KCNT1 inhibitors and methods of use

Abstract

To provide KCNT1 inhibitors and methods of use.SOLUTION: The present invention is directed to, in part, compounds and compositions useful for preventing and / or treating a neurological disease or disorder, a disease or condition relating to excessive neuronal excitability, and / or a gain-of-function mutation in a gene (e.g., KCNT1). Methods of treating a neurological disease or disorder, a disease or condition relating to excessive neuronal excitability, and / or a gain-of-function mutation in a gene such as KCNT1 are also provided herein.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 842,849, filed on May 3, 2019, and U.S. Provisional Patent Application No. 62 / 982,864, filed on February 28, 2020, the contents of each of which are hereby incorporated by reference in their entirety.

Background Art

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

Summary of the Invention

Means for Solving the Problems

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

[0004] In one aspect, the disclosure is a compound of formula (I):

Chemical Formula

[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): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein, and a pharmaceutically acceptable excipient to provide a pharmaceutical composition.

[0011] In another aspect, the present 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 pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0012] In another aspect, the present disclosure provides a method for treating a neurological disease or disorder, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), (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 pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), (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 pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient).

[0013] In another aspect, the present disclosure provides a method for treating a disease or condition associated with excessive neuronal excitability, the method comprising administering to a subject in need thereof a compound disclosed herein (e.g., a compound of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), (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 pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), (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 pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient).

[0014] In another aspect, the present disclosure provides a method of treating a disease or condition associated with a gain-of-function mutation of a gene (e.g., KCNT1), the method comprising administering to a subject in need of treatment a compound disclosed herein (e.g., a compound of formula ((I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), (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 pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula ((I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), (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 pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient).

[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 the group consisting of 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 encephalopathy, Lennox Gastaut syndrome, seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia).

[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, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation of 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, the disease or condition associated with excessive neuronal excitability, or the disease or condition associated with a gain-of-function mutation of a gene (e.g., KCNT1) is a muscle disorder (e.g., myotonia, neuromyotonia, muscle cramps, spasticity).

[0022] 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 of a gene (e.g., KCNT1) is selected from itching 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 of a gene (e.g., KCNT1) is selected from mental disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia).

[0024] In some embodiments, the neurological disease or disorder, or the disease or condition associated with excessive neuronal excitability and / or a gain-of-function mutation in a gene (e.g., KCNT1) is selected from the group consisting of learning disorders, fragile X, neural plasticity, and autism spectrum disorder.

[0025] In some embodiments, neurological diseases or disorders, diseases or conditions associated with excessive neuronal excitability, or diseases or conditions associated with gain-of-function mutations in a gene (e.g., KCNT1) are selected from the group consisting of epileptic encephalopathies with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, nodding epilepsy, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures in infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0026] Other objects and advantages will become apparent to those skilled in the art upon consideration of the following detailed description, examples, and claims of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[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 th Identified according to the inner cover of the Ed., specific functional groups are generally defined as described in the same book. In addition, the general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999, Smith and March, March’s Advanced Organic Chemistry, 5 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, accordingly, may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from the mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC), as well as the formation and crystallization of chiral salts, or the preferred isomers can be prepared by asymmetric synthesis. 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 Op tical Resolutions p.268 (E.L. 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 enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., is enantiomerically enriched). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is thus enantiomerically enriched in the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or more than 99.9% enantiomer. In certain embodiments, the weight is 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 with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R compound may contain, for example, about 90% excipient and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may contain, for example, at least about 95% by weight of the R compound and at most about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S compound may contain, for example, about 90% excipient and about 10% enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may contain, for example, at least about 95% by weight of the S compound and at most about 5% by weight of the R compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipient or carrier.

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

[0033] The following terms are intended to have the meanings presented below and are useful for understanding the description and intended scope of the present invention. When describing an invention that may include a compound and its pharmaceutically acceptable salts, a pharmaceutical composition containing such a compound, and methods of using such a compound and composition, the following terms, unless otherwise indicated when present, have the following meanings. Also, as described herein, it should be understood that any of the moieties defined below may be substituted with various substituents and that the substituted moieties are intended to be included within the ranges described for each of their definitions below. Unless otherwise specified, the term "substituted" is defined as described below. It should be further 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 objects of the article. By way of example, "analog" means one analog or more than one analog.

[0034] When a range of values is recited, each value within the range and subranges subsumed therein are intended to be encompassed. For example, "C 1-6 alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 、and C 5-6 alkyl.

[0035] As used herein, "alkyl" is, for example, a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms ("C 1-20refers to ")alkyl". In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C 1-10 alkyl"). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1-9 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 alkyl"). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom (C1 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 a 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 alkenyl"). In certain embodiments, alkenyl does not contain a triple bond. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2-10 alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2-9"(alkenyl). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 alkenyl). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 alkenyl). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 alkenyl). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 alkenyl). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4 alkenyl). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 alkenyl). In some embodiments, the alkenyl group has 2 carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. C 2-6 Examples of alkenyl groups include the aforementioned C 2-4 alkenyl groups, as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrieneyl (C8), and the like.

[0037] As used herein, "alkynyl" refers to a 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 alkynyl"). In certain embodiments, the alkynyl does not contain a double bond. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C2-10 (alkynyl). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C 2-9 alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2-8 alkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2-7 alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2-6 alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2-5 alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2-4 alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2-3 alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. C 2-6 Examples of alkenyl groups include the aforementioned C 2-4 alkynyl groups, as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like.

[0038] As used herein, "alkylene", "alkenylene", and "alkynylene" each refer to a divalent radical of an alkyl, alkenyl, and alkynyl group, respectively. When a carbon range or number 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 the linear carbon divalent chain. The "alkylene", "alkenylene", and "alkynylene" groups can be substituted with one or more substituents described herein or can be unsubstituted.

[0039] As used herein, "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system (a "C 6-14 aryl"). In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10 aryl", e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14"Aryl", for example, anthracyl). "Aryl" also includes cases where the aryl ring defined above is fused with one or more carbocyclic or heterocyclic groups, and the radical or point of attachment is on the aryl ring. In such cases, the ring system in which the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system is included. Typical aryl groups include, but are not limited to, acenaphthylene, 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 groups derived from trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

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

[0041] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system (a "5- to 10-membered heteroaryl") having ring carbon atoms provided in the aromatic ring system and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system (a "5- to 8-membered heteroaryl") having ring carbon atoms provided in the aromatic ring system and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system (a "5- to 6-membered heteroaryl") having ring carbon atoms provided in the aromatic ring system and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 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-fused bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-fused bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0043] Examples of representative heteroaryls include the following,

Chemical Structure

[0044] As used herein, "carbocyclic" or "carbocyclic ring" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C 3-10 carbocyclic") and 0 heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclic group has 3 to 8 ring carbon atoms ("C 3-8 carbocyclic"). In some embodiments, the carbocyclic group has 3 to 6 ring carbon atoms ("C 3-6 carbocyclic"). In some embodiments, the carbocyclic group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclic"). Exemplary C 3-6 carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-8 carbocyclic groups include, but are not limited to, the aforementioned C 3-6 carbocyclic groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrieneyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 carbocyclic groups include, but are not limited to, the aforementioned C 3-8 carbocyclic groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10 )), spiro[4.5]decan-1-yl (C 10 ), etc. As illustrated by the foregoing examples, in certain embodiments, the carbocyclic group is either monocyclic ("monocyclic carbocyclic") or contains a fused, bridged, or spiro ring system such as a bicyclic system ("bicyclic carbocyclic"), and may be saturated or partially unsaturated. "Carbocyclic" also includes cases where the carbocyclic ring defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the carbocyclic ring, and in such examples, the ring system where the number of carbons continues to specify the number of carbons in the carbocyclic ring system is included.

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

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

[0047] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system (a "5- to 10-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system (a "5- to 8-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system (a "5- to 6-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 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 thiirenyl. 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 pyrrol-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 Exemplary 5-membered heterocyclyl groups include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

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

[0050] When used to describe a compound or a group present in a compound, "hetero" means that one or more carbon atoms in the compound or group are replaced by heteroatoms of nitrogen, oxygen, or sulfur. Hetero can be applied 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, particularly 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, the 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 -NO2.

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

[0056] Generally, the term "substituted", whether or not 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 undergo spontaneous transformation by rearrangement, cyclization, elimination, or other reactions. Unless otherwise indicated, a "substituted" group has substituents at one or more substitutable positions of the group, and when two or more positions of any given structure are substituted, the substituents may be the same or different at each position.

[0057] A nitrogen atom may be substituted or unsubstituted, as valence permits, and includes primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen , -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclic, 3- to 14-membered heterocyclic, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups bonded to the nitrogen atom combine to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc , and R dd are as defined above.

[0058] These and other exemplary substituents are described in more detail in the "Modes for Carrying Out the Invention", "Examples", and "Claims". The invention is not intended to be limited in any way by the exemplary listing of substituents above.

[0059] Other definitions The term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19, and Gould describes them in Salt selection for basic drugs, International Journal of Pharmaceutics, 33 (1986) 201-217. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 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, valerate salts, and the like.Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N. + (C 1-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. .

[0060] As used herein, the "subject" for which administration is contemplated includes, but is not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents), or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)), and / or non-human animals such as mammals including primates (e.g., cynomolgus 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 an action (also "therapeutic treatment") that occurs while the subject is suffering from the specified disease, disorder, or condition and that reduces the severity of the disease, disorder, or condition or delays or retards the progression of the disease, disorder, or condition.

[0063] Generally, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response. As will be understood by those skilled in the art, the effective amount of the compounds 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 the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of the therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" may encompass an amount that improves the 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 invention contemplates administering a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, as a prophylactic agent, prior to the subject beginning to suffer from a designated disease, disorder, or condition. As used herein, "prophylactic treatment" contemplates an action that occurs prior to the subject beginning to suffer from a designated disease, disorder, or condition. As used herein and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of the 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" may encompass an amount that improves the overall prophylaxis, or enhances the prophylactic efficacy of another prophylactic agent.

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

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

[0068] Compounds and Compositions In one aspect, the disclosure provides a compound of Formula I:

Chemical formula

[0069] In another aspect, the present disclosure provides a compound of formula I:

Chemical formula

[0070] In some embodiments, the compound is a compound of formula I-I or formula I-II:

Chemical formula

[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 I-a:

Chemical formula

[0074] In some embodiments, the compound is a compound of formula I-b:

Chemical formula

[0075] In some embodiments, the compound is a compound of formula I-c:

Chemical formula

[0076] In some embodiments, the compound is a compound of formula I-d:

Chemical formula

[0077] In some embodiments, the compound is a compound of formula I-e:

Chemical formula

[0078] In some embodiments, the compound is a compound of formula I-f: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0079] In some embodiments, the compound is a compound of formula I-g: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0080] In some embodiments, the compound is a compound of formula I-h: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0081] In some embodiments, the compound is a compound of formula I-i: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0082] In some embodiments, the compound is a compound of formula I-j: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0083] In some embodiments, the compound is a compound of formula I-k: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0084] In some embodiments, the compound is a compound of formula I-l: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0085] In some embodiments, the compound is a compound of formula I-m: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0086] In some embodiments, the compound is a compound of formula I-n: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0087] In some embodiments, the compound is a compound of formula I-o: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0088] In some embodiments, the compound is a compound of formula I-p: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0089] In some embodiments, the compound is a compound of formula I-q:

Chemical formula

[0090] In some embodiments, the compound is a compound of formula I-r:

Chemical formula

[0091] In some embodiments, the compound is a compound of formula I-s:

Chemical formula

[0092] In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R2 is hydrogen. In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R2 is methyl.

[0093] In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R3 is hydrogen. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R3 is C 1-6 alkyl. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R3 is selected from the group consisting of methyl, ethyl, and isopropyl. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R3 is methyl. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R3 is ethyl.

[0094] In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R3 is C 1-6 C substituted with alkoxy 1-6 alkyl, -OH, or -C(O)OR8.

[0095] In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), ( I-q), (I-r), or (I-s)), R4 is hydrogen.

[0096] In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R3 and R4 together with the carbon to which they are attached form a C 3-7 cycloalkylene or a 3- to 7-membered heterocycle. In some embodiments, the C 3-7 cycloalkylene is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, the 3- to 7-membered heterocycle is selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0097] In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), each R5 is independently selected from the group consisting of 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(R9)2, and -C(O)OR8.

[0098] In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), each R5 is methyl. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), each R5 is halogen. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), each R5 is -F. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), each R5 is -Cl. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), each R5 is methoxy. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), each R5 is -CF3.In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), each R5 is -CHF2. Formula (I) (for example. In some embodiments of (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), each R5 is -C(O)OR8. In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), each R5 is cyclopropyl, cyclobutyl, or cyclopentyl.

[0099] In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R5 is independently selected from the group consisting of cyclopropyl, -OCH2CH3, -OCH2-CHF2, -O-cyclopropyl, -O-isopropyl, -NHCH3, -N(CH3)2, and -CH2OCH3.

[0100] In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), n is 1. In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), n is 2.

[0101] In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), n is 1 and R5 is in the meta position. In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), n is 2 and the two R5s are in the ortho and para positions. In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), n is 2 and the two R5s are in the meta and para positions. In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), n is 2 and the two R5s are in the meta position.

[0102] In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), ( I-q), (I-r), or (I-s)), R1 is C 1-6 alkyl optionally substituted with alkoxy, N(R9)2, C(O)N(R9)2, C 1-6 alkyl, N(R9)2, C(O)N(R9)2, C 3-7Cycloalkyl, 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., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R1 is C 1-6 Alkyl.

[0104] In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R1 is methyl. In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R1 is ethyl.

[0105] In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R1 is C 1-6It is haloalkyl. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R1 is -CH2-CHF2. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R1 is -CHF2.

[0106] In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R1 is C 3-7 It is cycloalkyl. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R1 is cyclopropyl. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R1 is cyclobutyl.

[0107] In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R1 is C 1-6 alkyl substituted with alkoxy 1-6 is alkyl. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R1 is C 1-6 alkyl substituted with methoxy.

[0108] In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R1 is C 3-7 alkyl substituted with cycloalkyl 1-6 is alkyl. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R1 is C 1-6 alkyl substituted with cyclopropyl.

[0109] In some embodiments of formula (I) (such as (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R1 is phenyl substituted with halogen.

[0110] In some embodiments of formula (I) (such as (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R 12 is C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl, and C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, or phenyl is optionally substituted with one or more substituents independently selected from halogen and C 1-6 alkoxy.

[0111] In some embodiments of formula (I) (such as (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), 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) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R 12 is C3 -7 cycloalkyl. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R 12 is cyclopropyl.

[0113] In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R 12 is C 1-6 alkyl. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R 12 is ethyl. In some embodiments of formula (I) (for example, (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R 12is methyl. In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R 12 is t-butyl. In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R 12 is isopropyl.

[0114] In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R 12 is C 1-6 haloalkyl. In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R 12 is -CF3. In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R 12 is -CHF2.

[0115] In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), R 12 is phenyl optionally substituted with -F.

[0116] In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I- j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), x is 1. In some embodiments of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), x is 2.

[0117] In another aspect, the present invention provides a compound of formula II:

Chemical formula

[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:

Chemical formula

[0120] In some embodiments, the compound is a compound of formula II-b:

Chemical formula

[0121] In some embodiments, the compound is a compound of formula II-c:

Chemical formula

[0122] In some embodiments, the compound is a compound of formula II-d:

Chemical formula

[0123] In some embodiments, the compound is a compound of formula II-e:

Chemical formula

[0124] In some embodiments, the compound is a compound of formula II-f:

Chemical formula

[0125] In some embodiments, the compound is a compound of formula II-g:

Chemical formula

[0126] In some embodiments, the compound is a compound of formula II-h:

Chemical formula

[0127] In some embodiments, the compound is a compound of formula II-i:

Chemical formula

[0128] In some embodiments, the compound is a compound of formula II-j:

Chemical formula

[0129] In some embodiments, the compound is a compound of formula II-k:

Chemical formula

[0130] In some embodiments, the compound is a compound of formula II-l:

Chemical formula

[0131] In some embodiments, the compound is a compound of formula II-m:

Chemical formula

[0132] In some embodiments, the compound is a compound of formula II-n:

Chemical formula

[0133] In some embodiments, the compound is a compound of Formula II-p:

Chemical formula

[0134] In some embodiments, the compound is a compound of Formula II-q:

Chemical formula

[0135] In some embodiments, the compound is a compound of Formula II-r:

Chemical formula

[0136] In some embodiments, the compound is a compound of Formula II-k1 or Formula II-k2:

Chemical formula

[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 R5 is in the meta position. 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 the two R5s are in the ortho and para positions. 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 the two R5s are in the meta and para positions. 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 the two R5s are in the 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)), R3 and R4, together with the carbon to which they are attached, form a C 3-7 cycloalkylene or a 3- to 7-membered heterocycle. In some embodiments, the C 3-7 cycloalkylene is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, the 3- to 7-membered heterocycle 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)), R4 is hydrogen there is.

[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)), R2 is hydrogen.

[0142] In some embodiments of formula (II) (for example, (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)), R2 is methyl.

[0143] In some embodiments of formula (II) (for example, (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 C 1-6 alkyl. In some embodiments of formula (II) (for example, (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 methyl. In some embodiments of formula (II) (for example, (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) (for example, (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 C 1-6 alkyl substituted with C alkoxy1-6 is alkyl, -OH, or -C(O)OR8.

[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)), R3 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 R5 is 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, -CN, C 1-6 alkylene-C 1-6 alkoxy, C 1-6 is independently selected from the group consisting of alkylene-N(R9)2, N(R9)2, and -C(O)OR8.

[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)), R5 is C 1-6It is alkyl. In some embodiments of formula (II) (for example, (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)), R5 is methyl.

[0148] In some embodiments of formula (II) (for example, (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)), R5 is halogen. In some embodiments of formula (II) (for example, (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)), R5 is -F. In some embodiments of formula (II) (for example, (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)), R5 is -Cl.

[0149] In some embodiments of formula (II) (for example, (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)), R5 is C 1-6It is a haloalkyl. In some embodiments of formula (II) (for example, (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)), R5 is CF3. In some embodiments of formula (II) (for example, (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)), R5 is CF2H.

[0150] In some embodiments of formula (II) (for example, (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)), R5 is C 1-6 alkoxy. In some embodiments of formula (II) (for example, (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)), R5 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)), R5 is C 3-10 is cycloalkyl. 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)), R5 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)), R5 is -C(O)OR8.

[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)), R1 is C 1-6 alkyl optionally substituted with alkoxy, C 1-6 N(R9)2, C(O)N(R9)2, C 3-7 is cycloalkyl, pyridyl, tetrahydropyranyl, or phenyl, C 1-6 is haloalkyl, C 3-7 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)), R1 is C 1-6 alkyl. 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)), R1 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)), R1 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)), R1 is C 1-6 haloalkyl. In some embodiments of formula (II) (e.g., (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), ( In some embodiments of (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), R1 is -CH2-CHF2. In some embodiments of formula (II) (for example, (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)), R1 is CHF2.

[0156] In some embodiments of formula (II) (for example, (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)), R1 is C 3-7 cycloalkyl. In some embodiments of formula (II) (for example, (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)), R1 is cyclopropyl, cyclobutyl, or cyclopentyl.

[0157] In some embodiments of formula (II) (for example, (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)), R1 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)), R1 is C 1-6 alkyl substituted with alkoxy 1-6 alkyl. 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)), R1 is C 1-6 alkyl substituted with N(R9)2 1-6 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), ( In some embodiments of (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) (for example, (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 haloalkyl, and phenyl optionally substituted with halogen, selected from the group consisting of.

[0162] In some embodiments of formula (II) (for example, (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. In some embodiments of formula (II) (for example, (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 haloalkyl. 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 CF3. 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)), R12 is CHF2.

[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 cycloalkyl. 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:

Chemical formula

[0167] In another aspect, the present invention relates to a compound of formula IV: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of C 1-6 alkyl and C 3-7 cycloalkyl, and C 1-6 alkyl or C 3-7 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen and C 1-6 alkoxy, R 12 is C 1-6 alkyl optionally substituted with one or more halogens or C 1-6 alkoxy, R2 is hydrogen or C 1-4 alkyl, R3 is selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl, and R4 is selected from C 1-6 alkyl and hydrogen, or R3 and R4 together with the carbon to which they are attached may form C 3-7 cycloalkylene or 3- to 7-membered heterocycle, and C 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 heterocycle may be optionally substituted with R7, R5 is halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C1-6 haloalkoxy, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, -C 1-6 alkylene-OH, OH, -C(O)OR8, -C(O)N(R9)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(R9)2, -OC(O)C 1-6 alkyl, and -O-C optionally substituted with one or more halogens 3-10 selected from the group consisting of cycloalkyl, R7 is phenyl, C 1-6 alkoxy, -OH, -O-(C 1-6 alkylene)-phenyl, C 3-10 cycloalkyl, -C(O)OR8, -C(O)N(R9)2, -NR 10 C(O)-R 11 , -CN, -S(O)2-C 1-6 alkyl, -S(O)2-N(R9)2, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, each independently selected from the group consisting of phenyl, C 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(R9)2, optionally substituted with one or more substituents independently selected from the group consisting of R8 is hydrogen or C 1-6 alkyl, each R9 is hydrogen, C 1-6 alkyl, and -(C 1-6 alkylene)-OH, independently selected from the group consisting of, or two R9s together with the nitrogen atom to which they are attached may form a heterocyclic ring optionally substituted with one or more substituents selected from halogen and -OH each R 10 is independently hydrogen or C 1-6 alkyl, R 11 is C1-6 Alkyl, C 1-6 Alkoxy, and -O-(C 1-6 selected from the group consisting of alkylene)-phenyl, n is selected from the group consisting of 0, 1, 2, and 3, the compound is

Chemical formula

[0168] In another aspect, the present invention relates to a compound of formula V:

Chemical formula

Chemical formula

[0169] In some embodiments of formula (III), (IV), or (V), R2 is hydrogen.

[0170] In some embodiments of formula (III), (IV), or (V), R3 is C 1-6 alkyl. In some embodiments of formula (III), (IV), or (V), R3 is methyl. In some embodiments of formula (III), (IV), or (V), R3 is ethyl.

[0171] In some embodiments of formula (III), (IV), or (V), R3 is C 1-6 alkyl substituted with C 1-6 alkoxy, -OH, or -C(O)OR8.

[0172] In some embodiments of formula (III), (IV), or (V), R4 is hydrogen.

[0173] In some embodiments of formula (III), (IV), or (V), R3 and R4, together with the carbon to which they are attached, form a C 3-7 cycloalkylene or a 3- to 7-membered heterocycle.

[0174] In some embodiments of formula (III), (IV), or (V), R5 is independently selected from the group consisting of cyclopropyl, -OCH2CH3, -OCH2-CHF2, -O-cyclopropyl, -O-isopropyl, -NHCH3, -N(CH3)2, and -CH2OCH3.

[0175] In some embodiments of formula (III), (IV), or (V), each R5 is methyl.

[0176] In some embodiments of formula (III), (IV), or (V), each R5 is halogen. In some embodiments of formula (III), (IV), or (V), each R5 is -F. In some embodiments of formula (III), (IV), or (V), each R5 is -Cl.

[0177] In some embodiments of formula (III), (IV), or (V), each R5 is methoxy.

[0178] In some embodiments of formula (III), (IV), or (V), each R5 is -CF3.

[0179] In some embodiments of formula (III), (IV), or (V), each R5 is -CHF2.

[0180] In some embodiments of formula (III), (IV), or (V), each R5 is -C(O)OR8.

[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 is in the meta position. In some embodiments of formula (III), (IV), or (V), n is 2, and the two R5s are in the ortho and para positions. In some embodiments of formula (III), (IV), or (V), n is 2, and the two R5s are in the meta and para positions. In some embodiments of formula (III), (IV), or (V), n is 2, and the two R5s are in the meta position.

[0184] In some embodiments of formula (III), (IV), or (V), R1 is C 1-6 alkyl. In some embodiments of formula (III), (IV), or (V), R1 is methyl. In some embodiments of formula (III), (IV), or (V), R1 is ethyl.

[0185] In some embodiments of formula (III), (IV), or (V), R1 is C 1-6 haloalkyl. In some embodiments of formula (III), (IV), or (V), R1 is -CH2-CHF2. In some embodiments of formula (III), (IV), or (V), R1 is -CHF2.

[0186] In some embodiments of formula (III), (IV), or (V), R1 is C 3-7 cycloalkyl. In some embodiments of formula (III), (IV), or (V), R1 is cyclopropyl.

[0187] In some embodiments of formula (III), (IV), or (V), R1 is phenyl substituted with halogen.

[0188] In some embodiments of formula (III), (IV), or (V), R12 is C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and phenyl, and is optionally substituted with one or more substituents each independently selected from halogen and C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, or phenyl is optionally substituted with one or more substituents each independently selected from halogen and C 1-6 alkoxy.

[0189] In some embodiments of formula (III), (IV), or (V), R 12 is C 3-7 cycloalkyl. 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 alkyl. In some embodiments of formula (III), (IV), or (V), R 12 is ethyl. 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 haloalkyl. In some embodiments of formula (III), (IV), or (V), R 12 is -CF3. In some embodiments of formula (III), (IV), or (V), R 12 is -CHF2.

[0192] In another aspect, the disclosure provides a compound of formula VI:

Chemical formula

[0193] In some embodiments of formula (VI), R 13 is selected from the group consisting of ethyl, tert-butyl, sec-butyl, isopropyl, 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 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: [Chemical] or a pharmaceutically 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, -O-C 3-10 optionally substituted with one or more halogens, cycloalkyl, or C 1-6 alkyl, and C 1-6 optionally substituted with one or more substituents selected from alkoxy, cycloalkyl substituted with 3-10 halogen, C

[0200] In some embodiments of formula (VI) (e.g., (VI-a)), R 17 is C 1-6 alkyl or cyclopropyl optionally substituted with C 1-6 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 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 C1-6 alkoxy, C 1-6 alkylene-C 1-6 alkoxy, or C 1-6 is haloalkoxy.

[0205] In some embodiments of formula (VI) (e.g., (VI-a)), R 17 is -OCH(CH3)2, -OCH3, -OCH2CH3, O-CH2CHF2, or -CH2OCH3.

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

[0207] In some embodiments of formula (VI) (e.g., (VI-a)), R 17 is CHF2 or CF3.

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

[0209] In another aspect, the present disclosure provides a compound of formula VII:

Chemical formula

[0210] In another aspect, the disclosure provides a compound of formula VII:

Chemical formula

[0211] In some embodiments of formula (VII), the compound is a compound of formula VII-a or formula VII-b:

Chemical formula

[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 halogen, C 1-6 alkyl, or C 1-6 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)), R 27 is OCH3.

[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 compound numbers 281, 282, 283, and 285 of the examples, or a pharmaceutically acceptable salt thereof.

[0221] In typical embodiments, the present invention is intended to encompass the compounds disclosed herein, as well as pharmaceutically acceptable salts, tautomers, polymorphs, and prodrugs of such compounds. In some embodiments, the present invention is directed to the compounds described herein, for example, pharmaceutically acceptable addition salts, pharmaceutically acceptable esters, solvates (e.g., hydrates) of addition salts, tautomers, hydrates and all polymorphs including polymorphs of solvates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, stereoisomers (as pure, or as racemic or non-racemic mixtures), or mixtures of stereoisomers of the compounds of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), (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)).

[0222] In any and all aspects, in some embodiments, the compounds of formula (I), (II), (III), (IV), or (V) are the compounds of Example Compound Numbers 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, 110, 111, 112, 113, 11 4, 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, 205, 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, 236, 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 pharmaceutically acceptable salt thereof, selected from the group consisting of.

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

[0224] The synthetic route exemplified 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 ethyl pyrazole-5-carboxylate C. Subsequently, hydrolysis of C provides carboxylic acid D. Carboxylic acid D can be coupled with amine E to form F, which can then be hydrolyzed to obtain carboxylic acid G.

Chemical formula

[0225] The synthetic route exemplified in Scheme 2 shows an exemplary procedure for preparing an amine-substituted oxadiazole intermediate L. In the first step, nitrile H is treated with hydroxylamine to provide N-hydroxyimidamide I. Subsequently, oxadiazole K is obtained by the cyclization of glycine J and I mediated by carbonyldiimidazole (CDI). Deprotection of K under acidic conditions provides an amine-substituted oxadiazole intermediate L.

Chemical formula

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

Chemical formula

[0227] As exemplified in Scheme 4, N-hydroxyimidamide I can be cyclized with carboxylic acid G mediated by CDI to obtain compound M (the compound of formula I).

Chemical formula

[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, but are not limited to, those described herein. or conditions include 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, 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 6 months of age) of mostly continuous, heterogeneous focal seizures that appear to migrate from one brain region and hemisphere to another. Patients with EIMFS generally have intellectual disability, speech impairment, and gait disturbances. Several genes have been implicated so far, but the gene most commonly associated with EIMFS is KCNT1. Several de novo variants in KCNT1, including V271F, G288S, R428Q, R474Q, R474H, R474C, I760M, A934T, P924L, G243S, H257D, A259D, R262Q, Q270E, L274I, F346L, C377S, R398Q, P409S, A477T, F502V, M516V, Q550del, K629E, K629N, I760F, E893K, M896K, R933G, R950Q, K1154Q, have been identified in patients with EIMFS (Barcia et al. (2012) Nat Genet. 44:1255-1260, Ishii et al. (2013) Gene 531:467--471, McTague et al. (2013) Brain. 136:1578-1591, Epi4K Consortium have been identified in patients with EIMFS (Barcia et al. (2012) Nat Genet. 44:1255-1260, Ishii et al. (2013) Gene 531:467--471, McTague et al. (2013) Brain. 136:1578-1591, Epi4K Consortium & Epilepsy Phenome / Genome Project. (2013) Nature 501:217-221, Lim et al. (2016) Neurogenetics, Ohba et al. (2015) Epilepsia 56:el21-el28, Zhou et al. (2018) Genes Brain Behav. e12456, Moller et al. (2015) Epilepsia. e114-20, Numis et al. (2018) Epilepsia. 1889-1898, Madaan et al. Brain Dev. 40(3):229-232, McTague et al. (2018) Neurology. 90(1):e55-e66, Kawasaki et al. (2017) J Pediatr. 191:270-274, Kim et al. (2014) Cell Rep. 9(5):1661-1672, Ohba et al. (2015) Epilepsia. 56(9):e121-8, Rizzo et al. (2016) Mol Cell Neurosci. 72:54-63, Zhang et al. (2017) Clin Genet. 91(5):717-724, Mikati et al. (2015) Ann Neurol. 78(6):995-9, Baumer et al. (2017) Neurology. 89(21):2212, Dilena et al. (2018) Neurotherapeutics. 15(4):1112-1126). These mutations are gain-of-function missense mutations that are dominant (i.e., present in only one allele), and when tested in Xenopus oocytes or mammalian expression systems, they cause changes in the function of the encoded potassium channels and lead to a significant increase in whole-cell current (see, for example, 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 has a later onset than EIMFS, generally occurring in mid-childhood and generally being in a non-severe state. It is characterized by nocturnal frontal lobe seizures and can cause mental, behavioral, and cognitive impairments in patients with the condition. ADNFLE is associated with genes encoding several neuronal nicotinic acetylcholine receptor subunits, although mutations in the KCNT1 gene are involved in more severe cases of the disease (Heron et al. (2012) Nat Genet. 44:1188-1190). Functional studies of the mutant KCNT1 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 composed of three features: nodding epilepsy, an interictal electroencephalogram (EEG) pattern called hypsarrhythmia, and mental retardation, although a diagnosis can be made 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). Treatments 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 relates to excessive neuronal excitability and / or in genes such as KCNT1 Diseases or conditions associated with gain-of-function mutations in the gene encoding the gene for which the gene is ... A therapeutic method for treating conditions affecting the immune system (e.g., myotonia, muscle spasms, spasticity), itch and pruritus, ataxia and cerebellar ataxia, psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia), learning disabilities, fragile X, neuroplasticity, and autism spectrum disorders) comprising administering to a 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 ... ), (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), and 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),((I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), (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)), or 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 pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable excipient, a method characterized by administering a pharmaceutical composition comprising to a subject in need of treatment.)

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

[0237] In other embodiments, the subject is first genotyped to identify the presence of a mutation in KCNT1, and then a standard in vitro assay such as that described in Milligan et al. (2015) Ann Neurol. 75(4):581-590 is used to confirm that this mutation is a gain-of-function mutation. Typically, whole-cell electrophysiology (such as that described in Milligan et al. (2015) Ann Neurol. 75(4):581-590, Barcia et al. (2012) Nat Genet. 44(11):1255-1259, Mikati et al. (2015) Ann Neurol. 78(6):995-999, or Rizzo et al. Mol Cell Neurosci. (2016) 72:54-63) is used to evaluate, and compared to the whole-cell current arising from the expression of wild-type KCNT1, if the expression of the mutant KCNT1 allele results in an increase in the whole-cell current, the presence of a gain-of-function mutation is confirmed. This increase in the whole-cell current can be, for example, an increase of at least or about 50%, 100%, 150%, 200%, 250%, 300%, 350%, 400% or more. It can then be confirmed that the subject has a disease or condition associated with a gain-of-function mutation in KCNT1.

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

[0239] The compounds disclosed herein (e.g., the compounds of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m) , (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), (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 pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a compound disclosed herein (e.g., a compound of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), (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 pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient) can also be used therapeutically for conditions associated with excessive neuronal excitability that are not necessarily the result of a gain-of-function mutation in KCNT1. Even if the disease is not the result of an increase in KCNT1 expression and / or activity, inhibition of KCNT1 expression and / or activity can still result in a reduction in neuronal excitability, thereby providing a therapeutic effect. Accordingly, the compounds disclosed herein (e.g., compounds of formula (I) (e.g., (I-I), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), (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- ceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., a compound disclosed herein (e.g., a compound of formula Compounds of (I) (for example, (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), (I (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), and a pharma- ceutically acceptable excipient. The composition) can be used to treat subjects with 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, for example compounds of formula (I), (e.g., (II), (I-II), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), or (I-s)), (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)) are usually administered in the form of a pharmaceutical composition. Accordingly, the present invention provides a pharmaceutical composition comprising, as an active ingredient, one or more of the described compounds, or a pharmaceutically acceptable salt or ester thereof, one or more pharmaceutically acceptable excipients, a carrier comprising an inert solid diluent and a filler, a diluent comprising a sterile aqueous solution and various organic solvents, a penetration enhancer, a solubilizer, and an adjuvant. The pharmaceutical composition 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, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.)).

[0241] The pharmaceutical composition can be administered in either single or multiple doses by any of the acceptable modes of administration of a drug, including, for example, intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or via a stent, or an impregnated or coated device such as, for example, an arterial insertion cylindrical polymer, by rectal, buccal, intranasal, and transdermal routes, having the same usefulness as described in those patents and patent applications incorporated herein by reference.

[0242] One mode for administration is parenteral, particularly by injection. Forms in which the novel composition of the invention can be incorporated for administration by injection include aqueous or oily suspensions, or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, and 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 glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be brought about by various antibacterial and antifungal agents such as, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal.

[0243] Sterile injectable solutions are prepared by incorporating the required amount of the compound according to the invention in a suitable solvent containing, optionally, various other ingredients enumerated above, followed by filter sterilization. Generally, dispersions are prepared by incorporating various sterilized active ingredients in a sterile vehicle containing a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques that yield a powder of the active ingredient and any additional desired ingredients from its sterile solution that has been previously sterile filtered.

[0244] Oral administration is another route for administration of the compounds according to the invention. Administration can be via capsules or enteric-coated tablets, etc. In the preparation of a pharmaceutical composition containing at least one compound described herein, the active ingredient is usually diluted by an excipient and / or enclosed in such a carrier which can be in the form of capsules, sachets, paper or other containers. When the excipient functions as a diluent, the excipient can be in the form of a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient (as above). Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. In addition, the formulation can include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweetening agents; and flavoring agents.

[0245]

[0246] ​The inventive composition can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by using procedures known in the art. Examples of 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 method of the present invention employs a transdermal delivery device (“patch”). Such transdermal patches can be used to provide a continuous or discontinuous infusion of the compounds of the present invention in a controlled amount. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. See, for example, U.S. Pat. Nos. 5,023,252, 492,445, and 5,001,139. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0247] The composition is preferably formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampule). The compounds are generally administered in pharmaceutically effective amounts. Preferably, for oral administration, each dosage unit contains from 1 mg to 2 g of the compounds described herein, and for parenteral administration, preferably from 0.1 to 700 mg of the compounds described herein. However, it will be understood that the actual amount of compound administered will usually be determined by the physician in view of relevant circumstances including the condition being 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 main active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of the compounds of the present invention. When referring to these pre-formulation compositions being homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, such that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0249] The tablets or pills of the present invention provide a dosage form that produces the advantage of long-term action or can be formulated by coating or other means to protect from the acidic gastric state. For example, a tablet or pill can include an inner dosage component and an outer dosage component, the latter being in the form of a coating that covers the former. The two components can be separated by an enteric layer that functions to withstand disintegration in the stomach and allows the inner component to pass through the duodenum intact or be released in a delayed manner. A variety of materials can be used for such enteric layers or coatings, examples of such materials including many polymeric acids, as well as mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0250] Compositions for inhalation or insufflation include solutions and suspensions, and powders, in a pharmaceutically acceptable aqueous or organic solvent, or mixtures thereof. Liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered via the oral or nasal respiratory route for local or systemic effects. Compositions in a pharmaceutically acceptable solvent can preferably be nebulized by the use of an inert gas. The nebulized solution can be inhaled directly from the nebulizing device or the nebulizing device can be attached to a face mask tent or intermittent positive pressure breathing apparatus. Solution, suspension, or powder compositions can be administered preferably orally or nasally from a device that delivers the formulation in a suitable manner.

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

Examples

[0252] To better understand the invention described herein, the following examples are provided. 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 as limiting their scope in any way.

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

[0254] In addition, as will be apparent to those of ordinary skill in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing unwanted reactions. The selection of suitable protecting groups for a particular functional group, as well as the conditions suitable for protection and deprotection, are well known in the art. For example, numerous protecting groups, as well as their introduction and removal, are described in T.W. Greene and P.G.M. Wuts, 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 performance liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). Note 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 hydride THF Tetrahydrofuran DMF N,N-Dimethylformamide DCM Dichloromethane EtOH Ethanol ACN Acetonitrile MeCN Acetonitrile CH3CN 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 MeNH2 Methylamine Cu(OAc)2 Copper(II) acetate DCC N,N’-Dicyclohexylcarbodiimide DCE Dichloroethane i-PrOH Isopropyl alcohol EtOAc Ethyl acetate HOBt Hydroxybenzotriazole HATU Hexafluorophosphate azabenzotriazole tetramethyluranium DEA Diethanolamine MeNHNH2 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 Ac2O Acetic anhydride PTFE Polytetrafluoroethylene Pd(dppf)Cl2 [1,1’-Bis(diphenylphosphino)ferrocene] palladium(II) dichloride DMS Dimethyl sulfate T3P Propylphosphonic anhydride solution PE Petroleum ether LCMS Liquid chromatography mass spectrometry

[0256] Synthesis of Examples 1.192 and 191 a) Synthesis of 191

Chemical formula

[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) were 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), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography using 10% EtOAc / PE to give compound A-268 (1.1 g, 3.8 mmol, 28% yield). LCMS: 302.1 (M-H), 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), TFA (1.5 mL) was added at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 8 h. The reaction mixture was concentrated and treated with saturated NaHCO3 solution (10 mL). The mixture was extracted with EtOAc (2 x 20 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give Compound A-269 (188 mg). The compound was used in the next step without further purification.

[0259] (R)-3-Cyclopropyl-1-methyl-N-(1-(3-(m-tolyl)-1,2,4-oxadiazol-5-yl)ethyl)-1H-pyrazole-5-carboxamide (191) Synthesis To a stirred solution of Compound A-269 (188 mg, 0.92 mmol) in THF (5.0 mL), 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) were added. 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), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel using 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. 11H NMR (400 MHz, CDCl3): δ 7.91 - 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 [Chemical formula] 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) were 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), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by column chromatography on silica gel using 10% EtOAc / PE to give compound A-270 (0.80 g, 2.62 mmol, yield 39%). LCMS: 302.1 (M-H), Rt 2.56 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 1 1H NMR (400 MHz, D MSO-d6): δ 7.82 - 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)ethane-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 treated with saturated NaHCO3 solution (10 mL). The mixture was extracted with EtOAc (2 x 20 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give compound A-271 (200 mg). 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), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel using 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 CO2, B = 0.5% isopropylamine in methanol; flow rate: 4.0 mL / min; wavelength: 210 nm. 1 H NMR (400 MHz, CDCl3): δ 7.91 - 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

Chemical Structure

[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 quenched by adding saturated NH4Cl (30 mL), and the mixture was extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 55 - 85% B over 7 min) to give the product (300 mg, 0.85 mmol, 47% yield) as a solid. LCMS R t = 1.11 min on chromatography with 2.0 min, 5 - 95 AB, C 19 H 22 N5O2[M + H] + MS ESI calculated value at + is 352.2, measured value is 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% - 40% B in 2.5 min, 40% for 0.35 min, then hold 40% - 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C) showed two peaks at 1.37 min and 1.61 min. The product was purified by SFC (Daicel CHIRALPAK AD-3 (50 mm × 3 mm, 5 μm); A = CO2 and B = EtOH (0.1% NH3H2O); 38 °C; 60 mL / min; 25% B; run for 12 min; 7 injections, Rt of peak 1 = 5.74 min, Rt of peak 2 = 10.1 min) and randomly assigned as enantiomer 1 (Rt = 1.37 min in analytical SFC) as 3 (73.33 mg, 0.21 mmol, yield 24%) as a solid, and enantiomer 2 (Rt = 1.61 min in analytical SFC) as 4 (77.03 mg, 0.22 mmol, yield 26%) as a solid. 3: 1 H NMR (400 MHz, CDCl3) 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 = 1.14 min in chromatography at 2.0 min, 10 - 80 AB, C 19 H 22 N5O2 [M + H] + Calculated MS ESI value in 352.2, measured value 352.1. 4: 1 H NMR (400 MHz, CDCl3) 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= Chromatography at 2.0 minutes, 1.12 minutes, 10 - 80 AB, C 19 H 22 N5O2[M + H] + MS ESI calculated value at is 352.2, measured value is 352.1.

[0266] Synthesis of Example 3.5 [Chemical formula] 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 hours to obtain a mixture. After cooling to room temperature, the reaction mixture was concentrated to remove most of the EtOH, and then diluted with H2O (20 mL). The mixture was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product (600 mg) as a solid. LCMS R t = Chromatography at 1.5 minutes, 0.46 minutes, 5 - 95 AB, C7H8FN2O[M + H] + MS ESI calculated value at is 155.1, measured value is 154.8.

[0267] 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 phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = water (0.05% NH4OH) and B = CH3CN; 49 - 79% B over 8 min) to give the product (23.03 mg, 64.8 μmol, 9% yield) as a solid. 1 H NMR (400 MHz, CDCl3) 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 by chromatography at 2.0 min, 10 - 80 AB, C 18 H 19 FN5O2 [M + H] + The calculated value of MS ESI at 356.1, the measured value 356.0.

[0268] Synthesis of Example 4.6

Chemical formula

[0269] 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 phases were washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a crude product. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 53 - 83% B over 8 min) to give the product (21.27 mg, 56.9 μmol, 13% yield) as a solid. 1 H NMR (400 MHz, CDCl3) 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 minutes by chromatography of 2.0 fractions, 10 - 80 AB, C 18 H 19 ClN5O2 [M + H] + The calculated value of MS ESI is 372.1, and the measured value is 372.0.

[0270] Synthesis of Example 5.7

Chemical Structure

[0271] 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 phases were washed with brine (20 mL), dried over Na2SO4, 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 = H2O (0.05% NH4OH v / v) and B = CH3CN; 41 - 71% B over 8 min) to give the product (52.31 mg, 140.1 μmol, 22% yield) as a solid. 1 H NMR (400 MHz, CDCl3) 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 = 1.12 min on a 2.0 min chromatography, 10 - 80 AB, C 18 H 18 F2N5O [M + H] + Calculated MS ESI for 374.1, found 374.0.

[0272] Synthesis of Example 6.8

Chemical Structure

[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-aminopropionate hydrochloride (419.97 mg, 3.01 mmol) in DCM (15 mL) was stirred at 20 °C for 16 h. The reaction mixture was quenched with saturated NH4Cl (20 mL). The mixture was extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product (500 mg) as an oil. LCMS R t Chromatography with retention time of 1.5 min, 0.72 min for 5 - 95 AB, C 12 1H 18 N3O3 [M + H] + The calculated value of MS ESI at 252.1, the measured value is 252.0.

[0274] To a solution of methyl 2-[(5-cyclopropyl-2-methylpyrazole-3-carbonyl)amino]propanoate (500 mg, 1.99 mmol) in THF (4 mL) was slowly added a solution of LiOH·H₂O (166.99 mg, 3.98 mmol) in water (4 mL). 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 the pH to 2, and the mixture was extracted with EtOAc (20 mL×2). The combined organic phases were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the crude product (350 mg) as an oil. LCMS R t = 0.67 min by chromatography at 1.5 min, 5 - 95 AB, C 11 H 16 N3O3[M + H] + Calculated value of MS ESI at 238.1, measured 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 H₂O (20 mL) and the mixture was extracted with EtOAc (20 mL×2). The combined organic phases were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Agela DuraShell (150 mm×25 mm, 5 μm), A = H₂O (10 mM NH₄HCO₃) and B = CH₃CN; 40 - 80% of B over 8.5 min) to obtain the product (40.74 mg, 114.60 μmol, 18% yield) as an oil. 1 H NMR (400 MHz, CDCl₃) 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 minutes by chromatography in 2 parts, 10 - 80 AB, C 18 H 19 FN5O2[M + H] + The calculated value of MS ESI is 356.1 and the measured value is 356.0 at

[0276] Synthesis of Example 7.9

Chemical Structure

[0277] 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 phases were washed with brine (20 mL), dried over Na2SO4, 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% NH4OH) and B = CH3CN; 49 - 79% B over 8 min) to give the product (53.21 mg, 143.1 μmol, 23% yield) as a solid. 1 H NMR (400 MHz, CDCl3) 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 by chromatography at 1.20 min, 10 - 80 AB, C 18 H 19 ClN5O2 [M + H] + Calculated MS ESI value for 372.1, found 372.0.

[0278] Synthesis of Example 8.10

Chemical Structure

[0279] Synthesis of Example 9.11

Chemical Structure

[0280] Synthesis of Example 10.12

Chemical Structure

[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 NH4Cl (20 mL) and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Welch Xtimate C18 (150 mm × 25 mm, 5 μm), A = H2O (10 mM NH4HCO3) and B = CH3CN; 20 - 50% B over 9 min) to give the product (26.89 mg, 65.60 mmol, 10% yield) as an oil. 1 H NMR (400 MHz, CDCl3) 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 by 2 - fraction chromatography, 10 - 80 AB, C 19 H 19 F3N5O2[M + H] + MS ESI calculated value in is 406.1, measured value 406.0.

[0282] Synthesis of Example 11.13

Chemical Structure

[0283] Synthesis of Examples 12.14 and 15

Chemical Structure

[0284] 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. Then N'-hydroxybenzamidine (126.25 mg, 0.93 mmol) was added and then the reaction mixture was 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 phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = water (0.05% NH4OH v / v) and B = CH3CN; 45 - 75% B over 8 min) to give the product (170 mg, 495.1 μmol, 59% yield) as a solid. LCMS R t = 1.5 min chromatography at 0.87 min, 5 - 95 AB, C 18 H 20 N5O2[M + H] + Calculated MS ESI value for 338.2, found 338.1.

[0285] 14 and 15: Analytical SFC (Daicel CHIRACEL OJ-H (150 mm × 4.6 mm, 5 μm), mobile phase: A: CO2 B: methanol (0.05% DEA), gradient: hold 5% for 0.5 min then 5% - 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 min and 3.73 min. The product was purified by SFC (Daicel Separated by CHIRALPAK AS (250 mm × 30 mm, 5 μm); A = CO2 and B = MeOH (0.1% 3H2O); 35 °C; 50 mL / min; 20% B; run for 9 min; 7 injections, Rt of peak 1 = 5.87 min, Rt of peak 2 = 7.39 min), enantiomer 1 randomly assigned as 14 (11.44 mg, 33.9 μmol, 7% yield) as a solid, and enantiomer 2 randomly assigned as 15 (31.75 mg, 94.1 μmol, 19% yield) as a solid with Rt = 3.40 min in analytical SFC. 14: 1 H NMR (400 MHz, CDCl3) 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 = 1.21 min in chromatography with 2.0 min, 10 - 80 AB, C 18 H 20 N5O2 [M + H] + Calculated value of MS ESI in 338.2, measured value 338.0. 15: 1 H NMR (400 MHz, CDCl3) 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 = 1.21 min in chromatography with 2.0 min, 10 - 80 AB, C 18 H 20 N5O2 [M + H] + Calculated value of MS ESI in 338.2, measured value 338.0.

[0286] Synthesis of Examples 13.16 and 17

Chemical Structure

[0287] Synthesis of Examples 14.19 and 20 [Chemical formula] A-27: To a solution of 1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (150 mg, 630 μmol), and 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 hours. The mixture was diluted with H2O (40 mL) and then extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 65 - 75% B over 8 minutes) to give the product (200 mg, 527.2 μmol, 84% yield) as an oil. LCMS R t = 3.97 minutes by chromatography at 7.0 minutes, 10 - 80AB, C 17 H 17 F3N5O2[M+H] + MS ESI calculated value in + is 380.13, measured value is 380.0.

[0288] 19 and 20: Analytical SFC (Daicel CHIRALCEL OJ-3 (150 mm × 4.6 mm, 3 μm), mobile phase: A: CO2 B: ethanol (0.05% DEA), gradient: 5% - 40% B in 5 minutes, hold at 40% for 0.5 minutes, then hold at 5% B for 1.5 minutes, flow rate: 2.5 mL / min, column temperature: 35 °C) showed two peaks at 2.53 minutes and 3.11 minutes. The product was separated by SFC (Daicel CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); A = CO2 and B = EtOH (0.1% NH3H2O); 35 °C; 50 mL / min; 25% B; run for 7 minutes; 6 injections, Rt of peak 1 = 3.45 minutes, Rt of peak 2 = 4.40 minutes) and randomly assigned as 19 (55.59 mg, 146.5 μmol, 28% yield) as the solid of enantiomer 1 (Rt = 2.53 minutes in analytical SFC) and 20 (61.98 mg, 163 μmol, 31% yield) as the solid of enantiomer 2 (Rt = 3.11 minutes in analytical SFC). 19: 1 H NMR (400 MHz, CDCl3) 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 minutes in chromatography at 2.0 minutes, 10 - 80 AB, C 17 H 17 F3N5O2 [M + H] + Calculated MS ESI value at 380.13, measured value 379.9. 20: 1 H NMR (400 MHz, CDCl3) 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 minutes in chromatography at 2.0 minutes, 10 - 80 AB, C 17 H 17F3N5O2[M+H] + MS ESI calculated value in + is 380.13, measured value is 379.9.

[0289] Synthesis of Example 15.21

Chemical Structure

[0290] Synthesis of Example 16.22

Chemical Structure

[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 h. The reaction mixture was concentrated to give a residue. The residue was diluted with H2O (20 mL) and washed with EtOAc (20 mL × 1). The aqueous phase was acidified to pH = 1 with 1 N HCl (20 mL). The mixture was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (70 mL), dried over Na2SO4, filtered, and concentrated to give a crude product (200 mg) as a solid. 1 H NMR (400 MHz, CDCl3) 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), and 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, diluted with H2O (10 mL), and then extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to give a crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 37 - 67% B over 8 min) to give the product (35.39 mg, 99.7 μmol, 24% yield) as a solid. 1 H NMR (400 MHz, CDCl3) 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 = 2.0 min of chromatography at 1.28 min, 10 - 80 AB, C 19 H 24 N5O2[M + H] + Calculated MS ESI value for 354.19, found 354.2 at

[0293] Synthesis of Examples 17.23 and 24

Chemical Structure

[0294] Synthesis of Examples 18.25 and 26

Chemical Structure

[0295] Synthesis of Examples 19, 29 and 30

Chemical Structure

[0296] Synthesis of Examples 20.31 and 32

Chemical Structure

[0297] The product was separated by SFC (Regis (S,S) Whelk-O1 (250 mm × 30 mm, 5 μm); A = CO2 and B = ethanol (0.1% NH3H2O); 38 °C; 60 mL / min; 60% B; run for 10 min; injected 3 times, Rt of peak 1 = 7.9 min, Rt of peak 2 = 5.5 min), and the enantiomer 1 randomly assigned as 31 (9.92 mg, 28.1 μmol, yield 33%) (Rt = 3.68 min on analytical SFC) was obtained as an oil, and the enantiomer 2 randomly assigned as 32 (9.16 mg, 25.9 μmol, yield 30%) (Rt = 4.40 min on analytical SFC) was obtained as an oil. 31 1 H NMR (400 MHz, DMSO-d6) 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 on chromatography with a retention time of 2.0 min, 10 - 80 AB, C 19 H 24 N5O2 [M + H] + Calculated value of MS ESI in 354.19, measured value 354.1. 32: 1 H NMR (400 MHz, DMSO-d6) 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 on chromatography with a retention time of 2.0 min, 10 - 80 AB, C 19 H 24 N5O2 [M + H] + Calculated value of MS ESI in 354.19, measured value 354.0.

[0298] Synthesis of Example 21.33

Chemical Structure

[0299] 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. Then the reaction mixture was diluted with H2O (15 mL) and washed with EtOAc (20 mL, discarded). The aqueous phase was acidified with 1 N HCl (20 mL) to adjust the pH to 1 and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine (70 mL), dried over Na2SO4, filtered, and concentrated to give the product (100 mg, 567.8 μmol, 90% yield) as a solid. 1 H NMR (400 MHz, DMSO-d6) δ H = 14.15 (br s, 1H), 8.13 (t, 1H), 6.86 (s, 1H), 2.26 (s, 3H).

[0300] To a mixture of 2-(difluoromethyl)-5-methyl-pyrazole-3-carboxylic acid (100 mg, 570 μmol), HATU (380.71 mg, 1 mmol), and 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, diluted with H2O (10 mL), and then extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 53 - 83% B over 8 min) to give the product (109.62 mg, 303.4 μmol, 61% yield) as an oil. 1 H NMR (400 MHz, 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 = 2.0 min chromatography at 1.24 min, 10 - 80 AB, C 17 H 18 F2N5O2 [M + H] + Calculated MS ESI value at 362.14, found 362.0.

[0301] Synthesis of Examples 22.34 and 35

Chemical Structure

[0302] Synthesis of Examples 23.36 and 37

Chemical formula

[0303] Synthesis of Examples 24.38 and 39

Chemical Structure

[0304] 38 and 39: Analytical SFC (Column: Daicel CHIRALCEL IC - 3 (150 mm × 4.6 mm, 3 μm), mobile phase: A: CO2 B: ethanol (0.05% DEA), gradient: 5% - 40% B in 5 min, hold at 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 separated by SFC (Daicel CHIRALCEL (250 mm × 30 mm, 5 μm); A = CO2 and B = EtOH; 38 °C; 50 mL / min; 30% B; run for 7 min; 4 injections, Rt of peak 1 = 3.75 min, Rt of peak 2 = 5.4 min), and randomly assigned as 38 (24.43 mg, 0.07 mmol, 41% yield) as enantiomer 1 (Rt = 3.42 min in analytical SFC) as an oil, and 39 (27.23 mg, 0.08 mmol, 45% yield) as enantiomer 2 (Rt = 4.26 min in analytical SFC) as an oil. 38: 1 H NMR (400 MHz, CD3CN) 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 = 1.25 min in chromatography at 2.0 min, 10 - 80 AB, C 18 H 22 N5O2 [M + H] + Calculated value of MS ESI at 340.2, measured value 340.1. 39: 1 H NMR (400 MHz, CD3CN) 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 = 1.25 min in chromatography at 2.0 min, 10 - 80 AB, C 18 H 22 N5O2 [M + H] +The calculated value by MS ESI was 340.2, and the measured value was 340.1.

[0305] Synthesis of Examples 25, 40 and 41

Chemical formula

[0306] A-37: To a solution of ethyl 1-isopropyl-4-methyl-pyrazole-3-carboxylate (190 mg, 0.97 mmol) in ethanol (9 mL) was added a solution of NaOH (116.18 mg, 2.9 mmol) in water (9 mL), and the mixture was stirred at 50 °C for 3 hours. After cooling to room temperature, the reaction mixture was concentrated to obtain a residue. The residue was diluted with H2O (30 mL) and washed with EtOAc (20 mL × 1). The aqueous phase was acidified with 1N HCl (20 mL) to adjust the pH to 1, and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine (70 mL), dried over Na2SO4, filtered, and concentrated to obtain the product (130 mg, 0.76 mmol, 78% yield) as a solid. LCMS R t= Chromatography for 1.5 minutes at 0.65 minutes, 5 - 95 AB, C8H 13 N2O2[M + H] + MS ESI calculated value at 169.09, measured value 168.9

[0307] To a mixture of 1 - isopropyl - 4 - methyl - pyrazole - 3 - carboxylic acid (130 mg, 0.77 mmol), HATU (317.25 mg, 0.83 mmol), and 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 hours. The mixture was concentrated, diluted with H2O (10 mL), and then extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 59 - 89% B over 8 minutes) to obtain the product (150 mg, 412.9 μmol, 99% yield) as an oil. LCMS R t = Chromatography for 1.5 minutes at 0.93 minutes, 5 - 95 AB, C 19 H 24 N5O2[M + H] + MS ESI calculated value at 354.19, measured value 354.2

[0308] 40 and 41: Analytical SFC (Regis (S,S) Whelk-O1 (250 mm × 4.6 mm, 5 μm), mobile phase: A: CO2 B: ethanol (0.05% DEA), gradient: 5% - 40% B in 5 min, hold at 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 separated by SFC (Regis (S,S) Whelk-O1 (250 mm × 30 mm, 5 μm); A = CO2 and B = methanol (0.1% DEA); 38 °C; 60 mL / min; 40% B; run for 12 min; 4 injections, Rt of peak 1 = 6.2 min, Rt of peak 2 = 9.0 min), and randomly assigned as 41 (47.98 mg, 135.8 μmol, 32% yield) as enantiomer 1 (Rt = 3.46 min in analytical SFC) as an oil, and 40 (51.51 mg, 145.7 μmol, 34% yield) as enantiomer 2 (Rt = 5.05 min in analytical SFC) as a solid. 41: 1 H NMR (400 MHz, DMSO-d6) 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 chromatography at 2.0 min, 10 - 80 AB, C 19 H 24 N5O2 [M + H] + Calculated value of MS ESI at 354.19, measured value 354.0. 40: 1 H NMR (400 MHz, DMSO-d6) 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 chromatography at 2.0 min, 10 - 80 AB, C 19 H24 N5O2[M+H] + MS ESI calculated value in it is 354.19, measured value is 354.0.

[0309] Synthesis of Examples 26.42 and 43 [Chemical formula] 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 hour, then N'-hydroxy-3-(trifluoromethyl)benzamidine (320 mg, 1.57 mmol) was added. The reaction mixture was stirred at 110 °C for 16 hours. After cooling to room temperature, the mixture was diluted with NH4Cl (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by column flash chromatography on silica gel (EtOAc in PE = 10% - 30% - 50%) to obtain the product (500 mg, 1.24 mmol, yield 79%) as an oil. LCMS R t Chromatography with R = 1.5 minutes at 0.95 minutes, 5 - 95 AB, C 12 H 11 F3N3O3[M - tBu + H] + MS ESI calculated value in it is 302.1, measured value is 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), 4 M HCl / 1,4-dioxane (20 mL) was added and the mixture was stirred at 20 °C for 8 hours. The mixture was concentrated to obtain the crude product (180 mg, 0.61 mmol, yield 79%) as a solid. LCMS R t Chromatography with R = 1.5 minutes at 0.69 minutes, 5 - 95 AB, C 11 H 11F3N3O[M+H] + MS ESI calculated value in + is 258.1, measured value is 258.0.

[0311] A - 42: A mixture of 5 - isopropyl - 2 - methyl - pyrazole - 3 - carboxylic acid (54.41 mg, 0.32 mmol), HOBt (92.03 mg, 0.68 mmol), Et3N (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) in DCM (20 mL) was stirred at 20 °C for 16 h under N2. The reaction mixture was quenched with saturated NH4Cl (20 mL), and the mixture was extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 20 - 80% B over 8 min) to give the product (85 mg, 0.21 mmol, 61% yield) as an oil. LCMS R t Chromatography with R = 1.5 min, retention time 0.93 min, 5 - 95 AB, C 19 H 21 F3N5O2[M+H] + MS ESI calculated value in + is 408.2, measured value is 408.1.

[0312] 42 and 43: Analytical SFC (Regis (R,R) Whelk - O1 (100 mm × 4.6 mm, 5 μm), mobile phase: A: CO2 B: ethanol (0.05% DEA) , Gradient: 5% - 40% B for 5 minutes, 40% B for 2.5 minutes, then hold 5% B for 2.5 minutes, Flow rate: 2.5 mL / min, Column temperature: 35 °C) showed two peaks at 3.15 minutes and Rt = 3.68 minutes. The product was separated by SFC (Regis (S,S) Whelk - O1 (250 mm × 30 mm, 5 μm); A = CO2 and B = EtOH; 38 °C; 65 mL / min; 30% B; run for 7 minutes; 6 injections, Rt of peak 1 = 4.43 minutes, Rt of peak 2 = 5.72 minutes), and randomly assigned as 42 (25.66 mg, 0.06 mmol, yield 31%) as enantiomer 1 (Rt = 3.15 minutes in analytical SFC) as an oil, and 43 (25.41 mg, 0.06 mmol, yield 32%) as enantiomer 2 (Rt = 3.68 minutes in analytical SFC) as an oil. 42: 1 1H NMR (400 MHz, CD3CN) 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 minutes in chromatography at 2.0 minutes, 10 - 80 AB, C 19 1H 21 F3N5O2[M + H] + MS ESI calculated value in is 408.2, measured value 408.1. 43: 1 1H NMR (400 MHz, CD3CN) δ H = 8.34 - 8.25 (m, 2H), 7.88 (d, 1H), 7.74 (t, 1H), 7.50 (d, 1H), 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 = 1.35 minutes in chromatography at 2.0 minutes, 10 - 80 AB, C 19 1H 21 F3N5O2[M + H] + MS ESI calculated value in is 408.2, measured value 408.1.

[0313] Synthesis of Example 27.44 [Chemical formula] To a mixture of 1-isopropyl-3-methyl-pyrazole-4-carboxylic acid (100 mg, 0.59 mmol) in DCM (10 mL), 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) were added, and the reaction mixture was stirred at 25 °C for 16 h. The reaction was quenched with H2O (10 mL) and then extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 17 - 47% B over 8 min) to give the product as an oil. Analytical SFC (Daicel CHIRALPAK AS-3 (150 mm × 4.6 mm, 3 μm), mobile phase: A: CO2 B: ethanol (0.05% DEA), gradient: 5% - 40% B in 5 min, 40% - 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 2.39 min (main peak, 91.6%) and 2.55 min (8.4%). Note: The condensation reaction causes some racemization. The product was then purified by SFC (Daicel CHIRALPAK AS-H (250 mm × 30 mm, 5 μm); A = CO2 and B = EtOH (0.1% NH3H2O); 38 °C; 65 mL / min; 20% B; run for 8.60 min; 50 injections, Rt of peak 1 = 5.57 min, Rt of peak 2 = 6.60 min) to give the product (66.75 mg, 0.19 mmol , 32% yield) as an oil. 11H NMR (400 MHz, CD3CN) 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 = 1.13 minutes by chromatography with a gradient of 10 - 80 AB, C 19 H 24 N5O2 [M + H] + Calculated value of MS ESI is 354.2, measured value is 354.0

[0314] Synthesis of Example 28.45

Chemical Structure

[0315] A-45: A mixture of 2-(tert-butoxycarbonylamino)-3-methylbutanoic 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 hour, then 3-fluoro-N-hydroxy-benzamidine (283.79 mg, 1.84 mmol) was added. The reaction mixture was stirred at 100 °C for 16 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% - 20% - 50%) to obtain the product (150 mg, 0.45 mmol, 24% yield) as an oil. LCMS R t Chromatography at 1.5 minutes, 0.96 minutes, 5 - 95 AB, C 17 H 23 FN3O3[M + H - Boc] + Calculated MS ESI value in is 280.1, measured value is 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), 4M HCl / 1,4-dioxane (10 mL, 40 mmol) was added and the reaction mixture was stirred at 20 °C for 2 hours The mixture was concentrated and the pH was adjusted to about 9 by adding saturated NaHCO3. The mixture was extracted with EtOAc (40 mL × 2), the combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain a crude product (150 mg) as an oil. LCMS R t Chromatography at 1.5 minutes, 0.696 minutes, 5 - 95 AB, C 12 H 14 FN3O[M + H] + Calculated MS ESI value in is 236.11, measured value is 236.1.

[0317] 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. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 59 - 89% B over 8 min) to give the product (75.38 mg, 412.9 μmol, 31% yield) as an oil. 1 H NMR (400 MHz, CDCl3) 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 by chromatography at 2.0 min, 5 - 95 AB, C 20 H 22 FN5O2 [M + H] + The calculated value of MS ESI in 384.2, the measured value is 384.2.

[0318] Synthesis of Examples 29.46 and 47

Chemical Structure

[0319] Synthesis of Example 30.48

Chemical Formula

[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 hour, then 3-fluoro-N-hydroxy-benzamidine (303.37 mg, 1.97 mmol) was added. The mixture was stirred at 100 °C for 16 hours. The mixture was cooled, then diluted with H2O (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% - 20% - 50%) to obtain the product (150 mg, 0.45 mmol, yield 23%) as an oil. LCMS R t = 1.5 minutes, retention time 0.94 minutes by chromatography, 5 - 95 AB, C 16H 21 FN3O3[M+H-Boc] + MS ESI calculated value in it is 266.1, measured value is 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), 4M HCl / 1,4-dioxane (10 mL, 40 mmol) was added, and the reaction mixture was stirred at 20 °C for 2 hours. The mixture was concentrated, and the pH was adjusted to about 9 by adding saturated NaHCO3. The mixture was extracted with EtOAc (40 mL × 2), the combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product (150 mg) as an oil. LCMS R t = 1.5 minutes, retention time 0.66 minutes by chromatography, 5-95 AB, C 11 H 14 ClFN3O[M+H] + MS ESI calculated value in it is 222.0, measured value is 222.0.

[0322] 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 NH4Cl (10 mL) and extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 55 - 85% B over 8 min) to give the product (77.37 mg, 0.21 mmol, 31% yield) as a solid. 1 H NMR (400 MHz, CDCl3) 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 by chromatography at 2.0 min, 5 - 95 AB, C 19 H 21 FN5O2 [M + H] + The calculated value of MS ESI at 370.2, the measured value 370.1.

[0323] Synthesis of Example 31.49

Chemical Structure

[0324] A-50: To tert-butyl 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), 4M HCl / 1,4-dioxane (10 mL, 40 mmol) was added, and the reaction mixture was stirred at 20 °C for 2 hours. The mixture was concentrated, and the pH was adjusted to about 9 by adding saturated NaHCO3. The mixture was extracted with EtOAc (40 mL × 2), the combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain a crude product (150 mg, 0.46 mmol, 88% yield) as an oil. LCMS R t Chromatography with an LCMS R retention time of 1.5 minutes shows a peak at 0.73 minutes, 5 - 95 AB, C 16 H 16 ClFN3O[M + H] + The calculated value of MS ESI for [M + H] is 284.1, and the measured value is 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. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 62 - 92% B over 8 min) to afford the product (42.55 mg, 0.10 mmol, 18% yield) as a solid. 1 H NMR (400 MHz, DMSO-d6) 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 by chromatography at 2.0 min, 5 - 95 AB, C 24 H 23 FN5O2[M + H] + The calculated MS ESI value for FN5O2[M + H] is 432.2, and the measured value is 432.1.

[0326] Synthesis of Example 32.50

Chemical Structure

[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), 4 M HCl in 1,4-dioxane (3 mL, 12 mmol) was added and the mixture was stirred at 15 °C for 1 hour. The mixture was concentrated to give the product 2-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]propane-2-amine hydrochloride (110 mg, 417.8 μmol, 96% yield) as a solid. Chromatography with LCMS Rt = 1.5 min gave 0.64 min, 5 - 95 AB, C 15 H 13 FN3O[M + H] + The calculated value of MS ESI in it is 222.1, and the measured value is 222.0.

[0328] 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) was added DIPEA (0.2 mL, 1.16 mmol), 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 phases were washed with water (20 mL × 2) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 52 - 82% B over 8 min) to give the product (116.91 mg, 0.32 mmol, 81% yield) as a solid. 1 H NMR (400 MHz, DMSO-d6) 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 by chromatography at 2.0 min, 10 - 80 AB, C 19 H 21 FN5O2 [M + H] + The calculated value of MS ESI at 370.2, the measured value 369.9.

[0329] Synthesis of Example 33.51

Chemical formula

[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), 4 M HCl in 1,4-dioxane (3 mL, 12 mmol) was added and the mixture was stirred at 15 °C for 1 hour. The mixture was concentrated to obtain the product (110 mg, 351.4 μmol, 93% yield) as a solid. Chromatography with LCMS Rt = 1.5 min showed 0.71 min, 5 - 95 AB, C 15 H 13 FN3O[M + H] + MS ESI calculated value in 270.1, measured value 270.0.

[0331] 51: 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-oxadiazole- To a mixture of 5-yl]-phenyl-methanamine hydrochloride (140 mg, 0.46 mmol), DIPEA (0.24 mL, 1.37 mmol) was added and the mixture was stirred at 20 °C for 2 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (20 mL × 2) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 60 - 90% B over 8 minutes) to give the product (88.39 mg, 0.21 mmol, 46% yield) as a solid. 1 H NMR (400 MHz, DMSO-d6) 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, 4H), 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 minutes by chromatography at 2.0 minutes, 10 - 80 AB, C 23 H 21 FN5O2[M + H] + The calculated value of MS ESI at was 418.2, the measured value was 418.0.

[0332] Synthesis of Example 34.52

Chemical Structure

[0333] A-57: To a solution of ethyl 1-isopropyl-3-methyl-pyrazole-4-carboxylate (300 mg, 1.53 mmol) in ethanol (5 mL), a solution of NaOH (122.29 mg, 3.06 mmol) in water (5 mL) was slowly added. The resulting mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to remove EtOH. 1N HCl (30 mL) was added to the aqueous phase to adjust the pH to 2, and the mixture was diluted with EtOAc (10 mL). The phases were separated, the organic phase was washed with brine (10 mL), dried over Na2SO4, and then concentrated to obtain the crude product (210 mg, 1.22 mmol, 80% yield) as a solid. LCMS Rt = 0.61 min on a chromatograph with a retention time of 2.0 min, 10 - 80 AB, C8H 13 N2O2 [M + H] +The calculated value by MS ESI was 169.1 and the measured value was 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, the residue was diluted with H2O (20 mL), and then extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 40 - 60% B over 9 min) to give the product. Analytical SFC (column: (Daicel CHIRALPAK AS-3 150 mm × 4.6 mm i.d., 3 μm, mobile phase: A: CO2 B: ethanol (0.05% DEA), gradient: 5% - 40% B in 5 min, 40% - 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 causes some racemization. The product was separated by SFC (Daicel CHIRALPAK AS-H (250 mm × 30 mm, 5 μm); A = CO2 and B = EtOH (0.1% NH3H2O); 38 °C; 60 mL / min; 20% B; run for 8 min; 10 injections, Rt of peak 1 = 4.8 min, Rt of peak 2 = 6 min) to give the product (50.77 mg, 0.14 mmol, 24% yield) (Rt = 2.55 min by analytical SFC) as a solid. 1 H NMR (400 MHz, CD3CN) 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 minutes, chromatogram at 1.20 minutes, 10 - 80 AB, C 19 H 24 N5O2[M + H] + MS ESI calculated value in is 354.2, measured value is 354.1.

[0335] Synthesis of Example 35.55

Chemical Structure

[0336] 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), and 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, diluted with H2O (10 mL), and then extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 44 - 74% B over 9 min) to afford the product (75.42 mg, 213.4 μmol, 51% yield) as an oil. 1 H NMR (400 MHz, DMSO-d6) δ H = 9.17 (d, 1H), 7.85 - 7.76 (m, 2H), 7.49 - 7.39 (m, 2H), 7.33 (s, 1H), 5.42 (quin, 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 by chromatography at 2.0 min, 10 - 80 AB, C 19 H 24 N5O2 [M + H] + The calculated value of MS ESI at 354.19, the measured value 354.0.

[0337] Synthesis of Examples 36.56 and 57

Chemical Structure

[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 to pH ca. 2 with HCl (1 N) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated to give the crude product (400 mg) as an oil. The combined organic phases were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated to give the crude product (400 mg) as an oil. 1 H NMR (400 MHz, DMSO-d6) 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 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 diluted with NH4Cl (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was 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, CDCl3) 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] 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 4 M 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 = 1.5 minutes chromatography at 0.61 minutes, 5 - 95 AB, C 10 H 11 MS ESI calculated value for FN3O[M + H]+ 208.1, found 207.7.

[0341] 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 diluted with NH4Cl (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Waters XBridge (150 mm × 25 mm, 5 μm), A = H2O (10 mM NH4HCO3) and B = CH3CN; 24 - 54% B over 8 min) to give the product (180 mg, 0.50 mmol, 70% yield) as an oil. LCMS R t = 0.88 min by chromatography at 1.5 min, 5 - 95 AB, C 18 H 21 FN5O2[M + H] + The calculated value of MS ESI is 358.2 and the measured value is 358.1 at.

[0342] 56 and 57: Analytical SFC (Daicel CHIRALPAK IC - 3 (150 mm × 4.6 mm, 3 μm), mobile phase: A: CO2 B: IPA (0.05% DEA), gradient: 5% - 40% B in 5.5 min, 40% for 3 min, then hold 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 40 °C) showed two peaks at 3.55 min and 4.32 min. The product was separated by SFC (Daicel CHIRALPAK IC (250 mm × 30 mm, 5 μm); A = CO2 and B = i - PrOH; 38 °C; 65 mL / min; 30% B; run for 7 min; 7 injections, Rt of peak 1 = 3.5 min, Rt of peak 2 = 4.7 min) and randomly assigned as enantiomer 1 (Rt = 3.55 min in analytical SFC) as 56 (75.09 mg, 0.21 mmol, 41% yield) as an oil and and as 57 (73.93 mg, 0.21 mmol, 41% yield), the enantiomer 2 (Rt = 4.32 min in analytical SFC) randomly assigned as an oil was obtained. 56: 1 H NMR (400 MHz, CDCl3) 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 by chromatography of 2, 10 - 80 AB, C 18 H 21 FN5O2[M + H] + Calculated value of MS ESI in 358.2, measured value 358.1. 57: 1 H NMR (400 MHz, CDCl3) 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 by chromatography of 2, 10 - 80 AB, C 18 H 21 FN5O2[M + H] + Calculated value of MS ESI in 358.2, measured value 358.1.

[0343] Synthesis of Example 37.58

Chemical formula

[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 4 M 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 ol) 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 Chromatography at 2.0 minutes gave 0.99 minutes, 10 - 80 AB, C 17 H 17 FN3O2[M + H] + The calculated value of MS ESI was 314.1, and the measured value was 314.0.

[0345] 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) was added 2-benzyloxy-1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (300 mg, 0.86 mmol), 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 × 3). The combined organic phases were washed with water (20 mL × 2) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 55 - 85% B over 9 min) to give the product (49.27 mg, 0.11 mmol, 12% yield) as an oil. 1 H NMR (400 MHz, DMSO-d6) 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), 5.61 (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 = 1.31 min by chromatography at 2.0 min, 10 - 80 AB, C 25 H 25 FN5O3[M + H] + The calculated value of MS ESI for

[0346] Synthesis of Example 38.54

Chemical formula

[0347] Synthesis of Example 39.59

Chemical Structure

[0348] Synthesis of Examples 40, 60 and 61

Chemical formula

[0349] Synthesis of Examples 41, 62 and 63

Chemical Structure

[0350] Synthesis of Examples 42.64 and 65

Chemical Structure

[0351] A solution of ethyl 2-cyclopropyl-5-(trifluoromethyl)pyrazole-3-carboxylate (180 mg, 0.73 mmol) in ethanol (3 mL) was added to 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 H2O (20 mL) and washed with EtOAc (20 mL × 1). The pH of the aqueous phase was adjusted to pH = 1 by adding 1 N HCl (20 mL), and then diluted with H2O (10 mL). The mixture was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (70 mL), dried over Na2SO4, filtered, and concentrated to give the product (160 mg, 661.7 μmol, 84% yield) as an oil. LCMS R t Chromatography at 1.5 minutes, retention time 0.79 minutes, 5-95 AB, C8H8F3N2O2 [M+H] + MS in ESI calculated value 221.05, measured value 221.1.

[0352] A mixture of 3-chlorobenzonitrile (1.2 g, 8.72 mmol), NH2OH HCl (1818.45 mg, 26.17 mmol), and NaOH (1046.74 mg, 26.17 mmol) in ethanol (9 mL) and water (3 mL) 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, and then diluted with H2O (100 mL). The mixture was extracted with EtOAc (150 mL × 2). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to give the crude product (1760 mg, 6.62 mmol, 76% yield) as a solid. LCMS R t Chromatography at 1.5 minutes, retention time 0.21 minutes, 5-95 AB, C7H8ClN2O [M+H] + MS ESI calculated value 171.02, measured value 170.9.

[0353] 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 diluted with NH4Cl (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product 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, CDCl3) 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 on a 1.5 min chromatography, 5 - 95 AB, C 15 H 19 ClN3O3 [M + H - t-Bu] + The calculated value of MS ESI in is 268.1, the measured value is 268.1.

[0354] To tert-butyl N-[1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (1480 mg, 4.57 mmol), 4N HCl / 1,4-dioxane (10 mL, 40 mmol) was added 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 on a 1.5 min chromatography, 5 - 95 AB, C 10 H 11 ClN3O [M + H] + MS in The calculated value of ESI is 224.05, the measured value is 224.0.

[0355] To a mixture of 2-cyclopropyl-5-(trifluoromethyl)pyrazole-3-carboxylic acid (160 mg, 0.73 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 15 °C for 2 h. The mixture was concentrated, diluted with H2O (10 mL), and then extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 59 - 89% B over 8 min) to give the product (140 mg, 322.6 μmol, 84% yield) as a solid. LCMS R t = 0.98 min by chromatography at 1.5 min, 5 - 95 AB, C 18 H 16 ClF3N5O2 [M + H] + Calculated MS ESI value for 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: CO2, B: IPA (0.05% DEA), gradient: 5% - 40% B in 5.5 minutes, then 5% B for 1.5 minutes, flow rate: 2.5 mL / min, column temperature: 35 °C) showed two peaks at 3.78 minutes and 4.30 minutes. The product was purified by SFC (Regis (S,S) Whelk-O1 (250 mm × 30 mm, 5 μm); A = CO2 and B = IPA (0.1% DEA); 38 °C; 60 mL / min; 35% B; run for 9 minutes; 8 injections, Rt of peak 1 = 4.7 minutes, Rt of peak 2 = 6.8 minutes) to obtain enantiomer 1 (Rt = 3.78 minutes in analytical SFC) as a solid (54.51 mg, 128 μmol, yield 39%) and enantiomer 2 (Rt = 4.30 minutes in analytical SFC) as a solid (55.53 mg, 130.4 μmol, yield 39%) randomly assigned. 65: 1 H NMR (400 MHz, CDCl3) 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 minutes chromatography at 1.43 minutes, 10 - 80 AB, C 18 H 16 ClF3N5O2 [M + H] + Calculated value for MS ESI in 426.09, measured value 426.0. 64: 1 H NMR (400 MHz, CDCl3) 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 minutes chromatography at 1.41 minutes, 10 - 80 AB, C 18 H16 ClF3N5O2[M+H] + MS ESI calculated value in it is 426.09, measured value is 426.0.

[0357] Synthesis of Example 43.66

Chemical Structure

[0358] A-73: To tert-butyl N-[1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]cyclohexyl]carbamate (260 mg, 0.72 mmol), 4 M HCl (3 mL, 12 mmol) in 1,4-dioxane was added, and the reaction mixture was stirred at 20 °C for 0.5 hour. The mixture was concentrated to obtain the crude product (210 mg, 705.3 μmol, 98% yield) as a solid. LCMS R t Chromatography with R = 1.5 minutes shows 0.71 minutes, 5 - 95 AB, C 14 H 17FN3O[M+H] + The calculated value by MS ESI in + is 262.13, and the measured value is 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), and 1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]cyclohexaneamine 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. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (15 mL × 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by preparative HPLC (Welch Xtimate C18 (150 mm × 25 mm, 5 μm), A = H2O (0.04% NH4OH + 10 mM NH4HCO3) and B = CH3CN; purified by 60 - 90% B over 7.5 min) to obtain the product (26.87 mg, 65.6 μmol, 20% yield) as a solid. 1 H NMR (400 MHz, DMSO-d6) 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 by chromatography at 2.0 min, 10 - 80AB, C 22 H 25 FN5O2[M+H] + The calculated value by MS ESI in + is 410.19, and the measured value is 410.0.

[0360] Synthesis of Example 44.67

Chemical Structure

[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 diluted with NH4Cl (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% - 50%) to give the product (230 mg, 0.58 mmol, 20% yield) as an oil. LCMS R t = 0.94 min on chromatography with retention time of 2.0 min, 10 - 80 AB, C 11 H 10 F2N3O3 [M + H - tBu] + MS ESI calculated value for [M + H - tBu] is 270.1, measured value is 270.0.

[0362] To tert-butyl N-[1-[3-(3,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (230 mg, 0.71 mmol) was added 4 M 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, diluted with H2O (20 mL), and the pH was adjusted to about 9 by adding solid NaHCO3. The solution was extracted with EtOAc (20 mL × 3). The combined organic phases were concentrated to give the crude product (300 mg, 0.99 mmol) as a solid.

[0363] 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 washed with H2O (20 mL) and then extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (column (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 63 - 75% B over 9 min) to give the product (15.72 mg, 39.2 μmol, 3% yield) as a solid. 1 H NMR (400 MHz, DMSO-d6) 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 = 1.32 min by chromatography at 2.0 min, 10 - 80 AB, C 16H 12 F5N5O2[M+H] + The MS ESI calculated value in it is 402.1, and the measured value is 402.0.

[0364] Synthesis of Example 45.68

Chemical formula

[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 hour, and 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 hours. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% - 50%) to obtain the product (300 mg, 0.55 mmol, 8% yield) as a solid. LCMS R t= 0.79 minutes by chromatography at 2.0, 10 - 80 AB, C 15 H20N4O3[M + H] + The calculated value of MS ESI at is 305.2, and the measured value is 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, diluted with H2O (20 mL), and the pH was adjusted to about 9 by adding NaHCO3 (solid). The mixture was extracted with EtOAc (20 mL×3). The combined organic phases were concentrated to give the crude product (150 mg, 0.11 mmol, yield 11%) as an oil. LCMS R t = 0.39 minutes by chromatography at 2.0, 10 - 80 AB, C 10 H 13 N4O[M + H] + The calculated value of MS ESI at is 205.1, and the measured value is 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), DIPEA (0.4 mL, 2.88 mmol), HOBt (194.92 mg, 1.44 mmol), and EDCI (276.52 mg, 1.44 mmol) were added, 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 2 It was stirred at 5 °C for 16 hours. The reaction mixture was washed with H2O (20 mL), and then the aqueous phase was extracted with DCM (20 mL × 2). The combined organic phases were concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 17 - 47% B over 8 minutes) to give the product (91.9 mg, 0.24 mmol, 33% yield) as a solid. 1 1H NMR (400 MHz, DMSO-d6) 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 minutes chromatography at 1.02 minutes, 10 - 80 AB, C 16 H 16 F3N6O2 [M + H] + Calculated MS ESI value at 381.1, measured value 380.9.

[0368] Synthesis of Examples 46.69 and 70

Chemical Structure

[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 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the ethanol, then diluted with H2O (10 mL) and the mixture was washed with EtOAc (10 mL × 2, discarded). The pH of the aqueous phase was adjusted to about pH 2 with 1 N HCl and then extracted with EtOAc (20 mL x 2). The combined organic phases were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product (450 mg) as a solid. 1 H NMR (400 MHz, DMSO - d6) δ H = 7.36 (s, 1H), 6.62 - 6.31 (m, 1H), 5.10 (dt, 2H).

[0370] A - 83: 2-(2,2 - difluoroethyl)-5-(trifluoromethyl)pyrazole - 3 - carboxylic acid (224.06 mg, 0.92 mmol) in DMF (10 mL), To a mixture of HATU (634.51 mg, 1.67 mmol) and DIPEA (0.44 mL, 2.5 mmol) was added 1-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (200 mg, 0.83 mmol), and the mixture was stirred at 25 °C for 16 h. The reaction was quenched with saturated NH4Cl (20 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 57 - 77% B over 9 min) to give the product (140 mg, 0.32 mmol, 39% yield) as a solid. LCMS R t = 0.94 min by chromatography at 1.5 min, 10 - 80 AB, C 18 H 17 F5N5O2[M+H] + Calculated MS ESI value for 430.1, found 430.2.

[0371] 69 and 70: The product was separated by SFC (Daicel CHIRALCEL OJ-3 (150 mm × 4.6 mm, 3 μm), mobile phase: A: CO2 B: ethanol (0.05% DEA), gradient: 5% - 40% B in 5 minutes, 40% - 5% B in 0.5 minutes, hold at 5% B for 1.5 minutes, flow rate: 2.5 mL / min, column temperature: 35 °C, ABPR: 1500 psi), which showed two peaks at 2.18 minutes and 2.59 minutes. The product was separated by SFC (Daicel CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); A = CO2 and B = EtOH (0.1% NH3H2O); 38 °C; 60 mL / min; 15% B; run for 7 minutes; 6 injections, Rt of peak 1 = 4.55 minutes, Rt of peak 2 = 5.55 minutes) and randomly assigned as 69 (37.48 mg, 87.3 mmol, 27% yield) as the solid of enantiomer 1 (Rt = 2.18 minutes in analytical SFC) and 70 (48.34 mg, 112.6 mmol, 34% yield) as the solid of enantiomer 2 (Rt = 2.59 minutes in analytical SFC). 69: 1 H NMR (400 MHz, DMSO-d6) 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 minutes in chromatography at 2.0 minutes, 10 - 80 AB, C 18 H 17 F5N5O2 [M + H] + Calculated value of MS ESI in 430.1, measured value 430.0. 70: 1 H NMR (400 MHz, DMSO-d6) 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 minutes in chromatography at 2.0 minutes, 10 - 80 AB, C 18H 17 F5N5O2[M+H] + The MS ESI calculated value in it is 430.1, and the measured value is 430.1.

[0372] Synthesis of Example 47.71

Chemical formula

[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 hour. 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 hours. The mixture was diluted with NH4Cl (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% - 30% - 50%) to give the product (1800 mg, 3.82 mmol, 19% yield) as a solid. Chromatography with LCMS Rt = 1.5 min gave 0.805 min, 5 - 95 AB, C 15 H 21 N4O3[M+H] + The calculated value of MS ESI in is 305.15, and the measured value is 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), 4 M HCl in 1,4-dioxane (10 mL, 40 mmol) was added and the reaction mixture was stirred at 40 °C for 5 hours under N2. After cooling to room temperature, the mixture was concentrated to give a residue. The residue was poured into ice water (20 mL) and the pH of the mixture was adjusted to about 9 by adding Na2CO3 (solid), and then extracted with EtOAc (20 mL × 2). The organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product (300 mg, 0.78 mmol, 69% yield) as a solid. Chromatography with LCMS Rt = 1.5 min gave 0.278 min, 5 - 95 AB, C 10 H 13 N4O[M+H] + The calculated value of MS ESI in is 205.1, and the measured value is 205.1.

[0375] 1-[3-(6-Methyl-2-pyridyl)-1,2,4-oxadiazol-5-yl]ethanamine (200 mg, 0.98 mmol) in DCM (10 mL), HO A mixture of Bt (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) was stirred at 25 °C for 16 h. The mixture was concentrated partially under reduced pressure to give a residue. The residue was diluted with H2O (30 mL) and the mixture was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to give a crude product. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 30 - 60% B over 9 min) to give the product (78.77 mg, 0.20 mmol, 21% yield) as a solid. 1 H NMR (400 MHz, CDCl3) δ H = 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 = 1.16 min by chromatography at 2.0 min, 10 - 80 AB, C 16 H 16 F3N6O2 [M + H] + Calculated MS ESI value for 381.12, found 381.1.

[0376] Synthesis of Example 48.72

Chemical formula

[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 water (4 mL) 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 H2O (20 mL). The mixture was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated to give the crude product (12500 mg, 66.38 mmol, 77% yield) as a solid. LCMS Rt = 1.5 min, chromatographed at 0.178 min, 5 - 95 AB, C8H 11 N2O [M + H] + The calculated value of MS ESI at 151.1, the measured 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 NH4Cl (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% - 30% - 50%) to give the product (290 mg, 0.86 mmol, 20% yield) as a solid. LCMS Rt = 1.5 min, chromatogram at 0.92 min, 5 - 95AB, C 17 H 24 N3O4[M + H - Boc] + Calculated MS ESI value in is 278.1, measured value is 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), 4M HCl in 1,4-dioxane (10 mL, 40 mmol) was added and the mixture was stirred at 40 °C for 5 h under N2. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a residue. The residue was poured into ice water (20 mL), the pH of the mixture was adjusted to about 9 with Na2CO3 (solid), and then extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product (180 mg, 0.63 mmol, 69% yield) as a solid. LCMS R t = 1.5 min, chromatogram at 0.678 min, 5 - 95AB, C 12 H 16 N3O2[M + H] + Calculated MS ESI value in is 234.1, measured value is 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 diluted with H2O (20 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to give a crude product. The crude product was purified by preparative HPLC (Boston Prime (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 50 - 80% B over 9 min) to give the product (77.3 mg, 0.19 mmol, 24% yield) as a solid. 1 H NMR (400 MHz, CDCl3) 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 on a 2.0 min chromatography, 10 - 80 AB, C 18 H 19 F3N5O3[M + H] + The calculated value of MS ESI for [M + H] is 410.2, and the measured value is 410.14.

[0381] Synthesis of Example 49.73

Chemical Structure

[0382] A-93: To a solution of ethyl 3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (1000 mg, 4.8 mmol) in MeCN (20 mL) were added Cs2CO3 (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). The reaction mixture was stirred at 90 °C for 1.5 h under N2. After cooling to room temperature, the mixture was diluted with H2O (30 mL) and then extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give a crude product. The crude product 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, CDCl3) δ H=8.26 - 7.85 (m, 1H), 7.21 (s, 1H), 4.45 (q, 2H), 1.43 (t, 3H).

[0383] A - 94: A solution of ethyl 2-(difluoromethyl)-5-(trifluoromethyl)pyrazole-3-carboxylate (70 mg, 0.27 mmol) in ethanol (3 mL) was added to 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 1 N HCl (1 mL), diluted with H2O (10 mL), and extracted with EtOAc (15 mL × 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to give the product (60 mg, 260.8 μmol, 96% yield) as a solid. 1 H NMR (400 MHz, CDCl3) 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) was added 1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethanamine hydrochloride (100 mg, 0.38 mmol), and the mixture was stirred at 25 °C for 2 h. The mixture was diluted with H2O (10 mL) and then extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% - 24%) to give the product (26.79 mg, 61.5 μmol, 16% yield) as an oil. 1 H NMR (400 MHz, CDCl3) 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 = 1.35 minutes by chromatography of 2.0 minutes, 10 - 80 AB, C 16 H 12 ClF5N5O2 [M + H] + MS ESI calculated value in is 436.1, measured value is 435.9.

[0385] Synthesis of Examples 50.74 and 75

Chemical Structure

[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 H2O (100 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% - 10%) to give the product (600 mg, 1.62 mmol, 22% yield) as a solid. LCMS R t = 2.0 min chromatography at 1.380 min, 10 - 80AB, C 11 H9Cl2N3O3[M + H - tBu] + MS ESI calculated value 302.0, measured 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), 4 M HCl in 1,4-dioxane (16.36 mL, 65.45 mmol) was added and the mixture was stirred at 25 °C for 16 h. The mixture was concentrated, diluted with H2O (20 mL), and the pH was adjusted to about 9 with NaHCO3 (solid). The mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were 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 Cl2N3O[M + H - tBu] + MS ESI calculated value 258.0, measured value 257.8.

[0388] 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), and EDCI (553.05 mg, 2.88 mmol) were added, and the mixture was stirred at 25 °C for 30 minutes. 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 hours. The reaction mixture was washed with H2O (30 mL), and the mixture was extracted with DCM (30 mL × 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 56 - 76% B over 9 minutes) to obtain the product (450 mg, 1.04 mmol, 72% yield) as an oil. LCMS R t = 1.318 minutes by chromatography at 2.0 minutes, 10 - 80 AB, C16H13Cl2F3N5O2 [M + H] + The calculated value of MS ESI is 434.0, and the measured value is 433.9.

[0389] 74 and 75: Analytical SFC (Daicel CHIRALCEL OJ-H (150 mm × 4.6 mm, 5 μm), mobile phase: A: CO2 B: ethanol (0.05% DEA), gradient: 5% - 40% B in 4.5 min, hold at 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 product was purified by SFC (Daicel CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); A = CO2 and B = EtOH (0.1% NH3H2O); 38 °C; 60 mL / min; 25% B; run for 7.76 min; 45 injections, Rt of peak 1 = 4.39 min, Rt of peak 2 = 5.76 min) and randomly assigned as enantiomer 1 (Rt = 2.943 min in analytical SFC) as 74 (176.6 mg, 0.41 mmol, 44% yield) as a solid, and enantiomer 2 (Rt = 3.79 min in analytical SFC) randomly assigned as 75 (211.15 mg, 0.49 mmol, 53% yield) as a solid. 74: 1 H NMR (400 MHz, DMSO-d6) 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 chromatography at 2.0 min, 10 - 80 AB, C 16 H 13 Cl2F3N5O2 [M + H] + Calculated value of MS ESI in 434.0, measured value 434.0. 75: 1 H NMR (400 MHz, DMSO-d6) 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 chromatography at 2.0 min, 10 - 80 AB, C 16 H 13 Cl2F3N5O2 [M + H] + Calculated value of MS ESI in 434.0, measured value 434.0.

[0390] Synthesis of Examples 51, 76 and 77 [Chemical formula] Analytical SFC (Daicel CHIRALCEL OJ-H (150 mm × 4.6 mm, 5 μm), mobile phase: A: CO2 B: ethanol (0.05% DEA), gradient: 5% - 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 min and 2.40 min. The product was separated by SFC (Daicel CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); A = CO2 and B = EtOH (0.1% NH3H2O); 38 °C; 60 mL / min; 10% B; run for 8.74 min; 120 injections, Rt of peak 1 = 5.95 min, Rt of peak 2 = 6.74 min) and randomly assigned as enantiomer 1 (Rt = 2.18 min in analytical SFC) as solid 76 (178.71 mg, 0.41 mmol) and enantiomer 2 (Rt = 2.40 min in analytical SFC) as solid 77 (138.05 mg, 0.34 mmol, yield 37%). 76: 1 H NMR (400 MHz, DMSO-d6) 400 MHz 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 chromatography at 2.0 min, 10 - 80 AB, C 16 H 13 F5N5O2 [M + H] + Calculated value of MS ESI in 402.1, measured value 402.0. 77: 11H NMR (400 MHz, DMSO-d6) 400 MHz 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 minutes by chromatography of 2.0 fractions, 10 - 80 AB, C 16 H 13 F5N5O2[M + H] + Calculated value of MS ESI in 402.1, measured value 402.0.

[0391] Synthesis of Examples 52.78 and 79

Chemical Structure

[0392] Synthesis of Examples 53.80 and 81

Chemical Structure

[0393] Synthesis of Examples 54, 82 and 83

Chemical Structure

[0394] Synthesis of Example 55.84

Chemical formula

[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 hour, and then N'-hydroxy-2-methyl-pyridine-4-carboxamidine (980 mg, 6.48 mmol) was added. Then, the reaction mixture was stirred at 70 °C for 16 hours. 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 phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by column flash chromatography on silica gel (EtOAc in PE = 0% - 20% - 50%) to obtain the product (220 mg, 0.66 mmol, 10% yield) as an oil. LCMS R t= Chromatography for 1.5 minutes at 0.70 minutes, 5 - 95 AB, C 15 H 21 N4O3[M + H] + MS ESI calculated value in is 305.2, measured value is 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 the mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated to obtain the crude product (180 mg, 0.74 mmol) as a solid. LCMS R t = Chromatography for 1.5 minutes at 0.12 minutes, 5 - 95 AB, C 10 H 13 N4O[M + H] + MS ESI calculated value in is 205.1, measured value is 205.2.

[0397] 84: A mixture of 2 - methyl - 5 - (trifluoromethyl)pyrazole - 3 - carboxylic acid (77.58 mg, 0.4 mmol), HOBt (120.01 mg, 0.89 mmol), Et3N (0.31 mL, 2.22 mmol), and EDCI (127.69 mg, 0.67 mmol) in DCM (7 mL) was stirred at 25 °C for 1 hour. 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 the mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with saturated NH4Cl (20 mL), and the mixture was extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0~10%~25%~50%) to obtain the product (63.51 mg, 0.17 mmol, yield 38%) as a solid. 1 H NMR (400 MHz, CD3CN) 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 Chromatography at 2.0 minutes, 0.90 minutes, 10 - 80 AB, C 16 H 16 F3N6O2 [M + H] + The calculated value of MS ESI at is 381.1, and the measured value is 380.9.

[0398] Synthesis of Example 56.85

Chemical Structure

[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 hour, then 3-cyano-N'-hydroxy-benzamidine (700 mg, 4.34 mmol) was added. The reaction mixture was then stirred at 70 °C for 16 hours. After cooling to room temperature, the mixture was diluted with water (60 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (EtOAc in PE = 0% - 30%) to give the product (400 mg, 0.77 mmol) as a solid. LCMS R t Chromatography retention time = 1.15 minutes at 2.0 minutes, 10 - 80AB, C 12 H ...

Claims

【Claim 1】 The invention described in the description.

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