-(1-methylprop-2-inyl)isoindoline-1,3-dione(C-8): A mixture of buta-3-in-2-ol (25 g, 357 mmol), phthalimide (53 g, 357 mmol), and triphenylphosphine (140 g, 535 mmol) in THF (500 mL) was mixed with DEAD (85 mL, 535 mmol) at 20°C. After stirring at 20°C for 16 hours, the mixture was poured into water (600 mL) and extracted with ethyl acetate (2 × 300 mL). The combined organic layer was washed with brine (2 × 300 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated. The residue was fermented at 25°C. PE / V DCM The mixture was polished from 6 / 1 (total 800 mL). The mother liquor was concentrated to obtain the product, which was purified by flash column (0-20% siRNA in PE) to obtain the product (27 g, 133 mmol, yield 37%) as a solid. 1 1H NMR (CDCl3, 400MHz) δH =7.92-7.83(m,2H), 7.78-7.70(m,2H), 5.35-5.08(m,1H), 2.35(d,1H), 1.72(d,3H).

[0204] 2-[(1R)-1-[3-(2-bromo-4-pyridyl)isoxazole-5-yl]ethyl]isoindoline-1,3-dione(C-9): To a mixture of 2-[(1R)-1-methylprop-2-inyl]isoindoline-1,3-dione (1.1 g, 5.7 mmol) in toluene (13 mL), K2CO3 (2.6 g, 19 mmol) and (4Z)-2-bromo-N-hydroxypyridine-4-carboximidoyl chloride (1.5 g, 6.4 mmol) were added. After stirring at 120°C for 3 hours, the mixture was poured into water (100 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phase was washed with brine (2 × 100 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / ethyl acetate = 5 / 1 to 3 / 1) to obtain the product (1.1 g, 2.8 mmol, yield 43%) as oil. The product (50 mg, 0.13 mmol) was purified by preparative TLC (PE / Â=3 / 1) to obtain the product (30 mg, 0.070 mmol, yield 55%) as a solid. 1 1H NMR (CDCl 3400MHz) δ H =8.50-8.40(m,1H), 7.92-7.84(m,3H), 7.80-7.74(m,2H), 7.68-7.60(m,1H), 6.69-6.63(m,1H), 5.77-5.69(m,1H), 1.94(d,3H).

[0205] 2-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]isoindoline-1,3-dione(C10): To a mixture of Cu (239 mg, 3.8 mmol) and 2,8-difluoro-5-(trifluoromethyl)-5H-dibenzo[b,d]thiophene-5-iumtrifluoromethanesulfonate (1.1 g, 2.5 mmol), 2-[(1R)-1-[3-(2-bromo-4-pyridyl)isoxazole-5-yl]ethyl]isoindorin-1,3-dione (500 mg, 1.3 mmol) in DMF (15 mL) was added under N2 conditions. The mixture was stirred at 0°C for 1 hour, then heated to 80°C and stirred for 3 hours. The mixture was extracted with RINKAN (3 × 50 mL). The combined organic phase was washed with saturated brine (3 × 30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The mixture was purified by silica gel chromatography (PE / Â=5 / 1~3 / 1) to obtain a solid product (350 mg, 0.90 mmol, yield 7%). The product (100 mg, 0.26 mmol) was purified by preparative TLC (DCM / acetone=50 / 1) to obtain a solid product (41 mg, 0.11 mmol, yield 41%). 1 1H NMR (CDCl3, 400MHz) δ H =8.84(d,1H), 8.06(s,1H), 7.94-7.84(m,3H), 7.81-7.71(m,2H), 6.73(d,1H), 5.81-5.69(m,1H), 1.96(d,3H). LCMS R t = 1.224 minutes by chromatography at 2.0 minutes, 10⁻⁸ AB, C 19 H 13 F3N3O3[M+H] + The MS ESI calculated value is 388.1, and the measured value is 388.1.

[0206] (1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethanamine(C-11): To a solution of 2-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]isoindoline-1,3-dione (150 mg, 0.39 mmol) in DCM (10 mL) and ethanol (2.0 mL), N2H4.H2O (0.12 mL, 2.3 mmol) was added dropwise at 25°C. The mixture was stirred at 25°C for 16 hours. The mixture was filtered, and the filter cake was washed with DCM (10 × 3 mL). The filtrate was concentrated and purified by silica gel chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to obtain the product (60 mg, 0.23 mmol, yield 60%) as oil. 1 1H NMR (CDCl3, 400MHz) δ H =8.84(d,1H), 8.11-8.02(m,1H), 7.88(d,1H), 6.62-6.55(m,1H), 4.42-4.28(m,1H), 1.60-1.58(m,5H).

[0207] 2-methyl-N-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide(3-3): To a solution of 2-methyl l-5-(trifluoromethyl)pyrazole-3-carboxylic acid (50 mg, 0.26 mmol), DIPEA (0.12 mL, 0.70 mmol), and HATU (177 mg, 0.47 mmol) in DMF (5.0 mL), (1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazole-5-yl]ethanamine (60 mg, 0.23 mmol) was added, and the mixture was stirred at 20°C for 1 hour. The residue was poured into water (15 mL) and stirred for 20 minutes. The aqueous phase was extracted with RINKAN (2 × 20 mL). The combined organic phase was washed with saturated brine (2 × 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by preparative TLC (DCM / acetone = 50 / 1) to obtain the product (61.57 mg, 0.14 mmol, yield 60%) as a solid. 1 1H NMR (CDCl3, 400MHz) δ H=8.86(d,1H), 8.06(s,1H), 7.91-7.83(m,1H), 6.85(s,1H), 6.64(s,1H), 6.33(d,1H), 5.60-5.46(m,1H), 4.23(s,3H), 1.75(d,3H). LCMS R t = 1.212 minutes by chromatography at 2.0 minutes, 10⁻⁸ AB, C 17 H 14 F6N5O2[M+H] + The MS ESI calculated value is 434.3, and the measured value is 434.3.

[0208] Examples 4 and 5. Synthesis of (S)-N-(1-(3-(2-cyclopropylpyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)benzamide (4) and (R)-N-(1-(3-(2-cyclopropylpyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)benzamide (5). Note that the stereochemistry was assigned randomly.

[0209] [ka]

[0210] Synthesis of 2-cyclopropyl isonicotinonitrile (A-20): To a stirred solution of A-19 (10 g, 72.18 mmol) in 1,4-dioxane (100 mL), K3PO4 (38.31 g, 180.44 mmol) and cyclopropylboronic acid (12.4 g, 144.35 mmol) were added at room temperature. The reaction mixture was purged with argon for 20 minutes. To this solution, silver oxide (3.35 g, 14.44 mmol) and Pd(dppf)Cl2 (5.28 g, 7.22 mmol) were added, and the reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and washed with ethyl acetate (50 mL). The organic layer was washed with water (3 × 25 mL), separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using 100-200 silica and 5-10% acetone / hexane as an eluent to obtain A-20 (5.3 g, 31.17 mmol, yield 43%) as a solid.

[0211] Synthesis of 2-cyclopropyl isonicotinic acid (A-21): To a stirred solution of A-20 (2 g, 13.87 mmol) in methanol / water (15 mL / 10 mL), NaOH (1.66 g, 41.62 mmol) was added, and the reaction mixture was stirred for 5 hours. The volatile solvent was removed under reduced pressure. The residue was diluted with water and extracted with ELISA. The aqueous layer was acidified with 1 N HCl. The precipitated solid was collected by filtration and dried under reduced pressure to obtain A-21 (1.7 g).

[0212] Synthesis of 2-cyclopropyl isonicotinamide (A-22): To a stirred solution of A-21 (1.5 g, 9.19 mmol) in DCM (20 mL) at 0°C, DMF (2.5 mL) and oxalyl chloride (2.33 g, 18.39 mmol) were added dropwise, and the resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under an inert nitrogen atmosphere to obtain a residue, which was dissolved in MeCN (20 mL) and charged with aqueous ammonia (20 mL). The reaction mixture was quenched with water (25 mL) and diluted with siRNA (2 × 50 mL). The organic layer was separated, dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain a residue, which was purified by column chromatography using 100-200 silica and 30-80% siRNA / hexane as an eluent to obtain A-22 (1.2 g, 6.51 mmol, 70% yield) as a solid.

[0213] Synthesis of 5-(2-cyclopropylpyridine-4-yl)-1,3,4-oxathiazol-2-one (A-23): To a stirred solution of A-22 (1.2 g, 6.51 mmol) in toluene (10 mL), chloromethanethioate (0.852 g, 6.51 mmol) was added at room temperature, and the reaction mixture was stirred at 120 °C for 16 hours. The reaction was quenched by adding water (50 mL), diluted with siRNA (2 × 100 mL), and the organic layer was separated. The separated organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain the residue, which was purified by column chromatography using 100-200 silica and 5-50% siRNA / hexane as an eluent to obtain A-23 (0.5 g, 2.01 mmol, 30% yield) as a solid.

[0214] Synthesis of 1-(3-(2-cyclopropylpyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethane-1-one (A-24): A mixture of A-23 (441.99 mg, 2.01 mmol) and acetyl cyanide (831.52 mg, 12.04 mmol) in 1,2-dichlorobenzene (10 mL) was stirred at 160°C for 24 hours. The reaction mixture was quenched with water (10 mL), diluted with siRNA (20 mL), the organic layer was separated, dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure to obtain the residue. This residue was purified by column chromatography using 100-200 silica and 10-50% siRNA / hexane as an eluent to obtain A-24 (300 mg, 0.734 mmol, yield 36%) as a solid.

[0215] Synthesis of (E)-N-(1-(3-(2-cyclopropylpyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethylidene)-2-methylpropane-2-sulfinamide (A-25): Titanium ethoxide (0.16 mL, 0.74 mmol) was added to a stirred solution of A-24 (180.73 mg, 0.74 mmol) and 2-methylpropane-2-sulfinamide (89.3 mg, 0.74 mmol) in toluene (10 mL), and the mixture was stirred at 80°C for 16 hours. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a residue, which was purified by column chromatography using 100-200 silica and 10-30% siRNA / hexane as an eluent to obtain A-25 (250 mg, 0.487 mmol, 66% yield) in liquid form.

[0216] Synthesis of N-(1-(3-(2-cyclopropylpyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)-2-methylpropane-2-sulfinamide (A-26): To a stirred solution of A-25 (250 mg, 0.72 mmol) in methanol (10 mL) at 0°C, sodium borohydride (54.28 mg, 1.43 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain A-26 (235 mg) as a solid.

[0217] Synthesis of 1-(3-(2-cyclopropylpyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethane-1-amine (A-27): To a stirred solution of A-26 (235 mg, 0.47 mmol) in 1,4-dioxane (2 mL) at 0°C, 4 M HCl in 1,4-dioxane (10 mL, 0.47 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to obtain the residue, which was purified by washing with diethyl ether to obtain A-27 (125 mg).

[0218] Step 9: Synthesis of (S)-N-(1-(3-(2-cyclopropylpyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)benzamide(4) and (R)-N-(1-(3-(2-cyclopropylpyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)benzamide(5): To a stirred solution of A-27 (282 mg, 1.02 mmol) and benzoic acid (149.51 mg, 1.22 mmol) in DCM (10 mL), HATU (581.9 mg, 1.53 mmol) and DIPEA (0.18 mL, 1.02 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and diluted with DCM (2 × 100 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain the residue. The residual compounds were purified by column chromatography using 100-200 silica and 30-80% siRNA / hexane as an eluent to obtain a racemic mixture, which was then purified by SFC column chromatography followed by chiral HPLC to obtain 4 (39.22 mg, 0.1109 mmol, yield 11%) and 5 (20.89 mg, 0.0593 mmol, yield 6%). Note: Absolute stereochemistry was randomly assigned.

[0219] 4: HPLC: Rt 7.411 min, Column: X-Select CSH C18 (4.6*150) mm 5u; Mobile phase: A - 0.1% formic acid aqueous solution: acetonitrile (95:05); B - acetonitrile; Flow rate: 1.0 mL / min; LCMS: 351.1 (M+H), Rt 1.639 min, X-Select CSH C18 (3.0*50) mm 2.5u; Mobile phase: A: 0.05% formic acid aqueous solution: ACN (95:5); B: 0.05% formic acid ACN solution; Flow rate: 1.2 mL / min; Chiral HPLC: Rt 7.89 min, 99.55%; Column: PHENOMENEX CELLULOSE-3, 250mm*4.6mm, 5u; Mobile phase: A: n-hexane + 0.1% TFA; B: ethanol: MEOH (50:50); Flow rate: 1.0 mL / min; Isocratic: 20% B. 1 1H NMR (400MHz, DMSO-d6)δ H =9.43-9.36(m,1H), 8.58(d,1H), 8.03(s,1H), 7.94(d,2H), 7.83(dd,1H), 7.64-7.57(m,1H ), 7.56-7.49(m,2H), 5.66-5.55(m,1H), 2.31-2.23(m,1H), 1.75(d,3H), 1.04-0.95(m,4H).

[0220] 5: HPLC: Rt 7.412 min, Column: X-Select CSH C18 (4.6*150) mm 5u; Mobile phase: A - 0.1% formic acid aqueous solution: acetonitrile (95:05); B - acetonitrile; Flow rate: 1.0 mL / min; LCMS: 351.1 (M+H), Rt 1.629 min, X-Select CSH C18 (3.0*50) mm 2.5u; Mobile phase: A: 0.05% formic acid aqueous solution: ACN (95:5); B: 0.05% formic acid ACN solution; Flow rate: 1.2 mL / min; Chiral HPLC: Rt 6.690 min, 100%; Column: PHENOMENEX CELLULOSE-3, 250mm*4.6mm, 5u; Mobile phase: A: n-hexane + 0.1% TFA; B: ethanol: MEOH (50:50); Flow rate: 1.0 mL / min; Isocratic: 20% B. 1 1H NMR (400MHz, DMSO-d6)δ H =9.43-9.35(m,1H), 8.58(d,1H), 8.03(s,1H), 7.94(d,2H), 7.83(dd,1H), 7.64-7.57(m,1H ), 7.56-7.49(m,2H), 5.66-5.56(m,1H), 2.32-2.22(m,1H), 1.75(d,3H), 1.05-0.94(m,4H).

[0221] Examples 6 and 7. Synthesis of (S)-3-chloro-N-(1-(3-(2-cyclopropylpyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)benzamide (6) and (R)-3-chloro-N-(1-(3-(2-cyclopropylpyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)benzamide (7). Note that the stereochemistry was randomly assigned.

[0222] [ka] To a stirred solution of A-27 (190 mg, 0.6900 mmol) and 3-chlorobenzoic acid (100.74 mg, 0.6400 mmol) in DCM (15 mL), HATU (392.06 mg, 1.03 mmol) and DIPEA (0.12 mL, 0.6900 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and diluted with DCM (2 × 100 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain the residue. The residue was purified by column chromatography using 100-200 silica and 30-80% siRNA / hexane as an eluent to obtain a racemic mixture, which was then purified by SFC column chromatography followed by chiral HPLC to obtain 6 (52.46 mg, 0.1348 mmol, 20% yield) and 7 (54.49 mg, 0.1412 mmol, 21% yield). Note that the stereochemistry was randomly assigned.

[0223] 6: HPLC: Rt 6.325 min, 98.93%; Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 u); Mobile phase-A: Aqueous solution of 0.05% TFA: ACN (95:5); Mobile phase-B: Mobile phase A: Acetonitrile (5:95); Flow rate: 1.0 mL / min, LCMS: 385.1 (M+H), Rt 2.354 min, Column: X-Bridge BEH C-18 (3.0 × 50 mm, 2.5 μm); Mobile phase: A: Aqueous solution of 0.025% FA, B: ACN; Flow rate: 1.2 ml / min (gradient); Chiral HPLC: Rt 9.649 min, 99.33% Column: CHIRAL PAK IG (250*4.6mm*5μm); Mobile phase A: 0.1% DEA in n-hexane solution; Mobile phase B: DCM:MEOH (50:50); AB: 75:25; Flow rate: 1.0 mL / min 1 1H NMR (400MHz, DMSO-d6)δ H=9.49(d,1H), 8.58(d,1H), 8.05-7.97(m,2H), 7.93-7.87(m,1H), 7.83(dd,1H), 7.72-7.64( m,1H), 7.61-7.53(m,1H), 5.60(quintet,1H), 2.31-2.22(m,1H), 1.74(d,3H), 1.04-0.93(m,4H).

[0224] 7:HPLC: Rt 6.322 min, 99.76%; Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 u); Mobile phase-A: Aqueous solution of 0.05% TFA: ACN (95:5); Mobile phase-B: Mobile phase A: Acetonitrile (5:95); Flow rate: 1.0 mL / min; LCMS: 385.1 (M+H), Rt 2.338 min, Column: X-Bridge BEH C-18 (3.0 × 50 mm, 2.5 μm); Mobile phase: A: Aqueous solution of 0.025% FA, B: ACN; Flow rate: 1.2 ml / min (gradient); Chiral HPLC: Rt 20.168 min, 99.31% Column: CHIRAL PAK IG (250*4.6mm*5μm); Mobile phase A: 0.1% DEA in n-hexane solution; Mobile phase B: DCM:MEOH (50:50); AB: 75:25; Flow rate: 1.0 mL / min 1 1H NMR (400MHz, DMSO-d6)δ H = 9.49(d,1H), 8.58(d,1H), 8.05-7.97(m,2H), 7.93-7.87(m,1H), 7.83(dd,1H), 7.71-7.65(m ,1H), 7.60-7.53(m,1H), 5.60(quintet,1H), 2.31-2.22(m,1H), 1.74(d,3H), 1.05-0.92(m,4H).

[0225] Examples 8 and 9. Synthesis of (S)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)piperidine-1-carboxamide (8) and (R)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)piperidine-1-carboxamide (9). Note that the stereochemistry was assigned randomly.

[0226] [ka] To a stirred solution of A-17 (300 mg, 1.17 mmol) and piperidine (0.23 mL, 2.33 mmol) in DCM (10 mL), CDI (378.25 mg, 2.33 mmol) and TEA (0.49 mL, 3.5 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 50 mL). The combined extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by combiflash column chromatography (100–200 silica gel) using 30–50% Â / hexane as an eluent, followed by preparative chiral HPLC, to obtain 8 (90 mg, 0.2365 mmol, yield 20%) and 9 (70 mg, 0.1897 mmol, yield 16%). Note that the stereochemistry was randomly assigned.

[0227] 8: HPLC: Rt: 8.242 min, 96.79%; Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5i); Mobile phase A: 0.1% FA aqueous solution; Mobile phase B: Acetonitrile; Flow rate: 1.2 mL / min LCMS: 369.1 (M+H), Rt 2.050 min, Column: X-Bridge BEH C-18 (3.0 × 50 mm, 2.5 μm); Mobile phase A: 0.025% FA aqueous solution, B: ACN; Flow rate: 1.2 ml / min Chiral HPLC: Rt: 5.535 min, 99.9%; Column: Chiral pak-IG (250*4.6mm) 5μm; Mobile phase A: 0.1% DEA in n-hexane solution; Mobile phase B:ETOH:MEOH(50:50);PROGRAM-AB 70:30;Flow rate:1.0 1 1H NMR (400MHz, DMSO-d6)δ H =8.92(d,1H), 8.32(s,1H), 8.20(d,1H), 7.16(s,1H), 6.96(d,1H), 5.11(quintet,1H), 3.37-3.32(m,2H), 3.30-3.23(m,2H), 1.60-1.38(m,9H).

[0228] 9:HPLC: Rt: 8.223 min, 99.83%; Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 0.1% FA aqueous solution; Mobile phase B: Acetonitrile; Flow rate: 1.2 mL / min LCMS: 369.1 (M+H), Rt 2.051 min, Column: X-Bridge BEH C-18 (3.0 × 50 mm, 2.5 μm); Mobile phase A: 0.025% FA aqueous solution, B: ACN; Flow rate: 1.2 ml / min (gradient); Chiral HPLC: Rt 7.686 min, 99.53%; Column: Chiral pak-IG (250 × 4.6 mm) 5 μm; Mobile phase A: 0.1% DEA n-hexane solution; Mobile phase B: ETOH:MEOH (50:50); Program AB 70:30;Flow rate: 1.0ML / min 1 1H NMR (400MHz, DMSO-d6)δ H =8.92(d,1H), 8.32(s,1H), 8.20(d,1H), 7.17(s,1H), 6.96(d,1H), 5.11(quintet,1H), 3.36(br s,2H), 3.30-3.22(m,2H), 1.59-1.39(m,9H).

[0229] Examples 10 and 11. Synthesis of (R)-1-methyl-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (10) and (S)-1-methyl-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (11). Note that the stereochemistry was randomly assigned.

[0230] [ka] Solution 1 was purified by chiral HPLC to obtain 10 (10 mg, 0.022 mmol, 8% yield) and 11 (10 mg, 0.022 mmol, 8% yield).

[0231] 10: HPLC: Rt9.349 min, 99.77%; Column: X-Select CSH C18 (4.6 x 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid in water: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min LCMS:450.9(M+H), Rt2.117min, Column:X-select CSH C18(3*50)mm, 2.5μM, 1H NMR(400MHz,DMSO-d6)δ 9.55(d,1H), 8.99(d,1H), 8.46(s,1H), 8.42(d,1H), 7.48(s,1H), 5.66-5.58(m,1H), 4.15(s,3H), 1.71(d,3H). Chiral method: Rt 4.458 min, 99.93%; Column: PHENOMENEX CELLULOSE-3 (250 mm × 4.6 mm, 5 u) - Mobile phase: A) n-hexane + 0.1% TFA B) EtOH:MeOH (50:50), isocratic: 20% B; Wavelength: 240 nm, Flow rate: 1.0 mL / min.

[0232] 11:HPLC: Rt 9.352 min, 99.87%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min; LCMS: 449.2 (MH), Rt 2.182 min, Column: X-select CSH C18 (3 × 50) mm, 2.5 μm; 1¹H NMR (400MHz, DMSO-d6) δ 9.55 (d,1H), 8.99 (d,1H), 8.46 (s,1H), 8.42 (d,1H), 7.48 (s,1H), 5.66-5.58 (m,1H), 4.15 (s,3H), 1.71 (d,3H). Chiral method: Rt 6.579 min, 99.87%; Column: PHENOMENEX CELLULOSE-3 (250mm × 4.6mm, 5u) - Mobile phase: A) n-hexane + 0.1% TFA B) EtOH:MeOH (50:50), isocratic: 20%B; Wavelength: 240nm, Flow rate: 1.0mL / min.

[0233] Example 11-1. Synthesis of 2-methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (11-1) [ka]

[0234] 3-Bromo-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (C-17) A mixture of 3-bromo-5-chloro-1,2,4-thiadiazole (10.0 g, 50.1 mmol) and 1-ethoxyvinyltri-n-butyltin (20.5 mL, 60.2 mmol) in DMF (150 mL) was mixed with Pd(PPh3)2Cl2 (3.52 g, 5.01 mmol) under N2 conditions, and the reaction mixture was heated at 60°C for 4 hours. The reaction mixture was quenched with aqueous KF (10.0 g in 300 mL of water), stirred for 30 minutes, and filtered. The mixture was extracted with Depositphotos (2 × 300 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / Depositphotos = 20 / 1) to obtain the product (7.0 g, 29.8 mmol, yield 59%) as a solid. 1 1H NMR (CDCl3, 400MHz) δ H =5.53(d,1H), 4.58(d,1H), 4.02(q,2H), 1.43(t,3H).

[0235] 5-(1-ethoxyvinyl)-3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole(C-18) To a solution of 3-bromo-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (2.0 g, 8.51 mmol) in DME (20.0 mL, 8.51 mmol) and water (4.0 mL), Cs2CO3 (8.31 g, 25.5 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (3.02 g, 11.1 mmol), and Pd(dppf)Cl2 (622 mg, 0.85 mmol) were added under N2. After stirring at 100°C for 1.5 hours, the reaction mixture was cooled to 25°C, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum / ethyl acetate = 10 / 1 to obtain the product (1.80 g, 5.97 mmol, yield 70%) as oil. 1 1H NMR (CDCl3, 400MHz) δ H =8.87(d,1H), 8.57(s,1H), 8.37(d,1H), 5.63(d,1H), 4.62(d,1H), 4.13-3.95(m,2H), 1.47(t,3H).

[0236] 1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]etanone (C-19) To a solution of 5-(1-ethoxyvinyl)-3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole (1.80 g, 5.97 mmol) in acetone (20.0 mL), 3 M HCl (1.09 g, 29.9 mmol) was added at 25°C. After stirring at 25°C for 16 hours, the reaction mixture was quenched with saturated NaHCO3 (50.0 mL) and extracted with Depositphotos (2 × 50.0 mL). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (1.60 g, 5.86 mmol, 98% yield) as a solid, which was used directly in the next step. 1 1H NMR (CDCl3, 400MHz) δH =8.92(d,1H), 8.58(s,1H), 8.39(d,1H), 2.85(s,3H).

[0237] (R,E)-2-methyl-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethylidene]propan-2-sulfinamide(C-20) To a solution of 1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]etanone (300 mg, 1.10 mmol) in THF (10.0 mL), (R)-2-methylpropane-2-sulfinamide (200 mg, 1.65 mmol) and Ti(OEt)4 (751 mg, 3.29 mmol) were added under N2 conditions at 25°C. The mixture was heated to 65°C and stirred for 16 hours. The reaction mixture was quenched with saturated NaHCO3 (20.0 mL) and filtered. The filtrate was extracted with ELISA (2 × 20.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by SiO2 column chromatography (PE / Â=10 / 1) to obtain the product (120 mg, 0.32 mmol, yield 29%) as oil. 1 1H NMR (CDCl3, 400MHz) δ H =8.91(d,1H), 8.56(s,1H), 8.37(d,1H), 2.98(s,3H), 1.37(s,9H).

[0238] (R)-2-methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]propan-2-sulfinamide(C-21) To a solution of (R,E)-2-methyl-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethylidene]propan-2-sulfinamide (100 mg, 0.27 mmol) in THF (2.0 mL), L-Selectride (0.53 mL, 0.53 mmol) was added under N2 at -78°C. The reaction mixture was stirred at -78°C for 30 minutes. NH4Cl (10.0 mL) was added to the mixture at -78°C. The mixture was extracted with ELISA (2 × 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (110 mg, 0.29 mmol) as oil, which was used directly in the next step. LCMS R t = Chromatography for 1.0 min, 0.727 min, 5-95AB, C 14 H 18 F3N4OS2[M+H] + The MS ESI calculated value is 379.0, and the measured value is 379.0.

[0239] (1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethanamine hydrochloride (C-22) To a solution of (R)-2-methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]propan-2-sulfinamide (150 mg, 0.40 mmol) in 1,4-dioxane (1.0 mL), 4 M HCl / dioxane (2.0 mL, 1.98 mmol) was added at 25°C. After stirring at 25°C for 2 hours, the reaction mixture was concentrated under reduced pressure to obtain the product (100 mg, 0.32 mmol, yield 81%) as a solid. LCMS R t = Chromatography for 1.5 minutes, 0.744 minutes, 5-95AB, C 10 H 10 F3N4S[M+H] + The MS ESI calculated value is 274.8, and the measured value is 274.8.

[0240] 2-methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide(11-1) To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (62.5 mg, 0.32 mmol) in DCM (3.0 mL), DIPEA (0.45 mL, 2.57 mmol) and T3P (734 mg, 0.97 mmol) were added. After stirring at 25°C for 20 minutes, (1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethanamine hydrochloride (100 mg, 0.32 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (20.0 mL) and extracted with DCM (2 × 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product. This product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 μm, conditions: water (0.05% NH3H2O)-ACN, start B: 48, end B: 78, gradient time (min): 8, 100% B retention time (min): 2, flow rate (mL / min): 30, injection: 5) to obtain the product (90.0 mg, 0.20 mmol, yield 62%) as a solid. The product (90.0 mg, 0.20 mmol) was purified by SFC (column: DAIEL CHIRALCEL OJ (250 mm * 30 mm, 10 μm), conditions: 0.1% NH3H2O-EtOH, start B: 15%, end B: 15%, flow rate (mL / min): 60, injection: 30) to obtain the product (54.3 mg, 0.12 mmol, yield 60%) as a solid. 1 1H NMR (CDCl3, 400MHz) δ H =8.88(d,1H), 8.53(s,1H), 8.34(d,1H), 6.90(s,1H), 6.60(d,1H), 5.76-5.66(m,1H), 4.24(s,3H), 1.86(d,3H). 19 F NMR (376.5 MHz, CDCl3) δ F -62.206, -68.055. LCMS R t= 3.0 minutes chromatography for 2.496 minutes, 30-90AB, C 16 H 13 F6N6OS[M +H] + MS ESI calculated value: 451.2, measured value: 451.2. 99.72% ee.

[0241] Example 10-1. Synthesis of 2-methyl-N-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (10-1) [ka]

[0242] (S,E)-2-methyl-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethylidene]propan-2-sulfinamide(C-31) To a solution of 1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]etanone (300 mg, 1.10 mmol) in THF (10.0 mL), (S)-2-methylpropane-2-sulfinamide (200 mg, 1.65 mmol) and Ti(OEt)4 (751 mg, 3.29 mmol) were added under N2 conditions at 25°C. The mixture was heated to 65°C and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous solution NaHCO3 (20.0 mL) and filtered. The filtrate was extracted with ELISA (2 × 20.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by column chromatography with SiO2 (PE / siRNA = 10 / 1) to obtain the product (110 mg, 0.29 mmol, yield 27%) as oil.

[0243] (S)-2-methyl-N-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]propan-2-sulfinamide(C-32) To a solution of (S,E)-2-methyl-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethylidene]propan-2-sulfinamide (100 mg, 0.27 mmol) in THF (2.0 mL), L-Selectride (0.53 mL, 0.53 mmol) was added under N2 at -78°C. After stirring at -78°C for 30 minutes, saturated NH4Cl (10.0 mL) was added to the mixture at -78°C. The mixture was extracted with siRNA (2 × 20.0 mL). The combined organic layer was washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (100 mg, 0.26 mmol, 99% yield) as oil, which was used directly in the next step. LCMS R t = Chromatography for 1.0 min, 0.728 min, 5-95AB, C 14 H 18 F3N4OS2[M+H] + The MS ESI calculated value is 379.0, and the measured value is 379.0.

[0244] (1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethanamine hydrochloride (C-33) To a solution of (S)-2-methyl-N-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]propan-2-sulfinamide (130 mg, 0.34 mmol) in 1,4-dioxane (1.0 mL), HCl / dioxane (3.0 mL, 4 M) was added at 25°C. After stirring at 25°C for 2 hours, the reaction mixture was concentrated under reduced pressure to obtain the product (90.0 mg, 0.29 mmol, yield 84%) as a solid, which was used directly in the next step. LCMS R t = Chromatography for 1.5 minutes, 0.754 minutes, 5-95AB, C 10 H 10 F3N4S[M+H] + The MS ESI calculated value is 274.8, and the measured value is 274.8.

[0245] 2-methyl-N-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide(10-1) To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (56.2 mg, 0.29 mmol) in DCM (3.0 mL), T3P (661 mg, 0.87 mmol) and DIEA (0.40 mL, 2.32 mmol) were added. After stirring at 25°C for 20 minutes, (1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethanamine hydrochloride (90.0 mg, 0.29 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (20.0 mL) and extracted with DCM (2 × 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product. This product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 μm, conditions: water (0.05% NH3H2O)-ACN, start B: 47, end B: 77, gradient time (min): 8, 100% B retention time (min): 2, flow rate (mL / min): 30, injection: 4) to obtain the product (70.0 mg, 0.16 mmol, yield 54%) as a solid. The product (70.0 mg, 0.16 mmol) was purified by SFC (column: DAISEL CHIRALCEL OJ (250 mm * 30 mm, 10 μm), conditions: 0.1% NH3H2O ​​EtOH, start B: 15%, end B: 15%, flow rate (mL / min): 60, injection: 20) to obtain the product (22.9 mg, 0.05 mmol, yield 33%) as a solid. 1 1H NMR (CDCl3, 400MHz) δ H =8.88(d,1H), 8.53(s,1H), 8.33(d,1H), 6.90(s,1H), 6.63(d,1H), 5.77-5.64(m,1H), 4.24(s,3H), 1.85(d,3H). 19 F NMR (376.5 MHz, CDCl3) δ F -62.206, 68.046. LCMS R t= 3.0 minutes chromatography for 2.451 minutes, 30-90AB, C 16 H 13 F6N6OS[M +H] + MS ESI calculated value: 451.1, measured value: 451.1. 100% ee.

[0246] Examples 12 and 13. Synthesis of (S)-N-(1-(3-(2-cyclopropylpyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (12) and (R)-N-(1-(3-(2-cyclopropylpyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (13). Note that the stereochemistry was assigned randomly.

[0247] [ka] To a stirred solution of A-27 (125 mg, 0.31 mmol) and 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (66.07 mg, 0.34 mmol) in DCM (10 mL), HATU (117.65 mg, 0.31 mmol) and DIPEA (0.11 mL, 0.62 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and diluted with DCM (2 × 100 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain the residue. The residue was purified by column chromatography using 100-200 silica and 30-80% alkylammonium hexane as an eluent to obtain a racemic mixture, which was then purified by SFC column chromatography to obtain 12 (10 mg, 0.0234 mmol, 8% yield) and 13 (10 mg, 0.0234 mmol, 8% yield).

[0248] 12:HPLC: Rt 8.686 min, 99.87%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min; LCMS: 422.9 (M+H), Rt 1.89 min, Column: X-select CSH C18 (3 × 50) mm, 2.5 μm; 1 H NMR(400MHz,DMSO-d6)δ 9.46(d,1H), 8.61(d,1H), 7.85(s,1H), 7.66-7.64(m,1H), 7.45(s,1H), 5.50- 5.45(m,1H), 4.13(s,3H), 2.30-2.26(m,1H), 1.68(d,3H), 1.03-0.97(m,4H). Chiral method: Rt 4.755 min, 100%; Column: PHENOMENEX CELLULOSE-3 (250 mm × 4.6 mm, 5 u) - Mobile phase: A) n-hexane + 0.1% TFA B) EtOH:MeOH (50:50), isocratic: 20% B; Wavelength: 240 nm, Flow rate: 1.0 mL / min.

[0249] 13:HPLC: Rt 8.348 min, 97.85%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min; LCMS: 422.9 (M + H), Rt 1.894 min, Column: X-select CSH C18 (3 × 50) mm, 2.5 μm; 1 H NMR(400MHz,DMSO-d6)δ 9.46(d,1H), 8.61(d,1H), 7.85(s,1H), 7.66-7.64(m,1H), 7.44(s,1H), 5.50- 5.46(m,1H), 4.13(s,3H), 2.30-2.26(m,1H), 1.68(d,3H), 1.03-0.97(m,4H). Chiral method: Rt 8.044 min, 100%; Column: PHENOMENEX CELLULOSE-3 (250 mm × 4.6 mm, 5 u) - Mobile phase: A) n-hexane + 0.1% TFA B) EtOH:MeOH (50:50), isocratic: 20% B; Wavelength: 240 nm, Flow rate: 1.0 mL / min.

[0250] Examples 12-1 and 13-1. Synthesis of 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide and 2-methyl-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide [ka]

[0251] 3-(2-cyclopropyl-4-pyridyl)-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (C-23) To a solution of 3-bromo-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (2.0 g, 8.51 mmol) in DME (10.0 mL, 8.51 mmol) and water (2.0 mL), 2-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.29 g, 9.36 mmol), Cs2CO3 (5.54 g, 17.0 mmol), and Pd(dppf)Cl2 (0.62 g, 0.85 mmol) were added under N2. The reaction mixture was stirred at 100°C for 1.5 hours. After cooling to 25°C, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum / ethyl acetate = 20 / 1 to obtain the product (1.60 g, 5.85 mmol, yield 69%) as oil. LCMS R t = 1.0 minute chromatography for 0.676 minutes, 5-95AB, C 14 H 16 N3OS[M+H] + The MS ESI calculated value is 274.0, and the measured value is 274.0.

[0252] 1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]etanone (C-24) To a solution of 3-(2-cyclopropyl-4-pyridyl)-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (1.6 g, 5.85 mmol) in acetone (20.0 mL), 3 M HCl (1.07 g, 29.3 mmol) was added at 25°C. After stirring at 25°C for 16 hours, the reaction mixture was quenched with saturated NaHCO3 (30.0 mL) and extracted with siRNA (2 × 30.0 mL). The combined organic layers were washed with brine (30.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (1.10 g, 4.48 mmol, yield 77%) as a solid, which was used directly in the next step. 1 1H NMR DMSO-d 6400MHz δ H =8.72(d,1H), 8.18(s,1H), 8.13(d,1H), 2.79(s,3H), 1.37-1.34(m,1H), 1.26-1.11(m,4H).

[0253] (S,E)-N-[1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethylidene]-2-methyl-propane-2-sulfinamide(C-25) To a solution of 1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]etanone (500 mg, 2.04 mmol) in THF (10.0 mL), (S)-2-methylpropane-2-sulfinamide (371 mg, 3.06 mmol) and Ti(OEt)4 (1.39 g, 6.11 mmol) were added at 25°C. After stirring at 50°C for 16 hours, the reaction mixture was cooled to 25°C, quenched with saturated NaHCO3 (10.0 mL), and filtered. The filtrate was extracted with ethyl acetate (2 × 20.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by chromatography column chromatography (ethyl acetate in PE, 5%-10%) to obtain the solid product (280 mg, 0.80 mmol, yield 39%). 1 1H NMR (CDCl3, 400MHz) δ H=8.60(d,1H), 8.00(s,1H), 7.91-7.88(m,1H), 2.97(s,3H), 2.23-2.11(m,1H), 1.37(s,9H), 1.15-1.00(m,4H).

[0254] (S)-2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]propan-2-sulfinamide(C-26) To a solution of (S,E)-N-[1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethylidene]-2-methyl-propane-2-sulfinamide (280 mg, 0.80 mmol) in THF (5.0 mL), L-Selectride (1.61 mL, 1.61 mmol) was added under N2 at -78°C. After stirring at -78°C for 1 hour, the reaction mixture was quenched with saturated NH4Cl (20.0 mL) and extracted with siRNA (2 × 20.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (200 mg, 0.57 mmol, yield 71%) as oil, which was used directly in the next step. LCMS R t = Chromatography for 1.5 minutes, 0.805 minutes, 5-95AB, C 16 H 23 N4OS2[M+H] + The MS ESI calculated value is 350.9, and the measured value is 350.9.

[0255] (1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethanamine(C-27) To a solution of (S)-2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]propan-2-sulfinamide (200 mg, 0.57 mmol) in 1,4-dioxane (3.0 mL), 4 M HCl / dioxane (0.43 mL, 1.71 mmol) was added at 25°C. After stirring at 25°C for 2 hours, the reaction mixture was quenched with saturated NaHCO3 (20.0 mL) and extracted with siRNA (2 × 20.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (140 mg, 0.57 mmol, 99% yield) as oil, which was used directly in the next step. LCMS R t = Chromatography for 1.5 minutes, 0.437 minutes, 5-95AB, C 12 H 15 N4S[M+H] + The MS ESI calculated value is 246.8, and the measured value is 246.8.

[0256] 2-Methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide & 2-Methyl-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (100 mg, 0.52 mmol) in DCM (2.0 mL), DIEA (0.47 mL, 2.71 mmol) and T3P (617 mg, 0.81 mmol) were added. After stirring at 25°C for 10 minutes, (1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethanamine hydrochloride (140 mg, 0.50 mmol) in DCM (2.0 mL) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (20.0 mL) and extracted with DCM (2 × 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product. This product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 μm, conditions: water (0.05% NH3H2O)-ACN, start B: 44, end B: 74, gradient time (min): 8, 100% B retention time (min): 2.8, flow rate (mL / min): 30, injection: 8) to obtain the product (90.0 mg, 0.21 mmol, yield 41%) as oil. This oil was then purified by SFC (column: (s,s)WHELK-O1 (250 mm*30 mm, 5 μm), conditions: 0.1% The mixture was purified by NH3H2O-EtOH (start B: 35%, end B: 35%, flow rate (ML / min): 80, injection: 50) to obtain 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (61.82 mg, 0.14 mmol, yield 68%) as a solid, and 2-methyl-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (10.76 mg, 0.03 mmol, yield 12%) as a solid.

[0257] 13-1: 1 1H NMR (CDCl3, 400MHz) δ H=8.58(d,1H), 7.96(s,1H), 7.87-7.84(m,1H), 6.89(s,1H), 6.69(d,1H), 5.76 -5.65(m,1H), 4.24(s,3H), 2.22-2.08(m,1H), 1.83(d,3H), 1.14-1.01(m,4H). 19 F NMR (376.5 MHz, CDCl3) δ F -62.212. LCMS R t = 2.131 minutes in chromatography at 3.0 minutes, 10⁻⁸ CD, C 18 H 18 F3N6OS[M+H] + MS ESI calculated value: 423.0, measured value: 423.0. 100% ee.

[0258] 12-1: 1 1H NMR (CDCl3, 400MHz) δ H =8.58(d,1H), 7.96(s,1H), 7.87-7.83(m,1H), 6.90(s,1H), 6.70(d,1H), 5.76 -5.65(m,1H), 4.24(s,3H), 2.22-2.08(m,1H), 1.83(d,3H), 1.13-1.00(m,4H). 19 F NMR (376.5 MHz, CDCl3) δ F -62.210. LCMS R t = 2.120 minutes in chromatography at 3.0 minutes, 10⁻⁸ CD, C 18 H 18 F3N6OS[M+H] + MS ESI calculated value: 423.0, measured value: 423.0. 99.5% ee.

[0259] Examples 12-2 and 13-2. Synthesis of 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide and 2-methyl-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide [ka]

[0260] (R,E)-N-[1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethylidene]-2-methyl-propane-2-sulfinamide(C-28) To a solution of 1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]etanone (500 mg, 2.04 mmol) in THF (10.0 mL), Ti(OEt)4 (1.39 g, 6.11 mmol) was added at 25°C. After stirring at 50°C for 16 hours, the reaction mixture was cooled to 25°C, quenched with saturated NaHCO3 (40.0 mL), and filtered. The filtrate was extracted with ethyl acetate (2 × 40.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by chromatography column chromatography (ethyl acetate in PE, 5%-10%) to obtain the solid product (300 mg, 0.86 mmol, yield 42%). 1 1H NMR (CDCl3, 400MHz) δ H =8.60(d,1H), 8.00(s,1H), 7.90(d,1H), 2.97(s,3H), 1.36(s,9H), 1.15-1.02(m,1H), 0.92-0.75(m,4H).

[0261] (R)-2-methyl-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]propan-2-sulfinamide(C-29) To a solution of (R,E)-N-[1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethylidene]-2-methyl-propane-2-sulfinamide (300 mg, 0.86 mmol) in THF (5.0 mL), L-Selectride (1.72 mL, 1.72 mmol) was added under N2 at -78°C. After stirring at -78°C for 1 hour, the reaction mixture was quenched with saturated NH4Cl (20.0 mL) and extracted with siRNA (2 × 20.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (350 mg, 1.00 mmol) as oil, which was used directly in the next step. LCMS R t = Chromatography for 1.5 minutes, 0.791 minutes, 5-95AB, C 16 H 23 N4OS2[M+H] + The MS ESI calculated value is 351.2, and the measured value is 351.2.

[0262] (1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethanamine hydrochloride (C-30) To a solution of (R)-2-methyl-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]propan-2-sulfinamide (330 mg, 0.94 mmol) in 1,4-dioxane (3.0 mL), 4 M HCl / dioxane (0.71 mL, 2.82 mmol) was added at 25°C. After stirring at 25°C for 2 hours, the reaction mixture was quenched with saturated NaHCO3 (20.0 mL) and extracted with siRNA (2 × 30.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (200 mg, 0.71 mmol, yield 75%) as oil, which was used directly in the next step. 1 1H NMR (DMSO-d 6400MHz) δ H=8.56(d,1H), 8.00(s,1H), 7.84-7.80(m,1H), 7.28(s,1H), 6.53(s,1H), 4.43(q,1H), 1.49(d,2H), 1.04-0.94(m,3H), 0.89-0.79(m,3H).

[0263] 2-Methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide & 2-Methyl-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (82.4 mg, 0.42 mmol) in DCM (2.0 mL), DIEA (0.62 mL, 3.54 mmol) and T3P (807 mg, 1.06 mmol) were added. After stirring at 25°C for 10 minutes, (1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethanamine hydrochloride (100 mg, 0.35 mmol) in DCM (2.0 mL) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (20.0 mL) and extracted with DCM (2 × 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product. This product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 μm, conditions: water (0.05% NH3H2O)-ACN, start B: 43, end B: 73, gradient time (min): 8, 100% B retention time (min): 2, flow rate (mL / min): 30, injection: 5) to obtain two products (80.0 mg, 0.19 mmol, yield 54%) as oil, which was used for SFC separation. The product (80.0 mg, 0.19 mmol) was separated by SFC (column: DAISEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm), conditions: 0.1% The mixture was purified by NH3H2O-EtOH (start B: 35%, end B: 35%, flow rate (mL / min): 80, injection: 45) to obtain 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (3.29 mg, 0.01 mmol, yield 4%) as a solid, and 2-methyl-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (34.82 mg, 0.08 mmol, yield 44%) as a solid.

[0264] 12-2: 1 1H NMR (CDCl3, 400MHz) δ H=8.58(d,1H), 7.96(s,1H), 7.87-7.84(m,1H), 6.89(s,1H), 6.69(d,1H), 5.76 -5.65(m,1H), 4.24(s,3H), 2.22-2.08(m,1H), 1.83(d,3H), 1.14-1.01(m,4H). 19 F NMR (376.5 MHz, CDCl3) δ F -62.186. LCMS R t = 2.296 minutes in chromatography at 3.0 minutes, 10⁻⁸ AB, C 18 H 18 F3N6OS[M+H] + MS ESI calculated value: 423.4, measured value: 423.4. 100% ee.

[0265] 13-2: 1 1H NMR (CDCl3, 400MHz) δ H =8.58(d,1H), 7.96(s,1H), 7.87-7.83(m,1H), 6.90(s,1H), 6.70(d,1H), 5.76 -5.65(m,1H), 4.24(s,3H), 2.22-2.08(m,1H), 1.83(d,3H), 1.13-1.00(m,4H). 19 F NMR (376.5 MHz, CDCl3) δ F -62.177. LCMS R t = 3.0 minutes chromatography for 2.265 minutes, 10⁻⁸⁰AB, C 18 H 18 F3N6OS[M+H] + MS ESI calculated value: 423.2, measured value: 423.2. 100% ee.

[0266] Examples 14 and 15. Synthesis of (S)-N-(1-(3-(2-cyclopropylpyridine-4-yl)isoxazole-5-yl)ethyl)benzamide (14) and (R)-N-(1-(3-(2-cyclopropylpyridine-4-yl)isoxazole-5-yl)ethyl)benzamide (15). Note that the stereochemistry was randomly assigned. [ka]

[0267] Synthesis of 2-cyclopropyl isonicotinate methyl (A-38): To a stirred solution of A-37 (4 g, 23.31 mmol) in 1,4-dioxane (50 mL), cyclopropylboronic acid (2.38 g, 27.98 mmol), K3PO4 (9.9 g, 46.63 mmol), and Ag2O (2.7 g, 11.66 mmol) were added. Pd(dppf)Cl2 (1.71 g, 2.33 mmol) was added to this solution, and the mixture was stirred at 100°C for 12 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography at 100-200 with 20-30% siRNA / hexane as an eluent to obtain A-38 (2.6 g, 14.12 mmol, yield 61%) as oil.

[0268] Synthesis of (2-cyclopropylpyridine-4-yl)methanol (A-39): To a stirred solution of A-38 (2.5 g, 14.11 mmol) in methanol (10 mL), NaBH4 (1.07 g, 28.22 mmol) was added at 0°C, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched with ice-cold water and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain A-39 (2 g, 12.8 mmol, 91%) as a liquid.

[0269] Synthesis of 2-cyclopropyl isonicotinaldehyde (A-40): To a stirred solution of A-40 (2 g, 13.41 mmol) in DCM (20 mL), desmartin periodinane (5.68 g, 13.41 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (50 mL), saturated sodium thiosulfate (20 mL), and saturated sodium bicarbonate (20 mL). The organic layer was separated and washed with water (2 × 30 mL) and saturated brine solution (30 mL). The organic layer was separated, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography at 100-200 using 20-30% toluene / hexane as an eluent to obtain A-40 (1.6 g, 8.83 mmol, 66%) as oil.

[0270] Synthesis of (Z)-2-cyclopropyl isonicotinaldehyde oxime (A-41): To a stirred solution of A-40 (1.6 g, 10.87 mmol) in ethanol (5 mL) and water (25 mL), hydroxylamine hydrochloride (0.91 g, 13.05 mmol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with HCl (50 mL). The organic layer was washed with water (2 × 20 mL) and saturated brine solution (20 mL). The organic layer was separated, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography at 100-200 using 20-30% HCl / hexane as an eluent to obtain A-41 (1.6 g, 6.35 mmol, 58%) as a solid.

[0271] Synthesis of (E)-2-cyclopropyl-N-hydroxyisonicotinimidoyl chloride (A-42): To a stirred solution of A-41 (1.6 g, 9.86 mmol) in DMF (20 mL), N-chlorosuccinimide (2.63 g, 19.73 mmol) was added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with Depositphotos (50 mL) and water (20 mL). The organic layer was washed with water (2 × 20 mL) and saturated brine solution (20 mL). The organic layer was separated, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography at 100-200 using 20-30% Depositphotos / hexane as an eluent to obtain A-42 (1.2 g, 4.91 mmol, 50%) as a solid.

[0272] Synthesis of 1-(3-(2-cyclopropylpyridine-4-yl)isoxazole-5-yl)ethane-1-ol (A-43): To a stirred solution of A-42 (1.2 g, 6.1 mmol) in THF (15 mL), buta-3-in-2-ol (0.86 g, 12.21 mmol) and triethylamine (0.62 g, 6.1 mmol) were added and the mixture was stirred at 60°C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with siRNA (50 mL). The organic layer was washed with water (2 × 20 mL) and saturated brine solution (20 mL). The organic layer was separated, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography at 100-200 using 20-30% siRNA / hexane as an eluent to obtain A-43 (0.8 g, 3.47 mmol, 57%) as oil.

[0273] Synthesis of 1-(3-(2-cyclopropylpyridine-4-yl)isoxazole-5-yl)ethane-1-one (A-44): Desmartin periodinane (2.95 g, 6.95 mmol) was added to a stirred solution of A-43 (0.8 g, 3.47 mmol) in DCM (20 mL). The reaction mixture was stirred at room temperature for 12 hours. After completion, the reaction mixture was diluted with DCM (30 mL), 10 mL of saturated sodium thiosulfate, and 10 mL of saturated bicarbonate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography at 100-200 with 70-80% siRNA / hexane as an eluent to obtain A-44 (0.62 g, 2.394 mmol, 69%) as a solid.

[0274] Synthesis of (E)-N-(1-(3-(2-cyclopropylpyridine-4-yl)isoxazole-5-yl)ethylidene)-2-methylpropane-2-sulfinamide (A-45): 1) To a stirred solution of A-44 (0.62 g, 2.72 mmol) in toluene (10 mL), Ti(OEt)4 (0.93 g, 4.07 mmol) was added and the mixture was stirred at 100 °C for 12 hours. 2) After completion, the reaction mixture was diluted with siRNA (30 mL) and water (10 mL) and filtered through a Celite pad. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography at 100-200 with 70-80% siRNA / hexane as an eluent to obtain A-45 (0.7 g, 1.3 mmol, 46.31%) as oil.

[0275] Synthesis of N-(1-(3-(2-cyclopropylpyridine-4-yl)isoxazole-5-yl)ethyl)-2-methylpropane-2-sulfinamide (A-46): Sodium borohydride (159.8 mg, 4.22 mmol) was added to a stirred solution of A-45 (700 mg, 2.11 mmol) in methanol (10 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (2 × 20 mL). The organic layer was separated, dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain A-46 (600 mg, 1.44 mmol, 68%).

[0276] Synthesis of 1-(3-(2-cyclopropylpyridine-4-yl)isoxazole-5-yl)ethane-1-amine (A-47): To a stirred solution of A-46 (700 mg, 2.1 mmol) in 1,4-dioxane (3 mL) at 0°C, 4M HCl 1,4-dioxane (10 mL, 2.1 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by polishing with diethyl ether to obtain A-47 (500 mg, 1.83 mmol, 87%).

[0277] Synthesis of (S)-N-(1-(3-(2-cyclopropylpyridine-4-yl)isoxazole-5-yl)ethyl)benzamide (14) and synthesis of (R)-N-(1-(3-(2-cyclopropylpyridine-4-yl)isoxazole-5-yl)ethyl)benzamide (15): Note that the stereochemistry is randomly assigned.

[0278] To a stirred solution of A-47 (200 mg, 0.73 mmol) and benzoic acid (106.98 mg, 0.88 mmol) in DCM (10 mL), HATU (416.37 mg, 1.1 mmol) and DIPEA (0.25 mL, 1.46 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 50 mL). The organic layer was separated, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by 100-200 silica gel column chromatography using 80% siRNA / hexane as an eluent to obtain a racemic mixture, which was then purified by SFC column chromatography to obtain 14 (15 mg, 0.045 mmol, 6%) and 15 (10 mg, 0.03 mmol, 4%).

[0279] 14: HPLC: Rt 6.55 min, 99.64%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min; LCMS: 333.9 (M + H), Rt 1.612 min, Column: X-select CSH C18 (3 × 50) mm, 2.5 μm; 1 H NMR(400MHz,DMSO-d6)δ 9.06(d,1H), 8.56(d,1H), 7.92(d,2H), 7.80(s,1H), 7.68(d,1H), 7.58-7.54(m,1H), 7.52- 7.45(m,2H), 7.15(s,1H), 5.44(p,1H), 2.25-2.20(m,1H), 1.61(d,3H), 1.10-0.97(m,4H). Chiral method: Rt 5.034 min, 100%; Column: PHENOMENEX CELLULOSE-3 (250 × 4.6 mm, 5 u), Mobile phase: A) n-hexane + 0.1% TFA, B) EtOH:MeOH (50:50), Isocratic: 35% B; Wavelength: 287 nm, Flow rate: 1.0 mL / min

[0280] 15:HPLC: Rt 6.86 min, 98.74%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min; LCMS: 334 (M+H), Rt 1.612 min, Column: X-select CSH C18 (3 × 50) mm, 2.5 μm. 1 H NMR(400MHz,DMSO-d6)δ 9.06(d,1H), 8.52(d,1H), 7.96(d,2H), 7.77(s,1H), 7.60-7.46(m,4H), 7.11(s,1H), 5.46-5.40(m 1H), 2.20-2.18(m,1H), 1.60(d,3H), 1.00-0.96(m,4H). Chiral method: Rt 5.523 min, 100%; Column: PHENOMENEX CELLULOSE-3 (250 × 4.6 mm, 5 u), Mobile phase: A) n-hexane + 0.1% TFA, B) EtOH:MeOH (50:50), Isocratic: 35% B; Wavelength: 287 nm, Flow rate: 1.0 mL / min

[0281] Examples 16 and 17. Synthesis of (R)-N-(1-(3-(2-cyclopropylpyridine-4-yl)isoxazole-5-yl)ethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (16) and (S)-N-(1-(3-(2-cyclopropylpyridine-4-yl)isoxazole-5-yl)ethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (17). Note that the stereochemistry was randomly assigned.

[0282] [ka] To a stirred solution of A-47 (200 mg, 0.73 mmol) and 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (170.05 mg, 0.88 mmol) in DCM (10 mL), HATU (322.7 mg, 0.85 mmol) and DIPEA (0.25 mL, 1.41 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 50 mL). The organic layer was separated, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by 100-200 silica gel column chromatography using 30-80% acetone / hexane as an eluent to obtain a racemic mixture, which was then purified by SFC column chromatography to obtain 16 (10 mg, 0.0245 mmol, 3%) and 17 (10 mg, 0.0245 mmol, 3%).

[0283] 16:HPLC: Rt 7.804 min, 99.35%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min; LCMS: 406.45 (M+H), Rt 1.921 min, Column: X-select CSH C18 (3 × 50) mm, 2.5 μm; 1H NMR(400MHz,DMSO-d6)δ 8.94(d,1H), 8.59(d,1H), 7.86-7.80(m,2H), 7.63(d,1H), 6.67(s,1H), 5.48- 5.40(m,1H), 3.93(s,3H), 2.35-2.25(m,1H), 1.67(d,3H), 1.05-0.95(m,4H). Chiral method: Rt: 10.283 mins, 100%; Column: YMC CHIRAL ART CELLULOSE-SC (250 × 4.6 mm, 5 u), Mobile phase: A) n-hexane + 0.1% isopropylamine, B) DCM:MeOH (50:50), Isocratic: 20% B; Wavelength: 287 nm, Flow rate: 1.0 mL / min

[0284] 17: HPLC: Rt 7.804 min, 99.35%; Column: X-Select CSH C18 (4.6 × 150) mm, 3.5 μm; Mobile phase: A: 0.1% formic acid aqueous solution: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min; LCMS: 406.45 (M+H), Rt 1.921 min, Column: X-select CSH C18 (3 × 50) mm, 2.5 μm; 1 H NMR(400MHz,DMSO-d6)δ 8.94(d,1H), 8.59(d,1H), 7.86-7.80(m,2H), 7.63(d,1H), 6.67(s,1H), 5.48- 5.40(m,1H), 3.93(s,3H), 2.30-2.25(m,1H), 1.67(d,3H), 1.05-0.95(m,4H). Chiral method: Rt: 12.792 mins, 97.84%; Column: YMC CHIRAL ART CELLULOSE-SC (250 × 4.6 mm, 5 u), Mobile phase: A) n-hexane + 0.1% isopropylamine, B) DCM:MeOH (50:50), Isocratic: 20% B; Wavelength: 287 nm, Flow rate: 1.0 mL / min

[0285] Examples 16-1 and 17-1. Synthesis of 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide and N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3-carboxamide. Note that the stereochemistry was randomly assigned.

[0286] [ka]

[0287] 2-[1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]isoindoline-1,3-dione(B-8) PCy3 (70.4 mg, 0.25 mmol) was added to a mixture of 2-[1-[3-(2-bromo-4-pyridyl)isoxazole-5-yl]ethyl]isoindoline-1,3-dione (1 g, 2.51 mmol), cyclopropylboronic acid (431.4 mg, 5.02 mmol), K3PO4 (1.07 g, 5.02 mmol), and Pd(OAc)2 (28.2 mg, 0.13 mmol) in water (5 mL) and toluene (25 mL). The mixture was stirred under N2 at 120 °C for 16 hours. The mixture was poured into water (30 mL) and stirred for 20 minutes. The aqueous phase was extracted with ELISA (3 × 20 mL). The combined organic phase was washed with saturated brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / Â5 / 1~3 / 1), and the product (240 mg, 0.47 mmol, yield 19%) was obtained as oil. LCMS R t = Chromatography for 1.5 minutes, 0.846 minutes, 5-95AB, C 21 H 18 N3O3[M+H] + MS ESI calculated value: 360.1, measured value: 360.0

[0288] 1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethanamine (B-9) To a solution of 2-[1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]isoindoline-1,3-dione (240 mg, 0.67 mmol) in DCM (10 mL) and ethanol (2 mL), NH2NH2.H2O (0.2 mL, 4.01 mmol) was added dropwise at 25°C. The mixture was stirred at 25°C for 16 hours. The mixture was filtered, and the filter cake was washed with DCM (10 × 3 mL). The mixture was concentrated to obtain the product (150 mg, 0.654 mmol, yield 98%) as a solid. LCMS R t = Chromatography for 1.5 minutes, 0.21 minutes, 5-95AB, C 13 H 16 N3O[M+H] + MS ESI calculated value: 230.1, measured value: 229.9

[0289] N-[1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3-carboxamide(B-10) To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (139.7 mg, 0.72 mmol) and HATU (497.5 mg, 1.31 mmol) in DMF (5 mL), Et3N (0.27 mL, 1.96 mmol) and 1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethanamine (150 mg, 0.65 mmol) were added. The mixture was stirred at 20°C for 12 hours, diluted with water (30 mL), and extracted with  (3 × 20 mL). The organic layer was washed with brine (3 × 30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to obtain the product, which was purified by flash chromatography on silica gel (MeOH in DCM = 0%~4%) to obtain the product (300 mg) as oil. 1 1H NMR (CDCl3, 400MHz) δ H=8.53(d,1H), 7.52-7.49(m,1H), 7.40-7.35(m,1H), 6.86(s,1H), 6.56-6.53(m,1H), 6.47( d,1H), 5.59-5.49(m,1H), 4.23(s,3H), 2.14-2.04(m,1H), 1.72(d,3H), 1.12-0.94(m,4H).

[0290] 2-Methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide & N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3-carboxamide A mixture of N-[1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3-carboxamide (300 mg, 0.740 mmol) was purified by SFC (column DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 μm), conditions 0.1% NH3H2O ​​ETOH, start B 30, end B 30, flow rate (ml / min) 60) to obtain peak 1 (90 mg) as a solid and peak 2 (87.6 mg, 0.213 mmol, yield 29%) as a solid.

[0291] The mixture from Peak 1 (90 mg) was purified by preparative TLC (DCM:MeOH = 10:1) to obtain 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (54.1 mg, 0.134 mmol, yield 60%) as a solid.

[0292] 16-1: 1 1H NMR (CDCl3, 400MHz) δ H=8.51(d,1H), 7.50(s,1H), 7.41-7.36(m,1H), 6.90(s,1H), 6.62(d,1H), 6.56(s,1H) , 5.60-5.45(m,1H), 4.22(s,3H), 2.15-2.10(m,1H), 1.72(d,3H), 1.12-0.96(m,4H). LCMS R t = 1.01 min chromatography in 2.0 mins, 10⁻⁸ AB, C 19 H 19 F3N5O2[M+H] + MS ESI calculated value: 406.1, measured value: 406.1

[0293] 17-1: 1 1H NMR (CDCl3, 400MHz) δ H =8.53(d,1H), 7.51(s,1H), 7.40-7.36(m,1H), 6.85(s,1H), 6.56(s,1H), 6.37(d,1H) , 5.60-5.47(m,1H), 4.23(s,3H), 2.13-2.01(m,1H), 1.72(d,3H), 1.13-0.99(m,4H). LCMS R t = Chromatography for 2.0 minutes, 1.00 minute, 10⁻⁸ AB, C 19 H 19 F3N5O2[M+H] + The MS ESI calculated value is 406.1, and the measured value is 406.1.

[0294] Example 16-2. Synthesis of 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (16-2) [ka]

[0295] 2-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]isoindoline-1,3-dione(C12) A mixture of 2-[-(1R)-1-[3-(2-bromo-4-pyridyl)isoxazole-5-yl]ethyl]isoindoline-1,3-dione (500 mg, 1.3 mmol), cyclopropylboronic acid (216 mg, 2.5 mmol), K3PO4 (533 mg, 2.5 mmol), and PCy3 (35 mg, 0.13 mmol) was added to H2O (5.0 mL) and toluene (25 mL) under N2 conditions. After stirring at 110 °C for 16 hours, the mixture was poured into water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with saturated brine (2 × 20 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / Â=5 / 1~3 / 1) to obtain the product (270 mg, 0.53 mmol, yield 42%) as oil. The mixture (70 mg, 0.19 mmol) was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*30 mm*3 μm, conditions: water (10 mM NH4HCO3)-CAN, start B: 40, end B: 70, gradient time (min): 9) and preparative TLC (DCM / acetone=50 / 1) to obtain the product (19.65 mg, 0.050 mmol, yield 28%) as solid. 1 1H NMR (CDCl3, 400MHz) δ H =8.52(d,1H), 7.92-7.84(m,2H), 7.80-7.72(m,2H), 7.51(s,1H), 7.41-7.37(m,1H), 6. 67-6.63(m,1H), 5.77-5.69(m,1H), 2.14-2.02(m,1H), 1.95(d,3H), 1.13-0.96(m,4H). LCMS R t = Chromatography for 2.0 minutes, 0.995 minutes, 10⁻⁸⁰AB, C 21 H 18 N3O3[M+H] + The MS ESI calculated value is 360.1, and the measured value is 360.1.

[0296] (1R)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethanamine(C-13) To a solution of 2-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]isoindoline-1,3-dione (100 mg, 0.28 mmol) in DCM (10 mL) and EtOH (2.0 mL), N2H4.H2O (0.080 mL, 1.7 mmol) was added dropwise at 25°C. After stirring at 25°C for 16 hours, the mixture was filtered, and the filter cake was washed with DCM (3 × 10 mL). The mixture was concentrated to obtain the product (60 mg, 0.26 mmol, yield 94%) as a solid. LCMS R t = Chromatography for 1.5 minutes, 0.203 minutes, 5-95AB, C 13 H 16 N3O[M+H] + MS ESI calculated value: 229.9, measured value: 229.9

[0297] 2-Methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (47 mg, 0.24 mmol) and HATU (166 mg, 0.44 mmol) in DMF (5.0 mL), Et3N (0.090 mL, 0.65 mmol) and (1R)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethanamine (50 mg, 0.22 mmol) were added at 20°C. After stirring for 1 hour, water (10 mL) was added, and the solution was extracted with  (3 × 10 mL). The organic layer was washed with brine (3 × 10 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the product. This product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm, conditions: water (10 mM NH₄HCO₃)-ACN, start: B 40, end: B 70, gradient time (min): 9), and further purified by preparative TLC (DCM / acetone = 50 / 1) to obtain the product (40.9 mg, 0.10 mmol, yield 58%) as a solid. 1 1H NMR (CDCl3, 400MHz) δ H=8.54(d,1H), 7.52(s,1H), 7.44-7.37(m,1H), 6.88-6.82(m,1H), 6.58-6.52(m,1H), 6.41-6. 33(m,1H), 5.58-5.47(m,1H), 4.23(s,3H), 2.20-2.06(m,1H), 1.73(d,3H), 1.13-0.98(m,4H). 19 F NMR (376.5 MHz, CDCl3) δ F -62.214. LCMS R t = 2.0 minutes chromatography for 0.980 minutes, 10⁻⁸⁰AB, C 19 H 19 F3N5O2[M+H] + The MS ESI calculated value is 406.2, and the measured value is 406.2.

[0298] Example 17-2. Synthesis of 2-methyl-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (17-2) [ka]

[0299] 2-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]isoindoline-1,3-dione(C14) Tricyclohexylphosphine (35 mg, 0.13 mmol) was added to a mixture of 2-[(1S)-1-[3-(2-bromo-4-pyridyl)isoxazole-5-yl]ethyl]isoindoline-1,3-dione (500 mg, 1.3 mmol), cyclopropylboronic acid (216 mg, 2.5 mmol), K3PO4 (533 mg, 2.5 mmol), and Pd(OAc)2 (14 mg, 0.060 mmol) in H2O (2.0 mL) and toluene (10 mL). The mixture was stirred under N2 at 110 °C for 16 hours, then poured into water (30 mL) and stirred for 20 minutes. The aqueous phase was extracted with ELISA (3 × 20 mL). The combined organic phase was washed with saturated brine (2 × 80 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / Â=5 / 1~3 / 1) to obtain the product (390 mg, 0.75 mmol, yield 61%) as oil. The product (100 mg, 0.28 mmol) was purified by HPLC (column: Phenomenex Gemini-NX 80*30 mm*3 μm, conditions: water (10 mM NH4HCO3)-CAN, start B: 42, end B: 72, gradient time (min): 9, 100% B retention time (min): 1.5, flow rate (mL / min): 30) to obtain the product (14.5 mg, 0.040 mmol, yield 36%) as solid. 1 1H NMR (CDCl3, 400MHz) δ H =8.52(d,1H), 7.89-7.85(m,2H), 7.78-7.74(m,2H), 7.51(s,1H), 7.40(d,1H), 6. 66(d,1H), 5.80-5.64(m,1H), 2.19-2.05(m,1H), 1.95(d,3H), 1.13-0.97(m,4H). LCMS R t = Chromatography for 1.5 minutes, 0.871 minutes, 5-95AB, C 21 H 18 N3O3[M+H] + MS ESI calculated value: 360.0, measured value: 360.0.

[0300] (1S)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethanamine(C-15) To a solution of 2-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]isoindoline-1,3-dione (140 mg, 0.39 mmol) in DCM (15 mL) and EtOH (3.0 mL), N2H4.H2O (0.12 mL, 2.3 mmol) was added dropwise at 25°C. After stirring at 25°C for 16 hours, the mixture was filtered, and the filtrate cake was washed with DCM (3 × 10 mL). The filtrate was concentrated to obtain the product (100 mg, 0.30 mmol, yield 78%) as a solid, which was used directly in the next step.

[0301] 2-Methyl-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (93 mg, 0.48 mmol) and HATU (332 mg, 0.87 mmol) in DMF (10 mL), Et3N (0.18 mL, 1.3 mmol) and (1S)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazole-5-yl]ethanamine (100 mg, 0.44 mmol) were added. After stirring at 20°C for 12 hours, the reaction mixture was diluted with water (30 mL) and extracted with  (3 × 20 mL). The organic layer was washed with water (3 × 30 mL) and brine (3 × 30 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated to obtain the product. This product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*30 mm*3 μm, conditions: water (10 mM NH₄HCO₃)-CAN, start B: 42, end B: 72, gradient time (min): 9, 100% B retention time (min): 1.5, flow rate (mL / min): 30) and SFC (column: DAISEL CHIRALPAK AD (250 mm*30 mm, 10 μm), conditions: 0.1% NH₃H₂O IPA, start B: 15%, end B: 15%, flow rate (mL / min): 50) to obtain the product (27.1 mg, 0.067 mmol, yield 46%) as a solid. 1 1H NMR (CDCl3, 400MHz) δ H=8.54(d,1H), 7.51(s,1H), 7.39(d,1H), 6.85(s,1H), 6.56(s,1H), 6.41-6.25(m,1H) , 5.64-5.45(m,1H), 4.23(s,3H), 2.18-2.02(m,1H), 1.73(d,3H), 1.14-0.98(m,4H). 19 F NMR (376.5 MHz, CDCl3) δ F = -62.223. LCMS R t = Chromatography for 1.5 minutes, 0.870 minutes, 5-95AB, C 19 H 19 F3N5O2[M+H] + The MS ESI calculated value is 405.9, and the measured value is 405.9.

[0302] Examples 18 and 19. Synthesis of (S)-3-chloro-N-(1-(3-(2-cyclopropylpyridine-4-yl)isoxazole-5-yl)ethyl)benzamide (18) and (R)-3-chloro-N-(1-(3-(2-cyclopropylpyridine-4-yl)isoxazole-5-yl)ethyl)benzamide (19). Note that the stereochemistry was randomly assigned.

[0303] [ka] To a stirred solution of 3-chlorobenzoic acid (0.204 g, 1.310 mmol) in DMF (2 mL), DIPEA (0.76 mL, 4.360 mmol) and HATU (0.663 g, 1.740 mmol) were added and the mixture was stirred for 5 minutes. To the resulting solution, a solution of A-47 (0.400 g, 1.744 mmol) in DMF (1 mL) was added at room temperature and the mixture was stirred for 15 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (4 × 10 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain crude A-48. Chiral separation of A-48 was performed by preparative chiral HPLC, yielding 18 (0.044 g, 0.119 mmol, yield 14%) and 19 (0.048 g, 0.125 mmol, yield 14%) as oil.

[0304] 18:LCMS:367.95(M+H), R t = 1.883 min, Column: Kinetex EVO C18 (50*3) mm; 2.6u; Mobile phase: A: 5mM ammonium bicarbonate aqueous solution; B: Acetonitrile; HPLC: R t = 5.400 min, 99.42%; Column; X SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Chiral HPLC: R t =8.100 min, 96.42%; Column: CHIRAL PAK IC (250 x 4.6 mm, 5 μm), Mobile phase: A) 0.1% DEA in n-hexane, B) EtOH (50:50), A:B:75:25; Flow rate: 1.00 mL / min 1 H NMR(400MHz,DMSO-d6)δ ppm 9.17(d,1H), 8.51(d,1H), 7.97(s,1H), 7.88(d,1H), 7.76(s,1H), 7.64(d,1H), 7.52-7.58( m,2H), 7.12(s,1H), 5.40-5.44(m,1H), 2.10-2.25(m,1H), 1.60(d,3H), 0.90-1.01(m,4H).

[0305] 19:LCMS:367.95(M+H), R t = 1.882 mins, Column: Kinetex EVO C18 (50*3) mm; 2.6u; Mobile phase: A: 5mM ammonium bicarbonate aqueous solution; B: acetonitrile; HPLC: R t =7.300 min, 96.20% column; X SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Chiral HPLC: R t =6.409 min, 97.83%; Column: CHIRAL PAK IC (250 x 4.6 mm, 5 μm), Mobile phase: A) 0.1% DEA in n-hexane, B) EtOH (50:50), A:B::75:25; Flow rate: 1.00 mL / min 1H NMR(400MHz,DMSO-d6)δ ppm 9.18(d,1H), 8.51(d,1H), 7.98(s,1H), 7.88(d,1H), 7.76(s,1H), 7.64(d,1H), 7.52-7.58( m,2H), 7.12(s,1H), 5.40-5.44(m,1H), 2.10-2.25(m,1H), 1.60(d,3H), 0.90-1.02(m,4H).

[0306] Examples 20 and 21. Synthesis of (R)-3-chloro-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)benzamide (20) and (S)-3-chloro-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)benzamide (21). Note that the stereochemistry was randomly assigned.

[0307] [ka] To a stirred solution of A-17 (0.200 g, 0.777 mmol) and 3-chlorobenzoic acid (0.243 g, 1.555 mmol) in DMF (5 mL), HATU (0.591 g, 1.555 mmol), followed by DIPEA (0.677 mL, 3.887 mmol), was added at room temperature, and the mixture was stirred for 15 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 25 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue (220 mg) in liquid form. The residue was purified by combiflash column chromatography eluting with 0-40% ethyl acetate in n-hexane to obtain A-49 (0.145 g) in solid form. Chiral separation of A-49 was performed by preparative chiral HPLC, yielding solids 20 (0.034 g, 0.086 mmol, 11% yield) and 21 (0.036 g, 0.088 mmol, 11% yield).

[0308] 20:LCMS:393.90(MH), R t=2.118 mins, Column: Kinetex EVO C18 (50*3) mm 2.6 μm; Mobile phase: A: 2.5 mM ammonium bicarbonate aqueous solution, B: acetonitrile; HPLC: R t =6.030 min, 99.20%; Column: X SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 5 mM ammonium acetate; Mobile phase B: acetonitrile; Flow rate: 1.0 mL / min; Chiral HPLC: R t = 7.878 mins, 99.25% column: Chiralpak IG (250 × 4.6 mm, 5 μm); mobile phase: A-0.1% DEA in n-hexane solution Mobile phase: DCM:MEOH(50:50);A:B:80:20;Flow rate: 1.0mL / min 1 H NMR(400MHz,DMSO-d6)δ ppm 9.21(d,1H), 8.93(d,1H), 8.34(s,1H), 8.22(d,1H), 7.99(t,1H), 7.89(d,1H), 7. 62-7.67(m,1H), 7.52-7.57(m,1H), 7.35(s,1H), 5.40-5.47(m,1H), 1.62(d,3H).

[0309] 21:LCMS:393.95(M+H), R t =2.119 mins, Column: Kinetex EVO C18 (50*3) mm 2.6 μm; Mobile phase: A: 2.5 mM ammonium bicarbonate aqueous solution, B: acetonitrile; HPLC: R t =12.29 min, 96.04%; Column: X SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 0.05% TFA aqueous solution: acetonitrile (95:05); Mobile phase B: 0.05% TFA aqueous solution: acetonitrile (5:95); Flow rate: 1.0 mL / min. Chiral HPLC: R t = 14.46 min, 99.57%; Column: Chiralpak IG (250 × 4.6 mm, 5 μm); Mobile phase: A - 0.1% DEA in n-hexane solution; Mobile phase: DCM:MEOH (50:50); A:B:80:20; Flow rate: 1.0 mL / min; 1H NMR(400MHz,DMSO-d6)δ ppm 9.20(d,1H), 8.92(d,1H), 8.33(s,1H), 8.21(d,1H), 7.98(t,1H), 7.88(d,1H), 7.64(dd,1H), 7.51-7.57(m,1H), 7.35(s,1H), 5.40-5.47(m,1H), 1.61(d,3H).

[0310] Examples 22 and 23. Synthesis of (R)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)benzamide (22) and (S)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)benzamide (23). Note that the stereochemistry was assigned randomly.

[0311] [ka] To a stirred solution of benzoic acid (0.142 g, 1.166 mmol) in 2 mL of DMF at 0°C, DIPEA (0.677 mL, 3.884 mmol) was added, followed by HATU (0.591 g, 1.554 mmol), and the mixture was stirred for 5 minutes. To the resulting solution, a solution of A-17 (0.200 g, 0.777 mmol) in 2 mL of DMF was added. The reaction mixture was allowed to cool to room temperature and stirred for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (4 × 10 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain residue A-50. The residue A-50 was subjected to chiral HPLC purification, yielding solids 22 (0.025 g, 0.069 mmol, 9% yield) and 23 (0.026 g, 0.072 mmol, 9% yield).

[0312] 22:LCMS:360.05(M+H), R t =2.022 mins, Column: Kinetex EVO C18 (50*3) mm 2.6 μm; Mobile phase: A: 2.5 mM ammonium bicarbonate aqueous solution, B: acetonitrile; HPLC: R t =6.920 minutes, 99.47% Column: X SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Chiral HPLC: R t =9.089 min, 100%; Column: Chiralpak IG (250 × 4.6 mm, 5 μm); Mobile phase: A-0.1% DEA in n-hexane solution; Mobile phase: DCM:MEOH (50:50); A:B:80:20; Flow rate: 1.0 mL / min 1 H NMR(400MHz,DMSO-d6)δ 9.07(d,1H), 8.92(d,1H), 8.34(s,1H), 8.22(dd,1H), 7.90-7.96(m,2H), 7.47-7.60(m,3H), 7.33(d,1H), 5.42-5.49(m,1H), 1.62(d,3H).

[0313] 23:LCMS:362.10(M+H), R t =2.165 min, Column: X-Bridge BEH C-18 (3.0*50 mm, 2.5 μm); Mobile phase: A: 0.02.5% formic acid aqueous solution, B: Acetonitrile; HPLC: R t = 5.580 min, 95.35%; Column: X SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 5 mM ammonium acetate; Mobile phase B: acetonitrile; Chiral HPLC: R t = 12.12 mins, 97.07%; Column: Chiralpak IG (250 × 4.6 mm, 5 μm); Mobile phase: A-0.1% DEA in n-hexane solution; Mobile phase: DCM:MEOH (50:50); A:B:80:20; Flow rate: 1.0 mL / min 1 H NMR(400MHz,DMSO-d6)δ 9.07(d,1H), 8.92(d,1H), 8.34(s,1H), 8.21(d,1H), 7.89-7.95(m,2H), 7.47-7.59(m,3H), 7.33(d,1H), 5.41-5.49(m,1H), 1.62(d,3H).

[0314] Examples 24 and 25. Synthesis of (R)-3-isopropyl-1-methyl-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (24) and (S)-3-isopropyl-1-methyl-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (25). Note that the stereochemistry was randomly assigned.

[0315] [ka] To a stirred solution of A-17 (0.300 g, 1.166 mmol) and 3-isopropyl-1-methyl-1H-pyrazole-5-carboxylic acid (0.226 g, 1.341 mmol) in DMF (5 mL), HATU (0.886 g, 2.332 mmol), followed by DIPEA (1.01 mL, 5.830 mmol) was added at room temperature, and the mixture was stirred for 15 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 25 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue A-51 (198 mg) as a liquid. The residue was purified by combiflash column chromatography eluting with 0-40% ethyl acetate in n-hexane to obtain A-51 (0.200 g) as a solid. Chiral separation of A-51 was performed by preparative chiral HPLC, yielding 24 (0.060 g, 0.147 mmol, yield 13%) and 25 (0.086 g, 0.211 mmol, yield 18%) as solids.

[0316] 24:LCMS:407.95(M+H), R t =2.722 mins, Column: Kinetex EVO C18 (50*3) mm 2.6 μm; Mobile phase: A: 2.5 mM ammonium bicarbonate aqueous solution, B: acetonitrile; HPLC: R t =4.959 minutes, 98.71% Column: X SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Chiral HPLC: R t = 7.233 min, 95.77%; Column: Chiralpak IG (250 × 4.6 mm, 5 μm); Mobile phase: A - n-hexane solution of 0.1% DEA; Mobile phase B: EtOH; A:B: 80:20; Flow rate: 1.0 mL / min 1 H NMR(400MHz,DMSO-d6)δ ppm 8.97(d,1H), 8.93(d,1H), 8.34(s,1H), 8.20-8.23(m,1H), 7.34(d,1H), 6.82(s,1 H), 5.35-5.42(m,1H), 3.99(s,3H), 2.84-2.91(m,1H), 1.59(d,3H), 1.20(d,6H).

[0317] 25:LCMS:408.20(M+H), R t =2.232 mins, Column: X-Bridge BEH C-18 (3.0*50 mm, 2.5 μm); Mobile phase: A: 0.02.5% formic acid aqueous solution, B: Acetonitrile; HPLC: R t =7.240 minutes, 94.88% Column: X SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Chiral HPLC: R t = 6.330 min, 99.04%; Column: Chiralpak IG (250 × 4.6 mm, 5 μm); Mobile phase: A - n-hexane solution of 0.1% DEA; Mobile phase B: EtOH; A:B: 80:20; Flow rate: 1.0 mL / min 1 H NMR(400MHz,DMSO-d6)δ ppm 8.97(d,1H), 8.93(d,1H), 8.34(s,1H), 8.21(d,1H), 7.34(d,1H), 6.82(s,1H), 5.35-5.42(m,1H), 3.99(s,3H), 2.84-2.91(m,1H), 1.59(d,,3H), 1.20(d,6H).

[0318] Examples 26 and 27. Synthesis of (R)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)cyclohexanecarboxamide (26) and (S)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)cyclohexanecarboxamide (27). Note that the stereochemistry was randomly assigned.

[0319] [ka] To a stirred reaction mixture of A-17 (0.200 g, 0.780 mmol) and cyclohexylcarboxylic acid (249.21 mg, 1.56 mmol) in DMF (5.00 mL), HATU (591.31 mg, 1.56 mmol), followed by N,N-diisopropylethylamine (0.68 mL, 3.89 mmol), was added at room temperature, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was quenched by adding water (10.0 mL), then extracted with RINKAN (2 × 25 mL), and the combined extract was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue A-52 (198 mg) as a liquid. The residue was purified by combiflash chromatography (on 100-200 silica gel) by elution with 0-40% siRNA in hexane, followed by reverse-phase preparative chiral HPLC, to obtain 26 (31 mg, 0.084 mmol, 11%) and 27 (32 mg, 0.087 mmol, 11%), both as solids.

[0320] 26:HPLC: Rt: 10.64 min, 99.51%; Column: X SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: Acetonitrile; LCMS: 366.05 (MH), Rt 2.184 min, Column: Kinetex EVO C18 (50 * 3) mm 2.6 μm; Mobile phase: A: 2.5 mM ammonium bicarbonate aqueous solution, B: Acetonitrile; Injection volume: 2 μL; Flow rate: 1.2 mL / min; Chiral HPLC: Rt: 7.479 min, 100%; Column: CHIRAL PAK IA (150 * 4.6 mm, 3 μm); Mobile phase A: 0.1% DEA in n-hexane solution; Mobile phase B: IPA. 1 H NMR(400MHz,DMSO-d6)δ 8.96-8.88(m,1H), 8.37(d,1H), 8.33-8.29(m,1H), 8.23-8.16(m,1H), 7.22-7.15(m,1H), 5.23-5.11(m,1H), 2.22-2.10(m,1H), 1.72(br d,4H), 1.66-1.56(m,1H), 1.52-1.42(m,3H), 1.42-1.28(m,2H), 1.25-1.08(m,3H).

[0321] 27:HPLC: Rt: 10.63 min, 99.85%; Column: X SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: Acetonitrile; LCMS: 368.05 (M + H), Rt 2.155 min, Column: Kinetex EVO C18 (50 * 3) mm 2.6 μm; Mobile phase A: 2.5 mM ammonium bicarbonate aqueous solution; B: Acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Chiral HPLC: Rt 12.717 min, 99.85%; Column: CHIRAL PAK IA (150 * 4.6 mm, 3 μm); Mobile phase A: 0.1% DEA in n-hexane solution; Mobile phase B: IPA. 1H NMR(400MHz,DMSO-d6)δ 8.95-8.90(m,1H), 8.37(d,1H), 8.33-8.29(m,1H), 8.20(dd,1H), 7.20-7.15(m,1H), 5.22-5.12(m,1H), 2.22-2.11(m,1H), 1.72(br d,4H), 1.66-1.57(m,1H), 1.46(d,3H), 1.42-1.28(m,2H), 1.28-1.11(m,3H).

[0322] Examples 28 and 29. Synthesis of (R)-2-phenyl-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)acetamide (28) and (S)-2-phenyl-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)acetamide (29). Note that the stereochemistry was assigned randomly.

[0323] [ka] To a solution of phenylacetic acid (127.04 mg, 0.930 mmol) in DMF (3 mL), N,N-diisopropylethylamine (0.68 mL, 3.89 mmol), HATU (591.31 mg, 1.56 mmol), and A-17 (dissolved in 1 mL of DMF, 200 mg, 0.78 mmol) were added at 0°C and stirred at room temperature for 12 hours. The reaction mixture was quenched by adding water (10.0 mL), then extracted with siRNA (2 × 25 mL), and the combined extract was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by combiflash column chromatography (100-200 silica gel) followed by reverse-phase preparative chiral HPLC to obtain 28 (38 mg, 0.101 mmol, 13%) and 29 (40 mg, 0.103 mmol, 13%), both as solids.

[0324] 28:HPLC: Rt: 10.02 min, 99.68%; Column: X SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: Acetonitrile; LCMS: 374.05 (MH), Rt 2.325 min, Column: Kinetex EVO C18 (50 * 3) mm 2.6 μm; Mobile phase: A: 2.5 mM ammonium bicarbonate aqueous solution; B: Acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Chiral HPLC: Rt: 11.139 min, 99.77%; Column: CHIRAL PAK IC (150 * 4.6 mm, 3 μm); Mobile phase A: 0.1% DEA in n-hexane solution; Mobile phase B: DCM: MEOH (50:50). 1 H NMR(400MHz,DMSO-d6)δ 8.97-8.88(m,1H), 8.86-8.76(m,1H), 8.33-8.25(m,1H), 8.21-8.13(m,1 H), 7.37-7.16(m,6H), 5.24-5.11(m,1H), 3.54-3.43(m,2H), 1.49(d,3H).

[0325] 29:HPLC: Rt: 7.17 min, 97.32%; Column: X SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 0.05% formic acid aqueous solution; Mobile phase B: Acetonitrile; LCMS: 374.05 (MH), Rt 2.109 min, Column: Kinetex EVO C18 (50 × 3) mm 2.6 μm; Mobile phase A: 2.5 mM ammonium bicarbonate aqueous solution; B: Acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Chiral HPLC: Rt 13.073 min, 100%; Column: CHIRAL PAK IC (150 × 4.6 mm, 3 μm); Mobile phase A: 0.1% DEA n-hexane solution; Mobile phase B: DCM:MEOH (50:50). 1 H NMR(400MHz,DMSO-d6)δ 8.97-8.91(m,1H), 8.85-8.77(m,1H), 8.32-8.24(m,1H), 8.20-8.12(m,1 H), 7.35-7.15(m,6H), 5.24-5.11(m,1H), 3.56-3.41(m,2H), 1.49(d,3H).

[0326] Examples 30 and 31. Synthesis of (R)-3-(difluoromethyl)-1-methyl-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (30) and (S)-3-(difluoromethyl)-1-methyl-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (31). Note that the stereochemistry was assigned randomly.

[0327] [ka] A stirred reaction mixture of A-17 (0.200 g, 0.780 mmol) and 3-(difluoromethyl)-1-methyl-1H-pyrazole-5-carboxylic acid (150.94 mg, 0.86 mmol) in DMF (5.00 mL) was mixed with HATU (443 mg, 3.5 mmol), followed by N,N-diisopropylethylamine (0.68 mL, 3.89 mmol) at room temperature, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was quenched by adding water (10.0 mL), then extracted with RINKAN (2 × 25 mL), and the combined extract was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue (198 mg) as a liquid. The residue was purified by combiflash column chromatography (100-200 silica gel) by elution with 0-40% siRNA in hexane, followed by reverse-phase preparative chiral HPLC, to obtain 30 (28 mg, 0.0663 mmol, 9%) and 31 (30 mg, 0.0711 mmol, 9%), both as solids.

[0328] 30:HPLC: Rt: 7.05 min, 98.38%; Column: X SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: Acetonitrile; LCMS: 413.95 (MH), Rt: 1.976 min, Column: Kinetex EVO C18 (50 × 3) mm 2.6 μm; Mobile phase: A: 2.5 mM aqueous solution of ammonium bicarbonate; B: Acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Chiral HPLC: Rt: 8.837 min, 97.21%; Column: CHIRAL PAK-IA (150 × 4.6 mm 3 μm); Mobile phase A: 0.1% DEA n-hexane; Mobile phase B: IPA. 1 H NMR(400MHz,DMSO-d6)δ 9.25-9.17(m,1H), 8.97-8.89(m,1H), 8.37-8.30(m,1H), 8.21(d,1H), 7.40-7.31(m ,1H), 7.27(s,1H), 7.21-6.88(m,1H), 5.46-5.34(m,1H), 4.11(s,3H), 1.61(d,3H).

[0329] 31:HPLC: Rt: 7.05 min, 98.37%; Column: X SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 5 mM ammonium bicarbonate; Mobile phase B: Acetonitrile; LCMS: 413.95 (MH), Rt 1.958 min, Column: Kinetex EVO C18 (50 × 3) mm 2.6 μm; Mobile phase: A: 2.5 mM aqueous solution of ammonium bicarbonate; B: Acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Chiral HPLC: Rt 12.893 min, 100%; Column: CHIRAL PAK-IA (150 × 4.6 mm 3 μm); Mobile phase A: 0.1% DEA n-hexane; Mobile phase B: IPA. 1 H NMR(400MHz,DMSO-d6)δ 9.28-9.17(m,1H), 8.99-8.90(m,1H), 8.35(s,1H), 8.23(br d,1H), 7.38(s,1H), 7.29(s,1H), 7.23-6.90(m,1H), 5.47-5.35(m,1H), 4.13(s,3H), 1.62(d,3H).

[0330] Examples 32 and 33. Synthesis of (R)-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)benzamide (32) and (S)-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)benzamide (33). Note that the stereochemistry was assigned randomly.

[0331] [ka] To a stirred reaction mixture of A-17 (300 mg, 1.17 mmol) and 3-(trifluoromethyl)benzoic acid (226.4 mg, 1.19 mmol) in DMF (5.00 mL), HATU (495 mg, 1.3 mmol), followed by N,N-diisopropylethylamine (0.7 mL, 5.83 mmol) was added at room temperature, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was quenched by adding water (10.0 mL), then extracted with RINKAN (2 × 25 mL), and the combined extract was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue (198 mg) as a colorless, viscous liquid. The residue was purified by combiflash column chromatography (100-200 silica gel) by elution with 0-40% Â in hexane, followed by reverse-phase preparative chiral HPLC, to obtain 32 (51 mg, 0.1186 mmol, 10%) and 33 (25 mg, 0.0578 mmol, 5%).

[0332] 32. HPLC: Rt: 5.795 min, 99.83%; Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase-A: 0.05% TFA: Acetonitrile (95:05); Mobile phase-B: Acetonitrile: 0.05% TFA (95:05); LCMS: 428.25 (MH), Rt 2.110 min, Column: X-SELECT CSH C18 (50 × 3) mm 2.5 μm; Mobile phase: A: 2.5 mM ammonium bicarbonate aqueous solution; B: Acetonitrile; Chiral HPLC: Rt: 9.192 min, 99.08%; Column: Chiral pak-IG (250 × 4.6 mm 5 μm); Mobile phase A: 0.1% DEA n-hexane solution; Mobile phase B: ETOH. 1 H NMR(400MHz,DMSO-d6)δ 9.34(d,1H), 8.93(d,1H), 8.34(s,1H), 8.28(s,1H), 8.26-8.17(m,2H), 7.95(br d,1H), 7.76(t,J=8Hz,1H), 7.38(s,1H), 5.53-5.40(m,1H), 1.64(d,3H).

[0333] 33. HPLC: Rt: 5.707 min, 99.37%; Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase-A: 0.05% TFA: Acetonitrile (95:05); Mobile phase-B: Acetonitrile: 0.05% TFA (95:05); LCMS: 428.20 (MH), Rt 2.097 min, Column: X-SELECT CSH C18 (50 × 3) mm 2.5 μm; Mobile phase: A: Aqueous solution of 2.5 mM ammonium bicarbonate; B: Acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Chiral HPLC: Rt 5.364 min, 99.74%, Column: Chial pak-IG (250 × 4.6 mm 5 μm); Mobile phase A: 0.1% DEA in n-hexane solution. 1 H NMR(400MHz,DMSO-d6)δ 9.34(d,1H), 8.93(d,1H), 8.38-8.17(m,4H), 7.95(d,1H), 7.81-7.72(m,1H), 7.37(s,1H), 5.52-5.42(m,1H), 1.64(d,3H).

[0334] Examples 34 and 35. Synthesis of (S)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-3,4-dihydroquinoline-1(2H)-carboxamide (34) and (R)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-3,4-dihydroquinoline-1(2H)-carboxamide (35). Note that the stereochemistry was randomly assigned.

[0335] [ka] To a stirred solution of A-17 (300 mg, 1.17 mmol) and 1,2,3,4-tetrahydroquinoline (310.7 mg, 2.33 mmol) in DCM (10 mL), CDI (378.25 mg, 2.33 mmol) and TEA (0.49 mL, 3.5 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 50 mL). The combined extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by combiflash column chromatography (100-200 silica gel) followed by preparative chiral HPLC to obtain 34 (55 mg, 0.1311 mmol, yield 11%) and 35 (60 mg, 0.1435 mmol, yield 12%).

[0336] 34:HPLC: Rt: 7.925 min, 99.23%; Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase-A: 0.05% TFA: Acetonitrile (95:05); Mobile phase-B: Acetonitrile: 0.05% TFA (95:05); LCMS: 417.2 (M + H), Rt 2.359 min, Column: X-Bridge BEH C-18 (3.0 × 50 mm, 2.5 μm); Mobile phase: A: Aqueous solution of 0.025% FA, B: ACN; Chiral HPLC: Rt: 4.904 min, 100%; Column: Chial pak-IA (150 × 4.6 mm, 3 μm) Acquisition date: 05-01-2021 13:08:58 IST; Mobile phase A: 0.1% DEA in n-hexane solution; Mobile phase B: DCM:MEOH; Flow rate: 0.70 mL / min 1 H NMR(400MHz,DMSO-d6)δ 8.93(d,1H), 8.33(s,1H), 8.24-8.19(m,1H), 7.49(d,1H), 7.32(d,1H), 7.26(s,1H), 7.13-7.05(m,2H), 6.96-6.89(m,1H), 5.23-5.13(m,1H), 3.71-3.56(m,2H), 2.74-2.65(m,2H), 1.86(quintet, 2H), 1.56(d,3H).

[0337] 35:HPLC: Rt: 7.926 min, 99.62%; Column: XSELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase-A: 0.05% TFA: Acetonitrile (95:05); Mobile phase-B: Acetonitrile: 0.05% TFA (95:05); LCMS: 417.1 (M + H), Rt 2.279 min, Column: Xselect CSH C18 (4.6 × 150 mm, 3.5 μm); Mobile phase: A: 0.025% mM aqueous formic acid, B: ACN; Chiral HPLC: Rt 7.094 min, 98.78%; Method file name: CHIRAL-A.lcm; Column:: CHIRAL PAK IA (150 mm × 4.6 mm, 3 μm); Mobile phase A: 0.1% DEA in n-hexane solution; Mobile phase B: DCM:MEOH (1:1); A:B::80:20; Flow rate: 0.70 mL / min 1H NMR(400MHz,DMSO-d6)δ 8.93(d,1H), 8.33(s,1H), 8.24-8.19(m,1H), 7.49(d,1H), 7.31(d,1H), 7.26(s,1H), 7.13-7.05(m,2H), 6.96-6.90(m,1H), 5.23-5.13(m,1H), 3.71-3.57(m,2H), 2.74-2.65(m,2H), 1.86(quintet, 2H), 1.56(d,3H).

[0338] Examples 36 and 37. Synthesis of (R)-1-cyclobutyl-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (36) and (S)-1-cyclobutyl-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-1H-pyrazole-5-carboxamide (37). Note that the stereochemistry was randomly assigned.

[0339] [ka] To a stirred solution of 2-cyclobutylpyrazole-3-carboxylic acid (226.4 mg, 1.36 mmol) and A-17 (300 mg, 1.17 mmol) in DMF (5 mL), HATU (495 mg, 1.3 mmol), followed by N,N-diisopropylethylamine (0.7 mL, 4.32 mmol), was added at 0°C, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was quenched by adding water (10 mL), then extracted with pharmaceutically acceptable ammonium compounds (2 × 25 mL). The combined extract was dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The residue was purified by combiflash column chromatography (100-200 silica gel) using 0-40% siRNA in hexane as an eluent, followed by reverse-phase preparative chiral HPLC, to obtain 36 (16 mg, 0.0383 mmol, yield 3%) and 37 (12 mg, 0.0291 mmol, 2%), both as solids.

[0340] 36:HPLC: Rt: 10.84 min, 97.10%; Column: X-SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 5 mM ammonium acetate; Mobile phase B: Acetonitrile; LCMS: 404.20 (MH), Rt 2.005 min, Column: X-SELECT CSH C18 (50 × 3) mm 2.5 μm; Mobile phase A: 2.5 mM aqueous solution of ammonium bicarbonate; B: Acetonitrile; Chiral HPLC: Rt: 20.326 min, 100%; Column: Chial pak-IG (250 × 4.6 mm 3 μm); Mobile phase A: 0.1% DEA in n-hexane solution; Mobile phase B: IPA; 1 H NMR(400MHz,DMSO-d6)δ 9.03(d,1H), 8.93(d,1H), 8.34(s,1H), 8.21(d,1H), 7.57(s,1H), 7.34(s,1H), 6.94(s,1 H), 5.65 (quintet, 1H), 5.45-5.33 (m, 1H), 2.38-2.25 (m, 4H), 1.84-1.69 (m, 2H), 1.60 (d, 3H).

[0341] 37:HPLC: Rt: 10.84 min, 98.44%; Column: X-SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 5 mM ammonium acetate; Mobile phase B: Acetonitrile; LCMS: 404.30 (MH), Rt 2.002 min, Column: X-SELECT CSH C18 (50 × 3) mm 2.5 μm; Mobile phase A: 2.5 mM aqueous solution of ammonium bicarbonate; B: Acetonitrile; Chiral HPLC: Rt 14.486 min, 100%; Column: Chial pak-IG (250 × 4.6 mm 3 μm); Mobile phase A: 0.1% DEA in n-hexane solution; Mobile phase B: IPA; 1 H NMR(400MHz,DMSO-d6)δ 9.34(d,1H), 8.93(d,1H), 8.34(s,1H), 8.21(d,1H), 7.57(s,1H), 7.34(s,1H), 6.94(s,1 H), 5.64 (quintet, 1H), 5.45-5.33 (m, 1H), 2.38-2.24 (m, 4H), 1.85-1.67 (m, 2H), 1.59 (d, 3H).

[0342] Examples 38 and 39. Synthesis of (S)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide (38) and (R)-N-(1-(3-(2-(trifluoromethyl)pyridine-4-yl)isoxazole-5-yl)ethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide (39). Note that the stereochemistry was randomly assigned.

[0343] [ka] To a stirred solution of A-17 (250 mg, 0.9700 mmol) and 3,4-dihydro-2H-1,4-benzoxazine (258.91 mg, 1.92 mmol) in DCM (10 mL), CDI (315.21 mg, 1.94 mmol) and TEA (0.41 mL, 2.92 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 50 mL). The combined extract was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by combiflash column chromatography (100-200 silica gel) using 30-50% Â / hexane as an eluent, followed by preparative chiral HPLC, to obtain 38 (70 mg, 0.1663 mmol, yield 17%) and 39 (55 mg, 0.1313 mmol, yield 13%).

[0344] 38:HPLC: Rt: 7.37 min, 99.41%; Column: ATLANTIS T3 (150 × 4.6 mm, 3.5 μm); Mobile phase A: Aqueous solution of 0.05% TFA; ACN (95; 05); Mobile phase B: Aqueous solution of 0.05% TFA; ACN (05; 95); LCMS: 419.1 (M + H), Rt 2.153 min, Column: X-Bridge BEH C-18 (3.0 × 50 mm, 2.5 μm); Mobile phase A: Aqueous solution of 0.025% FA, B: ACN; Chiral HPLC: Rt: 6.046 min, 100%; Column: Chiral pak-IG (250 × 4.6 mm, 5 μm); Mobile phase A: n-hexane solution of 0.1% DEA; 1 H NMR(400MHz,DMSO-d6)δ 8.93(d,1H), 8.33(s,1H), 8.21(d,1H), 7.50(d,1H), 7.57(d,1H), 7.27(d,1H), 6.96-6.89(m, 1H), 6.88-6.80(m,2H), 5.22-5.12(m,1H), 4.26-4.17(m,2H), 3.86-3.69(m,2H), 1.57(d,3H).

[0345] 39:HPLC: Rt: 7.17 min, 97.32%; Column: X SELECT CSH C18 (150 × 4.6 mm, 3.5 μm); Mobile phase A: 0.05% formic acid aqueous solution; Mobile phase B: Acetonitrile; LCMS: 374.05 (MH), Rt 2.109 min, Column: Kinetex EVO C18 (50 × 3) mm 2.6 μm; Mobile phase A: 2.5 mM ammonium bicarbonate aqueous solution; B: Acetonitrile; Injection volume: 2 μL, Flow rate: 1.2 mL / min; Chiral HPLC: Rt 13.073 min, 100%; Column: CHIRAL PAK IC (150 × 4.6 mm, 3 μm); Mobile phase A: 0.1% DEA n-hexane solution; Mobile phase B: DCM:MEOH (50:50). 1H NMR(400MHz,DMSO-d6)δ 8.93(d,1H), 8.33(s,1H), 8.21(d,1H), 7.49(d,1H), 7.31(d,1H), 7.26(d,1H), 7.12-7.05(m ,1H), 6.96-6.89(m,2H), 5.18(quintet,1H), 4.25-4.20(m,2H), 3.83-3.72(m,2H), 1.56(d,3H).

[0346] Example 40. 2-Methyl-N-[(1S)-1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (40) [ka]

[0347] 5-(1-ethoxyvinyl)-3-(2-methyl-4-pyridyl)-1,2,4-thiadiazole (C-34) To a mixture of 3-bromo-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (1.5 g, 6.38 mmol) in DME (30.0 mL), (2-methyl-4-pyridyl)boronic acid (1.05 g, 7.66 mmol), Cs2CO3 (6.24 g, 19.1 mmol), water (6.0 mL), and Pd(dppf)Cl2 (0.47 g, 0.64 mmol) were added. After stirring at 100°C for 3 hours, the mixture was filtered and concentrated, and the residue was purified by chromatography using silica gel (0-30% ethyl acetate in PE) to obtain the product (1.20 g, 4.61 mmol, yield 72%) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.63(d,1H), 8.04(s,1H), 7.97(d,1H), 5.60(d,1H), 4.57(d,1H), 4.08-3.99(m,2H), 2.66(s,3H), 1.49-1.41(m,3H).

[0348] 1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethanone (C-35) A mixture of 5-(1-ethoxyvinyl)-3-(2-methyl-4-pyridyl)-1,2,4-thiadiazole (1.20 g, 4.85 mmol) in acetone (15.0 mL) was mixed with HCl (8.0 mL, 2 M, 4.85 mmol). After stirring at 50°C for 16 hours, the mixture was diluted with water (15.0 mL) and extracted with RINKAN (3 × 10.0 mL). The combined organic phase was washed with brine (30.0 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product (1.10 g, 4.52 mmol, yield 93%) as oil. 1 1H NMR (400MHz, CDCl3)δ H =8.68(d,1H), 8.06(s,1H), 7.99(d,1H), 2.83(s,3H), 2.69(s,3H).

[0349] (R,E)-2-methyl-N-[1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethylidene]propan-2-sulfinamide(C-36) To a solution of 1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethanone (300 mg, 1.37 mmol) and (R)-2-methylpropane-2-sulfinamide (249 mg, 2.05 mmol) in THF (5.0 mL), Ti(OEt)4 (0.94 g, 4.10 mmol) was added. After stirring at 50°C for 16 hours, the mixture was poured into saturated NaHCO3 (20 mL) and diluted with ethyl acetate (10.0 mL). The resulting slurry was filtered and extracted with ethyl acetate (3 × 10.0 mL). The combined organic layers were washed with brine (2 × 30.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-30% ethyl acetate in PE) to obtain the product (550 mg) as oil. The crude product was purified by flash column (0-30% Â in PE) to obtain the product (350 mg, 1.09 mmol, yield 64%) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.69(d,1H), 8.27-8.11(m,2H), 2.97(s,3H), 2.83(s,3H), 1.37(s,9H).

[0350] (R)-2-methyl-N-[(1S)-1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]propan-2-sulfinamide(C-37) To a solution of (R,E)-2-methyl-N-[1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethylidene]propan-2-sulfinamide (350 mg, 1.09 mmol) in THF (4.0 mL), L-Selectride (2.17 mL, 2.17 mmol) was added at -78°C. After stirring at -78°C for 0.5 hours, the mixture was poured into saturated NH4Cl (20.0 mL) and extracted with siRNA (2 × 10.0 mL). The combined organic layer was washed with brine (2 × 20.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-10% MeOH in DCM) to obtain the product (270 mg, 0.832 mmol, yield 77%) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.65(d,1H), 8.21-7.95(m,2H), 5.10-4.89(m,1H), 2.75(s,3H), 1.84(d,3H), 1.34(s,9H).

[0351] (1S)-1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethanamine(C38) To a solution of (R)-2-methyl-N-[(1S)-1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]propan-2-sulfinamide (270 mg, 0.83 mmol) in 1,4-dioxane (5.0 mL), 4 M HCl / dioxane (3 mL) was added at 25°C. After stirring at 25°C for 1 hour, the mixture was concentrated to obtain the product as a solid. 1 1H NMR (MeOD, 400MHz) δ H =8.89(d,1H), 8.75(s,1H), 8.71-8.65(m,1H), 5.39-5.17(m,1H), 2.92(s,3H), 1.85(d,3H).

[0352] 2-methyl-N-[(1S)-1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide(40) To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (229 mg, 1.18 mmol) in DCM (8.0 mL), DIEA (937 mg, 7.26 mmol) and T3P (2.71 g, 2.72 mmol) were added. After stirring at 25°C for 20 minutes, (1S)-1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethanamine hydrochloride (200 mg, 0.91 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (10.0 mL) and extracted with DCM (2 × 15.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-10% MeOH in DCM) to obtain the product (300 mg, 0.757 mmol, yield 83%) as a solid. The product was purified by SFC (column DAICEL CHIRALPAK IG (250 mm*30 mm, 10 μm) conditions 0.1% NH3H2O ​​EtOH Start B 20% End B 20% Gradient time (min) 100% B retention time (min) Flow rate (ml / min) 60 Injection 35) to obtain the product (81.2 mg, 0.197 mmol, yield 26%) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.65(d,1H), 8.00(s,1H), 7.95-7.88(m,1H), 6.90(s,1H), 6.78-6.66(m,1H), 5.79-5.65(m,1H), 4.24(s,3H), 2.66(s,3H), 1.83(d,3H). 19 F NMR (376.5 MHz, CDCl3) δ F = -62.195. LCMS R t = 1.5 minutes chromatography for 0.895 minutes, 5-95AB, C 16 H 16 F3N6OS[M+H] +The MS ESI calculated value is 396.9, and the measured value is 396.9.

[0353] Example 41. (R)-1-Methyl-N-(1-(3-(2-methylpyridin-4-yl)-1,2,4-thiadiazol-5-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (41) [Chemical formula]

[0354] (S,E)-2-Methyl-N-[1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethylidene]propan-2-sulfinamide (C-39) Ti(OEt)4 (0.94 g, 4.10 mmol) was added to a solution of 1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethanone (300 mg, 1.37 mmol) and (S)-2-methylpropan-2-sulfinamide (249 mg, 2.05 mmol) in THF (5.0 mL). After stirring at 50 °C for 16 h, the mixture was poured into saturated NaHCO3 (20 mL) and diluted with EtOAc (10.0 mL). The resulting slurry was filtered and extracted with EtOAc (3 × 10.0 mL). The combined organic layers were washed with brine (2 × 30.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0 - 30% EtOAc in PE) to give the product (310 mg, 0.96 mmol, 70% yield) as an oil. 1 H NMR (400 MHz, CDCl3) δ H = 8.81 - 8.62 (m, 1H), 8.16 - 8.11 (m, 1H), 8.10 - 8.04 (m, 1H), 2.95 (s, 3H), 2.75 (s, 3H), 1.37 (s, 9H).

[0355] (S)-2-Methyl-N-[(1R)-1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]propan-2-sulfinamide (C-40) To a solution of (S,E)-2-methyl-N-[1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethylidene]propan-2-sulfinamide (310 mg, 0.96 mmol) in THF (4.0 mL), K-Selectride (1.92 mL, 1.92 mmol) was added at -78°C. After stirring at -78°C for 0.5 hours, the mixture was poured into saturated NH4Cl (20.0 mL) and extracted with siRNA (2 × 10.0 mL). The combined organic layer was washed with brine (2 × 20.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-10% MeOH in DCM) to obtain the product (200 mg, 0.616 mmol, yield 64%) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.65(d,1H), 8.19-8.00(m,2H), 5.11-4.92(m,1H), 2.77(s,3H), 1.84(d,3H), 1.40-1.26(m,9H).

[0356] (R)-1-(3-(2-methylpyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethanamine hydrochloride (C-41) To a solution of (S)-2-methyl-N-[(1R)-1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]propan-2-sulfinamide (200 mg, 0.62 mmol) in 1,4-dioxane (3.0 mL), 4 M HCl / dioxane (2.31 mL, 9.25 mmol) was added at 25°C. After stirring at 25°C for 1 hour, the mixture was concentrated to obtain the product (120 mg, 0.38 mmol) as a solid. 1 1H NMR (DMSO-d6, 400MHz) δ H =9.18-9.12(m,2H), 8.90(d,1H), 8.45(s,1H), 8.40-8.29(m,1H), 5.38-5.15(m,1H), 2.80(s,3H), 1.72(d,3H).

[0357] (R)-1-Methyl-N-(1-(3-(2-methylpyridin-4-yl)-1,2,4-thiadiazol-5-yl)ethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (41) To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (97.0 mg, 0.50 mmol) in DCM (8.0 mL) were added DIEA (409.0 mg, 3.17 mmol) and T3P (904 mg, 1.19 mmol). After stirring at 25 °C for 20 minutes, (1R)-1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethanamine hydrochloride (100 mg, 0.45 mmol) was added and the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with water (10.0 mL) and extracted with DCM (2 × 15.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated to give the product (140 mg, 0.32 mmol) as a solid, which was purified by SFC (column DAICEL CHIRALCEL OJ (250 mm * 30 mm, 10 μm), conditions: 0.1% NH3H2O-MeOH, start B: 20%, end B: 20%, flow rate (mL / min): 60, injection: 30) to give the product (113.2 mg, 0.29 mmol, yield 57%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H = 8.72 - 8.58 (m, 1H), 7.99 (s, 1H), 7.95 - 7.89 (m, 1H), 6.9 (s, 1H), 6.83 - 6.75 (m, 1H), 5.79 - 5.65 (m, 1H), 4.24 (s, 3H), 2.66 (s, 3H), 1.87 - 1.77 (m, 3H). 19 F NMR (376.5 MHz, CDCl3) δ F [[ID= = -62.183. LCMS R t = 1.241 minutes by chromatography at 2.0 minutes, 10 - 80 AB, C 16 H 16 F3N6OS [M + H]​​​​​Examples 42 and 43. 2-Methyl-N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide & 2-Methyl-N-[(1R)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide. [ka]

[0359] 4-Bromo-2-(methoxymethyl)pyridine(C43) To a mixture of (4-bromo-2-pyridyl)methanol (9.0 g, 47.9 mmol) in DMF (15.0 mL), NaH (2.30 g, 57.4 mmol, 60%) was added under N2 conditions at 0°C. After stirring for 30 minutes, a mixture of methyl iodide (3.29 mL, 52.6 mmol) in DMF (5.0 mL) was added, and the mixture was stirred at 15°C for 16 hours. The mixture was poured into ice water (30.0 mL), and the aqueous phase was extracted with ethyl acetate (3 × 30.0 mL). The combined organic phase was washed with brine (2 × 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (PE / ethyl acetate = 3 / 1 to 1 / 1) to obtain the product (9.0 g, 44.5 mmol, yield 93%) as oil. 1 1H NMR (CDCl3, 400MHz) δ H =8.36(d,1H), 7.63(d,1H), 7.37(dd,1H), 4.57(s,2H), 3.51-3.46(m,3H).

[0360] 2-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(C44) A mixture of 4-bromo-2-(methoxymethyl)pyridine (5.0 g, 24.8 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (6.91 g, 27.2 mmol), Pd(dppf)Cl2 (1.81 g, 2.47 mmol), and KOAc (4.86 g, 49.5 mmol) in 1,4-dioxane (50 mL) was stirred under N2 at 100°C for 3 hours. The mixture was cooled to 25°C, filtered, and concentrated to obtain the product (9.0 g, 36.1 mmol) as oil.

[0361] 5-(1-ethoxyvinyl)-3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole(C45) A mixture of 3-bromo-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (2.0 g, 8.51 mmol)[2-(methoxymethyl)-4-pyridyl]boronic acid (2.84 g, 17.0 mmol) and Cs2CO3 (5.54 g, 17.0 mmol) in DME (20.0 mL) and water (4.0 mL) was mixed with Pd(dppf)Cl2 (622 mg, 0.85 mmol) and heated in a microwave reactor at 90°C for 1.5 hours. After cooling to 25°C, the reaction mixture was quenched with water (40.0 mL) and extracted with HCl (2 × 40.0 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography using PE / HCl = 1 / 1 to obtain the product (2.10 g, 7.57 mmol, yield 89%) as oil. 1 1H NMR (CDCl3, 400MHz) δ H =8.71(d,1H), 8.34-8.23(m,1H), 8.07(d,1H), 5.63(d,1H), 4.71-4.63(m,2H), 4.59(d,1H), 4.09-4.02(m,2H), 3.53(s,3H), 1.46(t,3H).

[0362] 1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]etanone (C-46) A mixture of 5-(1-ethoxyvinyl)-3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole (2.19 g, 7.90 mmol) in acetone (20.0 mL) was mixed with 2 M HCl (7.90 mL, 15.8 mmol). After stirring at 50°C for 16 hours, the mixture was diluted with water (5.0 mL) and extracted with siRNA (3 × 5.0 mL). The combined organic phase was washed with brine (20.0 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the product (1.60 g, 5.78 mmol, yield 73%) as oil. LCMS R t = 0.861 minutes by chromatography at 1.5 minutes, 5-95AB, C 11 H 12 N3O2S[M+H] + The MS ESI calculated value is 250.1, and the measured value is 249.9.

[0363] (R,E)-N-[1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethylidene]-2-methyl-propane-2-sulfinamide(C47) To a solution of 1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethanone (1.0 g, 4.0 mmol) and (R)-2-methylpropane-2-sulfinamide (729 mg, 6.10 mmol) in THF (10.0 mL), Ti(OEt)4 (2.75 g, 12.0 mmol) was added. After stirring at 50°C for 16 hours, the mixture was poured into saturated NaHCO3 (20.0 mL) and diluted with siRNA (10.0 mL). The resulting slurry was filtered, and the mother liquor was extracted with siRNA (3 × 10.0 mL). The combined organic phase was washed with brine (2 × 30.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column to obtain the product (190 mg, 0.54 mmol, yield 22%) as oil. 1 1H NMR (CDCl3, 400MHz) δ H=8.74(d,1H), 8.46-8.41(m,1H), 8.25-8.18(m,1H), 4.84-4.78(m,2H), 3.57(s,3H), 2.97(s,3H), 1.37(s,9H).

[0364] R)-N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-2-methyl-propane-2-sulfinamide(C48) To a solution of (R,E)-N-[1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethylidene]-2-methyl-propane-2-sulfinamide (190 mg, 0.54 mmol) in THF (4.0 mL), K-Selectride (1.08 mL, 1.08 mmol) was added at -78°C. After stirring at -78°C for 0.5 hours, the mixture was poured into saturated NH4Cl (20.0 mL) and extracted with siRNA (2 × 10.0 mL). The combined organic layer was washed with brine (2 × 20.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column to obtain the product (130 mg, 0.37 mmol, yield 68%) as a solid. LCMS R t = 1.5 minutes chromatography for 0.803 minutes, 5-95AB, C 15 H 23 N4O2S2[M+H] + The MS ESI calculated value is 355.1, and the measured value is 355.1.

[0365] (1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethanamine hydrochloride (C-49) To a solution of (R)-2-methyl-N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]propan-2-sulfinamide (130 mg, 0.37 mmol) in 1,4-dioxane (5.0 mL), 4 M HCl / dioxane (6.0 mL, 1.83 mmol) was added at 25°C. After stirring at 25°C for 1 hour, the residue was filtered and concentrated to obtain the product (130 mg, 0.52 mmol) as a solid. 1 1H NMR (MeOD, 400MHz) δ H =8.94(d,1H), 8.82(s,1H), 8.78-8.74(m,1H), 5.32-5.24(m,1H), 4.99(s,2H), 4.88-4.87(m,2H), 3.64(s,3H), 1.85(d,3H).

[0366] 2-methyl-N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide(C50) To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (111 mg, 0.57 mmol) in DCM (2.0 mL), DIEA (0.91 mL, 5.19 mmol) and T3P (1.18 g, 1.56 mmol) were added at 25°C. After stirring for 10 minutes, (1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethanamine hydrochloride (130 mg, 0.52 mmol) was added, and the reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was quenched with water (20.0 mL) and extracted with DCM (2 × 20.0 mL). The combined organic layers were washed with brine (60.0 mL), dried over Na2SO4, filtered, and concentrated to obtain the product. This product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; conditions: water (10 mM NH4HCO3)-ACN; start B: 42-72% over 10 minutes) to obtain the product (75.0 mg, 0.18 mmol, yield 34%) as a solid.

[0367] 2-methyl-N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide & 2-methyl-N-[(1R)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide. Note that the stereochemistry is randomly assigned.

[0368] 2-methyl-N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (75.0 mg, 0.18 mmol) was prepared using SFC (DAICEL CHIRALCEL AY-H (250 mm * 30 mm, 5 μm); conditions: 0.1% Purified by NH3H2O-EtOH (start B:15~15), 2-methyl-N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (61.5 mg, 0.14 mmol, yield 82%) was obtained as a solid, and 2-methyl-N-[(1R)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (2.46 mg, 0.01 mmol, yield 3%) was obtained as a solid.

[0369] 42: 1 1H NMR (CDCl3, 400MHz) δ H =8.68(d,1H), 8.24(s,1H), 8.04-7.98(m,1H), 6.98-6.87(m,2H), 5.75-5.66(m,1H), 4.66(s,2H), 4.23(s,3H), 3.52(s,3H), 1.82(d,3H). 19 F NMR (376.5 MHz, CDCl3) δ F = -62.160. LCMS R t = Chromatography for 2.0 minutes, 0.951 minutes, 10⁻⁸ AB, C17 H 18 F3N6O2S[M+H] + The MS ESI calculated value is 427.1, and the measured value is 427.1.

[0370] 43: 1 1H NMR (CDCl3, 400MHz) δ H =8.71(d,1H), 8.26(s,1H), 8.03(d,1H), 6.92(s,1H), 6.79(d,1H), 5.77-5.66(m,1H), 4.68(s,2H), 4.24(s,3H), 3.53(s,3H), 1.83(d,3H). 19 F NMR (376.5 MHz, CDCl3) δ F = -62.169. LCMS R t = Chromatography for 2.0 minutes, 0.957 minutes, 10⁻⁸⁰AB, C 17 H 18 F3N6O2S[M+H] + The MS ESI calculated value is 427.1, and the measured value is 427.1. [ka]

[0371] (R,E)-N-[1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethylidene]-2-methyl-propane-2-sulfinamide(C-51) To a solution of 1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]etanone (300 mg, 1.20 mmol) and (S)-2-methylpropane-2-sulfinamide (219 mg, 1.81 mmol) in THF (5.0 mL), Ti(OEt)4 (823 mg, 3.61 mmol) was added. After stirring at 50°C for 16 hours, the mixture was poured into saturated NaHCO3 (20.0 mL) and diluted with ELISA (10.0 mL). The resulting slurry was filtered, and the mother liquor was extracted with ELISA (3 × 10.0 mL). The combined organic phases were washed with brine (2 × 30.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-30% Â in PE) to obtain the product (90.0 mg, 0.26 mmol, yield 21%) as oil. 1 1H NMR (CDCl3, 400MHz) δ H =8.73(d,1H), 8.32-8.24(m,1H), 8.07(dd,1H), 4.69(s,2H), 3.54(s,3H), 2.97(s,3H), 1.37(s,9H).

[0372] (R)-N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-2-methyl-propane-2-sulfinamide(C-52) To a solution of (R,E)-N-[1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethylidene]-2-methyl-propane-2-sulfinamide (150 mg, 0.43 mmol) in THF (4.0 mL), K-Selectride (0.85 mL, 0.85 mmol) was added at -78°C. After stirring at -78°C for 0.5 hours, the mixture was poured into saturated NH4Cl (20.0 mL) and extracted with siRNA (2 × 10.0 mL). The combined organic layer was washed with brine (2 × 20.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-10% MeOH in DCM) to obtain the product (120 mg, 0.34 mmol, yield 80%) as a solid. 11H NMR (CDCl3, 400MHz) δ H =8.70(d,1H), 8.25(s,1H), 8.03(dd,1H), 5.07-4.98(m,1H), 4.67(s,2H), 3.66(d,1H), 3.53(s,3H), 1.84(d,3H), 1.33(s,9H).

[0373] (1R)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethanamine hydrochloride (C-53) To a solution of (S)-N-[(1R)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-2-methyl-propane-2-sulfinamide (120 mg, 0.34 mmol) in 1,4-dioxane (5.0 mL), 4 M HCl / dioxane (6.0 mL, 1.69 mmol) was added at 25°C. After stirring at 25°C for 1 hour, the residue was filtered and concentrated to obtain the product (84.0 mg, 0.29 mmol, yield 87%) as a solid, which was used directly in the next step.

[0374] N-[(1R)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3-carboxamide(C54) A mixture of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (84.7 mg, 0.44 mmol), T3P (766 mg, 1.01 mmol), and DIEA (0.47 mL, 2.68 mmol) in DCM (8.0 mL) was stirred at 25°C for 20 minutes. k(1R)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethanamine hydrochloride (84.0 mg, 0.29 mmol) was added. After stirring at 25°C for 1 hour, the reaction mixture was quenched with water (10.0 mL) and extracted with DCM (2 × 15.0 mL). The combined organic layer was washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated to obtain the product (100 mg, 0.23 mmol, yield 70%) as oil. 11H NMR (CDCl3, 400MHz) δ H =8.63(d,1H), 8.57-8.50(m,1H), 8.38-8.27(m,1H), 7.47-7.33(m,1H), 7.14-7.09( m,1H), 5.79-5.64(m,1H), 4.99-4.84(m,2H), 4.26(s,3H), 3.58(s,3H), 1.90(d,3H).

[0375] N-[(1R)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3-carboxamide&N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3-carboxamide A mixture of N-[(1R)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3-carboxamide (100 mg, 0.23 mmol) was processed on an SFC (DAICEL CHIRALCEL OJ column (250 mm * 30 mm, 10 μm), under the conditions 0.1% NH3H2O-EtOH, start B 15%, end B) The solution was purified by 15% concentration at a flow rate of 60 mL / min to obtain N-[(1R)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3-carboxamide (38.9 mg, 0.09 mmol, yield 39%) as a solid, and (R)-N-(1-(3-(2-(methoxymethyl)pyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (10.0 mg) as a solid. N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3-carboxamide (10.0 mg) was purified by SFC (DAICEL CHIRALCEL OJ column (250 mm*30 mm, 10 μm), conditions 0.1% NH3H2O-EtOH, start B 15%, end B 15%, flow rate (mL / min) 60) to obtain N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3-carboxamide (3.41 mg, 0.008 mmol, yield 34%) as a solid.

[0376] 43: 1 1H NMR (CDCl3, 400MHz) δ H =8.70(d,1H), 8.31-8.18(m,1H), 8.02(dd,1H), 6.96-6.87(m,1H), 6.80(d, 1H), 5.76-5.65(m,1H), 4.67(s,2H), 4.24(s,3H), 3.53(s,3H), 1.83(d,3H). 19F NMR (376.5 MHz, DMSO-d6) δ F -62.174. LCMS R t = 2.0 minutes chromatography for 0.948 minutes, 10⁻⁸⁰AB, C 17 H 18 F3N6O2S[M+H] + The MS ESI calculated value is 427.1, and the measured value is 427.0.

[0377] 42: 1 1H NMR (CDCl3, 400MHz) δ H =8.71(d,1H), 8.31-8.23(m,1H), 8.03(d,1H), 6.94-6.89(m,1H), 6.77(d,1 H), 5.81-5.61(m,1H), 4.68(s,2H), 4.24(s,3H), 3.53(s,3H), 1.83(d,3H). 19 F NMR (376.5 MHz, CDCl3) δ F -62.174. LCMS R t = 2.0 minutes chromatography for 0.956 minutes, 10⁻⁸ AB, C 17 H 18 F3N6O2S[M+H] + The MS ESI calculated value is 427.1, and the measured value is 427.1.

[0378] Example 44. Synthesis of 2-methyl-N-[(1S)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (44) [ka]

[0379] 5-(1-ethoxyvinyl)-3-(2-methoxypyridine-4-yl)-1,2,4-thiadiazole (C-55) A mixture of (2-methoxy-4-pyridyl)boronic acid (1.27 g, 8.29 mmol), 3-bromo-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (1.50 g, 6.38 mmol), and Cs2CO3 (4.16 g, 12.7 mmol) in water (1.0 mL) and DME (10.0 mL, 6.38 mmol) was added with Pd(dppf)Cl 2(0.7g、0.96mmol)を添加した . After stirring at 100 °C for 1 h, the mixture was filtered, and the filtrate was concentrated to remove dioxane. The aqueous layer was extracted with EtOAc (3 × 20.0 mL). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (10 - 40% EtOAc in PE) to give the product (1.30 g, 4.44 mmol, 70% yield) as an oil. 1 H NMR (CDCl3, 400 MHz) δ H = 8.35 - 8.26 (m, 1H), 7.82 - 7.69 (m, 1H), 7.63 (s, 1H), 5.58 (d, 1H), 4.56 (d, 1H), 4.06 - 3.97 (m, 5H), 1.50 - 1.39 (m, 3H).

[0380] 1-(3-(2-Methoxypyridin-4-yl)-1,2,4-thiadiazol-5-yl)ethenone (C-56) 12 HCl (2.0 mL, 4.94 mmol) was added to a mixture of 5-(1-ethoxyvinyl)-3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazole (1.30 g, 4.94 mmol) in acetone (15.0 mL). After stirring at 50 °C for 16 h, the mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the product (1.1 g, 4.21 mmol, 85% yield) as an oil. 1 H NMR (CDCl3, 400 MHz) δ H = 8.36 (d, 1H), 7.80 (d, 1H), 7.69 (s, 1H), 4.06 (s, 3H), 2.82 (s, 3H).

[0381] (R,E)-N-(1-(3-(2-methoxypyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethylidene)-2-methylpropane-2-sulfinamide(C-57) To a solution of 1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazole-5-yl]etanone (300 mg, 1.28 mmol) and (R)-2-methylpropane-2-sulfinamide (232 mg, 1.91 mmol) in THF (5.0 mL), Ti(OEt)4 (0.87 g, 3.83 mmol) was added. The mixture was stirred at 50°C for 16 hours, then cooled to 25°C, and poured into a rapidly stirred solution of NaHCO3 (10 mL). After stirring the solution for 5 minutes, Celite was mixed into the slurry, and the suspension was filtered through a Celite pad. The solid was washed with siRNA (3 × 10 mL), and the combined filtrate was transferred to a separatory funnel. The aqueous portion was separated and extracted with siRNA (2 × 10 mL), and the combined organic portion was dried over Na2SO4, filtered, and evaporated under reduced pressure. The product was purified by column chromatography (with the polarity increased by 5% to 20% ammonium in pentane as the eluent) to obtain the product (300 mg, 0.80 mmol, yield 63%) as oil. 1 1H NMR (CDCl3, 400MHz) δ H =8.32(d,1H), 7.74(d,1H), 7.64(s,1H), 4.02(s,3H), 2.95(s,3H), 1.36(s,9H).

[0382] (R)-N-((S)-1-(3-(2-methoxypyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)-2-methylpropane-2-sulfinamide(C-58) To a solution of (R,E)-N-[1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethylidene]-2-methyl-propane-2-sulfinamide (300 mg, 0.89 mmol) in THF (5 mL), K-Selectride (1.77 mL, 1.77 mmol) was added at -78°C. After stirring at -78°C for 0.5 hours, the mixture was poured into saturated NH4Cl (20 mL) and extracted with siRNA (2 × 10 mL). The combined organic layer was washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-50% siRNA in PE) to obtain the product (150 mg, 0.40 mmol, yield 45%) as a solid. 1 1H NMR (CDCl3, 400MHz) δ H =8.36-8.27(m,1H), 7.78-7.72(m,1H), 7.64(s,1H), 5.06-4.95(m,1H), 4.04(s,3H), 1.85-1.80(m,3H), 1.33(s,9H).

[0383] (1S)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethanamine(C-59) To a solution of (R)-N-[(1S)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-2-methyl-propane-2-sulfinamide (140 mg, 0.41 mmol) in 1,4-dioxane (5.0 mL), 4 M HCl / dioxane (6.0 mL, 2.06 mmol) was added at 25°C. After stirring at 25°C for 1 hour, the residue was filtered and concentrated to obtain (1S)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethanamine hydrochloride (120 mg, 0.508 mmol) as a solid. 1 1H NMR (MeOD, 400MHz) δ H =8.54-8.38(m,1H), 8.12-8.05(m,1H), 8.00(s,1H), 5.33-5.18(m,1H), 4.18(s,3H), 1.83(d,3H).

[0384] 2-methyl-N-[(1S)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide(44) To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (128 mg, 0.66 mmol) in DCM (8.0 mL), DIEA (524 mg, 4.06 mmol) and T3P (1.16 g, 1.52 mmol) were added. After stirring at 25°C for 20 minutes, (1S)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethanamine hydrochloride (120 mg, 0.51 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (20.0 mL) and extracted with DCM (2 × 15.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-60% siRNA in PE) to obtain the product (210 mg, 0.509 mmol) as a solid. The product was purified by SFC (Column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 μm) conditions: 0.1% NH3H2O ​​MeOH, Start B 30%, End B 30%, Gradient time (min): 100%, B retention time (min): 60, Flow rate (mL / min): 60, Injection: 30) to obtain the product (38.0 mg, 0.092 mmol, yield 18%) as a solid. 1 1H NMR (CDCl3, 400MHz) δ H =8.30(d,1H), 7.70(d,1H), 7.60(s,1H), 6.88(s,1H), 6.75-6.60(m,1H), 5.81-5.55(m,1H), 4.24(s,3H), 4.00(s,3H), 1.82(d,3H). 19 F NMR (376.5 MHz, CDCl3) δ F = -62.186. LCMS R t = 1.066 min chromatography in 1.5 min, 5-95AB, C 16 H 16 F3N6O2S[M+H] + The MS ESI calculated value is 412.9, and the measured value is 412.9.

[0385] Examples 44 and 45. Synthesis of (R)-N-(1-(3-(2-methoxypyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide and (S)-N-(1-(3-(2-methoxypyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide [ka]

[0386] (S,E)-N-(1-(3-(2-methoxypyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethylidene)-2-methylpropane-2-sulfinamide(C-60) To a solution of 1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazole-5-yl]etanone (300 mg, 1.28 mmol) in THF (5.0 mL), (S)-2-methylpropane-2-sulfinamide (232 mg, 1.91 mmol) and Ti(OEt)4 (0.87 g, 3.83 mmol) were added. After stirring at 50°C for 16 hours, the mixture was cooled to 25°C and poured into saturated NaHCO3 (10.0 mL). After stirring for 5 minutes, Celite was mixed into the slurry, and the suspension was filtered through a Celite pad. The solid was washed with ELISA (3 × 10.0 mL), and the combined filtrate was extracted with ELISA (2 × 10.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product, which was then purified by column chromatography (5%-20% siRNA in PE) to obtain the product (230 mg, 0.612 mmol, 48% yield) as oil. 1 1H NMR (CDCl3, 400MHz) δ H =8.34(d,1H), 7.83-7.77(m,1H), 7.68(s,1H), 4.06(s,3H), 2.95(s,3H), 1.36(s,9H).

[0387] (S)-N-((R)-1-(3-(2-methoxypyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)-2-methylpropane-2-sulfinamide(C61) To a solution of (S,E)-N-[1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethylidene]-2-methyl-propane-2-sulfinamide (200 mg, 0.59 mmol) in THF (3.0 mL), K-Selectride (1.18 mL, 1.18 mmol) was added at -78°C. After stirring at -78°C for 0.5 hours, the mixture was poured into saturated NH4Cl (20.0 mL) and extracted with ethyl acetate (2 × 10.0 mL). The combined organic layer was washed with brine (2 × 20.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column (0-50% ethyl acetate in PE) to obtain the product (100 mg, 0.27 mmol, yield 45%) as a solid. LCMS R t = Chromatography for 1.5 minutes, 0.921 minutes, 5-95AB, C 14 H 21 N4O2S2[M+H] + The MS ESI calculated value is 341.1, and the measured value is 341.1.

[0388] (R)-1-(3-(2-methoxypyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethanamine hydrochloride (C-62) To a solution of (S)-2-methyl-N-[(1R)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethyl]propan-2-sulfinamide (100 mg, 0.29 mmol) in dioxane (0.50 mL), 4 M HCl / dioxane (1.10 mL, 4.41 mmol) was added at 25°C. After stirring at 25°C for 1 hour, the reaction mixture was filtered, and the residue was washed with dioxane (5.0 mL) to obtain the product (80.0 mg, 0.24 mmol) as a solid. LCMS R t = 1.5 minutes chromatography for 0.679 minutes, 5-95AB, C 10 H 13 N4OS[M+H] +The MS ESI calculated value is 237.1, and the measured value is 237.1.

[0389] (R)-N-(1-(3-(2-methoxypyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(C63) To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (74.8 mg, 0.39 mmol) in DCM (8.0 mL), DIEA (306 mg, 2.37 mmol) and T3P (676 mg, 0.89 mmol) were added. After stirring at 25°C for 20 minutes, (1R)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazole-5-yl]ethanamine (70.0 mg, 0.30 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (10.0 mL) and extracted with DCM (2 × 15.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated to obtain the solid product (120 mg, 0.26 mmol). This was purified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 μm; conditions: water (10 mM NH4HCO3)-ACN; start B: 46, end B: 76) to obtain the solid product (60.0 mg, 0.131 mmol). LCMS R t = Chromatography for 1.0 min, 0.755 min, 5-95AB, C 16 H 16 F3N6O2S[M+H] + The MS ESI calculated value is 413.1, and the measured value is 413.1.

[0390] (R)-N-(1-(3-(2-methoxypyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide & (S)-N-(1-(3-(2-methoxypyridine-4-yl)-1,2,4-thiadiazole-5-yl)ethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide 2-Methyl-N-[(1R)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazole-5-yl]...

Claims

1. A compound having formula A-1, 【Chemistry 1】 X is CR ７ Or N is S, or X is CR ７ And Y is O, Ring A is a 6-membered heteroaryl (e.g., pyridyl), R １ However, phenyl, 5-6 member heteroaryl, -CH ２ - Selected from the group consisting of phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl, and the phenyl, 5-6 membered heteroaryl, -CH ２ - Phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl are present in one or more R ６ It is optionally replaced by, R ２ However, hydrogen or C １－６ It is alkyl, R ３ is selected from the group consisting of hydrogen, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, and C ３－８ cycloalkyl, and the C １－６ alkyl is optionally substituted with C １－６ alkoxy, or C １－６ haloalkoxy, and R ４ is hydrogen or R ３ and R ４ However, R ３ and R ４ Together with the carbon that is bonded to it, C ３－８ It can form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R ５ and R ６ However, each is independent of halogen and C １－６ Alkyl, C １－６ Alkylene-OC １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, -S(O) ２ R ８ , -S(O) ２ -N(R) ９ ) ２ , and C ３－８ Selected from the group consisting of cycloalkyl groups, R ７ However, hydrogen, C １－６ Alkyl and C １－６ Selected from the group consisting of haloalkyls, R ８ However, hydrogen or C １－６ It is alkyl, Each R ９ However, hydrogen, C １－６ Alkyl and -(C １－６ Independently selected from the group consisting of alkylene)-OH, or two R ９ However, the two Rs mentioned above ９ Together with the nitrogen atom bonded to it, it can form a heterocycle which is optionally substituted with one or more substituents independently selected from halogens and -OH groups. n is selected from the group consisting of 0, 1, 2, and 3. However, R ３ When is hydrogen and ring A is a 6-membered heteroaryl, R １ A compound, or a pharmaceutically acceptable salt thereof, provided that it is neither thiophene nor phenyl, A pharmaceutical composition comprising a pharmaceutically acceptable carrier.

2. The aforementioned compound is a compound of formula A-1A or formula A-1B. 【Chemistry 2】 The pharmaceutical composition according to claim 1, or a pharmaceutically acceptable salt thereof.

3. A compound having formula A-2, 【Transformation 3】 X is CR ７ Or N is S, or X is CR ７ And Y is O, Ring A is a 5-7 member heterocyclyl, R １ However, phenyl, 5-6 member heteroaryl, -CH ２ - Selected from the group consisting of phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl, and the phenyl, 5-6 membered heteroaryl, -CH ２ - Phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl are present in one or more R ６ It is optionally replaced by, R ２ However, hydrogen or C １－６ It is alkyl, R ３ However, hydrogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy and C ３－８ Selected from the group consisting of cycloalkyl, the C １－６ Alkyl is C １－６ Alkoxy or C １－６ Optionally substituted with a haloalkoxy, R ４ However, is it hydrogen, or R ３ and R ４ However, R ３ and R ４ Together with the carbon that is bonded to it, C ３－８ It can form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R ５ and R ６ However, each is independent of halogen and C １－６ Alkyl, C １－６ Alkylene-OC １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, -S(O) ２ R ８ , -S(O) ２ -N(R) ９ ) ２ , and C ３－８ Selected from the group consisting of cycloalkyl groups, R ７ However, hydrogen, C １－６ Alkyl and C １－６ Selected from the group consisting of haloalkyls, R ８ is hydrogen or C １－６ alkyl, and Each R ９ However, hydrogen, C １－６ Alkyl and -(C １－６ Independently selected from the group consisting of alkylene)-OH, or two R ９ However, the two Rs mentioned above ９ Together with the nitrogen atom bonded to it, it can form a heterocycle which is optionally substituted with one or more substituents independently selected from halogens and -OH groups. n is selected from the group consisting of 0, 1, 2, and 3. However, when R ３ is hydrogen and ring A is a 5- to 6-membered heterocyclyl, R １ is not thiophene or phenyl, a compound or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising a pharmaceutically acceptable carrier.

4. The aforementioned compound is a compound of formula A-2A, 【Chemistry 4】 Compounds in which q is 1 or 2, The pharmaceutical composition according to claim 3, or a pharmaceutically acceptable salt thereof.

5. X is N and Y is S, or X is CH and Y is O, and / or R ３ However, C １－６ Alkyl, or hydrogen, and / or R ２ but is hydrogen, and / or R ５ However, C １－６ Alkyl, C １－６ Alkylene-OC １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, or C ３－８ Cycloalkyl and / or R １ However, one or more R ６ Five- to six-membered heteroaryls (e.g., pyrazolyl) that are optionally substituted, one or more R ６ Phenyl compounds optionally substituted with one or more R ６ -CH is optionally substituted with ２ - Phenyl, or one or more R ６ A 10-membered heterocycline (e.g., a bicyclic heterocycline) that is optionally substituted with, and / or R ６ However, halogen, C １－６ Alkyl, or C １－６ It is a haloalkyl, A pharmaceutical composition according to any one of claims 1 to 4.

6. Compounds having formula I, 【Transformation 5】 or a pharmaceutically acceptable salt thereof, in the formula, X is CR ７ Or N is S, or X is CR ７ And Y is O, Ring A is selected from the group consisting of 6-membered heteroaryls and 5- to 7-membered heterocyclines. R １ However, phenyl, 5-6 member heteroaryl, -CH ２ - Selected from the group consisting of phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl, and the phenyl, 5-6 membered heteroaryl, -CH ２ - Phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl are present in one or more R ６ It is optionally replaced by, R ２ However, hydrogen or C １－６ It is alkyl, R ３ However, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy and C ３－８ Selected from the group consisting of cycloalkyl, the C １－６ Alkyl is C １－６ Alkoxy or C １－６ Optionally substituted with a haloalkoxy, R ４ However, is it hydrogen, or R ３ and R ４ However, R ３ and R ４ Together with the carbon that is bonded to it, C ３－８ It can form cycloalkylenes or 3- to 7-membered heterocycloalkylenes. R ５ and R ６ However, each is independent of halogen and C １－６ Alkyl, C １－６ Alkylene-OC １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, -S(O) ２ R ８ , -S(O) ２ -N(R) ９ ) ２ , and C ３－８ Selected from the group consisting of cycloalkyl groups, R ７ However, hydrogen, C １－６ Alkyl and C １－６ Selected from the group consisting of haloalkyls, R ８ However, hydrogen or C １－６ It is alkyl, Each R ９ However, hydrogen, C １－６ Alkyl and -(C １－６ Independently selected from the group consisting of alkylene)-OH, or two R ９ However, the two Rs mentioned above ９ Together with the nitrogen atom bonded to it, it can form a heterocycle which is optionally substituted with one or more substituents independently selected from halogens and -OH groups. n is selected from the group consisting of 0, 1, 2, and 3. However, R ３ When is hydrogen and ring A is a 6-membered heteroaryl or a 5-6 membered heterocyclyl, R １ A compound or a pharmaceutically acceptable salt thereof, provided that it is neither thiophene nor phenyl.

7. The compound according to claim 6, having formula I-A, 【Transformation 6】 or a pharmaceutically acceptable salt thereof, in the formula, A compound or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-membered heteroaryl or a 5- to 7-membered heterocyclyl.

8. A compound according to claim 6, having formula I-B, 【Transformation 7】 or a pharmaceutically acceptable salt thereof, in the formula, Ring A is phenyl or a 6-membered heteroaryl, R １ However, the phenyl or 5-6 member heteroaryl is one or more R ６ It is optionally replaced by and R ５ and R ６ However, each is independent of halogen and C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, -S(O) ２ R ８ , -S(O) ２ -N(R) ９ ) ２ , and C ３－８ A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of cycloalkyl compounds.

9. Ring A is a six-membered heteroaryl (e.g., pyridyl), and / or X is N and Y is S, or X is CH and Y is O, and / or R ３ However, C １－６ Alkyl (e.g., methyl), and / or R ２ but is hydrogen, and / or R ５ However, C １－６ Alkyl (e.g., methyl), C １－６ Alkylene-OC １－６ Alkyl (e.g., -CH) ２ OCH ３ ), C １－６ Haloalkyl (e.g., CF) ３ ), C １－６ Alkoxy (e.g., -OCH) ３ ), or C ３－８ It is cycloalkyl (e.g., cyclopropyl), and / or n is 0 or 1, and / or R １ However, one or more R ６ Five- to six-membered heteroaryls (e.g., pyrazolyl) optionally substituted with one or more R ６ Phenyl compounds optionally substituted with one or more R ６ -CH is optionally substituted with ２ - Phenyl, or one or more R ６ A 10-membered heterocycline (e.g., a bicyclic heterocycline) that is optionally substituted with, and / or R ６ However, halogen, C １－６ Alkyl, or C １－６ It is a haloalkyl, The compound according to claim 6.

10. The aforementioned compound is a compound of formula I-IA, formula I-IB, formula I-IA2, formula I-IB2, formula I-IA3, formula I-IA4, formula I-IB3, formula I-IB4, formula I-IC, formula I-IC2, formula I-IC3, or formula I-IC4, 【Transformation 8】 Compounds in which q is 1 or 2, The compound according to claim 6, or a pharmaceutically acceptable salt thereof.

11. R １ but, 【Chemistry 9】 A compound according to any one of claims 6 to 10, selected from the group consisting of the following, wherein m is 0, 1, or 2 in the formula.

12. The aforementioned compound, 【Chemistry 10】 【change】 【change】 The compound according to claim 6, selected from the group consisting of or pharmaceutically acceptable salts thereof.

13. A pharmaceutical composition comprising a compound according to any one of claims 6 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

14. A pharmaceutical composition according to any one of claims 1 to 5 and 13, for use in a method for treating a disease or condition related to a gain-of-function mutation of KCNT1.

15. The diseases or conditions associated with the gain-of-function mutations of KCNT1 include epilepsy, epileptic syndromes, encephalopathy (for example, infantile epilepsy with migratory focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox syndrome) Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, or cerebellar ataxia), hereditary or childhood epilepsy, hereditary or childhood epilepsy syndromes, cardiac dysfunction, cardiac arrhythmias, sudden unexpected death in epilepsy (SUDEP), Brugada syndrome, myocardial infarction, pain and related conditions (e.g., neuropathic pain, acute / chronic pain, or migraine), muscle disorders (e.g., myotonia, The pharmaceutical composition according to claim 14, wherein the present invention is neuromyotonia, muscle spasms, or spasticity), itching and pruritus, ataxia, mental disorders (e.g., major depression, anxiety, bipolar disorder, or schizophrenia), learning disabilities, fragile X, neuroplasticity, autism spectrum disorder, early-onset infantile epileptic encephalopathy, Dravet syndrome, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, benign familial neonatal-infant seizures, Rasmussen encephalitis, malignant migratory partial seizures in infants, or KCNT1 epileptic encephalopathy.

16. A compound according to any one of claims 6 to 12, for use in a method for treating a disease or condition related to a gain-of-function mutation of KCNT1.

17. The diseases or conditions associated with the gain-of-function mutations of KCNT1 include epilepsy, epileptic syndromes, encephalopathy (for example, infantile epilepsy with migratory focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox syndrome) Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, or cerebellar ataxia), hereditary or childhood epilepsy, hereditary or childhood epilepsy syndromes, cardiac dysfunction, cardiac arrhythmias, sudden unexpected death in epilepsy (SUDEP), Brugada syndrome, myocardial infarction, pain and related conditions (e.g., neuropathic pain, acute / chronic pain, or migraine), muscle disorders (e.g., myotonic pain). The compound according to claim 16, which is a neuromyotonia, muscle spasms, or spasticity, itching and pruritus, ataxia, mental disorders (e.g., major depression, anxiety, bipolar disorder, or schizophrenia), learning disabilities, fragile X, neuroplasticity, autism spectrum disorder, early-onset infantile epileptic encephalopathy, Dravet syndrome, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, benign familial neonatal-infant seizures, Rasmussen encephalitis, malignant migratory partial seizures in infants, or KCNT1 epileptic encephalopathy.

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