KCNT1 Inhibitors and Methods of Use

Abstract

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

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 842,849, filed May 3, 2019, and U.S. Provisional Patent Application No. 62 / 982,864, filed February 28, 2020, the contents of each of which are incorporated by reference in their entirety herein. [Background technology]

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

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

[0004] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention features a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined herein, and a pharma- ceutically acceptable excipient.

[0005] In another aspect, the present disclosure provides a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined herein.

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

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

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

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

[0010] In another aspect, the present disclosure provides a compound of formula (VII): [ka] The present invention features a pharmaceutical composition comprising a compound of formula (VII) or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined herein, and a pharma- ceutically acceptable excipient.

[0011] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), (III), (IV), (V), (VI) (e.g., (VI-a))), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0012] In another aspect, the disclosure provides a method of treating a neurological disease or disorder, the method comprising administering to a patient a compound disclosed herein (e.g., a compound of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), (III), (IV), (V), (VI) (e.g., (VI-a)), or (VII) (e.g., (VII-a) or (VII-b)), or a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., For example, the compounds disclosed herein (e.g., compounds of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)) (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II and a pharmaceutical composition comprising: (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1) or (II-k2)), (III), (IV), (V), (VI) (e.g., (VI-a)), or (VII) (e.g., (VII-a) or (VII-b)), or a pharma- ceutical acceptable salt thereof; and a pharma-ceutical composition comprising a pharma-ceutical acceptable salt thereof, and a pharma-ceutical acceptable excipient, to a subject in need of treatment.

[0013] In another aspect, the disclosure provides a method of treating a disease or condition associated with excessive neural excitability, the method comprising administering to a patient a compound disclosed herein (e.g., a compound of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), (II) (e.g., (II-a), (II-b), (II-c), (I (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), (III), (IV), (V), (VI) (e.g., (VI-a)), or (VII) (e.g., (VII-a) or (VII-b)), or a pharma- ceutically acceptable salt thereof), or a pharma- ceutical compound disclosed herein. Compositions (e.g., compounds disclosed herein (e.g., compounds of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)) (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), ( (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1) or (II-k2)), (III), (IV), (V), (VI) (e.g., (VI-a)), or (VII) (e.g., (VII-a) or (VII-b)), or a pharma- ceutical composition comprising the compound of formula (I) or (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1) or (II-k2), (III), (IV), (V), (VI) (e.g., (VI-a)), or (VII) (e.g., (VII-a) or (VII-b)), or a pharma- ceutical acceptable salt thereof), and a pharma- ceutical acceptable excipient, to a subject in need of treatment.

[0014] In another aspect, the disclosure provides a method of treating a disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1), the method comprising administering to a patient a compound disclosed herein (e.g., a compound of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), (II) (e.g., (II-a), (II-b), (II-c), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)). , (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), (III), (IV), (V), (VI) (e.g., (VI-a)), or (VII) (e.g., (VII-a) or (VII-b)), or a pharma- ceutically acceptable salt thereof), or any of the compounds described herein. The disclosed pharmaceutical compositions (e.g., a compound disclosed herein (e.g., a compound of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-m ... (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1) or (II-k2)), (III), (IV), (V), (VI) (e.g., (VI-a)), or (VII) (e.g., (VII-a) or (VII-b)), or a pharma- ceutical composition comprising the compound of formula (I) or (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1) or (II-k2)), (III), (IV), (V), (VI) (e.g., (VI-a)), or (VII) (e.g., (VII-a) or (VII-b)), or a pharma- ceutical acceptable salt thereof), and a pharma- ceutical acceptable excipient, to a subject in need of treatment.

[0015] 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.

[0016] 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 genetic or childhood epilepsy, or a genetic or childhood epilepsy syndrome.

[0017] In some embodiments, the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in a gene (eg, KCNT1) is cardiac dysfunction.

[0018] 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., epilepsy of infancy with migratory focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, Lennox Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia).

[0019] In some embodiments, the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from the group consisting of cardiac arrhythmia, sudden unexpected death in epilepsy, Brugada syndrome, and myocardial infarction.

[0020] In some embodiments, the neurological disease or disorder, disease or condition associated with excessive neural excitability, or disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.).

[0021] In some embodiments, the neurological disease or disorder, disease or condition associated with excessive neural excitability, or disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is a muscle disorder (e.g., myotonia, neuromyotonia, muscle spasms, spasticity).

[0022] 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 itch and pruritus, ataxia, and cerebellar ataxia.

[0023] In some embodiments, the neurological disease or disorder, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia).

[0024] 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 disabilities, fragile X, neuroplasticity, and autism spectrum disorder.

[0025] 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 onset epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, and the like. The present invention relates to a method for treating epilepsy in a patient with epilepsy, the method comprising administering to the patient a therapeutically effective amount of epilepsy medication, such as idiopathic cerebrovascular accidents, epilepsy caused by a combination of cerebrovascular and cerebrovascular diseases, including ...

[0026] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description, examples, and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] As generally described herein, the present invention provides compounds and compositions useful for preventing and / or treating diseases, disorders, or conditions described herein, such as diseases, disorders, or conditions 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 encephalopathies (e.g., epilepsy of infancy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathies, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, and Lennox syndrome. Gastaut syndrome, seizures, leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic seizures, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia, asymmetric tonic seizures), as well as cardiac dysfunction (e.g., cardiac arrhythmias, Brugada syndrome, sudden unexpected death in epilepsy, myocardial infarction), pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.), muscle disorders (e.g., myotonia, neuromyotonia, muscle spasms, spasticity), itch and pruritus, ataxia and cerebellar ataxia, psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia), learning disabilities, fragile X, neuroplasticity, and autism spectrum disorders.

[0028] definition chemical definition Definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 thIn addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Ed., 1999; and specific functional groups are generally defined as described therein. th Edition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3. rd Edition, Cambridge University Press, Cambridge, 1987.

[0029] The compounds described herein may contain one or more asymmetric centers and therefore may exist in the form of various isomers, for example, enantiomers and / or diastereomers.For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.Isomers may be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC), and the formation and crystallization of chiral salts, or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). Additionally, the invention encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0030] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is therefore in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight of the enantiomer. In certain embodiments, the weights are based on the total weight of all enantiomers or stereoisomers of the compound.

[0031] In the compositions provided herein, the enantiomerically pure compound may be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R compound may comprise, for example, about 90% of excipients and about 10% of the enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may comprise, for example, at least about 95% by weight of the R compound and at most about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S compound may comprise, for example, about 90% of excipients and about 10% of the enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may comprise, for example, at least about 95% by weight of the S compound and at most about 5% by weight of the R compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipients or carriers.

[0032] The compounds described herein may also contain one or more isotopic substitutions. For example, H is: 1 H, 2 H (D or deuterium), and 3H (T or tritium) and C can be in any isotopic form. 12 C. 13 C, and 14 C may be in any isotopic form, including 16 O and 18 O may be any isotopic form, including F. 18 F and 19 It can be any isotopic form containing F, etc.

[0033] The following terms are intended to have the meanings presented below and are useful in understanding the description and intended scope of the present invention. In describing the invention, which may include compounds and their pharma- ceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated. It should also be understood that, as described herein, any of the moieties defined below may be substituted with a variety of substituents, and each definition is intended to include such substituted moieties within their scope as described below. Unless otherwise indicated, the term "substituted" is as defined below. It should further be understood that the terms "group" and "radical" may be considered interchangeable as used herein. The articles "a" and "an" may be used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. By way of example, "analogue" means one analogue or more than one analogue.

[0034] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 Alkyl" is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0035] As used herein, "alkyl" refers to the radical of a linear or branched saturated hydrocarbon group having, for example, 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has one carbon atom (C 1 Alkyl). C 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0036] As used herein, "alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and, optionally, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2-20 In certain embodiments, an alkenyl does not contain a triple bond. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkenyl group has two carbon atoms ("C 2 The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2-4 Examples of alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ) etc. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4Alkenyl groups, as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ) etc.

[0037] As used herein, "alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and, optionally, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2-20 In certain embodiments, alkynyl does not contain a double bond. In some embodiments, alkynyl groups have 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 two carbon atoms ("C 2 The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ) etc. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkynyl groups, as well as pentynyl (C 5 ), Hexynyl (C 6 Additional examples of alkynyl include heptynyl (C 7 ), Octynyl (C 8 ) etc.

[0038] As used herein, "alkylene", "alkenylene", and "alkynylene" refer to the divalent radical of an alkyl, alkenyl, and alkynyl group, respectively. When a range or number of carbons is provided for a particular "alkylene", "alkenylene", or "alkynylene" group, it is understood that the range or number refers to the range or number of carbons in a linear divalent carbon chain. "Alkylene", "alkenylene", and "alkynylene" groups can be substituted or unsubstituted with one or more substituents described herein.

[0039] As used herein, "aryl" refers to a radical of a 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) that is monocyclic or polycyclic (e.g., bicyclic or tricyclic) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement). 6-14 In some embodiments, an aryl group has six ring carbon atoms ("C 6 aryl" (e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl", e.g., anthracyl). "Aryl" also includes ring systems in which the aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such instances the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Exemplary aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0040] As used herein, "heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in the cyclic arrangement) with ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring defined above is fused with one or more carbocyclyl or heterocyclyl groups, with the point of attachment being on the heteroaryl ring, in such instances the number of ring members continuing to specify the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which the heteroaryl ring defined above is fused with one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring, and in such instances the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring bearing the heteroatom (e.g., 2-indolyl) or on the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0041] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system ("5-10 membered heteroaryl") having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system ("5-8 membered heteroaryl") having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system ("5-6 membered heteroaryl") having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0042] 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, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0043] Representative examples of heteroaryls include: [ka] wherein each Z is carbonyl, N, NR65 , O, and S; R 65 are independently hydrogen, C 1 -C 8 Alkyl, C 3 -C 10 Carbocyclyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl.

[0044] As used herein, "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 Carbocyclyl). Exemplary C 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) and others. 3-8 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3-6 Carbocyclyl groups, as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ) and others. 3-10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic carbocyclyl"), which may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclyl ring, in such examples the number of carbons continuing to designate the number of carbons in the carbocyclic ring system.

[0045] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbons, and is used herein, for example, to include "C" derived from a cycloalkane. 4-8Cycloalkyl groups are referred to as "cycloalkyl groups". Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane. Unless otherwise specified, cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azide, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamide, sulfonyl, or thiocarbonyl. Cycloalkyl groups can be fused to other cycloalkyl, aryl, or heterocyclyl groups. In certain embodiments, cycloalkyl groups are unsubstituted, i.e., unsubstituted.

[0046] As used herein, "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system ("3- to 10-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl"), or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, where the point of attachment is on either the carbocyclyl or heterocyclyl ring or ring system, and a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, where in such instances the number of ring members continues to specify the number of ring members in the heterocyclyl ring system.

[0047] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0048] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. (Also referred to herein as 5,6-bicyclic heterocyclic rings) C 6 Exemplary 5-membered heterocyclyl groups fused to an aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0049] As used herein, "heterocylene" refers to a divalent radical of a heterocycle.

[0050] "Hetero", when used to describe a compound or a group present in a compound, means that one or more carbon atoms in the compound or group have been replaced with a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the above hydrocarbyl groups, such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g., heteroaryl, having 1 to 5, especially 1 to 3, heteroatoms.

[0051] As used herein, "cyano" refers to --CN.

[0052] As used herein, "halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is either fluoro or chloro.

[0053] As used herein, "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0054] As used herein, "nitro" refers to -NO 2 Refers to...

[0055] As used herein, "oxo" refers to -C=O.

[0056] In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not 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 of the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position.

[0057] Nitrogen atoms may be substituted or unsubstituted, where valence permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2, -P(=O)(NR cc ) 2 , C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl; or two R cc The groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be selected from 0, 1, 2, 3, 4, or 5 R dd is independently substituted with R aa , R bb , R cc , and R dd is as defined above.

[0058] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The invention is not intended to be limited in any way by the above exemplary recitation of substituents.

[0059] Other definitions The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. in J.Pharmaceutical Sciences (1977) 66:1-19 and Gould in Salt selection for basic drugs, International Journal of Pharmaceutics, 33 (1986) 201-217, describe pharmaceutically acceptable salts in detail. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharma- ceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or by using other methods used in the art, such as ion exchange. Other pharma-ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate. , lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts.Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N. + (C 1-4 Alkyl) 4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0060] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents), or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)), and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0061] Disease, disorder, and condition are used interchangeably herein.

[0062] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate the action of reducing the severity of the disease, disorder, or condition or slowing or retarding the progression of the disease, disorder, or condition (also "therapeutic treatment"), which occurs while a subject is afflicted with the specified disease, disorder, or condition.

[0063] In general, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of the compound of the invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.

[0064] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0065] In an alternative embodiment, the present invention contemplates administering a compound of the present invention, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable composition thereof, as a prophylactic agent before a subject begins to suffer from a specified disease, disorder, or condition. As used herein, "prophylactic treatment" contemplates an action that occurs before a subject begins to suffer from a specified disease, disorder, or condition. As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0066] As used herein, "disease or condition associated with a gain-of-function mutation in KCNT1" refers to a disease or condition that is associated with, is partially or completely caused by, or has one or more symptoms that are partially or completely caused by, a mutation in KCNT1 that results in a gain-of-function phenotype, i.e., increased activity of the potassium channel encoded by KCNT1, resulting in an increased whole-cell current.

[0067] As used herein, a "gain-of-function mutation" is a mutation in KCNT1 that causes an increase in the activity of the potassium channel encoded by KCNT1. The activity can be evaluated, for example, by ion flux assay or electrophysiology (for example, using whole-cell patch clamp technique). Typically, a gain-of-function mutation causes at least or about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400% or more increase compared to the activity of the potassium channel encoded by wild-type KCNT1.

[0068] Compounds and Compositions In one aspect, the present disclosure provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, X, Y, Z, Y', and Z' are each independently selected from CH and N, and the hydrogen of CH is R 5 and at least three selected from X, Y, Z, Y', and Z' are CH; R 1 But, C 1-6 Alkyl, C 3-10 is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; 1-6 Alkyl, C 3-10Cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, or phenyl is selected from the group consisting of halogen, C(O)N(R 9 ) 2 , N(R 9 ) 2 , C 3-7 Cycloalkyl, phenyl, 3-10 membered heteroaryl, and C 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy; R 12 But, C 1-6 Alkyl, C 3-10 is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heteroaryl, or phenyl is not halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy; Two R on adjacent carbons 12 But R 12 may be taken together with the two carbons to which they are attached to form a carbocyclic ring, x is 0, 1, or 2; R 2 is hydrogen or C 1-4 is alkyl, R 3 But hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; R 4 But, C 1-6 alkyl and hydrogen, or R 3 and R 4 But R 3 and R 4 Together with the carbon bonded to C 3-7 can form a cycloalkylene or a 3- to 7-membered heterocyclene; 1-6Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heteroaryl, phenyl, C 3-7 Cycloalkylene or 3- to 7-membered heterocyclene is one or more R 7 may be optionally substituted with Each R 5 But halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylene-N(R 9 ) 2 , C 1-6 Alkylene-OC 3-10 Cycloalkyl, C 1-6 Alkoxy, C optionally substituted with one or more halogens 3-10 Cycloalkyl-substituted C 1-6 Alkoxy, C 1-6 Haloalkoxy, one or more halogens or C 1-6 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, optionally substituted with alkoxy; 1-6 Alkylene-OH, C 1-6 Alkylene-C 1-6 Alkoxy, OH, N(R 9 ) 2 , -C(O)OR 8 , C(O)N(R 9 ) 2 , C 1-6 Alkylene -CN, -CN, -S(O) 2 -C 1-6 Alkyl, C 1-6 Alkylene-S(O) 2 -C 1-6 Alkyl, -S(O) 2 -N(R 9 ) 2 , -OC(O)C 1-6 Alkyl, one or more halogens or C 1-6 -OC optionally substituted with alkyl 3-10 Cycloalkyl and halogen, C 1-6 Alkyl, and C 1-6 C optionally substituted with one or more substituents selected from alkoxy 3-10cycloalkyl; n is selected from the group consisting of 0, 1, 2, and 3; R 7 But phenyl, C 1-6 Alkoxy, -OH, -N(R 9 ) 2 , -NR 9 -SO 2 -C 1-6 Alkyl, -O-(C 1-6 (alkylene)-phenyl, C 3-10 Cycloalkyl, -C(O)OR 8 , -C(O)N(R 9 ) 2 , -NR 10 C(O)-R 11 , -CN, -S(O) 2 -C 1-6 Alkyl, -S(O) 2 -N(R 9 ) 2 , 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl; 3-10 Cycloalkyl, 3- to 10-membered heterocyclyl, or 3- to 10-membered heteroaryl is C 1-6 Alkyl, halogen, -OH, C 1-6 Alkoxy, and -N(R 9 ) 2 and optionally substituted with one or more substituents each independently selected from the group consisting of: R 8 is hydrogen or C 1-6 is alkyl, Each R 9 But hydrogen, C 1-6 Alkyl, and -(C 1-6 or two R 9 But two R 9 together with the nitrogen atom to which is bonded, may form a heterocycle optionally substituted with one or more substituents each independently selected from halogen and -OH; Each R 10 are independently hydrogen or C 1-6 is alkyl, R 11 But, C 1-6 Alkyl, C 1-6 Alkoxy, and -O-(C 1-6 (alkylene)-phenyl; R 3 and R 4 are both hydrogen, then at least one selected from X, Y, Z, Y', and Z' is N, or a pharma- ceutically acceptable salt thereof.

[0069] In another aspect, the present disclosure provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, X, Y, Z, Y', and Z' are each independently selected from CH and N, and the hydrogen of CH is R 5 and at least three selected from X, Y, Z, Y', and Z' are CH; R 1 But, C 1-6 Alkyl, C 3-10 is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, or phenyl is selected from the group consisting of halogen, C(O)N(R 9 ) 2 , N(R 9 ) 2 , C 3-7 Cycloalkyl, phenyl, 3-10 membered heteroaryl, and C 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy; R 12 But, C 1-6 Alkyl, C 3-10 is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; 1-6 Alkyl, C 3-10Cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heteroaryl, or phenyl is not halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy; Two R on adjacent carbons 12 But R 12 may be taken together with the two carbons to which they are attached to form a carbocyclic ring, x is 0, 1, or 2; R 2 is hydrogen or C 1-4 is alkyl, R 3 But hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; R 4 But, C 1-6 alkyl and hydrogen, or R 3 and R 4 But R 3 and R 4 Together with the carbon bonded to C 3-7 can form a cycloalkylene or a 3- to 7-membered heterocyclene; 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heteroaryl, phenyl, C 3-7 Cycloalkylene or 3- to 7-membered heterocyclene is one or more R 7 may be optionally substituted with Each R 5 But halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylene-N(R 9 ) 2 , C 1-6 Alkylene-OC 3-10 Cycloalkyl, C 1-6 Alkoxy, C optionally substituted with one or more halogens 3-10Cycloalkyl-substituted C 1-6 Alkoxy, C 1-6 Haloalkoxy, one or more halogens or C 1-6 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, optionally substituted with alkoxy; 1-6 Alkylene-OH, C 1-6 Alkylene-C 1-6 Alkoxy, OH, N(R 9 ) 2 , -C(O)OR 8 , C(O)N(R 9 ) 2 , C 1-6 Alkylene -CN, -CN, -S(O) 2 -C 1-6 Alkyl, C 1-6 Alkylene-S(O) 2 -C 1-6 Alkyl, -S(O) 2 -N(R 9 ) 2 , -OC(O)C 1-6 Alkyl, one or more halogens or C 1-6 -OC optionally substituted with alkyl 3-10 Cycloalkyl and halogen, C 1-6 Alkyl, and C 1-6 C optionally substituted with one or more substituents selected from alkoxy 3-10 cycloalkyl; n is selected from the group consisting of 0, 1, 2, and 3; R 7 But phenyl, C 1-6 Alkoxy, -OH, -N(R 9 ) 2 , -NR 9 -SO 2 -C 1-6 Alkyl, -O-(C 1-6 (alkylene)-phenyl, C 3-10 Cycloalkyl, -C(O)OR 8 , -C(O)N(R 9 ) 2 , -NR 10 C(O)-R 11 , -CN, -S(O) 2-C 1-6 Alkyl, -S(O) 2 -N(R 9 ) 2 , 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl; 3-10 Cycloalkyl, 3- to 10-membered heterocyclyl, or 3- to 10-membered heteroaryl is C 1-6 Alkyl, halogen, -OH, C 1-6 Alkoxy, and -N(R 9 ) 2 and optionally substituted with one or more substituents each independently selected from the group consisting of: R 8 is hydrogen or C 1-6 is alkyl, Each R 9 But hydrogen, C 1-6 Alkyl, and -(C 1-6 or two R 9 But two R 9 together with the nitrogen atom to which is bonded, may form a heterocycle optionally substituted with one or more substituents each independently selected from halogen and -OH; Each R 10 are independently hydrogen or C 1-6 is alkyl, R 11 But, C 1-6 Alkyl, C 1-6 Alkoxy, and -O-(C 1-6 (alkylene)-phenyl; R 3 and R 4 are both hydrogen, then at least one selected from X, Y, Z, Y', and Z' is N, or a pharma- ceutically acceptable salt thereof; and a pharma- ceutically acceptable excipient.

[0070] In some embodiments, the compound is a compound of Formula II or Formula I-II: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0071] In some embodiments, one of X, Y, Z, Y', and Z' is N and the other four are CH.

[0072] In some embodiments, two of X, Y, Z, Y', and Z' are N and the other three are CH.

[0073] In some embodiments, the compound is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0074] In some embodiments, the compound is a compound of formula Ib: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0075] In some embodiments, the compound is a compound of formula Ic: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0076] In some embodiments, the compound is a compound of formula Id: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0077] In some embodiments, the compound is a compound of formula Ie: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0078] In some embodiments, the compound is a compound of formula If: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0079] In some embodiments, the compound is a compound of formula Ig: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0080] In some embodiments, the compound is a compound of formula Ih: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0081] In some embodiments, the compound is a compound of formula Ii: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0082] In some embodiments, the compound is a compound of formula Ij: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0083] In some embodiments, the compound is a compound of formula Ik: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0084] In some embodiments, the compound is a compound of formula II: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0085] In some embodiments, the compound is a compound of formula Im: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0086] In some embodiments, the compound is a compound of formula In: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0087] In some embodiments, the compound is a compound of formula Io: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0088] In some embodiments, the compound is a compound of formula Ip: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0089] In some embodiments, the compound is a compound of formula Iq: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0090] In some embodiments, the compound is a compound of formula Ir: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0091] In some embodiments, the compound is a compound of formula Is: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0092] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 2 is hydrogen. In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 2 is methyl.

[0093] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 3 is hydrogen. In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 3 is C 1-6 In some embodiments of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 3 is selected from the group consisting of methyl, ethyl, and isopropyl. In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 3 In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 3 is ethyl.

[0094] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 3 is C 1-6 Alkoxy-substituted C 1-6 Alkyl, -OH, or -C(O)OR 8 It is.

[0095] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 4 is hydrogen.

[0096] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 3 and R 4 is R 3 and R 4 Together with the carbon bonded to C 3-7 Forms a cycloalkylene or a 3- to 7-membered heterocyclene. In some embodiments, C 3-7 The cycloalkylene is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, the 3- to 7-membered heterocyclene is selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0097] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), each R 5 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, OC 3-10 Cycloalkyl, -OH, -CN,N(R 9 ) 2 , and -C(O)OR 8 are independently selected from the group consisting of:

[0098] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), each R 5 In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), each R 5 is a halogen. In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), each R 5In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), each R 5 In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), each R 5 In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), each R 5 -CF 3 In some embodiments of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), each R 5 -CHF 2 In some embodiments of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), each R 5 is -C(O)OR 8In some embodiments of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), each R 5 is cyclopropyl, cyclobutyl, or cyclopentyl.

[0099] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 5 is cyclopropyl, -OCH 2 CH 3 , -OCH 2 -CHF 2 , -O-cyclopropyl, -O-isopropyl, -NHCH 3 , -N(CH 3 ) 2 , and -CH 2 OCH 3 are each independently selected from the group consisting of:

[0100] In some embodiments of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), n is 1. In some embodiments of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), n is 2.

[0101] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), n is 1 and R 5 In some embodiments of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), n is 2 and two R 5 In some embodiments of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), n is 2 and two R 5 In some embodiments of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), n is 2 and two R 5 is in meta position.

[0102] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 1 is C 1-6C optionally substituted with alkoxy 1-6 Alkyl, N(R 9 ) 2 , C(O)N(R 9 ) 2 , C 3-7 Cycloalkyl, pyridyl, tetrahydropyranyl, or phenyl, C 1-6 Haloalkyl, C 3-7 It is selected from the group consisting of cycloalkyl, phenyl optionally substituted with halogen, and pyridyl optionally substituted with halogen.

[0103] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 1 is C 1-6 It is an alkyl.

[0104] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 1 In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 1 is ethyl.

[0105] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 1 is C 1-6 In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 1 is -CH 2 -CHF 2 In some embodiments of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 1 -CHF 2 It is.

[0106] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 1 is C 3-7 In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 1In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 1 is cyclobutyl.

[0107] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 1 is C 1-6 Alkoxy-substituted C 1-6 In some embodiments of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 1 is a methoxy-substituted C 1-6 It is an alkyl.

[0108] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 1 is C 3-7 Cycloalkyl-substituted C 1-6In some embodiments of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 1 is a cyclopropyl-substituted C 1-6 It is an alkyl.

[0109] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 1 is phenyl substituted with halogen.

[0110] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 12 is C 1-6 Alkyl, C 3-10 is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heteroaryl, or phenyl is selected from the group consisting of halogen and C 1-6 Optionally substituted with one or more substituents each independently selected from alkoxy.

[0111] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 12 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, and phenyl optionally substituted with halogen.

[0112] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 12 is C 3-7 In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 12 is cyclopropyl.

[0113] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 12 is C 1-6In some embodiments of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 12 In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 12 In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 12 is t-butyl. In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 12 is isopropyl.

[0114] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 12 is C 1-6In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 12 -CF 3 In some embodiments of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 12 -CHF 2 It is.

[0115] In some embodiments of Formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), R 12 is phenyl optionally substituted with -F.

[0116] In some embodiments of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), x is 1. In some embodiments of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), x is 2.

[0117] In another aspect, the present invention provides a compound of formula II: [ka] or a pharma- ceutically acceptable salt thereof, One or two selected from x, Y, Z, Y', and Z' are N, and the others are CH, and the hydrogen of CH is R 5 may be substituted with R 1 But, C 1-6 Alkyl, C 3-10 is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, or phenyl is selected from the group consisting of halogen, C(O)N(R 9 ) 2 , N(R 9 ) 2 , C 3-7 Cycloalkyl, phenyl, 3-10 membered heteroaryl, and C 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy; R 12 But, C 1-6 Alkyl, C 3-10 is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heteroaryl, or phenyl is not halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy; Two R on adjacent carbons 12 But R 12 may be taken together with the two carbons to which they are attached to form a carbocyclic ring, x is 0, 1, or 2; R 2 is hydrogen or C 1-4 is alkyl, R 3 But hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; R 4 But, C 1-6 alkyl and hydrogen, or R 3 and R 4 But R 3 and R 4 Together with the carbon bonded to C 3-7 can form a cycloalkylene or a 3- to 7-membered heterocyclene; 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heteroaryl, phenyl, C 3-7 Cycloalkylene or 3- to 7-membered heterocyclene is one or more R 7 may be optionally substituted with Each R 5 But halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylene-N(R 9 ) 2 , C 1-6 Alkylene-OC 3-10 Cycloalkyl, C 3-7 C optionally substituted with cycloalkyl 1-6 Alkoxy, C 1-6 Haloalkoxy, one or more halogens or C 1-6 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, optionally substituted with alkoxy; 1-6 Alkylene-OH, C 1-6 Alkylene-C 1-6 Alkoxy, OH, -N(R 9 ) 2 , -C(O)OR 8 , -C(O)N(R 9 ) 2 , -C 1-6 Alkylene -CN, -CN, -S(O)2 -C 1-6 Alkyl, C 1-6 Alkylene-S(O) 2 -C 1-6 Alkyl, -S(O) 2 -N(R 9 ) 2 , -OC(O)C 1-6 Alkyl, one or more halogens or C 1-6 -OC optionally substituted with alkyl 3-10 Cycloalkyl and halogen, C 1-6 Alkyl, and C 1-6 C optionally substituted with one or more substituents selected from alkoxy 3-10 cycloalkyl; n is selected from the group consisting of 1, 2, and 3; R 7 But phenyl, C 1-6 Alkoxy, -OH, -N(R 9 ) 2 , -NR 9 -SO 2 -C 1-6 Alkyl, -O-(C 1-6 (alkylene)-phenyl, C 3-10 Cycloalkyl, -C(O)OR 8 , -C(O)N(R 9 ) 2 , -NR 10 C(O)-R 11 , -CN, -S(O) 2 -C 1-6 Alkyl, -S(O) 2 -N(R 9 ) 2 , 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl; 3-10 Cycloalkyl, 3- to 10-membered heterocyclyl, or 3- to 10-membered heteroaryl is C 1-6 Alkyl, halogen, -OH, C 1-6 Alkoxy, and -N(R 9 ) 2 and optionally substituted with one or more substituents each independently selected from the group consisting of: R8 But hydrogen, C 1-6 Alkyl, and C 3-10 cycloalkyl; Each R 9 But hydrogen, C 1-6 Alkyl, and -(C 1-6 or two R 9 But two R 9 together with the nitrogen atom to which is bonded, may form a heterocycle optionally substituted with one or more substituents each independently selected from halogen and -OH; Each R 10 are independently hydrogen or C 1-6 is alkyl, R 11 But, C 1-6 Alkyl, C 1-6 Alkoxy, and -O-(C 1-6 The compound of formula II, or a pharma- ceutically acceptable salt thereof, is provided, wherein the compound is selected from the group consisting of: 1) alkylene)-phenyl;

[0118] In some embodiments, two of X, Y, Z, Y', and Z' are N and the other three are CH.

[0119] In some embodiments, the compound is a compound of formula II-a: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0120] In some embodiments, the compound is a compound of formula II-b: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0121] In some embodiments, the compound is a compound of formula II-c: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0122] In some embodiments, the compound is a compound of formula II-d: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0123] In some embodiments, the compound is a compound of formula II-e: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0124] In some embodiments, the compound is a compound of formula II-f: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0125] In some embodiments, the compound is a compound of formula II-g: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0126] In some embodiments, the compound is a compound of formula II-h: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0127] In some embodiments, the compound is a compound of formula II-i: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0128] In some embodiments, the compound is a compound of formula II-j: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0129] In some embodiments, the compound is a compound of formula II-k: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0130] In some embodiments, the compound is a compound of formula II-l: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0131] In some embodiments, the compound is a compound of formula II-m: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0132] In some embodiments, the compound is a compound of formula II-n: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0133] In some embodiments, the compound is a compound of formula II-p: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0134] In some embodiments, the compound is a compound of formula II-q: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0135] In some embodiments, the compound is a compound of formula II-r: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0136] In some embodiments, the compound is a compound of formula II-k1, or formula II-k2: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above.

[0137] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), or (II-r)), n is 1. In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), or (II-r)), n is 2.

[0138] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), or (II-r)), n is 1 and R 5 In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), or (II-r)), n is 2 and two R 5 In some embodiments of formula (II) (e.g., (II-a), (II-b), (II-c), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), or (II-r)), n is 2 and two R 5In some embodiments of formula (II) (e.g., (II-a), (II-b), (II-c), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), or (II-r)), n is 2 and two R 5 is in meta position.

[0139] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), or (II-r)), R 3 and R 4 is R 3 and R 4 Together with the carbon bonded to C 3-7 Forms a cycloalkylene or a 3- to 7-membered heterocyclene. In some embodiments, C 3-7 The cycloalkylene is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, the 3- to 7-membered heterocyclene is selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0140] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), or (II-r)), R 4 is hydrogen.

[0141] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), or (II-r)), R 2 is hydrogen.

[0142] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), or (II-r)), R 2 is methyl.

[0143] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 3 is C 1-6 In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 3 is methyl. In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R3 is ethyl.

[0144] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 3 is C 1-6 Alkoxy-substituted C 1-6 Alkyl, -OH, or -C(O)OR 8 It is.

[0145] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 3 is hydrogen.

[0146] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), each R 5 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, OC 3-10 Cycloalkyl, -CN, C 1-6 Alkylene-C 1-6 Alkoxy, C 1-6 Alkylene-N(R 9 ) 2 , N(R9 ) 2 , and -C(O)OR 8 are independently selected from the group consisting of:

[0147] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 5 is C 1-6 In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 5 is methyl.

[0148] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 5 is a halogen. In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 5is -F. In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 5 is -Cl.

[0149] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 5 is C 1-6 In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 5 CF 3 In some embodiments of formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 5 CF 2 It's H.

[0150] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 5 is C 1-6 In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 5 is methoxy.

[0151] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 5 is C 3-10 In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 5 is cyclopropyl.

[0152] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 5 is -C(O)OR 8 It is.

[0153] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 1 is C 1-6 C optionally substituted with alkoxy 1-6 Alkyl, N(R 9 ) 2 , C(O)N(R 9 ) 2 , C 3-7 Cycloalkyl, pyridyl, tetrahydropyranyl, or phenyl, C 1-6 Haloalkyl, C 3-7 It is selected from the group consisting of cycloalkyl, phenyl, and pyridyl.

[0154] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 1 is C 1-6In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 1 is methyl. In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 1 is ethyl.

[0155] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 1 is C 1-6 In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 1 is -CH 2 -CHF 2In some embodiments of formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 1 is CHF 2 It is.

[0156] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 1 is C 3-7 In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 1 is cyclopropyl, cyclobutyl, or cyclopentyl.

[0157] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 1 is phenyl substituted with halogen.

[0158] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 1 is C 1-6 Alkoxy-substituted C 1-6 In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 1 is N(R 9 ) 2 C replaced with 1-6 In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 1 is a C substituted with cyclopropyl, cyclobutyl, or cyclopentyl 1-6 It is an alkyl.

[0159] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), x is 0 or 1.

[0160] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), x is 1.

[0161] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 12 is C 1-6 Alkyl, C 1-6 It is selected from the group consisting of haloalkyl, and phenyl optionally substituted with halogen.

[0162] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 12 is C 1-6 In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 12is methyl. In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 12 is ethyl. In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 12 is t-butyl.

[0163] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 12 is C 1-6 In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 12 CF 3In some embodiments of formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 12 is CHF 2 It is.

[0164] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 12 is C 3-7 In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), R 12 is cyclopropyl.

[0165] In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), In some embodiments of Formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), x is 0.

[0166] In another aspect, the present invention provides a compound of formula III: [ka] or a pharma- ceutically acceptable salt thereof, R 1 But, C 1-6 Alkyl or C 3-7 Cycloalkyl, C 1-6 Alkyl or C 3-7 Cycloalkyl is one or more halogen or C 1-6 optionally substituted with alkoxy; R 12 But, C 3-10 is selected from the group consisting of cycloalkyl, 3- to 10-membered saturated heterocyclyl, and phenyl; 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, or phenyl is substituted with halogen and C 1-6 optionally substituted with one or more substituents each independently selected from alkoxy; R 2 is hydrogen or C 1-4 is alkyl, R 3 But, C 1-6 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; R 4 But, C 1-6 alkyl and hydrogen, or R 3 and R 4 But R 3 and R 4 Together with the carbon bonded to C 3-7can form a cycloalkylene or a 3- to 7-membered heterocyclene; 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heteroaryl, phenyl, C 3-7 Cycloalkylene or 3- to 7-membered heterocyclene is one or more R 7 may be optionally substituted with R 5 But halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heteroaryl, -C 1-6 Alkylene -OH, OH, -C(O)OR 8 , -C(O)N(R 9 ) 2 , -C 1-6 Alkylene -CN, -CN, -S(O) 2 -C 1-6 Alkyl, C 1-6 Alkylene-S(O) 2 -C 1-6 Alkyl, -S(O) 2 -N(R 9 ) 2 , -OC(O)C 1-6 -OC optionally substituted with alkyl and one or more halogens 1-3 cycloalkyl; R 7 But phenyl, C 1-6 Alkoxy, -OH, -O-(C 1-6 (alkylene)-phenyl, C 3-10 Cycloalkyl, -C(O)OR 8 , -C(O)N(R 9 ) 2 , -NR 10 C(O)-R 11 , -CN, -S(O) 2 -C 1-6 Alkyl, -S(O) 2 -N(R 9 ) 2, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl; 3-10 Cycloalkyl, 3- to 10-membered heterocyclyl, or 3- to 10-membered heteroaryl is C 1-6 Alkyl, halogen, -OH, C 1-6 Alkoxy, and -N(R 9 ) 2 and optionally substituted with one or more substituents each independently selected from the group consisting of: R 8 is hydrogen or C 1-6 is alkyl, Each R 9 But hydrogen, C 1-6 Alkyl, and -(C 1-6 or two R 9 But two R 9 together with the nitrogen atom to which is bonded, may form a heterocycle optionally substituted with one or more substituents each independently selected from halogen and -OH; Each R 10 are independently hydrogen or C 1-6 is alkyl, R 11 But, C 1-6 Alkyl, C 1-6 Alkoxy, and -O-(C 1-6 (alkylene)-phenyl; n is selected from the group consisting of 0, 1, 2, and 3; The compound is [ka] or a pharma- ceutically acceptable salt thereof, is provided.

[0167] In another aspect, the present invention provides a compound of formula IV: [ka] or a pharma- ceutically acceptable salt thereof, R1 But, C 1-6 Alkyl and C 3-7 cycloalkyl, C 1-6 Alkyl or C 3-7 Cycloalkyl is halogen and C 1-6 optionally substituted with one or more substituents independently selected from alkoxy; R 12 But one or more halogens or C 1-6 C optionally substituted with alkoxy 1-6 is alkyl, R 2 is hydrogen or C 1-4 is alkyl, R 3 But, C 1-6 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; R 4 But, C 1-6 alkyl and hydrogen, or R 3 and R 4 But R 3 and R 4 Together with the carbon bonded to C 3-7 can form a cycloalkylene or a 3- to 7-membered heterocyclene; 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heteroaryl, phenyl, C 3-7 Cycloalkylene or 3- to 7-membered heterocyclene is R 7 may be optionally substituted with R 5 But halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heteroaryl, -C 1-6 Alkylene -OH, OH, -C(O)OR 8 , -C(O)N(R 9 ) 2 , -C 1-6Alkylene -CN, -CN, -S(O) 2 -C 1-6 Alkyl, C 1-6 Alkylene-S(O) 2 -C 1-6 Alkyl, -S(O) 2 -N(R 9 ) 2 , -OC(O)C 1-6 -OC optionally substituted with alkyl and one or more halogens 3-10 cycloalkyl; R 7 But phenyl, C 1-6 Alkoxy, -OH, -O-(C 1-6 (alkylene)-phenyl, C 3-10 Cycloalkyl, -C(O)OR 8 , -C(O)N(R 9 ) 2 , -NR 10 C(O)-R 11 , -CN, -S(O) 2 -C 1-6 Alkyl, -S(O) 2 -N(R 9 ) 2 , 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl; 3-10 Cycloalkyl, 3- to 10-membered heterocyclyl, or 3- to 10-membered heteroaryl is C 1-6 Alkyl, halogen, -OH, C 1-6 Alkoxy, and -N(R 9 ) 2 and optionally substituted with one or more substituents each independently selected from the group consisting of: R 8 is hydrogen or C 1-6 is alkyl, Each R 9 But hydrogen, C 1-6 Alkyl, and -(C 1-6 or two R 9 But two R 9may be taken together with the nitrogen atom to which it is bonded to form a heterocycle optionally substituted with one or more substituents selected from halogen and -OH; Each R 10 are independently hydrogen or C 1-6 is alkyl, R 11 But, C 1-6 Alkyl, C 1-6 Alkoxy, and -O-(C 1-6 (alkylene)-phenyl; n is selected from the group consisting of 0, 1, 2, and 3; The compound is [ka] or a pharma- ceutically acceptable salt thereof, is provided.

[0168] In another aspect, the present invention provides a compound of formula V: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is phenyl or 3-10 membered heteroaryl, and the phenyl or 3-10 membered heteroaryl is selected from halogen and C 1-6 optionally substituted with one or more substituents independently selected from alkoxy; R 12 But, C 3-10 is selected from the group consisting of cycloalkyl, 3- to 10-membered saturated heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; 3-10 Cycloalkyl, 3-10 membered saturated heterocyclyl, 3-10 membered heteroaryl, or phenyl is optionally substituted with halogen and C 1-6 optionally substituted with one or more substituents each independently selected from alkoxy; R 2 is hydrogen or C 1-4 is alkyl, R 3 But, C1-6 Alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; R 4 But, C 1-6 alkyl and hydrogen, or R 3 and R 4 But R 3 and R 4 Together with the carbon bonded to C 3-7 can form a cycloalkylene or a 3- to 7-membered heterocyclene; 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heteroaryl, phenyl, C 3-7 Cycloalkylene or 3- to 7-membered heterocyclene is one or more R 7 may be optionally substituted with R 5 But halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heteroaryl, -C 1-6 Alkylene -OH, OH, -C(O)OR 8 , -C(O)N(R 9 ) 2 , -C 1-6 Alkylene -CN, -CN, -S(O) 2 -C 1-6 Alkyl, C 1-6 Alkylene-S(O) 2 -C 1-6 Alkyl, -S(O) 2 -N(R 9 ) 2 , -OC(O)C 1-6 Alkyl, and -OC 3-10 cycloalkyl; R 7 But phenyl, C 1-6 Alkoxy, -OH, -O-(C 1-6 (alkylene)-phenyl, C 3-7 Cycloalkyl, -C(O)OR 8, -C(O)N(R 9 ) 2 , -NR 10 C(O)-R 11 , -CN, -S(O) z -C 1-6 Alkyl, -S(O) z -N(R 9 ) 2 , 3- to 7-membered heterocyclyl, and 3- to 10-membered heteroaryl; 3-10 Cycloalkyl, 3- to 10-membered heterocyclyl, or 3- to 10-membered heteroaryl is C 1-6 Alkyl, halogen, -OH, C 1-6 Alkoxy, and -N(R 9 ) 2 and optionally substituted with one or more substituents each independently selected from the group consisting of: R 8 is hydrogen or C 1-6 is alkyl, Each R 9 But hydrogen, C 1-6 Alkyl, and -(C 1-6 or two R 9 But two R 9 together with the nitrogen atom to which is bonded, may form a heterocycle optionally substituted with one or more substituents each independently selected from halogen and -OH; Each R 10 are independently hydrogen or C 1-6 is alkyl, R 11 But, C 1-6 Alkyl, C 1-6 Alkoxy, and -O-(C 1-6 (alkylene)-phenyl; n is selected from the group consisting of 0, 1, 2, and 3; The compound is [ka] or a pharma- ceutically acceptable salt thereof, is provided.

[0169] In some embodiments of formula (III), (IV), or (V), R 2 is hydrogen.

[0170] In some embodiments of formula (III), (IV), or (V), R 3 is C 1-6 In some embodiments of formula (III), (IV), or (V), R 3 is methyl. In some embodiments of formula (III), (IV), or (V), R 3 is ethyl.

[0171] In some embodiments of formula (III), (IV), or (V), R 3 is C 1-6 Alkoxy-substituted C 1-6 Alkyl, -OH, or -C(O)OR 8 It is.

[0172] In some embodiments of formula (III), (IV), or (V), R 4 is hydrogen.

[0173] In some embodiments of formula (III), (IV), or (V), R 3 and R 4 is R 3 and R 4 Together with the carbon bonded to C 3-7 It forms a cycloalkylene or a 3- to 7-membered heterocyclene.

[0174] In some embodiments of formula (III), (IV), or (V), R 5 is cyclopropyl, -OCH 2 CH 3 , -OCH 2 -CHF 2 , -O-cyclopropyl, -O-isopropyl, -NHCH 3 , -N(CH 3 ) 2 , and -CH2 OCH 3 are each independently selected from the group consisting of:

[0175] In some embodiments of formula (III), (IV), or (V), each R 5 is methyl.

[0176] In some embodiments of formula (III), (IV), or (V), each R 5 is halogen. In some embodiments of formula (III), (IV), or (V), each R 5 In some embodiments of formula (III), (IV), or (V), each R 5 is -Cl.

[0177] In some embodiments of formula (III), (IV), or (V), each R 5 is methoxy.

[0178] In some embodiments of formula (III), (IV), or (V), each R 5 -CF 3 It is.

[0179] In some embodiments of formula (III), (IV), or (V), each R 5 -CHF 2 It is.

[0180] In some embodiments of formula (III), (IV), or (V), each R 5 is -C(O)OR 8 It is.

[0181] In some embodiments of formula (III), (IV), or (V), n is 1.

[0182] In some embodiments of formula (III), (IV), or (V), n is 2.

[0183] In some embodiments of Formula (III), (IV), or (V), n is 1 and R5 In some embodiments of formula (III), (IV), or (V), n is 2 and two R 5 In some embodiments of formula (III), (IV), or (V), n is 2 and two R 5 In some embodiments of formula (III), (IV), or (V), n is 2 and two R 5 is in meta position.

[0184] In some embodiments of formula (III), (IV), or (V), R 1 is C 1-6 In some embodiments of formula (III), (IV), or (V), R 1 is methyl. In some embodiments of formula (III), (IV), or (V), R 1 is ethyl.

[0185] In some embodiments of formula (III), (IV), or (V), R 1 is C 1-6 In some embodiments of formula (III), (IV), or (V), R 1 is -CH 2 -CHF 2 In some embodiments of formula (III), (IV), or (V), R 1 -CHF 2 It is.

[0186] In some embodiments of formula (III), (IV), or (V), R 1 is C 3-7 In some embodiments of formula (III), (IV), or (V), R 1 is cyclopropyl.

[0187] In some embodiments of formula (III), (IV), or (V), R 1 is phenyl substituted with halogen.

[0188] In some embodiments of formula (III), (IV), or (V), R 12 is C 1-6 Alkyl, C 3-10 is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heteroaryl, or phenyl is selected from the group consisting of halogen and C 1-6 Optionally substituted with one or more substituents each independently selected from alkoxy.

[0189] In some embodiments of formula (III), (IV), or (V), R 12 is C 3-7 In some embodiments of formula (III), (IV), or (V), R 12 is cyclopropyl.

[0190] In some embodiments of formula (III), (IV), or (V), R 12 is C 1-6 In some embodiments of formula (III), (IV), or (V), R 12 In some embodiments of formula (III), (IV), or (V), R 12 is methyl. In some embodiments of formula (III), (IV), or (V), R 12 is t-butyl.

[0191] In some embodiments of formula (III), (IV), or (V), R 12 is C 1-6 In some embodiments of formula (III), (IV), or (V), R 12 -CF 3 In some embodiments of formula (III), (IV), or (V), R 12 -CHF 2 It is.

[0192] In another aspect, the present disclosure provides a compound of formula VI: [ka] or a pharma- ceutically acceptable salt thereof, R 13 But, C 1-6 Alkyl or C 3-10 Cycloalkyl, C 1-6 Alkyl or C 3-10 cycloalkyl is optionally substituted with phenyl; R 14 is hydrogen, R 15 But, C 1-6 is alkyl or hydrogen; R 16 C optionally substituted with one or more halogens 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, or phenyl; Each R 17 But halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylene-N(R 20 ) 2 , C 1-6 Alkylene-OC 3-10 Cycloalkyl, C 3-7 C optionally substituted with cycloalkyl 1-6 Alkoxy, C 1-6 Haloalkoxy, one or more halogens or C 1-6 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, optionally substituted with alkoxy; 1-6 Alkylene-OH, C 1-6 Alkylene-C 1-6 Alkoxy, OH, -N(R 20 ) 2 , -C(O)OR 19 , -C(O)N(R 20 ) 2 , -C 1-6 Alkylene -CN, -CN, -S(O) 2 -C1-6 Alkyl, C 1-6 Alkylene-S(O) 2 -C 1-6 Alkyl, -S(O) 2 -N(R 20 ) 2 , -OC(O)C 1-6 Alkyl, one or more halogens or C 1-6 -OC optionally substituted with alkyl 3-10 Cycloalkyl and halogen, C 1-6 Alkyl, and C 1-6 C optionally substituted with one or more substituents selected from alkoxy 3-10 cycloalkyl; p is selected from the group consisting of 1, 2, and 3; R 19 But hydrogen, C 1-6 Alkyl, and C 3-10 cycloalkyl; Each R 20 are independently hydrogen or C 1-6 is alkyl, Each R 21 are independently hydrogen or C 1-6 or a pharma- ceutically acceptable salt thereof.

[0193] In some embodiments of formula (VI), R 13 is selected from the group consisting of ethyl, tert-butyl, sec-butyl, iso-propyl, benzyl, and cyclopentyl.

[0194] In some embodiments of formula (VI), R 15 is hydrogen.

[0195] In some embodiments of formula (VI), R 16 is C 1-6 It is an alkyl.

[0196] In some embodiments of formula (VI), R 16 is methyl or ethyl.

[0197] In some embodiments of Formula (VI), p is 1 or 2.

[0198] In some embodiments of Formula (VI), the compound is a compound of formula VI-a: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above for formula VI.

[0199] In some embodiments of Formula (VI) (e.g., (VI-a)), R 17 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene-C 1-6 Alkoxy, -OC optionally substituted with one or more halogens 3-10 Cycloalkyl, or halogen, C 1-6 Alkyl, and C 1-6 C optionally substituted with one or more substituents selected from alkoxy 3-10 It is cycloalkyl.

[0200] In some embodiments of Formula (VI) (e.g., (VI-a)), R 17 is C 1-6 Alkyl or C 1-6 Cyclopropyl optionally substituted with alkoxy.

[0201] In some embodiments of Formula (VI) (e.g., (VI-a)), R 17 is cyclopropyl optionally substituted with methyl or methoxy.

[0202] In some embodiments of Formula (VI) (e.g., (VI-a)), R 17 is C 1-6 It is an alkyl.

[0203] In some embodiments of Formula (VI) (e.g., (VI-a)), R 17 is methyl.

[0204] In some embodiments of Formula (VI) (e.g., (VI-a)), R 17 is C 1-6 Alkoxy, C 1-6 Alkylene-C 1-6 Alkoxy, or C 1-6 It is haloalkoxy.

[0205] In some embodiments of Formula (VI) (e.g., (VI-a)), R 17 is -OCH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , O-CH 2 CHF 2 , or -CH 2 OCH 3 It is.

[0206] In some embodiments of Formula (VI) (e.g., (VI-a)), R 17 is C 1-6 It is haloalkyl.

[0207] In some embodiments of Formula (VI) (e.g., (VI-a)), R 17 is CHF 2 or CF 3 It is.

[0208] In some embodiments of Formula (VI) (e.g., (VI-a)), the compound is selected from the group consisting of Example Compound Nos. 272, 247, 262, 273, 274, 275, 276, 277, 284, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, and 296, or a pharma- ceutically acceptable salt thereof.

[0209] In another aspect, the present disclosure provides a compound of formula VII: [ka] or a pharma- ceutically acceptable salt thereof, W is N or CH; R 23 But, C 1-6 is alkyl, R 24 is hydrogen, R 25 But, C 1-6 is alkyl or hydrogen; R 26 But one or more halogens or C 1-6 C optionally substituted with alkoxy 1-6 is alkyl, Each R 27 But halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 independently selected from the group consisting of alkoxy; The present invention features a compound of formula VII, or a pharma- ceutically acceptable salt thereof, wherein p is selected from the group consisting of 1, 2, and 3.

[0210] In another aspect, the present disclosure provides a compound of formula VII: [ka] or a pharma- ceutically acceptable salt thereof, W is N or CH; R 23 But, C 1-6 is alkyl, R 24 is hydrogen, R 25 But, C 1-6 is alkyl or hydrogen; R 26 But one or more halogens or C 1-6 C optionally substituted with alkoxy 1-6 is alkyl, Each R 27 But halogen, C 1-6 Alkyl, C 1-6Haloalkyl, and C 1-6 independently selected from the group consisting of alkoxy; a compound of formula VII, or a pharma- ceutically acceptable salt thereof, wherein p is selected from the group consisting of 1, 2, and 3; and a pharma- ceutically acceptable excipient.

[0211] In some embodiments of Formula (VII), the compound is a compound of formula VII-a or formula VII-b: [ka] or a pharma- ceutically acceptable salt thereof.

[0212] In some embodiments of formula (VII), p is 1.

[0213] In some embodiments of Formula (VII) (e.g., (VII-a) or (VII-b)), R 23 is tert-butyl.

[0214] In some embodiments of formula (VII), R 25 is hydrogen.

[0215] In some embodiments of formula (VII), R 26 is methyl.

[0216] In some embodiments of Formula (VII) (e.g., (VII-a) or (VII-b)), R 27 is a halogen, C 1-6 Alkyl, or C 1-6 It is an alkoxy.

[0217] In some embodiments of Formula (VII) (e.g., (VII-a) or (VII-b)), R 27 is fluoro.

[0218] In some embodiments of Formula (VII) (e.g., (VII-a) or (VII-b)), R27 is OCH 3 It is.

[0219] In some embodiments of Formula (VII) (e.g., (VII-a) or (VII-b)), R 27 is methyl.

[0220] In some embodiments of Formula (VII) (e.g., (VII-a) or (VII-b)), the compound is selected from the group consisting of Example Compound Nos. 281, 282, 283, and 285, or a pharma- ceutically acceptable salt thereof.

[0221] In an exemplary embodiment, the invention is meant to encompass the compounds disclosed herein, as well as the pharma- ceutically acceptable salts, tautomeric forms, polymorphs, and prodrugs of such compounds. In some embodiments, the present invention provides a compound as described herein, e.g., a compound of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), a compound of formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II- and m is 0, 1 or 2. The term "compound" includes phenyl, ...

[0222] In any and all aspects, in some embodiments, the compound of formula (I), (II), (III), (IV), or (V) is selected from the group consisting of Example Compound Nos. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 109, 110, 111, 112, 113, 114, 115, 116, 117 , 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 12 8, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139 , 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 2 05, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 23 6, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 263, 264, 265, 266, 267, 268, 269,270, 271, 278, 279, 280, 297, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, and 310, or a pharma- ceutically acceptable salt thereof.

[0223] General synthesis scheme Exemplary methods for preparing the compounds described herein are illustrated in the following synthetic schemes, which are provided for the purpose of illustrating the invention and should not be construed as limiting the scope or spirit of the invention in any manner.

[0224] The synthetic route illustrated in Scheme 1 shows an exemplary procedure for preparing carboxylic acid intermediates D and G. In the first step, compound A is reacted with hydrazine B to form ethylpyrazole-5-carboxylate C. Hydrolysis of C then provides carboxylic acid D. Carboxylic acid D is coupled with amine E to form F, which can then be hydrolyzed to provide carboxylic acid G. [ka]

[0225] The synthetic route illustrated in Scheme 2 shows an exemplary procedure for preparing amine-substituted oxadiazole intermediate L. In the first step, nitrile H is treated with hydroxylamine to provide N-hydroxyimide amide I. Carbonyldiimidazole (CDI) mediated cyclization of glycine J with I then affords oxadiazole K. Deprotection of K under acidic conditions provides amine-substituted oxadiazole intermediate L. [ka]

[0226] The synthetic route illustrated in Scheme 3 shows an exemplary procedure for preparing M (a compound of formula I). ​​Coupling of an amine-substituted oxadiazole amine L with a carboxylic acid D using standard peptide coupling procedures (e.g., HOBt in dichloromethane in the presence of DIPEA, and EDCI) provides compound M (a compound of formula I). [ka]

[0227] As illustrated in Scheme 4, N-hydroxyimide amide I can undergo CDI-mediated cyclization with carboxylic acid G to provide compound M (compound of formula I). [ka]

[0228] Treatment methods The compounds and compositions described above and herein can be used to treat neurological diseases or disorders, or diseases or conditions associated with excessive neuronal excitability and / or gain-of-function mutations in genes (e.g., KCNT1). Exemplary diseases, disorders, or conditions include epilepsy and other encephalopathies (e.g., epilepsy of infancy with migrating focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathies, developmental and epileptic encephalopathies (DEE), early infantile onset epileptic encephalopathy (EIEE), generalized epilepsy, focal epilepsy, multifocal epilepsy, temporal lobe epilepsy, Ohtahara syndrome, early myoclonic encephalopathy, and Lennox syndrome. Gastaut syndrome, drug-resistant epilepsy, seizures (e.g., frontal lobe seizures, generalized tonic-clonic seizures, asymmetric tonic seizures, focal seizures, leukodystrophies, myelinating leukodystrophies, leukoencephalopathy, and sudden unexpected death in epilepsy, cardiac dysfunction (e.g., cardiac arrhythmias, Brugada syndrome, myocardial infarction), pulmonary vascular disorders / bleeding, pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.), muscle disorders (e.g., myotonia, neuromyotonia, muscle spasms, spasticity), itch and pruritus, movement disorders (e.g., ataxia, and cerebellar ataxia), psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia, attention deficit hyperactivity disorder), neurodevelopmental disorders, learning disabilities, intellectual disability, fragile X, neuroplasticity, and autism spectrum disorders.

[0229] In some embodiments, the neurological disease or disorder, or disease or condition associated with excessive neural excitability and / or gain-of-function mutations in genes (e.g., KCNT1), is selected from EIMFS, ADNFLE, and West syndrome. In some embodiments, the neurological disease or disorder, or disease or condition associated with excessive neural excitability and / or gain-of-function mutations in genes (e.g., KCNT1), is selected from infantile spasms, epileptic encephalopathy, focal epilepsy, Otahara syndrome, developmental and epileptic encephalopathy, and Lennox Gastaut syndrome. In some embodiments, the neurological disease or disorder, or disease or condition associated with excessive neural excitability and / or gain-of-function mutations in genes (e.g., KCNT1), is seizures. In some embodiments, the neurological disease or disorder, or disease or condition associated with excessive neural excitability and / or gain-of-function mutations in genes (e.g., KCNT1), is selected from cardiac arrhythmia, Brugada syndrome, and myocardial infarction.

[0230] 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 disabilities, fragile X, intellectual disability, neuroplasticity, psychotic disorders, and autism spectrum disorders.

[0231] Thus, the compounds and compositions thereof can be administered to subjects with a neurological disease or disorder, or a 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, Ohtahara syndrome, developmental and epileptic encephalopathies, and Lennox-Gastaut syndrome, seizures, cardiac arrhythmias, Brugada syndrome, and myocardial infarction).

[0232] EIMFS is a rare and debilitating genetic condition characterized by early onset (before age 6 months) of nearly continuous heterogeneous focal seizures that appear to migrate from one brain region and hemisphere to another. Patients with EIMFS generally have intellectual disability, speech disorders, and gait disorders. To date, several genes have been implicated, but the gene most commonly associated with EIMFS is KCNT1. Several de novo mutations in KCNT1 have been identified in patients with EIMFS, including V271F, G288S, R428Q, R474Q, R474H, R474C, I760M, A934T, P924L, G243S, H257D, A259D, R262Q, Q270E, L274I, F346L, C377S, R398Q, P409S, A477T, F502V, M516V, Q550del, K629E, K629N, I760F, E893K, M896K, R933G, R950Q, and K1154Q (Barcia et al. (2012) Nat Genet. 44:1255-1260, Ishii ... al. (2013) Gene 531:467--471, McTague et al. (2013) Brain.136:1578-1591, Epi4K Consortium & Epilepsy Phenome / Genome Project. (2013) Nature 501:217-221, Lim et al. (2016) Neurogenetics, Ohba et al. al.(2015)Epilepsia 56:el21-el28, Zhou et al.(2018)Genes Brain Behav.e12456, Moller et al.(2015)Epilepsia.e114-20, Numis et al.(2018)Epilepsia.1889-1898, Madaan et al.Brain Dev.40(3):229-232, McTague et al. al. (2018) Neurology.90(1):e55-e66, Kawasaki et al. (2017) J Pediatr.191:270-274, Kim et al. (2014) Cell Rep.9(5):1661-1672, Ohba et al. (2015) Epilepsia.56(9):e121-8, Rizzo et al. (2016) Mol Cell Neurosci.72:54-63, Zhang et al. (2017) Clin Genet.91(5):717-724, Mikati et al. (2015) Ann Neurol.78(6):995-9, Baumer et al. al.(2017) Neurology.89(21):2212, Dilena et al.(2018) Neurotherapeutics.15(4):1112-1126). These mutations are dominant (i.e., present in only one allele) gain-of-function missense mutations that alter the function of the encoded potassium channels when tested in Xenopus oocytes or mammalian expression systems, causing a marked increase in whole-cell currents (see, e.g., Milligan et al. (2015) Ann Neurol. 75(4):581-590, Barcia et al. (2012) Nat Genet. 44(11):1255-1259, and Mikati et al. (2015) Ann Neurol. 78(6):995-999).

[0233] ADNFLE is a condition that has a later onset than EIMFS, generally occurring in mid-childhood, and is generally less severe. It is characterized by nocturnal frontal lobe seizures and can produce mental, behavioral, and cognitive impairments in patients with the condition. ADNFLE is associated with genes that code for several neuronal nicotinic acetylcholine receptor subunits, but mutations in the KCNT1 gene are involved in more severe cases of the disease (Heron et al. (2012) Nat Genet. 44:1188-1190). Functional studies of mutant KCNT1 genes associated with ADNFLE have shown that the underlying mutations (M896I, R398Q, Y796H, and R928C) are dominant gain-of-function mutations (Milligan et al. (2015) Ann Neurol. 75(4):581-590, Mikati et al. (2015) Ann Neurol. 78(6):995-999).

[0234] West syndrome is a severe form of epilepsy that consists of three features: infantile spasms, an interictal electroencephalogram (EEG) pattern termed hypsarrhythmia, and mental developmental delay, but can be diagnosed if one of these elements is missing. Mutations in KCNT1, including G652V and R474H, are associated with West syndrome (Fukuoka et al. (2017) Brain Dev 39:80-83 and Ohba et al. (2015) Epilepsia 56:el21-el28). Therapies targeting the KCNT1 channel suggest that these mutations are gain-of-function mutations (Fukuoka et al. (2017) Brain Dev 39:80-83).

[0235] In one aspect, the present invention provides a method for treating diseases or conditions associated with excessive neuronal excitation and / or gain-of-function mutations in genes such as KCNT1, including epilepsy and other encephalopathies (e.g., epilepsy of infancy with migratory focal seizures (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathies, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies (DEE), and Lennox syndrome. Gastaut syndrome, seizures, leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia, asymmetric tonic seizures), as well as cardiac dysfunction (e.g., cardiac arrhythmias, Brugada syndrome, sudden unexpected death in epilepsy, myocardial infarction), pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.), muscle disorders (e.g., myocardial infarction ... and (f) a compound of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If ... ), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), (II) (e.g., (II-a), (II-b), (II -c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (I (II-q), (II-r), (II-k1), or (II-k2)), (III), (IV), (V), (VI) (e.g., (VI-a)), or (VII) (e.g., (VII-a) or (VII-b)), or a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a compound disclosed herein (e.g., a compound of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is)), (II) (e.g. ), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), or a pharmaceutical composition comprising a compound of formula (III) (e.g., (III-a), (III-a1), (III-k1), (III-b), (III-b1), (III-b2), (III-c), (III-c1), (III-c2)), (III), (IV), (V), (VI) (e.g., (VI-a)), or (VII) (e.g., (VII-a) or (VII-b)), or a pharma- ceutical acceptable salt thereof) and a pharma-ceutical acceptable excipient to a subject in need of treatment.

[0236] In some embodiments, the subject who presents disease or condition that may be related to KCNT1 gain-of-function mutation is genotyped to confirm the presence of known KCNT1 gain-of-function mutation before administering the compound and its composition.For example, whole exome sequencing may be performed on the subject. Gain-of-function mutations associated with EIMFS can include, but are not limited to, V271F, G288S, R428Q, R474Q, R474H, R474C, I760M, A934T, P924L, G243S, H257D, A259D, R262Q, Q270E, L274I, F346L, C377S, R398Q, P409S, A477T, F502V, M516V, Q550del, K629E, K629N, I760F, E893K, M896K, R933G, R950Q, and K1154Q. Gain-of-function mutations associated with ADNFLE include, but are not limited to, M896I, R398Q, Y796H, R928C, and G288S. Gain-of-function mutations associated with West syndrome include, but are not limited to, G652V and R474H. Gain-of-function mutations associated with temporal lobe epilepsy include, but are not limited to, R133H and R565H. Gain-of-function mutations associated with Lennox-Gastaut include, but are not limited to, R209C. Gain-of-function mutations associated with seizures include, but are not limited to, A259D, G288S, R474C, R474H. Gain-of-function mutations associated with leukodystrophy include, but are not limited to, G288S and Q906H. Gain-of-function mutations associated with multifocal epilepsy include, but are not limited to, V340M. Gain-of-function mutations associated with EOE include, but are not limited to, F346L and A934T. Gain-of-function mutations associated with early-onset epileptic encephalopathy (EOEE) include, but are not limited to, R428Q. Gain-of-function mutations associated with developmental and epileptic encephalopathies include, but are not limited to, F346L, R474H, and A934T.Gain-of-function mutations associated with epileptic encephalopathy include, but are not limited to, L437F, Y796H, P924L, R961H. Gain-of-function mutations associated with early infantile onset epileptic encephalopathy (EIEE) include, but are not limited to, M896K. Gain-of-function mutations associated with drug-resistant epilepsy and generalized tonic-clonic seizures include, but are not limited to, F346L. Gain-of-function mutations associated with migratory partial seizures of infancy include, but are not limited to, R428Q. Gain-of-function mutations associated with leukoencephalopathy include, but are not limited to, F932I. Gain-of-function mutations associated with NFLE include, but are not limited to, A934T and R950Q. Gain-of-function mutations associated with Ohtahara syndrome include, but are not limited to, A966T. Gain-of-function mutations associated with infantile spasms include, but are not limited to, P924L. Gain-of-function mutations associated with Brugada syndrome include, but are not limited to, R1106Q. Gain-of-function mutations associated with Brugada syndrome include, but are not limited to, R474H.

[0237] In other examples, the subject is first genotyped to identify the presence of a mutation in KCNT1, and then the mutation is confirmed to be a gain-of-function mutation using standard in vitro assays such as those described in Milligan et al. (2015) Ann Neurol. 75(4): 581-590. Typically, the presence of a gain-of-function mutation is confirmed when expression of a mutant KCNT1 allele causes an increase in whole-cell current compared to the whole-cell current resulting from expression of wild-type KCNT1, as assessed using whole-cell electrophysiology (such as those 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). 75(4): This increase in whole cell current can be, for example, at least or about 50%, 100%, 150%, 200%, 250%, 300%, 350%, 400% or more increase.The subject can then be identified as having a disease or condition associated with a gain-of-function mutation in KCNT1.

[0238] In certain examples, the subject is identified as having a KCNT1 allele containing a gain-of-function mutation (e.g., V271F, G288S, R398Q, R428Q, R474Q, R474H, R474C, G652V, I760M, Y796H, M896I, P924L, R928C, or A934T).

[0239] The compounds disclosed herein (e.g., compounds of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), or a pharma- ceutical thereof) are disclosed herein. and acceptable salts thereof), or pharmaceutical compositions disclosed herein (e.g., a compound disclosed herein (e.g., a compound of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), ( The pharmaceutical composition comprising (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), (III), (IV), (V), (VI) (e.g., (VI-a)), or (VII) (e.g., (VII-a) or (VII-b)), or a pharma- ceutical acceptable salt thereof) and a pharma- ceutical acceptable excipient) also provides a method for treating excessive neuronal excitability, where the excessive neuronal excitability is not necessarily the result of a gain-of-function mutation in KCNT1. KCNT1 may be therapeutically used for conditions related to neural excitability. Even if the disease is not the result of increased KCNT1 expression and / or activity, inhibition of KCNT1 expression and / or activity may still result in reduced neural excitability, thereby providing a therapeutic effect. Thus, the compounds disclosed herein (e.g., compounds of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In),(Io), (Ip), (Iq), (Ir), or (Is)), (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1), or (II-k2)), (III), (IV), (V), (VI) (e.g., (VI-a)), or is (VII) (e.g., (VII-a) or (VII-b)), or a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a compound disclosed herein (e.g., a compound of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), (II) (e.g., ( (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-k1) or (II-k2)), (III), (IV), (V), (VI) (e.g., (VI-a)), or (VII) (e.g., (VII-a) or (VII-b)), or a pharma- ceutical acceptable salt thereof. The pharmaceutical composition comprising a KCNT1-containing compound (a compound which is an acceptable salt thereof) and a pharma- ceutical acceptable excipient) can be used to treat subjects having conditions associated with excessive neural excitability, such as epilepsy and other encephalopathies (e.g., infantile epilepsy with migratory focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, and Lennox Gastaut syndrome), or cardiac dysfunction (e.g., cardiac arrhythmias, Brugada syndrome, myocardial infarction), whether or not the disease or disorder is associated with a gain-of-function mutation in KCNT1.

[0240] Pharmaceutical Compositions and Routes of Administration Compounds provided according to the present invention include, for example, compounds of formula (I) (e.g., (II), (I-II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), or (Is)), (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II The compounds of the present invention are generally administered in the form of a pharmaceutical composition. ... The pharmaceutical compositions can be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.).

[0241] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of drugs, for example, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, including rectal, buccal, intranasal, and transdermal routes, as an inhalant, or via a stent or impregnated or coated device such as, for example, an arterially inserted cylindrical polymer, having similar utilities as described in those patents and patent applications incorporated by reference.

[0242] One mode for administration is parenterally, particularly by injection. Forms in which the novel composition of the present invention can be incorporated for administration by injection include aqueous or oily suspensions, or emulsions including sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in brine are also conventionally used for injection, but are less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0243] Sterile injectable solution is prepared by incorporating the compound according to the present invention in the required amount in a suitable solvent containing various other ingredients as listed above, as necessary, followed by sterilization by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients in a sterile vehicle that contains basic dispersion medium and other ingredients as listed above.In the case of sterile powder for preparing sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains powder of active ingredient and any additional desired ingredient from its sterile solution that has been previously sterilized and filtered.

[0244] Oral administration is another route for administration of the compounds according to the present invention. Administration may be via capsules or enteric coated tablets, etc. In preparing pharmaceutical compositions containing at least one compound described herein, the active ingredient is usually diluted by an excipient and / or enclosed in such a carrier, which may be in the form of a capsule, sachet, paper, or other container. When an excipient functions as a diluent, it may be in the form of a solid, semi-solid, or liquid material (as above) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solution, and sterile packaged powder.

[0245] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterilized water, syrup and methylcellulose.In addition, formulations can contain lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl and propylhydroxybenzoates; sweeteners; and flavoring agents.

[0246] The compositions of the invention can be formulated to provide quick, sustained, or delayed release of the active ingredient after administration to a patient by using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are provided in U.S. Pat. Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods of the invention employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the invention in controlled amounts. The construction and use of transdermal patches to deliver pharmaceutical agents is well known in the art. See, for example, U.S. Pat. Nos. 5,023,252, 492,445, and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0247] The composition is preferably formulated in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compound is generally administered in a pharmacologic effective amount. Preferably, for oral administration, each dosage unit contains 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably contains 0.1 to 700 mg of a compound described herein. However, it will be understood that the amount of compound actually administered will usually be determined by the physician in view of the relevant circumstances, including the condition to be treated, the route of administration selected, 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.

[0248] To prepare solid compositions such as tablets, the principal active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present invention. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition, such that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0249] The tablet or pill of the present invention can be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action or to protect against the acidic conditions of the stomach.For example, the tablet or pill can comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope covering the former.The two components can be separated by an enteric layer, which functions to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be delayed released.A variety of materials can be used for such enteric layer or coating, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0250] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharma- ceutically acceptable solvents, may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0251] In some embodiments, a pharmaceutical composition comprising a disclosed compound, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. EXAMPLES

[0252] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed in any way as limiting the scope thereof.

[0253] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise specified. Although optimal reaction conditions may vary with the particular reactants or solvents used, such conditions can be determined by those skilled in the art by routine optimization.

[0254] In addition, as will be clear to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.The selection of suitable protecting groups for specific functional groups, and the suitable conditions for protection and deprotection are well known in the art.For example, many protecting groups and their introduction and removal are described in TW Greene and PG M Huts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and the references cited therein.

[0255] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, trituration, high pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). It should be noted that flash chromatography can be performed either manually or via an automated system. The compounds provided herein can be characterized by known standard procedures such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS). NMR chemical shifts are reported in parts per million (ppm) and are generated using methods well known to those skilled in the art. List of abbreviations TEA Triethylamine NaH Sodium hydroxide THF Tetrahydrofuran DMF N,N-Dimethylformamide DCM Dichloromethane EtOH Ethanol ACN Acetonitrile MeCN Acetonitrile CH 3 CN Acetonitrile NaOMe Sodium methoxide CbzCl Benzyl chloroformate MsCl Methanesulfonyl chloride AcOH Acetic acid TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride Py Pyridine MeI Methyl iodide LiOH Lithium hydroxide MeNH 2 Methylamine Cu(OAc) 2 Copper(II) Acetate DCC N,N'-dicyclohexylcarbodiimide DCE Dichloroethane i-PrOH Isopropyl alcohol EtOAc Ethyl acetate HOBt Hydroxybenzotriazole HATU Azabenzotriazole Tetramethyluranium Hexafluorophosphate DEA Diethanolamine MeNHNH 2 Methylhydrazine EtONa Sodium Ethoxide SFC supercritical fluid chemistry DIPEA N,N-Diisopropylethylamine EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Boc tert-Butyloxycarbonyl DMSO Dimethyl sulfoxide Boc-L-Ala-OH N-(tert-butoxycarbonyl)-L-alanine IPA Isopropyl Alcohol Ac 2 O Acetic anhydride PTFE Polytetrafluoroethylene Pd(dppf)Cl 2 [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride DMS Dimethyl sulfate T 3 P Propylphosphonic anhydride solution PE Petroleum Ether LCMS Liquid Chromatography Mass Spectrometry

[0256] Example 1. Synthesis of 192 and 191 a) Synthesis of 191 [ka] Synthesis of N'-hydroxy-3-methylbenzimidamide (A-3) To a solution of 3-methylbenzonitrile (10 g, 85.36 mmol) in ethanol (200 mL) was added hydroxylamine hydrochloride (17.8 g, 256 mmol) and DIPEA (8.63 mL, 85.36 mmol). The reaction mixture was heated at 70° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated. The mixture was treated with water (100 mL) and extracted with EtOAc (2×100 mL). The organic layer was washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4 After drying and concentration, compound A-3 (9.3 g) was obtained.

[0257] Synthesis of tert-butyl (R)-(1-(3-(m-tolyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate (A-268) To a solution of compound A-3 (2.0 g, 13.32 mmol) in 1,4-dioxane (60 mL) was added (2R)-2-(tert-butoxycarbonylamino)propanoic acid (2.52 g, 13.32 mmol) and DCC (3.02 g, 14.65 mmol). The reaction mixture was heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated. The mixture was treated with water (30 mL) and extracted with EtOAc (2×40 mL). The organic layer was washed with brine (20 mL) and diluted with anhydrous Na 2 SO 4 Dry on a stover and concentrate. The crude was purified by column chromatography on silica gel with 10% EtOAc / PE to give compound A-268 (1.1 g, 3.8 mmol, 28% yield). LCMS: 302.1 (MH), Rt 2.57 min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile phase: A: 0.1% HCOOH in water:ACN (95:5), B:ACN; Flow rate: 1.5 mL / min.

[0258] Synthesis of (R)-1-(3-(m-tolyl)-1,2,4-oxadiazol-5-yl)ethan-1-amine (A-269) To a stirred solution of compound A-268 (500 mg, 1.65 mmol) in DCM (2.5 mL) was added TFA (1.5 mL) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 8 h. The reaction mixture was concentrated and washed with saturated NaHCO 3 The mixture was extracted with EtOAc (2x20 mL) and washed with brine (20 mL). The organic layer was washed with anhydrous Na 2 SO 4 Drying over and concentration gave compound A-269 (188 mg). The compound was used in the next step without further purification.

[0259] Synthesis of (R)-3-cyclopropyl-1-methyl-N-(1-(3-(m-tolyl)-1,2,4-oxadiazol-5-yl)ethyl)-1H-pyrazole-5-carboxamide (191) To a stirred solution of compound A-269 (188 mg, 0.92 mmol) in THF (5.0 mL) was added 3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylic acid (179 mg, 1.08 mmol), followed by T3P (1.17 mL, 1.97 mmol) and TEA (0.41 mL, 2.95 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was treated with water (20 mL) and extracted with EtOAc (2×20 mL). The organic layer was washed with brine (20 mL) and diluted with anhydrous Na 2 SO 4 After drying and concentration, the crude was purified by column chromatography on silica gel with 30% EtOAc / PE to give 191 (105 mg, 0.29 mmol, 30% yield) as a solid. HPLC: Rt 4.71 min, 99.2%; Column: X-Bridge C8 (50×4.6) mm, 3.5 μm; Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min LCMS: 352.1 (M+H), Rt 2.36 min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow rate: 1.5 mL / min Chiral method: Rt 1.79 min, SFC column: LUX A1; Mobile phase: 60:40 (A:B), A=liquid CO2 , B = 0.5% isopropylamine in methanol; flow rate: 4.0 mL / min; wavelength: 210 nm. 1 H NMR (400 MHz, CDCl 3 ):δ7.91-7.88(m,2H),7.42-7.34(m,2H),6.59(d,1H),6.32(s,1H),5.64-5.57(m,1H),4.12 (s,3H),2.45(s,3H),1.97-1.92(m,1H),1.75(d,3H),0.99-0.94(m,2H),0.78-0.74(m,2H).

[0260] b) Synthesis of 192 [ka] Synthesis of tert-butyl (S)-(1-(3-(m-tolyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate (A-270) To a solution of compound A-3 (1.0 g, 6.66 mmol) in 1,4-dioxane (60 mL) was added (2S)-2-(tert-butoxycarbonylamino)propanoic acid (1.37 g, 7.22 mmol) and DCC (1.51 g, 7.32 mmol). The reaction mixture was heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated. The mixture was treated with water (20 mL) and extracted with EtOAc (2×30 mL). The organic layer was washed with brine (20 mL) and anhydrous Na 2 SO 4 After drying and concentration, the crude was purified by column chromatography on silica gel with 10% EtOAc / PE to give compound A-270 (0.80 g, 2.62 mmol, yield 39%). LCMS: 302.1 (MH), Rt 2.56 min; Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 μm; Mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min 1 H NMR (400MHz, DMSO-d 6): δ7.82-7.78(m,2H),7.47-7.40(m,2H),5.00-4.93(m,1H),2.40(s,3H),1.51(d,3H),1.40(s,9H).

[0261] Synthesis of (S)-1-(3-(m-tolyl)-1,2,4-oxadiazol-5-yl)ethan-1-amine (A-271) To a stirred solution of compound A-270 (400 mg, 1.32 mmol) in DCM (2.4 mL) was added TFA (2.1 mL) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 8 h. The reaction mixture was concentrated and washed with saturated NaHCO 3 The mixture was extracted with EtOAc (2x20 mL) and washed with brine (20 mL). The organic layer was washed with anhydrous Na 2 SO 4 After drying and concentration, compound A-271 (200 mg) was obtained. The compound was used in the next step without further purification.

[0262] Synthesis of (S)-3-cyclopropyl-1-methyl-N-(1-(3-(m-tolyl)-1,2,4-oxadiazol-5-yl)ethyl)-1H-pyrazole-5-carboxamide (192) To a stirred solution of A-271 (200 mg, 0.98 mmol) in THF (10.0 mL) was added 3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylic acid (179 mg, 1.08 mmol), followed by T3P (1.17 mL, 1.97 mmol) and TEA (0.41 mL, 20.52 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was treated with water (20 mL) and extracted with EtOAc (2×20 mL). The organic layer was washed with brine (20 mL) and diluted with anhydrous Na 2 SO 4After drying and concentration, the crude was purified by column chromatography on silica gel with 30% EtOAc / PE to give 192 (80 mg, 0.22 mmol, 23% yield) as a solid. HPLC: Rt 4.68 min, 99.7%; Column: X-Bridge C8 (50×4.6) mm, 3.5 μm; Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min LCMS: 352.3 (M+H), Rt 2.37 min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm; Mobile phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow rate: 1.5 mL / min Chiral method: Rt 1.56 min, SFC column: LUX A1; Mobile phase: 60:40 (A:B), A=liquid CO 2 , B = 0.5% isopropylamine in methanol; flow rate: 4.0 mL / min; wavelength: 210 nm. 1 H NMR (400 MHz, CDCl 3 ):δ7.91-7.88(m,2H),7.42-7.34(m,2H),6.58(d,1H),6.32(s,1H),5.62-5.58(m,1H),4.12 (s,3H),2.45(s,3H),1.97-1.93(m,1H),1.75(d,3H),0.99-0.94(m,2H),0.78-0.74(m,2H).

[0263] Synthesis of Examples 2.3 and 4 [ka] A-6: A mixture of ethyl 5-cyclopropyl-1-methyl-pyrazole-3-carboxylate (1.4 g, 7.21 mmol) and NaOH (576.64 mg, 14.42 mmol) in ethanol (20 mL) and water (10 mL) was stirred at 20° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was then purified by H 2 The mixture was diluted with 20 mL of HO, acidified with 1 M HCl to pH 6, and extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine (30 mL) and diluted with Na 2 SO 4It was dried over hexane, filtered and concentrated to give the crude product (2000 mg) as a solid. LCMS R t = 0.46 min in 1.5 min chromatography, 5-95AB, C 8 H 11 N 2 O 2 [M+H] + MS ESI calculated value 167.1, found value 167.0.

[0264] A-7: A mixture of 5-cyclopropyl-1-methyl-pyrazole-3-carboxylic acid (300 mg, 1.81 mmol), 1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (432.72 mg, 1.81 mmol), TEA (913.38 mg, 9.03 mmol), EDCI (1038.21 mg, 5.42 mmol), and HOBt (731.84 mg, 5.42 mmol) in DCM (20 mL) was stirred at 20° C. for 16 h. The reaction was cooled to room temperature with saturated NH 4 The mixture was quenched by adding Cl (30 mL) and extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (10 mL) and diluted with Na 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 55-85% B over 7 min) gave the product (300 mg, 0.85 mmol, 47% yield) as a solid. LCMS R t = 1.11 min at 2.0 min chromatography, 5-95AB, C 19 H 22 N 5 O 2 [M+H] + MS ESI calculated value 352.2, found value 352.1.

[0265] 3 and 4: Analytical SFC (Daicel CHIRALPAK AD-3 (50 mm × 3 mm, 3 μm), mobile phase: A: CO2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 2.5 min, 40% for 0.35 min, then hold 40% to 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C) showed two peaks at 1.37 and 1.61 min. The products were purified by SFC (Daicel CHIRALPAK AD-3 (50 mm × 3 mm, 5 μm); A = CO 2 and B = EtOH (0.1% NH 3 H 2 0C; 38 °C; 60 mL / min; 25% B; 12 min run; 7 injections, peak 1 Rt = 5.74 min, peak 2 Rt = 10.1 min) to give enantiomer 1 (Rt = 1.37 min by analytical SFC) randomly assigned as 3 (73.33 mg, 0.21 mmol, 24% yield) as a solid, and enantiomer 2 (Rt = 1.61 min by analytical SFC) randomly assigned as 4 (77.03 mg, 0.22 mmol, 26% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.95-7.83(m,2H),7.43-7.29(m,3H),6.41(s,1H),5.71-5.60(m,1H),3.94( s,3H),2.43(s,3H),1.78-1.67(m,4H),1.07-0.96(m,2H),0.75-0.65(m,2H). LCMS R t = 2.0 min of chromatography at 1.14 min, 10-80AB, C 19 H 22 N 5 O 2 [M+H] + MS ESI calculated 352.2, found 352.1. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.94-7.84(m,2H),7.44-7.29(m,3H),6.41(s,1H),5.73-5.59(m,1H),3.94( s,3H),2.43(s,3H),1.79-1.67(m,4H),1.07-0.97(m,2H),0.74-0.66(m,2H). LCMS R t= 2.0 min of chromatography at 1.12 min, 10-80AB, C 19 H 22 N 5 O 2 [M+H] + MS ESI calculated value 352.2, found value 352.1.

[0266] Synthesis of Example 3.5 [ka] A-10: A mixture of 3-fluorobenzonitrile (500 mg, 4.13 mmol), hydroxylamine hydrochloride (860.66 mg, 12.39 mmol), and NaOH (495.42 mg, 12.39 mmol) in ethanol (6 mL) and water (2 mL) was stirred at 40° C. for 12 h to give a mixture. After cooling to room temperature, the reaction mixture was concentrated to remove most of the EtOH, and then diluted with H 2 The mixture was diluted with 20 mL of EtOAc (30 mL×2). The combined organic phase was washed with brine (30 mL) and diluted with Na 2 SO 4 It was dried over water, filtered and concentrated to give the crude product (600 mg) as a solid. LCMS R t = 0.46 min in 1.5 min chromatography, 5-95AB, C 7 H 8 FN 2 O[M+H] + MS ESI calculated value 155.1, found value 154.8.

[0267] 5: A mixture of 2-[(5-cyclopropyl-2-methyl-pyrazole-3-carbonyl)amino]propanoic acid (170 mg, 0.72 mmol) and CDI (127.8 mg, 0.79 mmol) in DMF (3 mL) was stirred at 15° C. for 1 h, then 3-fluoro-N′-hydroxy-benzamidine (110.44 mg, 0.72 mmol) was added. The reaction mixture was then stirred at 110° C. for 2 h. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (20 mL) and diluted with Na2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=water (0.05% NH 4 OH) and B=CH 3 Purification by CN; 49-79% B over 8 min) gave the product (23.03 mg, 64.8 μmol, 9% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.88(dd,1H),7.81-7.76(m,1H),7.52-7.46(m,1H),7.26-7.19(m,1H),6.52(d,1H),6.31(s,1H),5 .64-5.54(m,1H),4.10(s,3H),1.98-1.87(m,1H),1.75(d,3H),1.00-0.91(m,2H),0.78-0.72(m,2H). LCMS R t = 1.26 min in 2.0 min chromatography, 10-80AB, C 18 H 19 FN 5 O 2 [M+H] + MS ESI calculated value 356.1, found value 356.0.

[0268] Synthesis of Example 4.6 [ka] A-12: A mixture of 3-chlorobenzonitrile (500 mg, 3.63 mmol), hydroxylamine hydrochloride (757.69 mg, 10.9 mmol), and NaOH (436.14 mg, 10.9 mmol) in ethanol (6 mL) and water (2 mL) was stirred at 40° C. for 16 h. After cooling to room temperature, the reaction mixture was concentrated to remove most of the EtOH, and then diluted with H 2 The mixture was diluted with 20 mL of EtOAc (30 mL×2). The combined organic phase was washed with brine (30 mL) and diluted with Na 2 SO 4The crude product was purified by silica gel column (EtOAc in PE=0% to 60%) to give the product (70 mg, 410.3 μmol, 11% yield) as a solid. LCMS R t = 0.15 min with 1.5 min chromatography, 5-95AB, C 7 H 8 ClN 2 O[M+H] + MS ESI calculated value 171.0, found value 170.9.

[0269] 6: A mixture of 2-[(5-cyclopropyl-2-methyl-pyrazole-3-carbonyl)amino]propanoic acid (105 mg, 0.44 mmol) and CDI (78.94 mg, 0.49 mmol) in DMF (3 mL) was stirred at 15° C. for 1 h, then 3-fluoro-N′-hydroxy-benzamidine (67.95 mg, 0.40 mmol) was added. The reaction mixture was stirred at 110° C. for 2 h. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (20 mL) and diluted with Na 2 SO 4 The mixture was dried over ice and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 53-83% B over 8 min) gave the product (21.27 mg, 56.9 μmol, 13% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =8.09(t,1H),8.05-7.92(m,1H),7.53-7.48(m,1H),7.47-7.41(m,1H),6.51(d,1H),6.31(s,1H),5. 63-5.52(m,1H),4.10(s,3H),1.98-1.89(m,1H),1.75(d,3H),0.99-0.92(m,2H),0.78-0.71(m,2H). LCMS R t= 1.31 min in 2.0 min chromatography, 10-80AB, C 18 H 19 ClN 5 O 2 [M+H] + MS ESI calculated value 372.1, found value 372.0.

[0270] Synthesis of Example 5.7 [ka] A-14: A mixture of 2,6-difluorobenzonitrile (500 mg, 3.59 mmol), hydroxylamine hydrochloride (749.35 mg, 10.78 mmol), and NaOH (431.34 mg, 10.78 mmol) in ethanol (6 mL) and water (2 mL) was stirred at 40° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated to remove most of the EtOH, and then diluted with H 2 The mixture was diluted with 20 mL of EtOAc (30 mL×2). The combined organic phase was washed with brine (30 mL) and diluted with Na 2 SO 4 It was dried over water, filtered and concentrated to give the crude product (600 mg) as a solid. LCMS R t = 0.26 min in 1.5 min chromatography, 5-95AB, C 7 H 7 F 2 N 2 O[M+H] + MS ESI calculated value 173.0, found value 172.8.

[0271] 7: A mixture of 2-[(5-cyclopropyl-2-methyl-pyrazole-3-carbonyl)amino]propanoic acid (150 mg, 0.63 mmol) and CDI (112.77 mg, 0.70 mmol) in DMF (3 mL) was stirred at 15° C. for 1 h, then 2,6-difluoro-N′-hydroxy-benzamidine (119.71 mg, 0.70 mmol) was added. The reaction was then stirred at 110° C. for 2 h. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (20 mL) and diluted with Na 2 SO 4 The mixture was dried over ice and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H 2 O(0.05% NH 4 OH v / v) and B=CH 3 Purification by CN; 41-71% B over 8 min) afforded the product (52.31 mg, 140.1 μmol, 22% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.55-7.45(m,1H),7.07(t,2H),6.60(d,1H),6.27(s,1H),5.69-5.60(m,1H),4. 09(s,3H),1.96-1.86(m,1H),1.76(d,3H),0.96-0.88(m,2H),0.74-0.66(m,2H). LCMS R t = 2.0 min of chromatography at 1.12 min, 10-80AB, C 18 H 18 F 2 N 5 O[M+H] + MS ESI calculated value 374.1, found value 374.0.

[0272] Synthesis of Example 6.8 [ka] A-16: A mixture of 4-fluorobenzonitrile (500 mg, 4.13 mmol), hydroxylamine hydrochloride (860.66 mg, 12.39 mmol), and NaOH (495.42 mg, 12.39 mmol) in ethanol (6 mL) and water (2 mL) was stirred at 40° C. for 16 h. After cooling to room temperature, the reaction mixture was concentrated to remove most of the EtOH, and then diluted with H 2 The mixture was diluted with 20 mL of EtOAc (15 mL). The mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL) and diluted with Na 2 SO 4 It was dried over, filtered and concentrated to give the crude product (300 mg) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =8.70(s,1H),7.74-7.56(m,2H),7.19-6.98(m,2H),4.88(s,2H).

[0273] A-17: A mixture of 5-cyclopropyl-2-methyl-pyrazole-3-carboxylic acid (500 mg, 3.01 mmol), DIPEA (2.63 mL, 15.04 mmol), EDCI (865.18 mg, 4.51 mmol), HOBt (813.15 mg, 6.02 mmol), and methyl 2-aminopropanoate hydrochloride (419.97 mg, 3.01 mmol) in DCM (15 mL) was stirred at 20° C. for 16 h. The reaction mixture was diluted with saturated NH 4 The mixture was quenched with Cl (20 mL). The mixture was extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (10 mL) and diluted with Na 2 SO 4 It was dried over water, filtered and concentrated to give the crude product (500 mg) as an oil. LCMS R t = 0.72 min in 1.5 min chromatography, 5-95AB, C 12 H 18 N 3 O 3 [M+H] + MS ESI calculated value 252.1, found value 252.0.

[0274] A-18: A solution of methyl 2-[(5-cyclopropyl-2-methylpyrazole-3-carbonyl)amino]propanoate (500 mg, 1.99 mmol) in THF (4 mL) was treated with LiOH.H in water (4 mL). 2 A solution of 166.99 mg, 3.98 mmol) of 2H2O was slowly added. The resulting mixture was stirred at 20° C. for 2 h. The mixture was concentrated to remove THF. 1N HCl was added to the residue to adjust pH=2, and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL) and diluted with Na 2 SO 4 It was dried over water, filtered and concentrated to give the crude product (350 mg) as an oil. LCMS R t = 0.67 min in 1.5 min chromatography, 5-95AB, C 11 H 16 N 3 O 3 [M+H] + MS ESI calculated value 238.1, found value 238.0.

[0275] 8: A mixture of 2-[(5-cyclopropyl-2-methyl-pyrazole-3-carbonyl)amino]propanoic acid (150 mg, 0.63 mmol) and CDI (112.77 mg, 0.70 mmol) in DMF (10 mL) was stirred at 15° C. for 1 h, then 4-fluoro-N′-hydroxy-benzamidine (97.45 mg, 0.63 mmol) was added. The reaction mixture was then stirred at 110° C. for 16 h. After cooling to room temperature, the mixture was diluted with H 2 The mixture was diluted with 20 mL of EtOAc (20 mL×2) and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL) and diluted with Na 2 SO 4 The crude product was purified by preparative HPLC (Agela DuraShell (150 mm x 25 mm, 5 μm), A = H 2 HO (10 mM NH 4 HCO 3 ) and B=CH 3Purification by CN; 40-80% B over 8.5 min) afforded the product (40.74 mg, 114.60 μmol, 18% yield) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H =8.15-8.00(m,2H),7.23-7.13(m,2H),6.53(d,1H),6.30(s,1H),5.65-5.51(m,1H) ,4.10(s,3H),1.98-1.87(m,1H),1.74(d,3H),1.03-0.88(m,2H),0.81-0.68(m,2H). LCMS R t = 1.15 min, 10-80AB, C for 2 min chromatography 18 H 19 FN 5 O 2 [M+H] + MS ESI calculated value 356.1, found value 356.0.

[0276] Synthesis of Example 7.9 [ka] A-20: A mixture of 4-chlorobenzonitrile (494.5 mg, 3.59 mmol), hydroxylamine hydrochloride (749.35 mg, 10.78 mmol), and NaOH (431.34 mg, 10.78 mmol) in ethanol (6 mL) and water (2 mL) was stirred at 40° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated to remove most of the EtOH, and then diluted with H 2 The mixture was diluted with 20 mL of EtOAc (30 mL×2). The combined organic phase was washed with brine (30 mL) and diluted with Na 2 SO 4 It was dried over water, filtered and concentrated to give the crude product (600 mg) as a solid. LCMS R t = 0.43 min in 1.5 min chromatography, 5-95AB, C 7 H 8 ClN 2 O[M+H] + MS ESI calculated value 171.0, found value 170.8.

[0277] 9: A mixture of 2-[(5-cyclopropyl-2-methyl-pyrazole-3-carbonyl)amino]propanoic acid (150 mg, 0.63 mmol) and CDI (112.77 mg, 0.70 mmol) in DMF (3 mL) was stirred at 15° C. for 1 h, then 4-chloro-N′-hydroxy-benzamidine (118.64 mg, 0.70 mmol) was added. The reaction mixture was stirred at 110° C. for 2 h. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (20 mL) and diluted with Na 2 SO 4 The mixture was dried over ice and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC (Waters XBridge (150 mm×25 mm, 5 μm), A=water (0.05% NH 4 OH) and B=CH 3 Purification by CN; 49-79% B over 8 min) afforded the product (53.21 mg, 143.1 μmol, 23% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =8.06-7.97(m,2H),7.50-7.44(m,2H),6.52(d,1H),6.30(s,1H),5.58(quin,1H), 4.09(s,3H),1.98-1.60(m,1H),1.74(d,3H),1.00-0.91(m,2H),0.78-0.70(m,2H). LCMS R t = 2.0 min of chromatography at 1.20 min, 10-80AB, C 18 H 19 ClN 5 O 2 [M+H] + MS ESI calculated value 372.1, found value 372.0.

[0278] Synthesis of Example 8.10 [ka] A mixture of 1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (100 mg, 0.42 mmol), 5-isopropyl-2-methyl-pyrazole-3-carboxylic acid (70.17 mg, 0.42 mmol), HOBt (112.75 mg, 0.83 mmol), EDCI (119.96 mg, 0.63 mmol), and TEA (0.29 mL, 2.09 mmol) in DCM (20 mL) was stirred at 20° C. for 16 h. The mixture was concentrated and H 2 The mixture was diluted with 20 mL of EtOAc (10 mL) and then extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL) and 2 SO 4 The crude product was purified by preparative HPLC (Kromasil (150 mm x 30 mm, 5 μm), A = H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 55-85% B over 8 min) gave the product (44.51 mg, 0.13 mmol, 30% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H= 7.92-7.84(m,2H),7.42-7.30(m,2H),6.63(d,1H),6.46(s,1H),5.66-5.56(m ,1H),4.12(s,3H),3.05-2.94(m,1H),2.43(s,3H),1.75(d,3H),1.28(d,6H). LCMS R t = 2.0 min of chromatography at 1.30 min, 10-80AB, C 19 H 24 N 5 O 2 [M+H] + MS ESI calculated 354.19, found 354.1.

[0279] Synthesis of Example 9.11 [ka] A mixture of 1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (100 mg, 0.42 mmol), 2-tert-butyl-5-methyl-pyrazole-3-carboxylic acid (76.02 mg, 0.42 mmol), HOBt (112.75 mg, 0.83 mmol), EDCI (119.96 mg, 0.63 mmol), and TEA (0.29 mL, 2.09 mmol) in DCM (20 mL) was stirred at 20° C. for 16 h. The mixture was concentrated and H 2 The mixture was diluted with 20 mL of EtOAc (10 mL) and then extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL) and 2 SO 4 The crude product was purified by preparative HPLC (Kromasil (150 mm x 30 mm, 5 μm), A = H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 55-85% B over 8 min) gave the product (30.81 mg, 0.08 mmol, 20% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H= 7.96-7.83(m,2H),7.44(d,1H),7.39-7.29(m,2H),6.58(s,1H),5.71-5.60(m,1H),2.48(s,3H),2.47(s,3H),1.76(d,3H),1.67(s,9H). LCMS R t = 1.36 min in 2.0 min chromatography, 10-80AB, C 20 H 26 N 5 O 2 [M+H] + MS ESI calculated 368.20, found 368.2.

[0280] Synthesis of Example 10.12 [ka] A-19c: A mixture of 3-(trifluoromethyl)benzonitrile (500 mg, 2.92 mmol), hydroxylamine hydrochloride (609.13 mg, 8.77 mmol), and NaOH (350.63 mg, 8.77 mmol) in ethanol (6 mL) and water (2 mL) was stirred at 40° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with H 2 The mixture was diluted with 20 mL of EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL) and diluted with Na 2 SO 4 It was dried over, filtered and concentrated to give the crude product (300 mg) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.91(s,1H),7.83(d,1H),7.70(d,1H),7.59-7.50(m,1H),4.93(br s,2H).

[0281] 12: A mixture of 2-[(5-cyclopropyl-2-methyl-pyrazole-3-carbonyl)amino]propanoic acid (150 mg, 0.63 mmol) and CDI (112.77 mg, 0.70 mmol) in DMF (10 mL) was stirred at 15° C. for 1 h, then N′-hydroxy-3-(trifluoromethyl)benzamidine (129.07 mg, 0.63 mmol) was added. The reaction mixture was then stirred at 110° C. for 16 h. After cooling to room temperature, the mixture was diluted with NH 4 The mixture was diluted with Cl (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL) and Na 2 SO 4 The crude product was purified by preparative HPLC (Welch Xtimate C18 (150 mm x 25 mm, 5 μm), A = H 2 HO (10 mM NH 4 HCO 3 ) and B=CH 3 Purification by CN; 20-50% B over 9 min) gave the product (26.89 mg, 65.60 mmol, 10% yield) as an oil. 1H NMR (400 MHz, CDCl 3 ) δ H =8.36(s,1H),8.28(d,1H),7.79(d,1H),7.68-7.61(m,1H),6.52(d,1H),6.32(s,1H),5.67-5. 54(m,1H),4.10(s,3H),1.99-1.88(m,1H),1.76(d,3H),1.00-0.90(m,2H),0.81-0.68(m,2H). LCMS R t = 1.23 min in 2 min chromatography, 10-80AB, C 19 H 19 F 3 N 5 O 2 [M+H] + MS ESI calculated value 406.1, found value 406.0.

[0282] Synthesis of Example 11.13 [ka] A mixture of 1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (100 mg, 0.42 mmol), 5-tert-butyl-2-methyl-pyrazole-3-carboxylic acid (76.02 mg, 0.42 mmol), HOBt (112.75 mg, 0.83 mmol), EDCI (119.96 mg, 0.63 mmol), and TEA (0.29 mL, 2.09 mmol) in DCM (20 mL) was stirred at 15° C. for 16 h. The mixture was concentrated and H 2 The mixture was diluted with 20 mL of EtOAc (10 mL) and then extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL) and 2 SO 4 The crude product was purified by preparative HPLC (Kromasil (150 mm x 30 mm, 5 μm), A = H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 60-90% B over 8 min) gave the product (61 mg, 0.17 mmol, 39% yield) as a solid. 1H NMR (400 MHz, CDCl 3 ) δ H= 7.94-7.84(m,2H),7.41-7.31(m,2H),6.60-6.54(m,1H),6.48(s,1H), 5.65-5.57(m,1H),4.13(s,3H),2.43(s,3H),1.76(d,3H),1.33(s,9H). LCMS R t = 1.37 min in 2.0 min chromatography, 10-80AB, C 20 H 26 N 5 O 2 [M+H] + MS ESI calculated 368.20, found 368.1.

[0283] Synthesis of Examples 12.14 and 15 [ka] A-21a: A mixture of benzonitrile (370.67 mg, 3.59 mmol), hydroxylamine hydrochloride (749.35 mg, 10.78 mmol), and NaOH (431.34 mg, 10.78 mmol) in ethanol (6 mL) and water (2 mL) was stirred at 40° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated to remove most of the EtOH, then diluted with H 2 The mixture was diluted with 20 mL of EtOAc (30 mL×2). The combined organic phase was washed with brine (30 mL) and diluted with Na 2 SO 4 It was dried over hexane, filtered and concentrated to give the crude product (500 mg, 3.43 mmol, 95% yield) as a solid. LCMS R t = 0.29 min in 1.5 min chromatography, 5-95AB, C 7 H 9 N 2 O[M+H] + MS ESI calculated value 137.0, found value 136.8.

[0284] A-22: A mixture of 2-[(5-cyclopropyl-2-methyl-pyrazole-3-carbonyl)amino]propanoic acid (200 mg, 0.84 mmol) and CDI (150.35 mg, 0.93 mmol) in DMF (3 mL) was stirred at 15° C. for 1 h. N′-hydroxybenzamidine (126.25 mg, 0.93 mmol) was then added, and the reaction mixture was then stirred at 110° C. for 2 h to obtain a mixture. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (20 mL) and diluted with NaCl. 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=water (0.05% NH 4 OH v / v) and B=CH 3 Purification by CN; 45-75% B over 8 min) gave the product (170 mg, 495.1 μmol, 59% yield) as a solid. t = 0.87 min in 1.5 min chromatography, 5-95AB, C 18 H 20 N 5 O 2 [M+H] + MS ESI calculated value 338.2, found value 338.1.

[0285] 14 and 15: Analytical SFC (Daicel CHIRACEL OJ-H (150 mm × 4.6 mm, 5 μm), mobile phase: A:CO 2 B: Methanol (0.05% DEA,) gradient: hold 5% for 0.5 min, then 5% to 40% B in 3.5 min, 40% for 2.5 min, then hold 5% B for 1.5 min, flow rate: 3 mL / min, column temperature: 40 °C) showed two peaks at 3.40 and 3.73 min. The products were purified by SFC (Daicel CHIRALPAK AS (250 mm × 30 mm, 5 μm); A = CO 2 and B = MeOH (0.1% 3 H 20; 35 °C; 50 mL / min; 20% B; 9 min run; 7 injections, peak 1 Rt = 5.87 min, peak 2 Rt = 7.39 min) to give enantiomer 1 (Rt = 3.40 min by analytical SFC) randomly assigned as 14 (11.44 mg, 33.9 μmol, 7% yield) as a solid, and enantiomer 2 (Rt = 3.73 min by analytical SFC) randomly assigned as 15 (31.75 mg, 94.1 μmol, 19% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =8.08(dd,2H),7.56-7.46(m,3H),6.56(d,1H),6.31(s,1H),5.59(quin,1H),4. 10(s,3H),1.98-1.87(m,1H),1.75(d,3H),0.99-0.90(m,2H),0.77-0.68(m,2H). LCMS R t = 2.0 min of chromatography at 1.21 min, 10-80AB, C 18 H 20 N 5 O 2 [M+H] + MS ESI calculated 338.2, found 338.0.15: 1 H NMR (400 MHz, CDCl 3 ) δ H =8.08(dd,,2H),7.57-7.45(m,3H),6.56(d,1H),6.31(s,1H),5.59(quin,1H),4. 10(s,3H),1.99-1.88(m,1H),1.75(d,3H),1.00-0.91(m,2H),0.79-0.69(m,2H). LCMS R t = 2.0 min of chromatography at 1.21 min, 10-80AB, C 18 H 20 N 5 O 2 [M+H] + MS ESI calculated value 338.2, found value 338.0.

[0286] Examples 13. Synthesis of 16 and 17 [ka] To a mixture of 2,5-dimethylpyrazole-3-carboxylic acid (58.46 mg, 420 μmol), EDCI (119.96 mg, 630 μmol), TEA (0.29 mL, 2.09 mmol), and HOBt (112.75 mg, 830 μmol) in DCM (20 mL) was added 1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (100 mg, 420 μmol) and the mixture was stirred at 15° C. for 16 h. The mixture was concentrated and H 2 The mixture was diluted with 20 mL of EtOAc (10 mL) and then extracted with EtOAc (20 mL x 2). The organic layer was washed with brine (10 mL) and 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 37-67% B over 8 min) afforded A-23 (65 mg, 195.7 μmol, 47% yield) as an oil. LCMS R t = 0.78 min in 1.5 min chromatography, 5-95AB, C 17 H 20 N 5 O 2 [M+H] + MS ESI calculated value: 326.15, measured value: 326.7. Analytical SFC (Daicel CHIRALPAK IC-3 (150 mm × 4.6 mm, 3 μm), mobile phase: A:CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5 min, 40% for 2.5 min, then hold at 5% B for 2.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C) showed two peaks at 3.61 and 4.64 min. The products were analyzed by SFC (Daicel CHIRALPAK IC (250 mm × 30 mm, 5 μm); A = CO 2 and B = EtOH (0.1% NH 3 H 20; 38 °C; 65 mL / min; 30% B; 7 min run; 4 injections, peak 1 Rt = 3.75 min, peak 2 Rt = 5.50 min) to give enantiomer 1 (Rt = 3.61 min by analytical SFC) randomly assigned as 16 (12.35 mg, 38 μmol, 19% yield) as a solid, and enantiomer 2 (Rt = 4.64 min by analytical SFC) randomly assigned as 17 (11.51 mg, 35.4 μmol, 18% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H= 7.97-7.83(m,2H),7.44-7.31(m,2H),6.60(d,1H),6.44(s,1H),5.60(quin,1H),4.12(s,3H),2.44(s,3H),2.30(s,3H),1.75(d,3H). LCMS R t = 2.0 min of chromatography at 1.18 min, 10-80AB, C 17 H 20 N 5 O 2 [M+H] + MS ESI calculated 326.15, found 325.9. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.93-7.85(m,2H),7.43-7.31(m,2H),6.59(d,1H),6.44(s,1H),5.60(quin,1H),4.12(s,3H),2.44(s,3H),2.30(s,3H),1.75(d,3H). LCMS R t = 1.17 min in 2.0 min chromatography, 10-80AB, C 17 H 20 N 5 O 2 [M+H] + MS ESI calculated 326.15, found 326.0.

[0287] Synthesis of Examples 14.19 and 20 [ka] A-27: To a solution of 1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (150 mg, 630 μmol), 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (242.94 mg, 1.25 mmol), HATU (475.8 mg, 1.25 mmol) in DMF (10 mL), DIPEA (0.44 mL, 2.5 mmol) was added and the reaction mixture was stirred at 15° C. for 3 h. 2 The mixture was diluted with 200 mL of 2H2O (40 mL) and then extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (40 mL) and 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 65-75% B over 8 min) gave the product (200 mg, 527.2 μmol, 84% yield) as an oil. t = 3.97 min in 7.0 min chromatography, 10-80AB, C 17 H 17 F 3 N 5 O 2 [M+H] + MS ESI calculated 380.13, found 380.0.

[0288] 19 and 20: SFC for analysis (Daicel CHIRALCEL OJ-3 (150 mm × 4.6 mm, 3 μm), mobile phase: A: CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5 min, 40% for 0.5 min, then hold at 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C) showed two peaks at 2.53 and 3.11 min. The product was purified by SFC (Daicel CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); A = CO 2 and B = EtOH (0.1% NH 3 H 20; 35 °C; 50 mL / min; 25% B; 7 min run; 6 injections, peak 1 Rt = 3.45 min, peak 2 Rt = 4.40 min) to give enantiomer 1 (Rt = 2.53 min by analytical SFC) randomly assigned as 19 (55.59 mg, 146.5 μmol, 28% yield) as a solid, and enantiomer 2 (Rt = 3.11 min by analytical SFC) randomly assigned as 20 (61.98 mg, 163 μmol, 31% yield) as a solid. 19: 1 H NMR (400 MHz, CDCl 3 ) δ H= 7.91-7.85(m,2H),7.42-7.30(m,2H),6.93(s,1H),6.71(br d,1H),5.60(quin,1H),4.24(s,3H),2.44(s,3H),1.77(d,3H). LCMS R t = 1.33 min in 2.0 min chromatography, 10-80AB, C 17 H 17 F 3 N 5 O 2 [M+H] + MS ESI calculated value 380.13, found value 379.9. 20: 1 H NMR (400 MHz, CDCl 3 ) δ H =7.92-7.84(m,2H),7.43-7.32(m,2H),6.93(s,1H),6.71(br d,1H),5.60(quin,1H),4.24(s,3H),2.44(s,3H),1.77(d,3H). LCMS R t = 1.34 min in 2.0 min chromatography, 10-80AB, C 17 H 17 F 3 N 5 O 2 [M+H] + MS ESI calculated value 380.13, found value 379.9.

[0289] Synthesis of Example 15.21 [ka] A mixture of 1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (100 mg, 0.42 mmol), 5-(difluoromethyl)-2-methyl-pyrazole-3-carboxylic acid (73.48 mg, 0.42 mmol), HOBt (112.75 mg, 0.83 mmol), EDCI (119.96 mg, 0.63 mmol), and TEA (0.29 mL, 2.09 mmol) in DCM (20 mL) was stirred at 15° C. for 16 h. The mixture was concentrated and H 2 The mixture was diluted with 20 mL of EtOAc (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL) and 2 SO 4 The crude product was purified by preparative HPLC (Kromasil (150 mm x 30 mm, 5 μm), A = H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 53-83% B over 8 min) gave the product (96 mg, 0.26 mmol, 63% yield) as a solid. 1 H NMR (400MHz, DMSO-d 6 ) δ H= 9.40(d,1H),7.87-7.76(m,2H),7.51-7.37(m,2H),7.28(s,1H),7.06(t,1H),5.49-5.40(m,1H),4.09(s,3H),2.39(s,3H),1.67(d,3H). LCMS R t = 1.24 min in 2.0 min chromatography, 10-80AB, C 17 H 18 F 2 N 5 O 2 [M+H] + MS ESI calculated 362.14, found 362.1.

[0290] Synthesis of Example 16.22 [ka] A-29b: Cs in DMF (15 mL) 2CO 3 To a mixture of 2-bromopropane (1755.24 mg, 14.27 mmol) and 2-bromopropane (4649.64 mg, 14.27 mmol), methyl 3-methyl-1H-pyrazole-5-carboxylate (1000 mg, 7.14 mmol) was added, and the reaction mixture was then stirred at 100° C. for 2.5 h. After cooling to room temperature, the reaction mixture was diluted with H 2 The mixture was diluted with 2×O (100 mL) and then extracted with EtOAc (150 mL×2). The combined organic layers were washed with brine (150 mL) and 2 SO 4 Drying over, filtration and concentration gave the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0% to 5%) to give the product (620 mg, 3.24 mmol, 45% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =6.58(s,1H),5.46(spt,1H),3.86(s,3H),2.29(s,3H),1.48(d,6H). LCMS R t = 7.0 min of chromatography, 3.60 min, 0-60AB, C 9 H 15 N 2 O 2 [M+H] + MS ESI calculated value 183.11, found value 182.9.

[0291] A-29: To a solution of methyl 2-isopropyl-5-methyl-pyrazole-3-carboxylate (300 mg, 1.65 mmol) in ethanol (5 mL) was added a solution of NaOH (65.85 mg, 1.65 mmol) in water (5 mL). The mixture was stirred at 15° C. for 2 hours. The reaction mixture was concentrated to give a residue. The residue was purified by H 2 The mixture was diluted with 20 mL of HO (20 mL) and washed with EtOAc (20 mL x 1). The aqueous phase was acidified with 1N HCl (20 mL) to pH = 1. The mixture was extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine (70 mL) and diluted with Na 2 SO 4It was dried over, filtered and concentrated to give the crude product (200 mg) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =6.72(s,1H),5.50-5.40(m,1H),2.37-2.26(m,3H),1.50(d,6H).

[0292] 22: To a mixture of 2-isopropyl-5-methyl-pyrazole-3-carboxylic acid (140.33 mg, 0.83 mmol), HATU (317.25 mg, 0.83 mmol), DIPEA (0.29 mL, 1.67 mmol) in DCM (8 mL) was added 1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (100 mg, 0.42 mmol) and the mixture was stirred at 15° C. for 12 h. The mixture was concentrated and purified by H 2 The mixture was diluted with 20 mL of EtOAc (10 mL) and then extracted with EtOAc (20 mL x 2). The organic layer was washed with brine (30 mL) and 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 37-67% B over 8 min) gave the product (35.39 mg, 99.7 μmol, 24% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.93-7.82(m,2H),7.42-7.33(m,2H),6.59(br d,1H),6.39(s,1H),5.58(quin,1H),5.40(spt,1H),2.43(s,3H),2.32(s,3H),1.75(d,3H),1.48(dd,6H). LCMS R t = 1.28 min in 2.0 min chromatography, 10-80AB, C 19 H 24 N 5 O 2 [M+H] +MS ESI calculated 354.19, found 354.2.

[0293] Synthesis of Examples 17.23 and 24 [ka] Analytical SFC (Daicel CHIRALPAK AD-3 (150mm x 4.6mm, 3μm), mobile phase: A:CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5 min, 40% for 2.5 min, then hold at 5% B for 2.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C) showed two peaks at 3.76 and 4.09 min. The products were purified by SFC (Daicel CHIRALPAK AS (250 mm × 30 mm, 5 μm); A = CO 2 and B = MeOH (0.1% NH 3 H 2 0; 38 °C; 50 mL / min; 20% B; 10 min run; 8 injections, peak 1 Rt = 7.2 min, peak 2 Rt = 8.5 min) to give enantiomer 1 (Rt = 3.76 min by analytical SFC) randomly assigned as 23 (2.31 mg, 6.2 μmol, 13% yield) as a solid, and enantiomer 2 (Rt = 4.09 min by analytical SFC) randomly assigned as 24 (2.02 mg, 5.4 μmol, 11% yield) as a solid. 1 H NMR (400MHz, CD 3 CN)δ H =8.10-8.00(m,1H),8.00-7.94(m,1H),7.61-7.40(m,3H),6.46(s,1H),5.43(quin,1H ),3.96(s,3H),1.90-1.84(m,1H),1.69(d,3H),0.91-0.86(m,2H),0.68-0.63(m,2H). LCMS R t = 1.28 min in 2.0 min chromatography, 10-80AB, C 18 H 19 ClN 5 O 2 [M+H] + MS ESI calculated 372.1, found 372.0.24:1 H NMR (400MHz, CD 3 CN)δ H =8.09-8.01(m,1H),8.00 -7.95(m,1H),7.62-7.43(m,3H),6.46(s,1H),5.43(quin,1H),3.96(s,3 H),1.91-1.83(m,1H),1.69(d,3H),0.92-0.86(m,2H),0.69-0.62(m,2H). LCMS R t = 1.29 min in 2.0 min chromatography, 10-80AB, C 18 H 19 ClN 5 O 2 [M+H] + MS ESI calculated value 372.1, found value 371.9.

[0294] Synthesis of Examples 18.25 and 26 [ka] Analytical SFC (Regis, (S,S)Whelk-O1 (250mm x 4.6mm, 5μm), mobile phase: A:CO 2 B: Methanol (0.05% DEA,) gradient: hold 5% for 0.5 min, then 5% to 40% B in 3.5 min, 40% for 2.5 min, then hold 5% B for 1.5 min, flow rate: 3 mL / min, column temperature: 35 °C) showed two peaks at 3.51 and 4.72 min. The product was purified by SFC (Daicel CHIRALPAK AS (250 mm × 30 mm, 5 μm); A = CO 2 and B = MeOH (0.1% NH 3 H 2 0; 38 °C; 50 mL / min; 20% B; 9 min run; 5 injections, peak 1 Rt = 5.9 min, peak 2 Rt = 7.5 min) to give enantiomer 1 (Rt = 3.51 min by analytical SFC) randomly assigned as 25 (8.68 mg, 23.3 μmol, 17% yield) as a solid, and enantiomer 2 (Rt = 4.72 min by analytical SFC) randomly assigned as 26 (7.31 mg, 19.7 μmol, 15% yield) as a solid. 1H NMR (400 MHz, CDCl 3 ) δ H =8.06-7.99(m,2H),7.51-7.44(m,2H),6.53(d,1H),6.30(s,1H),5.59(quin,1H), 4.09(s,3H),2.00-1.89(m,1H),1.74(d,3H),0.99-0.92(m,2H),0.78-0.71(m,2H). LCMS R t = 1.29 min in 2.0 min chromatography, 10-80AB, C 18 H 19 ClN 5 O 2 [M+H] + MS ESI calculated 372.1, found 372.0.26: 1 H NMR (400 MHz, CDCl 3 ) δ H =8.08-7.97(m,2H),7.51-7.43(m,2H),6.52(d,1H),6.30(s,1H),5.58(quin,1H), 4.10(s,3H),1.99-1.87(m,1H),1.74(d,3H),1.00-0.91(m,2H),0.78-0.70(m,2H). LCMS R t = 1.27 min in 2.0 min chromatography, 10-80AB, C 18 H 19 ClN 5 O 2 [M+H] + MS ESI calculated value 372.1, found value 372.1.

[0295] Synthesis of Examples 19.29 and 30 [ka] The product was purified by SFC (Daicel CHIRALCEL OJ-3 (100 mm x 4.6 mm, 3 μm), mobile phase: A:CO 2B: ethanol (0.05% DEA), gradient: 5% to 40% B in 4.5 min, 40% for 0.5 min, then hold at 5% B for 1 min, flow rate: 2.8 mL / min, column temperature: 40 °C), showed two peaks at 1.91 min and 2.22 min. The product was analyzed by SFC (Daicel CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); A = CO 2 and B = 0.1% NH 3 .H 2 2O-EtOH; 35 °C; 60 mL / min; 25% B; 8 min run; 10 injections, Rt = 5.38 min for peak 1, Rt = 6.62 min for peak 2) to give enantiomer 1 (Rt = 1.91 min by analytical SFC) randomly assigned as 29 (12.72 mg, 0.03 mmol, 22% yield) as a solid, and enantiomer 2 (Rt = 2.22 min by analytical SFC) randomly assigned as 30 (15.52 mg, 0.04 mmol, 27% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H= 7.93-7.84(m,2H),7.43-7.30(m,2H),6.57(d,1H),6.48(s,1H),5.61(quin,1H),4.13(s,3H),2.44(s,3H),1.76(d,3H),1.33(s,9H). LCMS R t = 1.33 min in 2.0 min chromatography, 10-80AB, C 20 H 26 N 5 O 2 [M+H] + MS ESI calculated 368.20, found 368.2. 1 H NMR (400 MHz, CDCl 3 ) δ H= 7.93-7.85(m,2H),7.42-7.31(m,2H),6.56(d,1H),6.47(s,1H),5.61(quin,1H),4.13(s,3H),2.44(s,3H),1.76(d,3H),1.33(s,9H). LCMS R t = 1.32 min in 2.0 min chromatography, 10-80AB, C 20 H26 N 5 O 2 [M+H] + MS ESI calculated 368.20, found 368.2.

[0296] Synthesis of Examples 20.31 and 32 [ka] Analytical SFC (Regis, (R,R)Whelk-01 (100mm x 4.6mm, 5μm), mobile phase: A:CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5.5 min, 40% for 3 min, then hold at 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 40 °C) showed two peaks at 3.68 min and 4.40 min.

[0297] The product was separated into 1000 ml of SFC (Regis(S,S)Whelk-O1 (250 mm x 30 mm, 5 μm); A = CO 2 and B = ethanol (0.1% NH 3 H 2 0; 38 °C; 60 mL / min; 60% B; 10 min run; 3 injections, Rt = 7.9 min for peak 1, Rt = 5.5 min for peak 2) to give enantiomer 1 (Rt = 3.68 min by analytical SFC) randomly assigned as 31 (9.92 mg, 28.1 μmol, 33% yield) as an oil, and enantiomer 2 (Rt = 4.40 min by analytical SFC) randomly assigned as 32 (9.16 mg, 25.9 μmol, 30% yield) as an oil. 31 1 H NMR (400MHz, DMSO-d 6 ) δ H= 9.12(d,1H),7.85-7.74(m,2H),7.48-7.36(m,2H),6.66(s,1H),5.43- 5.27(m,2H),2.38(s,3H),2.18(s,3H),1.63(d,3H),1.36-1.27(m,6H). LCMS R t = 1.28 min in 2.0 min chromatography, 10-80AB, C 19 H 24N 5 O 2 [M+H] + MS ESI calculated 354.19, found 354.1. 1 H NMR (400MHz, DMSO-d 6 ) δ H =9.13(d,1H),7.85-7.76(m,2H),7.49-7.37(m,2H),6.66(s,1H),5.45- 5.26(m,2H),2.39(s,3H),2.19(s,3H),1.64(d,3H),1.37-1.28(m,6H). LCMS R t = 1.27 min in 2.0 min chromatography, 10-80AB, C 19 H 24 N 5 O 2 [M+H] + MS ESI calculated 354.19, found 354.0.

[0298] Synthesis of Example 21.33 [ka] A-31: A solution of methyl 3-methyl-1H-pyrazole-5-carboxylate (800 mg, 5.71 mmol) in MeCN (20 mL) was treated with Cs 2 CO 3 (3719.71 mg, 11.42 mmol), sodium 2-chloro-2,2-difluoro-acetate (1740.6 mg, 11.42 mmol), and 18-crown-6 (301.77 mg, 1.14 mmol) were added and the reaction mixture was incubated at 90 °C for 2 h with N 2 After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give a residue. 2 The mixture was diluted with 200 mL of 2H2O (50 mL) and extracted with EtOAc (40 mL x 2). The combined organic phase was washed with brine (60 mL) and 2 SO 4The mixture was dried over 100 ml, filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0%-5.5%-40%) to give the product (120 mg, 631.1 μmol, 11% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =8.03(t,1H),6.77(s,1H),3.92(s,3H),2.36(s,3H).

[0299] A-32: To a solution of methyl 2-(difluoromethyl)-5-methylpyrazole-3-carboxylate (120 mg, 631.1 μmol) in ethanol (2 mL) was added a solution of NaOH (25.24 mg, 631.1 μmol) in water (2 mL). The mixture was stirred at 20° C. for 2 h. The reaction mixture was then diluted with H 2 The aqueous phase was acidified with 1N HCl (20 mL) to adjust pH=1 and extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (70 mL) and diluted with Na 2 SO 4 It was dried over ice, filtered and concentrated to give the product (100 mg, 567.8 μmol, 90% yield) as a solid. 1 H NMR (400MHz, DMSO-d 6 ) δ H =14.15(br s,1H),8.13(t,1H),6.86(s,1H),2.26(s,3H).

[0300] 33: To a mixture of 2-(difluoromethyl)-5-methyl-pyrazole-3-carboxylic acid (100 mg, 570 μmol), HATU (380.71 mg, 1 mmol), DIPEA (0.35 mL, 2 mmol) in DCM (8 mL) was added 1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (120 mg, 500 μmol) and the mixture was stirred at 15° C. for 2 h. The mixture was concentrated and purified by H 2The mixture was diluted with 20 mL of EtOAc (10 mL) and then extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (30 mL) and 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 53-83% B over 8 min) gave the product (109.62 mg, 303.4 μmol, 61% yield) as an oil. 1 H NMR (400MHz, DMSO-d 6 ) δ H =9.55(d,1H),8.19(t,1H),7.85-7.75(m,2H),7.49-7.37(m,2H),7.02(s,1H),5.44(quin,1H),2.39(s,3H),2.28(s,3H),1.66(d,3H). LCMS R t = 1.24 min in 2.0 min chromatography, 10-80AB, C 17 H 18 F 2 N 5 O 2 [M+H] + MS ESI calculated 362.14, found 362.0.

[0301] Synthesis of Examples 22.34 and 35 [ka] Analytical SFC (CHIRALCEL OJ-3 (100mm x 4.6mm, 3μm), mobile phase: A:CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 4.5 min, 40% for 0.5 min, then hold at 5% B for 1 min, flow rate: 2.8 mL / min, column temperature: 40 °C) showed two peaks at 2.01 and 2.31 min. The product was purified by SFC (Daicel CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); A = CO 2 and B = 0.1% NH 3 .H2 3O-EtOH; 35 °C; 60 mL / min; 25% B; 8 min run; 10 injections, peak 1 Rt = 5.37 min, peak 2 Rt = 6.75 min) to give enantiomer 1 (Rt = 2.01 min by analytical SFC) as a solid, randomly assigned as (5.56 mg, 0.02 mmol, 13% yield), and enantiomer 2 (Rt = 2.31 min by analytical SFC) as a solid, randomly assigned as (10.86 mg, 0.03 mmol, 26% yield). 1 H NMR (400 MHz, CDCl 3 ) δ H= 7.92-7.86(m,2H),7.41-7.32(m,2H),6.60(d,1H),6.46(s,1H),5.61(quin, 1H),4.13(s,3H),3.04-2.95(m,1H),2.44(s,3H),1.76(d,3H),1.29(d,6H). LCMS R t = 1.29 min in 2.0 min chromatography, 10-80AB, C 19 H 24 N 5 O 2 [M+H] + MS ESI calculated 354.19, found 354.1. 1 H NMR (400 MHz, CDCl 3 ) δ H= 7.93-7.85(m,2H),7.42-7.31(m,2H),6.58(d,1H),6.45(s,1H),5.61(quin, 1H),4.13(s,3H),3.05-2.94(m,1H),2.44(s,3H),1.76(d,3H),1.29(d,6H). LCMS R t = 1.27 min in 2.0 min chromatography, 10-80AB, C 19 H 24 N 5 O 2 [M+H] + MS ESI calculated 354.19, found 354.1.

[0302] Synthesis of Examples 23.36 and 37 [ka] Analytical SFC (Daicel CHIRALCEL OJ-3 (100mm x 4.6mm, 3μm), mobile phase: A:CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 4.5 min, 40% for 2.5 min, then hold at 5% B for 1 min, flow rate: 2.8 mL / min, column temperature: 40 °C) showed two peaks at 1.94 and 2.38 min. The products were purified by SFC (Daicel CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); A = CO 2 and B = EtOH (0.1% NH 3 H 2 0; 38 °C; 50 mL / min; 20% B; 9 min run; 11 injections, Rt = 5.5 min for peak 1, Rt = 7.6 min for peak 2) to give enantiomer 1 (Rt = 1.94 min by analytical SFC) as a solid, randomly assigned as 36 (16.17 mg, 44.4 μmol, 17% yield), and enantiomer 2 (Rt = 2.38 min by analytical SFC) as a solid, randomly assigned as 37 (28.82 mg, 79.5 μmol, 30% yield). 1 H NMR (400MHz, DMSO-d 6 ) δ H =9.38(d,1H),7.85-7.77(m,2H),7.48-7.39(m,2H),7.27(s,1H),7.06(t,1H),5.44(quin,1H),4.09(s,3H),2.40(s,3H),1.66(d,3H). LCMS R t = 1.29 min in 2.0 min chromatography, 10-80AB, C 17 H 18 F 2 N 5 O 2 [M+H] + MS ESI calculated 362.1, found 362.3. 1 H NMR (400MHz, DMSO-d 6 ) δ H=9.39(d,1H),7.84-7.78(m,2H),7.48-7.39(m,2H),7.27(s,1H),7.06(t,1H),5.44(quin,1H),4.09(s,3H),2.39(s,3H),1.66(d,3H). LCMS R t = 1.23 min in 2.0 min chromatography, 10-80AB, C 17 H 18 F 2 N 5 O 2 [M+H] + MS ESI calculated value 362.1, found value 362.1.

[0303] Synthesis of Examples 24.38 and 39 [ka] A-34: 5-Ethyl-2-methyl-pyrazole-3-carboxylic acid (69.46 mg, 0.45 mmol), HOBt (135.3 mg, 1 mmol), Et 3 A mixture of N (0.35 mL, 2.5 mmol), EDCI (143.95 mg, 0.75 mmol), and 1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (120 mg, 0.5 mmol) was incubated at 20 °C for 16 h with N 2 The reaction was stirred under saturated NH 4 The mixture was quenched with Cl (20 mL) and extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (20 mL) and diluted with Na 2 SO 4 The crude product was purified by preparative HPLC (Agela DuraShell (150 mm x 25 mm, 5 μm), A = H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 34-74% B over 8 min) gave the product (88 mg, 0.26 mmol, 52% yield) as a solid.

[0304] 38 and 39: Analytical SFC (column: Daicel CHIRALCEL IC-3 (150 mm × 4.6 mm, 3 μm), mobile phase: A:CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5 min, 40% for 2.5 min, then hold at 5% B for 2.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C) showed two peaks at 3.42 min and Rt = 4.26 min. The product was purified by SFC (Daicel CHIRALCEL (250 mm × 30 mm, 5 μm); A = CO 2 and B=EtOH; 38 °C; 50 mL / min; 30% B; 7 min run; 4 injections, peak 1 Rt=3.75 min, peak 2 Rt=5.4 min) to give enantiomer 1 (Rt=3.42 min by analytical SFC) randomly assigned as 38 (24.43 mg, 0.07 mmol, 41% yield) as an oil, and enantiomer 2 (Rt=4.26 min by analytical SFC) randomly assigned as 39 (27.23 mg, 0.08 mmol, 45% yield) as an oil. 1 H NMR (400MHz, CD 3 CN)δ H =7.87(s,1H),7.83(d,1H),7.49(br d,1H),7.44-7.37(m,2H),6.61(s,1H),5.50-5.37(m,1H),3.99(s,3H),2.60(q,2H),2.41(s,3H),1.69(d,3H),1.21(t,3H). LCMS R t = 2.0 min of chromatography at 1.25 min, 10-80AB, C 18 H 22 N 5 O 2 [M+H] + MS ESI calculated 340.2, found 340.1. 1 H NMR (400MHz, CD 3 CN)δ H=7.87(s,1H),7.83(d,1H),7.48(br d,1H),7.44-7.37(m,2H),6.61(s,1H),5.49-5.39(m,1H),3.99(s,3H),2.60(q,2H),2.41(s,3H),1.69(d,3H),1.21(t,3H). LCMS R t = 2.0 min of chromatography at 1.25 min, 10-80AB, C 18 H 22 N 5 O 2 [M+H] + MS ESI calculated value 340.2, found value 340.1.

[0305] Synthesis of Examples 25.40 and 41 [ka] A-36: Cs in DMF (6 mL) 2 CO 3 To a mixture of 4-methyl-1H-pyrazole-5-carboxylate (1310 mg, 4.02 mmol) and 2-bromopropane (494.61 mg, 4.02 mmol) was added ethyl 4-methyl-1H-pyrazole-5-carboxylate (310 mg, 2.01 mmol), and the reaction mixture was then stirred at 100° C. for 2 h. After cooling to room temperature, the reaction mixture was 2 The mixture was diluted with 200 mL of 2H2O (40 mL) and then extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL) and 2 SO 4 Drying over, filtration and concentration gave the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0%-5%-20%) to give the product (190 mg, 0.97 mmol, 48% yield) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.26(s,1H),4.65-4.50(m,1H),4.40(q,2H),2.28(s,3H),1.50(d,6H),1.40(t,3H).

[0306] A-37: To a solution of ethyl 1-isopropyl-4-methyl-pyrazole-3-carboxylate (190 mg, 0.97 mmol) in ethanol (9 mL), a solution of NaOH (116.18 mg, 2.9 mmol) in water (9 mL) was added and the mixture was stirred at 50° C. for 3 h. After cooling to room temperature, the reaction mixture was concentrated to give a residue. The residue was purified by H 2 The aqueous phase was acidified with 1N HCl (20 mL) to adjust pH=1 and extracted with EtOAc (50 mLx2). The combined organic phase was washed with brine (70 mL) and diluted with Na 2 SO 4 The mixture was dried over hexane, filtered and concentrated to give the product (130 mg, 0.76 mmol, 78% yield) as a solid. LCMS R t = 0.65 min with 1.5 min chromatography, 5-95AB, C 8 H 13 N 2 O 2 [M+H] + MS ESI calculated 169.09, found 168.9.

[0307] A-38: To a mixture of 1-isopropyl-4-methyl-pyrazole-3-carboxylic acid (130 mg, 0.77 mmol), HATU (317.25 mg, 0.83 mmol), DIPEA (0.29 mL, 1.67 mmol) in DCM (8 mL), 1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine (100 mg, 0.42 mmol) was added and the mixture was stirred at 15° C. for 2 h. The mixture was concentrated and purified by H 2 The mixture was diluted with 20 mL of EtOAc (10 mL) and then extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (30 mL) and 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4 OH) and B=CH 3Purification by CN; 59-89% B over 8 min) gave the product (150 mg, 412.9 μmol, 99% yield) as an oil. LCMS R t = 0.93 min in 1.5 min chromatography, 5-95AB, C 19 H 24 N 5 O 2 [M+H] + MS ESI calculated 354.19, found 354.2.

[0308] 40 and 41: Analytical SFC (Regis (S,S) Whelk-O1 (250 mm × 4.6 mm, 5 μm), mobile phase: A:CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5 min, 40% for 2.5 min, then hold at 5% B for 2.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C) showed two peaks at 3.46 min and 5.05 min. The product was purified by SFC (Regis (S,S) Whelk-O1 (250 mm × 30 mm, 5 μm); A = CO 2 and B = methanol (0.1% DEA); 38 °C; 60 mL / min; 40% B; 12 min run; 4 injections, peak 1 Rt = 6.2 min, peak 2 Rt = 9.0 min) to give enantiomer 1 (Rt = 3.46 min by analytical SFC) randomly assigned as 41 (47.98 mg, 135.8 μmol, 32% yield) as an oil, and enantiomer 2 (Rt = 5.05 min by analytical SFC) randomly assigned as 40 (51.51 mg, 145.7 μmol, 34% yield) as a solid. 1 H NMR (400MHz, DMSO-d 6 ) δ H= 8.66(d,1H),7.84-7.75(m,2H),7.68(s,1H),7.47-7.37(m,2H),5.39(quin, 1H),4.55-4.42(m,1H),2.39(s,3H),2.17(s,3H),1.66(d,3H),1.43(d,6H). LCMS R t = 1.36 min in 2.0 min chromatography, 10-80AB, C 19 H 24 N 5O 2 [M+H] + MS ESI calculated 354.19, found 354.0. 1 H NMR (400MHz, DMSO-d 6 ) δ H =8.66(d,1H),7.85-7.76(m,2H),7.68(s,1H),7.48-7.37(m,2H),5.39(quin ,1H),4.55-4.43(m,1H),2.39(s,3H),2.17(s,3H),1.66(d,3H),1.43(d,6H). LCMS R t = 1.33 min in 2.0 min chromatography, 10-80AB, C 19 H 24 N 5 O 2 [M+H] + MS ESI calculated 354.19, found 354.0.

[0309] Synthesis of Examples 26.42 and 43 [ka] A-40: A mixture of 2-(tert-butoxycarbonylamino)propanoic acid (296.58 mg, 1.57 mmol) and CDI (279.58 mg, 1.72 mmol) in DMF (30 mL) was stirred at 15 °C for 1 h, then N'-hydroxy-3-(trifluoromethyl)benzamidine (320 mg, 1.57 mmol) was added. The reaction mixture was stirred at 110 °C for 16 h. After cooling to room temperature, the mixture was treated with NH 4 The mixture was diluted with Cl (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic phase was washed with brine (30 mL) and 2 SO 4 The crude product was purified by column flash chromatography on silica gel (EtOAc in PE=10%-30%-50%) to give the product (500 mg, 1.24 mmol, 79% yield) as an oil. LCMS R t = 0.95 min, 5-95AB, C with 1.5 min chromatography 12 H11 F 3 N 3 O 3 [M-tBu+H] + MS ESI calculated value 302.1, measured value 302.1.

[0310] A-41: To a solution of tert-butyl N-[1-[3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl]ethyl]carbamate (240 mg, 0.67 mmol) in 1,4-dioxane (3 mL), 4M HCl / 1,4-dioxane (20 mL) was added and the mixture was stirred at 20° C. for 8 h. The mixture was concentrated to give the crude product (180 mg, 0.61 mmol, 79% yield) as a solid. LCMS R t = 0.69 min in 1.5 min chromatography, 5-95AB, C 11 H 11 F 3 N 3 O[M+H] + MS ESI calculated value 258.1, found value 258.0.

[0311] A-42: 5-isopropyl-2-methyl-pyrazole-3-carboxylic acid (54.41 mg, 0.32 mmol), HOBt (92.03 mg, 0.68 mmol), Et 3 A mixture of N (0.24 mL, 1.7 mmol), EDCI (97.92 mg, 0.51 mmol), and 1-[3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (100 mg, 0.34 mmol) was incubated at 20 °C for 16 h with N 2 The reaction mixture was stirred under reduced pressure. 4 The mixture was quenched with Cl (20 mL) and extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (20 mL) and diluted with Na 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime (150 mm x 30 mm, 5 μm), A = H 2 O(0.05% NH 4OH) and B=CH 3 Purification by CN; 20-80% B over 8 min) gave the product (85 mg, 0.21 mmol, 61% yield) as an oil. LCMS R t = 0.93 min in 1.5 min chromatography, 5-95AB, C 19 H 21 F 3 N 5 O 2 [M+H] + MS ESI calculated value 408.2, found value 408.1.

[0312] 42 and 43: Analytical SFC (Regis(R,R) Whelk-O1 (100 mm × 4.6 mm, 5 μm), mobile phase: A:CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5 min, 40% for 2.5 min, then hold at 5% B for 2.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C) showed two peaks at 3.15 min and Rt = 3.68 min. The product was purified by SFC (Regis (S,S) Whelk-O1 (250 mm × 30 mm, 5 μm); A = CO 2 and B=EtOH; 38 °C; 65 mL / min; 30% B; 7 min run; 6 injections, peak 1 Rt=4.43 min, peak 2 Rt=5.72 min) to give enantiomer 1 (Rt=3.15 min by analytical SFC) randomly assigned as 42 (25.66 mg, 0.06 mmol, 31% yield) as an oil, and enantiomer 2 (Rt=3.68 min by analytical SFC) randomly assigned as 43 (25.41 mg, 0.06 mmol, 32% yield) as an oil. 1 H NMR (400MHz, CD 3 CN)δ H =8.36-8.23(m,2H),7.88(d,1H),7.74(t,1H),7.50(d,1H),6.64(s,1H),5 .46(quin,1H),3.99(s,3H),3.00-2.85(m,1H),1.71(d,3H),1.23(d,6H). LCMS R t = 1.36 min in 2.0 min chromatography, 10-80AB, C 19 H21 F 3 N 5 O 2 [M+H] + MS ESI calculated value 408.2, found value 408.1. 1 H NMR (400MHz, CD 3 CN)δ H =8.34-8.25(m,2H),7.88(d,1H),7.74(t,H),7.50(d1H),6.65(s,1H),5. 46(quin,1H),3.99(s,3H),2.99-2.86(m,1H),1.71(d,3H),1.23(d,6H). LCMS R t = 2.0 min of chromatography at 1.35 min, 10-80AB, C 19 H 21 F 3 N 5 O 2 [M+H] + MS ESI calculated value 408.2, found value 408.1.

[0313] Synthesis of Example 27.44 [ka] To a mixture of 1-isopropyl-3-methyl-pyrazole-4-carboxylic acid (100 mg, 0.59 mmol) in DCM (10 mL) was added HOBt (160.69 mg, 1.19 mmol), EDCI (227.96 mg, 1.19 mmol), DIPEA (0.33 mL, 2.38 mmol), and (1R)-1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine (120.84 mg, 0.59 mmol) and the reaction mixture was stirred at 25 °C for 16 h. 2 The mixture was quenched with O (10 mL) and then extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (30 mL) and diluted with Na 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4OH) and B=CH 3 Purification by elution with 100% ethanol (CN; 17-47% B over 8 min) gave the product as an oil. Analytical SFC (Daicel CHIRALPAK AS-3 (150 mm × 4.6 mm, 3 μm), mobile phase: A:CO 2 B: Ethanol (0.05% DEA), gradient: 5% to 40% B in 5 min, 40% to 5% B in 0.5 min, hold 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C, ABPR: 1500 psi) showed 2.39 min (main peak, 91.6%) and 2.55 min (8.4%). Note: The condensation reaction results in some racemization. The product was then purified by SFC (Daicel CHIRALPAK AS-H (250 mm × 30 mm, 5 μm); A = CO 2 and B = EtOH (0.1% NH 3 H 2 0; 38 °C; 65 mL / min; 20% B; 8.60 min run; 50 injections, peak 1 Rt = 5.57 min, peak 2 Rt = 6.60 min) to give the product (66.75 mg, 0.19 mmol, 32% yield) as an oil. 1 H NMR (400MHz, CD 3 CN)δ=8.00(s,1H),7.89(s,1H),7.86(d,1H),7.48-7.38(m,2H),7.06(br d,1H),5.50-5.40(m,1H),4.46(quin,1H),2.44(s,3H),2.39(s,3H),1.69(d,3H),1.48(d,6H). LCMS R t = 2.0 min of chromatography at 1.13 min, 10-80AB, C 19 H 24 N 5 O 2 [M+H] + MS ESI calculated value 354.2, found value 354.0.

[0314] Synthesis of Example 28.45 [ka] A-10: A mixture of 3-fluorobenzonitrile (2.2 g, 18.17 mmol), hydroxylamine hydrochloride (3.79 g, 54.5 mmol), and NaOH (2.18 g, 54.5 mmol) in ethanol (24 mL) and water (8 mL) was stirred at 40° C. for 12 hours to give a mixture. After cooling to room temperature, the reaction mixture was concentrated to remove most of the EtOH, and then H 2 The mixture was diluted with 20 mL of EtOAc (30 mL×2). The combined organic phase was washed with brine (15 mL) and diluted with Na 2 SO 4 It was dried over water, filtered and concentrated to give the crude product (3200 mg) as a solid. LCMS R t = 0.16 min in 1.5 min chromatography, 5-95AB, C 7 H 8 FN 2 O[M+H] + MS ESI calculated 155.05, found 155.1.

[0315] A-45: A mixture of 2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid (400 mg, 1.84 mmol) and CDI (328.39 mg, 2.03 mmol) in DMF (20 mL) was stirred at 20° C. for 1 h, followed by the addition of 3-fluoro-N-hydroxy-benzamidine (283.79 mg, 1.84 mmol). The reaction mixture was stirred at 100° C. for 16 h. After cooling to room temperature, the mixture was diluted with H 2 The mixture was diluted with 20 mL of EtOAc (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL) and 2 SO 4 The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 20% to 50%) to give the product (150 mg, 0.45 mmol, 24% yield) as an oil. LCMS R t = 0.96 min in 1.5 min chromatography, 5-95AB, C 17 H 23 FN 3 O 3[M+H-Boc] + MS ESI calculated value 280.1, found value 280.1.

[0316] A-46: To a solution of tert-butyl N-[1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-methyl-propyl]carbamate (200 mg, 0.60 mmol) in 1,4-dioxane (10 mL) was added 4M HCl / 1,4-dioxane (10 mL, 40 mmol) and the reaction mixture was stirred at 20° C. for 2 h. The mixture was concentrated and the pH was adjusted to 10 with saturated NaHCO 3 The mixture was adjusted to pH 9 by adding 10 mL of EtOAc (40 mL×2), and the combined organic phase was washed with brine (10 mL) and diluted with Na 2 SO 4 It was dried over water, filtered and concentrated to give the crude product (150 mg) as an oil. LCMS R t = 0.696 min in 1.5 min chromatography, 5-95AB, C 12 H 14 FN 3 O[M+H] + MS ESI calculated 236.11, found 236.1.

[0317] 45: A mixture of 1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-methyl-propan-1-amine (150 mg, 0.64 mmol), HOBt (172.32 mg, 1.28 mmol), EDCI (183.34 mg, 0.96 mmol), TEA (0.44 mL, 3.19 mmol), and 5-cyclopropyl-2-methyl-pyrazole-3-carboxylic acid (105.96 mg, 0.64 mmol) in DCM (20 mL) was stirred at 20° C. for 16 h. 2 The mixture was diluted with 20 mL of 2H2O and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL) and 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 59-89% B over 8 min) gave the product (75.38 mg, 412.9 μmol, 31% yield) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.89(d,1H),7.79(td,1H),7.52-7.42(m,1H),7.23(dt,1H),6.53(br d,1H),6.33(s,1H),5.44(dd,1H),4.09(s,3H),2.45-2.36(m,1H),1.98 -1.90(m,1H),1.10-1.01(m,6H),0.98-0.92(m,2H),0.79-0.74(m,2H). LCMS R t = 1.35 min in 2.0 min chromatography, 5-95AB, C 20 H 22 FN 5 O 2 [M+H] + MS ESI calculated 384.2, found 384.2.

[0318] Examples 29. Synthesis of 46 and 47 [ka] Analytical SFC (Regis(S,S)Whelk-O1 (250mm x 4.6mm, 5μm), mobile phase: A:CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5 min, 40% for 2.5 min, then hold at 5% B for 2.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C) showed two peaks at 5.34 min and 6.12 min. The product was purified by SFC (Regis (S,S) Whelk-O1 (250 mm × 30 mm, 5 μm); A = CO 2and B = ethanol (0.1% DEA); 38 °C; 60 mL / min; 40% B; 8 min run; 5 injections, peak 1 Rt = 4.6 min, peak 2 Rt = 5.8 min) to give enantiomer 1 (Rt = 5.34 min by analytical SFC) randomly assigned as 46 (25.02 mg, 69.2 μmol, 25% yield) as an oil, and enantiomer 2 (Rt = 6.12 min by analytical SFC) randomly assigned as 47 (28.95 mg, 80.1 μmol, 29% yield) as an oil. 1 H NMR (400MHz, DMSO-d 6 ) δ H= 9.55(d,1H),8.18(t,1H),7.85-7.74(m,2H),7.50-7.36(m,2H),7.02(s,1H),5.44(quin,1H),2.39(s,3H),2.28(s,3H),1.66(d,3H). LCMS R t = 1.29 min in 2.0 min chromatography, 10-80AB, C 17 H 18 F 2 N 5 O 2 [M+H] + MS ESI calculated 362.14, found 362.1. 1 H NMR (400MHz, DMSO-d 6 ) δ H =9.56(d,1H),8.19(t,1H),7.88-7.71(m,2H),7.53-7.35(m,2H),7.03(s,1H),5.45(quin,1H),2.40(s,3H),2.29(s,3H),1.67(d,3H). LCMS R t = 1.26 min in 2.0 min chromatography, 10-80AB, C 17 H 18 F 2 N 5 O 2 [M+H] + MS ESI calculated 362.14, found 362.0.

[0319] Synthesis of Example 30.48 [ka] A-10: A mixture of 3-fluorobenzonitrile (2.2 g, 18.17 mmol), hydroxylamine hydrochloride (3.79 g, 54.5 mmol), and NaOH (2.18 g, 54.5 mmol) in ethanol (24 mL) and water (8 mL) was stirred at 40° C. for 12 hours to give a mixture. After cooling to room temperature, the reaction mixture was concentrated to remove most of the EtOH, and then H 2 The mixture was diluted with 20 mL of EtOAc (30 mL×2). The combined organic phase was washed with brine (15 mL) and diluted with Na 2 SO 4 It was dried over water, filtered and concentrated to give the crude product (3200 mg) as a solid. LCMS R t = 0.16 min in 1.5 min chromatography, 5-95AB, C 7 H 8 FN 2 O[M+H] + MS ESI calculated 155.05, found 155.1.

[0320] A-47: A mixture of 2-(tert-butoxycarbonylamino)butanoic acid (400 mg, 1.97 mmol) and CDI (351.04 mg, 2.16 mmol) in DMF (20 mL) was stirred at 20° C. for 1 h, followed by the addition of 3-fluoro-N-hydroxy-benzamidine (303.37 mg, 1.97 mmol). The mixture was stirred at 100° C. for 16 h. The mixture was cooled and then H 2 The mixture was diluted with 20 mL of EtOAc (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL) and 2 SO 4 The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 20% to 50%) to give the product (150 mg, 0.45 mmol, 23% yield) as an oil. LCMS R t = 0.94 min in 1.5 min chromatography, 5-95AB, C 16 H 21 FN 3 O3 [M+H-Boc] + MS ESI calculated 266.1, found 266.1.

[0321] A-48: To a solution of tert-butyl N-[1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]propyl]carbamate (200 mg, 0.62 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl / 1,4-dioxane (10 mL, 40 mmol) and the reaction mixture was stirred at 20° C. for 2 h. The mixture was concentrated and the pH was adjusted to 10 with saturated NaHCO 3 The mixture was adjusted to pH 9 by adding 10 mL of EtOAc (40 mL×2), and the combined organic phase was washed with brine (10 mL) and diluted with Na 2 SO 4 It was dried over water, filtered and concentrated to give the crude product (150 mg) as an oil. LCMS R t = 0.66 min in 1.5 min chromatography, 5-95AB, C 11 H 14 ClFN 3 O[M+H] + MS ESI calculated value 222.0, found value 222.0.

[0322] 48: A mixture of 1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]propan-1-amine (150 mg, 0.68 mmol), HOBt (183.24 mg, 1.36 mmol), EDCI (194.97 mg, 1.02 mmol), TEA (0.47 mL, 3.39 mmol), and 5-cyclopropyl-2-methyl-pyrazole-3-carboxylic acid (12.67 mg, 0.68 mmol) in DCM (20 mL) was stirred at 20° C. for 16 h. The mixture was diluted with saturated NH 4 The mixture was diluted with Cl (10 mL) and extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (10 mL) and 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 55-85% B over 8 min) gave the product (77.37 mg, 0.21 mmol, 31% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.88(dd,1H),7.82-7.76(m,1H),7.51-7.44(m,1H),7.26-7.19(m,1H),6.50(br d,1H),6.32(s,1H),5.53-5.45(m,1H),4.09(s,3H),2.23-2.11(m,1H),2.10-1. 98(m,1H),1.98-1.88(m,1H),1.06(t,3H),0.98-0.91(m,2H),0.78-0.72(m,2H). LCMS R t = 1.28 min in 2.0 min chromatography, 5-95AB, C 19 H 21 FN 5 O 2 [M+H] + MS ESI calculated value 370.2, found value 370.1.

[0323] Synthesis of Example 31.49 [ka] A-49: A mixture of 2-(tert-butoxycarbonylamino)-3-phenyl-propanoic acid (400 mg, 1.51 mmol) and CDI (268.93 mg, 1.66 mmol) in DMF (20 mL) was stirred at 20° C. for 1 h, followed by the addition of 3-fluoro-N-hydroxy-benzamidine (232.4 mg, 1.51 mmol). The mixture was stirred at 100° C. for 16 h. The mixture was cooled and then H 2 The mixture was diluted with 20 mL of EtOAc (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL) and 2 SO 4The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 20% to 50%) to give the product (150 mg, 0.39 mmol, 26% yield) as an oil. LCMS R t = 0.98 min in 1.5 min chromatography, 5-95AB, C 21 H 23 FN 3 O 3 [M+2H-Boc] + MS ESI calculated value 328.1, found value 328.1.

[0324] A-50: To tert-utyl N-[1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-phenyl-ethyl]carbamate (200 mg, 0.52 mmol) in 1,4-dioxane (10 mL) was added 4M HCl / 1,4-dioxane (10 mL, 40 mmol) and the reaction mixture was stirred at 20° C. for 2 h. The mixture was concentrated and the pH was adjusted to 100 with saturated NaHCO 3 The mixture was adjusted to pH 9 by adding 10 mL of EtOAc (40 mL×2), and the combined organic phase was washed with brine (10 mL) and diluted with Na 2 SO 4 It was dried over water, filtered and concentrated to give the crude product (150 mg, 0.46 mmol, 88% yield) as an oil. LCMS R t = 0.73 min in 1.5 min chromatography, 5-95AB, C 16 H 16 ClFN 3 O[M+H] + MS ESI calculated 284.1, found 284.1.

[0325] 49: A mixture of 1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-phenyl-ethanamine (150 mg, 0.53 mmol), HOBt (143.1 mg, 1.06 mmol), EDCI (152.5 mg, 0.79 mmol), TEA (0.37 mL, 2.65 mmol), and 5-cyclopropyl-2-methyl-pyrazole-3-carboxylic acid (87.99 mg, 0.53 mmol) in DCM (20 mL) was stirred at 20° C. for 16 h. 2 The mixture was diluted with 20 mL of 2H2O and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL) and 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 62-92% B over 8 min) gave the product (42.55 mg, 0.10 mmol, 18% yield) as a solid. 1 H NMR (400MHz, DMSO-d 6 ) δ H =9.17(d,1H),7.86(d,1H),7.77-7.70(m,1H),7.68-7.60(m,1H),7.48(dt,1H),7.35-7.26(m,4H),7.24-7.18(m,1H),6.60(s,1H) ),5.62-5.50(m,1H),3.84(s,3H),3.49-3.42(m,1H),3.38-3.34(m,1H),1.90-1.81(m,1H),0.90-0.84(m,2H),0.64-0.58(m,2H). LCMS R t = 1.37 min in 2.0 min chromatography, 5-95AB, C 24 H 23 FN 5 O 2 [M+H] + MS ESI calculated value 432.2, found value 432.1.

[0326] Synthesis of Example 32.50 [ka] A-51: A mixture of 2-(tert-butoxycarbonylamino)-2-methyl-propanoic acid (580.16 mg, 2.85 mmol) and CDI (462.86 mg, 2.85 mmol) in DMF (6 mL) was stirred at 15° C. for 1 h, then 3-fluoro-N-hydroxy-benzamidine (400 mg, 2.6 mmol) was added. The reaction mixture was then stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (20 mL) and diluted with Na 2 SO 4 The mixture was dried over ice, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 60%) to give the product (140 mg, 344.1 μmol, 13% yield) as a solid. LCMS Rt = 1.5 min chromatography 0.91 min, 5-95AB, C 12 H 13 FN 3 O 3 [M+Ht-Bu] + MS ESI calculated 266.1, found 266.0.

[0327] A-52: To N-[1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methyl-ethyl]carbamate (140 mg, 0.44 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (3 mL, 12 mmol) and the mixture was stirred at 15° C. for 1 h. The mixture was concentrated to give the product 2-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]propan-2-amine hydrochloride (110 mg, 417.8 μmol, 96% yield) as a solid. LCMS Rt=1.5 min, chromatographic run 0.64 min, 5-95AB, C 15 H 13 FN 3 O[M+H] +MS ESI calculated value 222.1, found value 222.0.

[0328] 50: To a mixture of 5-cyclopropyl-2-methyl-pyrazole-3-carboxylic acid (77.39 mg, 0.47 mmol), HATU (177.06 mg, 0.47 mmol), and 2-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]propan-2-amine hydrochloride (100 mg, 0.39 mmol) in DMF (6 mL), DIPEA (0.2 mL, 1.16 mmol) was added and the mixture was stirred at 20° C. for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×2). The combined organic phase was washed with water (20 mL×2) and brine (20 mL) and diluted with Na 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 52-82% B over 8 min) afforded the product (116.91 mg, 0.32 mmol, 81% yield) as a solid. 1 H NMR (400MHz, DMSO-d 6 ) δ H =8.93(s,1H),7.85(d,1H),7.73(d,1H),7.67-7.59(m,1H),7.50-7.40(m,1H),6.72(s, 1H),3.83(s,3H),1.93-1.84(m,1H),1.75(s,6H),0.92-0.86(m,2H),0.68-0.60(m,2H). LCMS R t = 1.32 min in 2.0 min chromatography, 10-80AB, C 19 H 21 FN 5 O 2 [M+H] + MS ESI calculated value 370.2, found value 369.9.

[0329] Synthesis of Example 33.51 [ka] A-53: A mixture of 2-(tert-butoxycarbonylamino)-2-phenyl-acetic acid (717.29 mg, 2.85 mmol) and CDI (462.86 mg, 2.85 mmol) in DMF (6 mL) was stirred at 15° C. for 1 h, then 3-fluoro-N-hydroxy-benzamidine (400 mg, 2.6 mmol) was added. The reaction was then stirred at 100° C. for 2 h to give a mixture. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (20 mL) and diluted with Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 60%) to give the product (140 mg, 209.0 μmol, 8% yield) as a solid. LCMS Rt = 1.5 min chromatography 0.96 min, 5-95AB, C 16 H 13 FN 3 O 3 [M+Ht-Bu] + MS ESI calculated 314.1, found 314.1.

[0330] A-54: To tert-butyl N-[[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]-phenyl-methyl]carbamate (140 mg, 0.38 mmol) in 1,4-dioxane (6 mL) was added 4 M HCl in 1,4-dioxane (3 mL, 12 mmol) and the mixture was stirred at 15° C. for 1 h. The mixture was concentrated to give the product (110 mg, 351.4 μmol, 93% yield) as a solid. LCMS Rt=1.5 min chromatographic run 0.71 min, 5-95AB,C 15 H 13 FN 3 O[M+H] + MS ESI calculated value 270.1, found value 270.0.

[0331] 51: To a mixture of 5-cyclopropyl-2-methyl-pyrazole-3-carboxylic acid (91.32 mg, 0.55 mmol), HATU (208.94 mg, 0.55 mmol), and [3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]-phenyl-methanamine hydrochloride (140 mg, 0.46 mmol) in DMF (3 mL), DIPEA (0.24 mL, 1.37 mmol) was added and the mixture was stirred at 20° C. for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×2). The combined organic phase was washed with water (20 mL×2) and brine (20 mL) and diluted with Na 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 60-90% B over 8 min) gave the product (88.39 mg, 0.21 mmol, 46% yield) as a solid. 1 H NMR (400MHz, DMSO-d 6 ) δ H =9.61(d,1H),7.84(d,1H),7.77-7.70(m,1H),7.67-7.58(m,1H),7.56-7.50(m,2H),7.49-7.38(m,4 H),6.78(s,1H),6.64(d,1H),3.94(s,3H),1.92-1.82(m,1H),0.91-0.82(m,2H),0.66-0.56(m,2H). LCMS R t = 1.41 min in 2.0 min chromatography, 10-80AB, C 23 H 21 FN 5 O 2 [M+H] + MS ESI calculated value 418.2, found value 418.0.

[0332] Synthesis of Example 34.52 [ka] A-57b: Cs in DMF (30 mL) 2 CO 3 To a mixture of 2-bromopropane (3.19 g, 25.95 mmol) and 2-bromopropane (8.45 g, 25.95 mmol), ethyl 3-methyl-1H-pyrazole-4-carboxylate (2 g, 12.97 mmol) was added and the reaction mixture was stirred at 100° C. for 2.5 h. After cooling to room temperature, the reaction mixture was diluted with saturated NH 4 The mixture was diluted with Cl (50 mL) and then extracted with EtOAc (50 mL x 2), and the organic layer was washed with brine (50 mL) and Na 2 SO 4 Drying over, filtration and concentration gave the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0% to 30%) to give the product (300 mg, 1.53 mmol, 12% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H = 7.85 (s, 1H), 4.51-4.34 (m, 1H), 4.28 (q, 2H), 2.46 (s, 3H), 1.50 (d, 6H), 1.34 (t, 3H). LCMS Rt = 7.0 min chromatography at 3.25 min, 0-60AB, C 10 H 17 N 2 O 2 [M+H] + MS ESI calculated value 197.1, found value 197.0.

[0333] A-57: To a solution of ethyl 1-isopropyl-3-methyl-pyrazole-4-carboxylate (300 mg, 1.53 mmol) in ethanol (5 mL) was slowly added a solution of NaOH (122.29 mg, 3.06 mmol) in water (5 mL). The resulting mixture was stirred at 25° C. for 2 h. The mixture was concentrated under reduced pressure to remove EtOH. The aqueous phase was adjusted to pH=2 by the addition of 1N HCl (30 mL) and the mixture was diluted with EtOAc (10 mL). The phases were separated and the organic phase was washed with brine (10 mL) and Na 2 SO 4Drying over rt and then concentration gave the crude product (210 mg, 1.22 mmol, 80% yield) as a solid. LCMS Rt=2.0 min chromatograph 0.61 min, 10-80AB, C 8 H 13 N 2 O 2 [M+H] + MS ESI calculated value 169.1, found value 168.8.

[0334] 52: A mixture of 1-isopropyl-3-methyl-pyrazole-4-carboxylic acid (100 mg, 0.59 mmol), HOBt (160.69 mg, 1.19 mmol), EDCI (227.96 mg, 1.19 mmol), DIPEA (0.33 mL, 2.38 mmol), and (1S)-1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine (120.84 mg, 0.59 mmol) in DCM (10 mL) was stirred at 25° C. for 16 h. The mixture was concentrated and the residue was purified by H 2 The mixture was diluted with 20 mL of 2H2O and then extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (20 mL) and brine (20 mL) and diluted with Na 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime (150 mm x 30 mm, 5 μm), A = H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 40-60% B over 9 min) gave the product. Analytical SFC (column: (Daicel CHIRALPAK AS-3 150 mm x 4.6 mm i.d., 3 μm, mobile phase: A:CO 2B: Ethanol (0.05% DEA), gradient: 5% to 40% B in 5 min, 40% to 5% B in 0.5 min, hold at 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C, ABPR: 1500 psi showed two peaks at 2.52 min (11.1%) and 2.73 min (main peak, 88.9%). Note: The condensation reaction results in some racemization. The products were analyzed by SFC (Daicel CHIRALPAK AS-H (250 mm × 30 mm, 5 μm); A = CO 2 and B = EtOH (0.1% NH 3 H 2 0; 38 °C; 60 mL / min; 20% B; 8 min run; 10 injections, peak 1 Rt = 4.8 min, peak 2 Rt = 6 min) to give the product (50.77 mg, 0.14 mmol, 24% yield) as a solid (Rt = 2.55 min by analytical SFC). 1 H NMR (400MHz, CD 3 CN)δ H = 7.96 (s, 1H), 7.86 (s, 1H), 7.83 (br d, 1H), 7.44-7.36 (m, 2H), 7.04 (br d, 1H), 5.46-5.37 (m, 1H), 4.47-4.36 (m, 1H), 2.41 (s, 3H), 2.36 (s, 3H), 1.66 (d, 3H), 1.44 (d, 6H). LCMS Rt = 2.0 min, 10-80AB, C 19 H 24 N 5 O 2 [M+H] + MS ESI calculated value 354.2, found value 354.1.

[0335] Synthesis of Example 35.55 [ka] A-59: To a solution of ethyl 2-isopropyl-4-methyl-pyrazole-3-carboxylate (220 mg, 1.12 mmol) in ethanol (5 mL) was added a solution of NaOH (134.52 mg, 3.36 mmol) in water (5 mL). The mixture was stirred at 20° C. for 2 h. The reaction mixture was concentrated to give a residue, which was then purified by H 2The mixture was diluted with 20 mL of HO and extracted with 1× EtOAc (20 mL). The aqueous phase was adjusted to pH = 1 by adding 1N HCl (20 mL), which was then diluted with 20 mL of EtOAc. 2 The mixture was diluted with 200 mL of EtOAc (10 mL). The mixture was extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine (70 mL) and diluted with Na 2 SO 4 It was dried over, filtered and concentrated to give the product (130 mg) as a solid. t = 0.70 min in 2.0 min chromatography, 5-95AB, C 8 H 13 N 2 O 2 [M+H] + MS ESI calculated 169.09, found 169.0.

[0336] 55: To a mixture of 2-isopropyl-4-methyl-pyrazole-3-carboxylic acid (129.45 mg, 0.77 mmol), HATU (315.92 mg, 0.83 mmol), DIPEA (0.29 mL, 1.66 mmol) in DCM (8 mL) was added 1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (100 mg, 0.42 mmol) and the reaction mixture was stirred at 20° C. for 12 h. The mixture was concentrated and purified by H 2 The mixture was diluted with 20 mL of EtOAc (10 mL) and then extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (30 mL) and 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 44-74% B over 9 min) gave the product (75.42 mg, 213.4 μmol, 51% yield) as an oil. 1 H NMR (400MHz, DMSO-d 6 ) δ H=9.17(d,1H),7.85-7.76(m,2H),7.49-7.39(m,2H),7.33(s,1H),5.42(qui n,1H),4.80(spt,1H),2.39(s,3H),2.15(s,3H),1.65(d,3H),1.36(d,6H). LCMS R t = 1.24 min in 2.0 min chromatography, 10-80AB, C 19 H 24 N 5 O 2 [M+H] + MS ESI calculated 354.19, found 354.0.

[0337] Examples 36. Synthesis of 56 and 57 [ka] A-60b: A solution of ethyl 5-methyl-2,4-dioxo-hexanoate (2 g, 10.74 mmol) in ethanol (20 mL) at 5 °C was treated with methylhydrazine (1.36 g, 11.81 mmol, H 2 Aqueous solution of 1,2-dichloromethane (40% in 0) was added dropwise. The reaction mixture was stirred at 5° C. for 3 h and then concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in PE=0%-10%-50%) to give the product (700 mg, 3.57 mmol, 33% yield) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H= 6.70-6.59(m,1H),4.43-4.24(m,2H),4.12(s,3H),3.07-2.77(m,1H),1.38(t,3H),1.26(d,6H).

[0338] A-60: A mixture of ethyl 5-isopropyl-2-methyl-pyrazole-3-carboxylate (700 mg, 3.57 mmol) and NaOH (428.03 mg, 10.70 mmol) in ethanol (10 mL) and water (10 mL) was stirred at 20° C. for 2 h. The reaction mixture was concentrated under reduced pressure to remove EtOH and then extracted with EtOAc (10 mL). The aqueous phase was acidified with HCl (1N) to pH approx. 2 and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (15 mL) and diluted with Na 2 SO 4 It was dried over, filtered and concentrated to give the crude product (400 mg) as an oil. 1 H NMR (400MHz, DMSO-d 6 ) δ H= 13.17(br s,1H),6.62(s,1H),3.99(s,3H),2.91-2.80(m,1H),1.17(d,6H).

[0339] A-61: A mixture of 2-(tert-butoxycarbonylamino)propanoic acid (1227.52 mg, 6.49 mmol) and CDI (1157.16 mg, 7.14 mmol) in DMF (20 mL) was stirred at 15° C. for 1 h, then 3-fluoro-N′-hydroxy-benzamidine (1000 mg, 6.49 mmol) was added. The reaction mixture was then stirred at 110° C. for 16 h. The mixture was cooled and then NH 4 The mixture was diluted with Cl (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (15 mL) and 2 SO 4 Drying over, filtration and concentration gave the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0%-30%-50%) to give the product (600 mg, 1.95 mmol, 30% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H=7.89-7.78(m,2H),7.76-7.70(m,1H),7.68-7.60(m,1H),7.50-7.43(m,1H),5.02-4.93(m,1H),1.51(d,3H),1.40(s,9H).

[0340] A-62: To a mixture of tert-butyl N-[1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (200 mg, 0.65 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in 1,4-dioxane (10 mL, 40 mmol). The reaction mixture was stirred at 20° C. for 16 h. The reaction mixture was concentrated to give the crude product (200 mg) as an oil. LCMS R t = 0.61 min in 1.5 min chromatography, 5-95AB, C 10 H 11 FN 3 MS ESI calculated for O[M+H]+: 208.1, found: 207.7.

[0341] A-63: A mixture of 5-isopropyl-2-methyl-pyrazole-3-carboxylic acid (120 mg, 0.71 mmol), DIPEA (0.62 mL, 3.57 mmol), HOBt (192.82 mg, 1.43 mmol), EDCI (205.16 mg, 1.07 mmol), and 1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (173.85 mg, 0.71 mmol) in DCM (15 mL) was stirred at 20° C. for 16 h. The mixture was cooled to NH 4 The mixture was diluted with Cl (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (15 mL) and 2 SO 4 The crude product was purified by preparative HPLC (Waters XBridge (150 mm×25 mm, 5 μm), A=H 2 HO (10 mM NH 4 HCO 3 ) and B=CH 3Purification by CN; 24-54% B over 8 min) gave the product (180 mg, 0.50 mmol, 70% yield) as an oil. LCMS R t = 0.88 min in 1.5 min chromatography, 5-95AB, C 18 H 21 FN 5 O 2 [M+H] + MS ESI calculated value 358.2, found value 358.1.

[0342] 56 and 57: Analytical SFC (Daicel CHIRALPAK IC-3 (150 mm x 4.6 mm, 3 μm), mobile phase: A: CO 2 B: IPA (0.05% DEA), gradient: 5% to 40% B in 5.5 min, 40% for 3 min, then hold at 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 40 °C) showed two peaks at 3.55 and 4.32 min. The products were analyzed by SFC (Daicel CHIRALPAK IC (250 mm × 30 mm, 5 μm); A = CO 2 and B=i-PrOH; 38 °C; 65 mL / min; 30% B; 7 min run; 7 injections, Rt for peak 1 = 3.5 min, Rt for peak 2 = 4.7 min) to give enantiomer 1 (Rt = 3.55 min by analytical SFC) randomly assigned as 56 (75.09 mg, 0.21 mmol, 41% yield) as an oil, and enantiomer 2 (Rt = 4.32 min by analytical SFC) randomly assigned as 57 (73.93 mg, 0.21 mmol, 41% yield) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.91-7.86(m,1H),7.82-7.76(m,1H),7.51-7.44(m,1H),7.26-7.19(m,1H),6.56(br d,1H),6.45(s,1H),5.65-5.56(m,1H),4.12(s,3H),3.06-2.94(m,1H),1.76(d,3H),1.29(d,6H). LCMS R t = 1.26 min in 2 min chromatography, 10-80AB, C 18 H 21 FN5 O 2 [M+H] + MS ESI calculated 358.2, found 358.1. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.91-7.86(m,1H),7.82-7.75(m,1H),7.52-7.44(m,1H),7.26-7.19(m,1H),6.56(br d,1H),6.45(s,1H),5.66-5.56(m,1H),4.12(s,3H),3.05-2.95(m,1H),1.76(d,3H),1.29(d,6H). LCMS R t = 1.26 min in 2 min chromatography, 10-80AB, C 18 H 21 FN 5 O 2 [M+H] + MS ESI calculated value 358.2, found value 358.1.

[0343] Synthesis of Example 37.58 [ka] A-64: A mixture of 3-benzyloxy-2-(tert-butoxycarbonylamino)propanoic acid (843.03 mg, 2.85 mmol) and CDI (462.86 mg, 2.85 mmol) in DMF (6 mL) was stirred at 15° C. for 1 h, then 3-fluoro-N-hydroxy-benzamidine (400 mg, 2.6 mmol) was added. The reaction mixture was stirred at 110° C. for 16 h. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (20 mL) and diluted with Na 2 SO 4 The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 60%) to give the product (260 mg, 0.58 mmol, 22% yield) as an oil. LCMS R t = 2.0 min of chromatography at 1.45 min, 10-80AB, C 22H 25 FN 3 O 4 [M+H-tBu] + MS ESI calculated value 358.1, found value 358.1.

[0344] A-65: A mixture of tert-butyl N-[2-benzyloxy-1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (260 mg, 0.63 mmol) and 4M HCl in 1,4-dioxane (5 mL, 20 mmol) was stirred at 25° C. for 16 hours. The mixture was concentrated to give the product (300 mg, 0.59 mmol, 94% yield) as a solid. LCMS R t = 2.0 min of chromatography at 0.99 min, 10-80AB, C 17 H 17 FN 3 O 2 [M+H] + MS ESI calculated value 314.1, found value 314.0.

[0345] 58: To a mixture of 5-cyclopropyl-2-methyl-pyrazole-3-carboxylic acid (171.03 mg, 1.03 mmol), HATU (391.33 mg, 1.03 mmol), and DIPEA (0.45 mL, 2.57 mmol) in DMF (3 mL), 2-benzyloxy-1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (300 mg, 0.86 mmol) was added and the mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with water (20 mL x 2) and brine (20 mL) and concentrated to dryness. 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4 OH) and B=CH 3Purification by CN; 55-85% B over 9 min) gave the product (49.27 mg, 0.11 mmol, 12% yield) as an oil. 1 H NMR (400MHz, DMSO-d 6 )δ=9.16(d,1H),7.86(d,1H),7.74(m,1H),7.64(m,1H),7.48(m,1H),7.37-7.21(m,5H),6.69(s,1H),5.6 1(q,1H),4.59(s,2H),4.02(m,2H),3.93(s,3H),1.97-1.76(m,1H),0.95-0.84(m,2H),0.69-0.56(m,2H). LCMS R t = 2.0 min of chromatography at 1.31 min, 10-80AB, C 25 H 25 FN 5 O 3 [M+H] + MS ESI calculated value 462.1, found value 462.1.

[0346] Synthesis of Example 38.54 [ka] To a mixture of N-[2-benzyloxy-1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]ethyl]-5-cyclopropyl-2-methyl-pyrazole-3-carboxamide (70 mg, 0.15 mmol) in DCM (3 mL) was added BBr 3 (0.03 mL, 0.30 mmol) was added and the mixture was stirred at 20° C. for 2 h. The reaction mixture was stirred at 20° C. for 2 h. 2 The mixture was diluted with 2×DCM (5 mL) and extracted with DCM (2×5 mL). The combined organic phase was washed with brine (10 mL) and diluted with Na 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4OH) and B = CH3CN; 39-69% B) over 9 min to give the product (21.67 mg, 0.06 mmol, 38% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =9.01(d,1H),7.87(d,1H),7.80-7.73(m,1H),7.65(m,1H),7.48(m,1H),6.73(s,1H),5.26 -5.44(m,2H),3.88-4.05(m,5H),1.81-1.99(m,1H),0.79-0.99(m,2H),0.53-0.74(m,2H). LCMS R t = 2.0 min of chromatography at 1.12 min, 10-80AB, C 18 H 19 FN 5 O 3 [M+H] + MS ESI calculated value 372.1, found value 372.1.

[0347] Synthesis of Example 39.59 [ka] A-67: To a mixture of ethyl 1-isopropyl-5-methyl-pyrazole-4-carboxylate (650 mg, 3.31 mmol) in ethanol (5 mL) and water (5 mL), NaOH (264.97 mg, 6.62 mmol) was added and the mixture was stirred at 50° C. for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the ethanol, and the residue was then purified by H 2 The mixture was diluted with 2×200 and washed with EtOAc (5 mL×2). The pH of the aqueous phase was adjusted to pH 2 with 1N HCl and then extracted with EtOAc (20 mL×2). The combined organic phase was diluted with 2×200 and washed with EtOAc (20 mL×2). 2 20 mL) and brine (10 mL). 2 SO 4 The mixture was dried over hexane, filtered and concentrated to give the product (520 mg, 3.09 mmol, 93% yield) as a solid. LCMS R t = 0.63 min in 1.5 min chromatography, 10-80AB, C 8H 13 N 2 O 2 [M+H] + MS ESI calculated 169.1, found 169.0. 59: A mixture of 1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine (241.68 mg, 1.19 mmol), HOBt (321.37 mg, 2.38 mmol), DIPEA (0.62 mL, 3.57 mmol), EDCI (455.91 mg, 2.38 mmol), and 1-isopropyl-5-methyl-pyrazole-4-carboxylic acid (200 mg, 1.19 mmol) in DCM (10 mL) was stirred at 20° C. for 16 h. The mixture was concentrated to give a residue. The residue was dissolved in EtOAc (20 mL) and washed with saturated NH 4 Cl (10 mL), water (10 mL), and brine (10 mL) were added, and the resulting solution was washed with Na 2 SO 4 The mixture was dried over 100° C., filtered and concentrated to give the crude product. The crude product was partially purified by flash chromatography on silica gel (EtOAc in PE=0% to 40% to 100%) to give the impure product. The impure product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 50-70% B over 9 min) gave the product (17.06 mg, 48.1 mmol, 4% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.93-7.85(m,2H),7.77(s,1H),7.41-7.30(m,2H),6.38(br d, 1H), 5.64 (quin, 1H), 4.50 (spt, 1H), 2.59 (s, 3H), 2.43 (s, 3H), 1.74 (d, 3H), 1.50 (d, 6H). LCMS R t = 1.24 min in 2.0 min chromatography, 10-80AB, C 19 H 24 N 5 O 2 [M+H]+ MS ESI calculated 354.2, found 354.2.

[0348] Synthesis of Examples 40.60 and 61 [ka] Analytical SFC (Daicel CHIRALCEL OJ-3 (150mm x 4.6mm, 3μm), mobile phase: A:CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5 min, 40% to 5% B in 0.5 min, hold 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C) showed two peaks at Rt = 3.00 min and Rt = 3.93 min. The product was purified by SFC (Daicel CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); A = CO 2 and B = ethanol (0.1% DEA); 38 °C; 60 mL / min; 20% B; 7 min run; 5 injections, peak 1 Rt = 5.2 min, peak 2 Rt = 5.4 min) to give enantiomer 1 (Rt = 3.00 min by analytical SFC) randomly assigned as 60 (16.59 mg, 44.9 μmol, 24% yield) as an oil, and enantiomer 2 (Rt = 3.93 min by analytical SFC) randomly assigned as 61 (26.44 mg, 71.6 μmol, 38% yield) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H= 7.88(d,1H),7.84-7.75(m,1H),7.50-7.42(m,1H),7.26-7.20(m,1H),6.50(br d,1H),6.32(s,1H),5.53-5.46(m,1H),4.09(s,3H),2.23-2.11(m,1H),2.10-1. 98(m,1H),1.98-1.89(m,1H),1.06(t,3H),0.99-0.92(m,2H),0.78-0.73(m,2H). LCMS R t = 1.23 min in 2.0 min chromatography, 10-80AB, C 19 H 21 FN 5 O 2[M+H] + MS ESI calculated 369.16, found 370.0. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.88(d,1H),7.83-7.74(m,1H),7.51-7.41(m,1H),7.27-7.20(m,1H),6.50(br d,1H),6.32(s,1H),5.53-5.45(m,1H),4.09(s,3H),2.22-2.11(m,1H),2.11-1. 98(m,1H),1.98-1.87(m,1H),1.06(t,3H),0.98-0.91(m,2H),0.78-0.73(m,2H). LCMS R t = 1.27 min in 2.0 min chromatography, 10-80AB, C 19 H 21 FN 5 O 2 [M+H] + MS ESI calculated 369.16, found 370.1.

[0349] Synthesis of Examples 41.62 and 63 [ka] Analytical SFC (Daicel CHIRALCEL OJ-3 (150mm x 4.6mm, 3μm), mobile phase: A:CO 2 B: Ethanol (0.05% DEA), gradient: 5%-40% B in 5 min, 40% for 2.5 min, then hold at 5% B for 2.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C ABPR: 1500 psi) showed two peaks at 2.60 min and Rt = 3.27 min. The product was purified by SFC (Daicel CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); A = CO 2 and B = EtOH (0.1% NH 3 H 20C; 38 °C; 60 mL / min; 15% B; 10 min run; 5 injections, peak 1 Rt = 5.7 min, peak 2 Rt = 8.5 min) to give enantiomer 1 (Rt = 2.60 min by analytical SFC) randomly assigned as 62 (22.57 mg, 58.9 μmol, 33% yield) as a solid, and enantiomer 2 (Rt = 3.27 min by analytical SFC) randomly assigned as 63 (25.47 mg, 66.2 μmol, 37% yield) as a solid. 1 H NMR (400MHz, DMSO-d 6 ) δ H =9.02(d,1H),7.86(d,1H),7.74(br d,1H),7.69-7.60(m,1H),7.47(dt,1H),6.75(s,1H),5.13(t,1H),3.91(s,3H),2.46 -2.36(m,1H),1.92-1.84(m,1H),1.05(d,3H),0.95-0.85(m,5H),0.66-0.60(m,2H). LCMS R t = 1.33 min in 2.0 min chromatography, 10-80AB, C 20 H 23 FN 5 O 2 [M+H] + MS ESI calculated 384.2, found 384.2. 1 H NMR (400MHz, DMSO-d 6 ) δ H =9.02(d,1H),7.86(d,1H),7.74(br d,1H),7.70-7.60(m,1H),7.47(dt,1H),6.75(s,1H),5.13(t,1H),3.91(s,3H),2.46 -2.36(m,1H),1.92-1.84(m,1H),1.05(d,3H),0.96-0.85(m,5H),0.66-0.59(m,2H). LCMS R t = 1.33 min in 2.0 min chromatography, 10-80AB, C 20 H 23 FN 5 O 2 [M+H] + MS ESI calculated 384.2, found 384.2.

[0350] Example 42. Synthesis of 64 and 65 [ka] A-71b: Ethyl 3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (500 mg, 2.4 mmol), cyclopropylboronic acid (412.7 mg, 4.8 mmol), and Na in DCE (7 mL). 2 CO 3 A solution of (509.22 mg, 4.8 mmol) of Cu(OAc) in DCE (14 mL) was 2 A solution of 2 (436.32 mg, 2.4 mmol) and 2,2-bipyridine (450.2 mg, 2.88 mmol) was added. The reaction mixture was stirred at 70° C. for 4 h. After cooling to room temperature, the mixture was diluted with saturated NH 4 The mixture was diluted with Cl (20 mL) and then extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (40 mL) and 2 SO 4 Drying over, filtration and concentration gave the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0%-5%-50%) to give the product (180 mg, 0.73 mmol, 30% yield) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.07(s,1H),4.43-4.36(m,3H),1.41(t,3H),1.36-1.30(m,2H),1.14-1.07(m,2H).

[0351] A-71: To a solution of ethyl 2-cyclopropyl-5-(trifluoromethyl)pyrazole-3-carboxylate (180 mg, 0.73 mmol) in ethanol (3 mL) was added a solution of NaOH (87.03 mg, 2.18 mmol) in water (3 mL). The reaction mixture was stirred at 50° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with H 2The pH of the aqueous phase was adjusted to pH=1 by adding 1N HCl (20 mL) and then diluted with H2O (20 mL) and washed with EtOAc (20 mL x 1). 2 The mixture was diluted with 200 mL of EtOAc (10 mL). The mixture was extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine (70 mL) and diluted with Na 2 SO 4 The mixture was dried over hexane, filtered and concentrated to give the product (160 mg, 661.7 μmol, 84% yield) as an oil. LCMS R t = 0.79 min in 1.5 min chromatography, 5-95AB, C 8 H 8 F 3 N 2 O 2 [M+H] + MS ESI calculated 221.05, found 221.1.

[0352] A-12: 3-Chlorobenzonitrile (1.2 g, 8.72 mmol), NH in ethanol (9 mL) and water (3 mL). 2 A mixture of OH HCl (1818.45 mg, 26.17 mmol) and NaOH (1046.74 mg, 26.17 mmol) was stirred at 40° C. for 16 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the EtOH, then H 2 The mixture was diluted with 200 mL of EtOAc (100 mL). The mixture was extracted with EtOAc (150 mL x 2). The combined organic phase was washed with brine (100 mL) and diluted with Na 2 SO 4 It was dried over hexane, filtered and concentrated to give the crude product (1760 mg, 6.62 mmol, 76% yield) as a solid. LCMS R t = 0.21 min in 1.5 min chromatography, 5-95AB, C 7 H 8 ClN 2 O[M+H] + MS ESI calculated value 171.02, found value 170.9.

[0353] A-68: A mixture of 2-(tert-butoxycarbonylamino)propanoic acid (1.24 g, 6.54 mmol) and CDI (1.17 g, 7.19 mmol) in DMF (60 mL) was stirred at 15 °C for 1 h, then 3-chloro-N'-hydroxy-benzamidine (1.74 g, 6.54 mmol) was added. The reaction mixture was then stirred at 100 °C for 16 h. After cooling to room temperature, the mixture was treated with NH 4 The mixture was diluted with Cl (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (100 mL) and diluted with Na 2 SO 4 Drying over, filtration and concentration gave the crude product, which was purified by flash column chromatography on silica gel (EtOAc in PE=0%-30%-50%) to give the product (1480 mg, 4.29 mmol, 66% yield) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H =8.09(s,1H),7.97(d,1H),7.52-7.46(m,1H),7.45-7.39(m,1H),5.26-5.05(m,2H),1.64(br d,3H),1.47(s,9H). LCMS R t = 0.94 min in 1.5 min chromatography, 5-95AB, C 15 H 19 ClN 3 O 3 [M+Ht-Bu] + MS ESI calculated 268.1, found 268.1.

[0354] A-69: To tert-butyl N-[1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (1480 mg, 4.57 mmol) was added 4N HCl / 1,4-dioxane (10 mL, 40 mmol) and the reaction mixture was stirred at 20° C. for 0.5 h. The mixture was concentrated to give the crude product (1160 mg, 4.30 mmol, 94% yield) as a solid. LCMS R t = 0.66 min in 1.5 min chromatography, 5-95AB, C 10 H11 ClN 3 O[M+H] + MS ESI calculated 224.05, found 224.0.

[0355] A-70: To a mixture of 2-cyclopropyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (160 mg, 0.73 mmol), HATU (292.35 mg, 0.77 mmol), DIPEA (0.27 mL, 1.54 mmol) in DCM (8 mL), 1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (100 mg, 0.38 mmol) was added and the mixture was stirred at 15° C. for 2 h. The mixture was concentrated and purified by H 2 The mixture was diluted with 20 mL of EtOAc (10 mL) and then extracted with EtOAc (20 mL x 2). The organic layer was washed with brine (30 mL) and 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 59-89% B over 8 min) gave the product (140 mg, 322.6 μmol, 84% yield) as a solid. LCMS R t = 0.98 min in 1.5 min chromatography, 5-95AB, C 18 H 16 ClF 3 N 5 O 2 [M+H] + MS ESI calculated 426.19, found 426.1.

[0356] 64 and 65: Analytical SFC (column: REGIS (S,S) Whelk-O1 (100 mm × 4.6 mm inner diameter, 5.0 μm), mobile phase: A:CO 2, B: IPA (0.05% DEA), gradient: 5% to 40% B in 5.5 min, then 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C) showed two peaks at 3.78 and 4.30 min. The products were purified by SFC (Regis (S,S) Whelk-O1 (250 mm × 30 mm, 5 μm); A = CO 2 and B=IPA (0.1% DEA); 38° C.; 60 mL / min; 35% B; 9 min run; 8 injections, peak 1 Rt=4.7 min, peak 2 Rt=6.8 min) to give enantiomer 1 (Rt=3.78 min by analytical SFC) randomly assigned as (54.51 mg, 128 μmol, 39% yield) as a solid, and enantiomer 2 (Rt=4.30 min by analytical SFC) randomly assigned as (55.53 mg, 130.4 μmol, 39% yield) as a solid. 65: 1 H NMR (400 MHz, CDCl 3 ) δ H= 8.08(t,1H), 7.97(td,1H), 7.54-7.48(m,1H), 7.48-7.41(m,1H), 6.91(s,1H), 6.69(br d,1H), 5.63(quin,1H), 4.39(tt,1H), 1.79(d,3H), 1.40-1.28(m,2H), 1.16-1.05(m,2H). LCMS Rt=2.0 min, 10-80AB, C100 / AB, 100 / AB, 100 / AB, 100 / AB. 18 H 16 ClF 3 N 5 O 2 [M+H] + MS ESI calculated 426.09, found 426.0. 1 H NMR (400 MHz, CDCl 3 ) δ H= 8.08(t,1H), 7.97(td,1H), 7.54-7.49(m,1H), 7.47-7.41(m,1H), 6.91(s,1H), 6.70(br d,1H), 5.63(quin,1H), 4.39(tt,1H), 1.79(d,3H), 1.39-1.29(m,2H), 1.16-1.05(m,2H). LCMS Rt=2.0 min, 1.41 min, 10-80AB, C18 H 16 ClF 3 N 5 O 2 [M+H] + MS ESI calculated 426.09, found 426.0.

[0357] Synthesis of Example 43.66 [ka] A-72: A mixture of 1-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (0.79 g, 3.24 mmol) and CDI (0.58 g, 3.57 mmol) in DMF (10 mL) was stirred at 15° C. for 1 h, then 3-fluoro-N-hydroxy-benzamidine (0.5 g, 3.24 mmol) was added. The reaction mixture was then stirred at 100° C. for 16 h. After cooling to room temperature, the mixture was diluted with saturated NH 4 The mixture was diluted with Cl (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (50 mL) and Na 2 SO 4 The crude product was purified by flash column chromatography on silica gel (EtOAc in PE=0% to 20% to 50%) to give the product (260 mg, 0.66 mmol, 20% yield) as a solid. LCMS R t = 0.98 min in 1.5 min chromatography, 5-95AB, C 19 H 25 FN 3 O 3 [M+Ht-Bu] + MS ESI calculated value 306.2, found value 306.2.

[0358] A-73: To tert-butyl N-[1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]cyclohexyl]carbamate (260 mg, 0.72 mmol) was added 4M HCl in 1,4-dioxane (3 mL, 12 mmol) and the reaction mixture was stirred at 20° C. for 0.5 h. The mixture was concentrated to give the crude product (210 mg, 705.3 μmol, 98% yield) as a solid. LCMS R t = 0.71 min in 1.5 min chromatography, 5-95AB, C 14 H 17 FN 3 O[M+H] + MS ESI calculated 262.13, found 262.2.

[0359] 66: To a mixture of HATU (254.54 mg, 0.67 mmol), 5-cyclopropyl-2-methyl-pyrazole-3-carboxylic acid (55.62 mg, 0.33 mmol), 1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]cyclohexanamine hydrochloride (100 mg, 0.33 mmol) in DCM (8 mL), DIPEA (0.23 mL, 1.34 mmol) was added and the mixture was stirred at 25° C. for 3.5 h. 2 The mixture was diluted with 20 mL of 2H2O and extracted with EtOAc (15 mL x 2). The combined organic phase was washed with brine (20 mL) and 2 SO 4 The crude product was purified by preparative HPLC (Welch Xtimate C18 (150 mm x 25 mm, 5 μm), A = H 2 O(0.04% NH 4 OH + 10 mM NH 4 HCO 3 ) and B=CH 3 Purification by CN; 60-90% B over 7.5 min) afforded the product (26.87 mg, 65.6 μmol, 20% yield) as a solid. 1 H NMR (400MHz, DMSO-d 6 ) δ H=8.68(s,1H),7.85(d,1H),7.76-7.70(m,1H),7.67-7.58(m,1H),7.50-7.41(m,1H),6.73(s,1H),3.81(s,3H),2.33(br d,2H),2.15-2.01(m,2H),1.94-1.80(m,1H),1.74-1.51(m,5H),1.49-1.35(m,1H),0.93-0.83(m,2H),0.71-0.58(m,2H). LCMS R t = 1.32 min in 2.0 min chromatography, 10-80AB, C 22 H 25 FN 5 O 2 [M+H] + MS ESI calculated value 410.19, found value 410.0.

[0360] Synthesis of Example 44.67 [ka] A-75: A mixture of 3,4-difluorobenzonitrile (2 g, 14.38 mmol), hydroxylamine hydrochloride (3 g, 43.13 mmol), and NaOH (1.73 g, 43.13 mmol) in ethanol (24 mL) and water (8 mL) was stirred at 40° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the ethanol and then diluted with H 2 The mixture was diluted with 20 mL of EtOAc (30 mL×2). The combined organic phase was washed with brine (15 mL) and diluted with Na 2 SO 4 It was dried over water, filtered and concentrated to give the crude product (1.5 g, 7.20 mmol, 50% yield) as a solid. LCMS R t = 1.5 min of chromatography at 0.8 min, 5-95AB, C 7 H 7 F 2 N 2 O[M+H] + MS ESI calculated value 173.0, found value 173.0.

[0361] A-76: A mixture of 2-(tert-butoxycarbonylamino)propanoic acid (549.61 mg, 2.9 mmol) and CDI (518.11 mg, 3.2 mmol) in DMF (10 mL) was stirred at 15° C. for 1 h, then 3,4-difluoro-N′-hydroxy-benzamidine (500 mg, 2.9 mmol) was added. The reaction mixture was then stirred at 110° C. for 16 h. After cooling to room temperature, the mixture was treated with NH 4 The mixture was diluted with Cl (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL) and 2 SO 4 Drying over 100° C., filtration and concentration gave the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0% to 50%) to give the product (230 mg, 0.58 mmol, 20% yield) as an oil. LCMS R t = 2.0 min of chromatography at 0.94 min, 10-80AB, C 11 H 10 F 2 N 3 O 3 [M+H-tBu] + MS ESI calculated value 270.1, found value 270.0.

[0362] A-77: To tert-butyl N-[1-[3-(3,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (230 mg, 0.71 mmol) was added 4M HCl in 1,4-dioxane (6.91 mL, 27.63 mmol) and the reaction mixture was stirred at 25° C. for 16 h. The mixture was concentrated and diluted with H 2 Dilute with 20 mL of solid NaHCO 3 The pH was adjusted to pH 9 by adding 100 mL of 1,000 sucrose. The solution was extracted with EtOAc (20 mL x 3). The combined organic phase was concentrated to give the crude product (300 mg, 0.99 mmol) as a solid.

[0363] 67: A mixture of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (300 mg, 1.55 mmol), DIPEA (0.86 mL, 6.18 mmol), HOBt (417.69 mg, 3.09 mmol), and EDCI (592.55 mg, 3.09 mmol) in DCM (15 mL) was stirred at 25° C. for 30 min, then 1-[3-(3,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]ethanamine (348.03 mg, 1.55 mmol) was added and the mixture was stirred at 25° C. for 16 h. The reaction mixture was stirred at H 2 The combined organic phase was washed with brine (40 mL) and extracted with EtOAc (30 mL×3). 2 SO 4 The crude product was purified by preparative HPLC (column (Boston Prime C18 (150 mm x 30 mm, 5 μm), A = H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 63-75% B over 9 min) gave the product (15.72 mg, 39.2 μmol, 3% yield) as a solid. 1 H NMR (400MHz, DMSO-d 6 )δ=9.45(d,1H),8.12-7.94(m,1H),7.88(m,1H),7.72-7.60(m,1H),7.44(s,1H),5.45(quin,1H),4.13(s,3H),1.67(d,3H). LCMS R t = 2.0 min of chromatography at 1.32 min, 10-80AB, C 16 H 12 F 5 N 5 O 2 [M+H] + MS ESI calculated value 402.1, found value 402.0.

[0364] Synthesis of Example 45.68 [ka] A-79: A mixture of 5-methylpyridine-3-carbonitrile (1.9 g, 16.08 mmol), hydroxylamine hydrochloride (3.35 g, 48.25 mmol), and NaOH (1.93 g, 48.25 mmol) in ethanol (5 mL) and water (0.50 mL) was stirred at 40° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the EtOH, and then diluted with H 2 The mixture was diluted with 200 mL of EtOAc (40 mL). The mixture was extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine (30 mL) and diluted with Na 2 SO 4 The mixture was dried over hexane, filtered and concentrated to give the crude product (2.1 g, 12.79 mmol, 79% yield) as a solid. LCMS R t = 1.5 min of chromatography at 1.02 min, 5-95AB, C 7 H 9 N 3 O[M+H] + MS ESI calculated value 152.1, found value 152.0.

[0365] A-80: A mixture of 2-(tert-butoxycarbonylamino)propanoic acid (1251.64 mg, 6.62 mmol) and CDI (1179.9 mg, 7.28 mmol) in DMF (10 mL) was stirred at 15° C. for 1 h, then N′-hydroxy-5-methyl-pyridine-3-carboxamidine (1 g, 6.62 mmol) was added. The reaction mixture was stirred at 110° C. for 16 h. The mixture was subjected to H 2 The mixture was diluted with 200 mL of 2H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (30 mL) and 2 SO 4 The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 50%) to give the product (300 mg, 0.55 mmol, 8% yield) as a solid. LCMS R t = 2.0 min of chromatography at 0.79 min, 10-80AB, C 15 H 2 0N 4 O3 [M+H] + MS ESI calculated value 305.2, found value 304.9.

[0366] A-81: A mixture of tert-butyl N-[1-[3-(5-methyl-3-pyridyl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (300 mg, 0.99 mmol) and 4 M HCl in 1,4-dioxane (9.63 mL, 38.52 mmol) was stirred at 25° C. for 16 h. The mixture was concentrated and H 2 Dilute with 20 mL of NaHCO 3 The pH was adjusted to pH 9 by adding (solid). The mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was concentrated to give the crude product (150 mg, 0.11 mmol, 11% yield) as an oil. LCMS R t = 2.0 min of chromatography at 0.39 min, 10-80AB, C 10 H 13 N 4 O[M+H] + MS ESI calculated value 205.1, found value 204.9.

[0367] 68: To a solution of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (140 mg, 0.72 mmol) in DCM (20 mL) was added DIPEA (0.4 mL, 2.88 mmol), HOBt (194.92 mg, 1.44 mmol), and EDCI (276.52 mg, 1.44 mmol) and the mixture was stirred at 25° C. for 30 min. Then 1-[3-(5-methyl-3-pyridyl)-1,2,4-oxadiazol-5-yl]ethanamine (147.3 mg, 0.72 mmol) was added and the mixture was stirred at 25° C. for 16 h. The reaction mixture was stirred at H 2 The aqueous phase was washed with 20 mL of HO (20 mL), and then the aqueous phase was extracted with DCM (20 mL x 2). The combined organic phase was concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm x 30 mm, 5 μm), A = H 2 O(0.05% NH 4 OH) and B=CH 3Purification by CN; 17-47% B over 8 min) gave the product (91.9 mg, 0.24 mmol, 33% yield) as a solid. 1 H NMR (400MHz, DMSO-d 6 )δ=9.12(d,1H),8.59(d,1H),8.17(s,1H),6.94(s,1H),6.89(br d,1H),5.63(quin,1H),4.24(s,3H),2.44(s,3H),1.78(d,3H). LCMS R t = 2.0 min of chromatography at 1.02 min, 10-80AB, C 16 H 16 F 3 N 6 O 2 [M+H] + MS ESI calculated value 381.1, found value 380.9.

[0368] Synthesis of Examples 46.69 and 70 [ka] A-82b:CH 3 Cs in CN (15 mL) 2 CO 3 To a solution of 3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (500 mg, 2.4 mmol) was added ethyl 3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (1.57 g, 4.8 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (1.03 g, 4.8 mmol). The reaction mixture was stirred at 20° C. for 3 hours. The mixture was concentrated to give a residue. The residue was diluted with saturated NH 4 The mixture was diluted with Cl (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic phase was washed with water (30 mL) and brine (30 mL) and diluted with Na 2 SO 4 The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 15%) to give the product (400 mg, 1.44 mmol, 60% yield) as a solid. LCMS R t = 7.0 min of chromatography at 4.52 min, 0-60AB, C9 H 10 F 5 N 2 O 2 [M+H] + MS ESI calculated value 273.1, found value 272.9.

[0369] A-82: To a mixture of ethyl 2-(2,2-difluoroethyl)-5-(trifluoromethyl)pyrazole-3-carboxylate (400 mg, 1.47 mmol) in ethanol (5 mL) and water (5 mL), NaOH (117.57 mg, 2.94 mmol) was added and the mixture was stirred at 50° C. for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the ethanol and then diluted with H 2 The mixture was diluted with 2×10 mL of EtOAc (10 mL×2, discarded). The pH of the aqueous phase was adjusted to pH 2 with 1N HCl, then extracted with EtOAc (20 mL×2). The combined organic phase was diluted with 2×10 mL of EtOAc (10 mL×2, discarded). 2 20 mL) and brine (10 mL). 2 SO 4 It was dried over, filtered and concentrated to give the crude product (450 mg) as a solid. 1 H NMR (400MHz, DMSO-d 6 ) δ H =7.36(s,1H),6.62-6.31(m,1H),5.10(dt,2H).

[0370] A-83: To a mixture of 2-(2,2-difluoroethyl)-5-(trifluoromethyl)pyrazole-3-carboxylic acid (224.06 mg, 0.92 mmol), HATU (634.51 mg, 1.67 mmol), and DIPEA (0.44 mL, 2.5 mmol) in DMF (10 mL), 1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (200 mg, 0.83 mmol) was added and the mixture was stirred at 25 °C for 16 h. The reaction was quenched with saturated NH 4 The mixture was quenched with Cl (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (20 mL) and brine (20 mL) and diluted with Na 2 SO4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 57-77% B over 9 min) gave the product (140 mg, 0.32 mmol, 39% yield) as a solid. LCMS R t = 0.94 min in 1.5 min chromatography, 10-80AB, C 18 H 17 F 5 N 5 O 2 [M+H] + MS ESI calculated value 430.1, found value 430.2.

[0371] 69 and 70: The products were separated by SFC (Daicel CHIRALCEL OJ-3 (150 mm × 4.6 mm, 3 μm), mobile phase: A:CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5 min, 40% to 5% B in 0.5 min, hold 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C, ABPR: 1500 psi) showed two peaks at 2.18 and 2.59 min. The product was purified by SFC (Daicel CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); A = CO 2 and B = EtOH (0.1% NH 3 H 2 0; 38 °C; 60 mL / min; 15% B; 7 min run; 6 injections, peak 1 Rt = 4.55 min, peak 2 Rt = 5.55 min) to give enantiomer 1 (Rt = 2.18 min by analytical SFC) randomly assigned as 69 (37.48 mg, 87.3 mmol, 27% yield) as a solid, and enantiomer 2 (Rt = 2.59 min by analytical SFC) randomly assigned as 70 (48.34 mg, 112.6 mmol, 34% yield) as a solid. 1 H NMR (400MHz, DMSO-d 6 ) δ H=9.59(d,1H),7.85-7.75(m,2H),7.54(s,1H),7.48-7.38(m,2H),6.57-6.25(m,1H),5.46(quin,1H),5.10(dt,2H),2.39(s,3H),1.67(d,3H). LCMS R t = 1.38 min in 2.0 min chromatography, 10-80AB, C 18 H 17 F 5 N 5 O 2 [M+H] + MS ESI calculated value 430.1, found value 430.0. 1 H NMR (400MHz, DMSO-d 6 ) δ H =9.60(d,1H),7.86-7.77(m,2H),7.54(s,1H),7.49-7.39(m,2H),6.57-6.26(m,1H),5.47(quin,1H),5.10(dt,2H),2.40(s,3H),1.68(d,3H). LCMS R t = 1.37 min in 2.0 min chromatography, 10-80AB, C 18 H 17 F 5 N 5 O 2 [M+H] + MS ESI calculated value 430.1, found value 430.1.

[0372] Synthesis of Example 47.71 [ka] A-84: A mixture of 6-methylpyridine-2-carbonitrile (10 g, 84.65 mmol), hydroxylamine hydrochloride (17.65 g, 253.94 mmol), and NaOH (10.16 g, 253.94 mmol) in ethanol (24 mL) was stirred at 40° C. for 12 h. After cooling to room temperature, the mixture was concentrated to give a residue. The residue was purified by H 2 The mixture was diluted with 20 mL of EtOAc (30 mL×2). The combined organic phase was washed with brine (15 mL) and diluted with Na 2SO 4 The mixture was dried over ice, filtered and concentrated to give the crude product (8.2 g, 52.96 mmol, 62% yield) as a solid. LCMS Rt=1.5 min chromatography 0.153 min, 5-95AB, C 7 H 10 N 3 O[M+H] + MS ESI calculated 152.07, found 152.0.

[0373] A-85: A mixture of 2-(tert-butoxycarbonylamino)propanoic acid (3754.91 mg, 19.85 mmol) and CDI (3539.69 mg, 21.83 mmol) in DMF (30 mL) was stirred at 15° C. for 1 h. N-hydroxy-6-methyl-pyridine-2-carboxamidine (3 g, 19.85 mmol) was added and the reaction mixture was stirred at 110° C. for 16 h. The mixture was treated with NH 4 The mixture was diluted with Cl (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (15 mL) and 2 SO 4 The mixture was dried over ice, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%) to give the product (1800 mg, 3.82 mmol, 19% yield) as a solid. LCMS Rt = 1.5 min chromatography 0.805 min, 5-95AB, C 15 H 21 N 4 O 3 [M+H] + MS ESI calculated value 305.15, found value 305.2.

[0374] A-86: To tert-butyl-N-[1-[3-(6-methyl-2-pyridyl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (500 mg, 1.64 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (10 mL, 40 mmol) and the reaction mixture was incubated at 40 °C for 5 h under N 2After cooling to room temperature, the mixture was concentrated to give a residue. The residue was poured into ice water (20 mL) and added Na 2 CO 3 The pH of the mixture was adjusted to about pH 9 by adding (solid) and then extracted with EtOAc (20 mL x 2). The organic phase was washed with brine (50 mL) and anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated to give the crude product (300 mg, 0.78 mmol, 69% yield) as a solid. LCMS Rt=1.5 min chromatograph 0.278 min, 5-95AB, C 10 H 13 N 4 O[M+H] + MS ESI calculated value 205.1, found value 205.1.

[0375] 71: A mixture of 1-[3-(6-methyl-2-pyridyl)-1,2,4-oxadiazol-5-yl]ethanamine (200 mg, 0.98 mmol), HOBt (264.66 mg, 1.96 mmol), EDCI (375.46 mg, 1.96 mmol), DIPEA (0.54 mL, 3.92 mmol), and 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (190.09 mg, 0.98 mmol) in DCM (10 mL) was stirred at 25° C. for 16 h. The mixture was partially concentrated under reduced pressure to give a residue. The residue was purified by H 2 The mixture was diluted with 20 mL of 2H2O (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic phase was washed with water (20 mL) and brine (20 mL) and diluted with Na 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime (150 mm x 30 mm, 5 μm), A = H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 30-60% B over 9 min) gave the product (78.77 mg, 0.20 mmol, 21% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δH =7.94(d,1H),7.76(t,1H),7.33(d,1H),7.03-6.91(m,2H),5.73-5.57(m,1H),4.22(s,3H),2.68(s,3H),1.77(d,3H). LCMS R t = 2.0 min of chromatography at 1.16 min, 10-80AB, C 16 H 16 F 3 N 6 O 2 [M+H] + MS ESI calculated value 381.12, found value 381.1.

[0376] Synthesis of Example 48.72 [ka] A-90: To a solution of tert-butoxycarbonyl tert-butyl carbonate (2.02 g, 9.23 mmol) in THF (8 mL) was added 2-amino-3-methoxy-propanoic acid (1 g, 8.39 mmol) in THF (18 mL) and NaOH (671.59 mg, 16.79 mmol) in water (18 mL), and the mixture was stirred at 20° C. for 16 h. The mixture was partially concentrated to give a residue. The residue was purified by H 2 The mixture was diluted with 20 mL of HO (30 mL), extracted with EtOAc (30 mL x 2), and the organic phase was discarded. The aqueous phase was acidified with 10% aqueous acetic acid to pH 4, and the mixture was extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine (20 mL) and diluted with Na 2 SO 4 It was dried over, filtered and concentrated to give the product (1650 mg, 7.53 mmol, 89% yield) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H =8.05-7.75(m,1H),5.41(br s,1H),4.52-4.37(m,1H),3.86(br d,1H),3.63(dd,1H),3.38(d,3H),1.46(d,9H).

[0377] A-3: A mixture of 3-methylbenzonitrile (10 g, 85.36 mmol), hydroxylamine hydrochloride (17795.13 mg, 256.08 mmol), and NaOH (10.24 g, 256.08 mmol) in ethanol (12 mL) was stirred at 40° C. for 12 h. After cooling to room temperature, the reaction mixture was partially concentrated under reduced pressure to remove most of the EtOH, and then diluted with H 2 The mixture was diluted with 20 mL of EtOAc (30 mL×2). The combined organic phase was washed with brine (15 mL) and diluted with Na 2 SO 4 The mixture was dried over ice, filtered and concentrated to give the crude product (12500 mg, 66.38 mmol, 77% yield) as a solid. LCMS Rt=1.5 min chromatography 0.178 min, 5-95AB, C 8 H 11 N 2 O[M+H] + MS ESI calculated value 151.1, found value 151.1.

[0378] A-88: ​​A mixture of N-hydroxy-3-methyl-benzamidine (650.78 mg, 4.33 mmol) and CDI (772.92 mg, 4.77 mmol) in DMF (20 mL) was stirred at 15° C. for 1 h, then 2-(tert-butoxycarbonylamino)-3-methoxy-propanoic acid (950 mg, 4.33 mmol) was added. The reaction mixture was stirred at 110° C. for 16 h. The mixture was diluted with saturated NH 4 The mixture was diluted with Cl (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (15 mL) and 2 SO 4 The mixture was dried over ice, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%) to give the product (290 mg, 0.86 mmol, 20% yield) as a solid. LCMS Rt = 1.5 min chromatography 0.92 min, 5-95AB, C 17 H 24 N 3 O 4 [M+H-Boc]+ MS ESI calculated value 278.1, found value 334.2.

[0379] A-89: To tert-butyl-N-[2-methoxy-1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (290 mg, 0.87 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (10 mL, 40 mmol) and the mixture was incubated at 40 °C for 5 h under N 2 After cooling to room temperature, the mixture was concentrated under partial pressure to give a residue. The residue was poured into ice water (20 mL) and added Na 2 CO 3 The pH of the mixture was adjusted to about pH 9 with (solid) and then extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (50 mL) and anhydrous Na 2 SO 4 It was dried over hexane, filtered and concentrated to give the crude product (180 mg, 0.63 mmol, 69% yield) as a solid. LCMS R t = 0.678 min in 1.5 min chromatography, 5-95AB, C 12 H 16 N 3 O 2 [M+H] + MS ESI calculated value 234.1, found value 234.12.

[0380] 72: A mixture of 2-methoxy-1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine (180 mg, 0.77 mmol), HOBt (208.54 mg, 1.54 mmol), EDCI (295.85 mg, 1.54 mmol), DIPEA (0.43 mL, 3.09 mmol), and 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (149.78 mg, 0.77 mmol) in DCM (10 mL) was stirred at 25° C. for 16 h. The mixture was partially concentrated to give a residue. The residue was purified by HCl distillation. 2 The mixture was diluted with 20 mL of EtOAc (20 mL×2) and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (20 mL) and diluted with Na 2 SO4 The crude product was purified by preparative HPLC (Boston Prime (150 mm x 30 mm, 5 μm), A = H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 50-80% B over 9 min) gave the product (77.3 mg, 0.19 mmol, 24% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.91-7.85(m,2H),7.41-7.31(m,2H),7.05-7.00(m,1H),6.99(s,1H),5.70-5.64( m,1H),4.25(s,3H),4.09-4.03(m,1H),3.93-3.88(m,1H),3.41(s,3H),2.43(s,3H). LCMS R t = 1.33 min in 2.0 min chromatography, 10-80AB, C 18 H 19 F 3 N 5 O 3 [M+H] + MS ESI calculated value 410.2, found value 410.14.

[0381] Synthesis of Example 49.73 [ka] A-92: A solution of 2,2,2-trifluoroethanamine hydrochloride (414.34 mg, 30.58 mmol) in toluene (50 mL) was dissolved in NaNO in water (2.5 mL). 2 (2109.94 mg, 30.58 mmol) was added and the reaction mixture was stirred at 0° C. for 0.5 h. Ethyl prop-2-enoate (1000 mg, 10.19 mmol) was then added to the mixture and the mixture was stirred at 20° C. for 1 h. The mixture was then cooled to 5° C. for 1 h. 2 The mixture was diluted with 2×O (30 mL) and extracted with EtOAc (2×50 mL). The combined organic phase was washed with water (2×50 mL) and brine (60 mL) and diluted with Na 2 SO 4Drying over, filtration and concentration gave the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0% to 20%) to give the product (2000 mg, 9.61 mmol, 94% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =11.84(br s,1H),7.11(s,1H),4.45(q,2H),1.42(t,3H).

[0382] A-93: A solution of ethyl 3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (1000 mg, 4.8 mmol) in MeCN (20 mL) was treated with Cs 2 CO 3 (3130.59 mg, 9.61 mmol), followed by sodium 2-chloro-2,2-difluoro-acetate (1464.98 mg, 9.61 mmol) and 18-crown-6 (253.98 mg, 0.96 mmol) were added. The reaction mixture was stirred at 90 °C for 1.5 h under N 2 After cooling to room temperature, the mixture was stirred under H 2 The mixture was diluted with 200 mL of EtOAc (30 mL×2) and then extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (50 mL) and 2 SO 4 The mixture was dried over, filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0%-5%-10%) to give the product (100 mg, 387.4 μmol, 8.06% yield) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H =8.26-7.85(m,1H),7.21(s,1H),4.45(q,2H),1.43(t,3H).

[0383] A-94: To a solution of ethyl 2-(difluoromethyl)-5-(trifluoromethyl)pyrazole-3-carboxylate (70 mg, 0.27 mmol) in ethanol (3 mL) was added a solution of NaOH (32.54 mg, 0.81 mmol) in water (3 mL). The mixture was stirred at 20° C. for 2 h. The reaction mixture was quenched by adding 1N HCl (1 mL) and H 2 The mixture was diluted with 20 mL of 2H2O (10 mL) and extracted with EtOAc (15 mL x 2). The combined organic phase was washed with brine (20 mL) and 2 SO 4 Drying over, filtration and concentration gave the product (60 mg, 260.8 μmol, 96% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =8.21-7.81(m,1H),7.30(s,1H).

[0384] 73: To a mixture of 2-(difluoromethyl)-5-(trifluoromethyl)pyrazole-3-carboxylic acid (60 mg, 0.26 mmol), HATU (292.35 mg, 0.77 mmol), and DIPEA (0.27 mL, 1.54 mmol) in DCM (8 mL), 1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (100 mg, 0.38 mmol) was added and the mixture was stirred at 25° C. for 2 h. 2 The mixture was diluted with 20 mL of EtOAc (10 mL) and then extracted with EtOAc (20 mL x 2). The organic layer was washed with brine (30 mL) and 2 SO 4 Drying over, filtration and concentration gave the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0% to 24%) to give the product (26.79 mg, 61.5 μmol, 16% yield) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H=8.31-7.99(m,2H),7.99-7.95(m,1H),7.55-7.49(m,1H),7.48-7.42(m,1H),7.10(s,1H),6.95(br d,1H),5.62(quin,1H),1.80(d,3H). LCMS R t = 2.0 min of chromatography at 1.35 min, 10-80AB, C 16 H 12 ClF 5 N 5 O 2 [M+H] + MS ESI calculated value 436.1, found value 435.9.

[0385] Example 50. Synthesis of 74 and 75 [ka] A-96: A mixture of 2,4-dichlorobenzonitrile (3 g, 17.44 mmol), hydroxylamine hydrochloride (3.64 g, 52.32 mmol), and NaOH (2.09 g, 52.32 mmol) in ethanol (24 mL) and water (8 mL) was stirred at 40° C. for 16 h to give a suspension. After cooling to room temperature, the reaction mixture was partially concentrated under vacuum to remove most of the EtOH, then H 2 The mixture was diluted with 200 mL of EtOAc (50 mL×3). The mixture was extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried over hexane, filtered and concentrated to give the product (2 g, 7.72 mmol, 44% yield) as a solid. LCMS R t = 2.0 min of chromatography at 0.232 min, 10-80AB, C 7 H 7 Cl 2 N 2 O[M+H] + MS ESI calculated value 205.1, found value 204.8.

[0386] A-97: A mixture of 2-(tert-butoxycarbonylamino)propanoic acid (1.38 g, 7.32 mmol) and CDI (1.3 g, 8.05 mmol) in DMF (10 mL) was stirred at 15° C. for 1 h, then 2,4-difluoro-N′-hydroxy-benzamidine (1.5 g, 7.32 mmol) was added. The reaction mixture was then stirred at 110° C. for 16 h. After cooling to room temperature, the mixture was diluted with H 2 The mixture was diluted with 200 mL of 2H2O (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (40 mL) and 2 SO 4 The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10%) to give the product (600 mg, 1.62 mmol, 22% yield) as a solid. LCMS R t = 2.0 min of chromatography at 1.380 min, 10-80AB, C 11 H 9 Cl 2 N 3 O 3 [M+H-tBu] + MS ESI calculated value 302.0, found value 301.9.

[0387] A-98: To tert-butyl N-[1-[3-(2,4-dichlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (600 mg, 1.67 mmol) was added 4 M HCl in 1,4-dioxane (16.36 mL, 65.45 mmol) and the mixture was stirred at 25° C. for 16 h. The mixture was concentrated and diluted with H 2 Dilute with 20 mL of HO and adjust the pH to 10 with NaHCO 3 (solid) to adjust pH to about 9. The mixture was extracted with EtOAc (20 mL×3). The combined organic phase was concentrated to give the crude product (500 mg, 0.92 mmol, 55% yield) as an oil. LCMS R t = 2.0 min chromatography at 0.906 min, 10-80AB, C 10 H 10 Cl 2 N 3O[M+H-tBu] + MS ESI calculated value 258.0, found value 257.8.

[0388] A-99: To a mixture of 2-methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (280 mg, 1.44 mmol) in DCM (25 mL), DIPEA (0.8 mL, 5.77 mmol), HOBt (389.84 mg, 2.88 mmol), EDCI (553.05 mg, 2.88 mmol) were added and the mixture was stirred at 25° C. for 30 min. Then, 1-[3-(2,4-dichlorophenyl)-1,2,4-oxadiazol-5-yl]ethanamine (372.3 mg, 1.44 mmol) was added and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was stirred at H 2 The combined organic phase was washed with brine (30 mL) and the mixture was extracted with DCM (30 mL x 2). 2 SO 4 The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm), A=H 2 O(0.05% NH 4 OH) and B=CH 3 Purification by CN; 56-76% B over 9 min) gave the product (450 mg, 1.04 mmol, 72% yield) as an oil. LCMS R t = 2.0 min of chromatography at 1.318 min, 10-80AB, C16H13Cl2F3N5O2 [M+H] + MS ESI calculated value 434.0, found value 433.9.

[0389] 74 and 75: Analytical SFC (Daicel CHIRALCEL OJ-H (150 mm x 4.6 mm, 5 μm), mobile phase: A: CO 2B: ethanol (0.05% DEA), gradient: 5% to 40% B in 4.5 min, 40% for 5.5 min, then hold at 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 40 °C) showed two peaks at 2.94 min and 3.79 min. The products were purified by SFC (Daicel CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); A = CO 2 and B = EtOH (0.1% NH 3 H 2 0C; 38 °C; 60 mL / min; 25% B; 7.76 min run; 45 injections, peak 1 Rt = 4.39 min, peak 2 Rt = 5.76 min) to give enantiomer 1 (Rt = 2.943 min by analytical SFC) randomly assigned as 74 (176.6 mg, 0.41 mmol, 44% yield) as a solid, and enantiomer 2 (Rt = 3.79 min by analytical SFC) randomly assigned as 75 (211.15 mg, 0.49 mmol, 53% yield) as a solid. 1 H NMR (400MHz, DMSO-d 6 )δ=9.47(d,1H),7.96(d,1H),7.91(d,1H),7.66(dd,1H),7.45(s,1H),5.49(quin,1H),4.14(s,3H),1.68(d,3H). LCMS R t = 1.38 min in 2.0 min chromatography, 10-80AB, C 16 H 13 Cl 2 F 3 N 5 O 2 [M+H] + MS ESI calculated 434.0, found 434.0. 1 H NMR (400MHz, DMSO-d 6 )δ=9.46(d,1H),7.96(d,1H),7.91(d,1H),7.66(dd,1H),7.45(s,1H),5.49(quin,1H),4.14(s,3H),1.68(d,3H). LCMS R t = 1.38 min in 2.0 min chromatography, 10-80AB, C 16 H 13 Cl 2 F3 N 5 O 2 [M+H] + MS ESI calculated value 434.0, found value 434.0.

[0390] Example 51. Synthesis of 76 and 77 [ka] Analytical SFC (Daicel CHIRALCEL OJ-H (150mm x 4.6mm, 5μm), mobile phase: A:CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 4.5 min, 40% for 5.5 min, then hold at 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 40 °C) showed two peaks at 2.18 and 2.40 min. The products were purified by SFC (Daicel CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); A = CO 2 and B = EtOH (0.1% NH 3 H 2 0; 38 °C; 60 mL / min; 10% B; 8.74 min run; 120 injections, peak 1 Rt = 5.95 min, peak 2 Rt = 6.74 min) to give enantiomer 1 (Rt = 2.18 min by analytical SFC) randomly assigned as 76 (178.71 mg, 0.41 mmol) as a solid, and enantiomer 2 (Rt = 2.40 min by analytical SFC) randomly assigned as 77 (138.05 mg, 0.34 mmol, 37% yield). 1 H NMR (400MHz, DMSO-d 6 )400MHz δ=9.46(d,1H),8.05-7.96(m,1H),7.94-7.83(m,1H),7.74-7.59(m,1H),7.45(s,1H),5.46(quin,1H),4.14(s,3H),1.68(d,3H). LCMS R t = 1.33 min in 2.0 min chromatography, 10-80AB, C 16 H 13 F 5 N 5 O 2 [M+H]+ MS ESI calculated value 402.1, found value 402.0. 1 H NMR (400MHz, DMSO-d 6 )400MHz δ=9.46(d,1H),8.10-7.95(m,1H),7.93-7.82(m,1H),7.67(m,1H),7.45(s,1H),5.46(quin,1H),4.13(s,3H),1.68(d,3H). LCMS R t = 1.32 min in 2.0 min chromatography, 10-80AB, C 16 H 13 F 5 N 5 O 2 [M+H] + MS ESI calculated value 402.1, found value 402.0.

[0391] Examples 52. Synthesis of 78 and 79 [ka] Analytical SFC (Regis(S,S)Whelk-O1 (100mm x 4.6mm inner diameter, 5.0μm), mobile phase: A:CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5.5 min, 40% for 3 min, then hold at 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C) showed two peaks at 3.78 and 4.09 min. The product was purified by SFC (Regis (S,S) Whelk-O1 (250 mm × 30 mm, 5 μm); A = CO 2 and B=i-PrOH (0.1% DEA); 38 °C; 60 mL / min; 35% B; 9 min run; 6 injections, peak 1 Rt=6.3 min, peak 2 Rt=7.3 min) to give enantiomer 1 (Rt=3.78 min by analytical SFC) randomly assigned as 78 (35.11 mg, 92.3 μmol, 41% yield) as an oil, and enantiomer 2 (Rt=4.09 min by analytical SFC) randomly assigned as 79 (28.13 mg, 74 μmol, 33% yield) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δH= 9.13(s,1H),8.60(s,1H),8.22(s,1H),6.96(s,1H),6.90(br d,1H),5.68-5.57(m,1H),4.24(s,3H),2.46(s,3H),1.79(d,3H). LCMS R t = 2.0 min of chromatography at 1.05 min, 10-80AB, C 16 H 16 F 3 N 6 O 2 [M+H] + MS ESI calculated 381.12, found 381.1. 1 H NMR (400 MHz, CDCl 3 ) δ H =9.13(s,1H),8.64-8.54(m,1H),8.23-8.16(m,1H),6.95(s,1H),6.85- 6.75(m,1H),5.69-5.55(m,1H),4.24(s,3H),2.46(s,3H),1.79(d,3H). LCMS R t = 2.0 min of chromatography at 1.05 min, 10-80AB, C 16 H 16 F 3 N 6 O 2 [M+H] + MS ESI calculated value 381.12, found value 381.1.

[0392] Example 53. Synthesis of 80 and 81 [ka] Analytical SFC (Daicel CHIRALPAK IC-3 (150mm x 4.6mm inner diameter, 3μm), mobile phase: A:CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5 min, 40% for 2.5 min, then hold at 5% B for 2.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C, ABPR: 1500 psi) showed two peaks at 2.00 and 2.57 min. The products were analyzed by SFC (Daicel CHIRALPAK IC (250 mm × 30 mm, 5 μm); A = CO 2and B = EtOH (0.1% NH 3 H 2 0; 38 °C; 60 mL / min; 15% B; 7 min run; 6 injections, peak 1 Rt = 4.4 min, peak 2 Rt = 5.5 min) to give enantiomer 1 (Rt = 2.00 min by analytical SFC) randomly assigned as 80 (18.41 mg, 45.0 μmol, 26% yield) as an oil, and enantiomer 2 (Rt = 2.57 min by analytical SFC) randomly assigned as 81 (19.73 mg, 48.2 μmol, 28% yield) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.92-7.85(m,2H),7.40-7.31(m,2H),7.07-6.97(m,2H),5.70-5.64(m, 1H),4.25(s,3H),4.06(dd,1H),3.90(dd,1H),3.41(s,3H),2.43(s,3H). LCMS R t = 1.31 min in 2.0 min chromatography, 10-80AB, C 18 H 19 F 3 N 5 O 3 [M+H] + MS ESI calculated value 410.1, found value 410.1. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.92-7.85(m,2H),7.40-7.32(m,2H),7.06-6.98(m,2H),5.70-5.65(m, 1H),4.25(s,3H),4.06(dd,1H),3.90(dd,1H),3.41(s,3H),2.43(s,3H). LCMS R t = 1.31 min in 2.0 min chromatography, 10-80AB, C 18 H 19 F 3 N 5 O 3 [M+H] + MS ESI calculated value 410.1, found value 410.1.

[0393] Example 54. Synthesis of 82 and 83 [ka] Analytical SFC (Daicel CHIRALCEL OJ-3 (150mm x 4.6mm, 3μm), mobile phase: A:CO 2 B: Methanol (0.05% DEA), gradient: 5% to 40% B in 5 min, 40% to 5% B in 0.5 min, hold 5% for 1.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C) showed two peaks at 2.16 and 2.44 min. The product was purified by SFC (Regis (S,S) Whelk-O1 (250 mm × 30 mm, 5 μm); A = CO 2 and B=IPA (0.1% DEA); 38 °C; 60 mL / min; 35% B; 8 min run; 5 injections, peak 1 Rt=4.6 min, peak 2 Rt=5.8 min) to give enantiomer 1 (Rt=2.16 min by analytical SFC) randomly assigned as 82 (3.68 mg, 8.4 μmol, 14% yield) as an oil, and enantiomer 2 (Rt=2.44 min by analytical SFC) randomly assigned as 83 (7.25 mg, 16.6 μmol, 27% yield) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H= 8.31-7.99(m,2H),7.99-7.94(m,1H),7.54-7.50(m,1H),7.46(d,1H),7.10(s,1H),6.99-6.91(m,1H),5.68-5.57(m,1H),1.80(d,3H). LCMS R t = 1.39 min in 2.0 min chromatography, 10-80AB, C 16 H 12 ClF 5 N 5 O 2 [M+H] + MS ESI calculated 436.05, found 436.0. 1 H NMR (400 MHz, CDCl 3 ) δ H=8.30-7.99(m,2H),7.99-7.95(m,1H),7.54-7.49(m,1H),7.48-7.42(m,1 H),7.09(s,1H),6.96-6.88(m,1H),5.68-5.57(m,1H),1.82-1.78(m,3H). LCMS R t = 1.37 min in 2.0 min chromatography, 10-80AB, C 16 H 12 ClF 5 N 5 O 2 [M+H] + MS ESI calculated value 436.05, found value 436.1.

[0394] Synthesis of Example 55.84 [ka] A-101: A mixture of hydroxylamine hydrochloride (3.53 g, 50.79 mmol), 2-methylpyridine-4-carbonitrile (2 g, 16.93 mmol), and NaOH (2.03 g, 50.79 mmol) in ethanol (24 mL) was stirred at 40° C. for 16 h. After cooling to room temperature, the reaction mixture was concentrated under vacuum to remove most of the EtOH, and then diluted with H 2 The mixture was extracted with EtOAc (30 mL×2) and the combined organic phase was washed with brine (20 mL) and diluted with Na 2 SO 4 It was dried over hexane, filtered and concentrated to give the crude product (1.45 g, 9.59 mmol, 56% yield) as a solid. LCMS R t = 0.11 min in 1.5 min chromatography, 5-95AB, C 7 H 10 N 3 O[M+H] + MS ESI calculated value 152.1, found value 152.0.

[0395] A-102: A mixture of 2-(tert-butoxycarbonylamino)propanoic acid (1.22 g, 6.48 mmol) and CDI (1.16 g, 7.13 mmol) in DMF (20 mL) was stirred at 25° C. for 1 h, and then N′-hydroxy-2-methyl-pyridine-4-carboxamidine (980 mg, 6.48 mmol) was added. The reaction mixture was then stirred at 70° C. for 16 h. After cooling to room temperature, the mixture was diluted with NaCl (30 mL) and the mixture was extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine (30 mL) and Na 2 SO 4 The crude product was purified by column flash chromatography on silica gel (EtOAc in PE=0%-20%-50%) to give the product (220 mg, 0.66 mmol, 10% yield) as an oil. LCMS R t = 0.70 min in 1.5 min chromatography, 5-95AB, C 15 H 21 N 4 O 3 [M+H] + MS ESI calculated value 305.2, found value 305.7.

[0396] A-103: To a mixture of tert-butyl N-[1-[3-(2-methyl-4-pyridyl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (220 mg, 0.72 mmol) in ethyl acetate (3 mL), ethyl acetate / HCl (15 mL, 60 mmol) was added and stirred at 25° C. for 3 h. The reaction mixture was concentrated to give the crude product (180 mg, 0.74 mmol) as a solid. LCMS R t = 0.12 min in 1.5 min chromatography, 5-95AB, C 10 H 13 N 4 O[M+H] + MS ESI calculated value 205.1, measured value 205.2.

[0397] 84: 2-Methyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (77.58 mg, 0.4 mmol), HOBt (120.01 mg, 0.89 mmol), Et 3 A mixture of N (0.31 mL, 2.22 mmol) and EDCI (127.69 mg, 0.67 mmol) was stirred for 1 h at 25° C. Then 1-(3-(2-methylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)ethanamine hydrochloride (100 mg, 0.44 mmol) was added to the mixture and stirred for 16 h at 25° C. The reaction mixture was diluted with saturated NH 4 The mixture was quenched with Cl (20 mL) and extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (20 mL) and diluted with Na 2 SO 4 Drying over, filtration and concentration gave the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0-10%-25%-50%) to give the product (63.51 mg, 0.17 mmol, 38% yield) as a solid. 1 H NMR (400MHz, CD 3 CN)δ H =8.67(d,1H),7.81(s,1H),7.74(d,1H),6.95(s,1H),6.75(d,1H),5.62(q,1H),4.24(s,3H),2.67(s,3H),1.79(d,3H). LCMS R t = 0.90 min, 10-80AB, C at 2.0 min chromatography 16 H 16 F 3 N 6 O 2 [M+H] + MS ESI calculated value 381.1, found value 380.9.

[0398] Synthesis of Example 56.85 [ka] A-105: A mixture of hydroxylamine hydrochloride (0.54 g, 7.8 mmol), benzene-1,3-dicarbonitrile (1 g, 7.8 mmol), and NaOH (0.31 g, 7.8 mmol) in ethanol (20 mL) was stirred at 40° C. for 16 h. After cooling to room temperature, the reaction mixture was partially concentrated under reduced pressure to remove most of the EtOH, and then diluted with H 2 The mixture was diluted with 20 mL of EtOAc (30 mL×3). The combined organic phase was washed with brine (30 mL) and diluted with Na 2 SO 4 It was dried over hexane, filtered and concentrated to give the crude product (1.4 g, 6.06 mmol, 77% yield) as a solid. LCMS R t = 1.5 min of chromatography at 0.14 min, 5-95AB, C 8 H 8 N 3 O[M+H] + MS ESI calculated 162.1, found 162.0.

[0399] A-106: A mixture of (2S)-2-(tert-butoxycarbonylamino)propanoic acid (821.84 mg, 4.34 mmol) and CDI (774.73 mg, 4.78 mmol) in DMF (15 mL) was stirred at 25° C. for 1 h, then 3-cyano-N′-hydroxy-benzamidine (700 mg, 4.34 mmol) was added. The reaction mixture was then stirred at 70° C. for 16 h. After cooling to room temperature, the mixture was diluted with water (60 mL) and extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (30 mL) and diluted with Na 2 SO 4 Drying over 100° C., filtration and concentration gave the crude product. The crude product was purified by flash column chromatography on silica gel (EtOAc in PE=0% to 30%) to give the product (400 mg, 0.77 mmol) as a solid. LCMS R t = 2.0 min of chromatography at 1.15 min, 10-80AB, C 12 H 10 N 4 O 3 [M+H-tBu]+ MS ESI calculated value 259.1, found value 258.9.

[0400] A-107: A mixture of tert-butyl N-[(1S)-1-[3-(3-cyanophenyl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (400 mg, 1.27 mmol) and 4 M HCl in 1,4-dioxane (15 mL, 60 mmol) was stirred at 25° C. for 16 h. The mixture was concentrated and H 2 Dilute with 20 mL of NaHCO 3 The mixture was basified with (solid) to pH 8. The mixture was extracted with EtOAc (30 mL x 3) and the combined organic phase was washed with brine (30 mL) and Na 2 SO 4 It was dried over, filtered and concentrated to give the crude product (410 mg, 1.60 mmol, 29% yield) as an oil.

[0401] 85: To a mixture of 1-isopropyl-3-methyl-pyrazole-4-carboxylic acid (100 mg, 0.59 mmol) in DCM (10 mL) was added HOBt (160 mg, 1.19 mmol), EDCI (228 mg, 1.19 mmol), DIPEA (0.33 mL, 2.38 mmol), and 3-[5-[(1S)-1-aminoethyl]-1,2,4-oxadiazol-3-yl]benzonitrile (152.84 mg, 0.71 mmol) and the mixture was stirred at 25 °C for 16 h. The reaction was analyzed by H 2 The mixture was quenched with O (10 mL) and then extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (30 mL) and diluted with Na 2 SO 4 Drying over, filtration and concentration gave the crude product, which was purified using flash chromatography on silica gel (EtOAc in PE=0% to 20%) to give the product (66 mg, 0.18 mmol, 30% yield) as a solid. 1 H NMR (400 MHz, CDCl 3)δ=8.40(s,1H),8.34(d,1H),7.86(s,1H),7.82(d,1H),7.64(t,1H),6.27(br d,1H),5.70-5.57(m,1H),4.53-4.40(m,1H),2.56(s,3H),1.76(d,3H),1.54(d,6H). LCMS R t = 2.0 min of chromatography at 1.10 min, 10-80AB, C 19 H 20 N 6 O 2 [M+H] + MS ESI calculated value 365.2, found value 365.2.

[0402] Synthesis of Example 57.86 [ka] A-109: A mixture of 4-chloro-3-fluoro-benzonitrile (1 g, 6.43 mmol), hydroxylamine hydrochloride (1.34 g, 19.29 mmol), NaOH (0.77 g, 19.29 mmol) in ethanol (24 mL) and water (8 mL) was stirred at 40° C. for 12 h. After cooling to room temperature, the mixture was partially concentrated under reduced pressure to give a residue. The residue was purified by H 2 The mixture was diluted with 20 mL of 2H2O and extracted with EtOAc (30 mL x 2). The combined organic phase was washed with brine (15 mL) and 2 SO 4 The mixture was dried over ice, filtered and concentrated to give the crude product (1 g, 2.74 mmol, 43% yield) as a solid. LCMS Rt=1.5 min. Chromatography 0.33 min, 5-95AB, C 7 H 7 ClFN 2 O[M+H] + MS ESI calculated 189.02, found 188.7.

[0403] A-110: A mixture of 4-chloro-3-fluoro-N-hydroxy-benzamidine (1 g, 5.3 mmol) and CDI (945.78 mg, 5.83 mmol) in DMF (30 mL) was stirred at 25° C. for 1 h, followed by the addition of (2S)-2-(tert-butoxycarbonylamino)propanoic acid (1 g, 5.3 mmol). The reaction mixture was then stirred at 80° C. for 16 h. After cooling to room temperature, the mixture was treated with NH 4 The mixture was diluted with Cl (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (15 mL) and 2 SO 4 The mixture was dried over ice, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%) to give the product (350 mg, 0.99 mmol, 19% yield) as a solid. LCMS Rt = 1.5 min chromatography 0.96 min, 5-95AB, C 15 H 18 ClFN 3 O 3 [M+H-BOC] + MS ESI calculated 286.09, found 286.1.

[0404] A-111: To tert-butyl N-[(1S)-1-[3-(4-chloro-3-fluoro-phenyl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (350 mg, 1.02 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (10 mL, 40 mmol) and the reaction mixture was incubated at 30 °C for 5 h under N 2 After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue. The residue was poured into ice water (20 mL) and the mixture was diluted with Na 2 CO 3 (solid) to pH 9, extracted with EtOAc (20 mL x 2), the organic phase washed with brine (20 mL), and anhydrous Na 2 SO 4The mixture was dried over ice, filtered and concentrated to give the crude product (250 mg, 0.99 mmol, 69% yield) as an oil. LCMS Rt=1.5 min. Chromatography 0.68 min., 5-95AB, C 10 H 10 ClFN 3 O[M+H] + MS ESI calculated value 242.04, found value 241.8.

[0405] 86: A mixture of 1-isopropyl-3-methyl-pyrazole-4-carboxylic acid (100 mg, 0.59 mmol), HOBt (160.69 mg, 1.19 mmol), EDCI (227.96 mg, 1.19 mmol), DIPEA (0.33 mL, 2.38 mmol), and (1S)-1-[3-(4-chloro-3-fluoro-phenyl)-1,2,4-oxadiazol-5-yl]ethanamine (172.41 mg, 0.71 mmol) in DCM (10 mL) was stirred at 25° C. for 16 h. The mixture was concentrated to give a residue. The residue was purified by H 2 The mixture was diluted with 20 mL of 2H2O (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic phase was washed with water (20 mL) and brine (20 mL) and diluted with Na 2 SO 4 It was dried over, filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0% to 50%) to give the product.

[0406] Analytical SFC (Regis(S,S)Whelk-01 (100mm x 4.6mm inner diameter, 5.0μm), mobile phase: A:CO 2 B: ethanol (0.05% DEA), gradient: 5% to 40% B in 5.5 min, 40% for 3 min, then hold at 5% B for 1.5 min, flow rate: 2.5 mL / min) showed two peaks at 4.41 min (12.4%) and 5.48 min (87.6%). The product was purified by SFC (Regis(S,S)Whelk-O1 (250 mm × 30 mm, 5 μm); A = CO 2 and B = EtOH (0.1% NH 3 H 20; 38 °C; 60 mL / min; 40% B; 10 min run; 5 injections, peak 1 Rt = 5.6 min, peak 2 Rt = 8.2 min) to give the product (100.73 mg, 0.26 mmol, 43% yield) as a solid (analytical SFC Rt = 5.48 min). 1 H NMR (400 MHz, CDCl 3 ) δ H = 7.91-7.80 (m, 3H), 7.53 (t, 1H), 6.26 (br d, 1H), 5.74-5.53 (m, 1H), 4.52-4.38 (m, 1H), 2.54 (s, 3H), 1.74 (d, 3H), 1.52 (d, 6H). LCMS Rt = 2.0 min chromatography at 1.18 min, 10-80AB, C 18 H 20 ClFN 5 O 2 [M+H] + MS ESI calculated value 392.12, found value 391.9.

[0407] Synthesis of Example 58.87 [ka] A-113: To a mixture of 3,4-difluorobenzonitrile (2 g, 14.38 mmol) and hydroxylamine hydrochloride (3 g, 43.13 mmol) in ethanol (24 mL) was added NaOH (1.73 g, 43.13 mmol). The mixture was stirred at 40° C. for 16 h. The mixture was subjected to H 2 The mixture was diluted with 20 mL of 2H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic phase was washed with brine (20 mL) and 2 SO 4 It was dried over water, filtered and concentrated to give the crude product (3 g, 16.11 mmol) as a solid. LCMS R t = 0.13 min in 1.5 min chromatography, 5-95AB, C 7 H 7 F 2 N 2 O[M+H] + MS ESI calculated value 173.0, found value 173.1.

[0408] A-114: A mixture of (2S)-2-(tert-butoxycarbonylamino)propanoic acid (1099.23 mg, 5.81 mmol) and CDI (1036.22 mg, 6.39 mmol) in DMF (15 mL) was stirred at 25° C. for 1 h, then 3,4-difluoro-N′-hydroxy-benzamidine (1000 mg, 5.81 mmol) was added. The reaction mixture was then stirred at 70° C. for 16 h. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (30 mL) and diluted with NaCl. 2 SO 4 Drying over, filtration and concentration gave the crude product, which was purified by flash column chromatography on silica gel (EtOAc in PE=0% to 20%) to give the product (700 mg, 2.15 mmol, 37% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H =7.96-7.88(m,1H),7.88-7.83(m,1H),7.32-7.28(m,1H),5.16(s,2H),1.63(d,3H),1.47(s,9H).

[0409] A-115: A colorless mixture of tert-butyl N-[(1S)-1-[3-(3,5-difluorophenyl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (700 mg, 2.15 mmol) and HCl / EtOAc (10 mL, 4 M) was stirred at 25° C. for 6 h. The mixture was concentrated to give the crude product as a solid, which was used directly without further purification. LCMS R t = 0.61 min in 2 min chromatography, 10-80AB, C 10 H 10 F 2 N 3 O[M+H] + MS ESI calculated value 226.1, found value 225.8.

[0410] 87: To a mixture of 1-isopropyl-3-methyl-pyrazole-4-carboxylic acid (100 mg, 0.59 mmol) in DCM (15 mL) was added HOBt (160.69 mg, 1.19 mmol), EDCI (227.96 mg, 1.19 mmol), DIPEA (0.33 mL, 2.38 mmol), and (1S)-1-[3-(3,5-difluorophenyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (171.13 mg, 0.65 mmol) and the mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with saturated NH 4 The mixture was quenched with Cl (15 mL) and then extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (30 mL) and diluted with Na 2 SO 4 The mixture was dried over 100° C., filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0%-30%-50%) to give the impure product, which was purified by preparative TLC (silica gel, PE:EtOAc=5:2) to give the product. The product was triturated from DCM (1 mL) and n-hexane (5 mL) to give the product (160.64 mg, 0.43 mmol, 72% yield) as a solid. 1 H NMR (400MHz, DMSO-d 6 ) δ H =8.55(d,1H),8.27(s,1H),8.02-7.94(m,1H),7.90-7.83(m,1H),7.70-7.60(m,1 H),5.41-5.30(m,1H),4.48-4.33(m,1H),2.29(s,3H),1.61(d,3H),1.40(d,6H). LCMS R t = 1.13 min in 2 min chromatography, 10-80AB, C 18 H 20 F 2 N 5 O 2 [M+H] + MS ESI calculated value 376.2, found value 376.0.

[0411] Synthesis of Example 59.88 [ka] A-117: A mixture of 3-chloro-4-fluoro-benzonitrile (1 g, 6.43 mmol), hydroxylamine hydrochloride (1.34 g, 19.29 mmol), NaOH (0.77 g, 19.29 mmol) in ethanol (24 mL) and water (8 mL) was stirred at 40° C. for 12 h. After cooling to room temperature, the mixture was partially concentrated under reduced pressure to give a residue, which was then purified by H 2 The mixture was diluted with 20 mL of EtOAc (30 mL×2). The combined organic phase was washed with brine (15 mL) and diluted with Na 2 SO 4 The mixture was dried over ice, filtered and concentrated to give the crude product (1 g, 3.35 mmol, 52% yield) as a solid. LCMS Rt=1.5 min chromatography 0.29 min, 5-95AB, C 7 H 7 ClFN 2 O[M+H] + MS ESI calculated value 189.0, found value 188.8.

[0412] A-118: A mixture of 3-chloro-4-fluoro-N-hydroxy-benzamidine (1 g, 5.3 mmol) and CDI (945.78 mg, 5.83 mmol) in DMF (15 mL) was stirred at 25° C. for 1 h, followed by the addition of (2S)-2-(tert-butoxycarbonylamino)propanoic acid (1 g, 5.3 mmol). The reaction mixture was then stirred at 70° C. for 16 h. After cooling to room temperature, the mixture was treated with NH 4 The mixture was diluted with Cl (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (15 mL) and 2 SO 4 The mixture was dried over ice, filtered and concentrated to give the crude product...

Claims

1. Compounds of Formula I: 【Chemistry 295】 or a pharma- ceutically acceptable salt thereof, X, Y, Z, Y′, and Z′ are each independently selected from CH and N, and the hydrogen of CH is R ５ wherein at least three selected from X, Y, Z, Y', and Z' are CH; R １ But, C １－６ Alkyl, C ３－１０ is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, or phenyl is selected from the group consisting of halogen, C(O)N(R ９ ) ２ , N(R ９ ) ２ , C ３－７ Cycloalkyl, phenyl, 3- to 10-membered heteroaryl, and C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy; R １２ But, C １－６ Alkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, or phenyl is selected from the group consisting of halogen, —OH, —CN, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy; Two R on adjacent carbons １２ But, R １２ may be taken together with the two carbons to which they are attached to form a carbocyclic ring, x is 0, 1, or 2; R ２ is hydrogen or C １－４ is alkyl, R ３ is hydrogen, C １－６ Alkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; R ４ But, C １－６ alkyl and hydrogen, or R ３ and R ４ But, R ３ and R ４ Together with the carbon bonded to C ３－７ cycloalkylene or 3- to 7-membered heterocyclene, １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, phenyl, C ３－７ Cycloalkylene or 3- to 7-membered heterocyclene is one or more R ７ may be optionally substituted with Each R ５ But halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkylene-N(R ９ ) ２ , C １－６ Alkylene -O-C ３－１０ Cycloalkyl, C １－６ Alkoxy, C optionally substituted with one or more halogens ３－１０ Cycloalkyl-substituted C １－６ Alkoxy, C １－６ Haloalkoxy, one or more halogens or C １－６ 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, optionally substituted with alkoxy; １－６ Alkylene-OH,C １－６ Alkylene-C １－６ Alkoxy, OH, N(R ９ ) ２ , -C(O)OR ８ , C(O)N(R ９ ) ２ , C １－６ Alkylene -CN, -CN, -S(O) ２ -C １－６ Alkyl, C １－６ Alkylene-S(O) ２ -C １－６ Alkyl, -S(O) ２ -N(R ９ ) ２ , -OC(O)C １－６ Alkyl, one or more halogens or C １－６ -O-C optionally substituted with alkyl ３－１０ Cycloalkyl, and halogen, C １－６ Alkyl, and C １－６ C optionally substituted with one or more substituents selected from alkoxy ３－１０ cycloalkyl; n is selected from the group consisting of 0, 1, 2, and 3; R ７ But phenyl, C １－６ Alkoxy, -OH, -N(R ９ ) ２ , -NR ９ -SO ２ -C １－６ Alkyl, —O—(C １－６ alkylene)-phenyl, C ３－１０ Cycloalkyl, -C(O)OR ８ , -C(O)N(R ９ ) ２ , -NR １０ C(O)-R １１ , -CN, -S(O) ２ -C １－６ Alkyl, -S(O) ２ -N(R ９ ) ２ , 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl; ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, or 3- to 10-membered heteroaryl is C １－６ Alkyl, halogen, -OH, C １－６ Alkoxy, and -N(R ９ ) ２ and optionally substituted with one or more substituents each independently selected from the group consisting of: R ８ is hydrogen or C １－６ is alkyl, Each R ９ is hydrogen, C １－６ Alkyl, and -(C １－６ or two R ９ The two R ９ together with said nitrogen atom bound to Each R １０ are independently hydrogen or C １－６ is alkyl, R １１ But, C １－６ Alkyl, C １－６ Alkoxy, and —O—(C １－６ (alkylene)-phenyl; R ３ and R ４ are both hydrogen, then at least one selected from X, Y, Z, Y', and Z' is N, or a pharma- ceutically acceptable salt thereof; and a pharma- ceutically acceptable excipient.

2. 2. The pharmaceutical composition of claim 1, wherein one of X, Y, Z, Y', and Z' is N and the other four are CH.

3. The compound is a compound of formula Ia: 【Chemical 296】 Compound of formula I-b: 【Chemical 297】 Compound of formula I-c: 【Chemical 298】 Compound of formula I-d: 【Chemical 299】 Compound of formula Ie: 【Chemistry 300】 Compound of formula If: 【Chemistry 301】 Compound of formula I-g: 【Chemistry 302】 Compound of formula I-h: 【Chemistry 303】 Compound of formula I-i: 【Chemistry 304】 Compound of formula Ij: 【Chemistry 305】 Compound of formula Ik: 【Chemistry 306】 Compound of formula I-l: 【Chemistry 307】 Compound of formula Im: 【Chemistry 308】 Compound of formula In: 【Chemistry 309】 Compound of formula I-o: 【Chemistry 310】 Compound of formula Ip: 【Chemistry 311】 Compound of formula Iq: 【Chemistry 312】 Compound of formula I-r: 【Chemistry 313】 or Compound of formula Is: 【Chemistry 314】 or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

4. R ２ The pharmaceutical composition of any one of claims 1 to 3, wherein is hydrogen or methyl.

5. R ３ is hydrogen, C １－６ Alkyl or C １－６ Alkoxy-substituted C １－６ Alkyl, -OH, or -C(O)OR ８ The pharmaceutical composition according to any one of claims 1 to 4,

6. R ３ The pharmaceutical composition of any one of claims 1 to 5, wherein is methyl.

7. R ４ The pharmaceutical composition of any one of claims 1 to 6, wherein is hydrogen.

8. Each R ５ But halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ３－１０ Cycloalkyl, O-C ３－１０ Cycloalkyl, —OH, —CN, N(R ９ ) ２ and -C(O)OR ８ The pharmaceutical composition of any one of claims 1 to 7, independently selected from the group consisting of:

9. Each R ５ But, C １－６ Haloalkyl and C １－６ The pharmaceutical composition of any one of claims 1 to 8, wherein said at least one radical is independently selected from alkoxy.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein n is 1 or 2.

11. R １ But, C １－６ Alkoxy, N(R ９ ) ２ , C(O)N(R ９ ) ２ , C ３－７ C optionally substituted with cycloalkyl, pyridyl, tetrahydropyranyl, or phenyl １－６ Alkyl; C １－６ Haloalkyl; C ３－７ The pharmaceutical composition of any one of claims 1 to 10, wherein the aryl group is selected from the group consisting of cycloalkyl; phenyl optionally substituted with halogen; and pyridyl optionally substituted with halogen.

12. R １ But, C １－６ Alkyl and C １－６ The pharmaceutical composition of any one of claims 1 to 11, wherein the aryl group is selected from the group consisting of haloalkyl.

13. R １２ But, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ The pharmaceutical composition of any one of claims 1 to 12, wherein the aryl group is selected from the group consisting of cycloalkyl, and phenyl optionally substituted with halogen.

14. R １２ But -CF ３ and -CHF ２ The pharmaceutical composition according to any one of claims 1 to 13, which is selected from the group consisting of:

15. The pharmaceutical composition of any one of claims 1 to 14, wherein x is 1 or 2.

16. Compound of Formula II: 【Chemistry 315】 or a pharma- ceutically acceptable salt thereof, One or two selected from X, Y, Z, Y′, and Z′ are N, the others are CH, and the hydrogen of CH is R ５ may be substituted with R １ But, C １－６ Alkyl, C ３－１０ is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, or phenyl is selected from the group consisting of halogen, C(O)N(R ９ ) ２ , N(R ９ ) ２ , C ３－７ Cycloalkyl, phenyl, 3- to 10-membered heteroaryl, and C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy; R １２ But, C １－６ Alkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, or phenyl is selected from the group consisting of halogen, —OH, —CN, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy; Two R on adjacent carbons １２ But, R １２ may be taken together with the two carbons to which they are attached to form a carbocyclic ring, x is 0, 1, or 2; R ２ is hydrogen or C １－４ is alkyl, R ３ is hydrogen, C １－６ Alkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; R ４ But, C １－６ alkyl and hydrogen, or R ３ and R ４ But, R ３ and R ４ Together with the carbon bonded to C ３－７ cycloalkylene or 3- to 7-membered heterocyclene, １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, phenyl, C ３－７ Cycloalkylene or 3- to 7-membered heterocyclene is one or more R ７ may be optionally substituted with Each R ５ But halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkylene-N(R ９ ) ２ , C １－６ Alkylene -O-C ３－１０ Cycloalkyl, C ３－７ C optionally substituted with cycloalkyl １－６ Alkoxy, C １－６ Haloalkoxy, one or more halogens or C １－６ 3- to 10-membered heterocyclyl optionally substituted with alkoxy, 3- to 10-membered heteroaryl, -C １－６ Alkylene-OH,C １－６ Alkylene-C １－６ Alkoxy, OH, -N(R ９ ) ２ , -C(O)OR ８ , -C(O)N(R ９ ) ２ , -C １－６ Alkylene -CN, -CN, -S(O) ２ -C １－６ Alkyl, C １－６ Alkylene-S(O) ２ -C １－６ Alkyl, -S(O) ２ -N(R ９ ) ２ , -OC(O)C １－６ Alkyl, one or more halogens or C １－６ -O-C optionally substituted with alkyl ３－１０ Cycloalkyl, and halogen, C １－６ Alkyl, and C １－６ C optionally substituted with one or more substituents selected from alkoxy ３－１０ cycloalkyl; n is selected from the group consisting of 1, 2, and 3; R ７ But phenyl, C １－６ Alkoxy, -OH, -N(R ９ ) ２ , -NR ９ -SO ２ -C １－６ Alkyl, —O—(C １－６ alkylene)-phenyl, C ３－１０ Cycloalkyl, -C(O)OR ８ , -C(O)N(R ９ ) ２ , -NR １０ C(O)-R １１ , -CN, -S(O) ２ -C １－６ Alkyl, -S(O) ２ -N(R ９ ) ２ , 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl; ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, or 3- to 10-membered heteroaryl is C １－６ Alkyl, halogen, -OH, C １－６ Alkoxy, and -N(R ９ ) ２ and optionally substituted with one or more substituents each independently selected from the group consisting of: R ８ is hydrogen, C １－６ Alkyl, and C ３－１０ cycloalkyl; Each R ９ is hydrogen, C １－６ Alkyl, and -(C １－６ or two R ９ The two R ９ together with said nitrogen atom bound to Each R １０ are independently hydrogen or C １－６ is alkyl, R １１ But, C １－６ Alkyl, C １－６ Alkoxy, and —O—(C １－６ The compound of formula II, wherein R is an alkyl group, R is an alkylene)-phenyl, or a pharma- ceutically acceptable salt thereof.

17. The compound is a compound of formula II-a: 【Chemistry 316】 Compound of formula II-b: 【Chemistry 317】 Compound of formula II-c: 【Chemistry 318】 Compound of formula II-d: 【Chemical 319】 Compound of formula II-e: 【Chemistry 320】 Compound of formula II-f: 【Chemistry 321】 Compound of formula II-g: 【Chemistry 322】 Compound of formula II-h: 【Chemical 323】 Compound of formula II-i: 【Chemical 324】 Compound of formula II-j: 【Chemistry 325】 Compound of formula II-k: 【Chemical 326】 Compound of formula II-l: 【Chemical 327】 Compound of formula II-m: 【Chemical 328】 Compounds of formula II-n: 【Chemical 329】 Compound of formula II-p: 【Chemistry 330】 Compound of formula II-q: 【Chemistry 331】 Compound of formula II-r: 【Chemical 332】 or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined in claim 16.

18. The compound is a compound of formula II-k1 or II-k2: 【Chemical 333】 or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined in claim 16.

19. Compound of Formula III: 【Chemical 334】 or a pharma- ceutically acceptable salt thereof, R １ But, C １－６ Alkyl or C ３－７ cycloalkyl, １－６ Alkyl or C ３－７ Cycloalkyl is selected from the group consisting of one or more halogens or C １－６ optionally substituted with alkoxy; R １２ But, C ３－１０ cycloalkyl, 3- to 10-membered saturated heterocyclyl, and phenyl; ３－１０ Cycloalkyl, 3- to 10-membered saturated heterocyclyl, or phenyl is selected from the group consisting of halogen and C １－６ optionally substituted with one or more substituents each independently selected from alkoxy; R ２ is hydrogen or C １－４ is alkyl, R ３ But, C １－６ Alkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; R ４ But, C １－６ alkyl and hydrogen, or R ３ and R ４ But, R ３ and R ４ Together with the carbon bonded to C ３－７ cycloalkylene or 3- to 7-membered heterocyclene, １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, phenyl, C ３－７ Cycloalkylene or 3- to 7-membered heterocyclene is one or more R ７ may be optionally substituted with R ５ But halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ haloalkoxy, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, -C １－６ Alkylene -OH, OH, -C(O)OR ８ , -C(O)N(R ９ ) ２ , -C １－６ Alkylene -CN, -CN, -S(O) ２ -C １－６ Alkyl, C １－６ Alkylene-S(O) ２ -C １－６ Alkyl, -S(O) ２ -N(R ９ ) ２ , -OC(O)C １－６ Alkyl and —O—C optionally substituted with one or more halogens １－３ cycloalkyl; R ７ But phenyl, C １－６ Alkoxy, -OH, -O-(C １－６ alkylene)-phenyl, C ３－１０ Cycloalkyl, -C(O)OR ８ , -C(O)N(R ９ ) ２ , -NR １０ C(O)-R １１ , -CN, -S(O) ２ -C １－６ Alkyl, -S(O) ２ -N(R ９ ) ２ , 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl; ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, or 3- to 10-membered heteroaryl is C １－６ Alkyl, halogen, -OH, C １－６ Alkoxy, and -N(R ９ ) ２ and optionally substituted with one or more substituents each independently selected from the group consisting of: R ８ is hydrogen or C １－６ is alkyl, Each R ９ is hydrogen, C １－６ Alkyl, and -(C １－６ or two R ９ The two R ９ together with the nitrogen atom to which is bonded, may form a heterocycle optionally substituted with one or more substituents each independently selected from halogen and -OH; Each R １０ are independently hydrogen or C １－６ is alkyl, R １１ But, C １－６ Alkyl, C １－６ Alkoxy, and —O—(C １－６ (alkylene)-phenyl; n is selected from the group consisting of 0, 1, 2, and 3; The compound is 【Chemical 335】 or a pharma- ceutically acceptable salt thereof, which is not a compound of formula III or a pharma- ceutically acceptable salt thereof.

20. Compound of Formula IV: 【Chemical 336】 or a pharma- ceutically acceptable salt thereof, R １ But, C １－６ Alkyl and C ３－７ cycloalkyl, １－６ Alkyl or C ３－７ Cycloalkyl is selected from halogen and C １－６ optionally substituted with one or more substituents independently selected from alkoxy; R １２ is one or more halogen or C １－６ C optionally substituted with alkoxy １－６ is alkyl, R ２ is hydrogen or C １－４ is alkyl, R ３ But, C １－６ Alkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; R ４ But, C １－６ alkyl and hydrogen, or R ３ and R ４ But, R ３ and R ４ Together with the carbon bonded to C ３－７ cycloalkylene or 3- to 7-membered heterocyclene, １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, phenyl, C ３－７ Cycloalkylene or 3- to 7-membered heterocyclene is R ７ may be optionally substituted with R ５ But halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ haloalkoxy, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, -C １－６ Alkylene -OH, OH, -C(O)OR ８ , -C(O)N(R ９ ) ２ , -C １－６ Alkylene -CN, -CN, -S(O) ２ -C １－６ Alkyl, C １－６ Alkylene-S(O) ２ -C １－６ Alkyl, -S(O) ２ -N(R ９ ) ２ , -OC(O)C １－６ Alkyl and —O—C optionally substituted with one or more halogens ３－１０ cycloalkyl; R ７ But phenyl, C １－６ Alkoxy, -OH, -O-(C １－６ alkylene)-phenyl, C ３－１０ Cycloalkyl, -C(O)OR ８ , -C(O)N(R ９ ) ２ , -NR １０ C(O)-R １１ , -CN, -S(O) ２ -C １－６ Alkyl, -S(O) ２ -N(R ９ ) ２ , 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl; ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, or 3- to 10-membered heteroaryl is C １－６ Alkyl, halogen, -OH, C １－６ Alkoxy, and -N(R ９ ) ２ and optionally substituted with one or more substituents each independently selected from the group consisting of: R ８ is hydrogen or C １－６ is alkyl, Each R ９ is hydrogen, C １－６ Alkyl, and -(C １－６ or two R ９ The two R ９ together with said nitrogen atom bonded to form a heterocycle optionally substituted with one or more substituents selected from halogen and -OH; Each R １０ are independently hydrogen or C １－６ is alkyl, R １１ But, C １－６ Alkyl, C １－６ Alkoxy, and —O—(C １－６ (alkylene)-phenyl; n is selected from the group consisting of 0, 1, 2, and 3; The compound is 【Chemical 337】 or a pharma- ceutically acceptable salt thereof, which is not a compound of formula IV or a pharma- ceutically acceptable salt thereof.

21. Compound of Formula V: 【Chemical 338】 or a pharma- ceutically acceptable salt thereof, R １ is phenyl or 3- to 10-membered heteroaryl, said phenyl or 3- to 10-membered heteroaryl being selected from halogen and C １－６ optionally substituted with one or more substituents independently selected from alkoxy; R １２ But, C ３－１０ cycloalkyl, 3- to 10-membered saturated heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; ３－１０ Cycloalkyl, 3- to 10-membered saturated heterocyclyl, 3- to 10-membered heteroaryl, or phenyl is selected from the group consisting of halogen and C １－６ optionally substituted with one or more substituents each independently selected from alkoxy; R ２ is hydrogen or C １－４ is alkyl, R ３ But, C １－６ Alkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; R ４ But, C １－６ alkyl and hydrogen, or R ３ and R ４ But, R ３ and R ４ Together with the carbon bonded to C ３－７ cycloalkylene or 3- to 7-membered heterocyclene, １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, phenyl, C ３－７ Cycloalkylene or 3- to 7-membered heterocyclene is one or more R ７ may be optionally substituted with R ５ But halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ haloalkoxy, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, -C １－６ Alkylene -OH, OH, -C(O)OR ８ , -C(O)N(R ９ ) ２ , -C １－６ Alkylene -CN, -CN, -S(O) ２ -C １－６ Alkyl, C １－６ Alkylene-S(O) ２ -C １－６ Alkyl, -S(O) ２ -N(R ９ ) ２ , -OC(O)C １－６ Alkyl, and —O—C ３－１０ cycloalkyl; R ７ But phenyl, C １－６ Alkoxy, -OH, -O-(C １－６ alkylene)-phenyl, C ３－７ Cycloalkyl, -C(O)OR ８ , -C(O)N(R ９ ) ２ , -NR １０ C(O)-R １１ , -CN, -S(O) ｚ -C １－６ Alkyl, -S(O) ｚ -N(R ９ ) ２ , 3- to 7-membered heterocyclyl, and 3- to 10-membered heteroaryl, ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, or 3- to 10-membered heteroaryl is C １－６ Alkyl, halogen, -OH, C １－６ Alkoxy, and -N(R ９ ) ２ and optionally substituted with one or more substituents each independently selected from the group consisting of: R ８ is hydrogen or C １－６ is alkyl, Each R ９ is hydrogen, C １－６ Alkyl, and -(C １－６ or two R ９ The two R ９ together with said nitrogen atom bound to Each R １０ are independently hydrogen or C １－６ is alkyl, R １１ But, C １－６ Alkyl, C １－６ Alkoxy, and —O—(C １－６ (alkylene)-phenyl; n is selected from the group consisting of 0, 1, 2, and 3; The compound is 【Chemical 339】 or a pharma- ceutically acceptable salt thereof, which is not a compound of formula V:

22. The compound is 【Chemical 347】 【Chemical 348】 【Chemical 349】 【Chemistry 350】 【Chemistry 351】 【Chemical 352】 【Chemical 353】 【Chemical 354】 【Chemistry 355】 【Chemical 356】 【Chemical 357】 【Chemical 358】 【Chemical 359】 【Hua360】 【Chemistry 361】 【Chemical 362】 【Chemistry 363】 【Chemistry 364】 【Chemistry 365】 【Hua366】 【Chemical 367】 【Chemistry 368】 【Chemical 369】 【Hua370】 【Chemical 371】 【Chemical 372】 【Chemical 373】 【Chemical 374】 【Chemical 375】 【Chemical 376】 【Chemical 377】 【Chemical 378】 【Chemical 379】 【Hua380】 【Chemistry 381】 【Chemical 382】 【Chemical 383】 【Chemical 384】 【Chemistry 385】 【Chemistry 386】 【Chemical 387】 【Chemistry 388】 【Chemical 389】 【Chemical 390】 【Chemical 391】 【Chemical 392】 【Chemical 393】 【Chemical Formula 394】 【Chemical 395】 A pharmaceutical composition according to any one of claims 1 to 15 or a compound according to any one of claims 16 to 21, selected from the group consisting of:

23. Compound of Formula VI: 【Chemistry 340】 or a pharma- ceutically acceptable salt thereof, R １３ But, C １－６ Alkyl or C ３－１０ cycloalkyl, １－６ Alkyl or C ３－１０ cycloalkyl is optionally substituted with phenyl; R １４ is hydrogen, R １５ But, C １－６ is alkyl or hydrogen; R １６ C optionally substituted with one or more halogens １－６ Alkyl, C １－６ Alkoxy, C ３－１０ cycloalkyl, or phenyl; Each R １７ But halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkylene-N(R ２０ ) ２ , C １－６ Alkylene -O-C ３－１０ Cycloalkyl, C ３－７ C optionally substituted with cycloalkyl １－６ Alkoxy, C １－６ Haloalkoxy, one or more halogens or C １－６ 3- to 10-membered heterocyclyl optionally substituted with alkoxy, 3- to 10-membered heteroaryl, -C １－６ Alkylene-OH,C １－６ Alkylene-C １－６ Alkoxy, OH, -N(R ２０ ) ２ , -C(O)OR １９ , -C(O)N(R ２０ ) ２ , -C １－６ Alkylene -CN, -CN, -S(O) ２ -C １－６ Alkyl, C １－６ Alkylene-S(O) ２ -C １－６ Alkyl, -S(O) ２ -N(R ２０ ) ２ , -OC(O)C １－６ Alkyl, one or more halogens or C １－６ -O-C optionally substituted with alkyl ３－１０ Cycloalkyl, and halogen, C １－６ Alkyl, and C １－６ C optionally substituted with one or more substituents selected from alkoxy ３－１０ cycloalkyl; p is selected from the group consisting of 1, 2, and 3; R １９ is hydrogen, C １－６ Alkyl, and C ３－１０ cycloalkyl; Each R ２０ are independently hydrogen or C １－６ is alkyl, Each R ２１ are independently hydrogen or C １－６ or a pharma- ceutically acceptable salt thereof. 【Request 24】 【Chemical 350】 or a pharma- ceutically acceptable salt thereof; and and a pharma- ceutically acceptable excipient.

25. A pharmaceutical composition comprising a compound according to any one of claims 16 to 23, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

26. 1. A composition for treating a disease or condition associated with a gain-of-function mutation in KCNT1 in a subject in need of such treatment, the compound being a compound of formula I: 【Chemical 344】 or a pharma- ceutically acceptable salt thereof, X, Y, Z, Y′, and Z′ are each independently selected from CH and N, and the hydrogen of CH is R ５ wherein at least three selected from X, Y, Z, Y', and Z' are CH; R １ But, C １－６ Alkyl, C ３－１０ is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, or phenyl is selected from the group consisting of halogen, C(O)N(R ９ ) ２ , N(R ９ ) ２ , C ３－７ Cycloalkyl, phenyl, 3- to 10-membered heteroaryl, and C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy; R １２ But, C １－６ Alkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, or phenyl is selected from the group consisting of halogen, —OH, —CN, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy; Two R on adjacent carbons １２ But, R １２ may be taken together with the two carbons to which they are attached to form a carbocyclic ring, x is 0, 1, or 2; R ２ is hydrogen or C １－４ is alkyl, R ３ is hydrogen, C １－６ Alkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl; R ４ But, C １－６ alkyl and hydrogen, or R ３ and R ４ But, R ３ and R ４ Together with the carbon bonded to C ３－７ cycloalkylene or 3- to 7-membered heterocyclene, １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, phenyl, C ３－７ Cycloalkylene or 3- to 7-membered heterocyclene is one or more R ７ may be optionally substituted with Each R ５ But halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkylene-N(R ９ ) ２ , C １－６ Alkylene -O-C ３－１０ Cycloalkyl, C １－６ Alkoxy, C optionally substituted with one or more halogens ３－１０ Cycloalkyl-substituted C １－６ Alkoxy, C １－６ Haloalkoxy, one or more halogens or C １－６ 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, optionally substituted with alkoxy; １－６ Alkylene-OH,C １－６ Alkylene-C １－６ Alkoxy, OH, N(R ９ ) ２ , -C(O)OR ８ , C(O)N(R ９ ) ２ , C １－６ Alkylene -CN, -CN, -S(O) ２ -C １－６ Alkyl, C １－６ Alkylene-S(O) ２ -C １－６ Alkyl, -S(O) ２ -N(R ９ ) ２ , -OC(O)C １－６ Alkyl, one or more halogens or C １－６ -O-C optionally substituted with alkyl ３－１０ Cycloalkyl, and halogen, C １－６ Alkyl, and C １－６ C optionally substituted with one or more substituents selected from alkoxy ３－１０ cycloalkyl; n is selected from the group consisting of 0, 1, 2, and 3; R ７ But phenyl, C １－６ Alkoxy, -OH, -N(R ９ ) ２ , -NR ９ -SO ２ -C １－６ Alkyl, —O—(C １－６ alkylene)-phenyl, C ３－１０ Cycloalkyl, -C(O)OR ８ , -C(O)N(R ９ ) ２ , -NR １０ C(O)-R １１ , -CN, -S(O) ２ -C １－６ Alkyl, -S(O) ２ -N(R ９ ) ２ , 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl; ３－１０ Cycloalkyl, 3- to 10-membered heterocyclyl, or 3- to 10-membered heteroaryl is C １－６ Alkyl, halogen, -OH, C １－６ Alkoxy, and -N(R ９ ) ２ and optionally substituted with one or more substituents each independently selected from the group consisting of: R ８ is hydrogen or C １－６ is alkyl, Each R ９ is hydrogen, C １－６ Alkyl, and -(C １－６ or two R ９ The two R ９ together with said nitrogen atom bound to Each R １０ are independently hydrogen or C １－６ is alkyl, R １１ But, C １－６ Alkyl, C １－６ Alkoxy, and —O—(C １－６ (alkylene)-phenyl; R ３ and R ４ are both hydrogen, then at least one selected from X, Y, Z, Y', and Z' is N, or a pharma- ceutically acceptable salt thereof; The disease or condition associated with the gain-of-function mutation of KCNT1 is epilepsy, epilepsy syndrome, encephalopathy (e.g., migratory focal seizures in infancy (MMFSI, EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox syndrome, Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, or cerebellar ataxia), genetic or childhood epilepsy, genetic or childhood epilepsy syndromes, cardiac dysfunction, cardiac arrhythmias, sudden unexpected death in epilepsy (SUDEP), Brugada syndrome, myocardial infarction, pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine), itch and pruritus, ataxia, and cerebellar ataxia, SCN1A, The composition is selected from the group consisting of epileptic encephalopathy with SCN2A, SCN8A mutations, early infantile onset epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

27. The compound is a compound of formula I-c, wherein R １ CH ３ , R ２ H, R ３ CH ３ , R ４ H, R ５ is CF ３ , R １２ is CF ３ 4. The pharmaceutical composition of claim 3, wherein n is 1 and x is 1.

28. 2. The pharmaceutical composition of claim 1, wherein the one or more hydrogens is deuterium.

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