KCNT1 INHIBITORS CONTAINING A PYRAZOLE CORE AND METHODS OF USE - Patent application

Abstract

Disclosed herein are compounds comprising a pyrazole core and their pharma- ceutically acceptable salts, and compositions useful for the prophylaxis and / or treatment of neurological disorders, disorders associated with excessive neuronal excitability, or disorders associated with gain-of-function mutations in genes, such as KCNT1. Methods for treating neurological disorders, disorders associated with excessive neuronal excitability, or disorders associated with gain-of-function mutations in genes, such as KCNT1, are also provided herein.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 334,322, filed April 25, 2022, and U.S. Provisional Patent Application No. 63 / 386,013, filed December 5, 2022, the contents of which are incorporated by reference in their entireties herein.

[0002] The present disclosure is directed generally to KCNT1 inhibitors that contain a pyrazole core, as well as pharmaceutical compositions and methods of treatment involving the use of such compounds. [Background technology]

[0003] Potassium sodium-activated channel subfamily T member 1 (KCNT1) is one of the genes in a family of genes involved in providing the instructions for making potassium channels. KCNT1 is involved in the regulation of Slack (calcium-activated K + These channels are found in neurons throughout the brain and transmit the sodium-activated potassium current I KNa This delayed outward current can regulate neuronal excitability and the rate of adaptation in response to sustained stimulation. Abnormal Slack activity is associated with the development of early-onset epilepsy and intellectual disability. Thus, sodium-activated potassium channels, such as abnormal KCNT1 or abnormal I KNa Pharmaceutical compounds that selectively modulate KCNT1 are useful for treating neurological diseases or disorders, or diseases or conditions associated with excessive neuronal excitability and / or KCNT1 gain-of-function mutations. Summary of the Invention

[0004] Described herein are compounds and compositions useful for the prevention and / or treatment of diseases, disorders, or conditions, such as neurological disorders, disorders associated with excessive neuronal excitability, or disorders associated with gain-of-function mutations in genes, such as KCNT1.

[0005] In some embodiments, compounds of Formula (I) having a pyrazole core, [ka] During the ceremony, R 1 is selected from a 5- or 6-membered heteroaryl or aryl, wherein said heteroaryl or said aryl optionally includes at least one substituent independently selected from alkyl, haloalkyl, carbocyclyl, or -CN; R 2 is -H, R 3 is selected from -H or alkyl; R 4 is selected from -H or alkyl; or R 3 and R 4 together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl; Z, [ka] haloalkyl, or alkoxy; Ring A is selected from 5- or 6-membered heteroaryl, aryl, heterocyclyl, or carbocyclyl; R 5 is independently selected from alkyl, carbocyclyl, alkoxy, -C(O)NH2, -CN, or halogen, where the alkyl, carbocyclyl, or alkoxy optionally includes at least one halogen substituent, or the alkyl optionally includes at least one -OH substituent; n is 0, 1, 2, 3, or 4; L is absent or -NR a -, -CH2-, or -O-; R a is selected from -H or alkyl; R 6 is selected from -H or alkyl; R 7 is alkyl; or a pharma- ceutically acceptable salt thereof.

[0006] In certain embodiments, a compound of formula (II) having a pyrazole core, [ka] During the ceremony, R 1 is selected from pyrazolyl or phenyl, wherein the pyrazolyl or the phenyl is C 1-4 Alkyl, C 1-4 Haloalkyl, or C 3-5 optionally including at least one substituent independently selected from carbocyclyl; R 2 is -H, R 3 But -H or C 1-4 alkyl, R 4 But -H or C 1-4 alkyl; or R 3 and R 4 together with the carbon atom to which they are attached form an optionally substituted 3- to 5-membered carbocyclyl or heterocyclyl; Ring A is selected from pyridyl, phenyl, pyrimidinyl, piperidinyl, or cyclopentyl; R 5 But, C 1-4 Alkyl, C 3-5 Carbocyclyl, C 1-4 alkoxy, -C(O)NH2, -CN, or halogen, where the alkyl, the carbocyclyl, or the alkoxy optionally comprises at least one halogen substituent, or the alkyl optionally comprises at least one -OH substituent; n is 0, 1, 2, 3, or 4; L is absent or -NR a -, -CH2-, or -O-; R a is -H or C 1-4 alkyl, R 6 is -H or C 1-4 alkyl, R 7 But, C 1-4 Disclosed herein are compounds of formula (II), or a pharma- ceutically acceptable salt thereof, wherein: R is alkyl;

[0007] In certain embodiments, R 1 is pyrazolyl containing at least one substituent selected from -CH, -CF, -C(CH), -CHF, -CH(CH), or cyclopropyl; in certain embodiments, R 1 is phenyl. In certain embodiments, R 4 is selected from -H or -CH3, and in certain embodiments, R 3 and R 4 together with the carbon atom to which they are attached form an optionally substituted cyclopropyl, cyclobutyl, or oxetanyl. In certain embodiments, ring A is pyridyl, and in certain embodiments, R 5 is independently selected at each occurrence from -CH, -CHCH, -CF, -OCH, -OCHCH, -OCH(CH), -CHOH, -CN, -C(O)NH, or cyclopropyl. In certain embodiments of the present disclosure, n is 0, 1, or 2, and in certain embodiments, L is absent. In certain embodiments, R 6 is selected from -H or -CH3, and in certain embodiments, R 7 is selected from -CH3 or -CH2CH3.

[0008] In various aspects of the disclosure, the compound of formula (I) is a compound of formula (II-A), formula (II-B), or formula (II-C): [ka] or a pharma- ceutically acceptable salt thereof.

[0009] In certain embodiments, the compound of formula (I) is a compound of formula (III-A), formula (III-B), or formula (III-C): [ka] During the ceremony, R 1a is selected from -CH3, -C(CH3)3, -CHF2, -CH(CH3)2, or cyclopropyl; R 1b is selected from -CH3, -CF3, -C(CH3)3, -CHF2, -CH(CH3)2, or cyclopropyl; R 5 However, each occurrence, independently, 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 3-5 carbocyclyl, or a pharma- ceutically acceptable salt thereof.

[0010] In certain embodiments, the compound of formula (I) is a compound of formula (III-Ai), formula (III-Bi), or formula (III-Ci), [ka] During the ceremony, R 1a is selected from -CH3, -C(CH3)3, -CHF2, -CH(CH3)2, or cyclopropyl; R 1b is selected from -CH3, -CF3, -C(CH3)3, -CHF2, -CH(CH3)2, or cyclopropyl; R 5is selected from -CF3, -CH3, -CH2CH3, -OCH3, -OCH2CH3, or cyclopropyl, or a pharma- ceutically acceptable salt thereof.

[0011] In certain embodiments, a compound of formula (I) selected from formula (III-Di) or formula (III-Ei): [ka] During the ceremony, R 1a is selected from -CH3, -C(CH3)3, -CHF2, -CH(CH3)2, or cyclopropyl; R 1b is selected from -CH3, -CF3, -C(CH3)3, -CHF2, -CH(CH3)2, or cyclopropyl; R 5 Disclosed herein are compounds of formula (I), selected from formula (III-Di) or formula (III-Ei), or a pharma- ceutically acceptable salt thereof, wherein is selected from -F or -CN.

[0012] In certain embodiments, the compound of formula (I) is [ka] Selected from TIFF2025514140000009.tif247170TIFF2025514140000010.tif243170TIFF2025514140000011.tif207170.

[0013] In another aspect, there is provided a method of treating a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with a gain-of-function mutation in a gene by administering to a subject in need of such treatment an effective amount of any of the compounds described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein comprising such a compound or a pharma- ceutically acceptable salt thereof.

[0014] In some embodiments, the methods provided include treating a disorder associated with a gain-of-function mutation in KCNT1.

[0015] In some variations, the neurological disorder, disorder associated with excessive neuronal excitability, or disorder associated with a gain-of-function mutation in a gene (eg, KCNT1) is epilepsy, an epilepsy syndrome, or an encephalopathy.

[0016] In some variations, the neurological disorder, disorder associated with excessive neural excitability, or disorder 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 variations, the neurological disorder, disorder associated with excessive neural excitability, or disorder associated with a gain-of-function mutation in a gene (eg, KCNT1) is cardiac dysfunction.

[0018] In some variations, the neurological disorder, disorder associated with excessive neural excitability, or disorder 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., malignant migratory focal seizures of infancy (MMFSI) or epilepsy in infancy 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), seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, or cerebellar ataxia.

[0019] In some variations, the neurological disorder, disorder associated with excessive neural excitability, or disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from cardiac arrhythmia, Brugada syndrome, or myocardial infarction.

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

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

[0022] In some variations, the neurological disorder, disorder associated with excessive neural excitability, or disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from itch and pruritus, ataxia, or cerebellar ataxia.

[0023] In some variations, the neurological disorder, disorder associated with excessive neural excitability, or disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is a psychiatric disorder (e.g., major depression, anxiety, bipolar disorder, schizophrenia).

[0024] In other variations, the neurological disorder, disorder associated with excessive neural excitability, or disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from a learning disability, fragile X, neuroplasticity, or autism spectrum disorder.

[0025] In yet other variations, the neurological disorder, disorder associated with excessive neural excitability, or disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from epileptic encephalopathy with SCN1A, SCN2A, and / or SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

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

[0027] Provided herein in certain aspects are compounds and compositions useful for the prevention and / or treatment of a disease, disorder, or condition described herein, e.g., a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1). Exemplary diseases, disorders, or conditions include epilepsy and other encephalopathies (e.g., MMFSI or EIMFS, ADNFLE, West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, and Lennox-Gastaut syndrome, seizures, leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic seizures, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia, asymmetric tonic seizures), cardiac dysfunction (e.g., cardiac arrhythmias, Brugada syndrome, myocardial infarction), pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.), muscle disorders (e.g., myotonia, neurogenic myotonia, muscle spasms, spasticity), itch and pruritus, ataxia and cerebellar ataxia, and psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia).

[0028] I. Definition Unless otherwise defined, all technical terms, designations, and other technical and scientific terms or glossaries used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In some instances, terms having commonly understood meanings are defined herein for clarity and / or ready reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference to what is commonly understood in the art.

[0029] Throughout this disclosure, various aspects of the claimed subject matter are presented in a range format. It should be understood that the description in range format is merely for convenience and brevity, and should not be construed as an inflexible limitation on the scope of the claimed subject matter. Thus, the description of a range should be considered to specifically disclose all possible subranges as well as individual numerical values ​​within that range. For example, when a range of values ​​is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit between the upper and lower limits of that range, and any other stated or intervening value within that stated range, is encompassed in the disclosure, unless the context clearly indicates otherwise, subject to any specifically excluded limit value within the stated range. When a stated range includes one or both of the limits, a range excluding one or both of those included limits is also included in the disclosure. In some embodiments, two opposing open-ended ranges are provided for a feature, and such descriptions contemplate that a combination of those two ranges is provided herein. For example, in some embodiments, a feature may be described as being greater than about 10 units and the feature may be described (e.g., in a separate sentence) as being less than about 20 units, and thus a range of about 10 units to about 20 units is described herein.

[0030] The term "about" as used herein refers to a normal error range for each value that is readily known in the art. With reference to "about," a value or parameter herein includes (and describes) the variation that is directed to the value or parameter itself. For example, a statement that refers to "about X" includes the statement of "X."

[0031] As used herein, including the appended claims, the singular forms "a," "or," and "the" include plural referents unless the context clearly dictates otherwise. For example, "a" or "an" means "at least one" or "one or more." It is understood that aspects and variations described herein include embodiments that "consist of" and / or "consist essentially of" such aspects and variations.

[0032] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0033] As used herein, the terms "in some embodiments," "in other embodiments," and the like refer to embodiments of all aspects of the disclosure unless the context clearly indicates otherwise.

[0034] 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 Ed., inside cover, and specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry, and specific functional moieties and reactivities are described in, for example, Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 thEdition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3. rd Edition, Cambridge University Press, Cambridge, 1987.

[0035] The following terms are intended to have the meanings presented below and are useful in understanding the description and intended scope of the present disclosure. In describing certain aspects of the present disclosure, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated. It is also understood that, as described herein, any of the moieties defined below may be substituted with various substituents, and each definition is intended to include such substituted moieties within their scope as described below. Unless otherwise indicated, the term "substituted" is to be defined as described below. It is further understood that the terms "group" and "radical" can be considered interchangeable when used herein. The articles "a" and "an" can be used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or more than one analogue.

[0036] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 "Alkyl" means C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3Alkyl, C 1-2 Alkyl, C 2-6 Alkyl, C 2-5 Alkyl, C 2-4 Alkyl, C 2-3 Alkyl, C 3-6 Alkyl, C 3-5 Alkyl, C 3-4 Alkyl, C 4-6 Alkyl, C 4-5 Alkyl, and C 5-6 Alkyl is intended to be included.

[0037] "Alkyl" refers to, for example, the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, an alkyl group has one carbon atom ("C alkyl"). 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0038] "Alkenyl" refers to the radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2-20 In certain embodiments, the alkenyl does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.

[0039] "Alkoxy" refers to a radical of a straight chain or branched hydrocarbon group having a single bond to oxygen, e.g., 1 to 20 carbon atoms. In some embodiments, an alkoxy has 1 to 2 carbon atoms, such as -OCH3 or -OCH2CH3.

[0040] "Alkynyl" refers to the radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and, optionally, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2-20 In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2-3In some embodiments, an alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkynyl groups include, as well as, pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like.

[0041] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared within the cyclic array) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl", e.g., anthracyl). "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Exemplary aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0042] "Hetero", when used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound or group are replaced with a heteroatom, which is nitrogen, oxygen, or sulfur. Hetero can apply to any of the above mentioned alkyl groups, such as alkyl, e.g., heteroalkyl, alkenyl, e.g., heteroalkenyl, alkynyl, e.g., heteroalkynyl, carbocyclyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, having 1 to 5, especially 1 to 3, heteroatoms.

[0043] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared within the cyclic array) having ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or at a nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in either or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring, and in such cases the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, where the point of attachment is on either the aryl ring or the heteroaryl ring, and in such cases the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., either on the ring with a heteroatom (e.g., 2-indolyl) or on the ring without a heteroatom (e.g., 5-indolyl).

[0044] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system ("5-10 membered heteroaryl") having ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system. In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system ("5-8 membered heteroaryl") having ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system. In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system ("5-6 membered heteroaryl") having ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system. In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0045] As used herein, "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 Carbocyclyl). Exemplary C 3-6Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-5 The carbocyclyl group is the aforementioned C 3-6 Examples of carbocyclyl groups include, but are not limited to, cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3-10 The carbocyclyl group is the aforementioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic carbocyclyl"), which may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring, and in such cases the number of carbons continues to designate the number of carbons in the carbocyclic ring system.

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

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

[0048] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three 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] "Cyano" refers to -CN.

[0050] "Halo" or "halogen" refers to fluorine atoms (i.e., fluoro or -F), chlorine atoms (i.e., chloro or -Cl), bromine atoms (i.e., bromo or -Br), and iodine atoms (i.e., iodo or -I). In certain embodiments, a halo group is fluoro or chloro.

[0051] "Haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0052] In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen (e.g., carbon or nitrogen atom) present in a group is replaced with a permissible substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position.

[0053] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. The general concept of pharmaceutically acceptable salts has been discussed in the art, including, for example, Berge et al., J Pharmaceutical Sciences (1977) 66:1-19, which describes pharmaceutically acceptable salts in detail. Pharmaceutically acceptable salts of the compounds described herein 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 pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxy-ethanesulfonate. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-butyl salts. + (C 1-4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0054] The term "release modifying polymer" refers to a polymer used in formulations (e.g., tablets and capsules) to modify the release rate of a drug upon administration to a subject. For example, release modifying polymers are used to dissolve a drug over time so that it is released more slowly and steadily into the bloodstream. For example, the release modifying polymer is a release controlling polymer. For example, the release modifying polymer or release controlling polymer is an HPMC polymer. In some embodiments, the release modifying polymer may include a hydrophilic matrix polymer (e.g., hypromellose, hydroxyl-propylmethylcellulose (HPMC)), a hydrophobic matrix polymer (e.g., ethylcellulose, Ethocel), or a polyacrylate polymer (e.g., Eudragit® RL100, Eudragit® RS100).

[0055] The term "diluent" as used herein refers to an excipient used to increase weight and improve content uniformity. For example, diluents include cellulose derivatives (e.g., microcrystalline cellulose), starch (e.g., hydrolyzed starch and partially pregelatinized starch), anhydrous lactose, lactose monohydrate, dibasic calcium phosphate (DCP), sugar alcohols (e.g., sorbitol, xylitol, and mannitol).

[0056] As used herein, the term "lubricant" refers to an excipient used to promote powder flow by reducing interparticle friction and cohesion. For example, lubricants include fumed silica (e.g., colloidal silicon dioxide), talc, and magnesium carbonate.

[0057] The term "lubricant" as used herein refers to an excipient used to prevent ingredients from clumping together and sticking to tablet punches or capsule filling machines. Lubricants are also used to ensure that tablet formation and ejection can occur with low friction between the solids and the die wall. For example, lubricants include magnesium stearate, calcium stearate, stearic acid, talc, silica, and fats (e.g., vegetable stearin).

[0058] As used herein, the term "coating" refers to an excipient that protects tablet ingredients from deterioration due to moisture in the air and also makes large or unpleasant tasting tablets easier to swallow.

[0059] The embodiments disclosed herein are not intended to be limited in any way by the above list of exemplary chemical groups and substituents. Those skilled in the art will recognize that some embodiments are possible within the scope and spirit of the present disclosure. The following description is illustrative of the present disclosure and, of course, should not be construed as limiting the scope of the invention described herein in any way.

[0060] II. Compounds and Compositions In one embodiment, a compound of formula (I) having a pyrazole core, [ka] During the ceremony, R 1is selected from a 5- or 6-membered heteroaryl or aryl, wherein said heteroaryl or said aryl optionally includes at least one substituent independently selected from alkyl, haloalkyl, carbocyclyl, or -CN; R 2 is -H, R 3 is selected from -H or alkyl; R 4 is selected from -H or alkyl; or R 3 and R 4 together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl; Z, [ka] haloalkyl, or alkoxy; Ring A is selected from 5- or 6-membered heteroaryl, aryl, heterocyclyl, or carbocyclyl; R 5 is independently selected from alkyl, carbocyclyl, alkoxy, -C(O)NH2, -CN, or halogen, where the alkyl, carbocyclyl, or alkoxy optionally includes at least one halogen substituent, or the alkyl optionally includes at least one -OH substituent; n is 0, 1, 2, 3, or 4; L is absent or -NR a -, -CH2-, or -O-; R a is selected from -H or alkyl; R 6 is selected from -H or alkyl; R 7 is alkyl, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

[0061] In some embodiments, the compound of formula (II) having a pyrazole core is [ka] During the ceremony, R 1 is selected from pyrazolyl or phenyl, wherein the pyrazolyl or the phenyl is C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-5 optionally including at least one substituent independently selected from carbocyclyl; R 2 is -H, R 3 is selected from -H or alkyl; R 4 But -H or C 1-4 alkyl; or R 3 and R 4 together with the carbon atom to which they are attached form an optionally substituted 3- to 5-membered carbocyclyl or heterocyclyl; Ring A is selected from pyridyl, phenyl, pyrimidinyl, piperidinyl, or cyclopentyl; R 5 But, C 1-4 Alkyl, C 3-5 Carbocyclyl, C 1-4 alkoxy, -C(O)NH2, -CN, or halogen, where the alkyl, the carbocyclyl, or the alkoxy optionally comprises at least one halogen substituent, or the alkyl optionally comprises at least one -OH substituent; n is 0, 1, 2, 3, or 4; L is absent or -NR a -, -CH2-, or -O-; R a is -H or C 1-4 alkyl, R 6 is -H or C 1-4 alkyl, R 7 But, C 1-4 Provided is a compound of formula (II), or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, wherein: R is alkyl;

[0062] In some variations of all of the above, the compound is an optically active compound. In some variations, the compound is a single enantiomer. In one particular variation, the compound is the (R)-enantiomer. In other variations, the compound is the (S)-enantiomer.

[0063] In some embodiments, R 1 is pyrazolyl that includes at least one substituent independently selected from -CH, -CF, -C(CH), -CHF, -CH(CH), or cyclopropyl. 1 is phenyl.

[0064] In some embodiments, R 4 is selected from -H or -CH3. 3 and R 4 together with the carbon atom to which they are attached form an optionally substituted cyclopropyl, cyclobutyl, or oxetanyl.

[0065] In some embodiments, ring A is pyridyl. In certain embodiments, R 5 is independently at each occurrence -CH3, -CH2CH3, -CF3, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2OH, -CN, -C(O)NH2, or cyclopropyl.

[0066] In some embodiments, n is 0, 1, or 2. In some embodiments, L is absent.

[0067] In some embodiments, R 6 is selected from -H or -CH3. 7is selected from -CH3 or -CH2CH3.

[0068] In certain embodiments, a compound of Formula (II-A), Formula (II-B), or Formula (II-C) having a pyrazole core: [ka] or a pharma- ceutically acceptable salt thereof is provided.

[0069] In one embodiment, a compound of Formula (III-A), (III-B), or (III-C) having a pyrazole core, [ka] During the ceremony, R 1a and R 1b Each of the above independently represents C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-5 carbocyclyl, R 5 However, each occurrence, independently, 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 3-5 carbocyclyl is selected from the group consisting of aryl, aryl, aryl and aryl groups.

[0070] In another embodiment, a compound of Formula (III-Ai), (III-Bi), or (III-Ci) having a pyrazole core, [ka] During the ceremony, R 1a and R 1b each is independently selected from -CH3, -CF3, -C(CH3)3, -CHF2, -CH(CH3)2, or cyclopropyl; R 5is selected from -CF3, -CH3, -CH2CH3, -OCH3, -OCH2CH3, or cyclopropyl, or a pharma- ceutically acceptable salt thereof.

[0071] In another embodiment, a compound of formula (III-Di) or (III-Ei) [ka] During the ceremony, R 1a and R 1b each is independently selected from -CH3, -CF3, -C(CH3)3, -CHF2, -CH(CH3)2, or cyclopropyl; R 5 is selected from -F or -CN, or a pharma- ceutically acceptable salt thereof.

[0072] In some variations of Formula (III-A), Formula (III-B), Formula (III-C), Formula (III-Ai), Formula (III-Bi), Formula (III-Ci), Formula (III-Di), or Formula (III-Ei), R 1a is selected from -CH, -C(CH), -CHF, -CH(CH), or cyclopropyl. 1a is selected from -CH3, -C(CH3)3, or -CH(CH3)2. In yet another variation, R 1a is cyclopropyl.

[0073] In another embodiment, there is provided a compound of formula (IV) having a pyrazole core, [ka] During the ceremony, R 1a and R 1b each is independently selected from -CH3, -CF3, or -CHF2; R 3is -H, R 4 is -H or C 1-4 alkyl, There is provided a compound of formula (IV), or a stereoisomer or a pharma- ceutically acceptable salt thereof, wherein n is 1 or 2.

[0074] In some embodiments of formula (IV), R 4 is C 1-4 In certain embodiments, R 4 is methyl. In some variations of the foregoing, the compound is an optically active compound. In some variations, the compound is a single enantiomer. In one particular variation, the compound is the (R)-enantiomer. In other variations, the compound is the (S)-enantiomer.

[0075] In some variations of the compound of formula (IV), when n is 1, R 5 is selected from -CF3, -OCH3, or -OCH2CH3. In another variation of the compound of formula (IV), when n is 2, one of R 5 is -CH3, and the other R 5 is selected from -F or -Cl, R 6 is selected from -H or -CH3.

[0076] In one aspect, there is provided a compound selected from the compounds in Table A below, or a pharma- ceutically acceptable salt thereof. TIFF2025514140000020.tif222170TIFF2025514140000021.tif216170TIFF2025514140000022.tif220170TIFF20255141400 00023.tif217170TIFF2025514140000024.tif209170TIFF2025514140000025.tif209170TIFF2025514140000026.tif184170

[0077] In some embodiments, the compound is compound Nos. 1001, 1002, 1019, 1033-1037, 1039, 1041-1051, or 1053-1057, or a pharma- ceutically acceptable salt thereof. In some variations, the compound is compound Nos. 1034, 1035, 1039, 1044-1051, or 1054-1057, or a pharma- ceutically acceptable salt thereof.

[0078] The compounds described herein may contain one or more asymmetric centers and therefore may exist in the form of various isomers, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may exist 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 mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The embodiments disclosed herein additionally encompass the compounds described herein as individual isomers substantially free of other isomers, or as mixtures of various isomers.

[0079] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is therefore in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound contains more than 75% by weight, e.g., 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% by weight of an enantiomer. In certain embodiments, these weights are based on the total weight of all enantiomers or stereoisomers of the compound.

[0080] In certain aspects, compositions comprising the compounds described herein are provided. In some embodiments, the enantiomerically pure compounds can be present in the compositions with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R compound can comprise, for example, about 90% of excipients and about 10% of enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition can comprise, for example, at least about 95% by weight of the R compound and at most about 5% by weight of the S compound based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S compound can comprise, for example, about 90% of excipients and about 10% of the enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition can comprise, for example, at least about 95% by weight of the S compound and at most about 5% by weight of the R compound based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipients or carriers.

[0081] The compounds described herein may also include one or more isotopic substitutions. For example, H is:1 H, 2 H (D or deuterium), and 3 H may be in any isotopic form, including T or tritium, and C may be 12 C. 13 C, and 14 It may be in any isotopic form, including C. O is 16 O and 18 O may be in any isotopic form, including F. 18 F and 19 It may be any isotopic form containing F.

[0082] III. Treatment method The compounds and compositions described above and herein can be used to treat neurological disorders, disorders associated with excessive neuronal excitability, or disorders associated with gain-of-function mutations in genes (e.g., KCNT1).

[0083] In some aspects, methods are provided for treating a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with a gain-of-function mutation in a gene by administering to a subject in need of such treatment an effective amount of any of the compounds described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharma- ceutically acceptable salt thereof.

[0084] Exemplary diseases, disorders, or conditions include epilepsy and other encephalopathies (e.g., MMFSI or EIMFS, ADNFLE, West syndrome, infantile spasms, epileptic encephalopathies, developmental and epileptic encephalopathies (DEE), early infantile epileptic encephalopathies (EIEE), generalized epilepsy, focal epilepsy, multifocal epilepsy, temporal lobe epilepsy, Ohtahara syndrome, early myoclonic encephalopathy, Lennox-Gastaut syndrome, drug-resistant epilepsy, seizures (frontal lobe seizures, generalized tonic-clonic seizures, asymmetric tonic seizures, focal seizures), leukodystrophies, hypomyelinated ... and leukoencephalopathy), cardiac dysfunction (e.g., cardiac arrhythmias, Brugada syndrome, myocardial infarction), pulmonary vasculopathy / 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 disabilities, fragile X, neuroplasticity, and autism spectrum disorders.

[0085] In some embodiments, the neurological disorder, disorder associated with excessive neural excitability, or disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from EIMFS, ADNFLE, or West syndrome. In some embodiments, the neurological disorder, disorder associated with excessive neural excitability, or disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, or Lennox-Gastaut syndrome. In some embodiments, the neurological disorder, disorder associated with excessive neural excitability, or disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is seizures. In some embodiments, the neurological disorder, disorder associated with excessive neural excitability, or disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from cardiac arrhythmia, Brugada syndrome, or myocardial infarction.

[0086] In some embodiments, the neurological disorder, disorder associated with excessive neural excitability, or disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from a learning disability, fragile X, intellectual disability, neuroplasticity, a psychiatric disorder, or an autism spectrum disorder.

[0087] Thus, the compounds, pharma- ceutically acceptable salts thereof, and compositions disclosed herein can be administered to subjects having a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with a gain-of-function mutation in a gene such as KCNT1 (e.g., EIMFS, ADNFLE, West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, Lennox-Gastaut syndrome, seizures, cardiac arrhythmias, Brugada syndrome, and myocardial infarction).

[0088] EIMFS is a rare and debilitating genetic condition characterized by early onset (before age 6 months) of nearly continuous heterogeneous focal seizures that appear to migrate from one brain region and hemisphere to another. Patients with EIMFS are generally intellectually disabled, non-verbal, and non-ambulatory. To date, several genes have been implicated, but the gene most commonly associated with EIMFS is KCNT1. Several de novo mutations in KCNT1 have been identified in patients with EIMFS, including V271F, G288S, R428Q, R474Q, R474H, R474C, I760M, A934T, P924L, G243S, H257D, A259D, R262Q, Q270E, L274I, F346L, C377S, R398Q, P409S, A477T, F502V, M516V, Q550del, K629E, K629N, I760F, E893K, M896K, R933G, R950Q, and K1154Q.Barcia et al.(2012)Nat Genet.44:1255-1260、Ishii 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 can be dominant (i.e., present in only one allele) gain-of-function missense mutations and can result in altered function of the encoded potassium channel that causes a significant increase in whole-cell currents when tested in Xenopus oocytes or mammalian expression systems (see, e.g., Milligan et al. (2015) Ann Neurol. 75(4):581-590, Barcia et al. (2012) Nat Genet. 44(11):1255-1259, and Mikati et al. (2015) Ann Neurol. 78(6):995-999).

[0089] ADNFLE is a condition that has a later onset than EIMFS, generally occurring in mid-childhood, and is generally less severe. It is characterized by nocturnal frontal lobe seizures and can result in psychiatric, behavioral, and cognitive disorders in patients with the condition. ADNFLE is associated with genes that code for several neuronal nicotinic acetylcholine receptor subunits, but mutations in the KCNT1 gene are involved in more severe cases of the disease (Heron et al. (2012) Nat Genet. 44:1188-1190). Functional studies of mutant KCNT1 genes associated with ADNFLE have shown that the underlying mutations (M896I, R398Q, Y796H, and R928C) are dominant gain-of-function mutations (Milligan et al. (2015) Ann Neurol. 75(4):581-590, Mikati et al. (2015) Ann Neurol. 78(6):995-999).

[0090] West syndrome is a severe form of epilepsy consisting of a triad of infantile spasms, an interictal electroencephalogram (EEG) pattern called hypsarrhythmia, and mental retardation, although the diagnosis can be made without one of these elements. Mutations in KCNT1, including G652V and R474H, have been associated with West syndrome (Fukuoka et al. (2017) Brain Dev 39:80-83 and Ohba et al. (2015) Epilepsia 56:el21-el28). Therapies targeting the KCNT1 channel suggest that these mutations are gain-of-function mutations (Fukuoka et al. (2017) Brain Dev 39:80-83).

[0091] In one aspect, the present invention is directed to treating disorders associated with excessive neuronal excitability or disorders associated with gain-of-function mutations in genes such as KCNT1 (e.g., epilepsy and other encephalopathies (e.g., MMFSI or EIMFS), ADNFLE, West syndrome, infantile spasms, epileptic encephalopathies, focal epilepsy, Ohtahara syndrome, DEE, Lennox-Gastaut syndrome, seizures, leukodystrophies, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic seizures, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia, asymmetric tonic seizures), cardiac dysfunction (e.g., cardiac arrhythmias, Brugada syndrome, myocardial infarction, Disclosed herein is a method of treating chronic pain, rheumatoid arthritis ...

[0092] In some examples, subjects who present disorders that may be associated with KCNT1 gain-of-function mutations are genotyped to confirm the presence of known KCNT1 gain-of-function mutations before administering the compounds or pharma- ceutically acceptable salts or compositions disclosed herein.For example, whole exome sequencing can be performed on the subjects. Gain of function mutations associated with EIMFS may include, but are not limited to, V271F, G288S, R428Q, R474Q, R474H, R474C, I760M, A934T, P924L, G243S, H257D, A259D, R262Q, Q270E, L274I, F346L, C377S, R398Q, P409S, A477T, F502V, M516V, Q550del, K629E, K629N, I760F, E893K, M896K, R933G, R950Q, and K1154Q. Gain-of-function mutations associated with ADNFLE may include, but are not limited to, M896I, R398Q, Y796H, R928C, and G288S. Gain-of-function mutations associated with West syndrome may include, but are not limited to, G652V and R474H. Gain-of-function mutations associated with temporal lobe epilepsy may include, but are not limited to, R133H and R565H. Gain-of-function mutations associated with Lennox-Gastaut may include, but are not limited to, R209C. Gain-of-function mutations associated with seizures may include, but are not limited to, A259D, G288S, R474C, and R474H. Gain-of-function mutations associated with leukodystrophies may include, but are not limited to, G288S and Q906H. Gain-of-function mutations associated with multifocal epilepsy may include, but are not limited to, V340M. Gain-of-function mutations associated with early-onset epilepsy (EOE) may include, but are not limited to, F346L and A934T. Gain-of-function mutations associated with early-onset epileptic encephalopathy (EOEE) may include, but are not limited to, R428Q. Gain-of-function mutations associated with developmental and epileptic encephalopathies may include, but are not limited to, F346L, R474H, and A934T.Gain-of-function mutations associated with epileptic encephalopathy may include, but are not limited to, L437F, Y796H, P924L, and R961H. Gain-of-function mutations associated with early infantile epileptic encephalopathy (EIEE) may include, but are not limited to, M896K. Gain-of-function mutations associated with drug-resistant epilepsy and generalized tonic-clonic seizures may include, but are not limited to, F346L. Gain-of-function mutations associated with infantile partial seizures may include, but are not limited to, R428Q. Gain-of-function mutations associated with leukoencephalopathy may include, but are not limited to, F932I. Gain-of-function mutations associated with NFLE may include, but are not limited to, A934T and R950Q. Gain-of-function mutations associated with Ohtahara syndrome may include, but are not limited to, A966T. Gain-of-function mutations associated with infantile spasms may include, but are not limited to, P924L. Gain-of-function mutations associated with Brugada syndrome may include, but are not limited to, R1106Q. Gain-of-function mutations associated with Brugada syndrome may include, but are not limited to, R474H.

[0093] In other examples, subjects are first genotyped to identify the presence of a KCNT1 mutation, and then the mutation is confirmed to be a gain-of-function mutation using a standard in vitro assay, such as the assay described in Milligan et al. (2015) Ann Neurol. 75(4):581-590. Typically, the presence of a gain-of-function mutation is confirmed when expression of the mutant KCNT1 allele results in an increase in whole-cell current compared to the whole-cell current resulting from expression of wild-type KCNT1, which can be assessed using 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). This increase in whole-cell current can be, for example, at least or about 50%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, or more. As a result, the subject can be identified as having a disease or condition associated with a gain-of-function mutation in KCNT1.

[0094] In certain instances, the subject is identified as having a KCNT1 allele that includes a gain-of-function mutation (e.g., V271F, G288S, R398Q, R428Q, R474Q, R474H, R474C, G652V, I760M, Y796H, M896I, P924L, R928C, or A934T).

[0095] The compounds disclosed herein or their pharma- ceutically acceptable salts, or pharmaceutical compositions disclosed herein (e.g., pharmaceutical compositions comprising the compounds disclosed herein or their pharma- ceutically acceptable salts and pharma- ceutical acceptable excipients) can also be used therapeutically for conditions associated with excessive neural excitability, where the excessive neural excitability is not necessarily the result of a KCNT1 gain-of-function mutation. Even if the disease is not the result of increased KCNT1 expression and / or activity, inhibition of KCNT1 expression and / or activity can still result in decreased neural excitability and thus provide a therapeutic effect. Thus, the compounds disclosed herein or pharma- ceutically acceptable salts thereof, or compositions disclosed herein, can be used to treat subjects having conditions associated with excessive neural excitability, such as epilepsy and other encephalopathies (e.g., EIMFS, ADNFLE, West syndrome, infantile spasms, epileptic encephalopathies, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathies, Lennox-Gastaut syndrome, seizures), or cardiac dysfunction (e.g., cardiac arrhythmias, Brugada syndrome, myocardial infarction), regardless of whether the disorder is associated with a gain-of-function mutation in KCNT1.

[0096] In some variations of the foregoing, the "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents), or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)), and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0097] In some variations of the foregoing, the term "treating" or "treatment" as used herein contemplates an action taken while a subject is afflicted with a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or slows or retards the progression of the disease, disorder, or condition ("therapeutic treatment"). In some variations, "treating" or "treatment" refers to a method or procedure for obtaining beneficial or desired results, e.g., clinical results. Beneficial or desired results can include: (1) alleviating one or more symptoms caused by or associated with a disease, disorder, or condition; (2) reducing the severity of a disease, disorder, or condition; (3) slowing or halting the onset or progression of one or more symptoms caused by or associated with a disease, disorder, or condition (e.g., stabilizing the disease, disorder, or condition); and (4) relieving disease, for example, by causing regression of one or more clinical symptoms (e.g., ameliorating the pathology, enhancing the effect of another drug, slowing or halting the progression of a disease, improving quality of life, and / or prolonging survival).

[0098] In some variations of the above, the "effective amount" of a compound or its pharma- ceutically acceptable salt refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of a compound or its pharma- ceutically acceptable salt may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound or its pharma- ceutically acceptable salt, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.

[0099] In some embodiments, a therapeutically effective amount of a compound disclosed herein or a pharma- ceutically acceptable salt thereof is administered to a subject (e.g., a human). In some variations of the foregoing, a "therapeutically effective amount" of a compound or a pharma- ceutically acceptable salt thereof is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound or a pharma- ceutical acceptable salt thereof means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0100] In some embodiments, the method provided includes treating a disorder associated with a gain-of-function mutation of KCNT1. In some variations, a "disorder associated with a gain-of-function mutation of KCNT1" refers to a disorder having one or more symptoms associated with, partially or completely caused by, or partially or completely caused by a mutation of KCNT1 that results in a gain-of-function phenotype, i.e., an increase in the activity of the potassium channel encoded by KCNT1 that results in an increase in whole-cell current. In some variations, a "gain-of-function mutation of KCNT1" is a mutation of KCNT1 that results in an increase in the activity of the potassium channel encoded by KCNT1. Activity can be evaluated, for example, by ion flux assay or electrophysiology (e.g., using 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.

[0101] IV. Pharmaceutical Compositions and Routes of Administration The compounds provided according to the present invention or their pharma- ceutically acceptable salts are usually administered in the form of pharmaceutical compositions. Thus, disclosed herein are pharmaceutical compositions comprising one or more of the described compounds or their pharma- ceutically acceptable salts or esters as active ingredients, one or more pharma- ceutical acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions may be prepared in a manner disclosed in the pharmaceutical art, for example, in Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985) and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.).

[0102] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of drugs having utilities similar to those described, for example, in the patents and patent applications incorporated by reference, including rectal, buccal, intranasal, and transdermal routes, by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as, for example, a stent or an arterially inserted cylindrical polymer.

[0103] One mode of administration is parenteral, particularly by injection. Forms in which the novel compositions disclosed herein may be incorporated for administration by injection include aqueous or oily suspensions, or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Saline solutions are also used for injection in a conventional manner. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be provided by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0104] Sterile injectable solutions are prepared by incorporating the compound disclosed herein or its pharma- ceutically acceptable salt in the required amount in a suitable solvent containing various other ingredients as listed above, as necessary, and then sterilizing by filtration.Generally, dispersions are prepared by incorporating various sterilized active ingredients in a sterile vehicle containing a basic dispersion medium and other desired ingredients from those listed above.In the case of sterile powders for preparing sterile injectable solutions, exemplary preparation methods include vacuum drying and freeze-drying techniques, which obtain a powder of active ingredient and any additional desired ingredients from its previously sterile-filtered solution.

[0105] Oral administration is another route of administration of the compounds disclosed herein or their pharma- ceutically acceptable salts. Administration may be via capsules or enteric coated tablets, etc. In making pharmaceutical compositions containing at least one compound described herein or its pharma- ceutically acceptable salts, the active ingredient may be diluted by an excipient and / or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, it may be in the form of a solid, semi-solid, or liquid material (as described above) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment (e.g., containing up to 10% by weight of the active compound), soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0106] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose.In certain embodiments, the compositions disclosed herein can additionally include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents.

[0107] The compositions disclosed herein 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. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems that include 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 embodiment for use in the methods disclosed herein may use a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds disclosed herein or pharma-ceutically acceptable salts thereof in controlled amounts. The construction and use of transdermal patches to deliver pharmaceutical agents are described, for example, in U.S. Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0108] The compositions disclosed herein may be formulated in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable for human subjects and other mammals as a unitary dosage, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compounds are generally administered in a pharma- ceutical effective amount. Preferably, for oral administration, each dosage unit contains about 1 mg to about 2 g of a compound described herein or a pharma- ceutical acceptable salt thereof, and for parenteral administration, preferably about 0.1 to about 700 mg of a compound described herein or a pharma- ceutical acceptable salt thereof. However, it will be understood that the amount of the compound or a pharma- ceutical acceptable salt thereof actually administered will usually be determined by the physician in consideration of the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound or its pharma- ceutical acceptable salt to be administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0109] To prepare solid compositions such as tablets, the primary active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compounds disclosed herein or a pharma- ceutically acceptable salt thereof. When these preformulation compositions are said to be homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition, which allows the composition to be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0110] The tablets or pills disclosed herein can be coated or otherwise compounded to provide a dosage form that provides sustained release benefits or to protect against the acidic conditions of the stomach.For example, the tablet or pill can comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope over the former.These two components can be separated by an enteric layer that functions to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be released in a delayed manner.Various materials can be used for such enteric layers or coatings, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0111] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described herein. In certain embodiments, the compositions are administered by oral or nasal respiratory routes for local or systemic effect. Compositions in pharma-ceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered from a device that delivers the formulation in an appropriate manner, for example, orally or nasally.

[0112] In some embodiments, a pharmaceutical composition is provided comprising a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient and / or carrier.

[0113] Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above detailed description or the following examples, but rather is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications may be made to this description without departing from the spirit or scope of the embodiments disclosed herein, as defined in the claims. EXAMPLES

[0114] In order that the embodiments described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed as in any way limiting the scope thereof.

[0115] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are provided, it will be understood that other process conditions can also be used unless otherwise specified. Optimum 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.

[0116] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are described in the art. For example, numerous protecting groups and their introduction and removal are described in TW Greene and PG M Huts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0117] The compounds provided herein may 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). It should be noted that flash chromatography can be performed either manually or via an automated system. The compounds provided herein may 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 described in the art.

[0118] Abbreviation CDCl3 Deuterated Chloroform DCM Dichloromethane DEAD Diethyl azodicarboxylate DIPEA N,N-Diisopropylethylamine DMF Dimethylformamide DMSO Dimethyl sulfoxide DMSO-d6 Deuterated dimethyl sulfoxide-d6 EtOAc Ethyl acetate EtOH Ethanol HATU 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate IPA Isopropyl Alcohol MeOH Methanol T3P Propanephosphonic anhydride TFA Trifluoroacetic acid THF Tetrahydrofuran

[0119] I. Synthesis and Characterization of Exemplary Compounds Exemplary methods for preparing the compounds described herein are illustrated in the following synthetic schemes, which are provided for illustrative purposes and should not be construed as limiting the scope or spirit of the embodiments disclosed herein in any manner.

[0120] Certain exemplary compounds described herein are produced as a mixture of enantiomers. To separate the enantiomers, the mixture was further purified by preparative chiral HPLC according to the analytical conditions set forth in Table 1 below and as specified herein for a given compound. TIFF2025514140000027.tif206170TIFF2025514140000028.tif173170

[0121] Example 1 Synthesis and Characterization of Exemplary Compounds Based on Synthetic Scheme A [ka]

[0122] Step 1 To a stirred solution of compound 1 (1 eq.) in DMF (0.6 M), cesium carbonate (2 eq.) and alkyl halide (1 eq.) were added at about 0° C., and then stirring was continued at about 60° C. for approximately 12 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue obtained was then purified by flash column chromatography eluting with ethyl acetate / heptane mixture to give compound 2.

[0123] Step 2 In a sealed tube, to a stirred solution of compound 3 (1 eq.) in DMF (0.64 M), alkyl halide (1.5 eq.) and potassium carbonate (1.5 eq.) were added and then stirred at about 100° C. for approximately 4 hours. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2, which was used in step 3 below without further purification.

[0124] Step 3 To a stirred solution of compound 2 (1 eq.) in water:THF (1:3) (0.35M) mixture, lithium hydroxide hydrate (2 eq.) was added at about 0° C., and then stirring was continued at room temperature for approximately 16 hours. After the reaction was completed, the organic solvent was distilled off under reduced pressure. Water was added to the crude residue, which was acidified with 2N aqueous hydrochloric acid. The precipitate was filtered to give compound 4, which was used in the following step 4 without further purification.

[0125] Step 4 To a stirred solution of compound 4 (1 eq.) and N,O-dimethylhydroxylamine hydrochloride (2 eq.) in DCM (0.8M), HATU (1.5 eq.) and DIPEA (3 eq.) were added at about 0° C., and then stirring was continued at the same temperature for approximately 4 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography eluting with ethyl acetate / hexane mixture to give compound 5.

[0126] Step 5 To a stirred solution of compound 5 (1 eq.) in dry THF (0.2 M), methylmagnesium bromide solution (3 M, 2 eq.) was added at about 0° C., and then stirring was continued at the same temperature for approximately 2 h. After the reaction was completed, the reaction mixture was diluted with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography eluting with ethyl acetate / hexane mixture to give compound 6.

[0127] Step 6 To a stirred solution of compound 7 (1 eq.) and 1-ethoxyvinyltri-n-butyltin (1.2 eq.) in DMF (0.4 M) was added bis(triphenylphosphine)palladium(II) dichloride (10 mol%) under nitrogen atmosphere. After stirring at about 60° C. for approximately 4 h, the reaction mixture was quenched with aqueous potassium fluoride, stirred for approximately 30 min, and filtered. The filtrate was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate / petroleum ether mixtures to give compound 8.

[0128] Step 7 To a stirred solution of compound 8 (1 eq.) in acetone (0.36 M) was added 3 M aqueous hydrochloric acid (2.8 eq.) at about 25° C. After stirring at about 25° C. for approximately 16 hours, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide compound 6, which was used directly in step 8 below.

[0129] Step 8 To a stirred solution of compound 6 (1 eq.) and compound 9 (1.5 eq.) in toluene (0.4M), titanium(IV) isopropoxide (2 eq.) was added and then stirred at about 80° C. for approximately 12 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography eluting with ethyl acetate / hexane mixture to give compound 10.

[0130] Step 9 To a stirred solution of compound 10 (1 eq.) in methanol (0.45M), sodium borohydride (2 eq.) was added in small portions at about 0° C., and then stirring was continued at room temperature for approximately 2 hours. After the reaction was completed, the reaction mixture was quenched using water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography eluting with ethyl acetate / hexane mixture to give compound 11.

[0131] Step 10 To a stirred solution of compound 11 (1 eq.) in 1,4-dioxane (1M) was added 4M HCl in dioxane (6 eq.) at about 0° C., and then stirring was continued at room temperature for approximately 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was washed with diethyl ether to give compound 12.

[0132] Step 11 To a stirred solution of compound 12 (1 eq.) and compound 13 (2 eq.) in DCM (0.2M), HATU (1.5 eq.) and DIPEA (3 eq.) were added at about 0° C., and then stirring was continued at about 0° C. for approximately 2 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography eluting with ethyl acetate / hexane mixture to give compound 14.

[0133] Step 12 To a stirred solution of compound 14 (1 eq.) in a mixture of water:1,4-dioxane (1:4) (0.07M) was added cesium carbonate (2 eq.) and a boronic acid or boronic ester (2 eq.) at room temperature. The reaction mixture was degassed under argon for approximately 5 minutes, after which bis(triphenylphosphine)palladium(II) dichloride (5 mol%) was added. The reaction mixture was microwaved at about 100° C. for approximately 1 hour. The reaction mixture was allowed to cool to room temperature, filtered through a pad of Celite, and washed with ethyl acetate. The filtrate was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography eluting with ethyl acetate to give compound 15 and compound 16 as a mixture of enantiomers.

[0134] To separate these enantiomers, the mixture was further purified by preparative chiral HPLC (CHIRAL PAK AD-H (250 × 4.6 mm, 5 μm), mobile phase A: 0.1% DEA in n-hexane, mobile phase B: ETOH:MEOH (50:50), program-AB 90:10, flow rate: 1.0 ml / min) to give compound 15 and compound 16.

[0135] Step 13 A stirred solution of compound 6 (1 equiv.), boronic acid or boronic ester (1.3 equiv.), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (5 mol %), and cesium carbonate (3 equiv.) in a mixture of water:1,4-dioxane (1:10) (0.35 M) was stirred under a nitrogen atmosphere at about 80° C. for approximately 16 hours. The mixture was cooled to about 25° C., filtered, and concentrated to provide the crude product, which was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether mixtures to provide compound 17.

[0136] Step 14 To a stirred solution of compound 17 (1 eq.) in THF (0.15 M) was added rac-(R)-2-methylpropane-2-sulfinamide (18) or rac-(S)-2-methylpropane-2-sulfinamide (19) (1.5 eq.) and titanium(IV) isopropoxide (10 eq.) under nitrogen atmosphere at about 25° C. The mixture was heated to about 65° C. and stirred for approximately 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate solution and filtered. The filtrate was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate / petroleum ether mixtures to give compound 20 or compound 21, depending on the enantiomer of the sulfinamide used.

[0137] Step 15 To a stirred solution of compound 20 or compound 21 (1 eq.) in THF (0.13 M) was added L-Selectride (2 eq.) at about -78°C. After stirring at about -78°C for approximately 0.5 h, the mixture was poured onto saturated aqueous ammonium chloride solution and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography eluting with 0-10% MeOH / DCM to give compound 22 or compound 23.

[0138] Step 16 To a stirred solution of compound 13 (1.2 eq.) in DCM (0.05M) was added DIPEA (8 eq.) and T3P (3 eq.). After stirring for approximately 30 minutes at about 25° C., compound 24 or compound 25 (1 eq.) was added and the reaction was stirred for approximately 16 hours at about 25° C. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate / petroleum ether mixture. This material was further purified by supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ (250 mm×30 mm, 10 μm), conditions: 0.1% NH3H2O-EtOH, B start: 15, B end: 15) to give compound 15 or compound 16.

[0139] Step 17 To a stirred solution of compound 15 and compound 16 (1 eq.) in DMSO (0.24M) was added potassium carbonate (3 eq.) followed by 30% hydrogen peroxide (10 eq.) at room temperature and then stirring was continued at room temperature for approximately 12 hours. After the starting material was observed to be consumed, the reaction was quenched by addition of water and extracted with ethyl acetate. The combined organic layer was washed with water and brine. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography eluting with 50-60% EtOAc:heptane to give compound 1022.

[0140] Compounds 1001-1018, 1020-1022, and 1031 were prepared from commercially available starting materials generally following the synthetic scheme A and steps described above.

[0141] Exemplary compounds prepared according to Synthesis Scheme A were characterized by NMR, HPLC, and LCMS. NMR and LCMS data, as well as chiral separation methods (where applicable), are provided in Table 2 below. For compound numbers 1001 and 1002, the following SFC chiral method was used: Column: Chiralcel OJ-3 150×4.6 mm ID, 3 μm. Mobile phase: A: CO2, Mobile phase B: Ethanol (0.05% DEA). Gradient: 5%-40% B over 5 min and 40%-50% B over 0.5 min, hold at 5% B for 1.5 min. Flow rate: 2.5 mL / min. Column temperature: 35° C. ABPR: 1500 psi. TIFF2025514140000030.tif223170TIFF2025514140000031.tif231170TIFF2025514140000032.tif161170

[0142] Example 2 Synthesis and Characterization of Exemplary Compounds Based on Synthetic Scheme B [ka]

[0143] Step 18 To a stirred solution of compound 27 (1 eq.) in 1,4-dioxane (0.1 M) in a sealed tube, phenol 28 (2 eq.), N,N-dimethylglycine (0.6 eq.), copper iodide (20 mol%), and cesium carbonate (2 eq.) were added and then stirred at approximately 130° C. for about 4 hours. After the reaction was complete, water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue obtained was then purified by Combi-Flash chromatography eluting with 40% ethyl acetate / heptane to give compound 29.

[0144] Step 19 To a stirred solution of compound 27 (400 mg, 1.05 mmol) in 1,4-dioxane (0.13 M) was added compound 30 (3 eq.) and aqueous potassium carbonate (2 eq.) at room temperature. The reaction mixture was purged with argon for approximately 10 minutes. To the resulting solution, bis(diphenylphosphino)ferrocene]palladium(II) dichloride (10 mol%) was added and the solution was stirred at about 100° C. for approximately 12 hours. The reaction mixture was allowed to cool to room temperature and filtered through a Celite pad, which was washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography eluting with 50-60% EtOAc / heptane followed by achiral preparative chromatography to give compound 31.

[0145] Step 20 To a stirred solution of compound 27 (1 eq.) and amine compound (2 eq.) in DMSO (0.27 M), L-proline (40 mol%) and copper(I) iodide (20 mol%) were added at room temperature, and then stirring was continued at about 90° C. for approximately 16 hours. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite, which was washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography eluting with ethyl acetate / heptane mixtures, followed by achiral preparative chromatography to give compound 32.

[0146] Step 21 To a stirred solution of compound 27 (1 eq.) in 1,4-dioxane (0.1M) was added sodium tert-butoxide (2 eq.) and amine compound (2 eq.) at room temperature. The reaction mixture was purged with argon for approximately 10 minutes. To this solution, tris(dibenzylideneacetone)dipalladium(0) (10 mol%) and Brettphos (20 mol%) were added and the solution was stirred at about 130° C. for approximately 16 hours. The reaction mixture was allowed to cool to room temperature and filtered through a Celite pad, which was washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography eluting with ethyl acetate / heptane mixture to give compound 32.

[0147] Compounds 1023-1028 and 1032 were prepared from commercially available starting materials generally following the synthetic scheme B and steps described above.

[0148] Exemplary compounds prepared according to Synthetic Scheme B were characterized by NMR, HPLC, and LCMS. The NMR and LCMS data are provided in Table 3 below. TIFF2025514140000034.tif200170

[0149] Example 3 Synthesis and Characterization of Exemplary Compounds Based on Synthetic Scheme C [ka]

[0150] Step 22 To a stirred solution of compound 33 (1 eq.) in methanol (0.35M), lithium borohydride (6 eq.) was added in small portions at about 0° C., and then stirring was continued at room temperature for approximately 1 hour. After the reaction was complete, the reaction mixture was quenched by adding ammonium chloride solution at about 0° C. and extracted with ethyl acetate. The combined organic layers were washed with water, followed by brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography eluting with ethyl acetate / heptane mixture to give compound 34.

[0151] Step 23 To a stirred solution of compound 34 (1 eq.) and phthalidimide (35) (1.1 eq.) in THF (0.2M), triphenylphosphine (1.5 eq.) and DEAD (1.5 eq.) were added at about 0° C., and then stirring was continued at room temperature for approximately 16 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography eluting with ethyl acetate / hexane mixture to give compound 36.

[0152] Step 24 To a stirred solution of compound 36 (1 eq.) in DCM:EtOH (1:1) (0.1M) was added hydrazine hydrate (6 eq.) at room temperature, and then stirring was continued at the same temperature for approximately 12 hours. After the reaction was complete, the reaction mixture was quenched using water and filtered through a short Celite pad. The organic layer of the filtrate was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude residue (compound 37) was used in the following reaction step without further purification.

[0153] Step 25 To a stirred solution of compound 37 (1 eq.) and compound 38 or benzoic acid (1 eq.) in DCM (0.1M), HATU (1.5 eq.) and DIPEA (3 eq.) were added at about 0° C., and then stirring was continued at about 0° C. for approximately 2 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography eluting with ethyl acetate / hexane mixture to obtain compound 39 or compound 40.

[0154] Step 26 To a stirred solution of compound 39 or compound 40 (1 eq.) in water:1,4-dioxane (1:4) (0.07 M) was added cesium carbonate (2 eq.) and boronic acid or boronic ester (2 eq.) at room temperature. The reaction mixture was degassed under argon for approximately 5 minutes, after which bis(triphenylphosphine)palladium(II) dichloride (5 mol%) was added. The reaction mixture was microwaved at about 100° C. for approximately 1 hour. The reaction mixture was then allowed to cool to room temperature, filtered through a celite pad, and washed with ethyl acetate. The filtrate was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography eluting with ethyl acetate to give compound 41 or compound 42.

[0155] Compounds 1019, 1029, 1030, 1033, and 1036-1041 were prepared from commercially available starting materials generally following the synthetic scheme C and steps above.

[0156] Exemplary compounds prepared according to Synthetic Scheme C were characterized by NMR, HPLC, and LCMS. The NMR and LCMS data are provided in Table 4 below. TIFF2025514140000036.tif220170TIFF2025514140000037.tif46170

[0157] Example 4 Synthesis and Characterization of Exemplary Compounds Based on Synthetic Scheme D [ka]

[0158] Step 27 A suspension of compound 43 (1 eq.) in 7M ammonia in methanol (1 eq.) was stirred for approximately 24 hours at about 60° C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and washed with diethyl ether to give compound 44, which was used in the following step 28 without further purification.

[0159] Step 28 A suspension of compound 44 (1 eq.) in phosphoryl chloride (9 eq.) was heated at about 110° C. for approximately 16 hours. After the reaction was complete, the reaction was cooled to room temperature, concentrated to dryness under reduced pressure, and poured onto ice. The mixture was neutralized by adding 50% aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue obtained was then purified by flash column chromatography eluting with ethyl acetate / hexane mixture to give compound 45.

[0160] Step 29 To a stirred solution of compound 45 (1 eq.) and titanium isopropoxide (2.5 eq.) in THF (0.2M) was added 1M ethylmagnesium bromide (3.5 eq.) at about -78°C. The resulting solution was stirred for approximately 10 minutes. The solution was then allowed to warm to room temperature and stirred for approximately 2 hours, after which boron trifluoride diethyl etherate (4 eq.) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, 1N hydrochloric acid and diethyl ether were added, followed by 10% sodium hydroxide solution. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 46.

[0161] Step 30 To a stirred solution of compound 47 (1 eq.) and compound 46 (2 eq.) in DCM (0.1M), HATU (1.5 eq.) and DIPEA (3 eq.) were added at about 0° C., and then stirring was continued at about 0° C. for approximately 2 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography eluting with ethyl acetate / hexane mixture to give compound 48.

[0162] Step 31 To a stirred solution of compound 48 (1 eq.) in water:1,4-dioxane (1:4) (0.07 M) at room temperature was added cesium carbonate (2 eq.) and boronic acid or boronic ester (2 eq.). The reaction mixture was degassed under argon for approximately 5 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (5 mol%) was added. The reaction mixture was degassed and then heated at about 130° C. for approximately 16 hours. The reaction mixture was then allowed to cool to room temperature and filtered through a pad of Celite, which was washed with ethyl acetate. The filtrate was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue obtained was then purified by column chromatography eluting with ethyl acetate / n-hexane to give compound 49.

[0163] Compounds 1034 and 1035 were prepared from commercially available starting materials generally following the synthetic scheme D and steps above.

[0164] Exemplary compounds prepared according to Synthetic Scheme D were characterized by NMR, HPLC, and LCMS. The NMR and LCMS data are provided in Table 5 below. TIFF2025514140000039.tif62170

[0165] Example 5 - Synthesis of 1-methyl-N-(2-(1-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-5-yl)propan-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 1063) [ka]

[0166] Step 1: Synthesis of methyl 3-bromo-1-methyl-1H-pyrazole-5-carboxylate (2) To a stirred solution of compound 1 (5.0 g, 24.389 mmol) in DMF (50 mL) was added Cs2CO3 (15.8 g, 48.778 mmol) and methyl iodide (6.9 g, 48.778 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi-Flash chromatography (eluted with 40-50% EtOAc in heptane) to give the title compound 2 (3.3 g, 15.031 mmol, 61% yield) as an off-white solid.

[0167] Step 2: Synthesis of (3-bromo-1-methyl-1H-pyrazol-5-yl)methanol (3) To a stirred solution of compound 2 (3.8 g, 17.348 mmol) in methanol (50 mL) was added lithium borohydride (1.89 g, 86.742 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated NH4Cl solution at 0° C. and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the title compound 3 (2.9 g, crude) as an off-white solid. This compound was used directly in the next step without further purification.

[0168] Step 3: Synthesis of 3-bromo-5-(bromomethyl)-1-methyl-1H-pyrazole (4) To a stirred solution of compound 3 (3.0 g, 15.704 mmol) in DCM (20 mL), triphenylphosphine (6.1 g, 23.557 mmol) and CBr4 (7.8 g, 23.557 mmol) were added at 0° C. and the reaction mixture was stirred at room temperature for 3 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluted with 10-20% EtOAc in heptane) to give the title compound 4 (2.8 g, 10.5 mmol, 66.7% yield) as an off-white solid.

[0169] Step 4: Synthesis of 2-(3-bromo-1-methyl-1H-pyrazol-5-yl)acetonitrile (6) To a stirred solution of compound 4 (2.8 g, 11.027 mmol) in ACN (25 mL), TBAF (1.1 mL, 16.541 mmol) and TMSCN (2.07 mL, 16.541 mmol) were added dropwise at 0° C. The reaction mixture was stirred at room temperature for 6 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluted with 10-20% EtOAc in heptane) to give the title compound 5 (1.6 g, 7.278 mmol, 66.0% yield) as a yellow liquid.

[0170] Step 5: Synthesis of 2-(3-bromo-1-methyl-1H-pyrazol-5-yl)-2-methylpropanenitrile (6) To a stirred solution of compound 5 (0.1 g, 0.499 mmol) in THF (20 mL), nBuLi (1.6 M in hexane, 0.7 mL, 1.249 mmol) was added at 0 °C and the mixture was stirred for 10 min. To this solution, methyl iodide (0.14 g, 0.999 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with ice-cold water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by Combi-Flash chromatography (eluted with 20-30% EtOAc in heptane) to give the title compound 6 (0.1 g, 0.346 mmol, 69.2% yield) as a colorless liquid.

[0171] Step 6: Synthesis of 2-(3-bromo-1-methyl-1H-pyrazol-5-yl)-2-methylpropanamide (7): To a stirred solution of compound 6 (0.1 g, 0.438 mmol) in DMSO (10 mL) was added K2CO3 (0.06 g, 0.438 mmol) at 0 °C. To this solution, H2O2 (0.07 mL, 2.192 mmol) was added at a temperature of 0 °C, and the reaction was stirred at room temperature for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The combined organic layer was washed with water, followed by brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound 7 (0.1 g, crude) as a colorless liquid. This compound was used directly in the next step without further purification.

[0172] Step 7: Synthesis of 2-(3-bromo-1-methyl-1H-pyrazol-5-yl)propan-2-amine (8) To a stirred solution of compound 7 (0.1 g, 0.406 mmol) in ACN:water (2:2 mL) was added bis(trifluoroacetoxy)-iodobenzene (0.174 g, 0.406 mmol) at 0° C., and the reaction was stirred at room temperature for 24 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water and extracted with methyl tert-butyl ether. The aqueous layer was basified with 10% NaOH solution and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound 8 (0.07 g, crude) as a light brown solid. This compound was used directly in the next step without further purification.

[0173] Step 8: Synthesis of N-(2-(3-bromo-1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (10) To a stirred solution of compound 9 (0.097 g, 0.504 mmol) in DCM (5 mL) was added DIPEA (0.24 mL, 1.375 mmol) and HATU (0.26 g, 0.687 mmol) at 0° C. To this solution, compound 8 (0.1 g, 0.458 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by Combi-Flash chromatography (eluted with 40-50% EtOAc in heptane) to give the title compound 9 (0.13 g, 0.125 mmol, 27.3% yield) as an off-white solid.

[0174] Step 9: Synthesis of 3-(difluoromethyl)-1-methyl-N-(2-(1-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-5-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (compound 1063) To a stirred solution of compound 9 (0.13 g, 0.329 mmol) in 1,4-dioxane:water (4:1 mL), compound 10 (0.108 g, 0.395 mmol) was added followed by Cs2CO3 (0.21 g, 0.659 mmol) and the reaction mixture was degassed with argon gas for 15 minutes. To this solution, Pd(PPh3)4Cl2 (23.1 mg, 0.033 mmol) was added under argon atmosphere. The reaction mixture was stirred at 130° C. for 16 hours. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a celite pad and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluting with 50-60% EtOAc in heptane) to afford the title compound 1063 (23 mg, 0.049 mmol, 15.0% yield) as an off-white solid.

[0175] Data for compound 1063: HPLC: Rt 7.618 min, 99.14%. Column: X-Select CSH C18 (4.6 x 150) mm 5u, Mobile phase: A- 0.1% formic acid in water:acetonitrile (95:05), B- acetonitrile, Flow rate: 1.0 mL / min, Gradient program: Time (min) / B concentration: 0.01 / 10, 6.0 / 90, 10.0 / 100, 12.0 / 100, 14 / 10, 18.0 / 10. LCMS: 461.00 (M+H), Rt 1.961 min, 99.04%. Column: X-Select CSH C18 (3.0 × 50) mm 2.5 um, Mobile phase: A: 0.05% formic acid in water:ACN (95:05), B: 0.05% formic acid in ACN, Injection volume: 2.0 μL, Flow rate: 1.2 mL / min, Column oven temperature: 50 °C, Gradient program: 2% B to 98% B over 2.0 min, hold until 3.0 min, 2% B at 3.2 min until 4.0 min. 1H NMR(400MHz,DMSO-d6):δ 8.79(s,1H),8.75(d,J=5.1Hz,1H),8.19(s,1H),8.05(d,J=4.8Hz,1H),7.52(s,1H),7.09(s,1H),4.03(s,3H),3.90(s,3H),1.74(s,6H).

[0176] Example 6 - Synthesis of 1-methyl-N-(1-(1-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-5-yl)cyclobutyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Compound 1063) [ka]

[0177] Step 1: Synthesis of methyl 3-bromo-1-methyl-1H-pyrazole-5-carboxylate (2) To a stirred solution of compound 1 (5.0 g, 24.389 mmol) in DMF (50 mL) was added Cs2CO3 (15.8 g, 48.778 mmol) and methyl iodide (6.9 g, 48.778 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi-Flash chromatography (eluted with 40-50% EtOAc in heptane) to give the title compound 2 (3.3 g, 15.031 mmol, 61% yield) as an off-white solid.

[0178] Step 2: Synthesis of (3-bromo-1-methyl-1H-pyrazol-5-yl)methanol (3) To a stirred solution of compound 2 (3.8 g, 17.348 mmol) in methanol (50 mL) was added lithium borohydride (1.89 g, 86.742 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated NH4Cl solution at 0° C. and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the title compound 3 (2.9 g, crude) as an off-white solid. This compound was used directly in the next step without further purification.

[0179] Step 3: Synthesis of 3-bromo-5-(bromomethyl)-1-methyl-1H-pyrazole (4) To a stirred solution of compound 3 (3.0 g, 15.704 mmol) in DCM (20 mL), triphenylphosphine (6.1 g, 23.557 mmol) and CBr4 (7.8 g, 23.557 mmol) were added at 0° C. and the reaction mixture was stirred at room temperature for 3 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluted with 10-20% EtOAc in heptane) to give the title compound 4 (2.8 g, 10.5 mmol, 66.7% yield) as an off-white solid.

[0180] Step 4: Synthesis of 2-(3-bromo-1-methyl-1H-pyrazol-5-yl)acetonitrile (5) To a stirred solution of compound 4 (2.8 g, 11.027 mmol) in ACN (25 mL), TBAF (1.1 mL, 16.541 mmol) and TMSCN (2.07 mL, 16.541 mmol) were added dropwise at 0° C. The reaction mixture was stirred at room temperature for 6 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluted with 10-20% EtOAc in heptane) to give the title compound 5 (1.6 g, 7.278 mmol, 66.0% yield) as a yellow liquid.

[0181] Step 5: Synthesis of 1-(3-bromo-1-methyl-1H-pyrazol-5-yl)cyclobutane-1-carbonitrile (7) To a stirred mixture of compound 5 (1.2 g, 5.998 mmol), compound 6 (9.17 mL, 89.982 mmol) was added TEBAC (0.41 g, 1.799 mmol) in 50% aqueous NaOH (5.9 g, 149.97 mmol). The reaction mixture was stirred at 50° C. for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with ice-cold water and extracted with DCM. The combined organic layers were washed with water, followed by brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by Combi-Flash chromatography (eluted with 10-20% EtOAc in heptane) to give the title compound 7 (1.0 g, 2.415 mmol, 40.2% yield) as a colorless liquid.

[0182] Step 6: Synthesis of 1-(1-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-5-yl)cyclobutane-1-carbonitrile (9) To a stirred solution of compound 7 (0.4 g, 1.666 mmol) in 1,4-dioxane:water (8:2 mL), compound 8 (0.54 g, 1.999 mmol) was added followed by Cs2CO3 (1.0 g, 3.331 mmol) and the reaction mixture was degassed with argon gas for 15 minutes. To this solution, Pd(PPh3)4Cl2 (0.11 g, 0.166 mmol) was added under argon atmosphere. The reaction mixture was stirred at 110° C. for 12 hours. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a celite pad and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluting with 30-40% EtOAc in heptane) to give the title compound 9 (60 mg, 0.099 mmol, 23.9% yield) as an off-white solid.

[0183] Step 7: Synthesis of 1-(1-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-5-yl)cyclobutane-1-carboxamide (10) To a stirred solution of compound 9 (0.2 g, 0.653 mmol) in DMSO (2 mL) was added K2CO3 (0.09 g, 0.653 mmol) and H2O2 (0.1 mL, 3.264 mmol) dropwise at 0 °C. The reaction was stirred at room temperature for 12 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water, and the precipitated solid was filtered off and dried in vacuum to give the title compound 10 (0.15 g, crude) as an off-white solid. This compound was used directly in the next step without further purification.

[0184] Step 8: Synthesis of 1-(1-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-5-yl)cyclobutan-1-amine (11) To a stirred solution of compound 10 (0.15 g, 0.462 mmol) in 1,4-dioxane:water (4:2 mL), NaOH (0.04 g, 1.156 mmol) was added at 0° C., followed by NaOCI (0.85 g, 1.156 mmol), and the reaction mixture was stirred at 80° C. for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, and extracted with DCM, followed by brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound 11 (0.14 g, crude) as a colorless liquid. This compound was used directly in the next step without further purification.

[0185] Step 9: Synthesis of 1-methyl-N-(1-(1-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-5-yl)cyclobutyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (compound 1064) To a stirred solution of compound 12 (0.086 g, 0.445 mmol) in DCM (5 mL) was added DIPEA (0.21 mL, 1.215 mmol) and HATU (0.23 g, 0.607 mmol) at 0° C. To this solution, compound 11 (0.12 g, 0.405 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by Combi-Flash chromatography (eluted with 40-50% EtOAc in heptane) to give the title compound compound 1064 (30 mg, 0.060 mmol, 14.9% yield) as an off-white solid.

[0186] Data: HPLC: Rt 7.704 min, 95.28%. Column: X-Select CSH C18 (4.6 x 150) mm 5u, Mobile phase: A - 0.1% formic acid in water:acetonitrile (95:05), B - acetonitrile, Flow rate: 1.0 mL / min, Gradient program: Time (min) / B concentration: 0.01 / 10, 6.0 / 90, 10.0 / 100, 12.0 / 100, 14 / 10, 18.0 / 10. LCMS: 473.20 (M+H), Rt 1.913 min, 96.99%. Column: X-Select CSH (3.0 x 50) mm 2.5u, Mobile phase: A: 0.05% formic acid in water:ACN (95:5), B: 0.05% formic acid in ACN, Injection volume: 2.0μL, Flow rate: 1.2mL / min, Column oven temperature: 50C, Gradient program: 0%B to 98%B over 2.0min, hold until 3.0min, 0%B at 3.2 until 4.0min. 1 H NMR(400MHz,CDCl3)δ 8.71(d,J=5.1Hz,1H),8.07(s,1H),7.84(d,J=5.1Hz,1H),6.84(s,1H),6.79(s,1H),6.40( s,1H),4.15(s,3H),3.94(s,3H),2.83-2.71(m,4H),2.26-2.15(m,1H),2.09-2.00(m,1H).

[0187] II. Efficacy of Exemplary Compounds in Inhibiting KCNT1 Example B1 KCNT1-patch clamp assay Inhibition of KCNT1 (KNa1.1, Slack) was evaluated using a tetracycline-inducible cell line (HEK-TREX). Currents were recorded using a SyncroPatch 384PE automated patch clamp system. Pulse generation and data collection were performed with PatchController384 V1.3.0 and DataController384 V1.2.1 (Nanion Technologies). Access resistance and apparent membrane capacitance were estimated using built-in protocols. Currents were recorded in perforated patch mode (10 μM escin) from cell populations. Cells were lifted, triturated and resuspended at 800,000 cells / ml. Cells were allowed to recover in a cell hotel before the experiment. Currents were recorded at room temperature. The external solution contained NaCl 105 mM, NMDG 40 mM, KCl 4 mM, MgCl2 1 mM, CaCl2 5 mM, and HEPES 10 mM (pH=7.4, osmolality approx. 300 mOsm). The extracellular solution was used as the washing solution, the reference solution, and the compound delivery solution. The internal solution contained NaCl 70 mM, KF 70 mM, KCl 10 mM, EGTA 5 mM, HEPES 5 mM, and escin 0.01 mM (pH=7.2, osmolality approx. 295 mOsm). Escin was made in a 5 mM stock solution in water, aliquoted, and stored at -20°C. Compound plates were made at 2-fold concentrations in the extracellular solution. Compounds were diluted 1:2 when added to the recording wells. The amount of DMSO in the extracellular solution was kept constant at the level used for the highest test concentration. Holding potentials from -80 mV to 0 mV in 100 ms steps were used. Mean currents were measured during the step to 0 mV. 100 μM bepridil was used to completely inhibit KCNT1 currents to allow offline subtraction of non-KCNT1 currents. Average current means from three sweeps were calculated and percent inhibition for each compound was calculated. Percent inhibition as a function of compound concentration was fitted to the Hill equation to obtain IC 50 , slope, minimum, and maximum parameters were derived. If KCNT1 inhibition was less than 50% at the highest tested concentration or IC 50 If it is not possible to calculate IC 50 Percent inhibition was reported instead of the mean.

[0188] The results of this example are summarized in Table 6 below. In this table, "A" denotes an IC of 1 μM or less. 50 "B" indicates inhibition between 1 μM and 20 μM, and "C" indicates inhibition of 20 μM or more. TIFF2025514140000042.tif215170

[0189] Example B2: Pharmacokinetics Pharmacokinetic data for Compound 1063 and Compound 1064 were obtained as detailed herein.

[0190] Kinetic solubility assay: The kinetic solubility assay used the shake flask method followed by HPLC-UV analysis. The following stepwise procedure was used: 1) Samples are weighed out and dissolved in 100% DMSO as 10 mM stock solutions. Approximately 10 μL (compound / media) of stock solution is required for this assay. 2) Test compounds and controls (10 mM in DMSO, 10 μL / vial) are added to 50 mM pH 7.4 phosphate buffer (490 μL / well) placed in Mini-Uniprep filters. 3) Vortex the kinetic solubility samples for 2 minutes. 4) The solubility solution is incubated and shaken at room temperature on an orbital shaker at 800 rpm for 24 hours. 5) Centrifuge at 4000 rpm for 10 minutes at 20°C. 6) After the samples are directly filtered through a syringeless filter device, 400 μL (with or without dilution) of each solubility supernatant is transferred to a 96 deep well for analysis. 7) Determine the test compound concentration of the filtrate using HPLC-UV. 8) Then, inject at least five UV standard solutions from low to high concentration into the HPLC, then test the kinetic solubility supernatants in duplicate. 9) QC samples are used to monitor the kinetic solubility determination process.

[0191] Log D: The Log D assay is a miniaturized 1-octanol / buffer shake flask method followed by LC / MS / MS analysis. It is typically measured by determining the partitioning of a compound between an organic solvent (1-octanol) and an aqueous buffer (0.1 M phosphate buffer, pH 7.4, various buffer pHs can be set). Since log D is pH dependent, the pH of the aqueous phase is always specified and is typically measured at pH 7.4, which is the physiological pH of body fluids. The following Log D method was used to calculate the Log D values ​​in Table 8 below. 1) Dissolve the appropriate test compound to a 10 mM solution in 100% DMSO. 2) Transfer test compounds (10 mM in DMSO, 2 μL / well) and QC samples (10 mM in DMSO, 2 μL / well) from storage tubes into 96-well polypropylene cluster tubes. 3) Add buffer-saturated 1-octanol (149 μL / well) and 1-octanol saturated buffer (149 μL / well) to the wells, respectively. 4) Each tube is mixed vigorously on its side for 3 minutes, then shaken at 880 rpm for 1 hour at room temperature. 5) Centrifuge the tube at 4000 rpm for 5 minutes. 6) Using the internal standard (IS) solution, dilute the samples in the buffer layer by 20 times and the samples in the 1-octanol layer by 200 times. Note: The dilution factor is mainly based on the properties of the compound. 7) Analyze the samples using a triple quadrupole mass spectrometer. Correct the peak areas by the dilution factor and the embedded internal standard, and calculate the results using the ratio of the corrected peak areas (Log D value). 8) QC samples are used to monitor process Log D determinations. 9) Data analysis: The Log D value of each compound is calculated by the following equation:

number

[0192] The different dilution values ​​in the equation are implemented using different dilution factors for sample handling.

[0193] MW, XLogP, and TPSA: All of these data points were calculated using Dotmatics.

[0194] Liver Microsomal Metabolic Stability Assay (NADPH): 1) Test compounds were incubated with 1.0 μM liver microsomes (pooled from multiple donors) at 37° C. in the presence of NADPH (approximately 1.0 mM) at 0.5 mg / ml microsomal protein. 2) Positive controls include testosterone (3A4 substrate), propafenone (2D6), and diclofenac (2C9), also incubated with microsomes in the presence of NADPH. 3) Time samples (0, 5, 15, 30, 45, and 60 min) are removed and immediately mixed with cold acetonitrile containing an internal standard (IS) and test compound incubated with microsomes without NADPH for 60 min. 4) Duplicates (n=2) for each test condition. 5) The samples are analyzed by LC / MS / MS and the disappearance of the test compound is assessed based on the peak area ratio of analyte / IS (no standard curve). 6) Provides a summary of the Excel data, intrinsic clearance calculations, and T1 / 2 values. 7) Calculate microsomal clearance using the following equation:

number

number

number

[0195] The microsomal protein (mg) / liver weight (g) is 45 for the five species. Liver weight values ​​of 40 g / kg, 30 g / kg, 32 g / kg, 20 g / kg, and 88 g / kg are used for rats, monkeys, dogs, humans, and mice, respectively. Liver clearance is calculated as CL using the following equation: int(mic) Calculate using:

number

Claims

1. A compound of formula (I) having a pyrazole core, 【Chemistry 1】 During the ceremony, R １ However, it is selected from a 5-membered or 6-membered heteroaryl or aryl, wherein the heteroaryl or aryl optionally comprises at least one substituent independently selected from alkyl, haloalkyl, carbocykyl, or -CN. R ２ However, it is -H, R ３ However, it is selected from -H or alkyl, R ４ However, it is selected from -H or alkyl, or R ３ and R ４ However, together with the carbon atoms to which they are bonded, they form optionally substituted 3- to 6-membered carbocykries or heterocyclines. Z is 【Chemistry 2】 Selected from haloalkyl or alkoxy, Ring A is selected from a 5-membered or 6-membered heteroaryl, aryl, heterocyclyl, or carbocyclyl. R ５ These independently form alkyl, carbocyric, alkoxy, and -C(O)NH ２ Selected from , -CN, or halogen, wherein the alkyl, the carbocyric, or the alkoxy optionally contains at least one halogen substituent, or the alkyl optionally contains at least one -OH substituent. n is 0, 1, 2, 3, or 4, L is absent or -NR ａ -, -CH ２ - or -O- and is selected from R ａ However, it is selected from -H or alkyl, R ６ However, it is selected from -H or alkyl, R ７ A compound of formula (I) that is alkyl, or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) is a compound of formula (II) having a pyrazole core, 【Transformation 3】 During the ceremony, R １ However, it is selected from pyrazolyl or phenyl, where the pyrazolyl or phenyl is C １－４ Alkyl, C １－４ Haloalkyl, or C ３－５ It optionally comprises at least one substituent independently selected from the carbocyclyl, R ２ However, it is -H, R ３ However, it is selected from -H or alkyl, R ４ However, -H or C １－４ Selected from alkyl groups, or R ３ and R ４ However, together with the carbon atoms to which they are bonded, they form optionally substituted 3- to 5-membered carbocykries or heterocyclines. Ring A is selected from pyridyl, phenyl, pyrimidinyl, piperidinyl, or cyclopentyl. R ５ However, C １－４ Alkyl, C ３－５ Carbocyclyl, C １－４ Alkoxy, -C(O)NH ２ Selected from , -CN, or halogen, wherein the alkyl, the carbocyric, or the alkoxy optionally contains at least one halogen substituent, or the alkyl optionally contains at least one -OH substituent. n is 0, 1, 2, 3, or 4, L is absent, or -NR ａ -ien-CH ２ - or -O- are selected, R ａ However, -H or C １－４ Selected from alkyl groups, R ６ However, -H or C １－４ Selected from alkyl groups, R ７ However, C １－４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is an alkyl compound of formula (II), or a pharmaceutically acceptable salt thereof.

3. R １ However, -CH ３ , -CF ３ , -C(CH ３ ) ３ ,-CHF ２ , -CH(CH ３ ) ２ , or pyrazolyl comprising at least one substituent selected from cyclopropyl, A compound according to claim 1 or 2, wherein R1 is phenyl, or a pharmaceutically acceptable salt thereof.

4. R ４ is -H or -CH ３ Selected from, or The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3 and R4, together with the carbon atoms to which they are bonded, form optionally substituted cyclopropyl, cyclobutyl, or oxetanyl.

5. The compound according to claim 1 or 2, wherein ring A is pyridyl, or a pharmaceutically acceptable salt thereof.

6. R ５ However, at each occurrence, independently, -CH ３ ien-CH ２ CH ３ , -CF ３ , -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ ien-CH ２ OH, -CN, -C(O)NH ２ A compound according to claim 1 or 2, selected from , or cyclopropyl, or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

8. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is absent.

9. R ６ is -H or -CH ３ A compound according to claim 1 or 2, selected from, or a pharmaceutically acceptable salt thereof.

10. R ７ ga-CH ３ or -CH ２ CH ３ A compound according to claim 1 or 2, selected from, or a pharmaceutically acceptable salt thereof.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II-A), formula (II-B), formula (II-C), formula (III-A), formula (III-B), or formula (III-C) having a pyrazole core, 【Chemistry 4】 During the ceremony, R1a is selected from -CH3, -C(CH3)3, -CHF2, -CH(CH3)2, or cyclopropyl. R1b is selected from -CH3, -CF3, -C(CH3)3, -CHF2, -CH(CH3)2, or cyclopropyl. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 5 is independently selected at each occurrence from a compound of formula (II-A), formula (II-B), formula (II-C), formula (III-A), formula (III-B), or formula (III-C), or a pharmaceutically acceptable salt thereof, selected from a C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or C3-5 carbocyryl.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (III-A-i), formula (III-B-i), or formula (III-C-i) having a pyrazole core, 【Transformation 5】 During the ceremony, R １ａ However, -CH ３ , -C(CH ３ ) ３ ,-CHF ２ , -CH(CH ３ ) ２ , or selected from cyclopropyl, R １ｂ However, -CH ３ , -CF ３ , -C(CH ３ ) ３ ,-CHF ２ , -CH(CH ３ ) ２ , or selected from cyclopropyl, R ５ However, -CF ３ ien-CH ３ ien-CH ２ CH ３ , -OCH ３ , -OCH ２ CH ３ A compound according to claim 11, or a pharmaceutically acceptable salt thereof, selected from a compound of formula (III-A-i), formula (III-B-i), or formula (III-C-i), selected from cyclopropyl, or a pharmaceutically acceptable salt thereof.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (III-D-i) or formula (III-E-i) having a pyrazole core, 【Transformation 6】 During the ceremony, R １ａ is selected from -CH ３ , -C(CH ３ ), -CHF ３ , -CH(CH ２ ), or cyclopropyl, ３ ), ２ and is selected from the group consisting of: R １ｂ is selected from -CH ３ , -CF ３ , -C(CH ３ ), -CHF ３ , -CH(CH ２ ), or cyclopropyl, and ３ is selected from -CH ２ , -CF R ５ The compound according to claim 11, or a pharmaceutically acceptable salt thereof, selected from a compound of formula (III-D-i) or formula (III-E-i) selected from -F or -CN, or a pharmaceutically acceptable salt thereof.

14. The following compounds: 【Transformation 7】 【change】 【change】 【change】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from any of the above, or an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition, A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient.

16. A method for treating a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with a gain-of-function mutation of a gene (e.g., KCNT1), comprising administering an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15, to a subject in need thereof, the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15, for use in the method.

17. The pharmaceutical composition according to claim 16, wherein the neurological disorder, the disorder related to excessive neuronal excitability, or the disorder related to a gain-of-function mutation in a gene (e.g., KCNT1) is epilepsy, epileptic syndrome, or encephalopathy.

18. The neurological disorder, the disorder related to excessive neuronal excitability, or the disorder related to a gain-of-function mutation in a gene (e.g., KCNT1) may be hereditary or childhood epilepsy, hereditary or childhood epilepsy syndrome, cardiac dysfunction, malignant migratory focal seizures in infants (MMFSI) or 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 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, cardiac arrhythmia, Brugada syndrome, myocardial infarction, pain and related conditions (e.g., neuropathic pain, acute / chronic pain, hemiplegia). Headache), muscle disorders (e.g., myotonia, neurogenic myotonia, muscle spasms, spasticity), itching and pruritus, ataxia, psychiatric disorders (e.g., major depression, anxiety, bipolar disorder, schizophrenia), learning disabilities, fragile X, neuroplasticity, autism spectrum disorder, epileptic encephalopathy with SCN1A, SCN2A, and / or SCN8A mutations, early infant epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, fever The pharmaceutical composition according to claim 16, wherein the patient has generalized epilepsy with sexual seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, benign familial neonatal-infant seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic childhood partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen encephalitis, infantile malignant migratory partial seizures, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

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