KCNT1 inhibitors comprising pyrazole core and methods of use

Abstract

Disclosed herein are compounds comprising a pyrazole core, as well as pharmaceutically acceptable salts thereof, and compositions useful for the prevention and / or treatment of neurological disorders, disorders associated with excessive neuronal excitability, or disorders associated with functional obtainable mutations in genes (e.g., KCNT1). Also provided herein are methods of treating a nervous system disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with a functionally obtained mutation in a gene such as KCNT1.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 334,322 filed on April 25, 2022 and U.S. Provisional Patent Application No. 63 / 386,013 filed on December 5, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure generally relates to KCNT1 inhibitors comprising a pyrazole core and to pharmaceutical compositions and methods of treatment using such compounds. Background Art

[0004] Potassium-sodium activated channel subfamily T member 1 ("KCNT1") is one of a family of genes responsible for providing instructions for making potassium channels. KCNT1 encodes a protein called Slack (e.g., calcium-activated K + These channels are present in neurons throughout the brain and can mediate 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. Aberrant Slack activity has been associated with the development of early-onset epilepsy and intellectual disability. Therefore, selective regulation of sodium-activated potassium channels (e.g., aberrant KCNT1 or aberrant I KNa ) can be used to treat neurological diseases or disorders or diseases or conditions associated with excessive neuronal excitability and / or KCNT1 gain-of-function mutations. Summary of the invention

[0005] Described herein are compounds and compositions useful for preventing and / or treating a disease, disorder, or condition (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)).

[0006] In some aspects, a compound of formula (I) having a pyrazole core is provided:

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein:

[0009] R 1 is selected from 5-membered or 6-membered heteroaryl or aryl, wherein the heteroaryl or the aryl optionally comprises at least one substituent, the at least one substituent being independently selected from alkyl, haloalkyl, carbocyclyl or -CN;

[0010] R 2 is -H;

[0011] R 3 Selected from -H or alkyl;

[0012] R 4 Selected from -H or alkyl;

[0013] or R 3 and R 4 Together with the carbon atom to which it is attached, it forms an optionally substituted 3- to 6-membered carbocyclic or heterocyclic group;

[0014] Z is selected from A haloalkyl or alkoxy group;

[0015] Ring A is selected from 5-membered or 6-membered heteroaryl, aryl, heterocyclyl or carbocyclyl;

[0016] R 5 is independently selected from alkyl, carbocyclyl, alkoxy, -C(O)NH2, -CN or halogen, wherein the alkyl, the carbocyclyl or the alkoxy optionally comprises at least one halogen substituent, or wherein the alkyl optionally comprises at least one -OH substituent;

[0017] n is 0, 1, 2, 3 or 4;

[0018] L is absent or selected from -NR a -, -CH2- or -O-;

[0019] R a Selected from -H or alkyl;

[0020] R 6 is selected from -H or alkyl; and

[0021] R 7 It is an alkyl group.

[0022] In certain embodiments, disclosed herein is a compound of formula (II) having a pyrazole core:

[0023]

[0024] or a pharmaceutically acceptable salt thereof, wherein

[0025] R 1 is selected from pyrazolyl or phenyl, wherein the pyrazolyl or the phenyl optionally comprises at least one substituent, the at least one substituent being independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-5 Carbocyclic group;

[0026] R 2 is -H;

[0027] R3 Select from -H or C 1-4 alkyl;

[0028] R 4 Select from -H or C 1-4 alkyl;

[0029] or R 3 and R 4 Together with the carbon atom to which it is attached, it forms an optionally substituted 3-5 membered carbocyclyl or heterocyclyl;

[0030] Ring A is selected from pyridyl, phenyl, pyrimidinyl, piperidinyl or cyclopentyl,

[0031] R 5 Selected from C 1-4 Alkyl, C 3-5 Carbocyclic group, C 1-4 Alkoxy, -C(O)NH2, -CN or halogen, wherein the alkyl, the carbocyclyl or the alkoxy optionally comprises at least one halogen substituent, or wherein the alkyl optionally comprises at least one -OH substituent;

[0032] n is 0, 1, 2, 3 or 4;

[0033] L is absent or selected from -NR a -, -CH2- or -O-;

[0034] R a Select from -H or C 1-4 alkyl;

[0035] R 6 Select from -H or C 1-4 Alkyl; and

[0036] R 7 C 1-4 alkyl.

[0037] In certain embodiments, R 1 is pyrazolyl, the pyrazolyl comprising at least one substituent selected from: -CH3, -CF3, -C(CH3)3, -CHF2, -CH(CH3)2 or cyclopropyl, and in certain embodiments, R 1 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 it is attached, it forms an optionally substituted cyclopropyl, cyclobutyl or oxetanyl. In certain aspects, Ring A is pyridyl, and in certain aspects, R 5is independently selected at each occurrence from: -CH3, -CH2CH3, -CF3, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2OH, -CN, -C(O)NH2, 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 Selected from -CH3 or -CH2CH3.

[0038] In various aspects of the present disclosure, the compound of formula (I) is selected from a compound of formula (II-A), a compound of formula (II-B) or a compound of formula (II-C):

[0039]

[0040]

[0041] or a pharmaceutically acceptable salt thereof.

[0042] In certain embodiments, the compound of formula (I) is selected from a compound of formula (III-A), a compound of formula (III-B), or a compound of formula (III-C):

[0043]

[0044] or a pharmaceutically acceptable salt thereof, wherein:

[0045] R 1a Selected from -CH3, -C(CH3)3, -CHF2, -CH(CH3)2 or cyclopropyl;

[0046] R 1b is selected from -CH3, -CF3, -C(CH3)3, -CHF2, -CH(CH3)2 or cyclopropyl; and

[0047] R 5 In each occurrence, independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 3-5 Carbocyclic group.

[0048] In certain embodiments, the compound of formula (I) is selected from the compound of formula (III-Ai), the compound of formula (III-Bi) or the compound of formula (III-Ci):

[0049]

[0050] or a pharmaceutically acceptable salt thereof, wherein:

[0051] R 1a Selected from -CH3, -C(CH3)3, -CHF2, -CH(CH3)2 or cyclopropyl;

[0052] R 1b is selected from -CH3, -CF3, -C(CH3)3, -CHF2, -CH(CH3)2 or cyclopropyl; and

[0053] R 5 Selected from -CF3, -CH3, -CH2CH3, -OCH3, -OCH2CH3 or cyclopropyl.

[0054] In certain embodiments, disclosed herein is a compound of formula (I) selected from a compound of formula (III-Di) or a compound of formula (III-Ei):

[0055]

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

[0057] R 1a Selected from -CH3, -C(CH3)3, -CHF2, -CH(CH3)2 or cyclopropyl;

[0058] R 1b is selected from -CH3, -CF3, -C(CH3)3, -CHF2, -CH(CH3)2 or cyclopropyl; and

[0059] R 5 Selected from -F or -CN.

[0060] In certain embodiments, the compound of formula (I) is selected from:

[0061]

[0062]

[0063]

[0064]

[0065] In other aspects, a method of treating a nervous system disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with a gain-of-function mutation in a gene is provided by administering to a subject in need thereof an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or any of the pharmaceutical compositions described herein comprising such a compound or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, provided methods relate to treating disorders associated with gain-of-function mutations in KCNT1.

[0067] In some variations, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (eg, KCNT1) is epilepsy, an epileptic syndrome, or an encephalopathy.

[0068] In some variations, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (eg, KCNT1) is an inherited or pediatric epilepsy or an inherited or pediatric epilepsy syndrome.

[0069] In some variations, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (eg, KCNT1) is a cardiac dysfunction.

[0070] In some variations, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from the group consisting of epilepsy and other encephalopathy (e.g., malignant migratory focal seizures of infancy (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, or cerebellar ataxia.

[0071] In some variations, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (eg, KCNT1) is selected from arrhythmia, Brugada syndrome, or myocardial infarction.

[0072] In some variations, the nervous system disorder, the disorder associated with excessive neuronal excitability, or the 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).

[0073] In some variations, the nervous system disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is a muscle disorder (e.g., myotonia, neuromyotonia, cramp muscle spasm, spasticity).

[0074] In some variations, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (eg, KCNT1) is selected from pruritus and pruritus, ataxia, or cerebellar ataxia.

[0075] In some variations, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is a psychiatric disorder (e.g., major depressive disorder, anxiety disorder, bipolar disorder, schizophrenia).

[0076] In other variations, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (eg, KCNT1) is selected from a learning disorder, fragile X, neuronal plasticity, or an autism spectrum disorder.

[0077] In yet other variations, the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from epileptic encephalopathy with SCN1A mutation, SCN2A mutation, and / or SCN8A mutation, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic partial epilepsy in children with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen encephalitis, encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0078] Other objects and advantages will become apparent to those skilled in the art from a consideration of the following detailed description. DETAILED DESCRIPTION

[0079] In certain aspects, provided herein are compounds and compositions that are useful for preventing and / or treating 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 encephalopathy (e.g., MMFSI or EIMFS, ADNFLE, West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic seizures, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia, asymmetric tonic seizures); cardiac dysfunction (e.g., arrhythmias, Brugada syndrome, myocardial infarction); pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.); muscle disorders (e.g., myotonia, neuromyotonia, cramping muscle spasms, spasticity); pruritus and pruritus; ataxia and cerebellar ataxia; and psychiatric disorders (e.g., major depressive disorder, anxiety, bipolar disorder, schizophrenia).

[0080] I. Definitions

[0081] Unless otherwise defined, all technical terms, symbols, and other technical and scientific terms or nouns 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 cases, terms with commonly understood meanings are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from what is generally understood in the art.

[0082] Throughout this disclosure, various aspects of the claimed subject matter are presented in the form of ranges. It should be understood that the description in the form of ranges is only for convenience and brevity, and should not be interpreted as a stubborn limitation on the scope of the claimed subject matter. Therefore, the description of the range should be regarded as having clearly disclosed all possible sub-ranges and individual numerical values ​​within the range. For example, in the case of providing a series of values, it should be understood that, unless the context clearly indicates otherwise, each intermediate value between the upper and lower limits of the range up to one-tenth of the lower limit and any other stated values ​​or intermediate values ​​within the stated range are all included in the present disclosure, subject to any clearly excluded limit in the stated range. In the case where the stated range includes one or two of the limits, the scope excluding any one or two of the included limits is also included in the present disclosure. In some embodiments, two relative and open ranges are provided for the feature, and in this description, it is contemplated that a combination of these two ranges is provided herein. For example, in some embodiments, a feature is described as being greater than about 10 units, and a feature is described (as in another sentence) as being less than about 20 units, and thus, a range of about 10 units to about 20 units is described herein.

[0083] As used herein, the term "about" refers to the common error range of the corresponding value that is readily known in the art. References herein to "about" a value or parameter include (and describe) variations for the value or parameter itself. For example, a description of "about X" includes a description of "X".

[0084] As used herein, including in the appended claims, the singular forms "a," "an," 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 should be understood that the aspects and variations described herein include embodiments that "consist of" and / or "consist essentially of" the aspects and variations.

[0085] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0086] As used herein, the terms "in some embodiments," "in other embodiments," etc. refer to embodiments of all aspects of the present disclosure, unless the context clearly dictates otherwise.

[0087] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry as well as 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, 5th ed., 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, 3rd ed., Cambridge University Press, Cambridge, 1987.

[0088] The following terms are intended to have the meaning presented below, and can be used to understand the description and expected scope of the present disclosure. In describing certain aspects of the present disclosure that can include compounds, pharmaceutical compositions containing such compounds, and methods using such compounds and compositions, unless otherwise specified, the following terms (if present) have the following meanings. It should also be understood that when described in this article, any part defined below can be substituted by various substituents, and the corresponding definition is intended to include such substituted parts within its scope as described below. Unless otherwise specified, the term "substituted" will be defined as described below. It should also be further understood that when used in this article, the term "group (group / radical)" can be considered interchangeable. The articles "one (a)" and "an (an)" can be used in this article to refer to one or more than one (that is, at least one) of the grammatical objects of the article. For example, "analog" means an analog or more than one analog.

[0089] When a range of values ​​is listed, it is intended that every value and subrange within the range be included. For example, “C 1-6 "Alkyl" is intended to cover C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl.

[0090] "Alkyl" refers to a free radical such as a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkyl group has from 1 to 10 carbon atoms (“C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2 In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). 1-6 Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like.

[0091] "Alkenyl" refers to a straight or branched chain hydrocarbon radical ("C-C") having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds). 2-20In some embodiments, an alkenyl group does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C 2-10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 In some embodiments, an alkenyl group has 2 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 the alkenyl group include the aforementioned C 2-4 Alkenyl and pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc.

[0092] "Alkoxy" refers to a straight or branched hydrocarbon group, such as a free radical having 1 to 20 carbon atoms and a single bond to oxygen. In some embodiments, the alkoxy group has 1-2 carbon atoms, such as -OCH3 or -OCH2CH 3。

[0093] "Alkynyl" refers to a straight or branched chain hydrocarbon radical ("C") having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds). 2-20 In some embodiments, an alkynyl group does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2-3 In some embodiments, an alkynyl group has 2 carbon atoms (a "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). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of the alkenyl group include the aforementioned C 2-4 Alkynyl and pentynyl (C5), hexynyl (C6), etc. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), etc.

[0094] "Aryl" refers to a radical having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons in common in the ring array) ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms (a "C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (a "C 10 In some embodiments, an aryl group has fourteen ring carbon atoms (“C 14 "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, wherein the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, The aryl group includes chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octaphene, octalene, ovalene, pentadiene, pentacene, cyclopentadiene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene. Specifically, the aryl group includes phenyl, naphthyl, indenyl and tetrahydronaphthyl.

[0095] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group have been replaced by nitrogen, oxygen or sulfur heteroatoms. Hetero can be applied to any of the above alkyl groups, such as alkyl, such as heteroalkyl; alkenyl, such as heteroalkenyl; alkynyl, such as heteroalkynyl; carbocyclyl, such as heterocyclyl; aryl, such as heteroaryl, and groups having 1 to 5, and specifically 1 to 3 heteroatoms.

[0096] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., with 6 or 10 π electrons shared in the ring array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom when valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in this case, the number of ring members continues to represent 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, wherein the point of attachment is on the aryl or heteroaryl ring, and in this case, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryls in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0097] In some embodiments, heteroaryl is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 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.

[0098] "Carbocyclyl" or "carbocycle" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, the 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 3-6In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 "Carbocyclyl"). Exemplary C 3-6 Carbocyclic 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. 3-5 Carbocyclic groups include but are not limited to the aforementioned C 3-6 Carbocyclic groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptenyl (C7), bicyclo [2.2.2] octenyl (C8), etc. Exemplary C 3-10 Carbocyclic groups include but are not limited to the aforementioned C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) etc. As illustrated by the foregoing examples, in certain embodiments, the carbocyclyl is a monocyclic ring ("monocyclic carbocyclyl") or contains a fused, bridged or spirocyclic ring system, such as a bicyclic ring system ("bicyclic carbocyclyl") and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in such cases, the number of carbons always refers to the number of carbons in the carbocyclyl ring system.

[0099] "Heterocyclyl" or "heterocycle" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom when valence permits. A heterocyclyl may be a monocyclic ring ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring; or ring systems in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system.

[0100] In some embodiments, heterocyclyl is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon (“5-10 membered heterocyclyl”). In some embodiments, heterocyclyl is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-8 membered heterocyclyl”). In some embodiments, heterocyclyl is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-6 membered heterocyclyl”). In some embodiments, 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen and sulfur.

[0101] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0102] "Cyano" refers to -CN.

[0103] "Halo" or "halogen" refers to a fluorine atom (ie, F or -F), a chlorine atom (ie, C or -Cl), a bromine atom (ie, Br or -Br), and an iodine atom (ie, I or -I). In certain embodiments, the halo group is fluorine or chlorine.

[0104] "Haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0105] In general, the term "substituted", whether or not preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., a carbon atom or a nitrogen atom) 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 (e.g., 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 substituent is the same or different at each position.

[0106] The term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and are 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., who described pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds described herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts with an amino group formed with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or an organic acid (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, sodium p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed when appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0107] The term "modified release polymer" refers to a polymer used in a formulation (e.g., tablets and capsules) to change the release rate of a drug after administration to a subject. For example, a modified release polymer is used to dissolve the drug over time so that it is released more slowly and more steadily into the bloodstream. For example, a modified release polymer is a controlled release polymer. For example, a modified release polymer or a controlled release polymer is an HPMC polymer. In some embodiments, the modified release polymer may include a hydrophilic matrix polymer (e.g., hydroxypropyl methylcellulose, hydroxy-propyl methylcellulose (HPMC)), a hydrophobic matrix polymer (e.g., ethylcellulose ethocel), or a polyacrylate polymer (e.g., RL100, RS100).

[0108] As used herein, the term "diluent" refers to an excipient used to increase weight and improve content uniformity. For example, diluents include cellulose derivatives (e.g., microcrystalline cellulose), starches (e.g., hydrolyzed starches and partially pregelatinized starches), anhydrous lactose, lactose monohydrate, dicalcium phosphate (DCP), sugar alcohols (e.g., sorbitol, xylitol, and mannitol).

[0109] As used herein, the term "glidant" refers to an excipient used to promote powder flow by reducing inter-particle friction and cohesion. For example, glidants include fumed silicon dioxide (e.g., colloidal silicon dioxide), talc, and magnesium carbonate.

[0110] As used herein, the term "lubricant" refers to an excipient used to prevent ingredients from clumping together and sticking to a tablet punch or capsule filling machine. Lubricants are also used to ensure that tablet formation and discharge can occur with low friction between the solid and the die wall. For example, lubricants include magnesium stearate, calcium stearate, stearic acid, talc, silicon dioxide, and fats (e.g., vegetable stearin).

[0111] As used herein, the term "coating" refers to excipients that protect tablet ingredients from deterioration due to moisture in the air and make large or unpleasant-tasting tablets easier to swallow.

[0112] The embodiments disclosed herein are not intended to be limited in any way by the above exemplary chemical groups and substituent lists. Those skilled in the art will recognize that within the scope and spirit of the present disclosure, there may be several embodiments. The following description illustrates the present disclosure and certainly should not be interpreted in any way as limiting the scope of the present invention as described herein.

[0113] II. Compounds and Compositions

[0114] In one aspect, a compound of formula (I) having a pyrazole core is provided:

[0115]

[0116] or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein:

[0117] R 1 is selected from 5-membered or 6-membered heteroaryl or aryl, wherein the heteroaryl or the aryl optionally comprises at least one substituent, the at least one substituent being independently selected from alkyl, haloalkyl, carbocyclyl or -CN;

[0118] R 2 is -H;

[0119] R 3 Selected from -H or alkyl;

[0120] R 4 Selected from -H or alkyl;

[0121] or R 3 and R 4 Together with the carbon atom to which it is attached, it forms an optionally substituted 3- to 6-membered carbocyclic or heterocyclic group;

[0122] Z is selected from A haloalkyl or alkoxy group;

[0123] Ring A is selected from 5-membered or 6-membered heteroaryl, aryl, heterocyclyl or carbocyclyl;

[0124] R 5 is independently selected from alkyl, carbocyclyl, alkoxy, -C(O)NH2, -CN or halogen, wherein the alkyl, the carbocyclyl or the alkoxy optionally comprises at least one halogen substituent, or wherein the alkyl optionally comprises at least one -OH substituent;

[0125] n is 0, 1, 2, 3 or 4;

[0126] L is absent or selected from -NR a -, -CH2- or -O-;

[0127] R a Selected from -H or alkyl;

[0128] R 6 is selected from -H or alkyl; and

[0129] R 7 It is an alkyl group.

[0130] In some embodiments, a compound of formula (II) having a pyrazole core is provided:

[0131]

[0132] or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein:

[0133] R 1 is selected from pyrazolyl or phenyl, wherein the pyrazolyl or the phenyl optionally comprises at least one substituent, the at least one substituent being independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-5 Carbocyclic group;

[0134] R 2 is -H;

[0135] R 3 Selected from -H or alkyl;

[0136] R 4 Select from -H or C 1-4 alkyl;

[0137] or R 3 and R 4 Together with the carbon atom to which it is attached, it forms an optionally substituted 3-5 membered carbocyclyl or heterocyclyl;

[0138] Ring A is selected from pyridyl, phenyl, pyrimidinyl, piperidinyl or cyclopentyl,

[0139] R 5 Selected from C 1-4 Alkyl, C 3-5 Carbocyclic group, C 1-4 Alkoxy, -C(O)NH2, -CN or halogen, wherein the alkyl, the carbocyclyl or the alkoxy optionally comprises at least one halogen substituent, or wherein the alkyl optionally comprises at least one -OH substituent;

[0140] n is 0, 1, 2, 3 or 4;

[0141] L is absent or selected from -NR a -, -CH2- or -O-;

[0142] R a Select from -H or C 1-4 alkyl;

[0143] R 6 Select from -H or C 1-4 Alkyl; and

[0144] R 7 C 1-4 alkyl.

[0145] In some variations of all of the foregoing variations, the compound is an optically active compound. In some variations, the compound is a single enantiomer. In certain variations, the compound is an (R)-enantiomer. In other variations, the compound is an (S)-enantiomer.

[0146] In some embodiments, R 1 is pyrazolyl, the pyrazolyl comprising at least one substituent independently selected from: -CH3, -CF3, -C(CH3)3, -CHF2, -CH-CH(CH3)2 or cyclopropyl. In certain variations, R 1 It is phenyl.

[0147] In some embodiments, R 4 In other embodiments, R 3 and R 4 Together with the carbon atom to which it is attached, it forms an optionally substituted cyclopropyl, cyclobutyl or oxetanyl.

[0148] In certain embodiments, Ring A is pyridinyl. 5 is independently at each occurrence -CH3, -CH2CH3, -CF3, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2OH, -CN, -C(O)NH2 or cyclopropyl.

[0149] In some embodiments, n is 0, 1, or 2. In some embodiments, L is absent.

[0150] In some embodiments, R 6 In other embodiments, R 7 Selected from -CH3 or -CH2CH3.

[0151] In certain aspects, a compound of formula (II-A), a compound of formula (II-B), or a compound of formula (II-C) having a pyrazole core is provided:

[0152]

[0153] or a pharmaceutically acceptable salt thereof.

[0154] In one aspect, a compound of formula (III-A), a compound of formula (III-B) or a compound of formula (III-C) having a pyrazole core is provided:

[0155]

[0156]

[0157] or a pharmaceutically acceptable salt thereof, wherein:

[0158] R 1a and R 1b Each of which is independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-5 a carbocyclyl group; and

[0159] R 5 In each occurrence, independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 3-5 Carbocyclic group.

[0160] In another aspect, a compound of formula (III-Ai), a compound of formula (III-Bi) or a compound of formula (III-Ci) having a pyrazole core is provided:

[0161]

[0162] or a pharmaceutically acceptable salt thereof, wherein:

[0163] R 1a and R 1b Each of is independently selected from -CH3, -CF3, -C(CH3)3, -CHF2, -CH(CH3)2 or cyclopropyl; and

[0164] R 5 Selected from -CF3, -CH3, -CH2CH3, -OCH3, -OCH2CH3 or cyclopropyl.

[0165] In another aspect, a compound of formula (III-Di) or a compound of formula (III-Ei) is provided:

[0166]

[0167] or a pharmaceutically acceptable salt thereof, wherein:

[0168] R 1a and R 1b Each of is independently selected from -CH3, -CF3, -C(CH3)3, -CHF2, -CH(CH3)2 or cyclopropyl; and

[0169] R 5 Selected from -F or -CN.

[0170] In some variations of Formula (III-A), (III-B), (III-C), (III-Ai), (III-Bi), (III-Ci), (III-Di), or (III-Ei), R 1a is selected from -CH3, -C(CH3)3, -CHF2, -CH(CH3)2 or cyclopropyl. 1a is selected from -CH3, -C(CH3)3 or -CH(CH3)2. In yet other variations, R 1a It is cyclopropyl.

[0171] In another aspect, a compound of formula (IV) having a pyrazole core is provided:

[0172]

[0173] or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein:

[0174] R 1a and R 1b Each of which is independently selected from -CH3, -CF3 or -CHF2;

[0175] R 3 is -H;

[0176] R 4 Select from -H or C 1-4 alkyl;

[0177] n is 1 or 2.

[0178] In some embodiments of Formula (IV), R 4 C 1-4 In certain embodiments, R 4 is methyl. In some of the foregoing variations, the compound is an optically active compound. In some variations, the compound is a single enantiomer. In certain variations, the compound is an (R)-enantiomer. In other variations, the compound is an (S)-enantiomer.

[0179] In some variations of the compound of formula (IV), when n is 1, R 5 In other variations of the compound of formula (IV), when n is 2, one R 5 is -CH3, and the other R 5 is selected from -F or -Cl; and R 6 Selected from -H or -CH3.

[0180] In one aspect, a compound or a pharmaceutically acceptable salt thereof is provided, which is selected from the compounds in Table A below.

[0181] Table A

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190] In some embodiments, the compound is compound No. 1001, No. 1002, No. 1019, No. 1033-1037, No. 1039, No. 1041-1051, or No. 1053-1057, or a pharmaceutically acceptable salt thereof. In some variations, the compound is compound No. 1034, No. 1035, No. 1039, No. 1044-1051, or No. 1054-1057, or a pharmaceutically acceptable salt thereof.

[0191] The compounds described herein may contain one or more asymmetric centers and thus may exist in various isomeric forms (e.g., enantiomers and / or diastereomers). For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers (including racemic mixtures and mixtures enriched in one or more stereoisomers). Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The embodiments disclosed herein additionally encompass the compounds described herein in the form of individual isomers substantially free of other isomers, as well as alternatively in the form of mixtures of various isomers.

[0192] 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 relative to the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that a compound contains more than 75% by weight, such as more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight of an enantiomer. In certain embodiments, weights are based on the total weight of all enantiomers or stereoisomers of the compound.

[0193] In certain aspects, compositions comprising compounds described herein are provided. In some embodiments, enantiomerically pure compounds may be present in the composition together with other active ingredients or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound may include, for example, about 90% of an excipient and about 10% of an enantiomerically pure R-compound. In certain embodiments, by the total weight of the compound, the enantiomerically pure R-compound in such a composition may, for example, include at least about 95% by weight of an R-compound and up to about 5% by weight of an S-compound. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound may include, for example, about 90% of an excipient and about 10% of an enantiomerically pure S-compound. In certain embodiments, by the total weight of the compound, the enantiomerically pure S-compound in such a composition may, for example, include at least about 95% by weight of an S-compound and up to about 5% by weight of an R-compound. In certain embodiments, the active ingredient may be formulated with very little or no excipient or carrier.

[0194] The compounds described herein may also contain one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H. 2 H (D or deuterium) and 3 H (T or tritium); C can be in any isotopic form, including 12 C. 13 C and 14 C; O can be in any isotopic form, including 16 O and 18 O and F can be in any isotopic form, including 18 F and 19 F.

[0195] III. Treatment Methods

[0196] The compounds and compositions described above and herein can be used to treat nervous system disorders, disorders associated with excessive neuronal excitability, or disorders associated with gain-of-function mutations in genes (eg, KCNT1).

[0197] In some aspects, methods are provided for treating a nervous system 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 thereof an effective amount of any of the compounds described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or a pharmaceutically acceptable salt thereof.

[0198] Exemplary diseases, disorders, or conditions include epilepsy and other encephalopathy (e.g., MMFSI or EIMFS, ADNFLE, West syndrome, infantile spasms, epileptic encephalopathy, developmental and epileptic encephalopathy (DEE), early infantile epileptic encephalopathy (EIEE), generalized epilepsy, focal epilepsy, multifocal epilepsy, temporal lobe epilepsy, Ohtahara syndrome, early myoclonic encephalopathy, Lennox-Gastaut syndrome, drug-resistant epilepsy, seizures (e.g., frontal lobe seizures, generalized tonic-clonic seizures, asymmetric tonic seizures, focal seizures), leukodystrophies, hypomyelinating leukodystrophies, and leukodystrophies. disease), cardiac dysfunction (e.g., 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, cramping muscle spasms, spasticity), pruritus and pruritus, movement disorders (e.g., ataxia and cerebellar ataxia), psychiatric disorders (e.g., major depressive disorder, anxiety disorders, bipolar disorder, schizophrenia, attention deficit hyperactivity disorder), neurodevelopmental disorders, learning disabilities, intellectual disabilities, fragile X, neuronal plasticity, and autism spectrum disorders.

[0199] In some embodiments, a nervous system disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from EIMFS, ADNFLE, and West syndrome. In some embodiments, a nervous system disorder, a disorder associated with excessive neuronal excitability, or a 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, a nervous system disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is an attack. In some embodiments, a nervous system disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from arrhythmia, Brugada syndrome, or myocardial infarction.

[0200] In some embodiments, the neurological disorder, disorder associated with excessive neuronal excitability, or disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from a learning disorder, fragile X, intellectual function, neuronal plasticity, a psychiatric disorder, or an autism spectrum disorder.

[0201] Thus, the compounds, pharmaceutically acceptable salts thereof, and compositions disclosed herein can be administered to subjects suffering from a neurological disorder, a disorder associated with excessive neuronal excitability, or a disease 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 encephalopathy, Lennox-Gastaut syndrome, seizures, arrhythmias, Brugada syndrome, and myocardial infarction).

[0202] EIMFS is a rare and debilitating genetic condition characterized by early onset of nearly continuous heterogeneous focal seizures (before 6 months of age) in which seizures appear to migrate from one brain region and hemisphere to another. Patients with EIMFS are generally intellectually impaired, nonverbal, and unable to walk. Although several genes have been implicated to date, the gene most commonly associated with EIMFS is KCNT1. Several novel mutations in KCNT1 were 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) Epilepsy 56:el21-el28; Zhou et al. (2018) Genes Brain & Behavior Behav., e12456; Moller et al., (2015) Epilepsy, e114-20; Numis et al., (2018) Epilepsy, 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) Epilepsy, 56(9):e121-8; Rizzo et al., (2016) Mol Cell Neurosci., 13(4):115-116; 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 gain-of-function missense mutations that are dominant (i.e., present on only one allele) and result in a functional change in the encoded potassium channel that results in a significant increase in whole-cell current when tested in Xenopus oocytes or mammalian expression systems (see, e.g., Milligan et al., (2015) Annals Neurosci 75(4):581-590; Barcia et al., (2012) Nature Genetics 44(11):1255-1259; and Mikati et al., (2015) Annals Neurosci 78(6):995-999).

[0203] The onset of ADNFLE is later than that of EIMFS, usually in mid-childhood, and is usually a less severe symptom. It is characterized by nocturnal frontal lobe attacks, and may cause mental, behavioral and cognitive disorders in patients with the symptom. Although ADNFLE is related to genes encoding several neuronal nicotinic acetylcholine receptor subunits, mutations in the KCNT1 gene have been implicated in more severe cases of the disease (Heron et al., (2012) Nature Genetics 44: 1188-1190). Functional studies of the mutant KCNT1 gene associated with ADNFLE show that basic mutations (M896I, R398Q, Y796H and R928C) are dominant gain-of-function mutations (Milligan et al., Annals of Neurology 75 (4): 581-590; Mikati et al., (2015); Mikati et al., (2015) Annals of Neurology 78 (6): 995-999).

[0204] West syndrome is a severe form of epilepsy consisting of a triad of infantile spasms, an interictal electroencephalogram (EEG) pattern known as hypsarrhythmia, and mental retardation, but a diagnosis of one of these elements missing can be made. Mutations in KCNT1, including G652V and R474H, have been associated with West syndrome (Fukuoka et al. (2017) Brain and Development 39:80-83 and Ohba et al. (2015) Epilepsy 56:el21-el28). Treatment targeting the KCNT1 channel suggests that these mutations are gain-of-function mutations (Fukuoka et al., (2017) Brain and Development 39:80-83).

[0205] In one aspect, disclosed herein is a method for treating 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., epilepsy and other encephalopathy (e.g., MMFSI or EIMFS), ADNFLE, West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, DEE, Lennox-Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, generalized tonic-clonic seizures, drug-resistant epilepsy, temporal lobe epilepsy, cerebellar ataxia, asymmetric tonic seizures), cardiac dysfunction ( For example, arrhythmias, Brugada syndrome, myocardial infarction), pain and related conditions (e.g., neuropathic pain, acute / chronic pain, migraine, etc.), muscle disorders (e.g., myotonia, neuromyotonia, cramping muscle spasms, spasticity), pruritus and pruritus, ataxia and cerebellar ataxia, psychiatric disorders (e.g., major depressive disorder, anxiety, bipolar disorder, schizophrenia), learning disabilities, fragile X, neuronal plasticity and autism spectrum disorders), the method comprising administering to a subject in need thereof a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0206] In some examples, prior to administering a compound disclosed herein or a pharmaceutically acceptable salt or composition thereof, a subject presenting with a condition that may be associated with a gain-of-function mutation in KCNT1 is genotyped to confirm the presence of a known gain-of-function mutation in KCNT1. For example, whole exome sequencing can be performed on the subject. The 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. The gain-of-function mutations associated with ADNFLE may include, but are not limited to, M896I, R398Q, Y796H, R928C, and G288S. The gain-of-function mutations associated with West syndrome may include, but are not limited to, G652V and R474H. The gain-of-function mutations associated with temporal lobe epilepsy may include, but are not limited to, R133H and R565H. The gain-of-function mutations associated with Lennox-Gastaut syndrome may include, but are not limited to, R209C. The gain-of-function mutations associated with seizures may include, but are not limited to, A259D, G288S, R474C and R474H. The gain-of-function mutations associated with leukodystrophy may include, but are not limited to, G288S and Q906H. The gain-of-function mutations associated with multifocal epilepsy may include, but are not limited to, V340M. The gain-of-function mutations associated with early-onset epilepsy (EOE) may include, but are not limited to, F346L and A934T. The gain-of-function mutations associated with early-onset epileptic encephalopathy (EOEE) may include, but are not limited to, R428Q. The gain-of-function mutations associated with developmental and epileptic encephalopathy 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 wandering 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.

[0207] In other examples, subjects are first genotyped to identify the presence of a mutation in KCNT1, and then this mutation is confirmed as a gain-of-function mutation using a standard in vitro assay such as the assay described in Milligan et al. (2015) Annals Neurology 75(4):581-590. Typically, the presence of a gain-of-function mutation is confirmed when the whole-cell current produced by expression of the mutant KCNT1 allele is increased compared to the whole-cell current produced by expression of wild-type KCNT1, as can be assessed using whole-cell electrophysiology (as described in: Milligan et al. (2015) Annals of Neurology 75(4):581-590; Barcia et al. (2012) Nature Genetics 44(11):1255-1259; Mikati et al. (2015) Annals of Neurology 78(6):995-999; or Rizzo et al. Mol Cell Neurosci. (2016) 72:54-63). Such an increase in whole-cell current can be, for example, an increase of at least or about 50%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, or more. The subject can then be confirmed to have a disease or condition associated with a gain-of-function mutation in KCNT1.

[0208] In specific examples, the subject is confirmed to have a KCNT1 allele containing a gain-of-function mutation (e.g., V271F, G288S, R398Q, R428Q, R474Q, R474H, R474C, G652V, I760M, Y796H, M896I, P924L, R928C, or A934T).

[0209] The compounds disclosed herein or their pharmaceutically acceptable salts or pharmaceutical compositions disclosed herein (e.g., pharmaceutical compositions comprising compounds disclosed herein or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients) can also be used therapeutically for conditions associated with excessive neuronal excitability, wherein the excessive neuronal excitability is not necessarily the result of a gain-of-function mutation in KCNT1. Even in cases where the disease is not the result of increased KCNT1 expression and / or activity, inhibition of KCNT1 expression and / or activity still results in reduced neuronal excitability, thereby providing a therapeutic effect. Therefore, the compounds disclosed herein or their pharmaceutically acceptable salts or pharmaceutical compositions disclosed herein can be used to treat subjects with conditions associated with excessive neuronal excitability (e.g., epilepsy and other encephalopathy (e.g., EIMFS, ADNFLE, West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, seizures) or cardiac dysfunction (e.g., arrhythmia, Brugada syndrome, myocardial infarction)), regardless of whether the condition is associated with a gain-of-function mutation in KCNT1.

[0210] In some of the foregoing variations, the "subject" contemplated for administration includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, 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.

[0211] As used herein, some of the foregoing variations "treating" or "treatment" contemplate actions that occur when a subject develops a specified disease, disorder, or condition that reduce the severity of the disease, disorder, or condition, or that delay or slow the progression of the disease, disorder, or condition (also referred to as "therapeutic treatment"). In some variations, "treating" or "treatment" refers to a method or procedure for obtaining a beneficial or desired result - e.g., a clinical result. Beneficial or desired results can include (1) alleviating one or more symptoms caused by or associated with the disease, disorder, or condition; (2) reducing the extent of the disease, disorder, or condition; (3) slowing or stopping the development or progression of one or more symptoms caused by or associated with the disease, disorder, or condition (e.g., stabilizing the disease, disorder, or condition); and (4) ameliorating the disease (e.g., improving the disease state, enhancing the effect of another drug, delaying or stopping the progression of the disease, improving the quality of life, and / or prolonging survival), such as by causing regression of one or more clinical symptoms.

[0212] In some of the aforementioned variations, an "effective amount" of a compound or a pharmaceutically acceptable salt thereof refers to an amount sufficient to elicit a desired biological response. As will be appreciated by one of ordinary skill in the art, the effective amount of a compound or a pharmaceutically acceptable salt thereof may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound or a pharmaceutically acceptable salt thereof, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.

[0213] In some embodiments, a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof is administered to a subject (e.g., a human). In some of the aforementioned variations, a "therapeutically effective amount" of a compound or a pharmaceutically acceptable salt thereof is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition or sufficient to delay one or more symptoms associated with a disease, disorder, or condition or to minimize the symptoms. A "therapeutically effective amount" of a compound or a pharmaceutically 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" may encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0214] In some embodiments, the methods provided are directed to treating a disease associated with a gain-of-function mutation of KCNT1. In some variations, a "disease associated with a gain-of-function mutation in KCNT1" refers to a disease associated with a mutation in KCNT1, partially or completely caused by the mutation, or having one or more symptoms partially or completely caused by the mutation, the mutation leading to a gain-of-function phenotype, i.e., an increase in the activity of a potassium channel encoded by KCNT1, thereby leading to an increase in whole-cell current. In some variations, a "gain-of-function mutation of KCNT1" is a mutation in KCNT1 that causes an increase in the activity of a potassium channel encoded by KCNT1. Activity can be assessed, for example, by ion flux assays or electrophysiology (e.g., using whole-cell patch clamp techniques). Typically, a gain-of-function mutation results in 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.

[0215] IV. Pharmaceutical Compositions and Routes of Administration

[0216] The compound or its pharmaceutically acceptable salt provided according to the present invention is usually applied in the form of a pharmaceutical composition. Therefore, disclosed herein is a pharmaceutical composition containing the following as an active ingredient: the compound or its pharmaceutically acceptable salt or ester and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants. The pharmaceutical composition can be applied alone or in combination with other therapeutic agents. Such compositions can be prepared in a manner disclosed in the pharmaceutical field, for example, including "Remington's Pharmaceutical Sciences", Mace Publishing Co., Philadelphia, Pa., 17th edition (1985); and "Modern Pharmaceutics", Marcel Dekker, 3rd edition (GS Banker and CT Rhodes, ed.).

[0217] The pharmaceutical composition can be administered in a single dose or in multiple doses by any of the accepted modes of administration for pharmaceutical agents with similar utilities (e.g., those described in the patents and patent applications incorporated by reference), including rectal, buccal, intranasal, and transdermal routes, intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or, for example, by impregnated or coated devices such as stents or arterial inserted cylindrical polymers.

[0218] A mode of administration is parenteral, specifically by injection. The novel composition disclosed herein can be incorporated to include aqueous or oil suspensions or emulsions with sesame oil, corn oil, cottonseed oil or peanut oil and elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical vehicles by injection. Routinely, aqueous solutions in saline are also used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils can also be used. Suitable fluidity can be maintained, for example, by using coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants. Prevention of the effects of microorganisms can be achieved by a variety of antibacterial and antifungal agents (such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).

[0219] Sterile injectable solutions are prepared by incorporating the compounds disclosed herein or their pharmaceutically acceptable salts in the desired amount in a suitable solvent together with the various other ingredients listed above, followed by filtration sterilization. Typically, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other desired ingredients from the ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, exemplary preparation methods include vacuum drying and freeze drying techniques that produce a powder consisting of the active ingredient plus any additional desired ingredients from a previously sterile filtered solution thereof.

[0220] Oral administration is another route for administering a compound as disclosed herein or a pharmaceutically acceptable salt thereof. Administration can be carried out through capsules or enteric coated tablets, etc. In the preparation of a pharmaceutical composition comprising at least one compound as described herein or a pharmaceutically acceptable salt thereof, the active ingredient can be diluted by an excipient and / or encapsulated in such a carrier that can be in the form of a capsule, a medicine bag, paper or other container. When the excipient acts as a diluent, it can be in the form of a solid, semisolid or liquid material (as described above), which acts as a vehicle, carrier or medium for the active ingredient. Therefore, the composition can be in the form of tablets, pills, powders, lozenges, medicine bags, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or in a liquid medium), ointments containing, for example, up to 10% by weight of an active compound, soft gelatin capsules and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0221] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. In certain embodiments, the compositions disclosed herein may additionally include lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners; and flavoring agents.

[0222] The compositions disclosed herein can be formulated so that after being applied to a patient by using procedures known in the art, a rapid, sustained or delayed release of the active ingredient is provided. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patents No. 3,845,770; No. 4,326,525; No. 4,902,514; and No. 5,616,345. Additional embodiments for the methods disclosed herein can employ transdermal delivery devices ("films"). Such transdermal films can be used to provide continuous or intermittent infusions of compounds disclosed herein or pharmaceutically acceptable salts thereof in controlled amounts. The construction and use of transdermal films for delivering medicaments are described in, for example, U.S. Patents Nos. 5,023,252, 4,992,445, and 5,001,139. Such membranes may be configured for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0223] The compositions disclosed herein can be formulated in unit dosage forms. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect and a suitable pharmaceutical excipient (e.g., tablets, capsules, ampoules). The compound is generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains about 1 mg to about 2 g of a compound described herein or a pharmaceutically acceptable salt thereof, and for parenteral administration, preferably about 0.1 mg to about 700 mg of a compound described herein or a pharmaceutically acceptable salt thereof. However, it should be understood that the amount of the compound or its pharmaceutically acceptable salt actually administered will generally be determined by the physician according to the relevant circumstances, including the condition to be treated; the route of administration selected; the actual compound or its pharmaceutically acceptable salt administered and its relative activity; the age, weight and response of the individual patient; the severity of the patient's symptoms, etc.

[0224] For the preparation of solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulated composition containing a homogeneous mixture of a compound disclosed herein or a pharmaceutically acceptable salt thereof. When these preformulated compositions are referred to as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0225] Tablets disclosed herein or pills can be coated or otherwise mixed, to provide a dosage form with an advantage of prolonged action time or protection from the acidic conditions of the stomach. For example, tablets or pills can comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope on the former. Two components can be separated by an enteric layer, which is used to resist the disintegration in the stomach and allows the inner component to be transmitted intactly into the duodenum or to be delayed release. Various materials can be used for such enteric layers or coatings, and such materials include many polymeric acids and polymeric acids and mixtures of materials such as shellac, hexadecanol and cellulose acetate.

[0226] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In certain embodiments, the composition is administered by oral or nasal respiratory routes to produce local or systemic effects. Compositions in pharmaceutically acceptable solvents may be atomized using inert gases. Atomized solutions may be inhaled directly from a nebulizer, or the nebulizer may be attached to a mask holder or an intermittent positive pressure breathing machine. Solutions, suspensions or powder compositions may be administered in an appropriate manner by a device for delivering the preparation, such as orally or nasally.

[0227] In some embodiments, a pharmaceutical composition is provided, comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient and / or carrier.

[0228] Using only routine experimentation, those skilled in the art will recognize or be able to ascertain many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the foregoing description or subsequent examples, but is as described in the appended claims. Those of ordinary skill 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 following claims.

[0229] Examples

[0230] 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 should not be construed in any way as limiting their scope.

[0231] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that, unless otherwise stated, other process conditions may also be used when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. Optimal reaction conditions may vary with the specific reactants or solvents used, but such conditions may be determined by those skilled in the art by routine optimization.

[0232] In addition, it is obvious to those skilled in the art that conventional blocking groups may be necessary to prevent certain functional groups from performing undesirable reactions. The selection of suitable blocking groups for specific functional groups and suitable conditions for protecting and deprotecting are described in the art. For example, various blocking groups and their introduction and removal are described in TW Greene and PGM Wuts, " Protecting Groups in Organic Synthesis ", second edition, Wiley, New York, 1991 and the references cited therein.

[0233] Compounds provided herein can be separated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, grinding, high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). Note that flash chromatography can be performed manually or by an automated system. Compounds provided herein can be characterized by known standard procedures, such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS). NMR chemical shifts are reported in parts per million (ppm) and are produced using methods described by those skilled in the art.

[0234] abbreviation

[0235] CDCl3 Deuterated chloroform

[0236] DCM Dichloromethane

[0237] DEAD Diethyl azodicarboxylate

[0238] DIPEA N,N-Diisopropylethylamine

[0239] DMF Dimethylformamide

[0240] DMSO Dimethyl sulfoxide

[0241] DMSO-d6 Deuterated dimethyl sulfoxide-d6

[0242] EtOAc Ethyl acetate

[0243] EtOH

[0244] HATU 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0245] IPA Isopropyl Alcohol

[0246] MeOH Methanol

[0247] T3P Propanephosphonic anhydride

[0248] TFA Trifluoroacetic acid

[0249] THF Tetrahydrofuran

[0250] I. Synthesis and Characterization of Exemplary Compounds

[0251] Exemplary methods for preparing the compounds described herein are shown in the following synthetic schemes. These schemes are given for illustrative purposes and should not be construed in any way as limiting the scope or spirit of the embodiments disclosed herein.

[0252] Certain exemplary compounds described herein are produced as mixtures of enantiomers. To separate the enantiomers, the mixture was further purified by preparative chiral HPLC according to the analytical conditions shown in Table 1 below and as specified herein for a given compound.

[0253] Table 1.

[0254]

[0255]

[0256]

[0257] Example 1

[0258] Synthesis and characterization of exemplary compounds based on synthetic scheme A

[0259] Step 1

[0260] At about 0 ° C, cesium carbonate (2 equivalents) and alkyl halide (1 equivalent) were added to a stirred solution (0.6 M) of compound 1 (1 equivalent) in DMF, and then stirring was continued for about 12 hours at about 60 ° C. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then, the crude residue obtained was purified by flash column chromatography, eluted with ethyl acetate / heptane mixture, to obtain compound 2.

[0261] Step 2

[0262] In a sealed tube, alkyl halide (1.5 eq.) and potassium carbonate (1.5 eq.) were added to a stirred solution (0.64 M) of compound 3 (1 eq.) in DMF, and stirring was then continued for about 4 hours at about 100 ° C. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2, which was used in the following step 3 without further purification.

[0263] Step 3

[0264] At about 0 ° C, lithium hydroxide hydrate (2 equivalents) was added to a stirred solution (0.35M) of compound 2 (1 equivalent) in a 1:3 water:THF mixture, and then stirring was continued at room temperature for about 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 obtain compound 4, which was used in the following step 4 without further purification.

[0265] Step 4

[0266] At about 0 ° C, HATU (1.5 eq.) and DIPEA (3 eq.) were added to a stirred solution (0.8 M) of compound 4 (1 eq.) and N, O-dimethylhydroxylamine hydrochloride (2 eq.) in DCM, and then stirring was continued for about 4 hours at the same temperature. 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. Then, the obtained crude residue was purified by column chromatography, eluted with ethyl acetate / hexane mixture to obtain compound 5.

[0267] Step 5

[0268] At about 0 ° C, methylmagnesium bromide solution (3M, 2 equivalents) was added to a stirred solution (0.2M) of compound 5 (1 equivalent) in dry THF, and then stirring was continued for about 2 hours at the same temperature. After the reaction was completed, the reaction mixture was diluted with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then, the obtained crude residue was purified by column chromatography, eluted with an ethyl acetate / hexane mixture to obtain compound 6.

[0269] Step 6

[0270] Under nitrogen atmosphere, bis(triphenylphosphine)palladium dichloride (II) (10 mol%) was added to a stirred solution of compound 7 (1 equivalent) and 1-ethoxyvinyl tri-n-butyltin (1.2 equivalents) in DMF (0.4M). After stirring for about 4 hours at about 60°C, the reaction mixture was quenched with an aqueous potassium fluoride solution, stirred for about 30 minutes, 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, eluted with an ethyl acetate / petroleum ether mixture to obtain compound 8.

[0271] Step 7

[0272] To a stirred solution (0.36 M) of compound 8 (1 eq.) in acetone was added 3 M aqueous hydrochloric acid (2.8 eq.) at about 25 °C. After stirring for about 16 hours at about 25 °C, the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give compound 6, which was used directly in step 8 below.

[0273] Step 8

[0274] Titanium isopropoxide (IV) (2 equivalents) is added to a stirred solution (0.4M) of compound 6 (1 equivalent) and compound 9 (1.5 equivalents) in toluene, and then stirring is continued for about 12 hours at about 80 ° C. After the reaction is completed, the reaction mixture is quenched with water and extracted with ethyl acetate. The organic layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then, the crude residue obtained is purified by column chromatography, eluted with ethyl acetate / hexane mixture, to obtain compound 10.

[0275] Step 9

[0276] At about 0 ° C, sodium borohydride (2 equivalents) was added to a stirred solution (0.45 M) of compound 10 (1 equivalent) in methanol, and then stirring was continued at room temperature for about 2 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. Then, the obtained crude residue was purified by column chromatography, eluted with ethyl acetate / hexane mixture, to obtain compound 11.

[0277] Step 10

[0278] To a stirred solution (1 M) of compound 11 (1 eq) in 1,4-dioxane was added 4M HCl in dioxane (6 eq) at about 0° C., and stirring was then continued at room temperature for about 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was washed with diethyl ether to obtain compound 12.

[0279] Step 11

[0280] At about 0 ° C, HATU (1.5 eq.) and DIPEA (3 eq.) were added to a stirred solution (0.2 M) of compound 12 (1 eq.) and compound 13 (2 eq.) in DCM, and then stirring was continued for about 2 hours at about 0 ° C. 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, eluted with ethyl acetate / hexane mixture to obtain compound 14.

[0281] Step 12

[0282] At room temperature, cesium carbonate (2 equivalents) and boric acid or boric acid ester (2 equivalents) are added to a stirred solution (0.07M) of compound 14 (1 equivalent) in a 1:4 water:1,4-dioxane mixture. The reaction mixture is degassed under argon for about 5 minutes, followed by the addition of bis(triphenylphosphine)palladium dichloride (II) (5mol%). The reaction mixture is microwaved for about 1 hour at about 100 ° C. The reaction mixture is allowed to cool to room temperature, filtered through a diatomaceous earth pad, and washed with ethyl acetate. The filtrate is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then, the obtained crude residue is purified by column chromatography, eluted with ethyl acetate, to obtain compounds 15 and 16 in a mixture of enantiomers.

[0283] In order to separate the 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 / 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.

[0284] Step 13

[0285] A stirred solution of compound 6 (1 eq.), boronic acid or boronic acid ester (1.3 eq.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5 mol%), and cesium carbonate (3 eq.) in a 1:10 mixture of water:1,4-dioxane (0.35 M) was stirred under a nitrogen atmosphere at about 80° C. for about 16 hours. The mixture was cooled to about 25° C., filtered, and concentrated to give a crude product, which was purified by flash chromatography on silica gel, eluting with ethyl acetate / petroleum ether mixtures to give compound 17.

[0286] Step 14

[0287] Under nitrogen atmosphere, at about 25 ° C, to a stirred solution (0.15M) of compound 17 (1 equivalent) in THF, racemic-(R)-2-methylpropane-2-sulfinamide (18) or racemic-(S)-2-methylpropane-2-sulfinamide (19) (1.5 equivalents) and titanium (IV) isopropoxide (10 equivalents) are added. The mixture is heated to about 65 ° C and stirred for about 16 hours. The reaction solution is quenched with saturated sodium bicarbonate aqueous solution and filtered. The filtrate is extracted with ethyl acetate. The combined organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by column chromatography on silica gel, eluted with ethyl acetate / petroleum ether mixture to obtain compound 20 or compound 21, depending on the enantiomer of the sulfinamide used.

[0288] Step 15

[0289] To a stirred solution (0.13 M) of compound 20 or compound 21 (1 eq) in THF was added L-Selectride (2 eq) at about -78°C. After stirring at about -78°C for about 0.5 h, the mixture was poured onto saturated aqueous ammonium chloride solution and extracted with ethyl acetate (x2). 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.

[0290] Step 16

[0291] DIPEA (8 equiv.) and T3P (3 equiv.) were added to a stirred solution (0.05 M) of compound 13 (1.2 equiv.) in DCM. After stirring for about 30 minutes at about 25 ° C., compound 24 or compound 25 (1 equiv.) was added, and the reaction solution was stirred for about 16 hours at about 25 ° C. The reaction solution was quenched with water and extracted with DCM. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography, eluted with ethyl acetate / petroleum ether mixture. The material was further purified by supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); condition: 0.1% NH3H2O-EtOH; start B: 15; end B: 15) to obtain compound 15 or compound 16.

[0292] Step 17

[0293] At room temperature, potassium carbonate (3 equivalents) was added to a stirred solution (0.24M) of compound 15 and compound 16 (1 equivalent) in DMSO, followed by the addition of 30% hydrogen peroxide (10 equivalents), and then stirring was continued at room temperature for about 12 hours. After observing that the starting material was consumed, the reaction solution was quenched by adding 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. Then, the crude residue obtained was purified by column chromatography, eluted with 50-60% EtOAc: heptane, to obtain compound 1022.

[0294] Compounds 1001-1018, 1020-1022 and 1031 were prepared from commercially available starting materials and generally according to Synthetic Scheme A and the steps described above.

[0295] Exemplary compounds prepared according to Synthesis Scheme A were characterized by NMR, HPLC and LCMS. Data for NMR and LCMS and chiral separation methods (where applicable) are provided in Table 2 below. For Compound No. 1001 and Compound No. 1002, the following SFC chiral method was used: Column: Chiralcel OJ-3 150 x 4.6 mm, ID, 3 μm. Mobile phase: A: CO2, B: Ethanol (0.05% DEA). Gradient: 5% B to 40% B in 5 minutes, and 40% B to 50% B in 0.5 minutes, maintaining 5% B for 1.5 minutes. Flow rate: 2.5 ml / min. Column temperature: 35°C. ABPR: 1500psi.

[0296] Table 2.

[0297]

[0298]

[0299]

[0300]

[0301] Example 2

[0302] Synthesis and characterization of exemplary compounds based on synthetic scheme B

[0303]

[0304] Step 18

[0305] In a sealed tube, phenol 28 (2 equivalents), N,N-dimethylglycine (0.6 equivalents), copper iodide (20 mol%) and cesium carbonate (2 equivalents) were added to a stirred solution (0.1 M) of compound 27 (1 equivalent) in 1,4-dioxane, and stirring was then continued at about 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 saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue obtained was then purified by Combi-flash chromatography, eluted with 40% ethyl acetate / heptane to obtain compound 29.

[0306] Step 19

[0307] At room temperature, compound 30 (3 equivalents) and aqueous potassium carbonate solution (2 equivalents) were added to a stirred solution (0.13M) of compound 27 (400 mg, 1.05 mmol) in 1,4-dioxane. The reaction mixture was purged with argon for about 10 minutes. Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mol%) was added to the resulting solution, and the solution was stirred at about 100 ° C for about 12 hours. The reaction mixture was allowed to cool to room temperature, and filtered through a diatomaceous earth pad, and the resulting solution was washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then, the obtained crude residue was purified by column chromatography, eluted with 50-60% EtOAc / heptane, followed by non-chiral preparation to obtain compound 31.

[0308] Step 20

[0309] To a stirred solution (0.27 M) of compound 27 (1 eq.) and the amine compound (2 eq.) in DMSO, L-proline (40 mol%) and copper (I) iodide (20 mol%) are added at room temperature, and stirring is then continued at about 90° C. for about 16 hours. The reaction mixture is allowed to cool to room temperature and filtered through a celite pad, and the resulting solution is washed with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue obtained is then purified by column chromatography, eluting with ethyl acetate / heptane, followed by achiral preparation to give compound 32.

[0310] Step 21

[0311] At room temperature, sodium tert-butoxide (2 equivalents) and an amine compound (2 equivalents) are added to a stirred solution (0.1 M) of compound 27 (1 equivalent) in 1,4-dioxane. The reaction mixture is purged with argon for about 10 minutes. Tris(dibenzylideneacetone)dipalladium(0) (10 mol%) and Brettphos (20 mol%) are added to this solution, and the solution is stirred at about 130 ° C for about 16 hours. The reaction mixture is allowed to cool to room temperature and filtered through a diatomaceous earth pad, and the resulting solution is washed with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then, the crude residue obtained is purified by column chromatography, eluted with an ethyl acetate / heptane mixture to obtain compound 32.

[0312] Compounds 1023-1028 and 1032 were prepared from commercially available starting materials and generally according to Synthetic Scheme B and the procedures described above.

[0313] Exemplary compounds prepared according to Synthesis Scheme B were characterized by NMR, HPLC and LCMS. The data for NMR and LCMS are provided in Table 3 below.

[0314] Table 3.

[0315]

[0316]

[0317] Example 3

[0318] Synthesis and characterization of exemplary compounds based on synthetic scheme C

[0319]

[0320] Step 22

[0321] At about 0 ° C, lithium borohydride (6 equivalents) was added to a stirred solution (0.35M) of compound 33 (1 equivalent) in methanol in portions, and then stirring was continued at room temperature for about 1 hour. After the reaction was completed, the reaction mixture was quenched by adding an ammonium chloride solution of about 0 ° C and extracted with ethyl acetate. The combined organic layer was washed with water, followed by brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then, the obtained crude residue was purified by column chromatography, eluted with ethyl acetate / heptane mixture to obtain compound 34.

[0322] Step 23

[0323] At about 0 ° C, triphenylphosphine (1.5 equivalents) and DEAD (1.5 equivalents) were added to a stirred solution (0.2M) of compound 34 (1 equivalent) and phthalimide (35) (1.1 equivalents) in THF, and then stirring was continued at room temperature for about 16 hours. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then, the obtained crude residue was purified by column chromatography, eluted with ethyl acetate / hexane mixture to obtain compound 36.

[0324] Step 24

[0325] At room temperature, hydrazine hydrate (6 equivalents) is added to the stirred solution (0.1M) of compound 36 (1 equivalent) in 1:1DCM:EtOH, and then stirring is continued for about 12 hours at the same temperature. After the completion of the reaction, the reaction mixture is quenched with water, and filtered through a short diatomaceous earth pad. The organic layer of the filtrate is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue (compound 37) obtained is used for the following reactions steps without further purification.

[0326] Step 25

[0327] At about 0 ° C, HATU (1.5 equivalents) and DIPEA (3 equivalents) were added to a stirred solution (0.1M) of compound 37 (1 equivalent) and compound 38 or benzoic acid (1 equivalent) in DCM, and then stirring was continued for about 2 hours at about 0 ° C. 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. Then, the obtained crude residue was purified by column chromatography, eluted with ethyl acetate / hexane mixture to obtain compound 39 or compound 40.

[0328] Step 26

[0329] At room temperature, cesium carbonate (2 equivalents) and boric acid or boric acid ester (2 equivalents) are added to a stirred solution (0.07M) of compound 39 or compound 40 (1 equivalent) in 1:4 water:1,4-dioxane. The reaction mixture is degassed under argon for about 5 minutes, followed by the addition of bis(triphenylphosphine)palladium dichloride (II) (5mol%). The reaction mixture is microwaved for about 1 hour at about 100 ° C. The reaction mixture is allowed to cool to room temperature, filtered through a diatomaceous earth pad, and washed with ethyl acetate. The filtrate is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then, the crude residue obtained is purified by column chromatography, eluted with ethyl acetate, to obtain compound 41 or compound 42.

[0330] Compounds 1019, 1029, 1030, 1033 and 1036-1041 were prepared from commercially available starting materials and generally according to Synthetic Scheme C and the procedures described above.

[0331] Exemplary compounds prepared according to Synthesis Scheme C were characterized by NMR, HPLC and LCMS. The data for NMR and LCMS are provided in Table 4 below.

[0332] Table 4.

[0333]

[0334]

[0335]

[0336] Example 4

[0337] Synthesis and characterization of exemplary compounds based on synthetic scheme D

[0338]

[0339] Step 27

[0340] A suspension of compound 43 (1 equivalent) in 7M ammonia in methanol (1 equivalent) was stirred at about 60° C. for about 24 hours. After the reaction was completed, 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.

[0341] Step 28

[0342] A suspension of compound 44 (1 equivalent) in phosphoryl chloride (9 equivalents) was heated at about 110 ° C for about 16 hours. After the reaction was completed, the reaction solution was allowed to cool to room temperature, concentrated to dryness under reduced pressure, and poured on ice. The mixture was neutralized by adding 50% sodium hydroxide aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then, the crude residue obtained was purified by flash column chromatography, eluted with ethyl acetate / hexane mixture, to obtain compound 45.

[0343] Step 29

[0344] At about -78 ° C, 1M ethylmagnesium bromide (3.5 equivalents) was added to a stirred solution (0.2M) of compound 45 (1 equivalent) and titanium isopropoxide (2.5 equivalents) in THF. The resulting solution was stirred for about 10 minutes. Then, the solution was allowed to heat to room temperature and stirred for about 2 hours, followed by the addition of boron trifluoride diethyl ether (4 equivalents). 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 the addition of 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 obtain compound 46.

[0345] Step 30

[0346] At about 0 ° C, HATU (1.5 eq.) and DIPEA (3 eq.) were added to a stirred solution (0.1 M) of compound 47 (1 eq.) and compound 46 (2 eq.) in DCM, and then stirring was continued for about 2 hours at about 0 ° C. 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, eluted with ethyl acetate / hexane mixture to obtain compound 48.

[0347] Step 31

[0348] At room temperature, cesium carbonate (2 equivalents) and boric acid or boric acid ester (2 equivalents) are added to a stirred solution (0.07M) of compound 48 (1 equivalent) in 1:4 water:1,4-dioxane. The reaction mixture is degassed under argon for about 5 minutes, followed by the addition of bis(triphenylphosphine)palladium dichloride (II) (5mol%). The reaction mixture is degassed, and then heated at about 130 ° C for about 16 hours. Then, the reaction mixture is allowed to cool to room temperature, and filtered through a diatomaceous earth pad, and the resulting solution is washed with ethyl acetate. The filtrate is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then, the crude residue obtained is purified by column chromatography, eluted with ethyl acetate / n-hexane, to obtain compound 49.

[0349] Compounds 1034 and 1035 were prepared from commercially available starting materials and generally according to Synthetic Scheme D and the procedures described above.

[0350] Exemplary compounds prepared according to Synthesis Scheme D were characterized by NMR, HPLC and LCMS. The data for NMR and LCMS are provided in Table 5 below.

[0351] Table 5.

[0352]

[0353] 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)

[0354]

[0355] Step 1: Synthesis of methyl 3-bromo-1-methyl-1H-pyrazole-5-carboxylate (2)

[0356] At 0 ° C, Cs was added to a stirred solution of compound 1 (5.0 g, 24.389 mmol) in DMF (50 mL)CO (15.8 g, 48.778 mmol) and methyl iodide (6.9 g, 48.778 mmol). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, followed by brine washing, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude compound was purified by Combi-Flash chromatography (eluted with 40-50% EtOAc / heptanes), to obtain the title compound 2 (3.3 g, 15.031 mmol, 61% yield) as an off-white solid.

[0357] Step 2: Synthesis of (3-bromo-1-methyl-1H-pyrazol-5-yl)methanol (3)

[0358] At 0 ° C, lithium borohydride (1.89 g, 86.742 mmol) was added to a stirred solution of compound 2 (3.8 g, 17.348 mmol) in methanol (50 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with a saturated NH4Cl solution at 0 ° C and extracted with EtOAc. The combined organic layer was washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the title compound 3 (2.9 g, crude product) as an off-white solid. This compound was used in the next step as such without any further purification.

[0359] Step 3: Synthesis of 3-bromo-5-(bromomethyl)-1-methyl-1H-pyrazole (4)

[0360] At 0 ° C, triphenylphosphine (6.1g, 23.557mmol) and CBr (7.8g, 23.557mmol) were added to the stirred solution of compound 3 (3.0g, 15.704mmol) in DCM (20mL), and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, followed by brine washing, over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluted with 10-20% EtOAc / heptane), to obtain the title compound 4 (2.8g, 10.5mmol, 66.7% yield) as an off-white solid.

[0361] Step 4: Synthesis of 2-(3-bromo-1-methyl-1H-pyrazol-5-yl)acetonitrile (6)

[0362] At 0 ° C, dropwise to the stirred solution of compound 4 (2.8g, 11.027mmol) in ACN (25mL) add TBAF (1.1mL, 16.541mmol) and TMSCN (2.07mL, 16.541mmol). The reaction mixture was stirred at room temperature for 6 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, followed by washing with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluted with 10-20% EtOAc / heptane), to obtain the title compound 5 (1.6g, 7.278mmol, 66.0% yield) in a yellow liquid.

[0363] Step 5: Synthesis of 2-(3-bromo-1-methyl-1H-pyrazol-5-yl)-2-methylpropionitrile (6)

[0364] At 0 ° C, nBuLi (1.6M in hexane, 0.7mL, 1.249mmol) was added to a stirred solution of compound 5 (0.1g, 0.499mmol) in THF (20mL), and mixing was continued for 10 minutes. Methyl iodide (0.14g, 0.999mmol) was added to this solution, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with ice-cold water and extracted with EtOAc. The combined organic layer was washed with water, followed by brine washing, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi-Flash chromatography (eluted with 20-30% EtOAc / heptanes), to obtain the title compound 6 (0.1g, 0.346mmol, 69.2% yield) as a colorless liquid.

[0365] Step 6: Synthesis of 2-(3-bromo-1-methyl-1H-pyrazol-5-yl)-2-methylpropanamide (7):

[0366] At 0 ° C, K2CO3 (0.06 g, 0.438 mmol) was added to a stirred solution of compound 6 (0.1 g, 0.438 mmol) in DMSO (10 mL). At 0 ° C, H2O2 (0.07 mL, 2.192 mmol) was added to this solution, and the reaction solution was stirred at room temperature for 12 hours. 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 washing, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound 7 (0.1 g, crude) as a colorless liquid. This compound was used in the next step as such without any further purification.

[0367] Step 7: Synthesis of 2-(3-bromo-1-methyl-1H-pyrazol-5-yl)propan-2-amine (8)

[0368] At 0 ° C, bis (trifluoroacetyloxy) -iodobenzene (0.174g, 0.406mmol) was added to the stirred solution of compound 7 (0.1g, 0.406mmol) in ACN: water (2: 2mL), and the reaction solution was stirred at room temperature for 24 hours. 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 alkalized with 10% NaOH solution and extracted with EtOAc. The combined organic layer was washed with water, followed by washing with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound 8 (0.07g, rough) as a light brown solid. This compound was used in the next step as such without any further purification.

[0369] 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)

[0370] At 0 ° C, DIPEA (0.24 mL, 1.375 mmol) and HATU (0.26 g, 0.687 mmol) were added to a stirred solution of compound 9 (0.097 g, 0.504 mmol) in DCM (5 mL). Compound 8 (0.1 g, 0.458 mmol) was added to this solution, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, followed by brine washing, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi-Flash chromatography (eluted with 40-50% EtOAc / heptanes) to obtain the title compound 9 (0.13 g, 0.125 mmol, 27.3% yield) as an off-white solid.

[0371] 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)

[0372] Compound 10 (0.108 g, 0.395 mmol) was added to a stirred solution of compound 9 (0.13 g, 0.329 mmol) in 1,4-dioxane: water (4:1 mL), followed by the addition of Cs2CO3 (0.21 g, 0.659 mmol), and the reaction mixture was degassed with argon for 15 minutes. Pd(PPh3)4Cl2 (23.1 mg, 0.033 mmol) was added to this solution under an 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 diatomaceous earth pad, and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, followed by washing with 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 / heptane) to give the title compound 1063 (23 mg, 0.049 mmol, 15.0% yield) as an off-white solid.

[0373] Data of compound 1063: HPLC: 7.618 minutes at room temperature, 99.14%. Column: X-Select CSH C18 (4.6*150) mm 5u Mobile phase: A - water containing 0.1% formic acid: 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), 1.961 minutes at room temperature, 99.04%. Column: X-Select CSH C18 (3.0*50) mm 2.5um Mobile phase: A: Water:ACN (95:05) containing 0.05% formic acid B: ACN containing 0.05% formic acid, Injection volume: 2.0 μL Flow rate: 1.2 ml / min Column oven temperature: 50°C Gradient program: 2% B to 98% B in 2.0 minutes, hold until 3.0 minutes, at 3.2 minutes, B concentration is 2% until 4.0 minutes. 1 H NMR (400MHz, DMSO-d6): δ8.79(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).

[0374] 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)

[0375]

[0376] Step 1: Synthesis of methyl 3-bromo-1-methyl-1H-pyrazole-5-carboxylate (2)

[0377] At 0 ° C, Cs was added to a stirred solution of compound 1 (5.0 g, 24.389 mmol) in DMF (50 mL)CO (15.8 g, 48.778 mmol) and methyl iodide (6.9 g, 48.778 mmol). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, followed by brine washing, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude compound was purified by Combi-Flash chromatography (eluted with 40-50% EtOAc / heptanes), to obtain the title compound 2 (3.3 g, 15.031 mmol, 61% yield) as an off-white solid.

[0378] Step 2: Synthesis of (3-bromo-1-methyl-1H-pyrazol-5-yl)methanol (3)

[0379] At 0 ° C, lithium borohydride (1.89 g, 86.742 mmol) was added to a stirred solution of compound 2 (3.8 g, 17.348 mmol) in methanol (50 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with a saturated NH4Cl solution at 0 ° C and extracted with EtOAc. The combined organic layer was washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the title compound 3 (2.9 g, crude product) as an off-white solid. This compound was used in the next step as such without any further purification.

[0380] Step 3: Synthesis of 3-bromo-5-(bromomethyl)-1-methyl-1H-pyrazole (4)

[0381] At 0 ° C, triphenylphosphine (6.1g, 23.557mmol) and CBr (7.8g, 23.557mmol) were added to the stirred solution of compound 3 (3.0g, 15.704mmol) in DCM (20mL), and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, followed by brine washing, over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluted with 10-20% EtOAc / heptane), to obtain the title compound 4 (2.8g, 10.5mmol, 66.7% yield) as an off-white solid.

[0382] Step 4: Synthesis of 2-(3-bromo-1-methyl-1H-pyrazol-5-yl)acetonitrile (5)

[0383] At 0 ° C, dropwise to the stirred solution of compound 4 (2.8g, 11.027mmol) in ACN (25mL) add TBAF (1.1mL, 16.541mmol) and TMSCN (2.07mL, 16.541mmol). The reaction mixture was stirred at room temperature for 6 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, followed by washing with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluted with 10-20% EtOAc / heptane), to obtain the title compound 5 (1.6g, 7.278mmol, 66.0% yield) in a yellow liquid.

[0384] Step 5: Synthesis of 1-(3-bromo-1-methyl-1H-pyrazol-5-yl)cyclobutane-1-carbonitrile (7)

[0385] To the stirred mixture of compound 5 (1.2g, 5.998mmol), compound 6 (9.17mL, 89.982mmol), 50% NaOH aqueous solution (5.9g, 149.97mmol) containing TEBAC (0.41g, 1.799mmol) was added. The reaction mixture was stirred at 50 ° C for 12 hours. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, and diluted with ice-cold water, and extracted with DCM. The combined organic layer was washed with water, followed by brine washing, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi-Flash chromatography (eluted with 10-20% EtOAc / heptane), to obtain the title compound 7 (1.0g, 2.415mmol, 40.2% yield) as a colorless liquid.

[0386] Step 6: Synthesis of 1-(1-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-5-yl)cyclobutane-1-carbonitrile (9)

[0387] Compound 8 (0.54 g, 1.999 mmol) was added to a stirred solution of compound 7 (0.4 g, 1.666 mmol) in 1,4-dioxane: water (8:2 mL), followed by the addition of Cs2CO3 (1.0 g, 3.331 mmol), and the reaction mixture was degassed with argon for 15 minutes. Pd(PPh3)4Cl2 (0.11 g, 0.166 mmol) was added to this solution under an 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 diatomaceous earth pad, and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, followed by brine washing, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Combi Flash chromatography (eluting with 30-40% EtOAc / heptane) to afford the title compound 9 (60 mg, 0.099 mmol, 23.9% yield) as an off-white solid.

[0388] Step 7: Synthesis of 1-(1-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-5-yl)cyclobutane-1-carboxamide (10)

[0389] At 0 ° C, K2CO3 (0.09 g, 0.653 mmol) and H2O2 (0.1 mL, 3.264 mmol) were added dropwise to a stirred solution of compound 9 (0.2 g, 0.653 mmol) in DMSO (2 mL). The reaction solution was stirred at room temperature for 12 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water, and the precipitated solid was filtered out, and the precipitated solid was dried in vacuo to obtain the title compound 10 (0.15 g, crude) as an off-white solid. This compound was used in the next step as such without any further purification.

[0390] Step 8: Synthesis of 1-(1-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-5-yl)cyclobutan-1-amine (11)

[0391] At 0 ° C, NaOH (0.04 g, 1.156 mmol) was added to a stirred solution of compound 10 (0.15 g, 0.462 mmol) in 1,4-dioxane: water (4: 2 mL), followed by the addition of NaOCI (0.85 g, 1.156 mmol), and the reaction mixture was stirred at 80 ° C for 16 hours. 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 extraction with brine. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound 11 (0.14 g, crude product) as a colorless liquid. This compound was used as such in the next step without any further purification.

[0392] 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)

[0393] At 0 ° C, DIPEA (0.21 mL, 1.215 mmol) and HATU (0.23 g, 0.607 mmol) were added to a stirred solution of compound 12 (0.086 g, 0.445 mmol) in DCM (5 mL). Compound 11 (0.12 g, 0.405 mmol) was added to this solution, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layer was washed with water, followed by brine washing, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Combi-Flash chromatography (eluted with 40-50% EtOAc / heptanes) to obtain the title compound compound 1064 (30 mg, 0.060 mmol, 14.9% yield) as an off-white solid.

[0394] Data: HPLC: 7.704 minutes at room temperature, 95.28%. Column: X-Select CSH C18 (4.6*150) mm 5u Mobile phase: A - water containing 0.1% formic acid: 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), 1.913 minutes at room temperature, 96.99%. Column: X-Select CSH (3.0*50) mm 2.5u Mobile phase: A: Water:ACN (95:5) containing 0.05% formic acid B: ACN containing 0.05% formic acid, Injection volume: 2.0 μL Flow rate: 1.2 ml / min Column oven temperature: 50°C Gradient program: 0% B to 98% B in 2.0 minutes, hold until 3.0 minutes, at 3.2 minutes, the B concentration is 0% until 4.0 minutes. 1 H NMR (400MHz, CDCl3) δ8.71(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).

[0395] II: Efficacy of exemplary compounds in inhibiting KCNT1

[0396] Example B1

[0397] KCNT1-patch clamp assay

[0398] The inhibition of KCNT1 (KNa1.1, Slack) was evaluated using a tetracycline-inducible cell line (HEK-TREX). Current was recorded using a SyncroPatch 384PE automated patch clamp system. Pulse generation and data collection were performed using PatchController384 V1.3.0 and DataController384 V1.2.1 (Nanion Technologies). Access resistance and apparent membrane capacitance were estimated using built-in protocols. Current was recorded in a perforated patch mode (10 μM aescin) from a cell population. Cells were lifted, wet-ground and resuspended at 800,000 cells / ml. Cells were allowed to recover in a cell bank before the experiment. Current was recorded at room temperature. The external solution contained the following (in mM): NaCl 105, NMDG 40, KCl 4, MgCl2 1, CaCl2 5 and HEPES10 (pH=7.4, osmotic pressure of about 300 mOsm). The extracellular solution was used as a washing solution, a reference solution, and a compound delivery solution. The internal solution contained the following (in mM): NaCl 70, KF 70, KCl 10, EGTA 5, HEPES 5, and aescin 0.01 (pH=7.2, osmotic pressure of about 295mOsm). Aescin was prepared in a 5mM stock aqueous solution, divided into equal parts, and stored at -20°C. Compound plates were created in an extracellular solution in a 2x concentrated manner. When added to the recording well, the compound was diluted to 1:2. The amount of DMSO in the extracellular solution was kept constant at a level for the highest test concentration. A clamping potential from -80mV to 0mV was used with a 100ms step. The average current was measured during the step to 0mV. 100 μM Bepridil was used to completely inhibit the KCNT1 current to allow the non-KCNT1 current to be subtracted offline. The average mean current from the 3 sweeps was calculated and the percent inhibition was calculated for each compound. The percent inhibition as a function of compound concentration was fit to the Hill equation to yield IC 50, slope, minimum parameter, and maximum parameter. If KCNT1 inhibition was less than 50% at the highest concentration tested, or if the IC 50 , the percentage of inhibition is reported instead of IC 50 .

[0399] The results from this example are summarized in Table 6 below. In this table, "A" means IC 50 is less than or equal to 1 μM; "B" indicates inhibition between 1 μM and 20 μM; and "C" indicates inhibition greater than or equal to 20 μM.

[0400] Table 6.

[0401]

[0402]

[0403] Example B2: Pharmacokinetics

[0404] Pharmacokinetic data were obtained for compounds 1063 and 1064 as detailed herein.

[0405] Kinetic solubility assay: Kinetic solubility assays were performed using a shake flask method followed by HPLC-UV analysis. The following step-by-step procedure was used:

[0406] 1) Samples were weighed and dissolved in 100% DMSO as a 10 mM stock solution. Approximately 10 μL (compound / media) of stock solution was required in this assay.

[0407] 2) Test compounds and controls (10 mM in DMSO, 10 μL / vial) were added to 50 mM pH 7.4 phosphate buffer (490 μL / well) placed in the Mini-Uniprep filter.

[0408] 3) Vortex the kinetic solubility samples for 2 minutes.

[0409] 4) The solubility solution was incubated and shaken at room temperature on an orbital shaker at 800 rpm for 24 hours.

[0410] 5) Centrifuge at 4000 rpm, 20°C for 10 minutes.

[0411] 6) 400 μL (with or without dilution) of each solubility supernatant was transferred to a 96-deep well for analysis, after which the samples were directly filtered through a syringe-free filtration device.

[0412] 7) Determine the test compound concentration of the filtrate using HPLC-UV.

[0413] 8) At least 5 UV standard solutions were then injected into the HPLC from low to high concentrations, and the kinetic solubility supernatants were then tested in duplicate.

[0414] 9) Use QC samples to monitor the progress of the kinetic solubility determination.

[0415] 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; a variable buffer pH can be set). Since log D is pH-dependent, the pH value of the aqueous phase is always specified and is typically measured at pH 7.4 (i.e., the physiological pH of body fluids). The following Log D method was used to calculate the Log D values ​​in Table 8 below:

[0416] 1) Dissolve the appropriate test compound in 100% DMSO to make a 10 mM solution.

[0417] 2) Transfer the test compounds (10 mM in DMSO; 2 μL / well) and QC samples (10 mM in DMSO; 2 μL / well) from the storage tubes to 96-well polypropylene cluster tubes.

[0418] 3) Buffer-saturated 1-octanol (149 μL / well) and 1-octanol-saturated buffer (149 μL / well) were added to the wells, respectively.

[0419] 4) Each tube was mixed vigorously on its side for 3 minutes and then shaken at 880 rpm for 1 hour at room temperature.

[0420] 5) Centrifuge the tube at 4000 rpm for 5 minutes.

[0421] 6) Dilute the buffer layer sample 20 times and the 1-octanol layer sample 200 times with the internal standard (IS) solution. Note: The dilution factor is mainly based on the characteristics of the compound.

[0422] 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 (Log D values) using the ratio of the corrected peak areas.

[0423] 8) Use QC samples to monitor process Log D determination.

[0424] 9) Data analysis: The Log D value of each compound was calculated by the following formula:

[0425]

[0426] For the treated samples, different dilution factors will be used to process the different dilution values ​​in the formula.

[0427] MW, XLogP and TPSA: These data points are calculated using Dotmatics.

[0428] Liver microsomal metabolic stability assay (NADPH):

[0429] 1) Test compounds were incubated at 37°C with liver microsomes (pooled from multiple donors) at 1.0 μM in the presence of NADPH (approximately 1.0 mM) at 0.5 mg / ml microsomal protein.

[0430] 2) Positive controls included testosterone (3A4 substrate), propafenone (2D6) and diclofenac (2C9). The positive controls were also incubated with microsomes in the presence of NADPH.

[0431] 3) Time samples (0, 5, 15, 30, 45 and 60 minutes) were taken and immediately mixed with cold acetonitrile containing internal standard (IS). Test compounds were also included that were incubated with the microsomes for 60 minutes without NADPH.

[0432] 4) Replicate points for each test condition (n=2).

[0433] 5) Samples were analyzed by LC / MS / MS; disappearance of test compounds was assessed based on the peak area ratio of analyte / IS (without standard curve).

[0434] 6) Excel data summary, calculated intrinsic clearance and T1 / 2 values ​​are provided.

[0435] 7) Calculate microsomal clearance using the formula:

[0436]

[0437] For the five species, mg microsomal protein / g liver weight is 45. For rat, monkey, dog, human and mouse, liver weight values ​​will be 40 g / kg, 30 g / kg, 32 g / kg, 20 g / kg and 88 g / kg, respectively. Hepatic clearance will be CL 固有(微粒体) Calculated using the following formula:

[0438]

[0439] The results from this example are summarized in Table 7 below.

[0440] Table 7.

[0441]

Claims

1. A compound of formula (I) having a pyrazole core: or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from 5-membered or 6-membered heteroaryl or aryl, wherein the heteroaryl or the aryl optionally comprises at least one substituent, the at least one substituent being independently selected from alkyl, haloalkyl, carbocyclyl or -CN; R 2 is -H; R 3 Selected from -H or alkyl; R 4 Selected from -H or alkyl; or R 3 and R 4 Together with the carbon atom to which it is attached, it forms an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl; Z is selected from A haloalkyl or alkoxy group; Ring A is selected from 5-membered or 6-membered heteroaryl, aryl, heterocyclyl or carbocyclyl; R 5 is independently selected from alkyl, carbocyclyl, alkoxy, -C(O)NH2, -CN or halogen, wherein the alkyl, the carbocyclyl or the alkoxy optionally comprises at least one halogen substituent, or wherein the alkyl optionally comprises at least one -OH substituent; n is 0, 1, 2, 3 or 4; L is absent or selected from -NR a -, -CH2- or -O-; R a Selected from -H or alkyl; R 6 is selected from -H or alkyl; and R 7 It is an alkyl group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (II) having a pyrazole nucleus: or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from pyrazolyl or phenyl, wherein the pyrazolyl or the phenyl optionally comprises at least one substituent, the at least one substituent being independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-5 Carbocyclic group; R 2 is -H; R 3 Selected from -H or alkyl; R 4 Select from -H or C 1-4 alkyl; or R 3 and R 4 Together with the carbon atom to which it is attached, it forms an optionally substituted 3-5 membered carbocyclyl or heterocyclyl; Ring A is selected from pyridyl, phenyl, pyrimidinyl, piperidinyl or cyclopentyl, R 5 Selected from C 1-4 Alkyl, C 3-5 Carbocyclic group, C 1-4 Alkoxy, -C(O)NH2, -CN or halogen, wherein the alkyl, the carbocyclyl or the alkoxy optionally comprises at least one halogen substituent, or wherein the alkyl optionally comprises at least one -OH substituent; n is 0, 1, 2, 3 or 4; L is absent or selected from -NR a -, -CH2- or -O-; R a Select from -H or C 1-4 alkyl; R 6 Select from -H or C 1-4 Alkyl; and R 7 C 1-4 alkyl.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is pyrazolyl, said pyrazolyl comprising at least one substituent selected from the group consisting of -CH3, -CF3, -C(CH3)3, -CHF2, -CH(CH3)2 or cyclopropyl.

4. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 It is phenyl.

5. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from -H or -CH3.

6. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Together with the carbon atom to which it is attached, it forms an optionally substituted cyclopropyl, cyclobutyl or oxetanyl. 7 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is a pyridyl group.

8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R 5 is independently selected at each occurrence from: -CH3, -CH2CH3, -CF3, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2OH, -CN, -C(O)NH2 or cyclopropyl. 9 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein L is absent.

11. A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from -H or -CH3.

12. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from -CH3 or -CH2CH3.

13. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein the compound of formula (I) is selected from a compound of formula (II-A), a compound of formula (II-B) or a compound of formula (II-C) having a pyrazole core: or a pharmaceutically acceptable salt thereof.

14. The compound or pharmaceutically acceptable salt thereof according to claim 13, wherein the compound of formula (I) is selected from the compound of formula (III-A), the compound of formula (III-B) or the compound of formula (III-C) having a pyrazole nucleus: or a pharmaceutically acceptable salt thereof, wherein: R 1a 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; and R 5 In each occurrence, independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 3-5 Carbocyclic group.

15. The compound or pharmaceutically acceptable salt thereof according to claim 14, wherein the compound of formula (I) is selected from the compound of formula (III-Ai), the compound of formula (III-Bi) or the compound of formula (III-Ci) having a pyrazole core: or a pharmaceutically acceptable salt thereof, wherein: R 1a 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; and R 5 Selected from -CF3, -CH3, -CH2CH3, -OCH3, -OCH2CH3 or cyclopropyl.

16. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the compound of formula (III-Di) or the compound of formula (III-Ei) having a pyrazole nucleus: or a pharmaceutically acceptable salt thereof, wherein: R 1a 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; and R 5 Selected from -F or -CN.

17. The compound according to claim 1, wherein the compound is selected from any of the following compounds or an enantiomer thereof or a pharmaceutically acceptable salt thereof:

18. A pharmaceutical composition comprising: A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof; and At least one pharmaceutically acceptable excipient.

19. A method for treating a nervous system disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with a gain-of-function mutation in a gene, wherein the method comprises administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18.

20. The method of claim 19, wherein the disorder is a disorder associated with a gain-of-function mutation in KCNT1.

21. The method of claim 19 or 20, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (eg, KCNT1) is epilepsy, an epileptic syndrome, or an encephalopathy.

22. The method of claim 19 or 20, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is hereditary or pediatric epilepsy or a hereditary or pediatric epilepsy syndrome.

23. The method of claim 19 or 20, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (eg, KCNT1) is a cardiac dysfunction.

24. The method of claim 19 or 20, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from epilepsy and other encephalopathy (e.g., malignant migratory focal seizures of infancy (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, and Lennox-Gastaut syndrome), seizures (e.g., generalized tonic-clonic seizures, asymmetric tonic seizures), leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy, or cerebellar ataxia.

25. The method of claim 19 or 20, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from the group consisting of arrhythmia, Brugada syndrome, and myocardial infarction.

26. The method of claim 19 or 20, wherein the nervous system disorder, the disorder associated with excessive neuronal excitability, or the 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).

27. The method of claim 19 or 20, wherein the nervous system disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is a muscle disorder (e.g., myotonia, neuromyotonia, cramp muscle spasm, spasticity).

28. The method of claim 19 or 20, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from pruritus and pruritus, ataxia, or cerebellar ataxia.

29. The method of claim 19 or 20, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is a psychiatric disorder (e.g., major depressive disorder, anxiety disorder, bipolar disorder, schizophrenia).

30. The method of claim 19 or 20, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from a learning disability, fragile X, neuronal plasticity, or autism spectrum disorder.

31. The method of claim 19 or 20, wherein the neurological disorder, the disorder associated with excessive neuronal excitability, or the disorder associated with a gain-of-function mutation in a gene (e.g., KCNT1) is selected from epileptic encephalopathy with SCN1A mutation, SCN2A mutation, and / or SCN8A mutation, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic partial epilepsy in children with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen encephalitis, encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

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