Kcnt1 inhibitors and methods of use

Abstract

The present invention relates, in part, to compounds and compositions useful for preventing and / or treating a neurological disease or disorder, a disease or condition associated with excessive neuronal excitability and / or a gain-of-function mutation in a gene (e.g., KCNT1). Also provided herein are methods of treating a neurological disease or disorder, a disease or condition associated with excessive neuronal excitability and / or a gain-of-function mutation in a gene (e.g., KCNT1).

Description

[0001] Cross-referencing related applications

[0002] This application claims priority and benefit 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

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

[0004] This document describes compounds and compositions suitable for the prevention and / or treatment of diseases, conditions, or symptoms, such as neurological diseases or conditions, diseases, conditions, or symptoms associated with excessive neuronal excitability and / or gain-of-function mutations in genes (e.g., KCNT1).

[0005] Therefore, in one aspect, this document provides a pharmaceutical composition comprising a compound having formula A:

[0006]

[0007] X is CR7 or N, and Y is S; or

[0008] X is CR7 and Y is O;

[0009] Ring A is selected from the group consisting of: phenyl, 6-membered heteroaryl, and 5-7-membered heterocyclic groups;

[0010] R1 is selected from the group consisting of: phenyl, 5-6-membered heteroaryl, -CH2-phenyl, 5-8-membered carbocyclic and 5-10-membered heterocyclic; wherein the phenyl, the 5-6-membered heteroaryl, the -CH2-phenyl, the 5-8-membered carbocyclic and the 5-10-membered heterocyclic are optionally substituted by one or more R6;

[0011] R2 is hydrogen or C. 1-6 alkyl;

[0012] R3is 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, wherein the C 1-6 alkyl is optionally substituted with C 1-6 alkoxy or C 1-6 haloalkoxy, and R4is hydrogen; or

[0013] R3and R4together with the carbon attached to R3and R4may form a C 3-8 cycloalkylene or 3-7 membered heterocycloalkylene;

[0014] R5and R6are each independently selected from the group consisting of 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;

[0015] R7is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;

[0016] R8is hydrogen or C 1-6 alkyl;

[0017] each R9is independently selected from the group consisting of hydrogen, C 1-6 alkyl, and -(C 1-6 alkylene)-OH, or two R9together with the nitrogen atom attached to the two R9may form a heterocyclic ring optionally substituted with one or more substituents each independently selected from halogen and -OH; and

[0018] n is selected from the group consisting of 0, 1, 2, and 3;

[0019] provided that when R3is hydrogen and ring A is 6-membered heterocyclyl or 6- membered heteroaryl, R1is not thiophene;

[0020] provided that when R3is hydrogen and ring A is 6-membered heteroaryl or 5- membered heterocyclyl, R1is not phenyl; or a pharmaceutically acceptable salt thereof,

[0021] and a pharmaceutically acceptable carrier.

[0022] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula A-1: A-1.

[0023]

[0024] X is CR7or N, and Y is S; or

[0025] X is CR7, and Y is O;

[0026] Ring A is 6-membered heteroaryl;

[0027] R1is selected from the group consisting of phenyl, 5-6 membered heteroaryl, -CH2- phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl; wherein the phenyl, the 5-6 membered heteroaryl, the -CH2-phenyl, the 5-8 membered carbocyclyl, and the 5-10 membered heterocyclyl are optionally substituted with one or more R6;

[0028] R2is hydrogen or C 1-6 alkyl;

[0029] R3is 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, wherein the C 1-6 alkyl is optionally substituted with C 1-6 alkoxy or C 1-6 haloalkoxy, and R4is hydrogen; or

[0030] R3and R4together with the carbon attached to R3and R4may form a C 3-8 cycloalkylene or 3-7 membered heterocycloalkylene;

[0031] R5and R6are each independently selected from the group consisting of 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;

[0032] R7is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;

[0033] R8is hydrogen or C 1-6 alkyl;

[0034] each R9is independently selected from the group consisting of hydrogen, C 1-6alkyl and -(C 1-6 alkylene)-OH, or both R9can be taken together with the nitrogen atom to which both R9are attached to form a heterocycle optionally substituted with one or more substituents each independently selected from the group consisting of halogen and -OH; and

[0035] n is selected from the group consisting of 0, 1, 2, and 3;

[0036] with the proviso that when R3is hydrogen and ring A is 6-membered heteroaryl, R1is not thienyl or phenyl; or a pharmaceutically acceptable salt thereof,

[0037] and a pharmaceutically acceptable carrier.

[0038] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula A-2:

[0039]

[0040] X is CR7or N, and Y is S; or

[0041] X is CR7, and Y is O;

[0042] ring A is 5-7 membered heterocyclyl;

[0043] R1is selected from the group consisting of phenyl, 5-6 membered heteroaryl, -CH2-phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl; wherein the phenyl, the 5-6 membered heteroaryl, the -CH2-phenyl, the 5-8 membered carbocyclyl, and the 5-10 membered heterocyclyl are optionally substituted with one or more R6;

[0044] R2is hydrogen or C 1-6 alkyl;

[0045] R3is 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, wherein the C 1-6 alkyl is optionally substituted with C 1-6 alkoxy or C 1-6 haloalkoxy, and R4is hydrogen; or

[0046] R3and R4can be taken together with the carbon to which R3and R4are attached to form a C 3-8 cycloalkylene or 3-7 membered heterocycloalkylene;

[0047] R5and R6are each independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkylene-O-C1-6 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;

[0048] R7is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;

[0049] R8is hydrogen or C 1-6 alkyl;

[0050] each R9is independently selected from the group consisting of hydrogen, C 1-6 alkyl, and -(C 1-6 alkylene)-OH, or two R9can together with the nitrogen atom to which the two R9are attached form a heterocyclic ring optionally substituted with one or more substituents each independently selected from the group consisting of halogen and -OH; and

[0051] n is selected from the group consisting of 0, 1, 2, and 3;

[0052] with the proviso that when R3is hydrogen and ring A is 5-6 membered heterocyclyl, R1is not thiophene or phenyl; or a pharmaceutically acceptable salt thereof,

[0053] and a pharmaceutically acceptable carrier.

[0054] In one aspect, provided herein is a compound of Formula I:

[0055]

[0056] or a pharmaceutically acceptable salt thereof, wherein:

[0057] X is CR7or N, and Y is S; or

[0058] X is CR7, and Y is O;

[0059] ring A is selected from the group consisting of phenyl, 6-membered heteroaryl, and 5-7 membered heterocyclyl;

[0060] R1is selected from the group consisting of phenyl, 5-6 membered heteroaryl, -CH2- phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl; wherein the phenyl, the 5-6 membered heteroaryl, the -CH2-phenyl, the 5-8 membered carbocyclyl, and the 5-10 membered heterocyclyl are optionally substituted with one or more R6;

[0061] R2is hydrogen or C 1-6 alkyl;

[0062] R3is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-8 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with C 1-6 alkoxy or C 1-6 haloalkoxy, and R4is hydrogen; or

[0063] R3and R4together with the carbon attached to R3and R4may form a C 3-8 cycloalkylene or 3-7 membered heterocycloalkylene;

[0064] R5and R6are each independently selected from the group consisting of 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;

[0065] R7is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;

[0066] R8is hydrogen or C 1-6 alkyl;

[0067] each R9is independently selected from the group consisting of hydrogen, C 1-6 alkyl, and -(C 1-6 alkylene)-OH, or two R9together with the nitrogen atom attached to the two R9may form a heterocyclic ring optionally substituted with one or more substituents each independently selected from halogen and -OH; and

[0068] n is selected from the group consisting of 0, 1, 2, and 3.

[0069] In one aspect, provided herein is a compound of Formula I-A:

[0070]

[0071] or a pharmaceutically acceptable salt thereof, wherein:

[0072] X is CR7or N, and Y is S; or

[0073] X is CR7, and Y is O;

[0074] Ring A is 6-membered heteroaryl or 5-7 membered heterocyclyl;

[0075] R1is selected from the group consisting of phenyl, 5-6 membered heteroaryl, -CH2- phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl; wherein the phenyl, the 5-6 membered heteroaryl, the -CH2-phenyl, the 5-10 membered carbocyclyl, and the 5-10 membered heterocyclyl are optionally substituted with one or more R6;

[0076] R2is hydrogen or C 1-6 alkyl;

[0077] R3is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-8 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with C 1-6 alkoxy or C 1-6 haloalkoxy, and R4is hydrogen; or

[0078] R3and R4together with the carbon attached to R3and R4may form a C 3-8 cycloalkylene or 3-7 membered heterocycloalkylene;

[0079] R5and R6are each independently selected from the group consisting of 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;

[0080] R7is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;

[0081] R8is hydrogen or C 1-6 alkyl;

[0082] each R9is independently selected from the group consisting of hydrogen, C 1-6 alkyl, and -(C 1-6 alkylene)-OH, or two R9together with the nitrogen atom attached to the two R9may form a heterocyclic ring, which is optionally substituted with one or more substituents each independently selected from halogen and -OH; and

[0083] n is selected from the group consisting of 0, 1, 2, and 3.

[0084] In one aspect, provided herein are compounds of Formula I-B:

[0085]

[0086] or a pharmaceutically acceptable salt thereof, wherein:

[0087] X is CR7or N, and Y is S; or

[0088] X is CR7, and Y is O;

[0089] Ring A is phenyl or 6-membered heteroaryl;

[0090] R1is phenyl or 5-6 membered heteroaryl, wherein the phenyl or the 5-6 membered heteroaryl is optionally substituted with one or more R6;

[0091] R2is hydrogen or C 1-6 alkyl;

[0092] R3is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-8 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with C 1-6 alkoxy or C 1-6 haloalkoxy, and R4is hydrogen; or

[0093] R3and R4together with the carbon attached to R3and R4may form a C 3-8 cycloalkylene or 3-7 membered heterocycloalkylene;

[0094] R5and R6are each independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S(O)2R8, -S(O)2-N(R9)2, and C 3-8 cycloalkyl;

[0095] R7is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;

[0096] R8is hydrogen or C 1-6 alkyl;

[0097] each R9is independently selected from the group consisting of hydrogen, C 1-6 alkyl, and -(C1-6 alkylene)-OH, or both R9can be taken together with the nitrogen atom to which both R9are attached to form a heterocyclic ring, which is optionally substituted with one or more substituents each independently selected from the group consisting of halogen and -OH; and

[0098] n is selected from the group consisting of 0, 1, 2, and 3.

[0099] In one aspect, the present disclosure provides a method of treating a neurological disease or disorder, wherein the method comprises administering to a subject in need thereof a compound disclosed herein (e.g., a compound of Formula (A), (A-l), (A-lA), (A-lB), (A-2), (A-2A), (I), (I-A), (I-IA), (I-IA2), (I-IA3), (I-IA4), (I-B), (I-IB), (I-IB2), (I-IB3), (I-IB4), (I-IC), (I-IC2), (I-IC3), (I-IC4), (II), (II-A), or (II-B), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of Formula (A), (A-l), (A-lA), (A-lB), (A-2), (A-2A), (I), (I-A), (I-IA), (I-IA2), (I-IA3), (I-IA4), (I-B), (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).

[0100] In another aspect, the present disclosure provides a method of treating a disease or condition associated with excessive neuronal excitability, wherein the method comprises administering to a subject in need thereof a compound disclosed herein (e.g., a compound of Formula (A), (A-l), (A-lA), (A-lB), (A-2), (A-2A), (I), (I-A), (I-IA), (I-IA2), (I-IA3), (I-IA4), (I-B), (I-IB), (I-IB2), (I-IB3), (I-IB4), (I-IC), (I-IC2), (I-IC3), (I-IC4), (II), (II-A), or (II-B), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of Formula (A), (A-l), (A-lA), (A-lB), (A-2), (A-2A), (I), (I-A), (I-IA), (I-IA2), (I-IA3), (I-IA4), (I-B), (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).

[0101] In another aspect, the present disclosure provides a method of treating a disease or condition associated with a gain-of-function mutation of a gene (e.g., KCNT1), wherein the method comprises administering to a subject in need thereof a compound disclosed herein (e.g., a compound of Formula (A), (A-l), (A-lA), (A-lB), (A-2), (A-2A), (I), (I-A), (I-IA), (I-IA2), (I-IA3), (I-IA4), (I-B), (I-IB), (I-IB2), (I-IB3), (I-IB4), (I-IC), (I-IC2), (I-IC3), (I-IC4), (II), (II-A), or (II-B), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of Formula (A), (A-l), (A-lA), (A-lB), (A-2), (A-2A), (I), (I-A), (I-IA), (I-IA2), (I-IA3), (I-IA4), (I-B), (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).

[0102] In some embodiments, the neurological disease or disorder, disease or condition associated with excessive neuronal excitability, or disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is epilepsy, an epilepsy syndrome, or an encephalopathy.

[0103] In some embodiments, the neurological disease or disorder, disease or condition associated with excessive neuronal excitability, or disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is a genetic or pediatric epilepsy or a genetic or pediatric epilepsy syndrome.

[0104] In some embodiments, the neurological disease or disorder, disease or condition associated with excessive neuronal excitability, or disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is a cardiac dysfunction.

[0105] In some embodiments, the neurological disease or disorder, disease or condition associated with excessive neuronal excitability, or disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from epilepsy and other encephalopathies (e.g., early infantile epileptic encephalopathy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia).

[0106] In some embodiments, the neurological disease or disorder, disease or condition associated with excessive neuronal excitability, or disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from the group consisting of cardiac arrhythmias, sudden death from epilepsy, Brugada syndrome, and myocardial infarction.

[0107] In some embodiments, the neurological disease or disorder, disease or condition associated with excessive neuronal excitability, or disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.).

[0108] In some embodiments, the neurological disease or disorder, disease or condition associated with excessive neuronal excitability, or disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is a muscle disorder (e.g., myotonia, neuromyotonia, cramp muscle spasm, spasticity).

[0109] In some embodiments, the neurological disease or disorder, disease or condition associated with excessive neuronal excitability, or disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from pruritus and pruritic conditions, ataxia and cerebellar ataxia.

[0110] In some embodiments, the neurological disease or disorder, disease or condition associated with excessive neuronal excitability, or disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from psychiatric disorders (e.g., major depressive disorder, anxiety disorder, bipolar disorder, schizophrenia).

[0111] In some embodiments, the neurological disease or disorder or disease or condition associated with excessive neuronal excitability and / or a gain-of-function mutation in a gene (e.g., KCNT1) is selected from the group consisting of learning disorders, fragile X syndrome, neuronal plasticity, and autism spectrum disorders.

[0112] In some embodiments, the neurological disease or disorder, disease or condition associated with excessive neuronal excitability, or disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from the group consisting of epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic pediatric partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexplained death in epilepsy, Rasmussen’s encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0113] Other objects and advantages will become apparent to those skilled in the art from consideration of the following detailed description and examples and claims. DETAILED DESCRIPTION

[0114] As generally described herein, the present application provides compounds and compositions useful for preventing and / or treating diseases, disorders, or conditions described herein (e.g., diseases, disorders, or conditions associated with excessive neuronal excitability, and / or diseases, disorders, or conditions associated with gain-of-function mutations in KCNT1). Exemplary diseases, disorders, or conditions include epilepsy and other brain disorders (e.g., early infantile epileptic encephalopathy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Tayasu's syndrome, developmental and epileptic encephalopathy and Lennox Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic seizures, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia, asymmetric tonic seizure), and cardiac dysfunction (e.g., arrhythmia, Brugada syndrome, sudden death from epilepsy, myocardial infarction), pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.), muscle disorders (e.g., myotonia, neuromyotonia, crampy muscle spasms, spasticity), itch and pruritus, ataxia and cerebellar ataxia, and psychiatric disorders (e.g., major depressive disorder, anxiety, bipolar disorder, schizophrenia).

[0115] Definitions

[0116] Chemical Definitions

[0117] Definitions of specific functional groups and chemical terms are described below. To the extent not already, the definitions herein follow those used by CAS version of the Periodic Table of the Elements. 版and specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry, as well as particular functional moieties and reactivity descriptions are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, 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, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0118] The compounds described herein can include one or more asymmetric centers and can thus occur as various stereoisomeric forms, such as enantiomeric and / or diastereomeric forms. For example, the compounds described herein can exist as individual enantiomers, diastereomers or geometric isomers, or as mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (E. L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present application additionally encompasses the compounds described herein in individual isomeric form substantially free of other isomers of the compounds, and alternatively in the form of mixtures of various isomers.

[0119] As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the “S” form of a compound is substantially free of the “R” form of the compound, and thus in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” means that the compound includes 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.

[0120] In the compositions provided herein, enantiomerically pure compounds can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such compositions can comprise, for example, at least about 95% by weight R-compound and at most about 5% by weight S-compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such compositions can comprise, for example, at least about 95% by weight S-compound and at most about 5% by weight R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0121] The compounds described herein can also include one or more isotopic substitutions. For example, H can be in any isotopic form, including 1 H, 2 H (deuterium or tritium), and 3 H (deuterium or tritium); C can be in any isotopic form, including 12 C, 13 C, and 14 C; O can be in any isotopic form, including 16 O, 18 O; F can be in any isotopic form, including 18 F, 19 F; and the like.

[0122] The following terms are intended to have the meanings presented herein, and are used for the understanding of the description of the present application and the claimed invention. The following terms, when present, have the following meanings unless otherwise indicated. It is further to be understood that any moiety defined below, when described herein, can be substituted with a variety of substituents, and the respective definitions are intended to include such substituted moieties within the scope as set forth below. Unless otherwise stated, the term “substituted” will be defined as set forth below. It is further to be understood that the term “group” or “radical” when used herein can be considered interchangeable. The article “a” can be used herein to refer to one or more than one (i.e., at least one) grammatical object of the article. By way of example, “analog” means one analog or more than one analog.

[0123] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C 1-6"Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0124] As used herein, "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1-20 Alkyl group). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1-10 Alkyl group). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1”). 1-9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has one carbon atom (“C1 alkyl”). 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc.

[0125] As used herein, the term "heteroalkyl" refers to an alkyl group in which at least one carbon atom has been replaced by an O or S atom. Heteroalkyl groups can be, for example, -O-C1-C 10Alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, or C1-C6 alkylene-OH groups. In some embodiments, "heterocyclic alkyl" can be a 2-8 membered heterocyclic alkyl group, indicating that the heterocyclic alkyl contains 2 to 8 atoms selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. In other embodiments, heteroalkyl can be a 2-6, 4-8, or 5-8 membered heteroalkyl group (which may contain, for example, 1 or 2 heteroatoms selected from the group consisting of oxygen and nitrogen). In some embodiments, heteroalkyl is an "alkyl" group in which 1 to 3 carbon atoms have been replaced by oxygen atoms. One type of heterocyclic group is an "alkoxy" group.

[0126] As used herein, “alkenyl” refers to a straight-chain or branched hydrocarbon group (“C”) having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds). 2-20 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C”). 2-10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2-9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2-8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2-7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3 Alkenyl (“C2-alkenyl”). In some embodiments, the alkenyl group has two carbon atoms (“C2-alkenyl”). One or more carbon-carbon double bonds may be internal (as in 2-butenyl) or terminal (as in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 Alkenyl groups include pentyl (C5), pentadienyl (C5), and hexenyl (C6). Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), and octtrienyl (C8).

[0127] As used herein, "alkynyl" refers to a straight or branched chain hydrocarbon radical ("C 2-20 ") having from 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). In certain embodiments, the alkynyl group has no double bonds. 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 "). In some embodiments, the alkynyl group has 2 carbon atoms ("C2alkynyl"). The one or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl).C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1- propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.C 2-6 Examples of alkenyl groups include the foregoing C 2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Other examples of alkynyl groups include heptynyl (C7), octynyl (C8), and the like.

[0128] As used herein, "alkylene," "alkenylene," and "alkynylene" refer to divalent radicals of alkyl, alkenyl, and alkynyl, respectively. When a range or number of carbons is provided for a particular "alkylene," "alkenylene," or "alkynylene," it is understood that the range or number refers to the range or number of carbons in the linear divalent chain. "Alkylene," "alkenylene," and "alkynylene" can be substituted or unsubstituted by one or more substituents as described herein.

[0129] As used herein, "aryl" refers to a radical ("C 6-14Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms (“C14”). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclic or heterocyclic groups, wherein said group or connecting point is on the aryl ring, and in such cases, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from: aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, chamomile, benzene, chrysene, hexabenzobenzene, fluoranthene, fluorene, hexabenzobenzene, hexanthene, hexalene, and asymmetric benzodiinden. e) Symmetrical benzodiindacene, indene, indene, naphthalene, octaphene, octalene, ovalene, pentadiene, pentaphene, cyclopentadiene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Aromatic groups, in particular, include phenyl, naphthyl, indene, and tetrahydronaphthyl.

[0130] As used herein, "heteroaryl" refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ring members sharing electrons in the ring system) having ring carbon atoms provided in the aromatic ring system and 1 to 4 heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclic rings, wherein the point of attachment is on the heteroaryl ring and in such instances the number of ring members designates the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl rings, wherein the point of attachment is on the aryl or heteroaryl ring and in such instances the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryls in which one ring contains no heteroatoms (e.g., indolyl, quinolyl, carbazolyl, and the like), the point of attachment can be on either ring, i.e., the ring bearing a heteroatom (e.g., 2-indolyl) or the ring containing no heteroatoms (e.g., 5-indolyl).

[0131] In some embodiments, a heteroaryl is a 5-10 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (e.g., "5-10 membered heteroaryl"). In some embodiments, a heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (e.g., "5-8 membered heteroaryl"). In some embodiments, a heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (e.g., "5-6 membered heteroaryl"). In some embodiments, a 5-6 membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0132] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0133] Examples of representative heteroaryl groups include the following:

[0134]

[0135] wherein each Z is selected from carbonyl, N, NR 65 , O, and S; and R 65 is independently hydrogen, C1-C8alkyl, C3-C 10 carbocyclyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl.

[0136] As used herein, “carbocyclyl” or “carbocyclic” refers to a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C 3--10 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclyl group has from 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”). In some embodiments, the carbocyclyl group has from 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”). In some embodiments, the carbocyclyl group has from 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”). Exemplary C 3-6Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). Example C 3-8 Carbocyclic groups include, but are not limited to, the aforementioned C 3-6 Carbocyclic groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptenyl (C7), bicyclo[2.2.2]octenyl (C8), etc. Example C 3-10 Carbocyclic groups include, but are not limited to, the aforementioned C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl(C 10 As illustrated in the foregoing examples, in some embodiments, the carbocyclic group is a monocyclic (“monocyclic carbocyclic”) or contains a fused, bridged, or spirocyclic system, such as a bicyclic system (“bicyclic carbocyclic”), and may be saturated or partially unsaturated. “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the carbocyclic ring, and in such cases, the number of carbons continues to represent the number of carbons in the carbocyclic system.

[0137] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group having 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbons, such as the "C" group derived from cycloalkanes. 4-8 "Cycloalkyl". Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane. Unless otherwise specified, the cycloalkyl group is optionally substituted at one or more ring positions with, for example, alkylyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amide, amidyl, amino, aryl, aralkyl, azide, carbamate, carbonate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclic, hydroxyl, imino, ketone, nitro, phosphate ester, phosphonic acid, phosphonite, sulfate ester, sulfate, sulfonylamino, sulfonyl, or thiocarbonyl. The cycloalkyl group may be fused with other cycloalkyl, aryl, or heterocyclic groups. In some embodiments, the cycloalkyl group is not substituted, i.e., it is not substituted.

[0138] As used herein, "heterocyclyl" or "heterocycle" refers to a radical of a 3- to 10-membered nonaromatic ring system having ring carbon atoms and from one to four ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or fused, bridged or spiro ring systems, such as bicyclic ring systems ("bicyclic heterocyclyl"), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein a heterocyclyl ring as defined above is fused to one or more carbocyclyl rings, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring; or ring systems wherein a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances the number of ring members continues to designate the number of ring members in the heterocyclyl ring system.

[0139] In some embodiments, the heterocyclyl is a 5-10 membered nonaromatic ring system having ring carbon atoms and from one to four ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, the heterocyclyl is a 5-8 membered nonaromatic ring system having ring carbon atoms and from one to four ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl is a 5-6 membered nonaromatic ring system having ring carbon atoms and from one to four ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has from one to three ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has from one to two ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0140] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0141] "Hetero" when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group has been replaced by a nitrogen, oxygen, or sulfur atom. Hetero can be applied to any of the hydrocarbyl groups described above, such as alkyl, e.g., heterocycloalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; and similar groups having from 1 to 5, and particularly 1 to 3, heteroatoms.

[0142] "Cyano" as used herein means -CN.

[0143] As used herein, "halo" or "halogen" means fluoro (F), chloro (CI), bromo (Br), and iodo (I). In certain embodiments, the halo group is fluoro or chloro.

[0144] As used herein, "haloalkyl" means an alkyl group substituted with one or more halogen atoms.

[0145] As used herein, "nitro" means -NO2.

[0146] As used herein, "oxo" means -C=0.

[0147] In general, the term "substituted" whether the term "optionally" precedes the term "substituted" or is absent, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an allowable substituent, e.g., a substituent that results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions and, when more than one position is substituted, the substituent groups can be identical or different at each position.

[0148] A nitrogen atom can be substituted or unsubstituted, and includes primary, secondary, tertiary, and quaternary nitrogen atoms, as valence permits. Exemplary nitrogen atom substituents include, but are not limited to: hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=0)R aa , -C(=0)N(R cc )2, -C02R aa , -S02R aa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -S02N(R cc )2, -S02R cc , -S02OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=0)SR cc , -C(=S)SR cc , -P(=0)2R aa , -P(=0)(R aa )2, -P(=0)2N(R cc )2, -P(=0)(NR cc )2, C 1-10alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, or two R cc groups bound to a nitrogen atom combine to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R aa , R bb , R cc and R dd are as defined above.

[0149] These and other exemplary substituents are described in more detail in the DETAILED DESCRIPTION, examples, and claims. The application is not intended to be limited in any way by the exemplary list of substituents described above.

[0150] Other Definitions

[0151] The term "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of this application include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acid, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, bisulfite, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N

[0152] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, middle-aged adult, or geriatric adult)) and / or a non-human animal, e.g., a mammal such as a primate (e.g., a cynomolgus monkey, a rhesus monkey), a bovine, a porcine, a equine, an ovine, a caprine, a rodent, a feline, and / or a canine. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0153] Diseases, disorders, and conditions are used interchangeably herein.

[0154] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” encompass an action that occurs when a subject is suffering from the specified disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or retards or slows the progression of the disease, disorder, or condition (also referred to as “therapeutic treatment”).

[0155] Generally, an “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the application can vary depending on, e.g., the biological endpoint desired, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.

[0156] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of the therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of symptoms, or enhances the therapeutic efficacy of another therapeutic agent.

[0157] In alternative embodiments, the present application encompasses administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, as a prophylactic prior to the onset of a specified disease, disorder, or condition in a subject. As used herein, “prophylactic treatment” encompasses an action that occurs prior to the onset of a specified disease, disorder, or condition in a subject. As used herein and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount that is sufficient to prevent a disease, disorder, or condition or one or more symptoms associated with the disease, disorder, or condition or to prevent recurrence thereof. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0158] As used herein, “a disease or condition associated with a gain-of-function mutation in KCNT1” refers to a disease or condition associated with, caused in part or in whole by, or having one or more symptoms caused in part or in whole by a mutation in KCNT1 that results in a gain-of-function phenotype, i.e., an increase in activity of a potassium channel encoded by KCNT1, resulting in an increase in whole-cell current.

[0159] As used herein, “a gain-of-function mutation” is a mutation in KCNT1 that results in an increase in activity of a potassium channel encoded by KCNT1. Activity can be assessed, for example, by ion flux assays or electrophysiology (e.g., using whole-cell patch clamp techniques). Typically, a gain-of-function mutation results in at least or about a 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, or more increase in activity compared to a potassium channel encoded by wild-type KCNT1.

[0160] Compounds and compositions

[0161] In one aspect, provided herein is a compound of Formula A:

[0162]

[0163] X is CR7or N, and Y is S; or

[0164] X is CR7, and Y is O;

[0165] Ring A is selected from the group consisting of phenyl, 6-membered heteroaryl, and 5-7 membered heterocyclyl;

[0166] R1is selected from the group consisting of phenyl, 5-6 membered heteroaryl, -CH2- phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl; wherein the phenyl, the 5-6 membered heteroaryl, the -CH2-phenyl, the 5-8 membered carbocyclyl, and the 5-10 membered heterocyclyl are optionally substituted with one or more R6;

[0167] R2is hydrogen or C 1-6 alkyl;

[0168] R3is 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, wherein the C 1-6 alkyl is optionally substituted with C 1-6 alkoxy or C 1-6 haloalkoxy, and R4is hydrogen; or

[0169] R3and R4together with the carbon attached to R3and R4may form a C 3-8 cycloalkylene or 3-7 membered heterocycloalkylene;

[0170] R5and R6are each independently selected from the group consisting of 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;

[0171] R7is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;

[0172] R8is hydrogen or C 1-6 alkyl;

[0173] each R9is independently selected from the group consisting of hydrogen, C 1-6 alkyl, and -(C 1-6 alkylene)-OH, or two R9together with the nitrogen atom attached to the two R9may form a heterocyclic ring optionally substituted with one or more substituents each independently selected from halogen and -OH; and

[0174] n is selected from the group consisting of 0, 1, 2, and 3;

[0175] provided that when R3is hydrogen and ring A is 6-membered heterocyclyl or 6-membered heteroaryl, R1is not thienyl;

[0176] provided that when R3is hydrogen and ring A is 6-membered heteroaryl or 5-membered heterocyclyl, R1is not phenyl; or a pharmaceutically acceptable salt thereof.

[0177] In another aspect, provided herein are compounds of Formula A-1:

[0178]

[0179] X is CR7or N, and Y is S; or

[0180] X is CR7, and Y is O;

[0181] ring A is 6-membered heteroaryl;

[0182] R1is selected from the group consisting of phenyl, 5-6 membered heteroaryl, -CH2- phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl; wherein the phenyl, the 5-6 membered heteroaryl, the -CH2-phenyl, the 5-8 membered carbocyclyl, and the 5-10 membered heterocyclyl are optionally substituted with one or more R6;

[0183] R2is hydrogen or C 1-6 alkyl;

[0184] R3is 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, wherein the C 1-6 alkyl is optionally substituted with C 1-6 alkoxy or C 1-6 haloalkoxy, and R4is hydrogen; or

[0185] R3and R4together with the carbon attached to R3and R4may form a C 3-8 cycloalkylene or 3-7 membered heterocycloalkylene;

[0186] R5and R6are each independently selected from the group consisting of 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;

[0187] R7is selected from the group consisting of hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;

[0188] R8is hydrogen or C 1-6 alkyl;

[0189] each R9is independently selected from the group consisting of hydrogen, C 1-6 alkyl and -(C 1-6 alkylene)-OH, or two R9can together with the nitrogen atom to which the two R9are attached form a heterocyclic ring optionally substituted with one or more substituents each independently selected from halogen and -OH; and

[0190] n is selected from the group consisting of 0, 1, 2, and 3;

[0191] with the proviso that when R3is hydrogen and ring A is 6-membered heteroaryl, R1is not thiophene or phenyl; or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments of Formula A or A-l, ring A is pyridyl.

[0193] In some embodiments of Formula A or A-l, the compound is a compound of Formula A-lA or Formula A-lB:

[0194]

[0195] or a pharmaceutically acceptable salt thereof.

[0196] In another aspect, provided herein is a compound of Formula A-2:

[0197]

[0198] X is CR7or N, and Y is S; or

[0199] X is CR7, and Y is O;

[0200] ring A is 5-7 membered heterocyclyl;

[0201] R1is selected from the group consisting of phenyl, 5-6 membered heteroaryl, -CH2- phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl; wherein the phenyl, the 5-6 membered heteroaryl, the -CH2-phenyl, the 5-8 membered carbocyclyl, and the 5-10 membered heterocyclyl are optionally substituted with one or more R6;

[0202] R2is hydrogen or C 1-6 alkyl;

[0203] R3is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-8 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with C 1-6 alkoxy or C 1-6 haloalkoxy, and R4 is hydrogen; or

[0204] R3 and R4 can together with the carbon to which R3 and R4 are attached form a C 3-8 cycloalkylene or 3-7 membered heterocycloalkylene;

[0205] R5 and R6 are each independently selected from the group consisting of 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;

[0206] R7 is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;

[0207] R8 is hydrogen or C 1-6 alkyl;

[0208] each R9 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, and -(C 1-6 alkylene)-OH, or two R9 can together with the nitrogen atom to which the two R9 are attached form a heterocyclic ring optionally substituted with one or more substituents each independently selected from halogen and -OH; and

[0209] n is selected from the group consisting of 0, 1, 2, and 3;

[0210] with the proviso that when R3 is hydrogen and ring A is 5-6 membered heterocyclyl, R1 is not thiophene or phenyl; or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments of Formula A or A-2, the compound is a compound of Formula A-2A:

[0212]

[0213] wherein q is 1 or 2;

[0214] or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments of Formula A, A-l, or A-2, X is N and Y is S. In other embodiments of Formula A, A-l, or A-2, X is CH and Y is O.

[0216] In some embodiments of Formula A, A-l, or A-2, R3is C 1-6 alkyl. For example, R3is methyl.

[0217] In some embodiments of Formula A, A-l, or A-2, R3is hydrogen.

[0218] In some embodiments of Formula A, A-l, or A-2, R2is hydrogen.

[0219] In some embodiments of Formula A, A-l, or A-2, R5is C 1-6 alkyl, C 1-6 alkylene-O-C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-8 cycloalkyl. For example, R5is cyclopropyl, -CF3, methyl, -OCH3, or -CH2OCH3.

[0220] In some embodiments of Formula A, A-l, or A-2, R1is a 5-6 membered heteroaryl optionally substituted with one or more R6. In some embodiments, the heteroaryl is pyrazolyl.

[0221] In some embodiments of Formula A, A-l, or A-2, R1is phenyl optionally substituted with one or more R6.

[0222] In some embodiments of Formula A, A-l, or A-2, R1is -CH2-phenyl optionally substituted with one or more R6. In some embodiments, the 10-membered heterocyclyl is a bicyclic heterocyclyl.

[0223] In some embodiments of Formula A, A-l, or A-2, R1is selected from the group consisting of:

[0224]

[0225] wherein m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0226] In some embodiments of Formula A, A-l, or A-2, R6is halogen, C 1-6 alkyl, or C 1-6 haloalkyl.

[0227] In another aspect, provided herein are compounds of Formula I:

[0228]

[0229] or a pharmaceutically acceptable salt thereof, wherein:

[0230] X is CR7or N, and Y is S; or

[0231] X is CR7, and Y is O;

[0232] Ring A is selected from the group consisting of phenyl, 6-membered heteroaryl, and 5-7 membered heterocyclyl;

[0233] R1is selected from the group consisting of phenyl, 5-6 membered heteroaryl, -CH2- phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl; wherein the phenyl, the 5-6 membered heteroaryl, the -CH2-phenyl, the 5-8 membered carbocyclyl, and the 5-10 membered heterocyclyl are optionally substituted with one or more R6;

[0234] R2is hydrogen or C 1-6 alkyl;

[0235] R3is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-8 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with C 1-6 alkoxy or C 1-6 haloalkoxy, and R4is hydrogen; or

[0236] R3and R4together with the carbon attached to R3and R4may form a C 3-8 cycloalkylene or 3-7 membered heterocycloalkylene;

[0237] R5and R6are each independently selected from the group consisting of 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;

[0238] R7is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;

[0239] R8is hydrogen or C 1-6 alkyl;

[0240] each R9is independently selected from the group consisting of hydrogen, C 1-6 alkyl and -(C 1-6 alkylene)-OH, or two R9can be taken together with the nitrogen atom attached to the two R9to form a heterocycle optionally substituted with one or more substituents each independently selected from halogen and -OH; and

[0241] n is selected from the group consisting of 0, 1, 2, and 3.

[0242] In another aspect, provided herein is a formula I-A:

[0243]

[0244] or a pharmaceutically acceptable salt thereof, wherein:

[0245] X is CR7or N, and Y is S; or

[0246] X is CR7, and Y is O;

[0247] Ring A is 6-membered heteroaryl or 5-7 membered heterocyclyl;

[0248] R1is selected from the group consisting of phenyl, 5-6 membered heteroaryl, -CH2- phenyl, 5-8 membered carbocyclyl, and 5-10 membered heterocyclyl; wherein the phenyl, the 5-6 membered heteroaryl, the -CH2-phenyl, the 5-10 membered carbocyclyl, and the 5-10 membered heterocyclyl are optionally substituted with one or more R6;

[0249] R2is hydrogen or C 1-6 alkyl;

[0250] R3is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-8 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with C 1-6 alkoxy or C 1-6 haloalkoxy, and R4is hydrogen; or

[0251] R3and R4can be taken together with the carbon attached to R3and R4to form a C 3-8 cycloalkylene or 3-7 membered heterocycloalkylene;

[0252] R5and R6are each independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkylene-O-C 1-6 alkyl, C 1-6haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S(O)2R8, -S(O)2-N(R9)2, and C 3-8 cycloalkyl;

[0253] R7is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;

[0254] R8is hydrogen or C 1-6 alkyl;

[0255] each R9is independently selected from the group consisting of hydrogen, C 1-6 alkyl, and -(C 1-6 alkylene)-OH, or two R9can together with the nitrogen atom to which the two R9are attached form a heterocyclic ring optionally substituted with one or more substituents each independently selected from the group consisting of halogen and -OH; and

[0256] n is selected from the group consisting of 0, 1, 2, and 3.

[0257] In another aspect, provided herein is a compound of Formula I-B:

[0258]

[0259] or a pharmaceutically acceptable salt thereof, wherein:

[0260] X is CR7or N, and Y is S; or

[0261] X is CR7, and Y is O;

[0262] Ring A is phenyl or 6-membered heteroaryl;

[0263] R1is phenyl or 5-6 membered heteroaryl, wherein the phenyl or the 5-6 membered heteroaryl is optionally substituted with one or more R6;

[0264] R2is hydrogen or C 1-6 alkyl;

[0265] R3is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-8 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with C 1-6 alkoxy, or C 1-6 haloalkoxy, and R4is hydrogen; or

[0266] R3and R4can together with the carbon to which R3and R4are attached form a C 3-8 cycloalkylene or 3-7 membered heterocycloalkylene;

[0267] R5and R6are each independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S(O)2R8, -S(O)2-N(R9)2, and C 3-8 cycloalkyl;

[0268] R7is selected from the group consisting of hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;

[0269] R8is hydrogen or C 1-6 alkyl;

[0270] each R9is independently selected from the group consisting of hydrogen, C 1-6 alkyl and -(C 1-6 alkylene)-OH, or two R9can together with the nitrogen atom to which the two R9are attached form a heterocyclic ring, which is optionally substituted with one or more substituents each independently selected from halogen and -OH; and

[0271] n is selected from the group consisting of 0, 1, 2, and 3.

[0272] In some embodiments of Formula I, I-A, or I-B, ring A is 6-membered heteroaryl. In some embodiments of Formula I, I-A, or I-B, ring A is pyridyl.

[0273] In some embodiments of Formula I, I-A, or I-B, X is N and Y is S.

[0274] In some embodiments of Formula I, I-A, or I-B, X is CH and Y is O.

[0275] In some embodiments of Formula I, I-A, or I-B, R3is C 1-6 alkyl. For example, R3is methyl.

[0276] In some embodiments of Formula I, I-A, or I-B, R2is hydrogen.

[0277] In some embodiments of Formula I or I-A, R5is C 1-6 alkyl, C 1-6 alkylene-O-C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 3-8cycloalkyl. For example, R5is cyclopropyl, -CF3, methyl, -OCH3, or -CH2OCH3,

[0278] In some embodiments of Formula I, I-A, or I-B, R5is C 3-8 cycloalkyl or C 1-6 haloalkyl. In some embodiments of Formula I, I-A, or I-B, R5is cyclopropyl or -CF3.

[0279] In some embodiments of Formula I, I-A, or I-B, n is 0 or 1. In some embodiments of Formula I, I-A, or I-B, n is 1. In some embodiments of Formula I, I-A, or I-B, n is 0.

[0280] In some embodiments of Formula I, I-A, or I-B, R1is 5-6 membered heteroaryl optionally substituted with one or more R6. In some embodiments, the heteroaryl is pyrazolyl.

[0281] In some embodiments of Formula I, I-A, or I-B, R1is phenyl optionally substituted with one or more R6.

[0282] In some embodiments of Formula I or I-A, R1is -CH2-phenyl optionally substituted with one or more R6.

[0283] In some embodiments of Formula I or I-A, R1is 10 membered heterocyclyl optionally substituted with one or more R6. In some embodiments, the 10 membered heterocyclyl is bicyclic heterocyclyl.

[0284] In some embodiments of Formula I, I-A, or I-B, R6is halo, C 1-6 alkyl or C 1-6 haloalkyl.

[0285] In some embodiments of Formula I, I-A, or I-B, R6is C 1-6 alkyl or C 1-6 haloalkyl.

[0286] In some embodiments of Formula I, I-A, or I-B, the compound is a compound of Formula I-IA or Formula I-IB:

[0287]

[0288] or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments of Formula I, I-A, or I-B, the compound is a compound of Formula I-IA2 or Formula I-IB2:

[0290]

[0291] Or its pharmaceutically acceptable salt.

[0292] In some embodiments of formula I, IA, or IB, the compound is a compound of formula I-IA3, I-IA4, I-IB3, or I-IB4:

[0293]

[0294] Or its pharmaceutically acceptable salt.

[0295] In some embodiments of Formula I or IA, the compound is a compound of Formula I-IC:

[0296]

[0297] Where q is 1 or 2;

[0298] Or its pharmaceutically acceptable salt.

[0299] In some embodiments of Formula I or IA, the compound is a compound of Formula I-IC2:

[0300]

[0301] Where q is 1 or 2;

[0302] Or its pharmaceutically acceptable salt.

[0303] In some embodiments of Formula I or IA, the compound is a compound of Formula I-IC3 or Formula I-IC4:

[0304]

[0305] Or its pharmaceutically acceptable salt.

[0306] In some implementations of Formula I, IA, or IB, R1 is selected from the following group:

[0307]

[0308] Where m is 0, 1, or 2. In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2.

[0309] In some embodiments of formula I, IA, or IB, R1 is a pyrazolyl or phenyl group optionally substituted with one or more R6 groups.

[0310] In one aspect, the present invention is characterized by compounds of formula (II):

[0311]

[0312] or a pharmaceutically acceptable salt thereof, wherein:

[0313] X is CR7or N, and Y is S; or

[0314] X is CR7, and Y is O;

[0315] Ring A is phenyl or 6-membered heteroaryl;

[0316] R1is phenyl or 5-6 membered heteroaryl, wherein the phenyl or the 5-6 membered heteroaryl is optionally substituted with one or more R6;

[0317] R2is hydrogen or C 1-6 alkyl;

[0318] R3is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-8 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with C 1-6 alkoxy or C 1-6 haloalkoxy, and R4is hydrogen; or

[0319] R3and R4together with the carbon attached to R3and R4may form a C 3-8 cycloalkylene or 3-7 membered heterocycloalkylene;

[0320] R5and R6are each independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S(O)2R8, -S(O)2-N(R9)2, and C 3-8 cycloalkyl;

[0321] R7is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;

[0322] R8is hydrogen or C 1-6 alkyl;

[0323] each R9is independently selected from the group consisting of hydrogen, C 1-6 alkyl, and -(C 1-6 alkylene)-OH, or two R9together with the nitrogen atom attached to the two R9may form a heterocyclic ring, which is optionally substituted with one or more substituents each independently selected from halogen and -OH; and

[0324] n is selected from the group consisting of 0, 1, 2, and 3.

[0325] In some embodiments, ring A is a 6-membered heteroaryl (e.g., pyridyl).

[0326] In some embodiments, X is N and Y is S. In some embodiments, X is CH and Y is O.

[0327] In some embodiments of Formula II, the compound is a compound of Formula II-A or Formula II-B:

[0328]

[0329] or a pharmaceutically acceptable salt thereof.

[0330] In some embodiments of Formula II, R3is C 1-6 alkyl (e.g., methyl).

[0331] In some embodiments of Formula II, R2is hydrogen.

[0332] In some embodiments of Formula II, n is 0 or 1. In some embodiments of Formula II, n is 1.

[0333] In some embodiments of Formula II, R5is C 3-8 cycloalkyl (e.g., cyclopropyl) or C 1-6 haloalkyl (e.g., CF3).

[0334] In some embodiments of Formula II, R1is a 5-6 membered heteroaryl (e.g., pyrazolyl) optionally substituted with one or more R6. In some embodiments of Formula II, R1is phenyl optionally substituted with one or more R6. In some embodiments of Formula II, R6is C 1-6 alkyl or C 1-6 haloalkyl.

[0335] In some embodiments, the compound is selected from the group consisting of:

[0336]

[0337]

[0338]

[0339]

[0340] or a pharmaceutically acceptable salt thereof.

[0341] In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (A), (A-l), (A-lA), (A-lB), (A-2), (A-2A), (I), (I-A), (I-IA), (I-IA2), (I-IA3), (I-IA4), (I-B), (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.

[0342] General synthetic schemes

[0343] Exemplary methods for preparing the compounds described herein are shown in the following synthetic schemes. These schemes are given for the purpose of illustration and should not be construed as limiting the scope or spirit of the present application in any way.

[0344] Scheme 1

[0345]

[0346] The synthetic route shown in Scheme 1 depicts an exemplary procedure for preparing intermediates D4 and E7. In the first step, compound D1 is reacted with (COCl)2and ammonia to form amide D2. Subsequently, amide D2 is reacted with chlorocarbonylsulfinyl chloride to form D3, which is reacted with a cyanide containing R3 to form D4. To form intermediate E7, carboxylic acid E1 is reacted with borane to form E2, which is subsequently reacted with Dess-Martin periodinane to form E3. Subsequently, E3 is reacted with hydroxylamine to form E4, which is reacted with N-chlorosuccinimide to form E5. Subsequently, E5 is reacted with an alcohol containing R3 to form E6, which is reacted with Dess-Martin periodinane to form intermediate E7.

[0347] Scheme 2

[0348]

[0349] The synthetic route shown in Scheme 2 represents an exemplary procedure for preparing a compound of Formula I from either intermediate D4 or E7 as described in Scheme 1. Intermediate D4 or E7 is reacted with a sulfonamide to form F, which is subsequently reduced to form G. Subsequently, G is reacted with an acid to form H, which is reacted with a carboxylic acid containing R1 to form a compound of Formula I.

[0350] Scheme 3

[0351]

[0352] The synthetic route shown in Scheme 3 depicts an exemplary procedure for preparing compounds J8 and J12 of formula I. In a first step, compound J1 is reacted with 1-ethoxyvinyltri-n-butyltin to form J2. Subsequently, J2 is reacted with an A-containing dioxaborane to form J3, which reacts with an acid to form J4. Subsequently, J4 is reacted with (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. Subsequently, 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.

[0353] Option 4

[0354]

[0355] The synthetic route shown in Scheme 4 depicts an exemplary procedure for preparing compounds K7 and K12 of formula I. In a first step, compound K1 or K8 is reacted with phthalimide to form K2 or K9, respectively. Subsequently, K2 or K9 is reacted with an A-containing carboxyimide chloride to form K4 or K10, which is then reacted with hydrazine to form K6 or K11. Subsequently, K6 or K11 is reacted with an R1-containing carboxylic acid to form K7 or K12.

[0356] Treatment

[0357] The compounds and compositions described above and herein can be used to treat a neurological disease or disorder or a disease or condition associated with excessive neuronal excitability and / or a gain-of-function mutation in a gene (e.g., KCNT1). Exemplary diseases, disorders, or conditions include epilepsy and other encephalopathies (e.g., early infantile myoclonic encephalopathy (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, developmental and epileptic encephalopathy (DEE), early infantile epileptic encephalopathy (EIEE), generalized epilepsy, focal epilepsy, multifocal epilepsy, temporal lobe epilepsy, Ohtahara syndrome, early myoclonic encephalopathy, and Lennox Gastaut syndrome, drug-resistant epilepsy, seizures (e.g., frontotemporal lobe seizures, generalized tonic-clonic seizures, asymmetric tonic seizures, focal seizures), leukodystrophy, hypomyelinating leukodystrophy, leukoencephalopathy, and sudden death in epilepsy, cardiac dysfunction (e.g., arrhythmia, Brugada syndrome, sudden death in epilepsy, and myocardial infarction), pulmonary vascular disease / hemorrhage, pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.), muscle disorders (e.g., myotonia, neuromyotonia, crampy muscle spasms, spasticity), pruritis and itch, movement disorders (e.g., ataxia and cerebellar ataxia), psychiatric disorders (e.g., major depressive disorder, anxiety, bipolar disorder, schizophrenia, attention deficit hyperactivity disorder), neurodevelopmental disorders, learning disorders, intellectual disability, fragile X syndrome, neuronal plasticity, and autism spectrum disorders.

[0358] In some embodiments, the neurological disease or disorder or a disease 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 disease or disorder or a disease 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 disease or disorder or a disease or condition associated with excessive neuronal excitability and / or a gain-of-function mutation in a gene (e.g., KCNT1) is a seizure. In some embodiments, the neurological disease or disorder or a disease or condition associated with excessive neuronal excitability and / or a gain-of-function mutation in a gene (e.g., KCNT1) is selected from arrhythmia, Brugada syndrome, and myocardial infarction.

[0359] In some embodiments, the neurological disease or disorder or disease or condition associated with excessive neuronal excitability and / or gain-of-function mutations in genes (e.g., KCNT1) is selected from the group consisting of learning disabilities, fragile X syndrome, intellectual functioning, neuronal plasticity, mental disorders, and autism spectrum disorders.

[0360] Accordingly, the compounds and compositions thereof can be administered to a subject having a neurological disease or disorder or disease or condition associated with excessive neuronal excitability and / or gain-of-function mutations in genes such as KCNT1 (e.g., EIMFS, ADNFLE, West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Dravet syndrome, developmental and epileptic encephalopathy, and Lennox Gastaut syndrome, seizures, arrhythmia, Brugada syndrome, and myocardial infarction).

[0361] EIMFS is a rare, debilitating genetic condition characterized by almost continuous, heterogeneous focal-onset seizures that begin early (before 6 months of age) with apparent migration from one brain region and hemisphere to another. Patients with EIMFS are generally intellectually impaired, nonverbal, and nonambulatory. While several genes have been implicated to date, the gene most commonly associated with EIMFS is KCNT1. Several de novo mutations in KCNT1 have been identified in patients with EIMFS, including V271F, G288S, R428Q, R474Q, R474H, R474C, I760M, A934T, P924L, G243S, H257D, A259D, R262Q, Q270E, L274I, F346L, C377S, R398Q, P409S, A477T, F502V, M516V, Q550del, K629E, K629N, I760F, E893K, M896K, R933G, R950Q, K1154Q (Barcia et al. (2012) Nat Genet. 44:1255-1260; Ishii et al. (2013) Gene 531:467-471; McTague et al. (2013) Brain. 136:1578-1591; Epi4K Consortium & Epilepsy Phenome / Genome Project. (2013) Nature 501:217-221; Lim et al. (2016) Neurogenetics; Ohba et al. (2015) Epilepsia 56:el21-el28; Zhou et al. (2018) Genes Brain Behav. e12456; Moller et al. (2015) Epilepsia e114-20; Numis et al. (2018) Epilepsia 1889-1898; Madaan et al., Brain Dev. 40(3):229-232; McTague et al. (2018) Neurology. 90(1):e55-e66; Kawasaki et al. (2017) J Pediatr. 191:270-274; Kim et al. (2014) Cell Rep. 9(5):1661-1672; Ohba et al. (2015) Epilepsia 56(9):e121-8; Rizzo et al. (2016) Mol Cell Neurosci.72:54-63; Zhang et al. (2017) Clin Genet. 91(5):717-724; Mikati et al. (2015) Ann Neurol. 78(6):995-9; Baumer et al. (2017) Neurology 89(21):2212; Dilena et al. (2018) Neurotherapeutics. 15(4): 1112-1126). These mutations are gain-of-function missense mutations that are dominant (i.e., present on only one allele) and result in functional changes to the encoded potassium channel that, when tested in oocyte or mammalian expression systems, cause a significant increase in whole-cell current (see, e.g., Milligan et al. (2015) Ann Neurol. 75(4):581-590; Barcia et al. (2012) Nat Genet. 44(11):1255-1259; and Mikati et al. (2015) Ann Neurol. 78(6):995-999).

[0362] ADNFLE has an onset time later than EIMFS, typically in middle age, and is generally a less severe condition. It is characterized by nocturnal frontal lobe seizures and can lead to mental, behavioral, and cognitive impairment in patients with the condition. While ADNFLE is associated with genes encoding several neuronal nicotinic acetylcholine receptor subunits, mutations in the KCNT1 gene have been implicated in more severe cases of the disease (Heron et al. (2012) Nat Genet. 44:1188-1190). Functional studies of the mutant KCNT1 gene associated with ADNFLE indicate 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).

[0363] West syndrome is a severe form of epilepsy consisting of infantile spasms triad, an ictal electroencephalogram (EEG) pattern called hypsarrhythmia, and mental retardation, but can be diagnosed with one of these elements missing. Mutations in KCNT1, including G652V and R474H, have been associated with West syndrome (Fukuoka et al. (2017) Brain Dev 39:80-83 and Ohba et al. (2015) Epilepsy 56:el21-el28). Therapies targeting the KCNT1 channel suggest that these mutations are gain-of-function mutations (Fukuoka et al. (2017) Brain Dev 39:80-83).

[0364] In one aspect, the application features a method of treating a disease or condition associated with excessive neuronal excitability and / or gain-of-function mutations in genes such as KCNT1 (e.g., epilepsy and other brain disorders (e.g., Epilepsy of infancy with migrating focal seizures (MMFSI, EIMFS), Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, Infantile spasms, Epileptic encephalopathy, Focal epilepsy, Tayasu's syndrome, Developmental and epileptic encephalopathy (DEE) and Lennox Gastaut syndrome, Seizures, Leukodystrophy, Leukencephalopathy, Intellectual disability, Multifocal epilepsy, Generalized tonic-clonic seizures, Drug-resistant epilepsy, Temporal lobe epilepsy, Cerebellar ataxia, Asymmetrical tonic seizure) and cardiac dysfunction (e.g., cardiac arrhythmia, Brugada syndrome, sudden death from epilepsy, myocardial infarction), pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.), muscle disorders (e.g., myotonia, neuromyotonia, crampy muscle spasms, spasticity), pruritis and prurigo, ataxia and cerebellar ataxia, psychiatric disorders (e.g., major depressive disorder, anxiety, bipolar disorder, schizophrenia), learning disabilities, Fragile X syndrome, neuronal plasticity, and autism spectrum disorders), the method comprising administering to a subject in need thereof a compound disclosed herein (e.g., a compound of Formula (A), (A-1), (A-1A), (A-1B), (A-2), (A-2A), (I), (I-A), (I-IA), (I-IA2), (I-IA3), (I-IA4), (I-B), (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) or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (A), (A-1), (A-1A), (A-1B), (A-2), (A-2A), (I), (I-A), (I-IA), (I-IA2), (I-IA3), (I-IA4), (I-B), (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).

[0365] In some examples, a subject presenting with a disease or condition that can be associated with a gain-of-function mutation in KCNT1 is genotyped prior to administration of the compounds and compositions thereof to confirm the presence of a known gain-of-function mutation in KCNT1. For example, a subject can be subjected to whole exome sequencing. Gain-of-function mutations associated with EIMFS can include, but are not limited to, V271F, G288S, R428Q, R474Q, R474H, R474C, I760M, A934T, P924L, G243S, H257D, A259D, R262Q, Q270E, L274I, F346L, C377S, R398Q, P409S, A477T, F502V, M516V, Q550del, K629E, K629N, I760F, E893K, M896K, R933G, R950Q, and K1154Q. Gain-of-function mutations associated with ADNFLE can include, but are not limited to, M896I, R398Q, Y796H, R928C, and G288S. Gain-of-function mutations associated with West syndrome can include, but are not limited to, G652V and R474H. Gain-of-function mutations associated with temporal lobe epilepsy can include, but are not limited to, R133H and R565H. Gain-of-function mutations associated with Lennox-Gastaut can include, but are not limited to, R209C. Gain-of-function mutations associated with seizures can include, but are not limited to, A259D, G288S, R474C, R474H. Gain-of-function mutations associated with Vanishing White Matter can include, but are not limited to, G288S and Q906H. Gain-of-function mutations associated with Multifocal Epilepsy can include, but are not limited to, V340M. Gain-of-function mutations associated with EOE can include, but are not limited to, F346L and A934T. Gain-of-function mutations associated with Early Onset Epileptic Encephalopathy (EOEE) can include, but are not limited to, R428Q. Gain-of-function mutations associated with Developmental and Epileptic Encephalopathy can include, but are not limited to, F346L, R474H, and A934T. Gain-of-function mutations associated with Epileptic Encephalopathy can include, but are not limited to, L437F, Y796H, P924L, R961H. Gain-of-function mutations associated with Early Infantile Epileptic Encephalopathy (EIEE) can include, but are not limited to, M896K. Gain-of-function mutations associated with Drug-Resistant Epilepsy and Generalized Tonic-Clonic Seizures can include, but are not limited to, F346L. Gain-of-function mutations associated with Infantile Migrational Partial Seizures can include, but are not limited to, R428Q. Gain-of-function mutations associated with Leukodystrophy can include, but are not limited to, F932I. Gain-of-function mutations associated with NFLE can include, but are not limited to, A934T and R950Q. Gain-of-function mutations associated with Ohtahara Syndrome can include, but are not limited to, A966T.Gain-of-function mutations associated with infantile spasms can include, but are not limited to, P924L. Gain-of-function mutations associated with Brugada syndrome can include, but are not limited to, R1106Q. Gain-of-function mutations associated with Brugada syndrome can include, but are not limited to, R474H.

[0366] In other examples, the subject is first subjected to a genotypic analysis to identify the presence of a gain-of-function mutation in KCNT1, and then the mutation is confirmed to be a gain-of-function mutation using a standard in vitro assay, such as the standard in vitro assay described in Milligan et al. (2015) Ann Neurol 75(4): 581-590. Generally, the presence of a gain-of-function mutation is confirmed when expression of the mutant KCNT1 allele results in an increase in whole-cell current compared to the whole-cell current produced by wild-type KCNT1 expression, as assessed using whole-cell electrophysiology, such as described in Milligan et al. (2015) Ann Neurol 75(4): 581-590; Barcia et al. (2012) Nat Genet 44(11): 1255-1259; Mikati et al. (2015) Ann Neurol 78(6): 995-999; or Rizzo et al. Mol Cell Neurosci (2016) 72: 54-63. This increase in whole-cell current can be, for example, an increase of at least or about 50%, 100%, 150%, 200%, 250%, 300%, 350%, 400% or more. The subject can then be confirmed to have a disease or condition associated with a gain-of-function mutation in KCNT1.

[0367] In particular examples, the subject is confirmed to have a KCNT1 allele containing a gain-of-function mutation (e.g., V271F, G288S, R398Q, R428Q, R474Q, R474H, R474C, G652V, I760M, Y796H, M896I, P924L, R928C, or A934T).

[0368] A compound disclosed herein (e.g., a compound of Formula (A), (A-l), (A-lA), (A-lB), (A-2), (A-2A), (I), (I-A), (I-IA), (I-IA2), (I-IA3), (I-IA4), (I-B), (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) or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (A), (A-l), (A-lA), (A-lB), (A-2), (A-2A), (I), (I-A), (I-IA), (I-IA2), (I-IA3), (I-IA4), (I-B), (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) can also be therapeutically useful for a condition associated with excessive neuronal excitability, where the excessive neuronal excitability is not necessarily a result of a gain-of-function mutation in KCNT1. Even in cases where the disease is not caused by an increase in KCNT1 expression and / or activity, inhibition of KCNT1 expression and / or activity can still result in a decrease in neuronal excitability, providing a therapeutic effect.Accordingly, a compound (e.g., a compound of Formula (A), (A-l), (A-lA), (A-lB), (A-2), (A-2A), (I), (I-A), (I-IA), (I-IA2), (I-IA3), (I-IA4), (I-B), (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) or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (A), (A-l), (A-lA), (A-lB), (A-2), (A-2A), (I), (I-A), (I-IA), (I-IA2), (I-IA3), (I-IA4), (I-B), (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) can also be used to treat a subject having a condition associated with excessive neuronal excitability, such as epilepsy and other brain disorders (e.g., early infantile epileptic encephalopathy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Dravet syndrome, developmental and epileptic encephalopathy, and Lennox Gastaut syndrome, seizures) or cardiac dysfunction (e.g., arrhythmia, Brugada syndrome, myocardial infarction), regardless of whether the disease or disorder is associated with a gain-of-function mutation in KCNTl.

[0369] Pharmaceutical compositions and routes of administration

[0370] The compounds according to the present application are generally administered in the form of pharmaceutical compositions. Thus, the present application provides pharmaceutical compositions containing as active ingredients one or more of the compounds described or a pharmaceutically acceptable salt or ester thereof, in combination with one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants. The pharmaceutical compositions can be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known per se (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker and C. Rhodes, Eds.).

[0371] The pharmaceutical compositions can be administered by any of the accepted modes of administration for agents having similar utilities, such as those described in the patents and patent applications incorporated by reference, including rectally, buccally, intranasally, and transdermally, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or, for example, via impregnated or coated devices such as stents, or arterial insertion cylindrical polymers.

[0372] One mode of administration is parenteral, particularly by injection. The novel compositions of the present application can be incorporated into forms for injection administration including aqueous or oil suspensions or emulsions, with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or aqueous solutions, and similar pharmaceutical vehicles. Saline solutions are also conventionally used for injection, but are not preferred for use in the context of the present application. Ethanol, propylene glycol, polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be employed. Proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0373] A sterile injectable solution can be prepared by incorporating the compound according to the application in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient from the previously sterile-filtered solution.

[0374] Oral administration is another route of administration of the compounds according to the application. Administration can be via a capsule or enteric coated tablet or the like. In the process of manufacturing a pharmaceutical composition comprising at least one compound described herein, the active ingredient is generally diluted by an excipient and / or enclosed in a sheath which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0375] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents.

[0376] The compositions of the present application can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art of pharmaceutical formulation. Controlled release pharmaceutical delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymeric matrices, wafers, or a mixture of the drug and a polymer. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present application employs transdermal delivery devices ("patches"). Such transdermal patches can contain the compound of the present application which are administered at a continuous rate over a prolonged period of time. Transdermal patches have the added advantage of being able to steer clear of the peptic and hepatic systems.

[0377] The compositions are preferably formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable for unitary dosing to human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with an appropriate pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. Preferably, each dosage unit contains from 1 mg to 2 g of a compound described herein for oral administration, and from 0.1 to 700 mg of a compound described herein for parenteral administration. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated; the chosen route of administration; the actual compound administered and its relative activity; the age, weight, and response of the individual patient; the severity of the patient's symptoms; and the like.

[0378] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present application. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed essentially evenly throughout the composition to allow the composition to be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0379] The tablets or pills of the application can be coated or otherwise compounded to provide a dosage form with prolonged action or a delayed onset of action or to protect the drug from the acidic conditions of the stomach. For example, the tablet or pill can comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[0380] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions for topical or systemic effect can be preferred. Preferred compositions are solutions in pharmaceutically acceptable solvents, suspensions, or powders. The use of inert gases such as

[0381] In some embodiments, the pharmaceutical compositions include a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0382] Examples

[0383] In order that the application herein described can be more fully understood, the following examples are set forth. Synthetic and biological examples described in the application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed to limit their scope in any way.

[0384] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that, where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions can vary with the particular reactants or solvent used, but such conditions can be determined by those skilled in the art by routine optimization.

[0385] Additionally, it will be apparent to those skilled in the art that conventional protecting groups can be necessary to prevent certain functional groups from undergoing undesired reactions. Selection of appropriate protecting groups for a particular functional group, as well as appropriate conditions for protection and deprotection, are well-known in the art. For example, numerous protecting groups and their introduction and removal are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, 2nded., Wiley, New York, 1991, and references cited therein.

[0386] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, trituration, high pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). Note that flash chromatography can be performed manually or through 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.

[0387] List of Abbreviations

[0388] THF tetrahydrofuran

[0389] TFA trifluoroacetic acid

[0390] DMF N,N-dimethylformamide

[0391] MeOH methanol

[0392] EtOH ethanol

[0393] DCM dichloromethane

[0394] MeCN or ACN acetonitrile

[0395] EtOAc ethyl acetate

[0396] DIPEA N,N,-diisopropylethylamine

[0397] HATU o-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0398] Ti(OEt)4 titanium(IV) ethoxide

[0399] Ti(OiPr)4 titanium(IV) isopropoxide

[0400] T3P propane phosphonic anhydride

[0401] L-selectride lithium tri-sec-butylborohydride

[0402] K-Selectride potassium tri-sec-butylborohydride

[0403] DIEA N,N-diisopropylethylamine

[0404] Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II)

[0405] Pd(PPh3)2Cl2 dichlorobis(triphenylphosphine)palladium(II)

[0406] DMSO dimethyl sulfoxide

[0407] DMS dimethyl sulfide

[0408] EGTA ethylene glycol-bis(β-aminoethylether)-N,N,N',N'-tetraacetic acid

[0409] NMDG N-methyl-D-glucamine

[0410] HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid

[0411] IC 50 Maximum inhibitory concentration

[0412] TLC thin layer chromatography

[0413] LCMS liquid chromatography-mass spectrometry

[0414] HPLC high performance liquid chromatography

[0415] SFC supercritical fluid chromatography

[0416] MS mass spectrometry

[0417] NMR nuclear magnetic resonance

[0418] Example 1. Synthesis of 1-methyl-3-(trifluoromethyl)-N-(1-(3-(2- (trifluoromethyl)pyridin-4-yl)-1,2,4-thiadiazol-5-yl)ethyl)-1H-pyrazole-5- carboxamide (1)

[0419]

[0420] Synthesis of 2-(trifluoromethyl)pyridine-4-carboxamide (A-2)

[0421] To a stirred solution of A-1 (10 g, 52.33 mmol) in DCM (10 mL) at 0 °C was added DMF (1 mL) and oxalyl chloride (4.71 mL, 54.94 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to get a residue which was dissolved in MeCN (100 mL) and charged with aqueous ammonia solution (150 mL, 52.33 mmol). The mixture was quenched using water (100 mL) and diluted with EtOAc (200 mL x 2). The organic layer was separated, dried over Na2S04, filtered and concentrated under reduced pressure to get a residue which was purified by column chromatography using 100-200 silica gel and 30-80% EtOAc / hexane as eluent to get A-2 (7 g, 33.13 mmol, 63% yield).

[0422] Synthesis of 5-[2-(trifluoromethyl)-4-pyridyl]-1,3,4-oxathiazol-2-one (A-3)

[0423] A solution of A-2 (1.5 g, 7.89 mmol) and chlorocarbonyl sulfinyl chloride (1.2 g, 9.47 mmol) in toluene (20 mL) was stirred at 120 °C for 16 h. The reaction was quenched with water (100 mL), diluted with EtOAc (100 mL x 2) and the organic layer was separated. The organic layer was dried over Na2S04, filtered and concentrated to get a residue which was purified by column chromatography using 100-200 silica gel and 5-50% EtOAc / hexane as eluent to get A-3 (1.5 g, 5.43 mmol, 69% yield).

[0424] Synthesis of 1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethanone (A-4)

[0425] 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 h. The reaction mixture was quenched with water (100 mL), diluted with EtOAc (100 mL x 2) and the organic layer was separated, dried over Na2S04, filtered and concentrated under reduced pressure to get a residue which was purified by column chromatography using 100-200 silica gel and 10-50% EtOAc / hexane as eluent to get A-4 (0.4 g, 1.39 mmol, 34% yield).

[0426] Synthesis of (E)-2-methyl-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethylidene]propane-2-sulfinamide (A-5)

[0427] 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) was added titanium(IV) ethoxide (0.12 mL, 0.55 mmol) and the mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched using water and diluted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to get a residue which was purified by column chromatography using 100-200 silica gel and 10-30% EtOAc / hexane as eluent to get A-5 (100 mg, 0.13 mmol, 36% yield) as a liquid.

[0428] Synthesis of 2-methyl-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4- thiadiazol-5-yl]ethyl]propane-2-sulfinamide (A-6)

[0429] To a stirred solution of A-5 (100 mg, 0.27 mmol) in methanol (10 mL) at 0 °C was added sodium borohydride (15.07 mg, 0.4 mmol) and the mixture was stirred at room temperature for 1 h. 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 get A-6 (80 mg, 0.10 mmol, 40% yield).

[0430] Synthesis of 1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethylamine hydrochloride (A-7)

[0431] To a stirred solution of A-6 (80 mg, 0.21 mmol) in 1,4 dioxane (5 mL) at 0 °C was added 4M HC1 in 1,4 dioxane (5 mL, 0.21 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to get a residue which was washed using diethyl ether to get A-7 (65 mg, 0.15 mmol, 69% yield).

[0432] Synthesis of 1-methyl-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)- 1,2,4-thiadiazol-5-yl)ethyl)-1H-pyrazole-5-carboxamide (1)

[0433] 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) was added HATU (102.79 mg, 0.27 mmol) and DIPEA (0.06 mL, 0.36 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h, then quenched with water (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 get a residue. The residue was purified by column chromatography using 100-200 silica gel and 30-80% EtOAc / hexane as eluent to get 1 (10 mg, 0.022 mmol, 12% yield). HPLC: Rt 9.346 min, 97.6%; Column: X-Select CSH C18 (4.6 X 150) mm, 3.5 pm; Mobile Phase: A: water + 0.1% formic acid: 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 pm. 1 H NMR (400 MHz, DMSO-d6) 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).

[0434] Examples 2 and 3. Synthesis of (S)-1 -methyl-3-(trifluoromethyl)-N-(1 -(3-(2- (trifluoromethyl)pyridin-4-yl)isoxazol-5-yl)ethyl)-1 H-pyrazole-5-carboxamide (2) and (R)-1 -methyl-3-(trifluoromethyl)-N-(1 -(3-(2-(trifluoromethyl)pyridin-4-yl)isoxazol-5- yl)ethyl)-1 H-pyrazole-5-carboxamide (3). Note that the stereochemistry is assigned arbitrarily.

[0435]

[0436] Synthesis of (2-(trifluoromethyl)pyridin-4-yl)methanol (A-9)

[0437] To a stirred solution of A-1 (7 g, 36.63 mmol) in THF (30 mL) was added borane DMS (2 M in THF) (36.6 mL, 73.26 mmol) at 0 °C and the mixture was stirred at room temperature for 3 h. Subsequently, the reaction mixture was heated to 50 °C for 12 h and then cooled to room temperature. The reaction mixture was quenched slowly at 0 °C using MeOH (30 mL) and stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure and the residue was cooled to 0 °C. The residue was made basic with 1 N sodium hydroxide (30 mL) and diluted with EtOAc (100 mL) and the phases were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford A-9 (2.8 g, 11.2 mmol, 31% yield) as an oil.

[0438] Synthesis of 2-(trifluoromethyl)pyridine-4-carbaldehyde (A-10)

[0439] To a stirred solution of A-9 (2.8 g, 15.81 mmol) in DCM (20 mL) was added Dess-Martin periodinane (13.41 g, 31.62 mmol) at 0 °C and stirred at room temperature for 16 h. 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 x 30 mL) followed by saturated brine solution (30 mL). The organic layer was then separated and dried over MgS04and concentrated under reduced pressure to afford A-10 (2.5 g, 7.56 mmol, 48% yield) as an oil.

[0440] Synthesis of (4Z)-2-(trifluoromethyl)pyridine-4-carbaldehyde oxime (A-11)

[0441] To a stirred solution of A-10 (2.5 g, 14.28 mmol) in ethanol (10 mL) and water (20 mL) was added Na2C03(1.82 g, 17.13 mmol), hydroxylamine hydrochloride (1.19 g, 17.13 mmol) and the mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated and the residue was diluted with EtOAc (20 mL) and water (10 mL) and separated. The organic layer was washed with water (2 x 10 mL), saturated brine solution (10 mL), separated, then dried over MgS04and concentrated under reduced pressure. Subsequently, the residue was purified by flash column chromatography using 30% EtOAc / hexane as eluent to afford A-11 (1.9 g, 9.36 mmol, 65% yield) as a solid.

[0442] Synthesis of (4E)-N-hydroxy-2-(trifluoromethyl)pyridine-4-carboximidamide chloride (A-12)

[0443] To a solution of A-11 (1.9 g, 9.99 mmol) in DMF (5 mL) was added N- chlorosuccinimide (2.67 g, 19.99 mmol) and the mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with EtOAc (50 mL) and water (20 mL) and the phases were separated. The organic layer was washed with water (2 x 20 mL), then a saturated aqueous solution of brine (20 mL) and the organic layer was separated and dried over MgSO4, then concentrated. The residue was purified by flash column chromatography eluting with 30% EtOAc / hexanes. The desired fractions were concentrated under reduced pressure to give A-12 (1.3 g, 4.39 mmol, 44% yield) as a solid.

[0444] Synthesis of 1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethanol (A-13)

[0445] To a stirred solution of A-12 (0.4 g, 1.78 mmol) in toluene (10 mL) at 0 °C was added but-3-yn-2-ol (0.25 g, 3.56 mmol) and triethylamine (0.18 g, 1.78 mmol) and stirred at room temperature for 1 h, then heated at 60 °C for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (20 mL) and water (10 mL), separated and the organic layer was washed with water (2 x 10 mL), then a saturated aqueous solution of brine (10 mL). The separated organic layer was dried over MgSO4, then concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with 80% EtOAc / hexanes. The desired fractions were concentrated under reduced pressure to give A-13 (0.45 g, 1.69 mmol, 95% yield) as an oil.

[0446] Synthesis of 1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethanol (A-13)

[0447] To a stirred solution of A-13 (0.45 g, 1.74 mmol) in DCM (10 mL) was added Dess-Martin periodinane (1.48 g, 3.49 mmol) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with DCM (30 mL) and saturated sodium thiosulfate (10 mL) and washed with saturated bicarbonate (10 mL). The organic layer was then separated, dried over MgSO4and evaporated to dryness to give a residue which was purified by flash column chromatography using 80% EtOAc / hexanes as eluent to give A-14 (0.2 g, 0.73 mmol, 42% yield) as a solid.

[0448] Synthesis of (NE)-2-methyl-N-[l-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5- yl]ethyl]propane-2-sulfonamide (A-16)

[0449] To a stirred solution of A-14 (0.15 g, 0.59 mmol) in toluene (10 mL) at room temperature was added 2-methyl-2-propane sulfonamide (0.11 g, 0.88 mmol) and titanium(IV) ethoxide (0.2 g, 0.88 mmol). The reaction mixture was heated to 80 °C for 12 h. The reaction mixture was diluted with water and EtOAc (30 mL) and separated. The organic layer was dried over MgS04and evaporated to dryness. Subsequently, the residue was purified by flash column chromatography using 80% EtOAc / hexanes as eluent to afford A-15 (0.14 g, 0.32 mmol, 54% yield) as an oil.

[0450] Synthesis of 2-methyl-N-[l-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5- yl]ethyl]propane-2-sulfonamide (A-16)

[0451] To a stirred solution of A-15 (0.46 g, 1.28 mmol) in methanol (5 mL) at 0 °C was added sodium borohydride (0.048 g, 1.28 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water, diluted with ethyl acetate and the organic layer was separated. The organic layer was dried over MgS04and concentrated under reduced pressure to afford a residue which was purified by flash column chromatography using 80% EtOAc / hexanes as eluent to afford A-16 (450 mg, 1,24 mmol, 97% yield).

[0452] Synthesis of l-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethylamine hydrochloride (A-17)

[0453] To a stirred solution of A-16 (430 mg, 1.19 mmol) in 1,4 dioxane (2 mL) at 0 °C was added 4M HC1 in 1,4 dioxane (8.6 mL, 61.6 mmol) and stirred at room temperature for 2 h. The reaction mixture was evaporated to afford A-17 (310 mg, 1.05 mmol, 89% yield).

[0454] Synthesis of (S)-1 -methyl-3-(trifluoromethyl)-N-(1 -(3-(2- (trifluoromethyl)pyridin-4-yl)isoxazol-5-yl)ethyl)-1 H-pyrazole-5-carboxamide (2) and (R)-1 -methyl-3-(trifluoromethyl)-N-(1 -(3-(2-(trifluoromethyl)pyridin-4- yl)isoxazol-5-yl)ethyl)-1 H-pyrazole-5-carboxamide (3). Note that the stereochemistry is assigned randomly.

[0455] To a stirred solution of A-17 (0.07 g, 0.24 mmol) in DCM (10 mL) at 0 °C was added 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). The mixture was stirred at room temperature for 6 h. 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 x 10 mL), saturated brine solution (10 mL), separated and dried over MgS04and concentrated to dryness to give a residue which was purified by flash column chromatography eluting with 80% EtOAc / hexane. The desired fractions were concentrated to dryness to give A-18 as an oil which was purified by chiral preparative HPLC to give 2 (10 mg, 0.023 mmol, 9% yield) and 3 (8 mg, 0.018 mmol, 8% yield). Note: the absolute stereochemistry is assigned randomly. Isolation was performed using preparative HPLC conditions SFC using the following conditions. DIACEL CHIRALPAK-IG (250 mm x 4.6 mm, 5 um), -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.

[0456] 2: HPLC: Rt 9.172 min, 99.7%; Column: X-Select CSH C18 (4.6 X 150) mm, 3.5 pm; Mobile phase: A: Water + 0.1% Formic acid: 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 pm. 1 H NMR (400 MHz, 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 (quin, 1H), 4.15 (s, 3H), 1.60 (d, 3H). Chiral method: Rt 5.392 min, 100%: DIACEL CHIRALPAK-IG (250 mm x 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.

[0457] 3: HPLC: Rt 9.146 min, 99.8%; Column: X-Select CSH C18 (4.6 X 150) mm, 3.5 pm; mobile phase: A: water + 0.1% formic acid: 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 pm. 1 H NMR (400 MHz, 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 (quin, 1H), 4.15 (s, 3H), 1.60 (d, 3H). Chiral method: Rt 5.392 min, 100%: DIACEL CHIRALPAK-IG (250 mm x 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.

[0458] Example 2-1. Synthesis of (S)-1 -methyl-3-(trifluoromethyl)-N-(1 -(3-(2- (trifluoromethyl)pyridin-4-yl)isoxazol-5-yl)ethyl)-1 H-pyrazole-5-carboxamide (2-1)

[0459]

[0460] Synthesis of (R,Z)-2-methyl-N-(1 -(3-(2-(trifluoromethyl)pyridin-4-yl)isoxazol-5- yl)ethylidene)propane-2-sulfmamide (A-31):

[0461] 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) was added titanium ethoxide (2.97 mL, 14.05 mmol) and the mixture was stirred at 65 °C for 6 h. The reaction mixture was quenched using water and diluted with ethyl acetate. The organic layer was separated, dried over anhydrous Na2S04and concentrated under reduced pressure to get A-31 (1.4 g, 1.17 mmol, 25% yield).

[0462] Synthesis of (R)-2-methyl-N-((S)-1-(3-(2-(trifluoromethyl)pyridin-4-yl)isoxazol-5- yl)ethyl)propane-2-sulfinamide (A-32):

[0463] To a stirred solution of A-31 (700 mg, 1.95 mmol) in THF (10 mL) was added L- selectride (221.76 mg, 5.84 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, treated with water and extracted with DCM (20 mL). The combined organic layer was dried over anhydrous Na2S04, filtered and evaporated to get a residue which was purified by column chromatography using 100-200 silica gel and 50-60% EtOAc / hexane as eluent to get A-32 (250 mg, 0.64 mmol, 32% yield) as a liquid.

[0464] Synthesis of (S)-1-(3-(2-(trifluoromethyl)pyridin-4-yl)isoxazol-5-yl)ethan-1-amine (A-33):

[0465] To a stirred solution of A-32 (250 mg, 0.69 mmol) in 1,4-dioxane (1 mL) was added 4M HC1 in dioxane (0.5 mL, 0.69 mmol) at 0 °C and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and triturated using diethyl ether to get A-33 (150 mg, 0.566 mmol, 81% yield) as a solid.

[0466] Synthesis of (S)-1-methyl-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridin-4- yl)isoxazol-5-yl)ethyl)-1H-pyrazole-5-carboxamide (2-1):

[0467] To a stirred solution of A-33 (180 mg, 0.7000 mmol) in DCM (10 mL) was added 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) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (20 mL), water (10 mL) and the organic layer was separated. The organic layer was washed with water (2 x 10 mL), saturated brine solution (10 mL), separated and dried over MgS04and concentrated under reduced pressure. Subsequently, the residue was purified by flash column chromatography eluting with 30-50% EtOAc / hexane followed by preparative HPLC to afford 2-1 (95 mg, 0.218 mmol, 31% yield). HPLC: Rt 8.484 min, 99.58%; Column: XSELECT CSH C18 (150 X 4.6 mm, 3.5 μ); Mobile Phase-A: Water + 0.1% TFA; Mobile Phase-B: Acetonitrile; LCMS: 434.1 (M+H), Rt 2.381 min, Column: X-Bridge BEH C-18 (3.0 X 50 mm, 2.5 μm); Mobile Phase: A: Water + 0.025% FA, B: ACN; Flow rate: 1.2 ml / min; Chiral HPLC: Rt 4.869 min, 98.80%; Column: CHIRAL PAK IG (250*4.6 mm*5 μm); Mobile Phase A: n-Hexane + 0.1% IP amine; Mobile Phase B: ET OH:MEOH (1 : 1); AB: 80:20; Flow rate: 1.0 mL / min. 1 H NMR (400 MHz, 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 (quin, 1H), 4.15 (s, 3H), 1.61 (d, 3H).

[0468] Example 3-1. Synthesis of (R)-1 -methyl-3-(trifluoromethyl)-N-(1 -(3-(2- (trifluoromethyl)pyridin-4-yl)isoxazol-5-yl)ethyl)-1 H-pyrazole-5-carboxamide (3-1):

[0469]

[0470] Synthesis of (S,E)-2-methyl-N-(1 -(3-(2-(trifluoromethyl)pyridin-4-yl)isoxazol-5- yl)ethylidene)propane-2-sulfmamide (A-34)

[0471] 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) was added titanium ethoxide (1.48 mL, 7.03 mmol) and the mixture was stirred at 90 °C for 6 h. The reaction mixture was quenched using water and diluted with ethyl acetate. The organic layer was separated, dried over anhydrous Na2S04and concentrated under reduced pressure to get A-34 (500 mg, 0.64 mmol, 27% yield).

[0472] Synthesis of (S)-2-methyl-N-((R)-1-(3-(2-(trifluoromethyl)pyridin-4-yl)isoxazol-5- yl)ethyl)propane-2-sulfmamide (A-35)

[0473] To a stirred solution of A-34 (500 mg, 1.39 mmol) in methanol (10 mL) was added sodium borohydride (105.6 mg, 2.78 mmol) at -40 °C and the reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched using water (25 mL) and diluted with EtOAc (2 x 50 mL). The organic layer was separated, dried over anhydrous Na2S04, filtered and evaporated to get a residue which was purified by column chromatography using 100-200 silica gel and 30-80% EtOAc / hexane as eluent to get A-35 (270 mg, 0.7322 mmol, 52% yield).

[0474] Synthesis of (R)-1-(3-(2-(trifluoromethyl)pyridin-4-yl)isoxazol-5-yl)ethan-1-amine (A-36)

[0475] To a stirred solution of A-35 (270 mg, 0.7500 mmol) in 1,4-dioxane (1 mL) was added 4M HC1 in dioxane (0.5 mL, 0.7500 mmol) at 0 °C and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was washed with diethyl ether to get A-36 (180 mg, 0.6578 mmol, 88% yield).

[0476] Synthesis of (R)-1-methyl-3-(trifluoromethyl)-N-(1-(3-(2-(trifluoromethyl)pyridin-4- yl)isoxazol-5-yl)ethyl)-1H-pyrazole-5-carboxamide (3-1):

[0477] To a stirred solution of A-36 (180. mg, 0.7000 mmol) in DCM (10 mL) was added 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) at 0 °C and the mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with DCM (20 mL), water (10 mL) and the organic layer was separated. The organic layer was washed with water (2 x 10 mL), saturated brine solution (10 mL), separated and dried over MgS04before concentrating to dryness. Subsequently, the residue was purified by flash column chromatography eluting with 30-50% EtOAc / hexane followed by preparative HPLC to afford 3-1 (70 mg, 0.1596 mmol, 23% yield). HPLC: Rt 7.85 min, 98.78%; Column: X SELECT CSH C18 (150 X 4.6 mm, 3.5 u); Mobile Phase A: Water + 0.05% TFA; ACN (95:05); Mobile Phase B: Water + 0.05% FA: 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 X 50 mm, 2.5 μm); Mobile Phase: A: Water + 0.025% FA, B: ACN; Flow Rate: 1.2 ml / min

[0478] 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 HNMR (400 MHz, 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 (quin, 1H), 4.15 (s, 3H), 1.61 (d, 3H).

[0479] Example 2-2 and 3-2. Synthesis of 2-methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4- pyridyl]isoxazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide and 2- methyl-N-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide. Note that stereochemistry is assigned randomly.

[0480]

[0481] (4E)-2-bromopyridine-4-carboxaldehyde oxime (B-2):

[0482] To a mixture of 2-bromopyridine-4-carboxaldehyde (20.0 g, 107 mmol) in water (120 mL) and MeOH (120 mL) was added NH2OH.HC1 (33.2 g, 161 mmol). The mixture was stirred at 60 °C for 12 h under N2. After cooling to 30 °C, the mixture was filtered, washed with water (50 mL) and concentrated to give the product as a solid (22.0 g, 76.6 mmol, 71% yield). 1 HNMR (DMSO-d6, 400 MHz) 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).

[0483] (4Z)-2-bromo-N-hydroxy-pyridine-4-carboximidate chloride (B-3):

[0484] To a mixture of (4E)-2-bromopyridine-4-carboxaldehyde oxime (22.0 g, 76.6 mmol) in DMF (60 mL) was added 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 min. The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with saturated brine (2 x 50 mL), dried over anhydrous Na2S04, filtered and concentrated. The mixture was triturated with PE (50 mL) to give the product as a solid (15.0 g, 63.7 mmol, 83% yield). LCMS R t = 0.849 min (in 1.5 min chromatography), 5-95 AB, C6H5BrClN2O [M+H] + MS ESI calculated for C6H5BrClN2O 234.9, found 236.7

[0485] 2-[1-[3-(2-bromo-4-pyridyl)isoxazol-5-yl]ethyl]isoindoline-1,3-dione (B-4):

[0486] To a mixture of 2-(1-methylprop-2-ynyl)isoindoline-1,3-dione (2.28 g, 11.5 mmol) in toluene (50.0 mL) was added Et3N (3.53 mL, 25.5 mmol) and (4Z)-2-bromo-N-hydroxy-pyridine-4-carboximidate chloride (3.0 g, 12.7 mmol). The mixture was stirred at 120 °C for 16 h. The mixture was poured into water (100 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with saturated brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give the product as an oil (1.30 g, 3.26 mmol, 26% yield). 1 H NMR (CDCI3, 400 MHz) 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).

[0487] 2-[1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethyl]isoindoline-1,3-dione (B-5):

[0488] To a mixture of Cu (479 mg, 7.5 mmol) and 2,8-difluoro-5-(trifluoromethyl)- 5H-dibenzo[b,d]thiophene-5-ium trifluoromethanesulfonate (2.20 g, 5.0 mmol) was added 2-[1-[3-(2-bromo-4-pyridyl)isoxazol-5-yl]ethyl]isoindoline-1,3-dione (1.0 g, 2.5 mmol) in DMF (15 mL) under N2. The mixture was stirred at 0 °C for 1 h, and then at 80 °C for 3 h. The mixture was poured into ice water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The mixture was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give the product as a solid (720 mg, 1.90 mmol, 74% yield). 1 H NMR (CDCI3, 400 MHz) 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).

[0489] 1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethanamine-[4,3-a]pyrazine (B-6):

[0490] To a solution of 2-[1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethyl]isoindoline-1,3-dione (300 mg, 0.77 mmol) in DCM (10 mL) and EtOH (2.0 mL) was added N2H4.H2O (0.23 mL, 4.70 mmol) dropwise at 25 °C. After stirring at 25 °C for 16 h, the mixture was filtered, and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated to give the product (200 mg, 0.78 mmol, 100% yield) as a solid, which was used directly in the next step.

[0491] 2-methyl-5-(trifluoromethyl)-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethyl]pyrazole-3-carboxamide (B-7):

[0492] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (125 mg, 0.64 mmol), DIEA (0.30 mL, 1.8 mmol), HATU (443 mg, 1.2 mmol) in DMF (2.0 mL) was added 1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethanamine (150 mg, 0.58 mmol) at 20 °C. After stirring for 1 h, the mixture was poured into water (15 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give the product (150 mg, 0.35 mmol, 59% yield) as a solid. 1 H NMR (CDCI3, 400 MHz) 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).

[0493] 2-methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide and 2-methyl-N-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide

[0494] A mixture of 2-methyl-5-(trifluoromethyl)-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5- yl]ethyl]pyrazole-3-carboxamide (200 mg, 0.46 mmol) was purified by SFC (column DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 pm), conditions: 0.1% NH3H2O-EtOH, start B: 15%, end B: 15%, flow rate (mL / min): 60) to give 2-methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (60.4 mg, 0.14 mmol, 30% yield, peak 1) as a solid and 2-methyl-N-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (69.1 mg, 0.16 mmol, 34% yield) as a solid.

[0495] 2-2: 1 H NMR (CDCI3, 400 MHz) 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, CDCI3) δ F = -62.214, -68.145. LCMS R t = 1.251 min (in 2.0 min chromatography), 10-80 AB, C 17 H 14 F6N5O2 [M+H] + MS ESI calculated for F6N5O2[M+H] 434.1, found 434.1.

[0496] 3-2: 1 H NMR (CDCI3, 400 MHz) 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 FNMR (376.5 MHz, CDC13) δ F = -62.214, -68.145. LCMS R t = 1.229 min (in 2.0 min chromatography), 10-80 AB, C 17 H 14 F6N5O2 [M+H] + MS ESI calculated for 434.2, found 434.2.

[0497] Example 2-3. Synthesis of 2-methyl-5-(trifluoromethyl)-N-[(1S)-1-[3-[2- (trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethyl]pyrazole-3-carboxamide (2-3)

[0498]

[0499] 2-[(1S)-1-methylprop-2-ynyl]isoindoline-1,3-dione (C-2):

[0500] To a mixture of (2R)-but-3-yn-2-ol (2.0 g, 29 mmol), phthalimide (4.2 g, 29 mmol) and PPh3(11 g, 43 mmol) in THF (25 mL) was added DEAD (6.8 mL, 43 mmol) at 25 °C. After stirring at 25 °C for 16 h, the mixture was poured into water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column (0-20% EtOAc / PE) to give the product as a solid. 1 H NMR (CDC13, 400 MHz) 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).

[0501] 2-[(1S)-1-[3-(2-bromo-4-pyridyl)isoxazol-5-yl]ethyl]isoindoline-1,3-dione (C-4):

[0502] To a mixture of 2-[(1S)-1-methylprop-2-ynyl]isoindoline-1,3-dione (1.1 g, 5.7 mmol) in toluene (13 mL) was added K2CO3 (2.6 g, 19 mmol) and (4Z)-2-bromo-N-hydroxy-pyridine-4-carboximidate chloride (1.5 g, 6.4 mmol). After stirring at 120 °C for 12 h, the mixture was poured into water (50 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with saturated brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give the product as a solid (1.1 g, 2.8 mmol, 43% yield). 1 H NMR (CDCI3 400 MHz) 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).

[0503] 2-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethyl]isoindoline-1,3-dione (C-5):

[0504] To a mixture of Cu (287.3 mg, 4.52 mmol) and 2,8-difluoro-5-(trifluoromethyl)- 5H-dibenzo[b,d]thiophen-5-ium trifluoromethanesulfonate (1.33 g, 3.01 mmol) in DMF (15 mL) was added 2-[(1S)-1-[3-(2-bromo-4-pyridyl)isoxazol-5-yl]ethyl]isoindoline-1,3-dione (600 mg, 1.51 mmol) and stirred at 0 °C for 1 h. After stirring at 80 °C for 3 h, the mixture was poured into water (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with saturated brine (3 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The mixture was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give the product as an oil (520 mg, 1.34 mmol, 89% yield). The product (100 mg, 0.26 mmol) was purified by SFC (column DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um), conditions Neu-ETOH, start B 40, end B 40, gradient time (min) 100% B) to give the product as a solid (17.0 mg, 0.0437 mmol, 24% yield). 1H NMR (CDC13, 400 MHz) 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, CDC13) δ F = -68.155. LCMS R t = 1.029 min (in 1.5 min chromatography), 5-95 AB, C 19 H 13 F3N3O3 [M+H] + MSESI calculated for F3N3O3 387.8, found 387.8.

[0505] (1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethanamine (C-6):

[0506] To a solution of 2-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethyl]isoindoline-1,3-dione (250 mg, 0.65 mmol) in DCM (10 mL) and EtOH (2 mL) was added N2H4.H2O (0.19 mL, 3.87 mmol) dropwise at 25 °C. After stirring at 25 °C for 16 h, the mixture was filtered, and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated to give the product (160 mg, 0.311 mmol, 48% yield) as a solid.

[0507] 2-methyl-5-(trifluoromethyl)-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethyl]pyrazole-3-carboxamide (2-3)

[0508] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (132.8 mg, 0.68 mmol), HATU (473 mg, 1.24 mmol) in DMF (10 mL) was added Et3N (0.26 mL, 1.87 mmol) and (1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethanamine (160 mg, 0.62 mmol). After stirring at 20 °C for 12 h, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL), the organic layer was washed with water (3 x 30 mL) and brine (3 x 30 mL), dried over Na2S04, filtered and concentrated. The residue was purified by silica gel flash chromatography (EtOAc / PE = 0% to 40%) to give the product as an oil (200 mg, 0.323 mmol, 52% yield). The product was purified by SFC (column DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um), conditions 0.1% NH3H20 ETOH, start B 25, end B 25, gradient time (min) 100% B) to give the product as a solid (72.2 mg, 0.166 mmol, 36% yield). 1 H NMR (CDC13, 400 MHz) 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, CDC13) δ F = -62.232, -68.164. LCMS R t = 1.022 min (in 1.5 min chromatography), 5-95 AB, C 17 H 14 F6N5O2 [M+H] + MS ESI calculated for 434.0, found 434.0.

[0509] Example 3-3. Synthesis of 2-methyl-N-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (3-3):

[0510]

[0511] 2-(1-methylprop-2-ynyl)isoindoline-1,3-dione (C-8):

[0512] To a mixture of but-3-yn-2-ol (25 g, 357 mmol), phthalimide (53 g, 357 mmol), triphenylphosphine (140 g, 535 mmol) in THF (500 mL) was added DEAD (85 mL, 535 mmol) at 20 °C. After stirring at 20 °C for 16 h, the mixture was poured into water (600 mL) and extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was triturated with PE at 25 °C to give the product as a solid (27 g, 133 mmol, 37% yield). PE / V DCM = 6 / 1 (total 800 mL) wet grinding. The mother liquor was concentrated to give the product which was purified by flash column (0-20% EtOAc / PE) to give the product as a solid (27 g, 133 mmol, 37% yield). 1 H NMR (CDCI3400 MHz) δ H = 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).

[0513] 2-[(1R)-1-[3-(2-bromo-4-pyridyl)isoxazol-5-yl]ethyl]isoindoline-1,3-dione (C-9):

[0514] To a mixture of 2-[(1R)-1-methylprop-2-ynyl]isoindoline-1,3-dione (1.1 g, 5.7 mmol) in toluene (13 mL) was added K2C03(2.6 g, 19 mmol) and (4Z)-2-bromo-N-hydroxy-pyridine-4-carboximidate chloride (1.5 g, 6.4 mmol). After stirring at 120 °C for 3 h, the mixture was poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (2 x 100 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give the product as an oil (1.1 g, 2.8 mmol, 43% yield). The product (50 mg, 0.13 mmol) was purified by preparative TLC (PE / EtOAc = 3 / 1) to give the product as a solid (30 mg, 0.070 mmol, 55% yield). 1 H NMR (CDCI3400 MHz) 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).

[0515] 2-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethyl]isoindoline-1,3-dione (C-10):

[0516] To a mixture of Cu (239 mg, 3.8 mmol) and 2,8-difluoro-5-(trifluoromethyl)-5H- dibenzo[b,d]thiophen-5-ium trifluoromethanesulfonate (1.1 g, 2.5 mmol) was added 2-[(1R)-1-[3-(2-bromo-4-pyridyl)isoxazol-5-yl]ethyl]isoindoline-1,3-dione (500 mg, 1.3 mmol) in DMF (15 mL) under N2. The mixture was stirred at 0 °C for 1 h, then heated to 80 °C, and stirred for 3 hours. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with saturated brine (3 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The mixture was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give the product as a solid (350 mg, 0.90 mmol, 7% yield). The product (100 mg, 0.26 mmol) was purified by preparative TLC (DCM / acetone = 50 / 1) to give the product as a solid (41 mg, 0.11 mmol, 41% yield). 1 HNMR (CDCI3, 400 MHz) 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 min (in 2.0 min chromatography), 10-80 AB, C 19 H 13 F3N3O3 [M+H] + MS ESI calculated for F3N3O3 [M+H] 388.1, found 388.1.

[0517] (1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethylamine (C-11):

[0518] To a solution of 2-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5- yl]ethyl]isoindoline-1,3-dione (150 mg, 0.39 mmol) in DCM (10 mL) and ethanol (2.0 mL) was added N2H4.H2O (0.12 mL, 2.3 mmol) dropwise at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was filtered, and the filter cake was washed with DCM (10 x 3 mL). The filtrate was concentrated and purified by silica gel chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to give the product (60 mg, 0.23 mmol, 60% yield) as an oil. 1 H NMR (CDC13, 400 MHz) 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).

[0519] 2-Methyl-N-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (3-3):

[0520] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (50 mg, 0.26 mmol), DIPEA (0.12 mL, 0.70 mmol), HATU (177 mg, 0.47 mmol) in DMF (5.0 mL) was added (1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]isoxazol-5-yl]ethanamine (60 mg, 0.23 mmol), the mixture was stirred at 20 °C for 1 h. The residue was poured into water (15 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic phase was washed with saturated brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM / acetone = 50 / 1) to give the product (61.57 mg, 0.14 mmol, 60% yield) as a solid. 1 H NMR (CDC13, 400 MHz) 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 min (in 2.0 min chromatography), 10-80 AB, C17 H 14 F6N5O2[M+H] + The calculated MS ESI value is 434.3, and the experimental value is also 434.3.

[0521] Examples 4 and 5. Synthesis of (S)-N-(1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-thiadiazol-5-yl)ethyl)benzamide (4) and (R)-N-(1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-thiadiazol-5-yl)ethyl)benzamide (5). Note that the stereochemistry is randomly specified.

[0522]

[0523] Synthesis of 2-cyclopropylisonicotinonitrile (A-20):

[0524] At room temperature, K3PO4 (38.31 g, 180.44 mmol) and cyclopropylboronic acid (12.4 g, 144.35 mmol) were added to a stirred solution of A-19 (10 g, 72.18 mmol) in 1,4-dioxane (100 mL). The reaction mixture was purged with argon for 20 min. Silver oxide (3.35 g, 14.44 mmol) and Pd(dppf)Cl2 (5.28 g, 7.22 mmol) were added to this solution, and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth mat, 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 gel and 5-10% EtOAc / hexane as eluent to give A-20 as a solid (5.3 g, 31.17 mmol, 43% yield).

[0525] Synthesis of 2-cyclopropylisonicotinic acid (A-21):

[0526] 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 h. The volatile solvent was removed under reduced pressure. The residue was diluted with water and extracted with EtOAc. The aqueous layer was acidified with 1 N HCl. The precipitated solid was collected by filtration and dried under reduced pressure to give A-21 (1.7 g).

[0527] Synthesis of 2-cyclopropylisonicotinamide (A-22):

[0528] To a stirred solution of A-21 (1.5 g, 9.19 mmol) in DCM (20 mL) at 0 °C was added DMF (2.5 mL) and oxalyl chloride (2.33 g, 18.39 mmol) dropwise and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under inert nitrogen atmosphere to get a residue which was dissolved in MeCN (20 mL) and charged with aqueous ammonia solution (20 mL). The reaction mixture was quenched using water (25 mL) and diluted with EtOAc (2 x 50 mL). The organic layer was separated, dried over anhydrous Na2S04, filtered and evaporated to get a residue which was purified by column chromatography using 100-200 silica gel and 30-80% EtOAc / hexane as eluent to get A-22 (1.2 g, 6.51 mmol, 70% yield) as a solid.

[0529] Synthesis of 5-(2-cyclopropylpyridin-4-yl)-1,3,4-oxathiazol-2-one (A-23):

[0530] To a stirred solution of A-22 (1.2 g, 6.51 mmol) in toluene (10 mL) at room temperature was added chlorothioformate (0.852 g, 6.51 mmol) and the reaction mixture was stirred at 120 °C for 16 h. The reaction was quenched by adding water (50 mL), diluted with EtOAc (2 x 100 mL) and the organic layer was separated. The organic layer was dried over anhydrous Na2S04, filtered and evaporated to get a residue which was purified by column chromatography using 100-200 silica gel and 5-50% EtOAc / hexane as eluent to get A-23 (0.5 g, 2.01 mmol, 30% yield) as a solid.

[0531] Synthesis of 1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-thiadiazol-5-yl)ethan-1-one (A-24):

[0532] 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 h. The reaction mixture was quenched using water (10 mL), diluted with EtOAc (20 mL) and the organic layer was separated, dried over anhydrous Na2S04, filtered and evaporated under reduced pressure to get a residue which was purified by column chromatography using 100-200 silica gel and 10-50% EtOAc / hexane as eluent to get A-24 (300 mg, 0.734 mmol, 36% yield) as a solid.

[0533] Synthesis of (E)-N-(1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-thiadiazol-5-yl)ethenyl)-2- methylpropane-2-sulfonamide (A-25):

[0534] To a stirred solution of A-24 (180.73 mg, 0.74 mmol) and 2-methylpropane-2-sulfonamide (89.3 mg, 0.74 mmol) in toluene (10 mL) was added titanium ethoxide (0.16 mL, 0.74 mmol) and stirred at 80 °C for 16 h. The reaction mixture was quenched using water and diluted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, evaporated under reduced pressure to get a residue which was purified by column chromatography using 100-200 silica gel and 10-30% EtOAC / hexane as eluent to get A-25 (250 mg, 0.487 mmol, 66% yield) as a liquid.

[0535] Synthesis of N-(1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-thiadiazol-5-yl)ethyl)-2- methylpropane-2-sulfonamide (A-26):

[0536] To a stirred solution of A-25 (250 mg, 0.72 mmol) in methanol (10 mL) at 0 °C was added sodium borohydride (54.28 mg, 1.43 mmol) and the mixture was stirred at room temperature for 1 h. 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 get A-26 (235 mg) as a solid.

[0537] Synthesis of 1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-thiadiazol-5-yl)ethan-1-amine (A-27):

[0538] To a stirred solution of A-26 (235. mg, 0.47 mmol) in 1,4-dioxane (2 mL) at 0 °C was added 4M HC1 in 1,4-dioxane (10 mL, 0.47 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to get a residue which was purified by washing with diethyl ether to get A-27 (125 mg).

[0539] Step-9: Synthesis of (S)-N-(1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-thiadiazol-5- yl)ethyl)benzamide (4) and (R)-N-(1-(3-(2-cyclopropylpyridin-4-yl)-1,2,4-thiadiazol-5- yl)ethyl)benzamide (5):

[0540] 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) was added HATU (581.9 mg, 1.53 mmol) and DIPEA (0.18 mL, 1.02 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and diluted with DCM (2 x 100 mL). The organic layer was dried over anhydrous Na2S04, filtered and evaporated to get a residue. The residue compound was purified by column chromatography using 100-200 silica gel and 30-80% EtOAc in hexane as eluent to get a racemic mixture which was then purified by SFC column chromatography followed by chiral HPLC to get 4 (39.22 mg, 0.1109 mmol, 11% yield) and 5 (20.89 mg, 0.0593 mmol, 6% yield). Note: Absolute stereochemistry assigned randomly.

[0541] 4: HPLC: Rt 7.411 min, Column: X-Select CSH C18 (4.6*150) mm 5u; Mobile Phase: A - Water + 0.1% Formic acid: 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: Water + 0.05% Formic acid: ACN (95:5); B: ACN + 0.05% Formic acid; Flow rate: 1.2. mL / min; Chiral HPLC: Rt 7.89 min, 99.55%; Column: PHENOMENEX CELLULOSE-3, 250 mm*4.6 mm, 5u; Mobile Phase: A: n-Hexane + 0.1% TFA; B: Ethanol: MEOH (50:50); Flow rate: 1.0 mL / min; Isocratic: 20% B. 1 H NMR (400 MHz, 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).

[0542] 5: HPLC: Rt 7.412 min, Column: X-Select CSH C18 (4.6*150) mm 5u; Mobile Phase: A - Water + 0.1% Formic Acid: 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: Water + 0.05% Formic Acid: ACN (95:5); B: ACN + 0.05% Formic Acid; Flow Rate: 1.2. mL / min; Chiral HPLC: Rt 6.690 min, 100%; Column: PHENOMENEX CELLULOSE-3, 250 mm*4.6 mm, 5u; Mobile Phase: A: n-Hexane + 0.1% TFA; B: Ethanol: MEOH (50:50); Flow Rate: 1.0 mL / min; Isocratic: 20% B. 1 H NMR (400 MHz, 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).

[0543] Examples 6 and 7. Synthesis of (S)-3-chloro-N-(l-(3-(2-cyclopropylpyridin-4-yl)-l,2,4- thiazol-5-yl)ethyl)benzamide (6) and (R)-3-chloro-N-(l-(3-(2-cyclopropylpyridin-4-yl)-l,2,4- thiazol-5-yl)ethyl)benzamide (7). Note that stereochemistry is assigned arbitrarily.

[0544]

[0545] 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) was added HATU (392.06 mg, 1.03 mmol) and DIPEA (0.12 mL, 0.6900 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and diluted with DCM (2 x 100 mL). The organic layer was dried over anhydrous Na2S04, filtered and evaporated to get a residue. The residue was purified by column chromatography using 100-200 silica gel and 30-80% EtOAc in hexane as eluent to get a racemic mixture which was then purified by SFC column chromatography followed by chiral HPLC to get 6 (52.46 mg, 0.1348 mmol, 20% yield) and 7 (54.49 mg, 0.1412 mmol, 21% yield). Note that stereochemistry is assigned randomly.

[0546] 6: HPLC: Rt 6.325 min, 98.93%; Column: XSELECT CSH C18 (150 X 4.6 mm, 3.5 u); Mobile Phase-A: Water + 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 X 50 mm, 2.5 pm); Mobile Phase: A: Water + 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*4.6 mm*5 pm); Mobile Phase A: n-Hexane + 0.1% DEA; Mobile Phase B: DCM:MEOH (50:50); AB: 75:25; Flow Rate: 1.0 mL / min. 1 H NMR (400 MHz, 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 (quin, 1H), 2.31 - 2.22 (m, 1H), 1.74 (d, 3H), 1.04 - 0.93 (m, 4H).

[0547] 7: HPLC: Rt 6.322 min, 99.76%; Column: XSELECT CSH C18 (150 X 4.6 mm, 3.5 u); Mobile Phase-A: Water + 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 X 50 mm, 2.5 pm); Mobile Phase: A: Water + 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*4.6 mm*5 pm); Mobile Phase A: n-Hexane + 0.1% DEA; Mobile Phase B: DCM:MEOH (50:50); AB: 75:25; Flow Rate: 1.0 mL / min. 1 H NMR (400 MHz, 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 (quin, 1H), 2.31 - 2.22 (m, 1H), 1.74 (d, 3H), 1.05 - 0.92 (m, 4H).

[0548] Example 8 and 9. Synthesis of (S)-N-(l-(3-(2-(trifluoromethyl)pyridin-4- yl)isoxazol-5-yl)ethyl)piperidine-l-carboxamide (8) and (R)-N-(l-(3-(2- (trifluoromethyl)pyridin-4-yl)isoxazol-5-yl)ethyl)piperidine-l-carboxamide (9). Note that stereochemistry is assigned arbitrarily.

[0549]

[0550] To a stirred solution of A-17 (300 mg, 1.17 mmol) and piperidine (0.23 mL, 2.33 mmol) in DCM (10 mL) was added CDI (378.25 mg, 2.33 mmol) and TEA (0.49 mL, 3.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 x 50 mL). The combined extracts were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash column chromatography (100-200 silica gel) using 30-50% EtOAc / hexane as eluent followed by preparative chiral HPLC to afford 8 (90 mg, 0.2365 mmol, 20% yield) and 9 (70 mg, 0.1897 mmol, 16% yield). Note that stereochemistry is assigned randomly.

[0551] 8: HPLC: Rt: 8.242 min, 96.79%; Column: XSELECT CSH C18 (150 X 4.6 mm, 3.5 ì); Mobile Phase-A: Water + 0.1% FA; Mobile Phase-B: Acetonitrile; Flow: 1.2 mL / min. LCMS: 369.1 (M+H), Rt 2.050 min, Column: X-Bridge BEH C-18 (3.0 X 50 mm, 2.5 ìm); Mobile Phase: A: Water + 0.025% FA, B: ACN; Flow: 1.2 ml / min Chiral HPLC: Rt: 5.535 min, 99.9%;

[0552] Column: Chiral pak-IG (250*4.6 mm) 5 ìm; Mobile Phase A: n-Hexane + 0.1% DEA

[0553] Mobile Phase B: ETOH: MEOH (50:50); PROGRAM-AB 70:30; Flow: 1.0 1 H NMR (400 MHz, DMSO-d6) d H = 8.92 (d, 1H), 8.32 (s, 1H), 8.20 (d, 1H), 7.16 (s, 1H), 6.96 (d, 1H), 5.11 (quin, 1H), 3.37 - 3.32 (m, 2H), 3.30 - 3.23 (m, 2H), 1.60 - 1.38 (m, 9H).

[0554] 9: HPLC: Rt: 8.223 min, 99.83%; Column: XSELECT CSH C18 (150 X 4.6 mm, 3.5 μ); Mobile Phase-A: Water + 0.1% FA; Mobile Phase-B: Acetonitrile; Flow: 1.2 mL / min. LCMS: 369.1 (M+H), Rt 2.051 min, Column: X-Bridge BEH C-18 (3.0 x 50 mm, 2.5 μm); Mobile Phase: A: Water + 0.025% FA, B: ACN; Flow: 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: n-Hexane + 0.1% DEA; Mobile Phase B: ETOH: MEOH (50:50); PROGRAM-AB 70:30; Flow: 1.0 ML / MIN 1 HNMR (400 MHz, 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 (quin, 1H), 3.36 (br s, 2H), 3.30-3.22 (m, 2H), 1.59-1.39 (m, 9H).

[0555] Example 10 and 11. Synthesis of (R)-1 -methyl-3-(trifluoromethyl)-N-(1 -(3-(2- (trifluoromethyl)pyridin-4-yl)-1,2,4-thiadiazol-5-yl)ethyl)-1 H-pyrazole-5-carboxamide (10) and (S)-1 -methyl-3-(trifluoromethyl)-N-(1 -(3-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4- thiadiazol-5-yl)ethyl)-1 H-pyrazole-5-carboxamide (11). Note that stereochemistry is assigned arbitrarily.

[0556]

[0557] 1 Purified by chiral HPLC to give 10 (10 mg, 0.022 mmol, 8% yield) and 11 (10 mg, 0.022 mmol, 8% yield).

[0558] 10: HPLC: Rt 9.349 min, 99.77%; Column: X-Select CSH C18 (4.6 X 150) mm, 3.5 pm; Mobile phase: A: Water + 0.1% Formic acid: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min. LCMS: 450.9 (M+H), Rt 2.117 min, Column: X-select CSH C18 (3*50) mm, 2.5 pm, 1 H NMR (400 MHz, 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 x 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.

[0559] 11: HPLC: Rt 9.352 min, 99.87%; Column: X-Select CSH C18 (4.6 X 150) mm, 3.5 pm; Mobile phase: A: Water + 0.1% Formic acid: ACN (95:05), B: ACN; Flow rate: 1.0 mL / min; LCMS: 449.2 (M-H), Rt 2.182 min, Column: X-select CSH C18 (3*50) mm, 2.5 pm; 1 H NMR (400 MHz, 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 (250 mm x 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.

[0560] Example 11-1. Synthesis of 2-methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4- thiadiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (11-1)

[0561]

[0562] 3-bromo-5-(l-ethoxyvinyl)-l,2,4-thiadiazole (C-17)

[0563] To a mixture of 3-bromo-5-chloro-l,2,4-thiadiazole (10.0 g, 50.1 mmol) and l-ethoxyvinyltri-n-butyltin (20.5 mL, 60.2 mmol) in DMF (150 mL) was added Pd(PPh3)2Cl2(3.52 g, 5.01 mmol) under N2, and the reaction mixture was heated at 60 °C for 4 h. The reaction mixture was quenched with an aqueous KF (10.0 g in 300 mL water) solution, and stirred for 30 min and filtered. The filtrate was extracted with EtOAc (2 x 300 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 20 / 1) to give the product as a solid (7.0 g, 29.8 mmol, 59% yield). 1 H NMR (CDC13, 400 MHz) δ H = 5.53 (d, 1H), 4.58 (d, 1H), 4.02 (q, 2H), 1.43 (t, 3H).

[0564] 5-(l-ethoxyvinyl)-3-[2-(trifluoromethyl)-4-pyridyl]-l,2,4-thiadiazole (C-18)

[0565] To a solution of 3-bromo-5-(l-ethoxyvinyl)-l,2,4-thiadiazole (2.0 g, 8.51 mmol) in DME (20.0 mL, 8.51 mmol) and water (4.0 mL) was added Cs2CO3(8.31 g, 25.5 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)pyridine (3.02 g, 11.1 mmol) and Pd(dppf)Cl2(622 mg, 0.85 mmol) under N2. After stirring at 100 °C for 1.5 h, the reaction mixture was cooled to 25 °C, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with petroleum / ethyl acetate = 10 / 1 to give the product as an oil (1.80 g, 5.97 mmol, 70% yield). 1 H NMR (CDC13, 400 MHz) 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).

[0566] 1 -[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethanone (C-19)

[0567] To a solution of 5-(1 -ethoxyethenyl)-3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4- thiadiazole (1.80 g, 5.97 mmol) in acetone (20.0 mL) was added 3M HCI (1.09 g, 29.9 mmol) at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was quenched with saturated NaHC03(50.0 mL) and extracted with EtOAc (2 x 50.0 mL). The combined organic layers were washed with brine (50.0 mL) and dried over Na2S04, filtered and concentrated under reduced pressure to give the product as a solid (1.60 g, 5.86 mmol, 98% yield) which was used directly in the next step. 1 H NMR (CDCI3, 400 MHz) δ H = 8.92 (d, 1H), 8.58 (s, 1H), 8.39 (d, 1H), 2.85 (s, 3H).

[0568] (R,E)-2-methyl-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazol-5- yl]ethylidene]propane-2-sulfonamide (C-20)

[0569] To a solution of 1 -[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethanone (300 mg, 1.10 mmol) in THF (10.0 mL) was added (R)-2-methylpropane-2- sulfonamide (200 mg, 1.65 mmol) and Ti(OEt)4(751 mg, 3.29 mmol) under N2at 25 °C. The mixture was heated to 65 °C and stirred for 16 h. The reaction mixture was quenched with aqueous saturated NaHC03(20.0 mL) and filtered. The filtrate was extracted with EtOAc (2 x 20.0 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The product was purified by Si02column chromatography (PE / EtOAc = 10 / 1 ) to give the product as an oil (120 mg, 0.32 mmol, 29% yield). 1 H NMR (CDCI3, 400 MHz) δ H= 8.91 (d, 1H), 8.56 (s, 1H), 8.37 (d, 1H), 2.98 (s, 3H), 1.37 (s, 9H).

[0570] (R)-2-methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazol-5- yl]ethyl]propane-2-sulfonamide (C-21)

[0571] To a solution of (R,E)-2-methyl-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4- thiadiazol-5-yl]ethylidene]propane-2-sulfonamide (100 mg, 0.27 mmol) in THF (2.0 mL) was added L-Selectride (0.53 mL, 0.53 mmol) at -78 °C under N2. The reaction mixture was stirred at -78 °C for 30 min. NH4Cl (10.0 mL) was added to the mixture at -78 °C. The mixture was extracted with EtOAc (2 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the product (110 mg, 0.29 mmol) as an oil, which was used directly in the next step. LCMS R t = 0.727 min (in 1.0 min chromatography), 5-95 AB, C 14 H 18 F3N4OS2 [M+H] + MS ESI calculated for F3N4OS2 379.0, found 379.0.

[0572] (1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethylamine hydrochloride (C-22)

[0573] To a solution of (R)-2-methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4- thiadiazol-5-yl]ethyl]propane-2-sulfonamide (150 mg, 0.40 mmol) in 1,4-dioxane (1.0 mL) was added 4 M HC1 / dioxane (2.0 mL, 1.98 mmol) at 25 °C. After stirring at 25 °C for 2 h, the reaction mixture was concentrated under reduced pressure to give the product (100 mg, 0.32 mmol, 81% yield) as a solid. LCMS R t = 0.744 min (in 1.5 min chromatography), 5-95 AB, C 10 H 10 F3N4S [M+H] +MS ESI calculated 274.8, found 274.8.

[0574] 2-Methyl-N-[(1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazol-5- yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (11-1)

[0575] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (62.5 mg, 0.32 mmol) in DCM (3.0 mL) was added DIPEA (0.45 mL, 2.57 mmol), T3P (734 mg, 0.97 mmol). After stirring at 25 °C for 20 min, (1S)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethanamine hydrochloride (100 mg, 0.32 mmol) was added and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (20.0 mL) and extracted with DCM (2 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL) and dried over Na2S04, filtered and concentrated under reduced pressure to give the product which was purified by preparative HPLC (Column: Phenomenex Gemini-NX 80*40 mm*3 pm, Conditions: Water (0.05% NH3H20)-ACN, Start B: 48, End B: 78, Gradient time (min): 8, 100% B hold time (min): 2, Flow rate (mL / min): 30, Injection: 5) to give the product as a solid (90.0 mg, 0.20 mmol, 62% yield). The product (90.0 mg, 0.20 mmol) was purified by SFC (Column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 pm), Conditions: 0.1% NH3H20-EtOH, Start B: 15%, End B: 15%, Flow rate (mL / min): 60, Injection: 30) to give the product as a solid (54.3 mg, 0.12 mmol, 60% yield). 1 H NMR (CDC13, 400 MHz) 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, CDC13) δ F -62.206, -68.055. LCMS R t= 2.496 min (in 3.0 min chromatogram), 30-90 AB, C 16 H 13 F6N6OS [M+H] + MS ESI calculated 451.2, found 451.2. 99.72% ee.

[0576] Example 10-1. Synthesis of 2-methyl-N-[(1R)-1-[3-[2-(trifluoromethyl)-4- pyridyl]-1,2,4-thiadiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (10-1)

[0577]

[0578] (S,E)-2-methyl-N-[1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazol-5- yl]ethylidene]propane-2-sulfonamide (C-31)

[0579] To a solution of 1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethanone (300 mg, 1.10 mmol) in THF (10.0 mL) was added (S)-2-methylpropane-2- sulfonamide (200 mg, 1.65 mmol) and Ti(OEt)4(751 mg, 3.29 mmol) at 25 °C under N2. The mixture was heated to 65 °C and stirred for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3solution (20.0 mL) and filtered. The filtrate was extracted with EtOAc (2 x 20.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by SiO2column chromatography (PE / EtOAc = 10 / 1) to give the product (110 mg, 0.29 mmol, 27% yield) as an oil.

[0580] (S)-2-methyl-N-[(1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazol-5- yl]ethyl]propane-2-sulfonamide (C-32)

[0581] To a solution of (S,E)-2-methyl-N-[l-[3-[2-(trifluoromethyl)-4-pyridyl]-l,2,4- thiazol-5-yl]ethylidene]propane-2-sulfmamide (100 mg, 0.27 mmol) in THF (2.0 mL) was added L-Selectride (0.53 mL, 0.53 mmol) at -78 °C under N2. After stirring at -78 °C for 30 min, saturated NH4CI (10.0 mL) was added to the mixture at -78 °C. The mixture was extracted with EtOAc (2 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give the product (100 mg, 0.26 mmol, 99% yield) as an oil, which was used directly in the next step. LCMS R t = 0.728 min (in 1.0 min chromatography), 5-95 AB, C 14 H 18 F3N4OS2 [M+H] + MS ESI calculated for F3N4OS2[M+H] 379.0, found 379.0.

[0582] (1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-l,2,4-thiazol-5-yl]ethylamine hydrochloride (C-33)

[0583] To a solution of (S)-2-methyl-N-[(lR)-l-[3-[2-(trifluoromethyl)-4-pyridyl]-l,2,4- thiazol-5-yl]ethyl]propane-2-sulfmamide (130 mg, 0.34 mmol) in 1,4-dioxane (1.0 mL) was added HC1 / dioxane (3.0 mL, 4 M) at 25 °C. After stirring at 25 °C for 2 h, the reaction mixture was concentrated under reduced pressure to give the product (90.0 mg, 0.29 mmol, 84% yield) as a solid, which was used directly in the next step. LCMS R t = 0.754 min (in 1.5 min chromatography), 5-95 AB, C 10 H 10 F3N4S [M+H] + MS ESI calculated for F3N4S [M+H] 274.8, found 274.8.

[0584] 2-methyl-N-[(lR)-l-[3-[2-(trifluoromethyl)-4-pyridyl]-l,2,4-thiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (10-1)

[0585] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (56.2 mg, 0.29 mmol) in DCM (3.0 mL) was added T3P (661 mg, 0.87 mmol), DIEA (0.40 mL, 2.32 mmol). After stirring at 25 °C for 20 min, (1R)-1-[3-[2-(trifluoromethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethanamine hydrochloride (90.0 mg, 0.29 mmol) was added and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (20.0 mL) and extracted with DCM (2 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL) and dried over Na2S04, filtered and concentrated under reduced pressure to give the product which was purified by preparative HPLC (Column: Phenomenex Gemini-NX 80*40 mm*3 pm, Conditions: Water (0.05% NH3H20)-ACN, Start B: 47, End B: 77, Gradient time (min): 8, 100% B hold time (min): 2, Flow rate (mL / min): 30, Injection: 4) to give the product as a solid (70.0 mg, 0.16 mmol, 54% yield). The product (70.0 mg, 0.16 mmol) was purified by SFC (Column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 pm), Conditions: 0.1% NH3H20 EtOH, Start B: 15%, End B: 15%, Flow rate (mL / min): 60, Injection: 20) to give the product as a solid (22.9 mg, 0.05 mmol, 33% yield). 1 H NMR (CDC13, 400 MHz) 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, CDC13) δ F -62.206, 68.046. LCMS R t = 2.451 min (in 3.0 min chromatography), 30-90 AB, C 16 H 13 F6N6OS [M+H] + MS ESI calculated for F6N6OS [M+H] 451.1, found 451.1. 100% ee.

[0586] Examples 12 and 13. Synthesis of (S)-N-(l-(3-(2-cyclopropylpyridin-4-yl)-l,2,4- thiazol-5-yl)ethyl)-l-methyl-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (12) and (R)-N-(l-(3-(2-cyclopropylpyridin-4-yl)-l,2,4-thiazol-5-yl)ethyl)-l-methyl-3- (trifluoromethyl)-lH-pyrazole-5-carboxamide (13).

[0587] Note that the stereochemistry is assigned randomly.

[0588]

[0589] 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) was added HATU (117.65 mg, 0.31 mmol) and DIPEA (0.11 mL, 0.62 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and diluted with DCM (2 x 100 mL). The organic layer was dried over anhydrous Na2S04, filtered and evaporated to get a residue. The residue was purified by column chromatography using 100-200 silica gel and 30-80% EtOAc / hexane as eluent to get a racemic mixture which was then purified by SFC column chromatography to get 12 (10 mg, 0.0234 mmol, 8% yield) and 13 (10 mg, 0.0234 mmol, 8% yield).

[0590] 12: HPLC: Rt 8.686 min, 99.87%; Column: X-Select CSH C18 (4.6 X 150) mm, 3.5 pm; Mobile Phase: A: Water + 0.1% Formic Acid: 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 pm; 1H NMR (400 MHz, DMSO-d6) δ 9.46 (d, 1 H), 8.61 (d, 1 H), 7.85 (s, 1 H), 7.66-7.64 (m, 1 H), 7.45 (s, 1 H), 5.50-5.45 (m, 1 H), 4.13 (s, 3 H), 2.30-2.26 (m, 1 H), 1.68 (d, 3 H), 1.03-0.97 (m, 4 H). Chiral method: Rt 4.755 min, 100%; Column: PHENOMENEX CELLULOSE-3 (250 mm x 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.

[0591] 13: HPLC: Rt 8.348 min, 97.85%; Column: X-Select CSH C18 (4.6 X 150) mm, 3.5 pm; mobile phase: A: water + 0.1 % formic acid: 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 pm; 1 H NMR (400 MHz, DMSO-d6) δ 9.46 (d, 1 H), 8.61 (d, 1 H), 7.85 (s, 1 H), 7.66-7.64 (m, 1 H), 7.44 (s, 1 H), 5.50-5.46 (m, 1 H), 4.13 (s, 3 H), 2.30-2.26 (m, 1 H), 1.68 (d, 3 H), 1.03-0.97 (m, 4 H). Chiral method: Rt 8.044 min, 100%; Column: PHENOMENEX CELLULOSE-3 (250 mm x 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.

[0592] Examples 12-1 and 13-1. Synthesis of 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)- 1,2,4-thiadiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide and 2-methyl-N- [(1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide

[0593]

[0594] 3-(2-cyclopropyl-4-pyridinyl)-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (C-23)

[0595] 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) was added 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) under N2. The reaction mixture was stirred at 100 °C for 1.5 h. 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 with petroleum ether / ethyl acetate = 20 / 1 to give the product as an oil (1.60 g, 5.85 mmol, 69% yield). LCMS R t = 0.676 min (in 1.0 min chromatography), 5-95 AB, C 14 H 16 N3OS [M+H] + MS ESI calculated for N3OS 274.0, found 274.0.

[0596] 1-[3-(2-cyclopropyl-4-pyridinyl)-1,2,4-thiadiazol-5-yl]ethanone (C-24)

[0597] To a solution of 3-(2-cyclopropyl-4-pyridinyl)-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (1.6 g, 5.85 mmol) in acetone (20.0 mL) was added 3M HC1 (1.07 g, 29.3 mmol) at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was quenched with saturated NaHC03(30.0 mL) and extracted with EtOAc (2 x 30.0 mL). The combined organic layers were washed with brine (30.0 mL) and dried over Na2S04, filtered and concentrated under reduced pressure to give the product as a solid (1.10 g, 4.48 mmol, 77% yield) which was used directly in the next step. 1 H NMR DMSO-d6 400MHz 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).

[0598] (S,E)-N-[1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethylidene]-2- methyl-propane-2-sulfmamide (C-25)

[0599] To a solution of (S,E)-N-[1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5- yl]ethylidene]-2-methyl-propane-2-sulfmamide (280 mg, 0.80 mmol) in THF (5.0 mL) was added L-Selectride (1.61 mL, 1.61 mmol) at -78 °C under N2. After stirring at -78 °C for 1 h, the reaction mixture was quenched with saturated NH4Cl (20.0 mL) and extracted with EtOAc (2 x 20.0 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the product (200 mg, 0.57 mmol, 71% yield) as an oil which was used directly in the next step. LCMS R 1 H NMR (CDCI3, 400 MHz) 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).

[0600] (S)-2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl] propane-2-sulfmamide (C-26)

[0601] To a solution of (S,E)-N-[1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5- yl]ethylidene]-2-methyl-propane-2-sulfmamide (280 mg, 0.80 mmol) in THF (5.0 mL) was added L-Selectride (1.61 mL, 1.61 mmol) at -78 °C under N2. After stirring at -78 °C for 1 h, the reaction mixture was quenched with saturated NH4Cl (20.0 mL) and extracted with EtOAc (2 x 20.0 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the product (200 mg, 0.57 mmol, 71% yield) as an oil which was used directly in the next step. LCMS R t = 0.805 min (in 1.5 min chromatography), 5-95 AB, C 16 H 23 N4OS2 [M+H] +MS ESI calculated for N4S [M+H] 246.8, found 246.8.

[0602] (1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethylamine (C-27)

[0603] To a solution of (S)-2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4- thiadiazol-5-yl]ethyl]propane-2-sulfmamide (200 mg, 0.57 mmol) in 1,4-dioxane (3.0 mL) was added 4M HC1 / dioxane (0.43 mL, 1.71 mmol) at 25 °C. After stirring at 25 °C for 2 h, the reaction mixture was quenched with saturated NaHC03(20.0 mL) and extracted with EtOAc (2 x 20.0 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to give the product (140 mg, 0.57 mmol, 99% yield) as an oil which was used directly in the next step. LCMS R t = 0.437 min (in 1.5 min chromatography), 5-95 AB, C 12 H 15 N4S [M+H] + MS ESI calculated for N4S [M+H] 246.8, found 246.8.

[0604] 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide and 2-methyl-N-[(1S)-1-[3-(2-cyclopropyl-4- pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide

[0605] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (100 mg, 0.52 mmol) in DCM (2.0 mL) was added DIEA (0.47 mL, 2.71 mmol), T3P (617 mg, 0.81 mmol). After stirring at 25 °C for 10 min, (1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-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 h. The reaction mixture was quenched with water (20.0 mL) and extracted with DCM (2 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL) and dried over Na2S04, filtered and concentrated under reduced pressure to give the product which was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 pm, conditions: water (0.05% NH3H20)-ACN, start B: 44, end B: 74, gradient time (min): 8, 100% B hold time (min): 2.8, flow rate (mL / min): 30, injection: 8) to give the product (90.0 mg, 0.21 mmol, 41% yield) as an oil which was purified by SFC (column: (s,s) WHELK-O1 (250 mm*30 mm, 5 pm), conditions: 0.1% NH3H20-EtOH, start B: 35%, end B: 35%, flow rate (mL / min): 80, injection: 50) to give 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (61.82 mg, 0.14 mmol, 68% yield) as a solid and 2-methyl-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (10.76 mg, 0.03 mmol, 12% yield) as a solid.

[0606] 13-1: 1 H NMR (CDC13, 400 MHz) 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, CDC13) δ F-62.212. LCMS R t = 2.131 min (in 3.0 min chromatogram), 10-80 CD, C 18 H 18 F3N6OS [M+H] + MS ESI calculated for F3N6OS 423.0, found 423.0. 100% ee.

[0607] 12-1 : 1 H NMR (CDC13, 400 MHz) 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, CDC13) δ F -62.210. LCMS R t = 2.120 min (in 3.0 min chromatogram), 10-80 CD, C 18 H 18 F3N6OS [M+H] + MS ESI calculated for F3N6OS 423.0, found 423.0. 99.5% ee.

[0608] Example 12-2 and 13-2. Synthesis of 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4- pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide and 2-methyl-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide

[0609]

[0610] (R,E)-N-[1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethylidene]-2- methyl-propane-2-sulfmamide (C-28)

[0611] Ti(OEt)4 (1.39 g, 6.11 mmol) was added to a solution of 1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]acetone (500 mg, 2.04 mmol) in THF (10.0 mL) at 25 °C. After stirring at 50 °C for 16 h, the reaction mixture was cooled to 25 °C and quenched with saturated NaHCO3 (40.0 mL), and filtered. The filtrate was extracted with EtOAc (2 × 40.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (EtOAc / PE, 5%–10%) to give a solid product (300 mg, 0.86 mmol, 42% yield). 1 H 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).

[0612] (R)-2-methyl-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]propane-2-sulfinamide (C-29)

[0613] L-Selectride (1.72 mL, 1.72 mmol) was added to a solution of (R,E)-N-[1-[3-(2-cyclopropyl-4-pyridinyl)-1,2,4-thiadiazol-5-yl]ethylene]-2-methyl-propane-2-sulfinamide (300 mg, 0.86 mmol) in THF (5.0 mL) at -78 °C under N2. After stirring at -78 °C for 1 h, the reaction mixture was quenched with saturated NH4Cl (20.0 mL) and extracted with EtOAc (2 × 20.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give an oily product (350 mg, 1.00 mmol), which was used directly in the next step. LCMS R t =0.791 min (in a 1.5 min chromatogram), 5-95AB, C 16 H 23 N4OS2[M+H] + The calculated MS ESI value is 351.2, and the experimental value is also 351.2.

[0614] (1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethylamine hydrochloride (C-30)

[0615] To a solution of (R)-2-methyl-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4- thiadiazol-5-yl]ethyl]propane-2-sulfmamide (330 mg, 0.94 mmol) in 1,4-dioxane (3.0 mL) was added 4M HC1 / dioxane (0.71 mL, 2.82 mmol) at 25 °C. After stirring at 25 °C for 2 h, the reaction mixture was quenched with saturated NaHC03(20.0 mL) and extracted with EtOAc (2 x 30.0 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to give the product (200 mg, 0.71 mmol, 75% yield) as an oil which was used directly in the next step. 1 H NMR (DMSO-d6400 MHz) 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).

[0616] 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide and 2-methyl-N-[(1S)-1-[3-(2-cyclopropyl-4- pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide

[0617] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (82.4 mg, 0.42 mmol) in DCM (2.0 mL) was added DIEA (0.62 mL, 3.54 mmol), T3P (807 mg, 1.06 mmol). After stirring at 25 °C for 10 min, (1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-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 h. The reaction mixture was quenched with water (20.0 mL) and extracted with DCM (2 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL) and dried over Na2S04, filtered and concentrated under reduced pressure to give the product which was purified by preparative HPLC (Column: Phenomenex Gemini-NX 80*40 mm*3 pm, Conditions: Water (0.05% NH3H20)-ACN, Start B: 43, End B: 73, Gradient time (min): 8, 100% B hold time (min): 2, Flow rate (mL / min): 30, Injection: 5) to give 2 product (80.0 mg, 0.19 mmol, 54% yield) as an oil which was used for SFC separation. The product (80.0 mg, 0.19 mmol) was purified by SFC (Column: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 pm), Conditions: 0.1% NH3H20-EtOH, Start B: 35%, End B: 35%, Flow rate (mL / min): 80, Injection: 45) to give 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (3.29 mg, 0.01 mmol, 4% yield) as a solid and 2-methyl-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (34.82 mg, 0.08 mmol, 44% yield) as a solid.

[0618] 12-2: 1 H NMR (CDC13, 400 MHz) 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). 19F NMR (376.5 MHz, CDC13) δ F -62.186. LCMS R t = 2.296 min (in 3.0 min chromatogram), 10-80 AB, C 18 H 18 F3N6OS [M+H] + MS ESI calculated for F3N6OS 423.4, found 423.4. 100% ee.

[0619] 13-2: 1 H NMR (CDC13, 400 MHz) 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, CDC13) δ F -62.177. LCMS R t = 2.265 min (in 3.0 min chromatogram), 10-80 AB, C 18 H 18 F3N6OS [M+H] + MS ESI calculated for F3N6OS 423.2, found 423.2. 100% ee.

[0620] Examples 14 and 15. Synthesis of (S)-N-(l-(3-(2-cyclopropylpyridin-4- yl)isoxazol-5-yl)ethyl)benzamide (14) and (R)-N-(l-(3-(2-cyclopropylpyridin-4- yl)isoxazol-5-yl)ethyl)benzamide (15). Note that stereochemistry is assigned arbitrarily.

[0621]

[0622] Synthesis of 2-cyclopropylisonicotinic acid methyl ester (A-38):

[0623] To a stirred solution of A-37 (4.g, 23.31 mmol) in 1,4-dioxane (50 mL) was added cyclopropylboronic acid (2.38 g, 27.98 mmol), K3PO4(9.9 g, 46.63 mmol) and Ag2O (2.7 g, 11.66 mmol). To this solution was added Pd(dppf)Cl2(1.71 g, 2.33 mmol) and the mixture was stirred at 100 °C for 12 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on 100-200 silica gel using 20-30% EtOAc / hexane as eluent to afford A-38 (2.6 g, 14.12 mmol, 61%) as an oil.

[0624] Synthesis of (2-cyclopropylpyridin-4-yl)methanol (A-39):

[0625] To a stirred solution of A-38 (2.5 g, 14.11 mmol) in methanol (10 mL) was added NaBH4(1.07 g, 28.22 mmol) at 0 °C and the mixture was stirred at room temperature for 6 h. 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 afford A-39 (2 g, 12.8 mmol, 91%) as a liquid.

[0626] Synthesis of 2-cyclopropylisonicotinaldehyde (A-40):

[0627] To a stirred solution of A-40 (2 g, 13.41 mmol) in DCM (20 mL) was added Dess-Martin periodinane (5.68 g, 13.41 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. 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, washed with water (2 x 30 mL) and saturated brine solution (30 mL). The organic layer was separated and dried over anhydrous MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography on 100-200 silica gel using 20-30% EtOAc / hexane as eluent to afford A-40 (1.6 g, 8.83 mmol, 66%) as an oil.

[0628] Synthesis of (Z)-2-cyclopropylisonicotinaldehyde oxime (A-41):

[0629] To a stirred solution of A-40 (1.6 g, 10.87 mmol) in ethanol (5 mL) and water (25 mL) was added hydroxylamine hydrochloride (0.91 g, 13.05 mmol) and stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was washed with water (2 x 20 mL) and saturated brine solution (20 mL). The organic layer was separated and dried over anhydrous MgS04and concentrated under reduced pressure. The residue was purified by column chromatography over 100-200 silica gel using 20-30% EtOAc / hexane as eluent to afford A-41 (1.6 g, 6.35 mmol, 58%) as a solid.

[0630] Synthesis of (E)-2-cyclopropyl-N-hydroxyisonicotinimidoyl chloride (A-42):

[0631] To a stirred solution of A-41 (1.6 g, 9.86 mmol) in DMF (20 mL) was added N- chlorosuccinimide (2.63 g, 19.73 mmol) and stirred at room temperature for 6 h. The reaction mixture was diluted with EtOAc (50 mL) and water (20 mL). The organic layer was washed with water (2 x 20 mL) and saturated brine solution (20 mL). The organic layer was separated and dried over anhydrous MgS04and concentrated under reduced pressure. The residue was purified by column chromatography over 100-200 silica gel using 20-30% EtOAc / hexane as eluent to afford A-42 (1.2 g, 4.91 mmol, 50%) as a solid.

[0632] Synthesis of 1-(3-(2-cyclopropylpyridin-4-yl)isoxazol-5-yl)ethan-1-ol (A-43):

[0633] To a stirred solution of A-42 (1.2 g, 6.1 mmol) in THF (15 mL) was added but-3-yn-2-ol (0.86 g, 12.21 mmol) and triethylamine (0.62 g, 6.1 mmol) and stirred at 60 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was washed with water (2 x 20 mL) and saturated brine solution (20 mL). The organic layer was separated and dried over anhydrous MgS04and concentrated under reduced pressure. The residue was purified by column chromatography over 100-200 silica gel using 20-30% EtOAc / hexane as eluent to afford A-43 (0.8 g, 3.47 mmol, 57%) as an oil.

[0634] Synthesis of 1-(3-(2-cyclopropylpyridin-4-yl)isoxazol-5-yl)ethan-1-one (A-44):

[0635] To a stirred solution of A-43 (0.8 g, 3.47 mmol) in DCM (20 mL) was added Dess-Martin periodinane (2.95 g, 6.95 mmol). The reaction mixture was stirred at room temperature for 12 h. After completion, the reaction mass was diluted with DCM (30 mL) and saturated sodium thiosulfate (10 mL) and saturated bicarbonate (10 mL). The organic layer was separated and dried over anhydrous MgS04and concentrated under reduced pressure. The residue was purified by column chromatography over 100-200 silica gel using 70-80% EtOAc / hexane as eluent to afford A-44 (0.62 g, 2.394 mmol, 69%) as a solid.

[0636] Synthesis of (E)-N-(1-(3-(2-cyclopropylpyridin-4-yl)isoxazol-5-yl)ethylidene)-2- methylpropane-2-sulfmamide (A-45):

[0637] To a stirred solution of A-44 (0.62 g, 2.72 mmol) in toluene (10 mL) was added Ti(OEt)4(0.93 g, 4.07 mmol) and stirred at 100 °C for 12 h.2) After completion, the reaction mass was diluted with EtOAc (30 mL) and water (10 mL) and filtered through a pad of celite. The organic layer was separated, dried over anhydrous MgS04and concentrated under reduced pressure. The residue was purified by column chromatography over 100-200 silica gel using 70-80% EtOAc / hexane as eluent to afford A-45 (0.7 g, 1.3 mmol, 46.31%) as an oil.

[0638] Synthesis of N-(1-(3-(2-cyclopropylpyridin-4-yl)isoxazol-5-yl)ethyl)-2-methylpropane-2- sulfenamide (A-46):

[0639] To a stirred solution of A-45 (700 mg, 2.11 mmol) in methanol (10 mL) was added sodium borohydride (159.8 mg, 4.22 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate (2 x 20 mL). The organic layer was separated, dried over anhydrous MgS04and concentrated under reduced pressure to afford A-46 (600 mg, 1.44 mmol, 68%).

[0640] Synthesis of 1-(3-(2-cyclopropylpyridin-4-yl)isoxazol-5-yl)ethan-1-amine (A-47):

[0641] 4M HCl / 1,4-dioxane (10 mL, 2.1 mmol) was added to a stirred solution of A-46 (700 mg, 2.1 mmol) in 1,4-dioxane (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by grinding with diethyl ether to give A-47 (500 mg, 1.83 mmol, 87%).

[0642] Synthesis of (S)-N-(1-(3-(2-cyclopropylpyridin-4-yl)isoxazo-5-yl)ethyl)benzamide (14) and synthesis of (R)-N-(1-(3-(2-cyclopropylpyridin-4-yl)isoxazo-5-yl)ethyl)benzamide (15): Note that the stereochemistry is randomly specified.

[0643] HATU (416.37 mg, 1.1 mmol) and DIPEA (0.25 mL, 1.46 mmol) were added 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) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After stirring, 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 silica gel column chromatography at 100–200 μm using 80% EtOAc / hexane as eluent to give a racemic mixture, which was then purified by SFC column chromatography to give 14 (15 mg, 0.045 mmol, 6%) and 15 (10 mg, 0.03 mmol, 4%).

[0644] 14: HPLC: Rt 6.55 min, 99.64%; Column: X-Select CSH C18 (4.6X150) mm, 3.5 μm; Mobile phase: A: Water + 0.1% formic acid: 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; 1H NMR (400 MHz, 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 x 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.

[0645] 15: HPLC: Rt 6.86 min, 98.74%; Column: X-Select CSH C18 (4.6 X 150) mm, 3.5 μm mobile phase: A: water + 0.1% formic acid: 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 (400 MHz, 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 x 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.

[0646] Examples 16 and 17. Synthesis of (R)-N-(l-(3-(2-cyclopropylpyridin-4-yl)isoxazol-5- yl)ethyl)-l-methyl-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (16) and (S)-N-(l-(3-(2- cyclopropylpyridin-4-yl)isoxazol-5-yl)ethyl)-l-methyl-3-(trifluoromethyl)-lH-pyrazole-5- carboxamide (17). Note that stereochemistry is assigned arbitrarily.

[0647]

[0648] 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) was added HATU (322.7 mg, 0.85 mmol) and DIPEA (0.25 mL, 1.41 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 x 50 mL). The organic layer was separated, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 100-200 silica gel with 30-80% EtOAc in hexane as eluent to get racemic mixture which was then purified by SFC column chromatography to get 16 (10 mg, 0.0245 mmol, 3%) and 17 (10 mg, 0.0245 mmol, 3%).

[0649] 16: HPLC: Rt 7.804 min, 99.35%; Column: X-Select CSH C18 (4.6 X 150) mm, 3.5 pm; Mobile Phase: A: Water + 0.1% Formic acid: 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 pm; 1 H NMR (400 MHz, DMSO-d6) d 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 min, 100%; Column: YMC CHIRAL ART CELLULOSE-SC (250 x 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.

[0650] 17: HPLC: Rt 7.804 min, 99.35%; Column: X-Select CSH C18 (4.6 X 150) mm, 3.5 pm; Mobile phase: A: water + 0.1% formic acid: 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 pm; 1 H NMR (400 MHz, 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 min, 97.84%; Column: YMC CHIRAL ART CELLULOSE-SC (250 x 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.

[0651] Examples 16-1 and 17-1. Synthesis of 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4- pyridyl)isoxazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide and N-[(1S)-1-[3-(2- cyclopropyl-4-pyridyl)isoxazol-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3- carboxamide. Note that the stereochemistry is arbitrarily assigned.

[0652]

[0653] 2-[1-[3-(2-cyclopropyl-4-pyridyl)isoxazol-5-yl]ethyl]isoindoline-1,3-dione (B-8)

[0654] To a mixture of 2-[l-[3-(2-bromo-4-pyridyl)isoxazol-5-yl]ethyl]isoindoline-l,3-dione (1 g, 2.51 mmol), cyclopropylboronic acid (431.4 mg, 5.02 mmol), K3PO4(1.07 g, 5.02 mmol), Pd(OAc)2(28.2 mg, 0.13 mmol) in water (5 mL) and toluene (25 mL) was added PCy3(70.4 mg, 0.25 mmol). The mixture was stirred at 120 °C for 16 h under N2. The mixture was poured into water (30 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with saturated brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give the product (240 mg, 0.47 mmol, 19% yield) as an oil. LCMS R t = 0.846 min (in 1.5 min chromatography), 5-95 AB, C 21 H 18 N3O3 [M+H] + MS ESI calculated for N3O3[M+H] 360.1, found 360.0

[0655] 1 -[3-(2-cyclopropyl-4-pyridyl)isoxazol-5-yl]ethylamine (B-9)

[0656] To a solution of 2-[l-[3-(2-cyclopropyl-4-pyridyl)isoxazol-5-yl]ethyl]isoindoline-l,3-dione (240 mg, 0.67 mmol) in DCM (10 mL) and ethanol (2 mL) was added dropwise NH2NH2.H2O (0.2 mL, 4.01 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was filtered, and the filter cake was washed with DCM (10 x 3 mL). The filtrate was concentrated to give the product (150 mg, 0.654 mmol, 98% yield) as a solid. LCMS R t = 0.21 min (in 1.5 min chromatography), 5-95 AB, C 13 H 16 N3O [M+H] + MS ESI calculated for N3O [M+H] 230.1, found 229.9

[0657] N-[l-[3-(2-cyclopropyl-4-pyridyl)isoxazol-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3-carboxamide (B-10)

[0658] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (139.7 mg, 0.72 mmol), HATU (497.5 mg, 1.31 mmol) in DMF (5 mL) was added Et3N (0.27 mL, 1.96 mmol) and 1-[3-(2-cyclopropyl-4-pyridyl)isoxazol-5-yl]ethanamine (150 mg, 0.65 mmol). The mixture was stirred at 20 °C for 12 h, diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The organic layer was washed with brine (3 x 30 mL), dried over Na2S04, filtered and the filtrate was concentrated to give the product which was purified by silica gel flash chromatography (MeOH / DCM = 0% to 4%) to give the product as an oil (300 mg). 1 H NMR (CDC13, 400 MHz) 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).

[0659] 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide and N-[(1S)-1-[3-(2-cyclopropyl-4- pyridyl)isoxazol-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3-carboxamide

[0660] A mixture of N-[1-[3-(2-cyclopropyl-4-pyridyl)isoxazol-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 um), conditions 0.1% NH3H2O ETOH, start B 30, end B 30, flow (ml / min) 60) to give peak 1 as a solid (90 mg) and peak 2 as a solid (87.6 mg, 0.213 mmol, 29% yield).

[0661] A mixture of Peak 1 (90 mg) was purified by preparative TLC (DCM:MeOH = 10:1) to give 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (54.1 mg, 0.134 mmol, 60% yield) as a solid.

[0662] 16-1: 1 H NMR (CDC13, 400 MHz) 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 (in 2.0 min chromatography), 10-80 AB, C 19 H 19 F3N5O2 [M+H] + MS ESI calculated for F3N5O2 406.1, found 406.1

[0663] 17-1: 1 H NMR (CDC13, 400 MHz) 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 = 1.00 min (in 2.0 min chromatography), 10-80 AB, C 19 H 19 F3N5O2 [M+H] + MS ESI calculated for F3N5O2 406.1, found 406.1.

[0664] Example 16-2. Synthesis of 2-methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (16-2)

[0665]

[0666] 2-[(1R)-1-[3-(2-cyclopropyl-4-pyridinyl)isoxazol-5-yl]ethyl]isoindoline-1,3-dione (C-12)

[0667] To a mixture of 2-[-(1R)-1-[3-(2-bromo-4-pyridinyl)isoxazol-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), PCy3(35 mg, 0.13 mmol) in H2O (5.0 mL) and toluene (25 mL) was added Pd(OAc)2(14 mg, 0.060 mmol) under N2. After stirring at 110 °C for 16 h, the mixture was poured into water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with saturated brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give the product (270 mg, 0.53 mmol, 42% yield) as an 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 give the product (19.65 mg, 0.050 mmol, 28% yield) as a solid. 1 H NMR (CDCI3, 400 MHz) 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 = 0.995 min (in 2.0 min chromatography), 10-80 AB, C 21 H 18 N3O3 [M+H] + MS ESI calculated for N3O3[M+H] 360.1, found 360.1.

[0668] (1R)-1-[3-(2-cyclopropyl-4-pyridinyl)isoxazol-5-yl]ethylamine (C-13)

[0669] To a solution of 2-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazol-5-yl]ethyl]isoindoline- 1,3-dione (100 mg, 0.28 mmol) in DCM (10 mL) and EtOH (2.0 mL) was added N2H4.H2O (0.080 mL, 1.7 mmol) dropwise at 25 °C. After stirring at 25 °C for 16 h, the mixture was filtered, and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated to give the product as a solid (60 mg, 0.26 mmol, 94% yield). LCMS R t = 0.203 min (in 1.5 min chromatography), 5-95 AB, C 13 H 16 N3O [M+H] + MS ESI calculated for N3O [M+H] 229.9, found 229.9

[0670] 2-Methyl-N-[(1R)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide

[0671] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (47 mg, 0.24 mmol), HATU (166 mg, 0.44 mmol) in DMF (5.0 mL) was added Et3N (0.090 mL, 0.65 mmol) and (1R)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazol-5-yl]ethylamine (50 mg, 0.22 mmol) at 20 °C. After stirring for 1 h, water (10 mL) was added and the solution was extracted with EtOAc (3 x 10 mL), the organic layer was washed with brine (3 x 10 mL), dried over Na2SO4, filtered and concentrated to give the product which 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 give the product as a solid (40.9 mg, 0.10 mmol, 58% yield). 1 H NMR (CDCI3, 400 MHz) 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 FNMR (376.5 MHz, CDC13) δ F -62.214. LCMS R t = 0.980 min (in 2.0 min chromatography), 10-80 AB, C 19 H 19 F3N5O2 [M+H] + MS ESI calculated for F3N5O2 406.2, found 406.2.

[0672] Example 17-2. Synthesis of 2-methyl-N-[(lS)-l-[3-(2-cyclopropyl-4-pyridinyl)isoxazol-5- yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (17-2)

[0673]

[0674] 2-[(lS)-l-[3-(2-cyclopropyl-4-pyridinyl)isoxazol-5-yl]ethyl]isoindoline-l,3-dione (C-14)

[0675] To a mixture of 2-[(1S)-1-[3-(2-bromo-4-pyridyl)isoxazol-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), Pd(OAc)2(14 mg, 0.060 mmol) in H2O (2.0 mL) and toluene (10 mL) was added tricyclohexylphosphine (35 mg, 0.13 mmol). After stirring under N2at 110 °C for 16 h, the mixture was poured into water (30 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with saturated brine (2 x 80 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give the product as an oil (390 mg, 0.75 mmol, 61% yield). The product (100 mg, 0.28 mmol) was purified by HPLC (column Phenomenex Gemini-NX 80*30 mm*3 pm; conditions: water (10 mM NH4HCO3)-CAN; start B: 42; end B: 72; gradient time (min): 9; 100% B hold time (min): 1.5; flow rate (mL / min): 30) to give the product as a solid (14.5 mg, 0.040 mmol, 36% yield). 1 H NMR (CDCI3, 400 MHz) 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 = 0.871 min (in 1.5 min chromatography), 5-95 AB, C 21 H 18 N3O3 [M+H] + MS ESI calculated for N3O3[M+H] 360.0, found 360.0.

[0676] (1S)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazol-5-yl]ethylamine (C-15)

[0677] To a solution of 2-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazol-5-yl]ethyl]isoindoline- 1,3-dione (140 mg, 0.39 mmol) in DCM (15 mL) and EtOH (3.0 mL) was added N2H4.H2O (0.12 mL, 2.3 mmol) dropwise at 25 °C. After stirring at 25 °C for 16 h, the mixture was filtered, and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated to give the product as a solid (100 mg, 0.30 mmol, 78% yield), which was used directly in the next step.

[0678] 2-methyl-N-[(1S)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide

[0679] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (93 mg, 0.48 mmol), HATU (332 mg, 0.87 mmol) in DMF (10 mL) was added Et3N (0.18 mL, 1.3 mmol) and (1S)-1-[3-(2-cyclopropyl-4-pyridyl)isoxazol-5-yl]ethylamine (100 mg, 0.44 mmol) at 20 °C. After stirring at 20 °C for 12 h, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL), the organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated to give the product which was purified by preparative HPLC (column Phenomenex Gemini-NX 80*30 mm*3 pm conditions: water (10 mM NH4HCO3)-CAN; start B: 42; end B: 72; gradient time (min): 9; 100% B hold time (min): 1.5; flow rate (mL / min): 30) and SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 pm); conditions: 0.1% NH3H2O IPA; start B: 15%; end B: 15%; flow rate (mL / min): 50) to give the product as a solid (27.1 mg, 0.067 mmol, 46% yield). 1 H NMR (CDCI3, 400 MHz) 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, CDC13) δ F = -62.223. LCMS R t = 0.870 min (in 1.5 min chromatography), 5-95 AB, C 19 H 19 F3N5O2 [M+H] + MS ESI calculated for F3N5O2 405.9, found 405.9.

[0680] Examples 18 and 19. Synthesis of (S)-3-chloro-N-(l-(3-(2- cyclopropylpyridin-4-yl)isoxazol-5-yl)ethyl)benzamide (18) and (R)-3-chloro-N-(l-(3-(2- cyclopropylpyridin-4-yl)isoxazol-5-yl)ethyl)benzamide (19). Note that stereochemistry is assigned arbitrarily.

[0681]

[0682] To a stirred solution of 3-chlorobenzoic acid (0.204 g, 1.310 mmol) in DMF (2 mL) was added DIPEA (0.76 mL, 4.360 mmol) and HATU (0.663 g, 1.740 mmol) and stirred for 5 min. To the resulting solution was added a solution of A-47 (0.400 g, 1.744 mmol) in DMF (1 mL) at rt and stirred for 15 h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (4 x 10 mL). The combined organic layers were washed with water (20 mL), separated and dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to get the crude material A-48. Chiral separation of A-48 was carried out by preparative chiral HPLC to get 18 (0.044 g, 0.119 mmol, 14% yield) and 19 (0.048 g, 0.125 mmol, 14% yield) as an oil.

[0683] 18: LCMS: 367.95 (M+H), R t = 1.883 min, Column: Kinetex EVO C18 (50*3) mm; 2.6 u; Mobile Phase: A: Water + 5 mM Ammonium bicarbonate; B: Acetonitrile; HPLC: R t= 5.400 min, 99.42 %; Column; X SELECT CSH C18 (150 X 4.6 mm, 3.5 um); 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) n-hexane + 0.1 % DEA, B) EtOH (50:50), A:B: 75:25; flow rate: 1.00 mL / min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (d, 1 H), 8.51 (d, 1 H), 7.97 (s, 1 H), 7.88 (d, 1 H), 7.76 (s, 1 H), 7.64 (d, 1 H), 7.52-7.58 (m, 2 H), 7.12 (s, 1 H), 5.40-5.44 (m, 1 H), 2.10-2.25 (m, 1 H), 1.60 (d, 3 H), 0.90-1.01 (m, 4 H).

[0684] 19: LCMS: 367.95 (M+H), R t = 1.882 min, Column: Kinetex EVO C18 (50*3) mm; 2.6 u; mobile phase: A: water + 5 mM ammonium bicarbonate; B: acetonitrile; HPLC: R t = 7.300 min, 96.20 % Column; X SELECT CSH C18 (150 X 4.6 mm, 3.5 um); 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) n-hexane + 0.1 % DEA, B) EtOH (50:50), A:B: 75:25; flow rate: 1.00 mL / min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (d, 1 H), 8.51 (d, 1 H), 7.97 (s, 1 H), 7.88 (d, 1 H), 7.76 (s, 1 H), 7.64 (d, 1 H), 7.52-7.58 (m, 2 H), 7.12 (s, 1 H), 5.40-5.44 (m, 1 H), 2.10-2.25 (m, 1 H), 1.60 (d, 3 H), 0.90-1.01 (m, 4 H).

[0685] Examples 20 and 21. Synthesis of (R)-3-chloro-N-(l-(3-(2-(trifluoromethyl)pyridin-4- yl)isoxazol-5-yl)ethyl)benzamide (20) and (S)-3-chloro-N-(l-(3-(2-(trifluoromethyl)pyridin-4- yl)isoxazol-5-yl)ethyl)benzamide (21). Note that stereochemistry is assigned arbitrarily.

[0686]

[0687] 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) was added HATU (0.591 g, 1.555 mmol) followed by DIPEA (0.677 mL, 3.887 mmol) at room temperature and stirred for 15 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to get a residue (220 mg) as a liquid. The residue was purified by column chromatography on Combiflash eluting with 0-40% ethyl acetate in n-hexane to get A-49 (0.145 g) as a solid. Chiral separation of A-49 was carried out by preparative chiral HPLC to get 20 (0.034 g, 0.086 mmol, 11% yield) and 21 (0.036 g, 0.088 mmol, 11% yield) both as solids.

[0688] 20： LCMS: 393.90 (M-H), R t = 2.118 min, Column: Kinetex EVO C18 (50*3) mm 2.6 μ; Mobile Phase: A: Water + 2.5 mM Ammonium bicarbonate, B: Acetonitrile; HPLC: R t = 6.030 min, 99.20%; Column: X SELECT CSH C18 (150 X 4.6 mm, 3.5 um); Mobile Phase A 5 mM Ammonium acetate; Mobile Phase B: Acetonitrile; Flow rate: 1.0 mL / min. Chiral HPLC: R t = 7.878 min, 99.25% Column: Chiralpak IG (250 X 4.6 mm, 5 μm); Mobile Phase: A - n-hexane + 0.1% DEA

[0689] Mobile phase: DCM:MEOH (50:50); A:B: 80:20; Flow rate: 1.0 mL / min. 1H NMR(400MHz,DMSO-d6)δppm 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).

[0690] 21： LCMS: 393.95 (M+H), R t = 2.119 min, column: Kinetex EVO C18 (50*3) mm 2.6 μm; mobile phase: A: water + 2.5 mM ammonium bicarbonate, B: acetonitrile; HPLC: R t =12.29 min, 96.04%; Column: X SELECT CSH C18 (150 x 4.6 mm, 3.5 μm); Mobile phase A: water + 0.05% TFA: acetonitrile (95:05); Mobile phase B: water + 0.05% TFA: acetonitrile (5:95); Flow rate: 1.0 mL / min. Chiral HPLC: R t =14.46 min, 99.57%; Column: Chiralpak IG (250 x 4.6 mm, 5 μm); Mobile phase: A-n-hexane + 0.1% DEA; Mobile phase: DCM:MEOH (50:50); A:B: 80:20; Flow rate: 1.0 mL / min; 1 H NMR(400MHz,DMSO-d6)δppm 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).

[0691] Examples 22 and 23. Synthesis of (R)-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)isoxazol-5-yl)ethyl)benzamide (22) and (S)-N-(1-(3-(2-(trifluoromethyl)pyridin-4-yl)isoxazol-5-yl)ethyl)benzamide (23). Note that stereochemistry is randomly specified.

[0692]

[0693] To a stirred solution of benzoic acid (0.142 g, 1.166 mmol) in DMF (2 mL) at 0 °C was added DIPEA (0.677 mL, 3.884 mmol) followed by HATU (0.591 g, 1.554 mmol) and stirred for 5 min. To the resulting solution was added a solution of A-17 (0.200 g, 0.777 mmol) in DMF (2 mL). The reaction mixture was allowed to reach room temperature and stirred for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (4 x 10 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to get a residue A-50. The residue A-50 was subjected to chiral HPLC purification to get 22 (0.025 g, 0.069 mmol, 9% yield) and 23 (0.026 g, 0.072 mmol, 9% yield) as a solid.

[0694] 22: LCMS: 360.05 (M+H), R t = 2.022 min, Column: Kinetex EVO C18 (50*3) mm 2.6 μ; Mobile Phase: A: Water + 2.5 mM Ammonium bicarbonate, B: Acetonitrile; HPLC: R t = 6.920 min, 99.47%

[0695] Column; X SELECT CSH C18 (150 X 4.6 mm, 3.5 um); Mobile Phase A 5 mM Ammonium bicarbonate; Mobile Phase B: Acetonitrile; Chiral HPLC: R t = 9.089 min, 100%; Column: Chiralpak IG (250 X 4.6 mm, 5 μm); Mobile Phase: A - n-Hexane + 0.1% DEA; Mobile Phase: DCM: MEOH (50:50); A:B: 80:20; Flow rate: 1.0 mL / min. 1 H NMR (400 MHz, 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).

[0696] 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: Water + 0.02.5% Formic acid, B: Acetonitrile; HPLC: R t= 5.580 min, 95.35%; Column: X SELECT CSH C18 (150 X 4.6 mm, 3.5 um); Mobile Phase A 5 mM Ammonium Acetate; Mobile Phase B: Acetonitrile; Chiral HPLC: R t = 12.12 min, 97.07%; Column: Chiralpak IG (250 X 4.6 mm, 5 μm); Mobile Phase: A - n-Hexane + 0.1% DEA; Mobile Phase: DCM:MEOH (50:50); A:B: 80:20; Flow rate: 1.0 mL / min. 1 H NMR (400 MHz, 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).

[0697] Examples 24 and 25. Synthesis of (R)-3-isopropyl-l-methyl-N-(l-(3-(2- (trifluoromethyl)pyridin-4-yl)isoxazol-5-yl)ethyl)-lH-pyrazole-5-carboxamide (24) and (S)-3-isopropyl-l-methyl-N-(l-(3-(2-(trifluoromethyl)pyridin-4-yl)isoxazol-5- yl)ethyl)-lH-pyrazole-5-carboxamide (25). Note that the stereochemistry is assigned arbitrarily.

[0698]

[0699] To a stirred solution of A-17 (0.300 g, 1.166 mmol) and 3-isopropyl-l-methyl-lH- pyrazole-5-carboxylic acid (0.226 g, 1.341 mmol) in DMF (5 mL) was added HATU (0.886 g, 2.332 mmol) followed by DIPEA (1.01 mL, 5.830 mmol) at room temperature and stirred for 15 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to get a residue A-51 (198 mg) as a liquid. The residue was purified by column chromatography using Combiflash eluting with 0-40% ethyl acetate in n-hexane to get A-51 (0.200 g) as a solid. Chiral separation of A-51 was carried out by preparative chiral HPLC to get 24 (0.060 g, 0.147 mmol, 13% yield) and 25 (0.086 g, 0.211 mmol, 18% yield) both as solids.

[0700] 24： LCMS: 407.95 (M+H), R t = 2.722 min, Column: Kinetex EVO C18 (50*3) mm 2.6 μ; Mobile Phase: A: Water + 2.5 mM Ammonium bicarbonate, B: Acetonitrile; HPLC: R t = 4.959 min, 98.71 %

[0701] Column; X SELECT CSH C18 (150 X 4.6 mm, 3.5 um); Mobile Phase A 5 mM Ammonium bicarbonate; Mobile Phase B: Acetonitrile; Chiral HPLC: R t = 7.233 min, 95.77 %; Column: Chiralpak IG (250 X 4.6 mm, 5 μm); Mobile Phase: A - n-Hexane + 0.1 % DEA; Mobile Phase B: EtOH; A:B: 80:20; Flow rate: 1.0 mL / min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.97 (d, 1 H), 8.93 (d, 1 H), 8.34 (s, 1 H), 8.20-8.23 (m, 1 H), 7.34 (d, 1 H), 6.82 (s, 1 H), 5.35-5.42 (m, 1 H), 3.99 (s, 3 H), 2.84-2.91 (m, 1 H), 1.59 (d, 3 H), 1.20 (d, 6 H).

[0702] 25： LCMS: 408.20 (M+H), R t = 2.232 min, Column: X-Bridge BEH C-18 (3.0*50 mm, 2.5 μm); Mobile Phase: A: Water + 0.02.5 % Formic acid, B: Acetonitrile; HPLC: R t = 7.240 min, 94.88 %

[0703] Column; X SELECT CSH C18 (150 X 4.6 mm, 3.5 um); Mobile Phase A 5 mM Ammonium bicarbonate; Mobile Phase B: Acetonitrile; Chiral HPLC: R t = 6.330 min, 99.04 %; Column: Chiralpak IG (250 X 4.6 mm, 5 μm); Mobile Phase: A - n-Hexane + 0.1 % DEA; Mobile Phase B: EtOH; A:B: 80:20; Flow rate: 1.0 mL / min. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.97 (d, 1 H), 8.93 (d, 1 H), 8.34 (s, 1 H), 8.21 (d, 1 H), 7.34 (d, 1 H), 6.82 (s, 1 H), 5.35 - 5.42 (m, 1 H), 3.99 (s, 3 H), 2.84 - 2.91 (m, 1 H), 1.59 (d, 3 H), 1.20 (d, 6 H).

[0704] Examples 26 and 27. Synthesis of (R)-N-(l-(3-(2-(trifluoromethyl)pyridin-4- yl)isoxazol-5-yl)ethyl)cyclohexanecarboxamide (26) and (S)-N-(l-(3-(2- (trifluoromethyl)pyridin-4-yl)isoxazol-5-yl)ethyl)cyclohexanecarboxamide (27). Note that stereochemistry is assigned arbitrarily.

[0705]

[0706] To a stirred reaction mixture of A-17 (0.200 g, 0.780 mmol) and cyclohexanecarboxylic acid (249.21 mg, 1.56 mmol) in DMF (5.00 mL) was added HATU (591.31 mg, 1.56 mmol) followed by N,N-diisopropylethylamine (0.68 mL, 3.89 mmol) at room temperature and stirred for 15 h at room temperature. The reaction mixture was quenched by the addition of water (10.0 mL) and then the reaction mixture was extracted with EtOAc (2 x 25 mL), the combined extracts were dried over anhydrous Na2S04, filtered, concentrated under reduced pressure to get a residue A-52 (198 mg) as a liquid. The residue was purified by Combi-Flash column chromatography (100-200 silica gel) eluting with 0-40% EtOAc / hexane followed by reverse phase preparative chiral HPLC to get 26 (31 mg, 0.084 mmol, 11%) and 27 (32 mg, 0.087 mmol, 11%) both as solids.

[0707] 26: HPLC: Rt: 10.64 min, 99.51 %; Column; X SELECT CSH C18 (150 X 4.6 mm, 3.5 um); Mobile Phase A: 5 mM Ammonium bicarbonate; Mobile Phase B: Acetonitrile; LCMS: 366.05 (M-H), Rt 2.184 min, Column: Kinetex EVO C18 (50*3) mm 2.6 u; Mobile Phase: A: Water + 2.5 mM Ammonium bicarbonate, B: Acetonitrile, Injection Volume: 2 pL; Flow rate: 1.2 mL / min; Chiral HPLC: Rt: 7.479 min, 100 %; Column: CHIRAL PAK IA (150*4.6 mm, 3 pm); Mobile Phase A: n-Hexane + 0.1 % DEA; Mobile Phase B: IPA. 1 H NMR (400 MHz, DMSO-d6) d 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).

[0708] 27: HPLC: Rt: 10.63 min, 99.85 %; Column: X SELECT CSH C18 (150 X 4.6 mm, 3.5 um); 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 u; Mobile Phase: A: Water + 2.5 mM Ammonium bicarbonate; B: Acetonitrile; Injection Volume: 2 pL, Flow rate: 1.2 mL / min; Chiral HPLC: Rt 12.717 min, 99.85 %; Column: CHIRAL PAK IA (150*4.6 mm, 3 pm); Mobile Phase A: n-Hexane + 0.1 % DEA; Mobile Phase B: IPA. 1 H NMR (400 MHz, DMSO-d6) d 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).

[0709] Examples 28 and 29. Synthesis of (R)-2-phenyl-N-(l-(3-(2-(trifluoromethyl)pyridin-4- yl)isoxazol-5-yl)ethyl)acetamide (28) and (S)-2-phenyl-N-(l-(3-(2-(trifluoromethyl)pyridin-4- yl)isoxazol-5-yl)ethyl)acetamide (29). Note that the stereochemistry is assigned arbitrarily.

[0710]

[0711] To a solution of phenylacetic acid (127.04 mg, 0.930 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.68 mL, 3.89 mmol), HATU (591.31 mg, 1.56 mmol) and A-17 (dissolved in 1 mL DMF, 200 mg, 0.78 mmol) at 0 °C and stirred at room temperature for 12 h. The reaction mixture was quenched by the addition of water (10.0 mL) and then the reaction mixture was extracted with EtOAc (2 x 25 mL), the combined extracts were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash column chromatography (100-200 silica gel), followed by reverse phase preparative chiral HPLC to give 28 (38 mg, 0.101 mmol, 13%) and 29 (40 mg, 0.103 mmol, 13%) both as solids.

[0712] 28: HPLC: Rt: 10.02 min, 99.68%; Column; X SELECT CSH C18 (150 X 4.6 mm, 3.5 um); Mobile Phase A: 5 mM Ammonium bicarbonate; Mobile Phase B: Acetonitrile; LCMS: 374.05 (M-H), Rt 2.325 min, Column: Kinetex EVO C18 (50*3) mm 2.6 u; Mobile Phase: A: Water + 2.5 mM Ammonium bicarbonate; B: Acetonitrile; Injection Volume: 2 pL, Flow rate: 1.2 mL / min; Chiral HPLC: Rt: 11.139 min, 99.77%; Column: CHIRAL PAK IC (150*4.6 mm, 3 pm); Mobile Phase A: n-Hexane + 0.1% DEA; Mobile Phase B: DCM:MEOH (50:50). 1 H NMR (400 MHz, DMSO-d6) d 8.97 - 8.88 (m, 1H), 8.86 - 8.76 (m, 1H), 8.33 - 8.25 (m, 1H), 8.21 - 8.13 (m, 1H), 7.37 - 7.16 (m, 6H), 5.24 - 5.11 (m, 1H), 3.54 - 3.43 (m, 2H), 1.49 (d, 3H).

[0713] 29: HPLC: Rt: 7.17 min, 97.32%; Column: X SELECT CSH C18 (150 X 4.6 mm, 3.5 um); Mobile Phase A: Water + 0.05% Formic Acid; Mobile Phase B: Acetonitrile; LCMS: 374.05 (M-H), Rt 2.109 min, Column: Kinetex EVO C18 (50*3) mm 2.6u; Mobile Phase: A: Water + 2.5 mM Ammonium bicarbonate; 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: n-Hexane + 0.1% DEA; Mobile Phase B: DCM:MEOH (50:50). 1 H NMR (400 MHz, 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, 1H), 7.35 - 7.15 (m, 6H), 5.24 - 5.11 (m, 1H), 3.56 - 3.41 (m, 2H), 1.49 (d, 3H).

[0714] Examples 30 and 31. Synthesis of (R)-3-(Difluoromethyl)-1-methyl-N-(1-(3-(2- (trifluoromethyl)pyridin-4-yl)isoxazol-5-yl)ethyl)-1H-pyrazole-5-carboxamide (30) and (S)-3-(Difluoromethyl)-1-methyl-N-(1-(3-(2-(trifluoromethyl)pyridin-4- yl)isoxazol-5-yl)ethyl)-1H-pyrazole-5-carboxamide (31). Note that stereochemistry is arbitrarily assigned.

[0715]

[0716] To a stirred reaction mixture of A-17 (0.200 g, 0.780 mmol) and 3-(difluoromethyl)-l- methyl-lH-pyrazole-5-carboxylic acid (150.94 mg, 0.86 mmol) in DMF (5.00 mL) was added HATU (443 mg, 3.5 mmol) followed by N,N-diisopropyl ethylamine (0.68 mL, 3.89 mmol) at room temperature and stirred for 15 h at room temperature. The reaction mixture was quenched by the addition of water (10.0 mL) and then the reaction mixture was extracted with EtOAc (2 x 25 mL), the combined extracts were dried over anhydrous Na2S04, filtered, concentrated under reduced pressure to get a residue (198 mg) as liquid. The residue was purified by Combi-Flash column chromatography (100-200 silica gel) eluting with 0-40% EtOAc / hexane followed by reverse phase preparative chiral HPLC to get 30 (28 mg, 0.0663 mmol, 9%) and 31 (30 mg, 0.0711 mmol, 9%) both as solids.

[0717] 30: HPLC: Rt: 7.05 min, 98.38%; Column; X SELECT CSH C18 (150 X 4.6 mm, 3.5 um); Mobile Phase A: 5 mM Ammonium bicarbonate; Mobile Phase B: Acetonitrile; LCMS: 413.95 (M-H), Rt: 1.976 min, Column: Kinetex EVO C18 (50*3) mm 2.6 u; Mobile Phase: A: Water + 2.5 mM Ammonium bicarbonate; B: Acetonitrile; Injection Volume: 2 pL, Flow rate: 1.2 mL / min; Chiral HPLC: Rt: 8.837 min, 97.21%; Column: CHIRAL PAK-IA (150 x 4.6 mm 3 pm); Mobile Phase A: 0.1% DEA n-Hexane; Mobile Phase B: IPA. 1 H NMR (400 MHz, 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).

[0718] 31 : HPLC: Rt: 7.05 min, 98.37%; Column; X SELECT CSH C18 (150X4.6 mm, 3.5 um); Mobile Phase A: 5 mM Ammonium bicarbonate; Mobile Phase B: Acetonitrile; LCMS: 413.95 (M-H), Rt 1.958 min, Column: Kinetex EVO C18 (50*3) mm 2.6 u; Mobile Phase: A: Water + 2.5 mM Ammonium bicarbonate; B: Acetonitrile; Injection Volume: 2 pL, Flow rate: 1.2 mL / min; Chiral HPLC: Rt 12.893 min, 100%; Column: CHIRAL PAK-IA (150 x 4.6 mm 3 pm); Mobile Phase A: 0.1% DEA n-Hexane, Mobile Phase B: IPA. 1 H NMR (400 MHz, 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).

[0719] Examples 32 and 33. Synthesis of (R)-3-(trifluoromethyl)-N-(l-(3-(2- (trifluoromethyl)pyridin-4-yl)isoxazol-5-yl)ethyl)benzamide (32) and (S)-3- (trifluoromethyl)-N-(l-(3-(2-(trifluoromethyl)pyridin-4-yl)isoxazol-5- yl)ethyl)benzamide (33). Note that stereochemistry is arbitrarily assigned.

[0720]

[0721] To a stirred reaction mixture of A-17 (300.mg, 1.17mmol) and 3- (trifluoromethyl)benzoic acid (226.4mg, 1.19mmol) in DMF (5.00 mL) was added HATU (495mg, 1.3mmol) followed by N,N-diisopropylethylamine (0.7mL, 5.83mmol) at room temperature and stirred for 15h at room temperature. The reaction mixture was quenched by the addition of water (10.0mL) and then the reaction mixture was extracted with EtOAc (2x25mL), the combined extracts were dried over anhydrous Na2S04, filtered, concentrated under reduced pressure to get a residue (198mg) as a colorless viscous liquid. The residue was purified by Combi-Flash column chromatography (100-200 silica gel) eluting with 0-40% EtOAc / hexane followed by reverse phase preparative chiral HPLC to get 32 (51mg, 0.1186mmol, 10%) and 33 (25mg, 0.0578mmol, 5%).

[0722] 32. HPLC: Rt: 5.795 min, 99.83%; Column: XSELECT CSH C18 (150 X 4.6 mm, 3.5 μ); Mobile Phase-A: 0.05% TFA: Acetonitrile (95:05); Mobile Phase-B: Acetonitrile: 0.05% TFA (95:05); LCMS: 428.25 (M-H), Rt 2.110 min, Column: X-SELECT CSH C18 (50*3) mm 2.5u; Mobile Phase: A: Water + 2.5 mM Ammonium bicarbonate; B: Acetonitrile; Chiral HPLC: Rt: 9.192 min, 99.08%; Column: Chiral pak-IG (250x4.6 mm 5 μm); Mobile Phase A: n-Hexane + 0.1% DEA; Mobile Phase B: ETOH. 1 H NMR (400 MHz, 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=8 Hz, 1H), 7.38 (s, 1H), 5.53 - 5.40 (m, 1H), 1.64 (d, 3H).

[0723] 33. HPLC: Rt: 5.707 min, 99.37%; Column: XSELECT CSH C18 (150 X 4.6 mm, 3.5 μ); Mobile Phase-A: 0.05% TFA: Acetonitrile (95:05); Mobile Phase-B: Acetonitrile: 0.05% TFA (95:05); LCMS: 428.20 (M-H), Rt 2.097 min, Column: X-SELECT CSH C18 (50*3) mm 2.5u; Mobile Phase: A: Water + 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 x 4.6 mm 5 μm); Mobile Phase A: n-Hexane + 0.1% DEA. 1 H NMR (400 MHz, 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).

[0724] Examples 34 and 35. Synthesis of (S)-N-(l-(3-(2-(trifluoromethyl)pyridin-4- yl)isoxazol-5-yl)ethyl)-3,4-dihydroquinoline-l(2H)-carboxamide (34) and (R)-N-(l-(3-(2-(trifluoromethyl)pyridin-4-yl)isoxazol-5-yl)ethyl)-3,4- dihydroquinoline-l(2H)-carboxamide (35). Note that the stereochemistry is assigned arbitrarily.

[0725]

[0726] 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) was added CDI (378.25 mg, 2.33 mmol) and TEA (0.49 mL, 3.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 x 50 mL). The combined extracts were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash column chromatography (100-200 silica gel), followed by preparative chiral HPLC to afford 34 (55 mg, 0.1311 mmol, 11% yield) and 35 (60 mg, 0.1435 mmol, 12% yield)

[0727] 34: HPLC: Rt: 7.925 min, 99.23 %; Column: XSELECT CSH C18 (150 X 4.6 mm, 3.5 µ); 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 X 50 mm, 2.5 µm); Mobile Phase: A: Water + 0.025 % FA, B: ACN; Chiral HPLC: Rt: 4.904 min, 100 %; Column: Chial pak-IA (150 x 4.6 mm, 3 µm) Date Acquired 05-01-2021 13:08:58 IST; Mobile Phase A: n-Hexane + 0.1 % DEA; Mobile Phase B: DCM: MEOH; Flow Rate: 0.70 mL / min. 1 HNMR (400 MHz, 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 (quin, 2H), 1.56 (d, 3H).

[0728] 35: HPLC: Rt: 7.926 min, 99.62 %; Column: XSELECT CSH C18 (150 X 4.6 mm, 3.5 µ); 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 X 150 mm, 3.5 µm); Mobile Phase: A: 0.025 % mM Formic acid in water, B: ACN; Chiral HPLC: Rt 7.094 min, 98.78 %; Method File Name: CHIRAL-A.lcm; Column: CHIRAL PAK IA (150 mm X 4.6 mm, 3 µm); Mobile Phase A: n-Hexane + 0.1 % DEA; Mobile Phase B: DCM: MEOH (1:1); A:B: 80:20; Flow Rate: 0.70 mL / min. 1H NMR (400 MHz, 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 (quin, 2H), 1.56 (d, 3H).

[0729] Examples 36 and 37. Synthesis of (R)-1-cyclobutyl-N-(1-(3-(2-(trifluoromethyl)pyridin-4- yl)isoxazol-5-yl)ethyl)-1H-pyrazole-5-carboxamide (36) and (S)-1-cyclobutyl-N-(1-(3-(2- (trifluoromethyl)pyridin-4-yl)isoxazol-5-yl)ethyl)-1H-pyrazole-5-carboxamide (37). Note that stereochemistry is assigned arbitrarily.

[0730]

[0731] 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) was added HATU (495 mg, 1.3 mmol) followed by N,N-diisopropylethylamine (0.7 mL, 4.32 mmol) at 0 °C and stirred at room temperature for 15 h. The reaction mixture was quenched by the addition of water (10 mL) and then the reaction mixture was extracted with EtOAc (2 x 25 mL), the combined extracts were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash column chromatography (100-200 silica gel) using 0-40% EtOAc / hexane as eluent followed by reverse phase preparative chiral HPLC to give 36 (16 mg, 0.0383 mmol, 3% yield) and 37 ((12 mg, 0.0291 mmol, 2%) both as solids.

[0732] 36: HPLC: Rt: 10.84 min, 97.10%; Column; X SELECT CSH C18 (150X4.6 mm, 3.5 um); Mobile phase A: 5 mM Ammonium acetate; Mobile phase B: Acetonitrile; LCMS: 404.20 (M-H), Rt 2.005 min, Column: X-SELECT CSH C18 (50*3) mm 2.5 u; Mobile phase: A: Water + 2.5 mM Ammonium bicarbonate; B: Acetonitrile; Chiral HPLC: Rt: 20.326 min, 100%; Column: Chial pak-IG (250x4.6 mm 3 pm); Mobile phase A: n-Hexane + 0.1% DEA; Mobile phase B: IPA; 1 H NMR (400 MHz, 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, 1H), 5.65 (quin, 1H), 5.45-5.33 (m, 1H), 2.38-2.25 (m, 4H), 1.84-1.69 (m, 2H), 1.60 (d, 3H).

[0733] 37: HPLC: Rt: 10.84 min, 98.44%; Column; X SELECT CSH C18 (150X4.6 mm, 3.5 um); Mobile phase A: 5 mM Ammonium acetate; Mobile phase B: Acetonitrile; LCMS: 404.30 (M-H), Rt 2.002 min, Column: X-SELECT CSH C18 (50*3) mm 2.5 u; Mobile phase: A: Water + 2.5 mM Ammonium bicarbonate; B: Acetonitrile; Chiral HPLC: Rt 14.486 min, 100%; Column: Chial pak-IG (250x4.6 mm 3 pm); Mobile phase A: n-Hexane + 0.1% DEA; Mobile phase B: IPA; 1 H NMR (400 MHz, 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, 1H), 5.65 (quin, 1H), 5.45-5.33 (m, 1H), 2.38-2.25 (m, 4H), 1.84-1.69 (m, 2H), 1.60 (d, 3H).

[0734] Examples 38 and 39. Synthesis of (S)-N-(l-(3-(2-(trifluoromethyl)pyridin-4- yl)isoxazol-5-yl)ethyl)-2,3-dihydro-4H-benzo[b][l,4]oxazin-4-carboxamide (38) and (R)-N-(l-(3-(2-(trifluoromethyl)pyridin-4-yl)isoxazol-5-yl)ethyl)-2,3-dihydro-4H- benzo[b][l,4]oxazin-4-carboxamide (39). Note that stereochemistry is assigned arbitrarily.

[0735]

[0736] To a stirred solution of A-17 (250 mg, 0.9700 mmol) and 3,4-dihydro-2H-l,4- benzoxazine (258.91 mg, 1.92 mmol) in DCM (10 mL) was added CDI (315.21 mg, 1.94 mmol) and TEA (0.41 mL, 2.92 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 x 50 mL). The combined extracts were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash column chromatography (100-200 silica gel) using 30-50% EtOAc / hexane as eluent followed by preparative chiral HPLC to afford 38 (70 mg, 0.1663 mmol, 17% yield) and 39 (55 mg, 0.1313 mmol, 13% yield).

[0737] 38: HPLC: Rt: 7.37 min, 99.41%; Column: ATLANTIS T3 (150 X 4.6 mm, 3.5 μ); Mobile Phase A: Water + 0.05% TFA; ACN (95; 05); Mobile Phase B: Water + 0.05% TFA; ACN (05; 95); LCMS: 419.1 (M+H), Rt 2.153 min, Column: X-Bridge BEH C-18 (3.0 X 50 mm, 2.5 μm); Mobile Phase: A: Water + 0.025% FA, B: ACN; Chiral HPLC: Rt: 6.046 min, 100%; Column: Chiral pak-IG (250 x 4.6 mm, 5 μm); Mobile Phase A: n-Hexane + 0.1% DEA; 1H NMR (400 MHz, 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).

[0738] 39: HPLC: Rt: 7.17 min, 97.32%; Column: X SELECT CSH C18 (150 X 4.6 mm, 3.5 um); Mobile Phase A: Water + 0.05% Formic Acid; Mobile Phase B: Acetonitrile; LCMS: 374.05 (M-H), Rt 2.109 min, Column: Kinetex EVO C18 (50*3) mm 2.6 u; Mobile Phase: A: Water + 2.5 mM Ammonium bicarbonate; B: Acetonitrile; Injection Volume: 2 pL, Flow rate: 1.2 mL / min; Chiral HPLC: Rt 13.073 min, 100%; Column: CHIRAL PAK IC (150*4.6 mm, 3 pm); Mobile Phase A: n-Hexane + 0.1% DEA; Mobile Phase B: DCM:MEOH (50:50). 1 H NMR (400 MHz, 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 (quin, 1H), 4.25-4.20 (m, 2H), 3.83-3.72 (m, 2H), 1.56 (d, 3H).

[0739] Example 40. 2-Methyl-N-[(1S)-1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (40)

[0740]

[0741] 5-(1-ethoxyvinyl)-3-(2-methyl-4-pyridyl)-1,2,4-thiadiazole (C-34)

[0742] To a mixture of 3-bromo-5-(l-ethoxyvinyl)-l,2,4-thiadiazole (1.5 g, 6.38 mmol) in DME (30.0 mL) was added (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). After stirring at 100 °C for 3 h, the mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (0-30% EtOAc / PE) to give the product as a solid (1.20 g, 4.61 mmol, 72% yield). 1 H NMR (400 MHz, CDC13) 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).

[0743] 1-[3-(2-Methyl-4-pyridyl)-l,2,4-thiadiazol-5-yl]ethanone (C-35)

[0744] To a mixture of 5-(l-ethoxyvinyl)-3-(2-methyl-4-pyridyl)-l,2,4-thiadiazole (1.20 g, 4.85 mmol) in acetone (15.0 mL) was added HC1 (8.0 mL, 2M, 4.85 mmol). After stirring at 50 °C for 16 h, the mixture was diluted with water (15.0 mL) and extracted with EtOAc (3 x 10.0 mL). The combined organic phases were washed with brine (30.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the product as an oil (1.10 g, 4.52 mmol, 93% yield). 1 H NMR (400 MHz, CDC13) δ H = 8.68 (d, 1H), 8.06 (s, 1H), 7.99 (d, 1H), 2.83 (s, 3H), 2.69 (s, 3H).

[0745] (R,E)-2-Methyl-N-[l-[3-(2-methyl-4-pyridyl)-l,2,4-thiadiazol-5-yl]ethylidene]propane-2- sulfonamide (C-36)

[0746] To a solution of l-[3-(2-methyl-4-pyridyl)-l,2,4-thiadiazol-5-yl]ethanone (300 mg, 1.37 mmol) in THF (5.0 mL) and (R)-2-methylpropane-2-sulfinamide (249 mg, 2.05 mmol) was added Ti(OEt)4(0.94 g, 4.10 mmol). After stirring at 50 °C for 16 h, the mixture was poured into saturated NaHC03(20 mL) and diluted with EtOAc (10.0 mL). The resulting slurry was filtered and extracted with EtOAc (3 x 10.0 mL). The combined organic layers were washed with brine (2 x 30.0 mL), dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by flash column (0-30% EtOAc / PE) to give the product as an oil (550 mg). The product was purified by flash column (0-30% EtOAc / PE) to give the product as a solid (350 mg, 1.09 mmol, 64% yield). 1 H NMR (400 MHz, CDC13) δ H = 8.69 (d, 1H), 8.27-8.11 (m, 2H), 2.97 (s, 3H), 2.83 (s, 3H), 1.37 (s, 9H).

[0747] (R)-2-methyl-N-[(lS)-l-[3-(2-methyl-4-pyridyl)-l,2,4-thiadiazol-5-yl]ethyl]propane-2- sulfinamide (C-37)

[0748] To a solution of (R,E)-2-methyl-N-[l-[3-(2-methyl-4-pyridyl)-l,2,4-thiadiazol-5-yl]ethylidene]propane-2-sulfinamide (350 mg, 1.09 mmol) in THF (4.0 mL) at -78 °C was added L-Selectride (2.17 mL, 2.17 mmol). After stirring at -78 °C for 0.5 h, the mixture was poured into saturated NH4C1 (20.0 mL) and extracted with EtOAc (2 x 10.0 mL). The combined organic layers were washed with brine (2 x 20.0 mL), dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by flash column (0-10% MeOH / DCM) to give the product as a solid (270 mg, 0.832 mmol, 77% yield). 1 H NMR (400 MHz, CDC13) δ H = 8.69 (d, 1H), 8.27-8.11 (m, 2H), 2.97 (s, 3H), 2.83 (s, 3H), 1.37 (s, 9H).

[0749] (1S)-1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethylamine (C-38)

[0750] To a solution of (R)-2-methyl-N-[(1S)-1-[3-(2-methyl-4-pyridyl)-1,2,4- thiadiazol-5-yl]ethyl]propane-2-sulfmamide (270 mg, 0.83 mmol) in 1,4-dioxane (5.0 mL) was added 4M HC1 / dioxane (3 mL) at 25 °C. After stirring at 25 °C for 1 h, the mixture was concentrated to give the product as a solid. 1 H NMR (400 MHz, MeOD) 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).

[0751] 2-methyl-N-[(1S)-1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (40)

[0752] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (229 mg, 1.18 mmol) in DCM (8.0 mL) was added DIEA (937 mg, 7.26 mmol) and T3P (2.71 g, 2.72 mmol). After stirring at 25 °C for 20 min, (1S)-1-[3-(2-methyl-4-pyridyl)-1,2,4- thiadiazol-5-yl]ethylamine hydrochloride (200 mg, 0.91 mmol) was added and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (10.0 mL) and extracted with DCM (2 x 15.0 mL). The combined organic layers were washed with brine (20.0 mL) and dried over Na2S04, filtered and concentrated. The residue was purified by flash column (0-10% MeOH / DCM) to give the product as a solid (300 mg, 0.757 mmol, 83% yield). The product was purified by SFC (column DAICEL CHIRALPAK IG (250 mm*30 mm, 10 pm), conditions 0.1% NH3H20 EtOH, start B 20%, end B 20%, gradient time (min), 100% B hold time (min), flow rate (ml / min) 60, injection 35) to give the product as a solid (81.2 mg, 0.197 mmol, 26% yield). 1 H NMR (400 MHz, 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, CDC13) δ F = -62.195. LCMS R t = 0.895 min (in 1.5 min chromatography), 5-95 AB, C 16 H 16 F3N6OS [M+H] + MS ESI calculated for F3N6OS 396.9, found 396.9.

[0753] Example 41. (R)-1 -Methyl-N-(1 -(3-(2-methylpyridin-4-yl)-1,2,4-thiadiazol-5- yl)ethyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (41)

[0754]

[0755] (S,E)-2-methyl-N-[1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethylidene]propane- 2-sulfonamide (C-39)

[0756] To a solution of 1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethanone (300 mg, 1.37 mmol) in THF (5.0 mL) and (S)-2-methylpropane-2-sulfonamide (249 mg, 2.05 mmol) was added Ti(OEt)4(0.94 g, 4.10 mmol). After stirring at 50 °C for 16 h, the mixture was poured into saturated NaHC03(20 mL) and diluted with EtOAc (10.0 mL). The resulting slurry was filtered and extracted with EtOAc (3 x 10.0 mL). The combined organic layers were washed with brine (2 x 30.0 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by flash column (0-30% EtOAc / PE) to give the product as an oil (310 mg, 0.96 mmol, 70% yield). 1 H NMR (400 MHz, CDC13) 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).

[0757] (S)-2-methyl-N-[(1R)-1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]propane-2- sulfonamide (C-40)

[0758] To a solution of (S,E)-2-methyl-N-[1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethylidene]propane-2-sulfonamide (310 mg, 0.96 mmol) in THF (4.0 mL) was added K-Selectride (1.92 mL, 1.92 mmol) at -78 °C. After stirring at -78 °C for 0.5 h, the mixture was poured into saturated NH4Cl (20.0 mL) and extracted with EtOAc (2 x 10.0 mL). The combined organic layers were washed with brine (2 x 20.0 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column (0-10% MeOH / DCM) to give the product as a solid (200 mg, 0.616 mmol, 64% yield). 1 H NMR (400 MHz, CDC13) 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).

[0759] (R)-1-(3-(2-methylpyridin-4-yl)-1,2,4-thiadiazol-5-yl)ethylamine hydrochloride (C-41)

[0760] To a solution of (S)-2-methyl-N-[(1R)-1-[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazol-5- yl]ethyl]propane-2-sulfonamide (200 mg, 0.62 mmol) in 1,4-dioxane (3.0 mL) was added 4M HC1 / dioxane (2.31 mL, 9.25 mmol) at 25 °C. After stirring at 25 °C for 1 h, the mixture was concentrated to give the product as a solid (120 mg, 0.38 mmol). 1 H NMR (DMSO-d6, 400 MHz) 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).

[0761] (R)-1 -Methyl- N-(1 -(3-(2-methylpyridin-4-yl)-1,2,4-thiadiazol-5- yl)ethyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (41 )

[0762] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (97.0 mg, 0.50 mmol) in DCM (8.0 mL) was added DIEA (409.0 mg, 3.17 mmml) and T3P (904 mg, 1.19 mmol). After stirring at 25 °C for 20 min, (1 R)-1 -[3-(2-methyl-4-pyridyl)-1,2,4-thiadiazol-5- yl]ethylamine hydrochloride (100 mg, 0.45 mmol) was added and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (10.0 mL) and extracted with DCM (2 x 15.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2S04, 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 % NH3H20-MeOH, start B: 20%, end B: 20%, flow (mL / min): 60, injection: 30) to give the product (113.2 mg, 0.29 mmol, 57% yield) as a solid. 1 H NMR (400 MHz, CDCI3) δ H = 8.72-8.58 (m, 1 H), 7.99 (s, 1 H), 7.95-7.89 (m, 1 H), 6.91 (s, 1 H), 6.83-6.75 (m, 1 H), 5.79-5.65 (m, 1 H), 4.24 (s, 3H), 2.66 (s, 3H), 1.87-1.77 (m, 3H). 19 F NMR (376.5 MHz, CDCI3) δ F = -62.183. LCMS R t = 1.241 min (in 2.0 min chromatography), 10-80 AB, C 16 H 16 F3N6OS [M+H] + MS ESI calculated for F3N6OS 397.1, found 397.1.

[0763] Example 42 and 43. 2-Methyl-N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridinyl]-1,2,4- thiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide and 2-methyl-N-[(1R)-1-[3-[2- (methoxymethyl)-4-pyridinyl]-1,2,4-thiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3- carboxamide.

[0764]

[0765] 4-Bromo-2-(methoxymethyl)pyridine (C-43)

[0766] To a mixture of (4-bromo-2-pyridinyl)methanol (9.0 g, 47.9 mmol) in DMF (15.0 mL) was added NaH (2.30 g, 57.4 mmol, 60%) at 0 °C under N2. After stirring for 30 min, a mixture of iodomethane (3.29 mL, 52.6 mmol) in DMF (5.0 mL) was added and the mixture was stirred at 15 °C for 16 h. The mixture was poured into ice water (30.0 mL) and the aqueous phase was extracted with EtOAc (3 x 30.0 mL). The combined organic phases were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE / EtOAc = 3 / 1 to 1 / 1) to give the product as an oil (9.0 g, 44.5 mmol, 93% yield). 1 H NMR (CDCI3, 400 MHz) δ H = 8.36 (d, 1H), 7.63 (d, 1H), 7.37 (dd, 1H), 4.57 (s, 2H), 3.51-3.46 (m, 3H).

[0767] 2-(Methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (C-44)

[0768] 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-dioxaborolane (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 at 100 °C for 3 h under N2. The mixture was cooled to 25 °C, filtered and concentrated to give the product as an oil (9.0 g, 36.1 mmol).

[0769] 5-(1-ethoxyethenyl)-3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazole (C-45)

[0770] To a mixture of 3-bromo-5-(1-ethoxyethenyl)-1,2,4-thiadiazole (2.0 g, 8.51 mmol), [2-(methoxymethyl)-4-pyridyl]boronic acid (2.84 g, 17.0 mmol) and Cs2C03(5.54 g, 17.0 mmol) in DME (20.0 mL) and water (4.0 mL) was added Pd(dppf)C12(622 mg, 0.85 mmol) and heated with a microwave reactor at 90 °C for 1.5 h. After cooling to 25 °C, the reaction mixture was quenched with water (40.0 mL) and extracted with EtOAc (2 x 40.0 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatography with PE / EtOAc = 1 / 1 to give the product as an oil (2.10 g, 7.57 mmol, 89% yield). 1 H NMR (CDC13, 400 MHz) 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).

[0771] 1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethenone (C-46)

[0772] To a mixture of 5-(1-ethoxyethenyl)-3-[2-(methoxymethyl)-4-pyridyl]-1,2,4- thiadiazole (2.19 g, 7.90 mmol) in acetone (20.0 mL) was added 2M HC1 (7.90 mL, 15.8 mmol). After stirring at 50 °C for 16 h, the mixture was diluted with water (5.0 mL) and extracted with EtOAc (3 x 5.0 mL). The combined organic phases were washed with brine (20.0 mL), dried over anhydrous Na2S04, filtered and concentrated to give the product as an oil (1.60 g, 5.78 mmol, 73% yield). LCMS R t = 0.861 min (in 1.5 min chromatography), 5-95 AB, C 11 H 12 N3O2S [M+H] + MS ESI calculated for N3O2S [M+H] 250.1, found 249.9.

[0773] (R,E)-N-[1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethylidene]-2-methyl-propane-2-sulfinamide (C-47)

[0774] Ti(OEt)4 (2.75 g, 12.0 mmol) was added to a solution containing 1-[3-[2-(methoxymethyl)-4-pyridinyl]-1,2,4-thiadiazol-5-yl] ethyl ketone (1.0 g, 4.0 mmol) in THF (10.0 mL) and (R)-2-methylpropane-2-sulfinamide (729 mg, 6.10 mmol). After stirring at 50 °C for 16 h, the mixture was poured into saturated NaHCO3 (20.0 mL) and diluted with EtOAc (10.0 mL). The resulting slurry was filtered, and the mother liquor was 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 rapid column chromatography to an oily product (190 mg, 0.54 mmol, 22% yield). 1 H 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).

[0775] R)-N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethyl]-2-methyl-propane-2-sulfinamide (C-48)

[0776] K-Selectride (1.08 mL, 1.08 mmol) was added to a solution of (R,E)-N-[1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethylene]-2-methyl-propane-2-sulfinamide (190 mg, 0.54 mmol) in THF (4.0 mL) at -78 °C. After stirring at -78 °C for 0.5 h, the mixture was poured into saturated NH4Cl (20.0 mL) and extracted with EtOAc (2 × 10.0 mL). The combined organic layers were washed with brine (2 × 20.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography to give the product as a solid (130 mg, 0.37 mmol, 68% yield). LCMS R t =0.803 min (in a 1.5 min chromatogram), 5-95AB, C15 H 23 N4O2S2[M+H] + MS ESI calculated for N4O2S2[M+H] 355.1, found 355.1.

[0777] (1S)-1-[3-[2-(Methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethylamine hydrochloride (C-49)

[0778] To a solution of (R)-2-methyl-N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4- thiadiazol-5-yl]ethyl]propane-2-sulfmamide (130 mg, 0.37 mmol) in 1,4-dioxane (5.0 mL) was added 4 M HC1 / dioxane (6.0 mL, 1.83 mmol) at 25 °C. After stirring at 25 °C for 1 h, the residue was filtered and concentrated to give the product as a solid (130 mg, 0.52 mmol). 1 H NMR (MeOD, 400 MHz) 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).

[0779] 2-Methyl-N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (C-50)

[0780] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (111 mg, 0.57 mmol) in DCM (2.0 mL) was added DIEA (0.91 mL, 5.19 mmol), T3P (1.18 g, 1.56 mmol) at 25 °C. After stirring for 10 min, (1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethanamine hydrochloride (130 mg, 0.52 mmol) was added and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with water (20.0 mL) and extracted with DCM (2 x 20.0 mL). The combined organic layers were washed with brine (60.0 mL) and dried over Na2S04, filtered and concentrated to give the product which was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 x 30 mm x 3 pm; conditions: water (10 mM NH4HC03)-ACN; start B: 42 to 72% B, 10 min) to give the product as a solid (75.0 mg, 0.18 mmol, 34% yield).

[0781] 2-methyl-N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide and 2-methyl-N-[(1R)-1-[3-[2-(methoxymethyl)-4- pyridyl]-1,2,4-thiadiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide. It is noted that the stereochemistry is assigned randomly

[0782] 2-methyl-N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (75.0 mg, 0.18 mmol) was purified by SFC (DAICEL CHIRALCEL AY-H (250 mm*30 mm, 5 pm); conditions: 0.1% NH3H20-EtOH; start B: 15 to 15) to give 2-methyl-N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4- thiadiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide as a solid (61.5 mg, 0.14 mmol, 82% yield) and 2-methyl-N-[(1R)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4- thiadiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide as a solid (2.46 mg, 0.01 mmol, 3% yield).

[0783] 42:1 H NMR (CDC13, 400 MHz) 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, CDC13) δ F = -62.160. LCMS R t = 0.951 min (in 2.0 min chromatogram), 10-80 AB, C 17 H 18 F3N6O2S [M+H] + MS ESI calculated for 427.1, found 427.1.

[0784] 43: 1 H NMR (CDC13, 400 MHz) 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, CDC13) δ F = -62.169. LCMS R t = 0.957 min (in 2.0 min chromatogram), 10-80 AB, C 17 H 18 F3N6O2S [M+H] + MS ESI calculated for 427.1, found 427.1.

[0785]

[0786] (R,E)-N-[1-[3-[2-(Methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethylidene]-2- methyl-propane-2-sulfonamide (C-51)

[0787] To a solution of l-[3-[2-(methoxymethyl)-4-pyridyl]-l,2,4-thiadiazol-5-yl]ethanone (300 mg, 1.20 mmol) in THF (5.0 mL) and (S)-2-methylpropane-2-sulfinamide (219 mg, 1.81 mmol) was added Ti(OEt)4(823 mg, 3.61 mmol). After stirring at 50 °C for 16 h, the mixture was poured into saturated NaHC03(20.0 mL) and diluted with EtOAc (10.0 mL). The resulting slurry was filtered, and the mother liquor was extracted with EtOAc (3 x 10.0 mL). The combined organic layers were washed with brine (2 x 30.0 mL), dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by flash column (0-30% EtOAc / PE) to give the product as an oil (90.0 mg, 0.26 mmol, 21% yield). 1 H NMR (CDC13, 400 MHz) 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).

[0788] (R)-N-[(lS)-l-[3-[2-(methoxymethyl)-4-pyridyl]-l,2,4-thiadiazol-5-yl]ethyl]-2- methyl-propane-2-sulfinamide (C-52)

[0789] To a solution of (R,E)-N-[l-[3-[2-(methoxymethyl)-4-pyridyl]-l,2,4-thiadiazol-5- yl]ethylidene]-2-methyl-propane-2-sulfinamide (150 mg, 0.43 mmol) in THF (4.0 mL) at -78 °C was added K-Selectride (0.85 mL, 0.85 mmol). After stirring at -78 °C for 0.5 h, the mixture was poured into saturated NH4C1 (20.0 mL) and extracted with EtOAc (2 x 10.0 mL). The combined organic layers were washed with brine (2 x 20.0 mL), dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by flash column (0-10% MeOH / DCM) to give the product as a solid (120 mg, 0.34 mmol, 80% yield). 1 H NMR (CDC13, 400 MHz) 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).

[0790] (1R)-1-[3-[2-(Methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethylamine hydrochloride (C-53)

[0791] To a solution of (S)-N-[(1R)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5- yl]ethyl]-2-methyl-propane-2-sulfmamide (120 mg, 0.34 mmol) in 1,4-dioxane (5.0 mL) was added 4 M HC1 / dioxane (6.0 mL, 1.69 mmol) at 25 °C. After stirring at 25 °C for 1 h, the residue was filtered and concentrated to give the product as a solid (84.0 mg, 0.29 mmol, 87% yield), which was used directly in the next step.

[0792] N-[(1R)-1-[3-[2-(Methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethyl]-2-methyl-5- (trifluoromethyl)pyrazole-3-carboxamide (C-54)

[0793] 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 min. (1R)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethylamine hydrochloride (84.0 mg, 0.29 mmol) was added. After stirring at 25 °C for 1 h, the reaction mixture was quenched with water (10.0 mL) and extracted with DCM (2 x 15.0 mL). The combined organic layers were washed with brine (20.0 mL) and dried over Na2S04, filtered and concentrated to give the product as an oil (100 mg, 0.23 mmol, 70% yield). 1 H NMR (CDC13, 400 MHz) 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).

[0794] N-[(1R)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethyl]-2-methyl-5- (trifluoromethyl)pyrazole-3-carboxamide and N-[(1S)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4- thiadiazol-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3-carboxamide

[0795] A mixture of N-[(1R)-1-[3-[2-(methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethyl]-2- methyl-5-(trifluoromethyl)pyrazole-3-carboxamide (100 mg, 0.23 mmol) was purified by SFC (column DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 pm), conditions 0.1% NH3H2O-EtOH, start B 15%, end B 15%, flow (mL / min) 60) to give N-[(1R)-1-[3-[2- (methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3- carboxamide (38.9 mg, 0.09 mmol, 39% yield) as a solid and (R)-N-(1-(3-(2- (methoxymethyl)pyridin-4-yl)-1,2,4-thiadiazol-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- thiadiazol-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3-carboxamide (10.0 mg) was purified by SFC (column DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 pm), conditions 0.1% NH3H2O-EtOH, start B 15%, end B 15%, flow (mL / min) 60) to give N-[(1S)-1-[3-[2- (methoxymethyl)-4-pyridyl]-1,2,4-thiadiazol-5-yl]ethyl]-2-methyl-5-(trifluoromethyl)pyrazole-3- carboxamide (3.41 mg, 0.008 mmol, 34% yield) as a solid.

[0796] 43: 1 H NMR (CDC13, 400 MHz) 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). 19 F NMR (376.5 MHz, DMSO-d6) δ F -62.174. LCMS R t = 0.948 min (in 2.0 min chromatogram), 10-80 AB, C 17 H 18 F3N6O2S [M+H] + MS ESI calculated for 427.1, found 427.0.

[0797] 42: 1 H NMR (CDC13, 400 MHz) 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, 1H), 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, CDC13) δ F -62.174. LCMS R t = 0.956 min (in 2.0 min chromatogram), 10-80 AB, C 17 H 18 F3N6O2S [M+H] + MS ESI calculated for 427.1, found 427.1.

[0798] Example 44. Synthesis of 2-methyl-N-[(1S)-1-[3-(2-methoxy-4-pyridyl)-1,2,4- thiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (44)

[0799]

[0800] 5-(1-ethoxyvinyl)-3-(2-methoxypyridin-4-yl)-1,2,4-thiazole (C-55)

[0801] To a mixture of (2-methoxy-4-pyridyl)boronic acid (1.27 g, 8.29 mmol) and 3-bromo-5-(l-ethoxyvinyl)-l,2,4-thiadiazole (1.50 g, 6.38 mmol) and Cs2C03(4.16 g, 12.7 mmol) in water (1.0 mL) and DME (10.0 mL, 6.38 mmol) was added Pd(dppf)Cl2(0.7 g, 0.96 mmol) under N2. 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 x 20.0 mL). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by flash column (10-40% EtOAc / PE) to give the product as an oil (1.30 g, 4.44 mmol, 70% yield). 1 H NMR (CDC13, 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).

[0802] 1-(3-(2-methoxypyridin-4-yl)-l,2,4-thiadiazol-5-yl)ethanone (C-56)

[0803] To a mixture of 5-(l-ethoxyvinyl)-3-(2-methoxy-4-pyridyl)-l,2,4-thiadiazole (1.30 g, 4.94 mmol) in acetone (15.0 mL) was added 12 HC1 (2.0 mL, 4.94 mmol). After stirring at 50 °C for 16 h, the mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2S04, filtered and concentrated to give the product as an oil (1.1 g, 4.21 mmol, 85% yield). 1 H NMR (CDC13, 400 MHz) δ H = 8.36 (d, 1H), 7.80 (d, 1H), 7.69 (s, 1H), 4.06 (s, 3H), 2.82 (s, 3H).

[0804] (R,E)-N-(l-(3-(2-methoxypyridin-4-yl)-l,2,4-thiadiazol-5-yl)ethylidene)-2- methylpropane-2-sulfonamide (C-57)

[0805] To a solution of l-[3-(2-methoxy-4-pyridyl)-l,2,4-thiadiazol-5-yl]ethanone (300 mg, 1.28 mmol) in THF (5.0 mL) and (R)-2-methylpropane-2-sulfinamide (232 mg, 1.91 mmol) was added Ti(OEt)4(0.87 g, 3.83 mmol). The mixture was stirred at 50 °C for 16 h, then cooled to 25 °C before pouring into a rapidly stirred solution of NaHC03(10 mL). After stirring the solution for 5 min, celite was stirred into the slurry and the suspension was filtered through a pad of celite. The solid was washed with EtOAc (3 x 10 mL) and the combined filtrate was transferred to a separatory funnel. The aqueous portion was separated and extracted with EtOAc (2 x 10 mL) and the combined organic portions were dried over Na2S04, filtered and evaporated under reduced pressure. The product was purified by column chromatography (polarity increasing from 5% to 20% EtOAc in pentane as eluent) to give the product as an oil (300 mg, 0.80 mmol, 63% yield). 1 H NMR (CDC13, 400 MHz) 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).

[0806] (R)-N-((S)-l-(3-(2-methoxypyridin-4-yl)-l,2,4-thiadiazol-5-yl)ethyl)-2- methylpropane-2-sulfinamide (C-58)

[0807] To a solution of (R,E)-N-[l-[3-(2-methoxy-4-pyridyl)-l,2,4-thiadiazol-5-yl]ethylidene]- 2-methyl-propane-2-sulfinamide (300 mg, 0.89 mmol) in THF (5 mL) at -78 °C was added K-Selectride (1.77 mL, 1.77 mmol). After stirring at -78 °C for 0.5 h, the mixture was poured into saturated NH4C1 (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by flash column (0-50% EtOAc / PE) to give the product as a solid (150 mg, 0.40 mmol, 45% yield). 1 H NMR (CDC13, 400 MHz) 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).

[0808] (1S)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethylamine (C-59)

[0809] To a solution of (R)-N-[(1S)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazol-5- yl]ethyl]-2-methyl-propane-2-sulfmamide (140 mg, 0.41 mmol) in 1,4-dioxane (5.0 mL) at 25 °C was added 4M HC1 / dioxane (6.0 mL, 2.06 mmol). After stirring at 25 °C for 1 h, the residue was filtered and concentrated to give (1S)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethylamine hydrochloride (120 mg, 0.508 mmol) as a solid. 1 H NMR (MeOD, 400 MHz) 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).

[0810] 2-methyl-N-[(1S)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (44)

[0811] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (128 mg, 0.66 mmol) in DCM (8.0 mL) was added DIEA (524 mg, 4.06 mmol) and T3P (1.16 g, 1.52 mmol). After stirring at 25 °C for 20 min, (1S)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethylamine hydrochloride (120 mg, 0.51 mmol) was added and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (20.0 mL) and extracted with DCM (2 x 15.0 mL). The combined organic layers were washed with brine (20.0 mL) and dried over Na2S04, filtered and concentrated. The residue was purified by flash column (0-60% EtOAc / PE) to give the product as a solid (210 mg, 0.509 mmol). 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 hold time (min), 60 mL / min, injection 30) to give the product as a solid (38.0 mg, 0.092 mmol, 18% yield). 1 H NMR (CDC13, 400 MHz) 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, CDC13) δ F MS ESI calc 412.9, found 412.9. t = 1.066 min (in 1.5 min chromatography), 5-95 AB, C 16 H 16 F3N6O2S [M+H] + MS ESI calc 412.9, found 412.9.

[0812] Examples 44 and 45. Synthesis of (R)-N-(1-(3-(2-methoxy-pyridin-4-yl)-1,2,4- thiadiazol-5-yl)ethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide and (S)-N-(1-(3-(2-methoxy-pyridin-4-yl)-1,2,4-thiadiazol-5-yl)ethyl)-1-methyl-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide

[0813]

[0814] (S,E)-N-(1-(3-(2-methoxypyridin-4-yl)-1,2,4-thiadiazol-5-yl)ethyl)-2- methylpropane-2-sulfonamide (C-61)

[0815] To a solution of 1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethanone (300 mg, 1.28 mmol) in THF (5.0 mL) was added (S)-2-methylpropane-2-sulfonamide (232 mg, 1.91 mmol) and Ti(OEt)4(0.87 g, 3.83 mmol). After stirring at 50 °C for 16 h, the mixture was cooled to 25 °C and poured into saturated NaHCO3(10.0 mL). After stirring for 5 min, celite was stirred into the slurry and the suspension was filtered through a celite pad. The solid was washed with EtOAc (3 x 10.0 mL) and the combined filtrate was extracted with EtOAc (2 x 10.0 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the product which was purified by column chromatography (EtOAc / PE, 5% to 20%) to give the product as an oil (230 mg, 0.612 mmol, 48% yield). 1 H NMR (CDCI3, 400 MHz) 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).

[0816] (S,E)-N-(1-(3-(2-methoxypyridin-4-yl)-1,2,4-thiadiazol-5-yl)ethyl)-2- methylpropane-2-sulfonamide (C-61)

[0817] To a solution of (S,E)-N-[l-[3-(2-methoxy-4-pyridyl)-l,2,4-thiadiazol-5- yl]ethylidene]-2-methyl-propane-2-sulfinamide (200 mg, 0.59 mmol) in THF (3.0 mL) was added K-Selectride (1.18 mL, 1.18 mmol) at -78 °C. After stirring at -78 °C for 0.5 h, the mixture was poured into saturated NH4Cl (20.0 mL) and extracted with EtOAc (2 x 10.0 mL). The combined organic layers were washed with brine (2 x 20.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column (0-50% EtOAc / PE) to give the product as a solid (100 mg, 0.27 mmol, 45% yield). LCMS R t = 0.921 min (in 1.5 min chromatography), 5-95 AB, C 14 H 21 N4O2S2 [M+H] + MS ESI calculated for N4O2S2[M+H] 341.1, found 341.1.

[0818] (R)-l-(3-(2-methoxy-pyridin-4-yl)-l,2,4-thiadiazol-5-yl)ethylamine hydrochloride (C-62)

[0819] To a solution of (S)-2-methyl-N-[(lR)-l-[3-(2-methoxy-4-pyridyl)-l,2,4- thiadiazol-5-yl]ethyl]propane-2-sulfinamide (100 mg, 0.29 mmol) in dioxane (0.50 mL) was added 4 M HC1 / dioxane (1.10 mL, 4.41 mmol) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was filtered, and the residue was washed with dioxane (5.0 mL) to give the product as a solid (80.0 mg, 0.24 mmol). LCMS R t = 0.679 min (in 1.5 min chromatography), 5-95 AB, C 10 H 13 N4OS [M+H] + MS ESI calculated for N4OS [M+H] 237.1, found 237.1.

[0820] (R)-N-(l-(3-(2-methoxy-pyridin-4-yl)-l,2,4-thiadiazol-5-yl)ethyl)-l-methyl-3- (trifluoromethyl)-lH-pyrazole-5-carboxamide (C-63)

[0821] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (74.8 mg, 0.39 mmol) in DCM (8.0 mL) was added DIEA (306 mg, 2.37 mmol), T3P (676 mg, 0.89 mmol). After stirring at 25 °C for 20 min, (1R)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethanamine (70.0 mg, 0.30 mmol) was added and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (10.0 mL) and extracted with DCM (2 x 15.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2S04, filtered and concentrated to give the product (120 mg, 0.26 mmol) as a solid which was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; conditions: water (10 mM NH4HC03)-ACN; start B: 46, end B: 76) to give the product (60.0 mg, 0.131 mmol) as a solid. LCMS R t = 0.755 min (in 1.0 min chromatography), 5-95 AB, C 16 16 F3N6O2S [M+H] + MS ESI calculated for F3N6O2S [M+H] 413.1, found 413.1.

[0822] (R)-N-(1-(3-(2-methoxy pyridin-4-yl)-1,2,4-thiadiazol-5-yl)ethyl)-1-methyl-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide and (S)-N-(1-(3-(2-methoxy pyridin-4-yl)- 1,2,4-thiadiazol-5-yl)ethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0823] ​2-methyl-N-[(1R)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (60.0 mg, 0.131 mmol) was purified by SFC (column DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 pm), conditions: 0.1% NH3H2O-MeOH, start B: 30%, end B: 30%, flow (mL / min): 60, injection: 30) as 2-methyl-N-[(1S)-1-[3-(2-methoxy-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (2.14 mg, 4% yield) and 2-methyl-N-[(1R)-1-[3-(2- methoxy-4-pyridyl)-1,2,4-thiadiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (35.4 mg, 59% yield) as solids.

[0824] 44: 1 H NMR (CDCI3, 400 MHz) δ H = 8.36-8.25 (m, 1H), 7.75-7.67 (m, 1H), 7.60 (s, 1H), 6.88 (s, 1H), 6.70-6.60 (m, 1H), 5.78-5.62 (m, 1H), 4.24 (s, 3H), 4.00 (s, 3H), 1.91-1.73 (m, 3H). 19 F NMR (376.5 MHz, CDCI3) δ F = -62.175. LCMS R t = 0.271 min (in 2.0 min chromatography), 50-100 AB, C 16 H 16 F3N6O2S [M+H] + MS ESI calculated for F3N6O2S [M+H] 413.1, found 413.1.

[0825] 45: 1 H NMR (CDCI3, 400 MHz) δ H = 8.41-8.21 (m, 1H), 7.77-7.65 (m, 1H), 7.60 (s, 1H), 6.89 (s, 1H), 6.77-6.55 (m, 1H), 5.70 (t, 1H), 4.24 (s, 3H), 4.00 (s, 3H), 1.92-1.73 (m, 3H). 19 F NMR (376.5 MHz, CDCI3) δ F = -62.177. LCMS Rt = 0.905 min (in 2.0 min chromatogram), 50-100 AB, C 16 H 16 F3N6O2S [M+H] + MS ESI calculated for C13H13F3N6O2S 413.1, found 413.1.

[0826] Examples 46 and 47: Synthesis of 2-methyl-N-[rac-(lS)-l-[3-(l-piperidinyl)-l,2,4- thiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide and 2-methyl-N-[rac-(lR)-l-[3-(l-piperidinyl)-l,2,4-thiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3- carboxamide

[0827]

[0828] 5-(l-Ethoxyvinyl)-3-(piperidin-l-yl)-l,2,4-thiazolium (C-64)

[0829] A mixture of 3-bromo-5-(l-ethoxyvinyl)-l,2,4-thiazolium (1.0 g, 4.25 mmol) and piperidine (1.81 g, 21.3 mmol) in DMF (10.0 mL) was stirred at 150 °C for 10 min. After cooling to 20 °C, the mixture was diluted with water (5.0 mL) and extracted with DCM (3 x 5.0 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by flash column (8-10% EtOAc / PE) to give the product (700 mg, 2.78 mmol, 65% yield) as an oil. 1 H NMR (CDC13, 400 MHz) δ H = 5.36 (d, 1H), 4.41 (d, 1H), 3.96 (q, 2H), 3.75-3.59 (m, 4H), 1.63 (s, 6H), 1.40 (t, 3H).

[0830] 1-(3-(Piperidin-l-yl)-l,2,4-thiazol-5-yl)ethenone (C-65)

[0831] To a mixture of 5-(l-ethoxyvinyl)-3-(l-piperidinyl)-l,2,4-thiadiazole (700 mg, 2.92 mmol) in acetone (8.0 mL) was added HC1 (2 M) (10.0 mL, 2.92 mmol). After stirring at 45 °C for 2 days, the mixture was diluted with water (10.0 mL) and extracted with EtOAc (3 x 10.0 mL). The combined organic phases were washed with brine (20.0 mL), dried over anhydrous Na2S04, filtered and concentrated to give the product (600 mg, 2.78 mmol, 95% yield) as an oil. 1 H NMR (CDC13, 400 MHz) δ H = 3.71 (s, 4H), 2.68 (s, 3H), 1.66 (s, 6H).

[0832] (R,E)-2-methyl-N-[l-[3-(l-piperidinyl)-l,2,4-thiadiazol-5-yl]ethylidene]propane-2- sulfonamide (C-66)

[0833] To a solution of l-[3-(l-piperidinyl)-l,2,4-thiadiazol-5-yl]ethanone (300 mg, 1.42 mmol) in THF (5.0 mL) and rac-(R)-2-methylpropane-2-sulfonamide (258 mg, 2.13 mmol) was added Ti(OEt)4(0.97 g, 4.26 mmol). After stirring at 50 °C for 16 h, the residue was poured into NaHC03(5.0 mL) and stirred for 20 min. The mixture was filtered over celite and the filtrate was extracted with EtOAc (3 x 5.0 mL). The combined organic phases were washed with brine (2 x 5.0 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1) to give the product (230 mg, 0.73 mmol, 52 yield) as a solid. 1 H NMR (CDC13, 400 MHz) δ H = 3.71-3.67 (m, 4H), 2.85-2.79 (m, 3H), 1.65 (s, 6H), 1.31 (s, 9H).

[0834] (R)-2-methyl-N-[(lS)-l-[3-(l-piperidinyl)-l,2,4-thiadiazol-5-yl]ethyl]propane-2- sulfonamide (C-67)

[0835] K-Selectride (1.46 mL, 1.46 mmol) was added to a solution of (R,E)-2-methyl-N-[1-[3-(1- piperidinyl)-1,2,4-thiadiazol-5-yl]ethylidene]propane-2-sulfmamide (230 mg, 0.73 mmol) in THF (3 mL) at -78 °C for 0.5 h. The mixture was poured into saturated NH4Cl (2.0 mL) and extracted with EtOAc (2 x 2.0 mL). The combined organic layers were washed with brine (2 x 2.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-10% MeOH / DCM) to give the product as a solid (200 mg, 0.63 mmol, 86% yield).1H NMR (CDCI3, 400 MHz) δ H = 4.87-4.76 (m, 1H), 3.72-3.65 (m, 4H), 1.75-1.70 (m, 3H), 1.67-1.62 (m, 6H), 1.41 (s, 1H), 1.29 (s, 9H).

[0836] (1S)-1-[3-(1-piperidinyl)-1,2,4-thiadiazol-5-yl]ethylamine (C-68)

[0837] To a solution of (R)-2-methyl-N-[(1S)-1-[3-(1-piperidinyl)-1,2,4-thiadiazol-5- yl]ethyl]propane-2-sulfmamide (200 mg, 0.63 mmol) in 1,4-dioxane (1.0 mL) was added 4 M HC1 / dioxane (1.0 mL, 19.9 mmol) at 25 °C. After stirring at 25 °C for 3 h, the reaction mixture was concentrated in vacuo to give the product as a solid (100 mg, 0.47 mmol, 75% yield).1H NMR (DMSO-d6, 400 MHz) δ H = 8.79-8.74 (m, 2H), 4.97-4.83 (m, 1H), 3.66-3.59 (m, 4H), 1.63-1.52 (m, 9H).

[0838] 2-methyl-N-[(1S)-1-[3-(1-piperidinyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (C-69)

[0839] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (90.6 mg, 0.47 mmol) in DCM (0.50 mL) was added DIEA (0.74 mL, 4.24 mmol), T3P (484 mg, 1.27 mmol) at 25 °C. After stirring for 20 min, (1S)-1-[3-(1-piperidinyl)-1,2,4-thiadiazol-5-yl]ethanamine hydrochloride (90.0 mg, 0.42 mmol) was added and the reaction was stirred at 25 °C for 16 h. The reaction was quenched with water (1.0 mL) and extracted with DCM (2 x 1.0 mL). The combined organic layers were washed with brine (1.0 mL) and dried over Na2S04, filtered and concentrated. The residue was purified by flash column (0-30% EtOAc / PE) to give the product as a solid (140 mg, 0.36 mmol, 85% yield). 1 H NMR (CDC13, 400 MHz) δ H = 6.83 (s, 1H), 6.67-6.61 (m, 1H), 5.56-5.48 (m, 1H), 4.23 (s, 3H), 3.69-3.64 (m, 4H), 1.69 (d, 3H), 1.65 (s, 6H).

[0840] 2-methyl-N-[(1S)-1-[3-(1-piperidinyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide and 2-methyl-N-[(1R)-1-[3-(1-piperidinyl)-1,2,4- thiadiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide

[0841] The residue of 2-methyl-N-[(1S)-1-[3-(1-piperidinyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (140 mg, 0.36 mmol) was purified by SFC (column DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 μm), conditions 0.1% NH3H2O ETOH, start B 25%, end B 25%, flow (mL / min) 60) to give 2-methyl-N-[(1S)-1-[3-(1-piperidinyl)-1,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide as a solid (75.3 mg, 0.19 mmol) and 2-methyl-N-[(1R)-1-[3-(1-piperidinyl)-1,2,4-thiadiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3- carboxamide as a solid (14.3 mg, 0.04 mmol).

[0842] 46:1 H NMR (CDC13, 400 MHz) δ H = 6.82 (s, 1H), 6.67-6.61 (m, 1H), 5.60-5.42 (m, 1H), 4.22 (s, 3H), 3.69-3.64 (m, 4H), 1.69 (d, 3H), 1.65 (s, 6H). LCMS R t = 1.623 min (in 2.0 min chromatography), 10-80 AB, C 15 H 20 F3N6OS [M+H] + MS ESI calculated for 389.1, found 389.1. 98.6% ee.

[0843] 47: 1 H NMR (CDC13, 400 MHz) δ H = 6.82 (s, 1H), 6.67-6.61 (m, 1H), 5.59-5.45 (m, 1H), 4.22 (s, 3H), 3.69-3.64 (m, 4H), 1.69 (d, 3H), 1.65 (s, 6H). LCMS R t = 1.622 min (in 2.0 min chromatography), 10-80 AB, C 15 H 20 F3N6OS [M+H] + MS ESI calculated for 389.1, found 389.1. 98.6% ee.

[0844]

[0845] (S,E)-2-methyl-N-(1-(3-(piperidin-1-yl)-1,2,4-thiadiazol-5-yl)ethylidene)propane-2- sulfonamide (C-70)

[0846] To a solution of l-[3-(l-piperidinyl)-l,2,4-thiadiazol-5-yl]ethanone (300 mg, 1.42 mmol) in THF (5.0 mL) was added rac-(S)-2-methylpropane-2-sulfinamide (258 mg, 2.13 mmol) and Ti(OEt)4(0.97 g, 4.26 mmol). After stirring at 50 °C for 16 h, the reaction was poured into NaHC03(5.0 mL) and stirred for 20 min. The mixture was filtered over celite and the filtrate was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (2 x 5.0 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by flash column (0-20% EtOAc / PE) to give the product as a solid (200 mg, 0.64 mmol, 45% yield). 1 H NMR (CDC13, 400 MHz) δ H = 3.72-3.64 (m, 4H), 2.82 (s, 3H), 1.65 (s, 6H), 1.31 (s, 9H).

[0847] (S)-2-methyl-N-(l-(3-(piperidin-l-yl)-l,2,4-thiadiazol-5-yl)ethyl)propane-2- sulfinamide (C-71)

[0848] To a solution of (S,E)-2-methyl-N-[l-[3-(l-piperidinyl)-l,2,4-thiadiazol-5- yl]ethylidene]propane-2-sulfinamide (200 mg, 0.64 mmol) in THF (3.0 mL) at -78 °C was added K-Selectride (1.27 mL, 1.27 mmol). After stirring at -78 °C for 30 min, the mixture was poured into saturated NH4C1 (2.0 mL) and extracted with EtOAc (2 x 2 mL). The combined organic layers were washed with brine (2 x 2.0 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by flash column (0-10% EtOAc / PE) to give the product as an oil (150 mg, 0.43 mmol, 68% yield).1H NMR (CDC13, 400 MHz) δ H = 4.83-4.78 (m, 1H), 3.74-3.68 (m, 4H), 1.75-1.71 (m, 4H), 1.69-1.61 (m, 6H), 1.29 (s, 9H).

[0849] (R)-l-(3-(piperidin-l-yl)-l,2,4-thiadiazol-5-yl)ethanamine hydrochloride (C-72)

[0850] To a solution of (S)-2-methyl-N-[l-[3-(l-piperidinyl)-l,2,4-thiadiazol-5- yl]ethyl]propane-2-sulfmamide (150 mg, 0.47 mmol) in 1,4-dioxane (1.0 mL) was added 4 M HC1 / dioxane (346 mg, 9.48 mmol) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was filtered, and the residue was washed with dioxane (5.0 mL) to give the product as a solid (100 mg, 0.42 mmol, 89% yield).1H NMR (DMSO-d6, 400 MHz) δ H = 8.80 (s, 3H), 4.90 (br d, 1H), 3.63 (br d, 3H), 1.58 (br d, 9H).

[0851] (R)-1 -Methyl- N-( 1 -(3 -(piperidin- 1 -yl)- 1,2,4-thiadiazol-5 -yl)ethyl)-3 -(trifluoromethyl)- 1 H-pyrazole-5-carboxamide (C-73)

[0852] To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (100.6 mg, 0.52 mmol) in DCM (2.0 mL) was added DIEA (608 mg, 4.71 mmol) and T3P (107 g, 1.41 mmol). After stirring at 25 °C for 30 min, (R)-1 -(3-(piperidin-1 -yl)-1,2,4-thiadiazol-5-yl)ethanamine hydrochloride (100 mg, 0.47 mmol) was added and the reaction was stirred at 25 °C for 1 h. The reaction was quenched with water (20.0 mL) and extracted with DCM (2 x 20.0 mL). The combined organic layers were washed with brine (60.0 mL), dried over Na2S04, filtered and concentrated in vacuo to give the product as an oil (200 mg, 0.46 mmol, 98% yield). 1 H NMR (CDC13, 400 MHz) δ H = 6.83 (s, 1H), 6.75-6.62 (m, 1H), 5.54-5.47 (m, 1H), 4.23 (s, 3H), 3.69-3.64 (m, 4H), 1.69 (d, 3H), 1.68-1.61 (m, 6H).

[0853] (R)-1 -Methyl- N-( 1 -(3 -(piperidin- 1 -yl)- 1,2,4-thiadiazol-5 -yl)ethyl)-3 -(trifluoromethyl)- 1 H-pyrazole-5-carboxamide and (S)-1 -Methyl- N-( 1 -(3 -(piperidin- 1 -yl)- 1,2,4-thiadiazol-5 -yl)ethyl)-3 -(trifluoromethyl)- 1 H-pyrazole-5-carboxamide

[0854] 2-methyl-N-[l-[3-(l-piperidinyl)-l,2,4-thiadiazol-5-yl]ethyl]-5- (trifluoromethyl)pyrazole-3-carboxamide (200 mg, 0.51 mmol) was purified by SFC (Column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 pm); Conditions: 0.1% NH3H2O-EtOH; Start B: 25; End B: 25) to give 2-methyl-N-[(lS)-l-[3-(l-piperidinyl)-l,2,4- thiadiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (10.4 mg, 0.03 mmol, 5% yield) as a solid and 2-methyl-N-[(lR)-l-[3-(l-piperidinyl)-l,2,4- thiadiazol-5-yl]ethyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (38.5 mg, 0.10 mmol, 19% yield) as a solid.

[0855] 46: 1 H NMR (CDCI3, 400 MHz) δ H = 6.83 (s, 1H), 6.65 (br d, 1H), 5.56-5.47 (m, 1H), 4.22 (s, 3H), 3.69-3.62 (m, 4H), 1.69 (d, 3H), 1.68-1.62 (m, 6H). 19 F NMR (376.5 MHz, CDCI3) δ F -62.168. LCMS R t = 1.070 min (in 2.0 min chromatography), 30-90 AB, C 15 H 20 F3N6OS [M+H] + MS ESI calculated for F3N6OS 389.1, found 389.1. 99.2% ee.

[0856] 47: 1 H NMR (CDCI3, 400 MHz) δ H = 6.83 (s, 1H), 6.65 (br d, 1H), 5.56-5.47 (m, 1H), 4.22 (s, 3H), 3.69-3.62 (m, 4H), 1.69 (d, 3H), 1.68-1.62 (m, 6H). 19 F NMR (376.5 MHz, CDCI3) δ F -62.168. LCMS R t = 1.073 min (in 2.0 min chromatography), 30-90 AB, C 15 H20 F3N6OS [M+H] + MS ESI calculated 389.1, found 389.1. 99.9% ee.

[0857] Example 48. Efficacy of exemplary compounds to inhibit KCNT1

[0858] KCNT1-WT-Basal- Patch clamp assay

[0859] Inhibition of KCNT1 (KNa1.1, Slack) was assessed using a tetracycline- inducible cell line (HEK-TREX). Currents were recorded using a SyncroPatch 384PE automated patch clamp system. Pulse generation and data acquisition were performed using PatchController384 V1.3.0 and DataController384 V1.2.1 (Nanion Technologies). Access resistance and apparent membrane capacitance were estimated using built-in protocols. Currents were recorded in perforated patch mode (10 mM Escin) from a population of cells. Cells were lifted, triturated and resuspended at 800,000 cells / ml. Prior to the experiment, cells were allowed to recover in the cell library. Currents were recorded at room temperature. The external solution contained the following (in mM): NaCl 105, NMDG 40, KCl 4, MgCl2 1, CaCl2 5 and HEPES 10 (pH=7.4, osmolarity ~300 mOsm). The extracellular solution was used as a wash, reference and compound delivery solution. The internal solution contained the following (in mM): NaCl 70, KF 70, KCl 10, EGTA 5, HEPES 5 and Escin 0.01 (pH=7.2, osmolarity ~295 mOsm). Escin was prepared in 5 mM aqueous stock solution, aliquoted and stored at -20 °C. Compounds plates were generated at 2x concentration in extracellular solution. When added to recording wells, compounds were diluted 1:2. The amount of DMSO in extracellular solution was kept constant at the level used for the highest test concentration. A holding potential of -80 mV to 0 mV with 100 ms step length was used. Mean currents were measured during step to 0 mV. KCNT1 currents were allowed to be subtracted offline using 100 mM Bepridil to completely inhibit KCNT1 currents. Mean currents from 3 sweeps were averaged and % inhibition was calculated for each compound. The % inhibition as a function of compound concentration was fitted to a Hill equation to give IC 50 , slope, minimum and maximum parameters. If KCNT1 inhibition was less than 50% at the highest test concentration, or if IC 50 could not be calculated, the % inhibition of IC 50 was reported instead.

[0860] The results of this assay are summarized in Table 1 below. In this table, "A" indicates an IC 50 ; "B" indicates inhibition between 1 μM and 20 μM; and "C" indicates inhibition greater than or equal to 20 μM.

[0861] Table 1

[0862]

[0863]

[0864] Equivalents and Range

[0865] In the claims, the articles "a," "an," and "the" can refer to one or more than one, unless indicated otherwise or otherwise evident from the context. If a group of one or more members is preceded by the phrase "comprising" or "including," the entire group of one or more members (that is, each individual member of the group or any subset of members of the group) is intended, unless otherwise indicated or otherwise evident from the context. In this specification, the term "another" means at least one, i.e., one or more. The term "about" means approximately or nearly, for example, within 10% of the stated value. The term "substantially" means largely or almost entirely, for example, within 10% of the stated value. The term "comprising" means including, but not limited to, and the term "comprises" has a similar meaning. The term "coupled" means directly or indirectly connected, for example, through one or more intervening elements.

[0866] Further, the present application encompasses all variations, combinations, and permutations of the one or more limitations, elements, terms, and descriptive terminology from one or more of the listed claims introduced into another claim. For example, any claim that follows depends from another claim can be modified to include one or more limitations found in any other claim that depends from the same base claim. Where elements are presented as lists, e.g., in Markush group format, it is understood that each subgroup of elements is also individually contemplated and can be removed from the group. It should be understood that, in general, where the application or aspects of the application are termed as comprising particular elements and / or features, certain embodiments of the application or aspects of the application consist of, or consist essentially of, such elements and / or features. Those embodiments have not been specifically enumerated herein for the sake of brevity, and each of such embodiments is therefore expressly reserved, in the absence of specific exclusion in such description. It should be further understood that the terms "comprising" and "including" are intended to be open-ended and allow for the inclusion of additional elements or steps, unless otherwise indicated or understood from the context. Where ranges are given, the endpoints are included. Further, unless otherwise indicated or understood from the context, values expressed as ranges are understood to assume any specific value or sub-range within the stated range, precise to the lower limit unit of the stated range, unless the context clearly dictates otherwise.

[0867] This application relates to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is any conflict between any incorporated reference and the specification, the specification is controlling. In addition, any particular embodiment of the application falling within the prior art can be expressly excluded from any one or more of the claims. Because such embodiments are considered to be known to those of ordinary skill in the art, they can be excluded even if not expressly excluded in the text herein. Any particular embodiment of the application can be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0868] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above description but is only limited as set forth in the claims that follow. Those skilled in the art will appreciate that various adaptations and modifications of the description can be configured without departing from the spirit and scope of the application as set forth in the claims that follow.

Claims

1. A pharmaceutical composition comprising a compound having formula A: （A）； in: X is CR7 and Y is O; Ring A is pyridinyl; R1 is selected from the group consisting of: phenyl, 5-6-membered heteroaryl, -CH2-phenyl, 5-8-membered carbocyclic and 5-10-membered heterocyclic; wherein the phenyl, 5-6-membered heteroaryl, -CH2-phenyl, 5-8-membered carbocyclic or 5-10-membered heterocyclic is optionally substituted by one or more R6; R2 is hydrogen; R3 is C 1-6 Alkyl group, and R4 is hydrogen; R5 is C 3-8 cycloalkyl or C 1-6 Haloalkyl, and R6 is selected from the group consisting of: halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-8 cycloalkyl; R7 is hydrogen; and n is 1; Or its pharmaceutically acceptable salt; and Pharmaceutically acceptable carrier.

2. The pharmaceutical composition according to claim 1, wherein R5 is C 1-6 Halogenated alkyl groups.

3. The pharmaceutical composition according to any one of claims 1 or 2, wherein R1 is a 5-6 membered heteroaryl group optionally substituted with one or more R6 groups.

4. The pharmaceutical composition according to claim 3, wherein the 5-6 heteroaryl group is a pyrazolyl group.

5. The pharmaceutical composition according to any one of claims 1 or 2, wherein R1 is a phenyl group optionally substituted with one or more R6 groups.

6. The pharmaceutical composition according to any one of claims 1 or 2, wherein R1 is a -CH2-phenyl group optionally substituted with one or more R6 groups.

7. The pharmaceutical composition according to any one of claims 1 or 2, wherein R1 is a 10-membered heterocyclic group optionally substituted with one or more R6.

8. The pharmaceutical composition according to claim 7, wherein the 10-membered heterocyclic group is a bicyclic heterocyclic group.

9. The pharmaceutical composition according to any one of claims 1 or 2, wherein R6 is a halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

10. A compound having formula I: （I）； Or its pharmaceutically acceptable salt, wherein: X is CR7 and Y is O; Ring A is pyridinyl; R1 is selected from the group consisting of: phenyl, 5-6-membered heteroaryl, -CH2-phenyl, 5-8-membered carbocyclic and 5-10-membered heterocyclic; wherein the phenyl, 5-6-membered heteroaryl, -CH2-phenyl, 5-8-membered carbocyclic or 5-10-membered heterocyclic is optionally substituted by one or more R6; R2 is hydrogen; R3 is C 1-6 Alkyl group, and R4 is hydrogen; R5 is C 3-8 cycloalkyl or C 1-6 Haloalkyl, and R6 is selected from the group consisting of: halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-8 cycloalkyl; R7 is hydrogen; and n is 1.

11. The compound according to claim 10, wherein R3 is methyl.

12. The compound according to any one of claims 10 or 11, wherein R5 is cyclopropyl or -CF3.

13. The compound according to any one of claims 10 or 11, wherein R1 is a 5-6 heteroaryl group optionally substituted with one or more R6 groups.

14. The compound according to claim 13, wherein the 5-6 heteroaryl group is a pyrazolyl group.

15. The compound according to any one of claims 10 or 11, wherein R1 is a phenyl group optionally substituted with one or more R6 groups.

16. The compound according to any one of claims 10 or 11, wherein R1 is a -CH2-phenyl optionally substituted with one or more R6.

17. The compound according to any one of claims 10 or 11, wherein R1 is a 10-membered heterocyclic group optionally substituted with one or more R6.

18. The compound according to claim 17, wherein the 10-membered heterocyclic group is a bicyclic heterocyclic group.

19. The compound according to any one of claims 10 or 11, wherein R6 is a halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

20. The compound according to any one of claims 10 or 11, wherein R6 is C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

21. The compound according to any one of claims 10 or 11, wherein R1 is selected from the group consisting of: ， Where m is 0, 1 or 2.

22. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , and , Or its pharmaceutically acceptable salt.

23. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 21, and a pharmaceutically acceptable excipient.

24. Use of the compound of any one of claims 10 to 21 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of claims 1 to 9 and 22 to 23 in the preparation of a medicament for treating a disease or condition associated with a gain-of-function mutation of KCNT1, wherein the disease or condition associated with a gain-of-function mutation of KCNT1 is epilepsy, epilepsy syndrome or encephalopathy.

25. The use according to claim 24, wherein the disease or symptom associated with the gain-of-function mutation of KCNT1 is hereditary or childhood epilepsy or hereditary or childhood epilepsy syndrome.

26. Use of the compound of any one of claims 10 to 21 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of claims 1 to 9 and 22 to 23 in the preparation of a medicament for treating diseases or conditions associated with gain-of-function mutations in KCNT1, wherein the diseases or conditions associated with gain-of-function mutations in KCNT1 are selected from the group consisting of: infantile epilepsy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, generalized tonic-clonic seizures, asymmetric tonic seizures, leukodystrophy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, and cerebellar ataxia.

27. Use of the compound of any one of claims 10 to 21 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of claims 1 to 9 and 22 to 23 in the preparation of a medicament for treating a disease or condition associated with a gain-of-function mutation of KCNT1, wherein the disease or condition associated with a gain-of-function mutation of KCNT1 is selected from the group consisting of: sudden death in epilepsy (SUDEP) and Brugada syndrome.

28. Use of the compound of any one of claims 10 to 21 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of claims 1 to 9 and 22 to 23 in the preparation of a medicament for treating a disease or condition associated with a gain-of-function mutation of KCNT1, wherein the disease or condition associated with a gain-of-function mutation of KCNT1 is selected from ataxia and cerebellar ataxia.

29. Use of the compound of any one of claims 10 to 21 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of claims 1 to 9 and 22 to 23 in the preparation of a medicament for treating diseases or conditions associated with gain-of-function mutations in KCNT1, wherein the diseases or conditions associated with gain-of-function mutations in KCNT1 are selected from the group consisting of: epileptic encephalopathy with SCN1A, SCN2A or SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal epilepsy, focal epilepsy with SCN3A mutations, sudden epileptic death (SUDEP), Rasmussen encephalitis, infantile malignant migratory partial seizures, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy and KCNT1 epileptic encephalopathy.

30. Use of the compound of any one of claims 10 to 21 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of claims 1 to 9 and 22 to 23 in the preparation of a medicament for treating diseases or conditions associated with gain-of-function mutations in KCNT1, wherein the diseases or conditions associated with gain-of-function mutations in KCNT1 are selected from the group consisting of: Dravet syndrome with SCN1A mutation, SCN2A epileptic encephalopathy, cryptogenic partial epilepsy of children with SCN3A mutation, and SCN8A epileptic encephalopathy.

31. Use of the compound of any one of claims 10 to 21 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of claims 1 to 9 and 22 to 23 in the preparation of a medicament for treating diseases or conditions associated with gain-of-function mutations in KCNT1, wherein the diseases or conditions associated with gain-of-function mutations in KCNT1 are selected from the group consisting of: epileptic encephalopathy, focal epilepsy, seizures, and leukoencephalopathy.