KV7 channel activator compositions and methods of use

Abstract

Provided herein are optionally substituted benzimidazole-1, 2-yl amides, pharmaceutical compositions comprising a therapeutically effective amount of such compounds and a pharmaceutically acceptable excipient, and methods of treating Kv7 related diseases with such compounds and pharmaceutical compositions, these diseases are, for example, epilepsy, amyotrophic lateral sclerosis, various types of pain, hyperactivity, dyskinesia, dyskinesia, mania and tinnitus.

Description

This application is a divisional application of the patent application with Chinese application number 201980033266.7, invention name “KV7 channel activator composition and use method” and application date of March 19, 2019 (PCT application number PCT / US2019 / 023039). Government interests

[0001] This invention was made with U.S. Government support under Grant No. U44NS093160 awarded by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. The U.S. Government has certain rights in this invention. CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application Nos. 62 / 644,902, filed on March 19, 2018, and 62 / 644,932, filed on March 19, 2018, and 62 / 663,438, filed on April 27, 2018, and 62 / 697,198, filed on July 12, 2018. The disclosure of each of these applications is incorporated herein by reference. Summary of the invention

[0003] Potassium (K) is present on the plasma membrane of most cell types. + ) channels are the most diverse class of all ion channels and are associated with a variety of physiological functions, including the regulation of the electrical properties of excitable cells. The main pore-forming (α) subunits of these highly selective cation channels are divided into three major structural classes based on the number of transmembrane (TM) and pore (P) regions: 6TM / 1P, 2TM / 1P, and 4TM / 2P K + The International Union of Pharmacology (IUPHAR) designated the Kv7 gene (originally called KCNQ, a name assigned by the HUGO Gene Nomenclature Committee (HGNC)) as a voltage-gated K + The Kv7 subfamily consists of five homologous pore-forming α subunits, Kv7.1-7.5, which have typical voltage-gated K +Channel structure: has 6 TM regions (S1-S6) (flanked by intracellular N-terminal and C-terminal domains), a typical voltage sensor domain located in S4 composed of alternating positively charged residues, and a single P region between S5 and S6 of each subunit. These channels form tetramers of predominantly α subunits, either homotetramers or heterotetramers. Neurons are known to express Kv7 channels composed of Kv7.2-7.5α subunits. Some of these gene products may be distributed only in neurons, while others (e.g., Kv7.4 and Kv7.5) can be found in other tissues such as smooth and skeletal muscle.

[0004] Native M channels and corresponding macroscopic M currents were first characterized in amphibian sympathetic neurons. M channels are noteworthy because they activate at membrane potentials at or near the resting membrane potential of the neuron, exhibit slow activation and non-inactivation, and M currents are reduced by muscarinic cholinergic agonists, demonstrating a G-protein coupled receptor (GPCR) and physiological K + It was not until the cloning of this subfamily of genes that the pharmacological and biophysical properties of Kv7.2 / 7.3 (and possibly Kv7.5 / 7.3) heteromultimers and the elusive 'M' channels were determined, providing new and significant evidence for their importance in neuronal regulation.

[0005] The distribution of these channels (both regionally and developmentally) and their biophysical characteristics support their role in providing persistent resistance to the excitatory effects of depolarization. Under physiological conditions, as demonstrated by native M channels, they can very effectively modulate the subthreshold excitability of certain neuronal populations and play an important role in regulating the frequency and ultimately the pattern of action potential discharges in many types of neurons. Their importance in neuronal regulation is highlighted by the discovery that neuronal Kv7 mutations lead to benign familial neonatal convulsions (BFNC), indicating that reducing or eliminating the effects of Kv7.2 and Kv7.3 channels can greatly alter neuronal excitability. Mutational analysis demonstrates their involvement in BFNC and suggests that they may serve as targets for antiepileptic drugs (AEDs).

[0006] Unlike established GPCR pharmacology terms, K +The mode of action of channel modulators, especially compounds that activate channels, is still being refined. The use of voltage clamp techniques for ion channel pharmacology studies enables detailed biophysical studies of whole-cell currents or single channels, allowing for some characterization of the nature of compound-channel interactions, but does not prevent continued confusion surrounding terminology. The terms opener or activator are often used throughout the literature, but do not adequately describe the mode of action of all these "positive modulator" compounds. Generally, openers or activators are expected to increase the open probability of a channel or increase macroscopic current amplitudes, but this nomenclature is indeed overly simplistic. For example, the first publicly disclosed Kv7 opener, retigabine, has a complex and interesting profile because it has inhibitory activity at higher membrane potentials. Neuronal Kv7 channel openers can work in concert with channel activity within the "normal" activation voltage range and enhance currents without significantly affecting the activation threshold, while others significantly change the activation threshold. In addition, some openers seem to completely eliminate the voltage dependence of activation. It is not clear whether these effects represent a continuum, as these effects are often concentration-dependent. Clearly, the interaction patterns of compounds that can increase channel currents are complex and in most cases not fully understood, and the significance of these features for neuronal responsiveness and system physiology is unclear. Retigabine is moderately potent and not highly specific, but it is a very effective opener for Kv7.2, Kv7.5, and heteromultimeric Kv7 channels, and its action is characterized by a significant increase in channel currents over a narrow voltage range. As described above, at higher positive voltages, the opener is less effective, and under some conditions, the channel current is significantly reduced at higher positive voltages relative to the control current (this "cross" voltage dependence of the opener action is a feature of many neuronal Kv7 channel openers). This effect is also concentration-dependent and more pronounced at higher concentrations.

[0007] The compounds provided herein may be effective against Kv7.2 / 7.3 heteromultimers and / or at least have a bias relative to Kv7.4 homomultimers. These compounds may have reduced adverse side effects compared to retigabine. DETAILED DESCRIPTION

[0008] Before describing the compositions and methods of the present invention, it should be understood that any invention is not limited to the specific processes, compositions or methods described, because these can vary. In addition, the processes, compositions and methods described in the specific embodiments are interchangeable. Therefore, for example, the compositions, dosage regimens, routes of administration, etc. described in the specific embodiments can be used in any method described in other specific embodiments. It should also be understood that the terms used in the description are only for the purpose of describing a specific type or embodiment, and are not intended to limit the scope of the present invention, which will be limited only by the appended claims. Unless otherwise clearly defined, all technical and scientific terms used herein have the same meanings as those generally understood by those of ordinary skill in the art. Although any methods similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, preferred methods are now described. All disclosures and references mentioned herein are incorporated by reference. Nothing herein should be interpreted as admitting that the present invention has no right to disclose content earlier than this due to previous inventions.

[0009] It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0010] As used herein, the term "about" means plus or minus 10% of the numerical value of the number used therewith. Therefore, about 50% means within the range of 45%-55%. Unless otherwise indicated, all numbers expressing the amount of components, characteristics (such as molecular weight, reaction conditions, etc.) used in the specification and claims should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise indicated, the numerical parameters listed in the specification and the attached claims are approximate values, which can vary according to the desired characteristics desired to be obtained. At the lowest level, and without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be interpreted according to the significant digits of the recorded numerical values ​​and by the usual rounding method.

[0011] When used in conjunction with a therapeutic agent, "administering" means administering the therapeutic agent directly into or onto a target tissue or administering the therapeutic agent to a subject, whereby the therapeutic agent has a positive effect on the tissue to which it is targeted. "Administering" a composition can be accomplished by oral administration, injection, infusion, absorption, or by any method combined with other known techniques. "Administering" can include the act of self-administering or administering by another person (e.g., a healthcare provider or device).

[0012] As used herein, the terms "comprising, comprise, comprises and comprised" are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0013] As used herein, the terms "consists of" or "consisting of" mean that the compositions or methods include the elements, steps or ingredients specifically recited in the particular embodiments or claims.

[0014] As used herein, the term "consisting essentially of or consists essentially of" means that the composition or method includes only the specified materials or steps, and those that do not materially affect the basic and novel characteristics of the claimed invention.

[0015] The term "improvement" is used to indicate that the present invention refers to the overall physical condition of an individual to whom an active agent has been administered. For example, if one or more symptoms of a condition, disease, or disorder (e.g., a neurodegenerative disorder) are alleviated by the administration of an active agent, the overall physical condition of the individual may be "improved." "Improvement" may also refer to a change in the appearance, form, characteristics, and / or physical properties of a tissue provided, applied, or administered, or any combination thereof.

[0016] The terms "inhibit," "suppress," "reduce," "interfere with," and / or "reduce" (and similar terms) generally refer to an action that directly or indirectly reduces a function, activity, or behavior relative to a natural, expected, or average condition, or relative to current conditions.

[0017] As used herein, the phrase "Kv7-related disease" is a disease, disorder or condition that is associated with a KCNQ2 gene mutation; associated with a KCNQ3 gene mutation; associated with a KCNQ4 gene mutation; associated with a KCNQ5 gene mutation; associated with a gene encoding a Kv7 potassium channel; associated with a non-mutated Kv7 potassium channel but a dysfunctional Kv7 potassium channel; associated with overexcitability of cells that is believed to cause the disease, disorder or condition; or a combination thereof. Regardless of causality, these Kv7-related diseases, disorders or conditions can be treated by activating the Kv7 potassium channel, even though the Kv7 potassium channel may not be the direct or indirect cause of the disease, disorder or condition.

[0018] Examples of Kv7-related disorders associated with KCNQ2 gene mutations include, but are not limited to, benign familial neonatal epileptic seizures (BFNS) or KCNQ2 encephalopathy (also known as KCNQ2 neonatal epileptic encephalopathy). Examples of Kv7-related disorders associated with KCNQ3 gene mutations include, but are not limited to, BFNS or KCNQ3-related developmental disorders. Examples of Kv7-related disorders associated with KCNQ4 gene mutations include, but are not limited to, autosomal dominant non-syndromic hearing loss. Examples of Kv7-related disorders associated with KCNQ5 gene mutations include, but are not limited to, non-syndromic intellectual disability or epileptic encephalopathy. Examples of disorders associated with overexcitement of cells believed to cause a disease, disorder, or condition include, but are not limited to, focal clonic seizures, generalized tonic-clonic seizures, neuropathic pain, overactive bladder, or smooth muscle disorders or a combination thereof.

[0019] In each of the embodiments disclosed herein, the compositions and methods can be used with or for a subject in need of such treatment (also referred to as "in need thereof"). As used herein, the phrase "in need thereof" means that a subject has been identified as having a need for a particular method or treatment and that treatment has been administered to the subject for that particular purpose.

[0020] As used herein, the term "therapeutic agent" means an agent used to treat, combat, ameliorate, or prevent (or any combination thereof) an undesirable condition, disorder, or disease in a subject.

[0021] As used herein, the terms "patient" and "subject" are interchangeable and can be used to refer to any biological organism that can be treated with the compounds of the present invention. Similarly, the terms "patient" and "subject" can include, but are not limited to, any non-human mammal, primate, or human. In some embodiments, the "patient" or "subject" is an adult, child, infant, or fetus. In some embodiments, the "patient" or "subject" is a human. In some embodiments, the "patient" or "subject" is a mammal, such as a mouse, rat, other rodent, rabbit, dog, cat, pig, cattle, sheep, horse, primate, or human.

[0022] As used herein, the terms "therapeutically effective amount" or "therapeutic dose" are interchangeable and may refer to the amount of an active agent or pharmaceutical compound or composition that will elicit a clinical, biological or medical response in a tissue, system, animal, individual or human that is desired by a researcher, veterinarian, physician or other clinical professional. A clinical, biological or medical response may include, for example, one or more of the following: (1) preventing a disease, condition or disorder in an individual who may be susceptible to the disease, condition or disorder but does not yet experience or exhibit the pathology or symptoms of the disease, condition or disorder, (2) inhibiting the disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder, or preventing further development of the pathology and / or symptoms of the disease, condition or disorder, and (3) ameliorating the disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder, or reversing the pathology and / or symptoms experienced or exhibited by the individual.

[0023] The term "treat", "treated" or "treating" can be used to refer to the prevention of a particular disorder, disease or condition, the alleviation of symptoms associated with a particular disorder, disease or condition, and / or the prevention of symptoms associated with a particular disorder, disease or condition. In some embodiments, the term refers to slowing down the progression of an obstacle, disease or condition or alleviating symptoms associated with a particular disorder, disease or condition. In some embodiments, the term refers to alleviating symptoms associated with a particular disorder, disease or condition. In some embodiments, the term refers to alleviating symptoms associated with a particular disorder, disease or condition. In some embodiments, the term refers to restoring a function that is impaired or lost due to a particular disorder, disease or condition.

[0024] "Pharmaceutically acceptable salts" means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. (1977) J. Pharm. Sciences, Vol. 6, 1-19, describe pharmaceutically acceptable salts in detail. Pharmaceutically acceptable "salts" are any acid addition salts, preferably pharmaceutically acceptable acid addition salts, including but not limited to halide salts, such as hydrobromide, hydrochloride, hydrofluoride and hydroiodide; inorganic acid salts, such as, for example, nitrates, perchlorates, sulfates and phosphates; organic acid salts, such as, for example, sulfonates (methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate, acetate, malate, fumarate, succinate, citrate, benzoate, gluconate, lactate, mandelate, mucate, pamoate, pantothenate, oxalate and maleate; and amino acid salts, such as, for example, aspartate or glutamate. The acid addition salts may be monoacid addition salts or diacid addition salts, such as dihydrohalide salts, disulfate salts, diphosphate salts or diorganic acid salts. In all cases, the acid addition salts are used as non-chiral reagents that are not selected based on any expected or known preference for interacting with or precipitating a particular optical isomer of the product of the present disclosure.

[0025] Unless otherwise indicated, when a compound or chemical structural feature (e.g., an aryl group) is referred to as "optionally substituted," it includes features that have no substituents (i.e., unsubstituted) or "substituted" features (meaning that the feature has one or more substituents). The term "substituent" has the broadest meaning known to those of ordinary skill in the art, and includes moieties that replace one or more hydrogen atoms attached to the parent compound or structural feature. In some embodiments, the substituent can be a common organic moiety known in the art, and its molecular weight (e.g., the sum of the atomic masses of the atoms of the substituent) is 15 g / mol to 50 g / mol, 15 g / mol to 100 g / mol, 15 g / mol to 150 g / mol, 15 g / mol to 200 g / mol, 15 g / mol to 300 g / mol, or 15 g / mol to 500 g / mol. In some embodiments, the substituent comprises or consists of: 0-30, 0-20, 0-10, or 0-5 carbon atoms, and 0-30, 0-20, 0-10, or 0-5 heteroatoms, wherein each heteroatom can independently be: N, O, S, Si, F, Cl, Br, or I, with the proviso that the substituent includes one C, N, O, S, Si, F, Cl, Br, or I atom. Examples of substituents include, but are not limited to, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonylamino, N-sulfonylamino, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, and the like.

[0026] For convenience, the term "molecular weight" used with respect to a moiety or part of a molecule indicates the sum of the atomic masses of the atoms in the part of the molecule (even though it may not be the entire molecule).

[0027] The following are structures associated with some of the chemical names referred to herein. These structures may be unsubstituted, as shown below, or when the structure is unsubstituted, substituents may be independently present in any position normally occupied by a hydrogen atom. The point of attachment is indicated, but otherwise attachment can occur at any position normally occupied by a hydrogen atom.

[0028] As used herein, the term "alkyl" has the broadest meaning generally understood in the art and may include moieties consisting of carbon and hydrogen that do not contain double or triple bonds. The alkyl group may be a linear alkyl group, a branched alkyl group, a cycloalkyl group, or a combination thereof, and in some embodiments, may contain 1 to 35 carbon atoms. In some embodiments, the alkyl group may include C 1-10 Straight-chain alkyl groups, such as methyl (-CH3), methylene (-CH2-), ethyl (-CH2CH3), ethylene (-C2H4-), n-propyl (-CH2CH2CH3), propylene (-C3H6-), n-butyl (-CH2CH2CH2CH3), n-pentyl (-CH2CH2CH2CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), etc.; C 3-10 Branched alkyl, such as C3H7 (e.g. isopropyl), C4H9 (e.g. branched butyl isomer), C5H 11 (e.g. branched pentyl isomers), C6H 13 (e.g. branched hexyl isomers), C7H 15 (e.g. branched heptyl isomers), etc.; C 3-10 Cycloalkyl, such as C3H5 (e.g. cyclopropyl), C4H7 (e.g. cyclobutyl isomers, such as cyclobutyl, methylcyclopropyl, etc.), C5H9 (e.g. cyclopentyl isomers, such as cyclopentyl, methylcyclobutyl, dimethylcyclopropyl, etc.), C6H 11 (e.g. cyclohexyl isomers), C7H 13 (e.g., cycloheptyl isomers), bicyclo[1.1.1]pentane, norbornane, etc.; and the like.

[0029] For optionally substituted moieties, such as optionally substituted alkyl, phrases such as "optionally substituted C 1-12 "Alkyl" refers to a C group which may be unsubstituted or may have one or more substituents. 1-12 alkyl, and does not limit the number of carbon atoms in any substituent. Thus, for example, since the parent alkyl group has 12 carbon atoms, CH2(CH2) 11 OCH3 is an optionally substituted C 1-12 Alkyl. Phrases such as "C 1-12 "Optionally substituted alkyl" refers to unsubstituted C 1-12 An alkyl group or a substituted alkyl group in which the alkyl group and all substituents together have 1 to 12 carbon atoms. For example, CH2CH2OCH3 is C 1-12 Optionally substituted alkyl, because the alkyl group (eg, ethyl) and the substituent (eg, methoxy) together contain 3 carbon atoms. A similar convention can be applied to other optionally substituted moieties, such as aryl and heterocyclyl.

[0030] The substituents on the alkyl group may be the same as those generally described above. In some embodiments, the substituents on the alkyl group are independently selected from F, Cl, Br, I, CN, CO H, -O-alkyl, ester groups, acyl groups, amine groups, amide groups, phenyl groups (including fused phenyl groups, resulting in an optionally substituted alkyl group such as indenyl, wherein the phenyl substituent is fused to the parent alkyl moiety) and may have a molecular weight of about 15 to about 100 or about 500.

[0031] As used herein, the term "aryl" has the broadest meaning generally understood in the art, and may include an aromatic ring, or an aromatic ring system, such as phenyl, naphthyl, and the like.

[0032] The term "heterocyclyl" includes any ring or ring system containing heteroatoms (such as N, O, S, P, etc.). Heterocyclyl includes heteroaryl rings or ring systems (such as those listed below) and non-aromatic rings or ring systems. Examples of non-aromatic heterocyclyls include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxalanyl, dithiolanyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino, etc.

[0033] The term "heteroaryl" also has the meaning understood by those of ordinary skill in the art, and includes "aryl" having one or more heteroatoms in a ring or ring system, such as pyridyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, oxadiazolyl, isoxazolyl, indolyl, quinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, and the like.

[0034] As used herein, the term "carbocyclyl" has the broadest meaning as generally understood in the art, and includes rings containing no heteroatoms, for example, cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; cycloalkenyl groups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl; cycloalkynyl groups, such as cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl; bridged cycloalkyl groups, such as bicyclo[1.1.1]pentane, norbornane, and the like; and aryl rings containing no heteroatoms.

[0035] If no stereochemistry is indicated, the name or structure drawing includes any stereoisomer, or any mixture of stereoisomers, and applicants reserve the right to specifically identify and claim compounds as a single stereoisomer or any specific mixture of stereoisomers.

[0036] Compounds described herein may contain asymmetric centers, and therefore may exist as enantiomers. When compounds according to embodiments herein have two or more asymmetric centers, they may also exist as diastereomers. Embodiments herein include all these possible stereoisomers, such as substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. In certain embodiments, formulas are shown without determining stereochemistry at certain positions. Embodiments herein include all stereoisomers of such formulas and pharmaceutically acceptable salts thereof. The diastereoisomer pairs of enantiomers may be separated, for example, by fractional crystallization from a suitable solvent, and the enantiomer pairs thus obtained may be separated into individual stereoisomers by conventional means (e.g., by using optically active acids or bases as resolving agents or on chiral HPLC columns). In addition, any enantiomer or diastereomer of a compound of formula may be obtained by stereospecific or stereoselective synthesis using optically pure or enantiomerically enriched starting materials or reagents of known configurations. The embodiments as described and claimed herein encompass within their scope the racemic forms of the compounds as well as individual enantiomers, diastereomers, and stereoisomerically enriched mixtures, and applicants reserve the right to specifically identify and claim the compounds in any such forms.

[0037] The compounds disclosed herein may exist as, and therefore include, all stereoisomers, conformational isomers, mixtures thereof in all ratios, and isotopic forms (such as deuterated compounds); and Applicants reserve the right to specifically identify and claim compounds in any such forms.

[0038] Disclosed herein is an example of the development of a Kv7.2 / 7.3 structure activity relationship that resulted in a significant increase in potency against this ion channel target. The EC of the known Kv7 activator ezagabine, as characterized by the Kv7.2 / 7.3 FluxOR potassium channel assay (Invitrogen, F20015), was 50 The species tested in the thallium flux assay (described in US 2017 / 0114022, US 2018 / 0148419 and WO 2018 / 081825) have a relative affinity of 1.1 μM to 1.1 μM. 50 values ​​(most of them were in the active range between 1 and 10 μM, and only a few (11%) had EC 50 The genera and species described herein distinguish themselves as Kv7 activators from previous chemical entities, as demonstrated by their superior activity against Kv7.2 / 7.3; the thallium flux EC values ​​of these compounds are ≤ 0.30 μM. 50 Values ​​ranged from ≤1 μM to ≤0.3 μM, including those with EC 50In certain preferred embodiments, the compounds of the present application have a R 2 Position has a small non-hydrogen substituent, combined with Increased substitution at the beta position to the carbonyl group of the optionally substituted hydrophobic alkyl group at position (such as any of Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13 or 14) generally results in Kv7.2 / 7.3EC 50 <1 μM.

[0039] Some embodiments include compounds represented by Formula 1C:

[0040] For Formula 1C, Bz can be an optionally substituted benzimidazole-1,2-yl. If the benzimidazole-1,2-yl is substituted, it can have 1, 2, 3 or 4 substituents. Any substituents may be included on the benzimidazole-1,2-yl. In some embodiments, some or all of the substituents on the benzimidazole-1,2-yl may have: 0 to 10 carbon atoms and 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br or I (provided that there is at least 1 non-hydrogen atom); and / or a molecular weight of 15g / mol to 500g / mol. In some embodiments, some or all of the substituents may each have a molecular weight of 15Da to 200Da, 15Da to 100Da or 15Da to 50Da, and consist of 2 to 5 chemical elements, wherein these chemical elements are independently C, H, O, N, S, F, Cl or Br. In some embodiments, Bz can be an optionally substituted benzimidazole-1,2-diyl. In some embodiments, Bz can be an optionally substituted benzimidazole-1,2,6-triyl.

[0041] For example, for Formula 1C, the substituent of Bz can be C 1-10 Optionally substituted alkyl, such as CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H 11 , cyclic C5H9, C6H 13 , cyclic C6H 11 etc., which may be optionally substituted; C 1-10 Optionally substituted alkoxy, for example OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 、Cyclic OC5H9、OC6H 13 、Cyclic OC6H 11 etc.; halogenated, such as F, Cl, Br, I; OH; CN; NO2; C 1-6 Fluoroalkyl, such as CF3, CF2H, C2F5, etc.; C1-6 Fluoroalkoxy, such as OCF3, OCF2H, OC2F5, etc.; C 1-10 Esters, such as -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl, etc.; C 1-10 Ketone, such as -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc.; or C 1-10 Amines, such as NH2, NH(CH3), N(CH3)2, N(CH3)C2H5, etc. In some embodiments, the substituents of Bz can be F, Cl, Br, I, CN, NO2, C 1-4 Alkyl, C 1-4 Alkyl-OH, C 1-3 O-alkyl, CF3, COH, C 1-4 CO-alkyl, CO2H, C 1-4 CO2-alkyl, NH2 or C 1-4 Alkylamino.

[0042] Some embodiments of Formula 1C may include compounds represented by Formula 2C:

[0043] For any relevant embodiment or structure diagram of Formula 1C or 2C herein as applicable below, D is optionally substituted C 3-6 Carbocyclic or C 2-5 Heterocyclyl. If D is a substituted cyclobutyl, it may have 1, 2, 3, 4, 5, 6 or 7 substituents. If D is a substituted phenyl, it may have 1, 2, 3, 4 or 5 substituents. If D is a substituted isoxazolyl, it may have 1 or 2 substituents. D may include any substituents. In some embodiments, some or all of the substituents of D may have: 0 to 10 carbon atoms and 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br or I (provided that there is at least 1 non-hydrogen atom); and / or a molecular weight of 15 g / mol to 500 g / mol. In some embodiments, some or all of the substituents may each have a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da or 15 Da to 50 Da, and are composed of 2 to 5 chemical elements, wherein these chemical elements are independently C, H, O, N, S, F, Cl or Br.

[0044] For any relevant embodiment or structure diagram of Formula 1C or 2C herein as applicable below, the substituent of D can be C 1-10 Optionally substituted alkyl, such as CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H 11, cyclic C5H9, C6H 13 , cyclic C6H 11 , bicyclo[1.1.1]pentane, norbornane, etc., which may be optionally substituted; C 1-10 Optionally substituted alkoxy, for example OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 、Cyclic OC5H9、OC6H 13 、Cyclic OC6H 11 etc.; halogenated, such as F, Cl, Br, I; OH; CN; NO2; C 1-6 Fluoroalkyl, such as CF3, CF2H, C2F5, etc.; C 1-6 Fluoroalkoxy, such as OCF3, OCF2H, OC2F5, etc.; C 1-10 Esters, such as -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl, etc.; C 1-10 Ketone, such as -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc.; or C 1-10 Amines, such as NH2, NH(CH3), N(CH3)2, N(CH3)C2H5, etc. In some embodiments, the substituents of D can be F, Cl, Br, I, CN, NO2, C 1-4 Alkyl, C 1-4 Alkyl-OH, C 1-3 O-alkyl, CF3, COH, C 1-4 CO-alkyl, CO2H, C 1-4 CO2-alkyl, NH2 or C 1-4 Alkylamino.

[0045] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein where applicable, in some embodiments, D is: Select C to replace 2-4 alkyl.

[0046] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein that apply below, in some embodiments, D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, bicyclo[1.1.1]pentane, norbornane, or isopropyl.

[0047] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein that apply below, in some embodiments, D is an optionally substituted cyclobutyl. In some embodiments, D is a cyclobutyl. In some embodiments, D is

[0048] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein that apply below, in some embodiments, D is isopropyl.

[0049] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein that apply below, in some embodiments, D is t-butyl or tert-butyl.

[0050] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein that apply below, in some embodiments, D is bicyclo[1.1.1]pentane.

[0051] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein that apply below, in some embodiments, D is an optionally substituted phenyl. In some embodiments, D is

[0052] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein that apply below, in some embodiments, D is an optionally substituted pyridyl group, such as an optionally substituted pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl. In some embodiments, D is

[0053] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein that apply below, in some embodiments, D is an optionally substituted isoxazolyl. In some embodiments, D is

[0054] For any relevant embodiment or structural diagram of Formula 1C or 2C as applicable herein, A is C 1-8 Alkyl, such as straight chain or branched Straight or branched chain Straight or branched chain Straight or branched chain Straight or branched chain Straight or branched chain Contains a ring Contains a ring Contains a ring Contains a ring or containing a bicyclic system

[0055] For any relevant embodiment or structure diagram of Formula 1C or 2C as applicable herein, X is H, F, CH3, SCF3, CF3, optionally substituted C 2-10In some embodiments, X is H. In some embodiments, X is CH3. In some embodiments, X is F. In some embodiments, X is CF3.

[0056] For any relevant embodiment or structural diagram of Formula 1C or 2C herein applicable below, if X is a substituted phenyl, it may have 1, 2, 3, 4 or 5 substituents. If X is a substituted pyridyl, it may have 1, 2, 3 or 4 substituents. In some embodiments, some or all of the substituents of X may have: 0 to 10 carbon atoms and 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br or I (provided that there is at least 1 non-hydrogen atom); and / or a molecular weight of 15 g / mol to 500 g / mol. In some embodiments, some or all of the substituents may each have a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da or 15 Da to 50 Da, and consist of 2 to 5 chemical elements, wherein these chemical elements are independently C, H, O, N, S, F, Cl or Br.

[0057] For any relevant embodiment or structure diagram of Formula 1C or 2C herein as applicable below, the substituent of X may be C 1-10 Optionally substituted alkyl, such as CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H 11 , cyclic C5H9, C6H 13 , cyclic C6H 11 etc., which may be optionally substituted; C 1-10 Optionally substituted alkoxy, for example OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 、Cyclic OC5H9、OC6H 13 、Cyclic OC6H 11 etc.; halogenated, such as F, Cl, Br, I; OH; CN; NO2; C 1-6 Fluoroalkyl, such as CF3, CF2H, C2F5, etc.; C 1-6 Fluoroalkoxy, such as OCF3, OCF2H, OC2F5, etc.; C 1-10 Esters, such as -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl, etc.; C 1-10 Ketone, such as -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc.; or C 1-10Amines, such as NH2, NH(CH3), N(CH3)2, N(CH3)C2H5, etc. In some embodiments, the substituents of X can be F, Cl, Br, I, CN, NO2, C 1-4 Alkyl, C 1-4 Alkyl-OH, C 1-3 O-alkyl, CF3, COH, C 1-4 CO-alkyl, CO2H, C 1-4 CO2-alkyl, NH2, SCF3 or C 1-4 Alkylamino.

[0058] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein as applicable below, Y is H, F, Cl, Br, I, or a moiety having a molecular weight of 15 Da to 300 Da and consisting of 2 to 5 chemical elements, wherein these chemical elements are independently C, H, O, N, S, F, Cl, or Br. In some embodiments, Y is H, F, Cl, Br, I, CN, -COH, C 1-6 -CO-alkyl, CF3, OH, C 1-5 O-alkyl, C 0-6 Amino or C 0-6 In some embodiments, Y is H, F, CF3, OH, C 1-5 O-alkyl, C 0-6 Amino or C 0-6 In some embodiments, Y is H. In some embodiments, Y is OH. In some embodiments, Y is F. In some embodiments, Y is CF3. In some embodiments, Y is C 1-3 O-alkyl, such as -OCH3, OC2H5, OC3H7, etc. In some embodiments, Y is C 0-6 In some embodiments, Y is an optionally substituted tetrahydropyranyl group, for example In some embodiments, Y may include C 1-8 Alkyl groups may include one or two C 3-6 In some embodiments, wherein Y comprises at least one carbocyclic ring, these rings may be connected to each other. In some embodiments, Y is -C(CF3)2OH (or 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl). In some embodiments, Y is (or methyl(2,2,2-trifluoroethyl)amino). In some embodiments, Y is dimethylamino.

[0059] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein as applicable below, in some embodiments, C 2-8 Alkyl groups, e.g.

[0060] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein as applicable below, in some embodiments, C 2-8 Hydroxyalkyl groups, e.g.

[0061] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein as applicable below, in some embodiments, C 2-8 Fluoroalkyl groups, e.g.

[0062] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein as applicable below, in some embodiments, C 2-8 Alkoxyalkyl, for example

[0063] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein as applicable below, in some embodiments, C 2-8 Hydroxyfluoroalkyl groups, e.g.

[0064] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein as applicable below, in some embodiments, is an optionally substituted 2-hydroxy-2-phenylethyl group, for example In some embodiments, for

[0065] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein as applicable below, in some embodiments, is an optionally substituted 2-hydroxy-2-phenylpyridinyl group, for example

[0066] For any relevant embodiments or structural diagrams of Formula 1C or 2C herein as applicable below, in some embodiments, is an optionally substituted C 2-8 Fluoroaminoalkyl groups, e.g.

[0067] For any relevant embodiment or structural diagram of Formula 1C or 2C herein as follows, it is applicable. Generally, R 1-18It may be H or any substituent, for example, a substituent having 0 to 12 atoms or 0 to 6 carbon atoms and 0 to 5 heteroatoms (wherein each heteroatom is independently O, N, S, F, Cl, Br, or I) and / or a molecular weight of 15 g / mol to 300 g / mol. 1-18 Any of may include: a) 1 or more alkyl moieties, which are optionally substituted by or optionally connected by or to: b) 1 or more functional groups, such as C=C, C≡C, CO, CO2, CON, NCO2, OH, SH, O, S, N, N=C, F, Cl, Br, I, CN, NO2, CO2H, NH2, etc.; or may be a substituent without an alkyl moiety, such as F, Cl, Br, I, NO2, CN, NH2, OH, COH, CO2H, etc. In some embodiments, each R 1-18 It is independently H, F, Cl, Br, I or a substituent having a molecular weight of 15 Da to 300 Da, 15 Da to 200 Da, 15 Da to 100 Da or 15 Da to 60 Da and consisting of 2 to 5 chemical elements, wherein these chemical elements are independently C, H, O, N, S, F, Cl or Br.

[0068] For any relevant structural diagram of Formula 1C or 2C, R 1-18 Some non-limiting examples may include R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 Can be H; F; Cl; Br; CN; C 1-3 Fluoroalkyl, such as CHF2, CF3, etc.; OH; NH2; C 1-6 alkyl, such as methyl, ethyl, propyl isomers (such as n-propyl and isopropyl), cyclopropyl, butyl isomers, cyclobutyl isomers (such as cyclobutyl and methylcyclopropyl), pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; optionally substituted C 1-7Alkoxy groups, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, -O-benzyl, etc.; C 1-4 Hydroxyalkyl, such as -CH2OH, -C2H4-OH, -C3H6-OH, C4H8-OH, etc.; C 2-5 -CO2-alkyl, for example, -CO2-CH3, -CO2-C2H5, -CO2-C3H7, -CO2-C4H9, etc.

[0069] For any relevant structural diagram of Formula 1C or 2C, each R A Can be independently H or C 1-12 Alkyl groups, including: a H 2a+1 A straight chain or branched alkyl group, or a a H 2a-1 wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, for example, a straight or branched chain alkyl having the formula: CH3, C2H5, C3H7, C4H9, C5H 11 、C6H 13 、C7H 15 、C8H 17 、C9H 19 , C 10 H 21 etc., or a cycloalkyl group having the formula: C3H5, C4H7, C5H9, C6H 11 、C7H 13 、C8H 15 、C9H 17 , C 10 H 19 In some embodiments, R A It can be H or optionally substituted C 1-6 In some embodiments, R A It can be H or optionally substituted C 1-3 In some embodiments, R A It can be H or CH3. In some embodiments, R A It can be H.

[0070] For any relevant structural diagram of Formula 1C or 2C, each R B Can be independently H or C 1-12 Alkyl groups, including: a H 2a+1A straight chain or branched alkyl group, or a a H 2a-1 wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, for example, a straight or branched chain alkyl having the formula: CH3, C2H5, C3H7, C4H9, C5H 11 、C6H 13 、C7H 15 、C8H 17 、C9H 19 , C 10 H 21 etc., or a cycloalkyl group having the formula: C3H5, C4H7, C5H9, C6H 11 、C7H 13 、C8H 15 、C9H 17 , C 10 H 19 In some embodiments, R B Can be H or C 1-3 In some embodiments, R B It can be H or CH3. In some embodiments, R B It can be H.

[0071] For any relevant structural diagram of Formula 1C or 2C (e.g., Formula 2C), in some embodiments, R 1 For H, F, Cl, Br, CN, OCH3, OH, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-5 In some embodiments, R 1 For H, Cl, Br, CN, OCH3, OCHF2, CHF2, CF3, -CO2CH2CH3, -CH2OH, or In some embodiments, R 1 is H. In some embodiments, R 1 is F. In some embodiments, R 1 In some embodiments, R 1 is Br. In some embodiments, R 1 In some embodiments, R 1 is OCH3. In some embodiments, R 1 is CHF2. In some embodiments, R 1 is CF3. In some embodiments, R 1 is -CO2CH2CH3. In some embodiments, R 1 is -CH2OH. In some embodiments, R1 for In some embodiments, R 1 for In some embodiments, R 1 for In some embodiments, R 1 for In some embodiments, R 1 -OCH3, -OH, -OCHF2, -O-benzyl, -CN, -CF3, -CH2OH, -COOCH2CH3, -C(CH3)2OH, -CHOHCH2CH3, -CHOHCH3, -CHF2, -CH(CH3)2, -C(CH2CH3)2OH, -CH2COOCH2CH3, -CH2C(CH3)2OH, -CH2COOH or -CH2CON(CH3)2. For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-5 Hydroxyalkyl.

[0072] For any relevant structural diagram of Formula 1C or 2C, in some embodiments, R 2 For H, F, Cl, Br, CN, OCH3, OCF3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-5 In some embodiments, R 2 is H. In some embodiments, R 2 is F. In some embodiments, R 2 is CH2OH. In some embodiments, R2 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 In some embodiments, R 2 It is -CH2OH, -CO2Me or -C(CH3)2OH.

[0073] For any relevant structural diagram of Formula 1C or 2C, in some embodiments, R 3 For H, F, Cl, Br, CN, OCH3, OCHF2, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-5 In some embodiments, R 3 is H. In some embodiments, R 3 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0074] For any relevant structural diagram of Formula 1C or 2C, in some embodiments, R 4 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-5 In some embodiments, R 4 is H. In some embodiments, R 4 is F. In some embodiments, R 4 is CH3. In some embodiments, R 4 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0075] For any relevant structural diagram of Formula 1C or 2C, in some embodiments, R 5 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-5 In some embodiments, R 5 is H. In some embodiments, R 5For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0076] For any relevant structural diagram of Formula 1C or 2C, in some embodiments, R 6 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-5 In some embodiments, R 6 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C1-4 Hydroxyalkyl.

[0077] For any relevant structural diagram of Formula 1C or 2C, in some embodiments, R 7 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-5 In some embodiments, R 7 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0078] For any relevant structural diagram of Formula 1C or 2C, in some embodiments, R 8 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-5 In some embodiments, R 8 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NRA COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0079] For any relevant structural diagram of Formula 1C or 2C, in some embodiments, R 9 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-5 In some embodiments, R 9 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0080] For any relevant structural diagram of Formula 1C or 2C, in some embodiments, R 10 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-5 In some embodiments, R 10 For the embodiments listed in this paragraph, in some embodiments, R1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0081] For any relevant structural diagram of Formula 1C or 2C, in some embodiments, R 11 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-5 In some embodiments, R 11 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0082] For any relevant structural diagram of Formula 1C or 2C, in some embodiments, R 12 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-5 In some embodiments, R 12 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0083] For any relevant structural diagram of Formula 1C or 2C, in some embodiments, R 13 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-5 In some embodiments, R 13 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONRA R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0084] For any relevant structural diagram of Formula 1C or 2C, in some embodiments, R 14 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-5 In some embodiments, R 14 is H. In some embodiments, R 14 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0085] In some embodiments of the invention, one or more hydrogen atoms are replaced with deuterium. It is well established that deuteration of physiologically active compounds provides the advantage of retaining the pharmacological characteristics of their hydrogen counterparts while positively affecting their metabolic consequences. Selective replacement of one or more hydrogens with deuterium in the compounds of the invention can improve the safety, tolerability and efficacy of the compound relative to its all hydrogen counterparts.

[0086] Methods for incorporating deuterium into compounds are well established. Using metabolic studies established in the art, the compounds of the invention can be tested to identify selective placement sites for deuterium isotopes where the isotopes are not metabolized. In addition, these studies identify metabolic sites as locations where deuterium atoms are placed.

[0087] In certain embodiments, the embodiments expressed herein do not encompass any compounds explicitly disclosed in U.S. Patent No. 9,481,653, WO 2016 / 040952, U.S. Provisional No. 62 / 579,770, U.S. Provisional No. 62 / 663,427, or U.S. Provisional No. 62 / 644,932.

[0088] In certain embodiments, the compound of Formula 1C has a Kv of 7.2 / 7.3 thallium flux EC 50 ≤10 μM. In certain embodiments, the compound of Formula 1C has a Kv7.2 / 7.3 thallium flux EC 50 ≤1 μM. In certain embodiments, the compound of Formula 1C has a Kv7.2 / 7.3 thallium flux EC 50 ≤0.3μM.

[0089] Some embodiments of Formula 1C may include a compound represented by Formula 8a: in D is optionally substituted cyclobutyl or tert-butyl; A is a C1 alkyl group; X is a substituted cyclobutyl group, wherein the substituent is F; Y is H; R 1 is C3 hydroxyalkyl or CN; R 2 and R 4 is H; R 3 is H or F; and When X is substituted by two fluorine atoms, these fluorine atoms are not geminal; or a pharmaceutically acceptable salt thereof.

[0090] Some embodiments of Formula 1C may include a compound represented by Formula 8b: in D is optionally substituted cyclobutyl or tert-butyl, wherein the optional substituents are selected from -CH3 and F; A is a C1 alkyl group; X is a substituted cyclobutyl group, wherein the substituent is F; Y is H; R1 Selected from C3 hydroxyalkyl, CN or F; R 2 Selected from H, F or -OCF3; R 3 Selected from H, F or -OCH3; R 4 is H or F; and When X is substituted by two fluorine atoms, these fluorine atoms are not geminal; or a pharmaceutically acceptable salt thereof.

[0091] Some embodiments of Formula 1C may include a compound represented by Formula 8c: in D is optionally substituted cyclobutyl, optionally substituted phenyl, or tert-butyl, wherein the optional substituents are selected from -CH3 and F; A is a C1 alkyl group; X is a substituted cyclobutyl group, wherein the substituent is F; Y is H; R 1 Selected from H, C3 hydroxyalkyl, CN, F or Cl; R 2 Selected from H, CN, F, Br or -OCF3; R 3 Selected from H, F or -OCH3; R 4 is H or F; and When X is substituted by two fluorine atoms, these fluorine atoms are not geminal; or a pharmaceutically acceptable salt thereof.

[0092] Some embodiments of Formula 1C may include a compound represented by Formula 9: in D is cyclobutyl; A is a C1 alkyl group; X is an optionally substituted cyclobutyl group, wherein the optional substituent is F; Y is H; R 1 is C3 hydroxyalkyl; R 2 and R 4 is H; R 3 is F; and When X is substituted by two fluorine atoms, these fluorine atoms are not geminal; or a pharmaceutically acceptable salt thereof.

[0093] Some embodiments of Formula 1C may include a compound represented by Formula 10: in D is optionally substituted C 2-5 Alkyl, wherein the optional substituents are selected from -CH3 and F; A is C 1-6 alkyl; X is H, F, -CH3, -CF3, -SCF3, pyridyl, optionally substituted C 1-3 alkyl, optionally substituted phenyl or optionally substituted cyclobutyl, wherein the optional substituent is F; Y is H, F, -OH or -CH3; R 1 H, C 3-4 Hydroxyalkyl, -CN, -OH, -CF3, -OCHF2, optionally substituted C 3-5 Heterocyclic group, optionally substituted C 1-5 Alkyl, optionally substituted C 1-7 Alkoxy, -NR A R B or halogen, wherein the optional substituents are selected from -OH and F; R 2 H, halogen, -CN, -OCH3, -COR A , -CF3, -OCF3, optionally substituted C1 alkyl, wherein R 2 The optional substituents are selected from -OCH3 and -COR A ; R 3 is H, halogen, -CF3, -OCHF2, -OCF3 or -OCH3; R 4 is H, halogen or C3 hydroxyalkyl; and R A and R B is CH3; or a pharmaceutically acceptable salt thereof.

[0094] Some embodiments of Formula 1C may include a compound represented by Formula 11: in D is optionally substituted C 2-5 Alkyl or optionally substituted phenyl, wherein the optional substituents are selected from -CH3 and F; A is C 1-6 alkyl; X is H, F, -CH3, -CF3, -SCF3, pyridyl, optionally substituted C1-3 alkyl, optionally substituted phenyl or optionally substituted cyclobutyl, wherein the optional substituent is F; Y is H, F, -OH or -CH3; R 1 H, C 3-4 Hydroxyalkyl, -CN, -OH, -CF3, -OCHF2, optionally substituted C 3-5 Heterocyclic group, optionally substituted C 1-5 Alkyl, optionally substituted C 1-7 Alkoxy, -NR A R B or halogen, wherein the optional substituents are selected from -OH and F; R 2 H, halogen, -CN, -OCH3, -COR A , -CF3, -OCF3, optionally substituted C 1-2 Alkyl, where R 2 The optional substituents are selected from -OCH3 and -COR A ; R 3 is H, halogen, -CF3, -OCHF2, -OCF3 or -OCH3; R 4 is H, halogen or C3 hydroxyalkyl; and R A and R B is CH3; or a pharmaceutically acceptable salt thereof.

[0095] Some embodiments of Formula 1C may include a compound represented by Formula 12: in D is an optionally substituted cyclobutyl group, wherein the optional substituent is -CH3; A is a C3 alkyl group; X is -CH3; Y is -CH3; R 1 is CN; R 2 and R 3 is F; and R 4 The sum is H; or a pharmaceutically acceptable salt thereof.

[0096] Some embodiments of Formula 1C may include a compound represented by Formula 13: in D is tert-butyl; A is a C1 alkyl group; X is an optionally substituted cyclobutyl group, wherein the optional substituent is F; Y is H; R 1 and R 4 is F; R 2 and R 3 is H; and When X is substituted by two fluorine atoms, these fluorine atoms are not geminal; or a pharmaceutically acceptable salt thereof.

[0097] Some embodiments of Formula 1C may include a compound represented by Formula 14: in D is optionally substituted C 2-5 Alkyl, wherein the optional substituents are selected from -CH3; A is C 1-6 alkyl; X is H, F, -CH3, -CF3, optionally substituted C 1-3 alkyl, optionally substituted phenyl or optionally substituted cyclobutyl, wherein the optional substituent is F; Y is H, F, -OH or -CH3; R 1 H, C 3-4 Hydroxyalkyl, -CN, -CF3, -OCH2CF3, -OCHF2, optionally substituted C 3-5 Heterocyclic group, optionally substituted C 1-5 Alkyl, optionally substituted C 1-7 Alkoxy, -NR A R B , F or Cl, wherein the optional substituents are selected from -OH and F; R 2 is F, Br, -CN, -OCH3, -OCF3 or -CF3; R 3 is H, halogen, -CF3, -OCHF2, -OCF3 or -OCH3; R 4 is H, fluorine or chlorine; and R A and R B is CH3; or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments of Formula 11, when X is substituted with 2 fluorine atoms, these fluorine atoms are not geminal;

[0099] Some embodiments of Formula 11 are further illustrated by compounds of Group I, Group II, and Group III, or pharmaceutically acceptable salts thereof.

[0100] In some embodiments, provided herein is any one of the following compounds of Group I or a pharmaceutically acceptable salt thereof:

[0101] In some embodiments, provided herein is any one of the following compounds of Group II or a pharmaceutically acceptable salt thereof:

[0102] In some embodiments, provided herein is any one of the following Group III compounds or a pharmaceutically acceptable salt thereof: How to use

[0103] Embodiments of the present invention relate to methods for treating Kv7-related disorders, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13 or 14, a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof. The disorder is selected from the group consisting of epilepsy, neonatal spasms, pain, migraine, neurotransmitter release disorders, smooth muscle contraction disorders, movement disorders, dystonia, mania, hearing disorders, neuropathic pain, inflammatory pain, persistent pain, cancer pain, postoperative pain, anxiety, substance abuse, schizophrenia, bladder disorders, vasculature disorders, tinnitus, benign familial neonatal epileptic seizures, epilepsy, neurological diseases caused by reduced basal M current (and subsequent neuronal hyperexcitability), sensorineural hearing loss, intellectual disability, epileptic encephalopathy, intractable epilepsy, cortical atrophy, neurological impairment, infantile spasms with hyperrhythmia, myoclonic tonic seizures, myoclonic seizures, tonic seizures, absence seizures and focal seizures with impaired consciousness, congenital neurological disorders with intellectual disability Or epileptic encephalopathy, benign familial neonatal seizures, severe epileptic encephalopathy, congenital neurodevelopmental disorders with non-syndromic intellectual disability or epileptic encephalopathy phenotype, neonatal spasms, neonatal epileptic seizures, epileptic encephalopathy, benign familial neonatal seizures type 1, benign familial neonatal seizures 1, neonatal seizures associated with hypoxic-ischemic injury, epileptic spasms, epileptic encephalopathy, early infantile epileptic encephalopathy 7, early infantile epileptic encephalopathy with delayed psychomotor development, generalized tonic seizures, globus pallidus morphology, apnea, cerebral edema, dystonia, facial erythema, hypotonia, febrile seizures, corpus callosum agenesis, hyperrhythmia, focal clonic seizures, generalized tonic-clonic seizures, myokymia, spastic quadriplegia, myokymia, gynecological system disorders, and combinations thereof. In embodiments, such compounds can be administered in pharmaceutical compositions as described herein.

[0104] In some embodiments, the gynecological system disorder is selected from the group consisting of premature delivery, postpartum hemorrhage, uterine atony, uterine perforation, uterine hyperstimulation, menorrhagia, uterine bleeding, menorrhagia, dysmenorrhea, and endometriosis.

[0105] The KCNQ gene encodes five Kv7 potassium channel subunits (1-5). Functional Kv7 potassium channels can be assembled using combinations of these five subunits arranged as homotetramers or heterotetramers. KCNQ2, KCNQ3, KCNQ4, and KCNQ5 are expressed in the nervous system and are associated with a range of disorders involving neuronal excitability.

[0106] Embodiments herein relate to methods of treating disorders associated with KCNQ subunits, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof. Embodiments herein relate to methods of treating disorders associated with KCNQ2 subunits, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof. Embodiments herein relate to methods of treating a disorder associated with a KCNQ3 subunit, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof. Embodiments herein relate to methods of treating a disorder associated with a KCNQ4 subunit, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof. Embodiments herein relate to methods of treating disorders associated with KCNQ5 subunits, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound having Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13 or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof.

[0107] Embodiments herein relate to methods of treating disorders associated with mutations in KCNQ subunits, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound having Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof. Embodiments herein relate to methods of treating disorders associated with mutations in KCNQ2 subunits, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound having Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof. Embodiments herein relate to methods of treating disorders associated with mutations in KCNQ3 subunits, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound having Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof. Embodiments herein relate to methods of treating disorders associated with mutations in KCNQ4 subunits, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound having Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof. Embodiments herein relate to methods of treating disorders associated with mutations in KCNQ5 subunits, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound having Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13 or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof.

[0108] The compounds described herein have been shown to activate Kv7 potassium channels. Mutations in the gene KCNQ3 encoding the Kv7 potassium channel lead to a variety of disorders. The embodiments herein relate to methods for treating disorders associated with KCNQ3 mutations, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13 or 14, a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof. Disorders associated with KCNQ3 mutations are selected from the group consisting of benign familial neonatal epileptic seizures, epilepsy, neurological diseases caused by reduced basal M currents (and subsequent neuronal hyperexcitation), and any combination thereof.

[0109] The compounds described herein have been shown to activate Kv7 potassium channels. Mutations in the gene KCNQ4 encoding the Kv7 potassium channel lead to a variety of disorders. The embodiments herein relate to methods for treating disorders associated with KCNQ4 mutations, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13 or 14, a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof. The disorder associated with KCNQ4 mutations is sensorineural hearing loss.

[0110] The compounds described herein have been shown to activate Kv7 potassium channels. Mutations in the gene KCNQ5 encoding the Kv7 potassium channel lead to a variety of disorders. The embodiments herein relate to methods for treating disorders associated with KCNQ5 mutations, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13 or 14, a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof. The disorder associated with KCNQ5 mutation is selected from the group consisting of intellectual disability, epileptic encephalopathy, refractory epilepsy, cortical atrophy, neurological impairment, infantile spasms with hyperrhythmic dysrhythmia, myoclonic tonic seizures, myoclonic seizures, tonic seizures, absence seizures and focal seizures with impaired consciousness, congenital neurological disorders with intellectual disability or epileptic encephalopathy, benign familial neonatal seizures, severe epileptic encephalopathy, congenital neurodevelopmental disorders with non-syndromic intellectual disability or epileptic encephalopathy phenotype, and any combination thereof.

[0111] The compounds described herein have been shown to activate Kv7 potassium channels. Mutations in the gene KCNQ2 encoding the Kv7 potassium channel lead to a variety of disorders. The embodiments herein relate to methods for treating disorders associated with KCNQ2 mutations, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13 or 14, a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof. The disorder associated with KCNQ2 mutation is selected from the group consisting of: neonatal spasms, neonatal seizures, epilepsy, benign familial neonatal epilepsy (KCNQ2-BFNE), epileptic encephalopathy (KCNQ2-NEE), benign familial neonatal convulsions type 1 (BFNC), benign familial neonatal seizures 1 (BFNS1), neonatal seizures associated with hypoxic-ischemic injury, epileptic spasms, epileptic encephalopathy, early infantile epileptic encephalopathy 7 (EIEE7), early infantile epileptic encephalopathy with psychomotor retardation, generalized tonic seizures, globus pallidus morphology, apnea, cerebral edema, dystonia, facial erythema, hypotonia, febrile seizures, corpus callosum agenesis, hyperrhythmia, focal clonic seizures, generalized tonic-clonic seizures, myokymia, spastic quadriplegia, myokymia, and combinations thereof. In embodiments, such compounds can be administered in pharmaceutical compositions as described herein.

[0112] Embodiments relate to methods of treating a condition associated with cellular hyperexcitability in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, or a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13 or 14, or a pharmaceutically acceptable salt thereof, wherein the hyperexcitability is treated.

[0113] Embodiments relate to methods of treating a Kv7-related disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, or a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13 or 14, or a pharmaceutically acceptable salt thereof, wherein the symptoms of the disorder are alleviated or improved due to activation of Kv7 potassium channels.

[0114] Embodiments relate to methods of treating a neurodegenerative disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, or a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is treated. A compound of Group I, Group II, Group III, or Table 1, or a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14 can be administered to any individual who exhibits symptoms of a neurodegenerative disease or an individual who is susceptible to a neurodegenerative disease. Non-limiting examples of neurodegenerative diseases that can be treated using a compound of Group I, Group II, Group III, or Table 1, or a compound having Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14 include amyotrophic lateral sclerosis (ALS), Huntington's disease, metabolically induced neural damage, Alzheimer's disease, Pick's disease, senile dementia, age-related cognitive dysfunction, vascular dementia, multi-infarct dementia, Lewy body dementia, neurodegenerative dementia, frontotemporal dementia (FTD), familial FTD, neurodegenerative movement disorders, ataxia, Friedreich's ataxia, multiple sclerosis, spinal muscular atrophy, primary lateral sclerosis, seizure disorders, motor neuron disorders or diseases, inflammatory demyelinating disorders, Parkinson's disease, hepatic encephalopathy, chronic encephalopathy, chronic encephalitis, or any combination thereof.

[0115] Embodiments relate to methods of treating a neurodegenerative disease (e.g., amyotrophic lateral sclerosis) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, or a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is treated. In embodiments, the subject is a subject with established ALS, a subject with an onset of amyotrophic lateral sclerosis symptoms for less than about 18 months, a subject with a plasma creatinine level of about 72 μM / L or greater, a subject concurrently administered with riluzole, a subject concurrently administered with dexpramipexole, and combinations thereof.

[0116] Embodiments relate to methods of treating amyotrophic lateral sclerosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, or a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13 or 14, or a pharmaceutically acceptable salt thereof, wherein amyotrophic lateral sclerosis is treated.

[0117] Embodiments relate to methods of treating amyotrophic lateral sclerosis in a subject diagnosed with definite amyotrophic lateral sclerosis, the method comprising administering to the subject a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, or a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, wherein amyotrophic lateral sclerosis is treated. In embodiments, definite amyotrophic lateral sclerosis is defined by the El Escorial diagnostic criteria. In embodiments, the subject is a subject with definite ALS, a subject with an onset of amyotrophic lateral sclerosis symptoms for less than about 18 months, a subject with a plasma creatinine level of about 72 μM / L or greater, a subject concurrently administered with riluzole, a subject concurrently administered with dexpramipexole, and combinations thereof.

[0118] Embodiments relate to methods of treating amyotrophic lateral sclerosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, or a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, wherein the subject is selected from: a subject with established amyotrophic lateral sclerosis, a subject with limb-onset amyotrophic lateral sclerosis, a subject with bulbar-onset amyotrophic lateral sclerosis, a subject with an onset of amyotrophic lateral sclerosis symptoms lasting less than about 18 months, a subject with high serum creatinine levels, a subject with low bicarbonate levels, a subject concurrently administered with riluzole, a subject concurrently administered with dexpramipexole, and combinations thereof, and wherein amyotrophic lateral sclerosis is treated. In certain embodiments, the method further comprises monitoring the subject for any clinical features associated with amyotrophic lateral sclerosis. In certain embodiments, the method further comprises initiating therapy with a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, or a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, upon diagnosis of ALS. In certain embodiments, the subject exhibits symptoms of ALS. In certain embodiments, the subject has definite ALS, probable ALS, possible ALS, or suspected ALS.

[0119] Embodiments relate to methods of treating amyotrophic lateral sclerosis in a subject diagnosed with established amyotrophic lateral sclerosis, the method comprising administering to the subject a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, or a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, wherein amyotrophic lateral sclerosis is treated. In some embodiments, established amyotrophic lateral sclerosis is the presence of El Escorial diagnostic criteria, duration of ALS symptom onset less than about 18 months, limb-onset ALS, plasma creatinine level of about 72 μM / L or higher, concurrent administration of riluzole, concurrent administration of dexpramipexole, ALSFRS-R score greater than 36.0, pre-study progression rate greater than or equal to 0.8 points per month, predicted relaxed (slow) vital capacity (SVC) percentage less than or equal to 102.0, ALSFRS-R fine motor domain score greater than 10.0 points, ALSFRS-R bulbar domain score greater than 9.0 points, ALS FRS-R gross motor domain score greater than 8.0 points, abnormal lingual nerve examination, abnormal pharyngeal, laryngeal and swallowing nerve examination, abnormal lower extremity nerve examination, abnormal upper extremity nerve examination, abnormal triceps nerve examination, abnormal muscle mass and volume nerve examination, abnormal biceps nerve examination, abnormal nerve examination, pulse rate greater than 81.0 beats per minute, diastolic blood pressure greater than 82.0 mmHg, systolic blood pressure less than or equal to 117.0 mmHg, creatinine value greater than 72.0 μmol / L, phosphorus value less than or equal to 1.090 μmol / L, platelet count less than or equal to 248.0 x 10 9 cells / L, cholesterol value less than or equal to 5.3 mmol / L, lactate dehydrogenase value less than or equal to 161.0 U / L, creatine phosphokinase value less than or equal to 184.0 U / L, bicarbonate value less than or equal to 21.6 mmol / L, triglyceride level less than or equal to 1.4 mmol / L, uric acid level greater than 320.0 μmol / L, gamma-glutamyl transferase (GGT) level greater than 37.0 U / L, total bilirubin level less than or equal to 6.0 μmol / L, urine pH less than or equal to 5.5, or any combination thereof.

[0120] Embodiments relate to methods of treating amyotrophic lateral sclerosis in a subject exhibiting amyotrophic lateral sclerosis symptoms, the method comprising administering to the subject a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, or a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, wherein the amyotrophic lateral sclerosis symptoms are treated. In some embodiments, the subject exhibits clinical features selected from the group consisting of: definite amyotrophic lateral sclerosis, duration of onset of amyotrophic lateral sclerosis symptoms less than about 18 months, limb-onset amyotrophic lateral sclerosis, plasma creatinine level of about 72 μM / L or greater, concurrent administration of riluzole, concurrent administration of dexpramipexole, ALSFRS-R score greater than 36.0, restudy progression rate greater than or equal to 0.8 points per month, predicted relaxed (slow) vital capacity (SVC) percentage less than or equal to 102.0, ALSFRS-R fine motor domain score greater than 10.0 points, ALSFRS-R bulbar domain score less than or equal to 10.0 points, score greater than 9.0 points, ALSFRS-R gross motor domain score greater than 8.0 points, abnormal lingual nerve examination, abnormal pharyngeal, laryngeal and swallowing nerve examination, abnormal lower extremity nerve examination, abnormal upper extremity nerve examination, abnormal triceps nerve examination, abnormal muscle mass and volume nerve examination, abnormal biceps nerve examination, abnormal nerve examination, pulse rate greater than 81.0 beats per minute, diastolic blood pressure greater than 82.0 mmHg, systolic blood pressure less than or equal to 117.0 mmHg, creatinine value greater than 72.0 μmol / L, phosphorus value less than or equal to 1.090 μmol / L, platelet count less than or equal to 248.0 x 10 9 cells / L, cholesterol value less than or equal to 5.3 mmol / L, lactate dehydrogenase value less than or equal to 161.0 U / L, creatine phosphokinase value less than or equal to 184.0 U / L, bicarbonate value less than or equal to 21.6 mmol / L, triglyceride level less than or equal to 1.4 mmol / L, uric acid level greater than 320.0 μmol / L, gamma-glutamyl transferase (GGT) level greater than 37.0 U / L, total bilirubin level less than or equal to 6.0 μmol / L, urine pH less than or equal to 5.5, or any combination thereof.

[0121] In some embodiments, administering a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, or a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, can include administering about 0.1 mg to about 1,500 mg, about 1 mg to about 1,500 mg, about 10 mg to about 1,500 mg, about 50 mg to about 1,500 mg, about 75 mg to about 1,500 mg, about 100 mg to about 1,500 mg, about 125 mg to about 1,500 mg, about 150 mg to about 1,500 mg, about 175 mg to about 1 ,500 mg, about 200 mg to about 1,500 mg, about 225 mg to about 1,500 mg, about 250 mg to about 1,500 mg, about 275 mg to about 1,500 mg, about 300 mg to about 1,500 mg, about 400 mg to about 1,500 mg, about 450 mg to about 1,500 mg, about 500 mg to about 1,500 mg, about 600 mg to about 1,500 mg, about 700 mg to about 1,500 mg, about 800 mg to about 1,500 mg, about 1,000 mg to about 1,500 mg and about 1,200 mg to about 1,500 mg daily dosage.

[0122] In some embodiments, the therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, or a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of about 0.1 mg to about 1,000 mg, about 50 mg to about 1,000 mg / day, about 100 mg to about 1,000 mg / day, about 150 mg to about 1,000 mg / day, about 300 mg to about 1,000 mg / day, about 50 mg to about 300 mg / day, and about 150 mg to about 300 mg / day.

[0123] Such therapeutically effective amounts can be administered once a day, or twice a day, three times a day, or four times a day in equal divided doses. In some embodiments, administering a therapeutically effective amount comprises administering a dose equal to about half of the daily dose twice a day. In some embodiments, a dose is administered every about 12 hours. In some embodiments, administering a therapeutically effective amount comprises administering about 25 mg twice a day, administering about 75 mg twice a day, administering about 150 mg twice a day, or administering about 300 mg twice a day. Pharmaceutical composition

[0124] The embodiments herein relate to pharmaceutical compositions comprising a therapeutically effective amount of a compound described herein or an acceptable salt thereof, such as a compound of Group I, Group II, Group III, Table 1, or a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13 or 14, or a pharmaceutically acceptable salt thereof. Pharmaceutical formulations containing such compounds and suitable carriers may be in various forms, including but not limited to solids, solutions, powders, fluid emulsions, fluid suspensions, semisolids and dry powders containing an effective amount of a compound of the invention. It is also known in the art that active ingredients may be included in such formulations together with pharmaceutically acceptable diluents, fillers, disintegrants, adhesives, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, wetting agents, humectants, solubilizers, antioxidants, preservatives, etc. The devices and methods for administration are known in the art and the skilled person may refer to various pharmacological references for guidance. See, for example, Modern Pharmaceutics, Banker and Rhodes, Marcel Dekker, Inc. (1979); and Goodman and Gilman, The Pharmaceutical Basis of Therapeutics, 6th ed., MacMillan Publishing Co., New York (1980), all of which are hereby incorporated by reference.

[0125] In some embodiments, a single unit dose of a compound of Group I, Group II, Group III, or Table 1, or a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of about 0.1 mg to about 1,500 mg, about 1 mg to about 1,500 mg, about 10 mg to about 1,500 mg, about 50 mg to about 1,500 mg, about 75 mg to about 1,500 mg, about 100 mg to about 1,500 mg, about 125 mg to about 1,500 mg, about 150 mg to about 1,500 mg, about 175 mg to about 1,500 mg. To about 1,500 mg, about 200 mg to about 1,500 mg, about 225 mg to about 1,500 mg, about 250 mg to about 1,500 mg, about 275 mg to about 1,500 mg, about 300 mg to about 1,500 mg, about 400 mg to about 1,500 mg, about 450 mg to about 1,500 mg, about 500 mg to about 1,500 mg, about 600 mg to about 1,500 mg, about 700 mg to about 1,500 mg, about 800 mg to about 1,500 mg, about 1,000 mg to about 1,500 mg and about 1,200 mg to about 1,500 mg.

[0126] In some embodiments, a single unit dose of a compound of Group I, Group II, Group III, or Table 1, or a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of about 25 mg to about 5,000 mg, about 50 mg to about 5,000 mg, about 100 mg to about 5,000 mg, about 150 mg to about 5,000 mg, about 200 mg to about 5,000 mg, about 250 mg to about 5,000 mg, about 300 mg to about 5,000 mg, about 400 mg to about 5,000 mg, about 450 mg to about 5,000 mg, about 100 mg to about 3,000 mg, or about 150 mg to about 5,000 mg. In some embodiments, the amount of a single unit dose can be 10 mg / day to 1,500 mg / day, or about 100 mg / day to 600 mg / day. In some embodiments, such single unit doses may be administered once a day or multiple times a day (eg, twice a day or three times a day).

[0127] In some embodiments, the single unit dosage further comprises a pharmaceutically acceptable carrier.

[0128] The compound can be formulated for parenteral or intravenous administration by injection (e.g., by bolus injection or continuous infusion). Injectable formulations can be present in unit dosage form, for example in ampoules or multidose containers, with the addition of preservatives. The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain preparatants, such as suspending agents, stabilizers, and / or dispersants.

[0129] Injectable preparations can be prepared according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution.

[0130] Other embodiments include compounds prepared as described above, which are formulated as solid dosage forms for oral administration, including capsules, tablets, pills, powders and granules. In such embodiments, the active compound can be mixed with one or more inert diluents (such as sucrose, lactose or starch). In normal practice, such dosage forms may also include other materials except the inert diluent, such as lubricants, such as magnesium stearate. In the case of capsules, tablets and pills, the dosage form may also include a buffer and may be prepared with an enteric coating in addition.

[0131] The preparation of the compounds of the present invention in solid dosage form can vary. For example, in one embodiment, a liquid or gelatin formulation can be prepared by mixing a compound (such as those described above) and adding a thickener to the liquid mixture to form gelatin. The gelatin can then be encapsulated in a unit dosage form to form a capsule. In another exemplary embodiment, the oily preparation of the compound prepared as described above can be lyophilized into a solid, which can be mixed with one or more pharmaceutically acceptable excipients, carriers or diluents to form a tablet.

[0132] Other embodiments that can be used for oral administration of the compounds of the invention include liquid dosage forms. In such embodiments, liquid dosages may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents (e.g., water) commonly used in the art. Such compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, as well as sweeteners, flavoring agents and aromatics.

[0133] In still other embodiments, the compounds described herein can be formulated into depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous implantation or intramuscular implantation) or by intramuscular injection. Depot injections can be administered at intervals of about 1 to about 6 months or longer. Thus, for example, the compound can be formulated with a suitable polymeric or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a slightly soluble derivative (e.g., as a slightly soluble salt). Experimental Section Solution 1

[0134] Scheme 1 shows a general method for the synthesis of lH-benzo[d]imidazol-2-ylamides 1.5. Appropriately substituted 1-fluoro-2-nitrobenzenes 1.1 are reacted with primary amines to give l-amino-2-nitrobenzenes 1.2. Alternatively, 1-chloro-2-nitrobenzene is reacted with primary amines under palladium catalysis to provide the desired l-amino-2-nitrobenzenes 1.2. The nitro group can be reduced to the corresponding amine by a variety of well-established methods to provide 1,2-diaminobenzenes 1.3. Reaction of 1.3 with cyanogen bromide affords lH-benzo[d]imidazol-2-amines 1.4. Coupling of the amides with appropriate carboxylic acids or acid chlorides can afford lH-benzo[d]imidazol-2-ylamides such as 1.5. Biological assays

[0135] Kv7.2 / 7.3 activation assay

[0136] The ability of compounds to enhance K currents in HEK cells containing Kv7.2 / 7.3 was assessed using planar patch clamp on the QPatch automated screening platform.

[0137] Cell Lines: hKv7.2 / 7.3 cell line was obtained from Chantest, Inc. (Cleveland, OH 44128) Catalog No. CT6147. These HEK cells express Kv7.2 / 7.3 ion channels when induced.

[0138] Cell culture: Cells were maintained in medium containing DMEM / F12 (50 / 50) (GIBCO catalog number 11330), 10% fetal bovine serum (FBS) (GIBCO catalog number 26140), 100 units / mL penicillin-streptomycin (GIBCO catalog number 15140), 0.005 mg / mL blasticidin (INVIVOGEN catalog number ant-bl-1), 0.5 mg / mL geneticin (GIBCO catalog number 10131), 0.1 mg / mL zeocin (GIBCO catalog number R25001). Cells for electrophysiological assays were maintained in medium without blasticidin, geneticin, and zeocin for 2 days, and channel expression was induced by adding tetracycline (BIOLINE catalog number BIO-87030) at a final concentration of 1 mg / mL. Cells were grown to approximately 75% confluence in T-175 flasks. Currents were recorded 24 hours after channel induction.

[0139] Compound Plate: Through the Biomek NX PTest compounds were prepared by serial dilutions on BECKMAN COULTER. Final dilutions were made in external recording solution with a final DMSO concentration of 0.1% DMSO. For single concentration screening, each plate had 10 μM retigabine as a positive control and 0.1% DMSO as a negative control.

[0140] Electrophysiology: On the day of the experiment, cells were washed with Hank's Balanced Salt Solution (HBBS) (Gibco catalog number 14175) and harvested with Tryple (Gibco catalog number 12604). The cells were then centrifuged at 2000 rpm for 5 minutes and centrifuged at approximately 3 x 10 6 Cells were resuspended in CHO-S-SFM (Gibco Catalog No. 12052) at 10 cells / mL. Cells were stirred for 30 minutes before starting the experiment. The external recording solution contained (in mM): NaCl (145), KCl (4), CaCl2 (2), MgCl2 (1), HEPES (10), and glucose (10); the pH was adjusted to 7.4 with NaOH, and the osmolarity was adjusted to 300-305 mOsM with sucrose when necessary. The internal solution contained (in mM): KCl (125), KF (10), EGTA (5), Na2ATP (5), MgCl2 (3.2), HEPES (5); the pH was adjusted to 7.2 with KOH, and the osmolarity was adjusted to 298-302 mOsM with sucrose.

[0141] Potassium channel activity was measured on QPatch HTX (Sophion Bioscience) using QPlate (48 wells / plate). Each cell was treated as an independent experiment and only one compound was tested per well. Potassium channel activity was elicited by holding at -80 mV and increasing to -30 mV for 2 s, followed by a 100 ms pulse to -120 mV.

[0142] Single concentration screening: Baseline conditions were obtained by recording 5 scans in external solution only (this operation was repeated three times for external solution). The effect of the test compound on the evoked current was then assessed by recording 5 scans in the presence of 3 μM compound solution. The steady-state current at the end of a 2 s pulse to -30 mV was measured to determine the fold increase relative to the baseline.

[0143] Table 2 summarizes the data from the Kv7.2 / 7.3 activation assay Table 2. Kv7.2 / 7.3QPatch single concentration screening results. a HPLC Method B b Increases in current relative to baseline from HEK cells co-expressing Kv7.2 / Kv7.3, measured using the Kv7.2 / 7.3 activation assay as described in the Biological Assay Methods section, at a compound concentration of 3 μM, are depicted as fold increases relative to baseline in the range of 1.2-2.9 (+), 3-3.9 (++), and >4 (+++); O indicates an open channel at the holding potential.

[0144] Thallium flux assay was used as a surrogate indicator of potassium channel activity.

[0145] The experimental protocol was adapted from the FluxORTMII Green Potassium Ion Channel Assay User Guide (Publication No. MAN0016084, Invitrogen). Conditions were optimized for the Kv7.2 / 7.3 cell line.

[0146] Cell lines: hKV7.2 / 7.3 cell line was obtained from Chantest, Inc. (Cleveland, OH 44128) catalog number CT6147.

[0147] Cell culture: Kv7.2 / 7.3 cells were maintained in medium containing DMEM / F12 (50 / 50) (Gibco catalog number 11330), 10% fetal bovine serum (FBS) (Gibco catalog number 26140), 100 units / mL penicillin-streptomycin (Gibco catalog number 15140), 0.005 mg / mL blasticidin (SIGMA 15205), 0.5 mg / mL geneticin (Gibco catalog number 10131), and 0.1 mg / mL zeocin (Gibco catalog number R25001). One day before the experiment, cells were seeded in 96-well clear bottom plates (Corning catalog number 353219) in medium without blasticidin, geneticin, or zeocin. Channel expression was induced by adding tetracycline (Bioline Cat. No. BIO87030) at a final concentration of 10 ng / mL.

[0148] Compound plates: Test compounds were diluted in a mixture of 0.1% DMSO / extracellular solution (eight point concentration range 0.014 μM to 30 μM). Serial dilutions were performed on a Biomek NXP (Beckman Coulter).

[0149] Measurements and data analysis: The ion channel modulating properties of novel compounds were characterized using a plate reader (Enspire, Perkin Elmer) with an excitation wavelength of 475 nm and an emission wavelength of 530 nm. After 15 seconds of baseline measurement, stimulation buffer containing thallium and potassium was injected. The final endpoint measurement was taken after 90 seconds. The response was normalized to the positive control (retigabine, maximum 30 μM). The average normalized response at each tested concentration was fit to the standard Hill equation to generate the EC50 and maximum response.

[0150] Table 3 summarizes the data for the thallium flux determination. Table 3. Kv7.2 / 7.3 thallium flux measurement results. a HPLC Method B c The measured EC50s for Kv7.2 / Kv7.3 activation, using the thallium flux assay as described in the Biological Assay Methods section, are depicted as ranging from 3-10 μM (*), 1-3 μM (**), and <1 μM (***).

[0151] The grouping of the alternative elements or embodiments disclosed herein should not be construed as limiting. Each group member may be mentioned or claimed individually, or mentioned or claimed in any combination with other members of the group found herein or other elements. It should be understood that, due to convenience and / or patentability, one or more members of a group may be included in a group or deleted from the group. When any such inclusion or deletion occurs, this specification is considered to contain a rewritten group to meet the written description of all Markush groups used in the appended claims.

[0152] Certain embodiments are described herein, including the best mode known to the inventor for carrying out the invention. Of course, variations of these described embodiments will be apparent to those of ordinary skill in the art after reading the above description. The inventors expect that the skilled person will appropriately apply such variations, and the inventors expect to practice the invention differently from the specific description herein. Therefore, the claims include all modifications and equivalents of the subject matter cited in the claims as permitted by applicable law. In addition, any combination of the above elements in all possible variations thereof is contemplated, unless otherwise indicated herein or otherwise clearly contradictory to the context.

[0153] Finally, it should be understood that the embodiments disclosed herein are intended to illustrate the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, for example, but not limitation, alternative embodiments may be utilized in accordance with the teachings herein. Therefore, the claims are not limited to the embodiments as precisely shown and described. KV7 activators and methods for treating ALS

[0154] In an embodiment, the disclosure relates to a method for treating a neurodegenerative disease (e.g., amyotrophic lateral sclerosis) in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound having Formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is treated.

[0155] In embodiments, the subject is a subject with established ALS, a subject with ALS symptom onset duration less than about 18 months, a subject with a plasma creatinine level of about 72 μM / L or greater, a subject concurrently administered riluzole, a subject concurrently administered dexpramipexole, and combinations thereof.

[0156] It has been demonstrated that motor neurons of ALS patients have reduced delayed rectifier potassium current amplitude, which may underlie the hyperexcitability observed in these diseased neurons. The embodiments described herein relate to compounds having Formula A-1 to A-44 or B-1 to B-7, or pharmaceutically acceptable salts thereof, which activate Kv7 channels to block hyperexcitability associated with ALS and improve motor neuron function and / or survival.

[0157] Embodiments relate to methods for treating a neurodegenerative disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is treated. A compound of Formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof can be administered to any individual exhibiting symptoms of a neurodegenerative disease or an individual susceptible to a neurodegenerative disease. Non-limiting examples of neurodegenerative diseases that can be treated using compounds of Formula A-1 to A-44 or B-1 to B-7, or pharmaceutically acceptable salts thereof, include amyotrophic lateral sclerosis (ALS), Huntington's disease, metabolically induced neural damage, Alzheimer's disease, Pick's disease, senile dementia, age-related cognitive dysfunction, vascular dementia, multi-infarct dementia, Lewy body dementia, neurodegenerative dementia, frontotemporal dementia (FTD), familial FTD, neurodegenerative movement disorders, ataxia, Friedreich's ataxia, multiple sclerosis, spinal muscular atrophy, primary lateral sclerosis, seizure disorders, motor neuron disorders or diseases, inflammatory demyelinating disorders, Parkinson's disease, hepatic encephalopathy, chronic encephalopathy, chronic encephalitis, or any combination thereof.

[0158] Embodiments relate to methods of treating a neurodegenerative disease (e.g., amyotrophic lateral sclerosis) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is treated. In embodiments, the subject is a subject with established ALS, a subject with amyotrophic lateral sclerosis symptom onset duration of less than about 18 months, a subject with a plasma creatinine level of about 72 μM / L or greater, a subject concurrently administered with riluzole, a subject concurrently administered with dexpramipexole, and combinations thereof.

[0159] Embodiments relate to methods of treating amyotrophic lateral sclerosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having Formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, wherein amyotrophic lateral sclerosis is treated.

[0160] Embodiments relate to methods of treating amyotrophic lateral sclerosis in a subject diagnosed with definite amyotrophic lateral sclerosis, the method comprising administering to the subject a therapeutically effective amount of a compound having Formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof, wherein amyotrophic lateral sclerosis is treated. In embodiments, definite amyotrophic lateral sclerosis is defined by the El Escorial diagnostic criteria. In embodiments, the subject is a subject with definite ALS, a subject with an onset of amyotrophic lateral sclerosis symptoms for less than about 18 months, a subject with a plasma creatinine level of about 72 μM / L or greater, a subject concurrently administered with riluzole, a subject concurrently administered with dexpramipexole, and combinations thereof.

[0161] Amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) is a progressive, debilitating motor neuron disease characterized by degeneration and dysfunction / death of upper and lower motor neurons. ALS is usually fatal, but the rate of disease progression may not be linear.

[0162] According to the embodiments described herein, the El Escorial World Federation of Neurology ALS diagnostic criteria are as follows (see also Brooks, BR, RG Miller et al. (2000). "El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis." Amyotrophic Lateral Sclerosis Other Motor Neuron Disord [ Amyotrophic lateral sclerosis Other motor neurone disorders ]1(5):293-9, which is incorporated by reference in its entirety). As used in the El Escorial World Federation of Neurology diagnostic criteria for ALS, the term "definite" is intended to mean that specific clinical exclusion criteria are met and no other diagnosis is possible based on clinical distribution or laboratory findings; the term "dementia" is intended to mean a progressive deterioration of specific cognitive functions; the term "onset" is intended to mean the time of the first subjective symptoms noticed by the patient and subsequently confirmed by examination; the term "likely" is intended to mean that specific clinical and exclusion criteria are met; the term "probable" is intended to mean specific clinical and exclusion criteria; and the term "worsening" is intended to mean an increase in muscle weakness in a previously affected segment or new onset of weakness in a previously unaffected segment.

[0163] The diagnosis of ALS requires the presence of: 1) signs of lower motor neuron (LMN) degeneration by clinical, electrophysiological, or neuropathological examination; 2) signs of upper motor neuron (UMN) degeneration by clinical examination; and 3) progressive spread of signs within one region or to other regions and absence of electrophysiological evidence of other disease processes that could explain the signs of LMN and / or UMN degeneration and neuroimaging evidence of other disease processes that could explain the observed clinical and electrophysiological signs.

[0164] In addition, the El Escorial World Federation of Neurology's ALS diagnostic criteria specify the following steps for the diagnosis of ALS. ALS is diagnosed by: 1) history, physical examination, and appropriate neurologic examination to identify clinical findings that suggest suspected, possible, probable, or definite ALS; 2) electrophysiologic examination to identify findings that confirm LMN degeneration in clinically relevant areas, identify LMN degeneration in clinically irrelevant areas, and exclude other disorders; 3) neuroimaging to identify findings that may exclude other disease processes; 4) clinical laboratory tests determined by clinical judgment to identify possible ALS-related syndromes; 5) neuropathologic examination (when appropriate) to identify findings that may confirm or exclude sporadic ALS, coexisting sporadic ALS, ALS-related syndromes, or ALS variants; 6) clinical and electrophysiologic examinations repeated at least six months apart to identify evidence of progression.

[0165] Definite ALS was defined based on clinical background alone as the presence of UMN and LMN signs in the medullary region and at least two other spinal territories, or the presence of UMN and LMN signs in three spinal territories. An important determinant for the diagnosis of definite ALS in the absence of electrophysiology, neuroimaging, and laboratory tests is the presence of UMN and LMN signs in multiple territories.

[0166] Probable ALS is defined based solely on clinical context as UMN and LMN signs in at least two regions. Although the regions may vary, certain UMN signs must precede (over) LMN signs. In patients with probable ALS, there may be many different combinations of UMN and LMN signs.

[0167] Probable ALS is defined based solely on the clinical context when UMN and LMN signs are present in only one area or only UMN signs are present in 2 or more areas or LMN signs precede UMN signs (the latter distribution of signs needs to be distinguished from multiple non-ALS processes). Unilimb ALS, progressive bulbar palsy without spinal UMN and / or LMN signs, and progressive primary lateral sclerosis without spinal LMN signs and progressive primary lateral sclerosis without spinal LMN signs constitute special cases that may develop LMN or UMN signs to meet the criteria for probable ALS over time or subsequently confirmed by specific LMN and UMN neuropathological findings at autopsy.

[0168] Although UMN pathology may be demonstrated at autopsy, suspected ALS only demonstrates LMN signs in 2 or more areas. However, at the time of diagnostic evaluation, only clinical signs are considered relevant for this classification.

[0169] The clinical signs of progressive LMN and UMN degeneration observed in ALS may occur: 1) in isolation (sporadic ALS), 2) in conjunction with other preexisting disease processes that do not develop concurrently with ALS (coexistent sporadic ALS), 3) in conjunction with laboratory-defined or epidemiologically defined abnormalities temporally related to ALS (ALS-associated syndromes), or 4) in conjunction with clinical, genetic, or epidemiological features that develop concurrently with ALS (ALS variants).

[0170] The physical and neurological examinations will allow a clinical diagnosis of ALS to be made to a certain degree of certainty as defined above; however, the history of disease onset, toxic exposures, past medical history, injuries, family history, geographic location, etc. must be combined with the clinical examination in determining whether the patient has an ALS-related syndrome or an ALS variant.

[0171] An ALS-related syndrome must meet clinical, electrophysiological, and neuroimaging criteria for possible, probable, or definite ALS. An ALS-related syndrome has unique laboratory-defined or epidemiologically defined features that are temporally related to the development of the ALS phenotype. If correction of the relevant laboratory-defined features does not result in correction of the ALS phenotype, patients should be considered to have an ALS-related syndrome in the same manner as patients with sporadic ALS.

[0172] ALS-related syndromes include: 1) monoclonal gammopathy (monoclonal gammopathy of undetermined significance, Waldenstrom's macroglobulinemia, osteosclerotic myeloma, etc.); 2) immune disorders and motor system degeneration (autoimmunity, high titer GMI ganglioside antibodies, etc.); 3) non-malignant endocrine abnormalities (hyperthyroidism, hyperparathyroidism, hypogonadism, etc.); 4) lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma); 5) infection (HIV-1, HTLV-I, encephalitis lethargica, varicella- Herpes zoster, brucellosis, cat scratch disease, Creutzfeldt-Jakob disease, syphilis, post-poliomyelitis, etc.); 6) acquired enzyme deficiency (detoxification enzymes, etc.); 7) exogenous toxins (lead, mercury, arsenic, thallium, cadmium, manganese, aluminum, organic pesticides, lupine seeds, etc.); 8) physical injury (electric shock, radiotherapy, etc.); 9) vascular (vasculitis; ischemic (Dejerine anterior medullary artery syndrome, etc.); 10) spinal cord myelopathy (painless myelopathy with no sensory signs, stable or progressive after surgery).

[0173] ALS variants must meet clinical, electrophysiological, and neuroimaging criteria for possible, probable, or definite ALS. The predominant presentation is seen in sporadic ALS but includes one or more of the following features, such as multiple phenotypes characterized by age of onset, site of onset, survival, and presumed inheritance.

[0174] Familial ALS variants in genetic linkage studies should be characterized by an established inheritance pattern in at least two generations and at least one clinically definitive or autopsy-proven case with convincing evidence to exclude other possible causes. Affected pairs occurring in a single generation are unlikely to be caused by a single gene effect.

[0175] Examples: a) ALS with defined inheritance and known gene product (hexosaminidase A / B deficiency, superoxide dismutase deficiency); b) ALS with defined inheritance and chromosomal linkage but no gene product (familial ALS linked to chromosome 21 or juvenile familial ALS linked to chromosome 2); c) ALS with defined inheritance and no known linkage or gene product (most cases or familial ALS); d) Geographic clustering (including disorders seen in the western Pacific, Guam, the Key Peninsula, northern Africa, Madras, etc.); e) Extrapyramidal signs (bradykinesia; cogwheel rigidity; tremor; clinically significant onset of supranuclear eye signs (pursuit abnormalities); familial or sporadic); f) Cerebellar degeneration (spinocerebellar abnormalities; familial or sporadic); g) Dementia (progressive cognitive abnormalities; familial or sporadic); h) Autonomic nervous system involvement (clinically significant abnormal cardiovascular reflexes; bowel or bladder control problems; familial or sporadic); i) Objective sensory abnormalities (decreased vibration sense; blunted discrimination; blunted cold sensitivity; familial or sporadic); j) Electrophysiological features in the diagnosis of ALS

[0176] Embodiments relate to methods of treating amyotrophic lateral sclerosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof, wherein the subject is selected from: a subject with established amyotrophic lateral sclerosis, a subject with limb-onset amyotrophic lateral sclerosis, a subject with bulbar-onset amyotrophic lateral sclerosis, a subject with an onset of amyotrophic lateral sclerosis symptoms lasting less than about 18 months, a subject with high serum creatinine levels, a subject with low bicarbonate levels, a subject concurrently administered with riluzole, a subject concurrently administered with dexpramipexole, and combinations thereof, and wherein amyotrophic lateral sclerosis is treated. In certain embodiments, the method further comprises monitoring the subject for any clinical features associated with amyotrophic lateral sclerosis. In certain embodiments, the method further comprises initiating therapy with a therapeutically effective amount of a compound having formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof upon diagnosis of amyotrophic lateral sclerosis. In certain embodiments, the subject exhibits symptoms of amyotrophic lateral sclerosis. In certain embodiments, the subject has definite ALS, probable ALS, possible ALS, or suspected ALS.

[0177] In certain embodiments, the subject has upper motor neuron degeneration and lower motor neuron degeneration in the medullary region and two other spinal regions. In certain embodiments, the subject has upper motor neuron degeneration and lower motor neuron degeneration in three spinal regions. In certain embodiments, the subject is selected from: subjects with symptom onset duration less than about 18 months, subjects with high serum creatinine levels, subjects with low serum sodium bicarbonate levels, subjects who are simultaneously administered riluzole, subjects who are simultaneously administered dextro-pramipexole, and combinations thereof. In certain embodiments, subjects with high serum creatinine levels are subjects with serum creatinine greater than about 72 μmol / L.

[0178] In embodiments, a subject with definite ALS is a subject diagnosed with definite ALS as defined by the El Escorial criteria. In certain embodiments, a subject with definite ALS is a subject with upper and lower motor neuron degeneration in the medullary region and two additional spinal regions. In certain embodiments, a subject with definite ALS is a subject with upper and lower motor neuron degeneration in three spinal regions.

[0179] Embodiments relate to methods of treating amyotrophic lateral sclerosis in a subject diagnosed with definite amyotrophic lateral sclerosis, the method comprising administering to the subject a therapeutically effective amount of a compound having formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof, wherein amyotrophic lateral sclerosis is treated. In some embodiments, definite amyotrophic lateral sclerosis is the presence of El Escorial diagnostic criteria, duration of symptom onset of amyotrophic lateral sclerosis less than about 18 months, limb-onset amyotrophic lateral sclerosis, plasma creatinine level of about 72 μM / L or greater, concurrent administration of riluzole, concurrent administration of dexpramipexole, ALSFRS-R score greater than 36.0, pre-study progression rate greater than or equal to 0.8 points per month, predicted relaxed (slow) vital capacity (SVC) percentage less than or equal to 102.0, ALSFRS-R fine motor domain score greater than 10.0 points, ALSFRS-R bulbar domain score greater than 9.0 points, ALS FRS-R gross motor domain score greater than 8.0 points, lingual nerve examination abnormal, pharyngeal, laryngeal and swallowing nerve examination abnormal, lower extremity nerve examination abnormal, upper extremity nerve examination abnormal, triceps nerve examination abnormal, muscle mass and volume nerve examination abnormal, biceps nerve examination abnormal, nerve examination abnormal, pulse rate greater than 81.0 beats per minute, diastolic blood pressure greater than 82.0 mmHg, systolic blood pressure less than or equal to 117.0 mmHg, creatinine value greater than 72.0 μmol / L, phosphorus value less than or equal to 1.090 μmol / L, platelet count less than or equal to 248.0 x 10 9cells / L, cholesterol value less than or equal to 5.3 mmol / L, lactate dehydrogenase value less than or equal to 161.0 U / L, creatine phosphokinase value less than or equal to 184.0 U / L, bicarbonate value less than or equal to 21.6 mmol / L, triglyceride level less than or equal to 1.4 mmol / L, uric acid level greater than 320.0 μmol / L, gamma-glutamyl transferase (GGT) level greater than 37.0 U / L, total bilirubin level less than or equal to 6.0 μmol / L, urine pH less than or equal to 5.5, or any combination thereof.

[0180] Embodiments relate to methods of treating amyotrophic lateral sclerosis in a subject exhibiting amyotrophic lateral sclerosis symptoms, the method comprising administering to the subject a therapeutically effective amount of a compound having Formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof, wherein the amyotrophic lateral sclerosis symptoms are treated. In some embodiments, the subject exhibits clinical features selected from the group consisting of: definite amyotrophic lateral sclerosis, duration of onset of amyotrophic lateral sclerosis symptoms less than about 18 months, limb-onset amyotrophic lateral sclerosis, plasma creatinine level of about 72 μM / L or greater, concurrent administration of riluzole, concurrent administration of dexpramipexole, ALSFRS-R score greater than 36.0, restudy progression rate greater than or equal to 0.8 points per month, predicted relaxed (slow) vital capacity (SVC) percentage less than or equal to 102.0, ALSFRS-R fine motor domain score greater than 10.0 points, ALSFRS-R bulbar domain score less than or equal to 10.0 points, score greater than 9.0 points, ALSFRS-R gross motor domain score greater than 8.0 points, abnormal lingual nerve examination, abnormal pharyngeal, laryngeal and swallowing nerve examination, abnormal lower extremity nerve examination, abnormal upper extremity nerve examination, abnormal triceps nerve examination, abnormal muscle mass and volume nerve examination, abnormal biceps nerve examination, abnormal nerve examination, pulse rate greater than 81.0 beats per minute, diastolic blood pressure greater than 82.0 mmHg, systolic blood pressure less than or equal to 117.0 mmHg, creatinine value greater than 72.0 μmol / L, phosphorus value less than or equal to 1.090 μmol / L, platelet count less than or equal to 248.0 x 10 9 cells / L, cholesterol value less than or equal to 5.3 mmol / L, lactate dehydrogenase value less than or equal to 161.0 U / L, creatine phosphokinase value less than or equal to 184.0 U / L, bicarbonate value less than or equal to 21.6 mmol / L, triglyceride level less than or equal to 1.4 mmol / L, uric acid level greater than 320.0 μmol / L, gamma-glutamyl transferase (GGT) level greater than 37.0 U / L, total bilirubin level less than or equal to 6.0 μmol / L, urine pH less than or equal to 5.5, or any combination thereof.

[0181] In certain embodiments, a subject with an ALS symptom onset duration of less than about 18 months is a subject with an onset of symptoms selected from the group consisting of less than 18 months, less than about 17 months, less than about 16 months, less than about 15 months, less than about 14 months, less than about 13 months, less than about 12 months, less than about 11 months, less than about 10 months, less than about 9 months, less than about 8 months, less than about 7 months, less than about 6 months, less than about 5 months, less than about 4 months, less than about 3 months, less than about 2 months, and less than about 1 month. In certain embodiments, a subject with an ALS symptom onset duration of less than about 18 months is a subject with an onset of symptoms selected from the group consisting of about 18 months, about 17 months, about 16 months, about 15 months, about 14 months, about 13 months, about 12 months, about 11 months, about 10 months, about 9 months, about 8 months, about 7 months, about 6 months, about 5 months, about 4 months, about 3 months, about 2 months, and about 1 month.

[0182] In certain embodiments, a subject with high serum creatinine level is a subject with serum creatinine level selected from greater than about 40 μmol / L, greater than about 45 μmol / L, greater than about 50 μmol / L, greater than about 55 μmol / L, greater than about 60 μmol / L, greater than about 65 μmol / L, greater than about 70 μmol / L, greater than about 72 μmol / L serum creatinine. In certain embodiments, a subject with high serum creatinine level is a subject with serum creatinine level selected from about 40 μmol / L, about 45 μmol / L, about 50 μmol / L, about 55 μmol / L, about 60 μmol / L, about 65 μmol / L, about 70 μmol / L, about 72 μmol / L serum creatinine.

[0183] In certain embodiments, the subject of riluzole is a subject receiving a stable riluzole dosing regimen. In certain embodiments, the subject of riluzole is a subject receiving about 50 mg of riluzole twice a day. In certain embodiments, the subject of riluzole is a subject receiving riluzole for more than about 30 days. In certain embodiments, the subject of riluzole is a subject receiving riluzole for about 60 days or longer. In certain embodiments, the subject of dexpramipexole is a subject receiving a stable dexpramipexole dosing regimen. In certain embodiments, the subject of dexpramipexole is a subject receiving about 75 mg of dexpramipexole twice a day. In certain embodiments, the subject of dexpramipexole is a subject receiving about 150 mg of dexpramipexole twice a day. In certain embodiments, the subject of dexpramipexole is a subject receiving about 300 mg of dexpramipexole twice a day.

[0184] In certain embodiments, the treatment of amyotrophic lateral sclerosis in the subject is selected from improved ALSFRS-R scores, improved CAFS grades, reduced mortality, increased life expectancy, and combinations thereof. In some embodiments, the subject exhibits an improvement of greater than 20% in the ALS Functional Rating Scale (Revised) (ALSFRS-R) score when compared to baseline. In a specific embodiment, the subject exhibits an improvement of greater than 30% in the ALS Functional Rating Scale (Revised) (ALSFRS-R) score when compared to baseline. ALSFRS-R measures 4 areas: lung function, bulbar function, and gross and fine motor skills. There are a total of 12 questions, each with a score of 0 to 4, for a possible total score of 48. These twelve questions and rating scales are provided in Cederbaum et al., 169 J. Neurol. Sci. [Journal of Neuroscience], 13-21 (1999) (incorporated herein in its entirety).

[0185] In some embodiments, treating ALS may include slowing the progression of ALS, reducing the intensity of symptoms associated with ALS, reducing the onset of symptoms associated with ALS, reducing weight loss associated with ALS, reversing weight loss associated with ALS, delaying mortality, and combinations thereof. In specific embodiments, symptoms associated with ALS may be, for example, reduced fine motor function, reduced gross motor function, reduced bulbar function, reduced respiratory function, and combinations thereof. In addition, in other embodiments, symptoms associated with ALS may include difficulty in daily activities, such as walking, speaking, eating, swallowing, writing, climbing stairs, cutting food, turning over in bed, dressing, maintaining hygiene, and combinations thereof, and other symptoms may be experienced, such as difficulty breathing, shortness of breath, orthopnea, respiratory insufficiency, increased drooling, and combinations thereof. In specific embodiments of the various methods, compounds of formula A-1 to A-44 or B-1 to B-7 or pharmaceutically acceptable salts thereof may be used to treat ALS. For example, in certain embodiments, individuals diagnosed with ALS within two years or less can be treated with a compound of Formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof to reduce, eliminate or slow the progression of ALS or ALS-related symptoms, such as, for example, loss of fine motor function, loss of gross motor function, loss of bulbar function, and loss of respiratory function. In other embodiments, a compound of Formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof can be administered to reduce or slow the progression of symptoms, including, but not limited to, tremors, loss of muscle control, loss of writing ability, loss of ability to move or turn over, loss of speech, inability to swallow, difficulty breathing, etc. In other embodiments, individuals with advanced symptoms or individuals diagnosed with ALS more than two years prior to the start of treatment can be treated with a compound of Formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, and such individuals can respond to treatment by showing a reduction or elimination of one or more symptoms associated with ALS, or in certain embodiments, for example, the rate of onset or progression of symptoms can be reduced; the rate of loss of motor function, loss of speech, and / or difficulty swallowing can be slowed and / or reduced.

[0186] In embodiments, a therapeutically effective amount of a compound of Formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, is administered to a subject, and the decline in muscle loss is reduced. In embodiments, a therapeutically effective amount of a compound of Formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, is administered to a subject, and the decline in serum creatinine is reduced. In further embodiments of the various methods, a compound of Formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, may be administered to a subject in need of treatment for excessive weight loss associated with ALS. Without wishing to be bound by theory, the dramatic weight loss that is a primary symptom of ALS may be related to increased energy expenditure, skeletal muscle hypermetabolism, and systemic wasting of muscle tissue known as cachexia.

[0187] In some embodiments, the method is performed for a period of time selected from at least about twelve months, at least about eighteen months, at least about two years, at least about four years, at least about six years, at least about eight years, at least about ten years, at least about twenty years, and until the death of the subject. In other embodiments, the method is performed at least daily for an indefinite period of time.

[0188] The present application provides a method for identifying a patient who responds to treatment with a compound of Formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof, the method comprising: diagnosing a patient with EEC-defined ALS; measuring the patient's serum creatinine level; and if the serum creatinine level is greater than about 72 μmol / L, identifying the patient as a responder. Some embodiments include methods for identifying a subject who may respond to treatment as described herein. In some embodiments, the subject will exhibit one or more of the following characteristics: Definite ALS as defined by the Escorial diagnostic criteria, duration of ALS symptom onset less than approximately 18 months, limb-onset ALS, plasma creatinine level of approximately 72 μM / L or greater, concomitant administration of riluzole, concomitant administration of dexpramipexole, ALSFRS-R score greater than 36.0, restudy progression rate greater than or equal to 0.8 points per month, percent predicted relaxed (slow) vital capacity (SVC) less than or equal to 102.0, ALSFRS-R fine motor domain score greater than 10.0 points, ALSFRS-R bulbar domain score greater than 9.0 points, ALSFRS-R gross motor domain score greater than 8.0 points, lingual nerve examination abnormal, pharyngeal, laryngeal and swallowing nerve examination abnormal, lower extremity nerve examination abnormal, upper extremity nerve examination abnormal, triceps nerve examination abnormal, muscle mass and volume nerve examination abnormal, biceps nerve examination abnormal, nerve examination abnormal, pulse rate greater than 81.0 beats per minute, diastolic blood pressure greater than 82.0 mmHg, systolic blood pressure less than or equal to 117.0 mmHg, creatinine value greater than 72.0 μmol / L, phosphorus value less than or equal to 1.090 μmol / L, platelet count less than or equal to 248.0 x 10 9cells / L, cholesterol value less than or equal to 5.3mmol / L, lactate dehydrogenase value less than or equal to 161.0U / L, creatine phosphokinase value less than or equal to 184.0U / L, bicarbonate value less than or equal to 21.6mmol / L, triglyceride level less than or equal to 1.4mmol / L, uric acid level greater than 320.0μmol / L, gamma-glutamyltransferase (GGT) level greater than 37.0U / L, total bilirubin level less than or equal to 6.0μmol / L, urine pH less than or equal to 5.5, or any combination thereof. In some embodiments, the subject will have at least one of the above characteristics. In some embodiments, the subject will have more than one of the above characteristics. In embodiments, the method further comprises monitoring the subject for any clinical features associated with amyotrophic lateral sclerosis. In embodiments, the method further comprises initiating therapy with a therapeutically effective amount of (6R)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole or a pharmaceutically acceptable salt thereof when amyotrophic lateral sclerosis is diagnosed. In certain embodiments, the subject exhibits symptoms of ALS. In certain embodiments, the subject has definite ALS, probable ALS, possible ALS, or suspected ALS.

[0189] The following are structures associated with some of the chemical names referred to herein. These structures may be unsubstituted, as shown below, or when the structure is unsubstituted, substituents may be independently present in any position normally occupied by a hydrogen atom. The point of attachment is indicated, but otherwise attachment can occur at any position normally occupied by a hydrogen atom.

[0190] Formula A and B

[0191] Some embodiments include compounds represented by Formula A-1:

[0192] For Formula A-1 or any embodiment of Formula A-1, A is an optionally substituted imidazo[4,5-b]pyridin-2-yl, such as an optionally substituted 1H-imidazo[4,5-b]pyridin-2-yl or an optionally substituted 3H-imidazo[4,5-b]pyridin-2-yl. If the imidazo[4,5-b]pyridin-2-yl is substituted, it may have 1, 2, 3, or 4 substituents. Any substituents may be included on the imidazo[4,5-b]pyridin-2-yl. In some embodiments, some or all of the substituents on the imidazo[4,5-b]pyridin-2-yl may have: 0 to 10 carbon atoms and 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I (provided that there is at least 1 non-hydrogen atom); and / or a molecular weight of 15 g / mol to 500 g / mol. For example, the substituent may be C 1-10 Optionally substituted alkyl, such as CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H 11 , cyclic C5H9, C6H 13 , cyclic C6H 11 etc., which may be optionally substituted; C 1-10 Optionally substituted alkoxy, for example OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 、Cyclic OC5H9、OC6H 13 、Cyclic OC6H 11 etc.; halogenated, such as F, Cl, Br, I; OH; CN; NO2; C 1-6 Fluoroalkyl, such as CF3, CF2H, C2F5, etc.; C 1-6 Fluoroalkoxy, such as OCF3, OCF2H, OC2F5, etc.; C 1-10 Esters, such as -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl, etc.; C 1-10 Ketone, such as -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc.; or C 1-10 Amines, such as NH2, NH(CH3), N(CH3)2, N(CH3)C2H5, etc.

[0193] In some embodiments, any or all of the substituents of 1H-imidazo[4,5-b]pyridin-2-yl or 3H-imidazo[4,5-b]pyridin-2-yl are independently CF3, Cl, CN, or OCH3. In some embodiments, A has a CF3 substituent. In some embodiments, A has a Cl substituent. In some embodiments, A has a CN substituent. In some embodiments, A has an OCH3 substituent.

[0194] In some embodiments of Formula A-1, A may be:

[0195] Some embodiments of Formula A-1 may include compounds represented by one or more of Formulas A-2 to A-42, or pharmaceutically acceptable salts thereof:

[0196] For any relevant embodiments or structural diagrams of Formula A-1 (e.g., Formulas A-1 to A-42) herein, L is CH2, CF2, C2H4 (e.g., CH2CH2, CH(CH3) etc.), C3H6 (e.g., CH2CH2CH2, CH2CH(CH3), CH(CH3)CH2, CH(CH3)2, etc.), O, CH2O, C2H4O (e.g., OCH2CH2 (wherein the O atom can be on either side of CH2CH2), CH2OCH2, OCH(CH3) etc.) or C3H6O.

[0197] In some embodiments of Formula A-1 (eg, Formulas A-1 to A-42), L is CH2, CF2, CH2CH2, CH(CH3)2, or CH(CH3).

[0198] In some embodiments of Formula A-1 (eg, Formulas A-1 to A-42), L is CH2.

[0199] In some embodiments of Formula A-1 (eg, Formulas A-1 to A-42), L is CH2CH2.

[0200] In some embodiments of Formula A-1 (eg, Formulas A-1 to A-42), L is CH(CH3)2.

[0201] In some embodiments of Formula A-1 (eg, Formulas A-1 to A-42), L is CH (CH3).

[0202] For any relevant embodiment or structure diagram of Formula A-1 (e.g., Formulas A-1 to A-42) herein, R 1 Can be C 1-12Optionally substituted alkyl, such as optionally substituted CH3, optionally substituted C2H5, optionally substituted C3H7, optionally substituted cyclic C3H5, optionally substituted C4H9, optionally substituted cyclic C4H7, optionally substituted C5H 11 , optionally substituted cyclic C5H9, optionally substituted C6H 13 , optionally substituted cyclic C6H 11 , optionally substituted bicyclo[2.2.1]hept-2-yl, optionally substituted bicyclo[3.1.1]hept-2-yl, etc.; C 1-12 Optionally substituted -O-alkyl, such as optionally substituted -O-CH3, optionally substituted -O-C2H5, optionally substituted -O-C3H7, optionally substituted cyclic -O-C3H5, optionally substituted -O-C4H9, optionally substituted cyclic -O-C4H7, optionally substituted -O-C5H 11 , optionally substituted cyclic -O-C5H9, optionally substituted -O-C6H 13 , optionally substituted cyclic-O-C6H 11 , optionally substituted (2,3-dihydro-1H-inden-1-yl)oxy, etc.; optionally substituted C 6-10 Aryl, such as optionally substituted phenyl; optionally substituted C 6-10 -O-aryl, such as optionally substituted -O-phenyl; or optionally substituted C 2-9 heterocyclyl, such as optionally substituted isoxazolyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrofuranyl, etc. In some embodiments, R 1 CH3, C 2-12 Optionally substituted alkyl, C 1-12 Optionally substituted -O-alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 6-10 -O-aryl or optionally substituted C 2-9 Heterocyclic group.

[0203] For any relevant embodiments or structural diagrams of Formula A-1 (e.g., Formulas A-1 to A-42) herein, in some embodiments, R 1 is an optionally substituted phenyl. 1 C 3-4 In some embodiments, R 1 is an optionally substituted bicyclo[2.2.1]hept-2-yl. In some embodiments, R 1 is an optionally substituted isoxazol-3-yl group. 1 is CF3. In some embodiments, R 1 is an optionally substituted cyclopentyl. 1is an optionally substituted cyclohexyl. 1 In some embodiments, R 1 is an optionally substituted bicyclo[3.1.1]hept-2-yl. In some embodiments, R 1 is an optionally substituted -O-phenyl. 1 is optionally substituted CH(CF3)2. In some embodiments, R 1 C 2-4 In some embodiments, R 1 is an optionally substituted adamantane-1-yl. In some embodiments, R 1 is an optionally substituted tetrahydro-2H-pyranyl. 1 is an optionally substituted (2,3-dihydro-1H-inden-1-yl)oxy group. In some embodiments, R 1 is an optionally substituted tetrahydrofuranyl group.

[0204] For any relevant embodiments or structural diagrams of Formula A-1 (e.g., Formulas A-1 to A-42) herein, in some embodiments, R 1 Can be one of the following:

[0205] For any relevant embodiment or structure diagram of Formula A-1 (e.g., Formula A-2 and A-42 to A-42) herein, R 2 For-R α -Cy. R α For key or C 1-12 Optionally substituted alkyl, such as CH2, C2H4, C3H6, C4H8, C5H 10 、C6H 12 , cyclic C3H5, cyclic C4H7, cyclic C5H9, cyclic C6H 11 Cy is H; optionally substituted C 6-10 Aryl, such as optionally substituted phenyl; or optionally substituted C 2-9 Heterocyclyl, for example, optionally substituted azetidinyl, optionally substituted oxetanyl, optionally substituted thietanyl, etc. In some embodiments, R 2 is an optionally substituted cyclobutyl or an optionally substituted 2-methylpropyl. 2 for:

[0206] In some embodiments of Formulas A-1 to A-44, R 2 In some embodiments, R2 It is 2-methylpropyl.

[0207] For any relevant embodiment or structural diagram of Formulas A-1 to A-44 herein below, it is applicable. Generally, R 3 -R 52 It may be H or any substituent, for example, a substituent having 0 to 12 atoms or 0 to 6 carbon atoms and 0 to 5 heteroatoms (wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I) and / or a molecular weight of 15 g / mol to 300 g / mol. 3 -R 52 Any of them may contain: a) one or more alkyl moieties, which are optionally substituted by or optionally connected by or to: b) one or more functional groups, such as C=C, C≡C, CO, CO2, CON, NCO2, OH, SH, O, S, N, N=C, F, Cl, Br, I, CN, NO2, CO2H, NH2, etc.; or may be a substituent without an alkyl moiety, such as F, Cl, Br, I, NO2, CN, NH2, OH, COH, CO2H, etc.

[0208] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 3 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 3 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers (such as n-propyl and isopropyl), cyclopropyl, butyl isomers, cyclobutyl isomers (such as cyclobutyl and methylcyclopropyl), pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 3 Can be H, F, Cl, Br, I, CN, C 1-12Optionally substituted alkyl, C 1-12 Optionally substituted -O-alkyl, optionally substituted C 2-9 Heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 -O-heterocyclyl, optionally substituted C 6-10 -O-aryl, C 1-12 Optionally substituted acylamino, C 1-12 Optionally substituted aminoacyl or optionally substituted C 1-12 In some embodiments, R 3 It can be H, CH3, OH, OCH3, NH2, NHCH3, N(CH3)2, COH, COCH3, CF3, Cl, CN or OCH3. In some embodiments, R 3 It can be H, CF3, Cl, CN or OCH3. In some embodiments, R 3 is H. In some embodiments, R 3 is CF3. In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 It is OCH3.

[0209] For any relevant embodiment or structural diagram of Formulas A-1 to A-44 herein as follows, each R A Can be independently H or C 1-12 Alkyl groups, including: a H a+1 A straight chain or branched alkyl group, or a group having the formula C a H a-1 wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, for example, a straight or branched chain alkyl having the formula: CH3, C2H5, C3H7, C4H9, C5H 11 、C6H 13 、C7H 15 、C8H 17 、C9H 19 , C 10 H 21 etc., or a cycloalkyl group having the formula: C3H5, C4H7, C5H9, C6H 11 、C7H 13 、C8H 15 、C9H 17 , C 10 H 19 In some embodiments, R ACan be H or C 1-6 In some embodiments, R A Can be H or C 1-3 In some embodiments, R A It can be H or CH3. In some embodiments, R A It can be H.

[0210] For any relevant embodiment or structural diagram of Formulas A-1 to A-44 herein as follows, each R B Can be independently H or C 1-12 Alkyl groups, including: a H a+1 A straight chain or branched alkyl group, or a group having the formula C a H a wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, for example, a straight or branched chain alkyl having the formula: CH3, C2H5, C3H7, C4H9, C5H 11 、C6H 13 、C8H 17 、C7H 15 、C9H 19 , C 10 H 21 etc., or a cycloalkyl group having the formula: C3H5, C4H7, C5H9, C6H 11 、C7H 13 、C8H 15 、C9H 17 , C 10 H 19 In some embodiments, R B Can be H or C 1-3 In some embodiments, R B It can be H or CH3. In some embodiments, R B It can be H.

[0211] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 4 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R4 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or -OC 1-6 Alkyl, for example, -O-methyl, -O-ethyl, isomers of -O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc. In some embodiments, R 4 Can be H, F, Cl, Br, I, CN, C 1-12 Optionally substituted alkyl, C 1-12 Optionally substituted -O-alkyl, optionally substituted C 2-9 Heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 -O-heterocyclyl, optionally substituted C 6-10 -O-aryl, C 1-12 Optionally substituted acylamino, C 1-12 Optionally substituted aminoacyl or optionally substituted C 1-12 In some embodiments, R 4 It can be H, CF3 or Cl. In some embodiments, R 4 is H. In some embodiments, R 4 is CF3. In some embodiments, R 4 For Cl.

[0212] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 5 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 5 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 5 Can be H, F, Cl, Br, I, CN, C 1-12 Optionally substituted alkyl, C 1-12 Optionally substituted -O-alkyl, optionally substituted C 2-9 Heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted C 2-9 -O-heterocyclyl, optionally substituted C 6-10 -O-aryl, C 1-12 Optionally substituted acylamino, C 1-12 Optionally substituted aminoacyl or optionally substituted C 1-12 In some embodiments, R 5 It can be H, F, Cl, CN, CF3, OH; NH2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 5 It can be H.

[0213] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 6 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 6 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 6 It can be H, F, Cl, CN, CF3, OH; NH2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 6 It can be H.

[0214] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 7 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 7 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 7 It can be H, F, Cl, CN, CF3, OH; NH2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 7 It can be H.

[0215] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 8 Some non-limiting examples may include R A 、F、Cl、CN、ORA , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 8 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 8 It can be H, F, Cl, CN, CF3, OH; NH2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 8 is H. In some embodiments, R 8 For F.

[0216] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 9 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 9 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 9 It can be H, F, Cl, CN, CF3, OH; NH2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 9 It can be H.

[0217] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 10 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 10 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 10 It can be H, F, Cl, CN, CF3, OH; NH2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 10 It can be H.

[0218] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 11 Some non-limiting examples may include R A 、F、Cl、CN、ORA , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 11 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 11 is H, CH3, F, Cl or CF3. In some embodiments, R 11 It can be H.

[0219] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 12 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 12 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 12is H, CH3, F, Cl or CF3. In some embodiments, R 12 It can be H.

[0220] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 13 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 13 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 13 is H, CH3, F, Cl or CF3. In some embodiments, R 13 It can be H.

[0221] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 14 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 14 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 14 is H, CH3, F, Cl or CF3. In some embodiments, R 14 It can be H.

[0222] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 15 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 15 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 15 is H, CH3, F, Cl or CF3. In some embodiments, R 15 It can be H.

[0223] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 16 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2RA ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 16 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 16 is H, CH3, F, Cl or CF3. In some embodiments, R 16 It can be H.

[0224] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 17 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 17 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 17 is H, CH3, F, Cl or CF3. In some embodiments, R 17 It can be H.

[0225] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 18 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 18 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 18 It can be H, F, Cl, OH, CN, CF3, CH3, CH2CH3, -OCH3 or -OCH2CH3. In some embodiments, R 18 It can be H.

[0226] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 19 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 19 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 19 It can be H, OH, CN, CF3, CH3, CH2CH3, -OCH3 or -OCH2CH3. In some embodiments, R 19 It can be H.

[0227] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 20 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 20 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 20 It can be H, F, Cl, OH, CN, CF3, CH3, CH2CH3, -OCH3 or -OCH2CH3. In some embodiments, R 20 It can be H.

[0228] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 21 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR ANR A COR B ,CONR A R B In some embodiments, R 21 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 21 It can be H, OH, CN, CF3, CH3, CH2CH3, -OCH3 or -OCH2CH3. In some embodiments, R 21 It can be H.

[0229] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 22 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 22 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 22 It can be H, F, Cl, OH, CN, CF3, CH3, CH2CH3, -OCH3 or -OCH2CH3. In some embodiments, R 22 It can be H.

[0230] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 23 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 23 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 23 It can be H, OH, CN, CF3, CH3, CH2CH3, -OCH3 or -OCH2CH3. In some embodiments, R 23 is H. In some embodiments, R 23 For CH3.

[0231] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 24 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 24 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 24 It can be H, F, Cl, OH, CN, CF3, CH3, CH2CH3, -OCH3 or -OCH2CH3. In some embodiments, R 24 is H. In some embodiments, R 24 For CH3.

[0232] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 25 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 25 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 25 It can be H, OH, CN, CF3, CH3, CH2CH3, -OCH3 or -OCH2CH3. In some embodiments, R 25 It can be H.

[0233] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 26 Some non-limiting examples may include R A 、F、Cl、CN、ORA , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 26 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 26 It can be H, F, Cl, OH, CN, CF3, CH3 or -OCH3. In some embodiments, R 26 It can be H.

[0234] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 27 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 27 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R27 It can be H, F, Cl, OH, CN, CF3, CH3 or -OCH3. In some embodiments, R 27 It can be H.

[0235] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 28 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 28 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 28 It can be H, F, CN, CF3 or CH3. In some embodiments, R 28 It can be H.

[0236] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 29 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 29 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 29 It can be H, F, Cl, OH, CN, CF3, CH3 or -OCH3. In some embodiments, R 29 It can be H.

[0237] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 30 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 30 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 30 It can be H, F, Cl, OH, CN, CF3, CH3, CH2CH3, -OCH3 or -OCH2CH3. In some embodiments, R 30 It can be H.

[0238] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 31 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A RB , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 31 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 31 It can be H, OH, CN, CF3, CH3, CH2CH3, -OCH3 or -OCH2CH3. In some embodiments, R 31 It can be H.

[0239] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 32 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 32 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 32It can be H, F, Cl, CN, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 32 It can be H.

[0240] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 33 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 33 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 33 It can be H, F, Cl, CN, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 33 is H. In some embodiments, R 33 For CH3.

[0241] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 34 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NRA COR B ,CONR A R B In some embodiments, R 34 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 34 It can be H, F, Cl, OH, CN, CF3, CH3, NH2, NHCH3, N(CH3)2 or -OCH3. In some embodiments, R 34 It can be H.

[0242] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 35 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 35 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 35 It can be H, F, CN, CF3, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2. In some embodiments, R 35is H. In some embodiments, R 35 For CH3.

[0243] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 36 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 36 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 36 It can be H, F, CN, CF3, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2. In some embodiments, R 36 is H. In some embodiments, R 36 For CH3.

[0244] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 37 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 37 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 37 It can be H, F, CN, CF3, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2. In some embodiments, R 37 is H. In some embodiments, R 37 For CH3.

[0245] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 38 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 38 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 38 It can be H, F, CN, CF3, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2. In some embodiments, R 38 is H. In some embodiments, R 38 For CH3.

[0246] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 39 Some non-limiting examples may include RA 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 39 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 39 It can be H, F, CN, CF3, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2. In some embodiments, R 39 It can be H.

[0247] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 40 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 40 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 40 It can be H, F, CN, CF3, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2. In some embodiments, R 40 It can be H.

[0248] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 41 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 41 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 41 It can be H, F, CN, CF3, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2. In some embodiments, R 41 is H. In some embodiments, R 41 For CH3.

[0249] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 42 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2RA ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 42 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 42 It can be H, CN, CF3, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2. In some embodiments, R 42 is H. In some embodiments, R 42 For CH3.

[0250] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 43 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 43 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 43It can be H, F, Cl, CN, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 43 It can be H.

[0251] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 44 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 44 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 44 It can be H, F, Cl, CN, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 44 It can be H.

[0252] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 45 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONRA R B In some embodiments, R 45 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 45 It can be H, F, Cl, CN, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 45 It can be H.

[0253] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 46 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 46 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 46It can be H, F, Cl, CN, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 46 It can be H.

[0254] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 47 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 47 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 47 It can be H, F, Cl, CN, CF3, OH; NH2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 47 It can be H.

[0255] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 48 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B,CONR A R B In some embodiments, R 48 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 48 It can be H, F, Cl, CN, CF3, OH; NH2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 48 It can be H.

[0256] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 49 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 49 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 49It can be H, F, Cl, CN, CF3, OH; NH2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 49 It can be H.

[0257] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 50 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 50 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 50 It can be H, F, Cl, CN, CF3, OH; NH2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 50 It can be H.

[0258] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 51 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A CORB ,CONR A R B In some embodiments, R 51 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 51 It can be H, F, Cl, CN, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 51 It can be H.

[0259] For any relevant embodiment or structure diagram of Formulas A-1 to A-44 herein, R 52 Some non-limiting examples may include R A 、F、Cl、CN、OR A , CF3, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 52 It can be H; F; Cl; CN; CF3; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 Alkoxy, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc. In some embodiments, R 52It can be H, F, Cl, CN, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 52 It can be H.

[0260] Some embodiments of Formula A-1 may include compounds represented by Formula A-43: in L is CH2; R 1 is an optionally substituted cyclic C3H5, wherein R 1 The optional substituent is CF3; R 2 is optionally substituted cyclobutyl; R 3 is an optionally substituted C3 alkyl group, wherein R 3 The optional substituent is OH; R 4 is H; and R 5 H or a pharmaceutically acceptable salt thereof.

[0261] Some embodiments of Formula A-1 may include compounds represented by Formula A-44: in L is CH2; R 1 is an optionally substituted C2 alkyl group, wherein R 1 The optional substituents are independently CF3 or CH3; R 2 is optionally substituted cyclobutyl; R 3 is an optionally substituted C3 alkyl group, wherein R 3 The optional substituent is OH; R 4 is H; and R 5 H or a pharmaceutically acceptable salt thereof.

[0262] Some embodiments of Formula A-1 include compounds represented by the following structures or pharmaceutically acceptable salts thereof:

[0263] Some embodiments include compounds represented by Formula B-1:

[0264] For formula B-1 or any embodiment of formula B-1, Bz can be an optionally substituted benzimidazole-1,2-yl. If the benzimidazole-1,2-yl is substituted, it can have 1, 2, 3 or 4 substituents. Any substituents may be included on the benzimidazole-1,2-yl. In some embodiments, some or all of the substituents on the benzimidazole-1,2-yl may have: 0 to 10 carbon atoms and 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br or I (provided that there is at least 1 non-hydrogen atom); and / or a molecular weight of 15 g / mol to 500 g / mol. In some embodiments, some or all of the substituents may each have a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da or 15 Da to 50 Da, and are composed of 2 to 5 chemical elements, wherein these chemical elements are independently C, H, O, N, S, F, Cl or Br. In some embodiments, Bz can be an optionally substituted benzimidazole-1,2-diyl. In some embodiments, Bz can be an optionally substituted benzimidazole-1,2,6-triyl.

[0265] For example, for Formula B-1 or any embodiment of Formula B-1, the substituent of Bz can be C 1-10 Optionally substituted alkyl, such as CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H 11 , cyclic C5H9, C6H 13 , cyclic C6H 11 etc., which may be optionally substituted; C 1-10 Optionally substituted alkoxy, for example OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 、Cyclic OC5H9、OC6H 13 、Cyclic OC6H 11 etc.; halogenated, such as F, Cl, Br, I; OH; CN; NO2; C 1-6 Fluoroalkyl, such as CF3, CF2H, C2F5, etc.; C 1-6 Fluoroalkoxy, such as OCF3, OCF2H, OC2F5, etc.; C 1-10 Esters, such as -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl, etc.; C 1-10 Ketone, such as -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc.; or C 1-10 Amines, such as NH2, NH(CH3), N(CH3)2, N(CH3)C2H5, etc. In some embodiments, the substituents of Bz can be F, Cl, Br, I, CN, NO2, C 1-4Alkyl, C 1-4 Alkyl-OH, C 1-3 O-alkyl, CF3, COH, C 1-4 CO-alkyl, CO2H, C 1-4 CO2-alkyl, NH2 or C 1-4 Alkylamino.

[0266] Some embodiments of Formula B-1 may include compounds represented by Formula B-2:

[0267] For any relevant embodiment or structure diagram of Formula B-1 or B-2 or B-3 to B-7 as applicable herein, D is an optionally substituted C 3-6 Carbocyclic or C 2-5 Heterocyclyl. If D is a substituted cyclobutyl, it may have 1, 2, 3, 4, 5, 6 or 7 substituents. If D is a substituted phenyl, it may have 1, 2, 3, 4 or 5 substituents. If D is a substituted isoxazolyl, it may have 1 or 2. D may include any substituents. In some embodiments, some or all of the substituents of D may have: 0 to 10 carbon atoms and 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br or I (provided that there is at least 1 non-hydrogen atom); and / or a molecular weight of 15 g / mol to 500 g / mol. In some embodiments, some or all of the substituents may each have a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da or 15 Da to 50 Da, and are composed of 2 to 5 chemical elements, wherein these chemical elements are independently C, H, O, N, S, F, Cl or Br.

[0268] For any relevant embodiment or structure diagram of Formula B-1 or B-2 or B-3 to B-7 as applicable herein, the substituent of D may be C 1-10 Optionally substituted alkyl, such as CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H 11 , cyclic C5H9, C6H 13 , cyclic C6H 11 etc., which may be optionally substituted; C 1-10 Optionally substituted alkoxy, for example OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 、Cyclic OC5H9、OC6H 13 、Cyclic OC6H 11 etc.; halogenated, such as F, Cl, Br, I; OH; CN; NO2; C 1-6 Fluoroalkyl, such as CF3, CF2H, C2F5, etc.; C1-6 Fluoroalkoxy, such as OCF3, OCF2H, OC2F5, etc.; C 1-10 Esters, such as -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl, etc.; C 1-10 Ketone, such as -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc.; or C 1-10 Amines, such as NH2, NH(CH3), N(CH3)2, N(CH3)C2H5, etc. In some embodiments, the substituents of D can be F, Cl, Br, I, CN, NO2, C 1-4 Alkyl, C 1-4 Alkyl-OH, C 1-3 O-alkyl, CF3, COH, C 1-4 CO-alkyl, CO2H, C 1-4 CO2-alkyl, NH2 or C 1-4 Alkylamino.

[0269] For any relevant embodiment or structural diagram of Formula B-1 or B-2 or B-3 to B-7 herein as applicable below, in some embodiments, D is: or optionally substituted C 2-4 alkyl.

[0270] For any relevant embodiments or structural diagrams of Formula B-1 or B-2 or B-3 to B-7 herein as applicable below, in some embodiments, D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, or isopropyl.

[0271] For any relevant embodiment or structure diagram of Formula B-1 or B-2 or B-3 to B-7 herein as applicable below, in some embodiments, D is an optionally substituted cyclobutyl. In some embodiments, D is a cyclobutyl. In some embodiments, D is

[0272] For any relevant embodiments or structural diagrams of Formula B-1 or B-2 or B-3 to B-7 herein as applicable below, in some embodiments, D is isopropyl.

[0273] For any relevant embodiments or structural diagrams of Formula B-1 or B-2 or B-3 to B-7 herein as applicable below, in some embodiments, D is t-butyl or tert-butyl.

[0274] For any relevant embodiment or structure diagram of Formula B-1 or B-2 or B-3 to B-7 as applicable herein, in some embodiments, D is an optionally substituted phenyl. In some embodiments, D is

[0275] For any relevant embodiment or structure diagram of Formula B-1 or B-2 or B-3 to B-7 herein as applicable below, in some embodiments, D is an optionally substituted pyridyl, such as an optionally substituted pyridin-2-yl, pyridin-3-yl or pyridin-4-yl. In some embodiments, D is

[0276] For any relevant embodiment or structure diagram of Formula B-1 or B-2 or B-3 to B-7 as applicable herein, in some embodiments, D is an optionally substituted isoxazolyl. In some embodiments, D is

[0277] For any relevant embodiment or structural diagram of Formula B-1 or B-2 or B-3 to B-7 as applicable herein, A is C 2-8 Alkyl, such as straight chain or branched Straight or branched chain Straight or branched chain Straight or branched chain Straight or branched chain Contains a ring Contains a ring Contains a ring Contains a ring or containing a bicyclic system

[0278] For any relevant embodiment or structure diagram of Formula B-1 or B-2 or B-3 to B-7 herein applicable below, X is H, F, CF3, optionally substituted phenyl, or optionally substituted pyridyl. In some embodiments, X is H. In some embodiments, X is F. In some embodiments, X is CF3.

[0279] For any relevant embodiment or structural diagram of formula B-1 or B-2 or B-3 to B-7 herein applicable below, if X is a substituted phenyl, it may have 1, 2, 3, 4 or 5 substituents. If X is a substituted pyridyl, it may have 1, 2, 3 or 4 substituents. In some embodiments, some or all of the substituents of X may have: 0 to 10 carbon atoms and 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br or I (provided that there is at least 1 non-hydrogen atom); and / or a molecular weight of 15 g / mol to 500 g / mol. In some embodiments, some or all of the substituents may each have a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da or 15 Da to 50 Da, and consist of 2 to 5 chemical elements, wherein these chemical elements are independently C, H, O, N, S, F, Cl or Br.

[0280] For any relevant embodiment or structure diagram of Formula B-1 or B-2 or B-3 to B-7 as applicable herein, the substituent of X may be C 1-10 Optionally substituted alkyl, such as CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H 11 , cyclic C5H9, C6H 13 , cyclic C6H 11 etc., which may be optionally substituted; C 1-10 Optionally substituted alkoxy, for example OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 、Cyclic OC5H9、OC6H 13 、Cyclic OC6H 11 etc.; halogenated, such as F, Cl, Br, I; OH; CN; NO2; C 1-6 Fluoroalkyl, such as CF3, CF2H, C2F5, etc.; C 1-6 Fluoroalkoxy, such as OCF3, OCF2H, OC2F5, etc.; C 1-10 Esters, such as -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl, etc.; C 1-10 Ketone, such as -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc.; or C 1-10 Amines, such as NH2, NH(CH3), N(CH3)2, N(CH3)C2H5, etc. In some embodiments, the substituents of X can be F, Cl, Br, I, CN, NO2, C 1-4 Alkyl, C 1-4 Alkyl-OH, C 1-3 O-alkyl, CF3, COH, C1-4 CO-alkyl, CO2H, C 1-4 CO2-alkyl, NH2 or C 1-4 Alkylamino.

[0281] For any relevant embodiments or structural diagrams of Formula B-1 or B-2 or B-3 to B-7 herein, Y is H, F, Cl, Br, I, or a moiety having a molecular weight of 15 to 300 Da and consisting of 2 to 5 chemical elements, wherein these chemical elements are independently C, H, O, N, S, F, Cl, or Br. In some embodiments, Y is H, F, Cl, Br, I, CN, -COH, C 1-6 -CO-alkyl, CF3, OH, C 1-5 O-alkyl, C 0-6 Amino or C 0-6 In some embodiments, Y is H, F, CF3, OH, C 1-5 O-alkyl, C 0-6 Amino or C 0-6 In some embodiments, Y is H. In some embodiments, Y is OH. In some embodiments, Y is F. In some embodiments, Y is CF3. In some embodiments, Y is C 1-3 O-alkyl, such as -OCH3, OC2H5, OC3H7, etc. In some embodiments, Y is C 0-6 In some embodiments, Y is an optionally substituted tetrahydropyranyl group, for example In some embodiments, Y may include C 1-8 Alkyl groups may include one or two C 3-6 In some embodiments, wherein Y comprises at least one carbocyclic ring, these rings may be connected to each other. In some embodiments, Y is -C(CF3)2OH (or 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl). In some embodiments, Y is (or methyl(2,2,2-trifluoroethyl)amino). In some embodiments, Y is dimethylamino.

[0282] For any relevant embodiment or structural diagram of Formula B-1 or B-2 or B-3 to B-7 herein as applicable below, in some embodiments, C 2-8 Alkyl groups, e.g.

[0283] For any relevant embodiment or structural diagram of Formula B-1 or B-2 or B-3 to B-7 herein as applicable below, in some embodiments, C 2-8 Hydroxyalkyl groups, e.g.

[0284] For any relevant embodiment or structural diagram of Formula B-1 or B-2 or B-3 to B-7 herein as applicable below, in some embodiments, C 2-8 Fluoroalkyl groups, e.g.

[0285] For any relevant embodiment or structural diagram of Formula B-1 or B-2 or B-3 to B-7 herein as applicable below, in some embodiments, C 2-8 Alkoxyalkyl, for example

[0286] For any relevant embodiment or structural diagram of Formula B-1 or B-2 or B-3 to B-7 herein as applicable below, in some embodiments, C 2-8 Hydroxyfluoroalkyl groups, e.g.

[0287] For any relevant embodiment or structural diagram of Formula B-1 or B-2 or B-3 to B-7 herein as applicable below, in some embodiments, is an optionally substituted 2-hydroxy-2-phenylethyl group, for example

[0288] For any relevant embodiment or structural diagram of Formula B-1 or B-2 or B-3 to B-7 herein as applicable below, in some embodiments, is an optionally substituted 2-hydroxy-2-phenylpyridinyl group, for example

[0289] For any relevant embodiment or structural diagram of Formula B-1 or B-2 or B-3 to B-7 herein as applicable below, in some embodiments, is an optionally substituted C 2-8 Fluoroaminoalkyl groups, e.g.

[0290] For any relevant embodiment or structure diagram of Formula B-1 or B-2 or B-3 to B-7 herein, as applicable below. 1-18 It may be H or any substituent, for example, a substituent having 0 to 12 atoms or 0 to 6 carbon atoms and 0 to 5 heteroatoms (wherein each heteroatom is independently O, N, S, F, Cl, Br, or I) and / or a molecular weight of 15 g / mol to 300 g / mol. 1-18Any of may include: a) 1 or more alkyl moieties, which are optionally substituted by or optionally connected by or to: b) 1 or more functional groups, such as C=C, C≡C, CO, CO2, CON, NCO2, OH, SH, O, S, N, N=C, F, Cl, Br, I, CN, NO2, CO2H, NH2, etc.; or may be a substituent without an alkyl moiety, such as F, Cl, Br, I, NO2, CN, NH2, OH, COH, CO2H, etc. In some embodiments, each R 1-18 It is independently H, F, Cl, Br, I or a substituent having a molecular weight of 15 Da to 300 Da, 15 Da to 200 Da, 15 Da to 100 Da or 15 Da to 60 Da and consisting of 2 to 5 chemical elements, wherein these chemical elements are independently C, H, O, N, S, F, Cl or Br.

[0291] For any relevant structural diagram of formula B-1 or B-2 or B-3 to B-7, R 1-18 Some non-limiting examples may include R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 Can be H; F; Cl; Br; CN; C 1-3 Fluoroalkyl, such as CHF2, CF3, etc.; OH; NH2; C 1-6 Alkyl, such as methyl, ethyl, propyl isomers (such as n-propyl and isopropyl), cyclopropyl, butyl isomers, cyclobutyl isomers (such as cyclobutyl and methylcyclopropyl), pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; C 1-6 Alkoxy groups, such as -O-methyl, -O-ethyl, -O-propyl isomers, -O-cyclopropyl, -O-butyl isomers, -O-cyclobutyl isomers, -O-pentyl isomers, -O-cyclopentyl isomers, -O-hexyl isomers, -O-cyclohexyl isomers, etc.; C 1-4 Hydroxyalkyl, such as -CH2OH, -C2H4-OH, -C3H6-OH, C4H8-OH, etc.; C 2-5-CO2-alkyl, for example, -CO2-CH3, -CO2-C2H5, -CO2-C3H7, -CO2-C4H9, etc.

[0292] For any relevant structural diagram of formula B-1 or B-2 or B-3 to B-7, each R A Can be independently H or C 1-12 Alkyl groups, including: a H a+1 A straight chain or branched alkyl group, or a group having the formula C a H a-1 wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, for example, a straight or branched chain alkyl having the formula: CH3, C2H5, C3H7, C4H9, C5H 11 、C6H 13 、C7H 15 、C8H 17 、C9H 19 , C 10 H 21 etc., or a cycloalkyl group having the formula: C3H5, C4H7, C5H9, C6H 11 、C7H 13 、C8H 15 、C9H 17 , C 10 H 19 In some embodiments, R A Can be H or C 1-6 In some embodiments, R A Can be H or C 1-3 In some embodiments, R A It can be H or CH3. In some embodiments, R A It can be H.

[0293] For any relevant structural diagram of formula B-1 or B-2 or B-3 to B-7, each R B Can be independently H or C 1-12 Alkyl groups, including: a H a+1 A straight chain or branched alkyl group, or a group having the formula C a H a-1 wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, for example, a straight or branched chain alkyl having the formula: CH3, C2H5, C3H7, C4H9, C5H 11 、C6H 13 、C7H 15 、C8H17 、C9H 19 , C 10 H 21 etc., or a cycloalkyl group having the formula: C3H5, C4H7, C5H9, C6H 11 、C7H 13 、C8H 15 、C9H 17 , C 10 H 19 In some embodiments, R B Can be H or C 1-3 In some embodiments, R B It can be H or CH3. In some embodiments, R B It can be H.

[0294] For any relevant structural diagram of Formula B-1 or B-2 or B-3 to B-7 (e.g., Formula B-2), in some embodiments, R 1 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-4 In some embodiments, R 1 For H, Cl, Br, CN, OCH3, CHF2, CF3, -CO2CH2CH3, -CH2OH, In some embodiments, R 1 is H. In some embodiments, R 1 In some embodiments, R 1 is Br. In some embodiments, R 1 In some embodiments, R 1 is OCH3. In some embodiments, R 1 is CHF2. In some embodiments, R 1 is CF3. In some embodiments, R 1 is -CO2CH2CH3. In some embodiments, R 1 is -CH2OH. In some embodiments, R 1 for In some embodiments, R 1 for In some embodiments, R 1 for In some embodiments, R 1 for In some embodiments, R 1For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-5 Hydroxyalkyl.

[0295] For any relevant structural diagram of Formula B-1 or B-2 or B-3 to B-7, in some embodiments, R 2 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-4 In some embodiments, R 2 is H. In some embodiments, R 2 is CH2OH. In some embodiments, R 2 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 In some embodiments, R 2 It is -CH2OH, -CO2Me or -C(CH3)2OH.

[0296] For any relevant structural diagram of Formula B-1 or B-2 or B-3 to B-7, in some embodiments, R 3 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-4 In some embodiments, R 3 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0297] For any relevant structural diagram of Formula B-1 or B-2 or B-3 to B-7, in some embodiments, R 4 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4-CO2-alkyl, C 1-4 Alkyl or C 1-4 In some embodiments, R 4 is H. In some embodiments, R 4 is CH3. In some embodiments, R 4 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0298] For any relevant structural diagram of Formula B-1 or B-2 or B-3 to B-7, in some embodiments, R 5 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-4 In some embodiments, R 5 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R BIn some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0299] For any relevant structural diagram of Formula B-1 or B-2 or B-3 to B-7, in some embodiments, R 6 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-4 In some embodiments, R 6 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0300] For any relevant structural diagram of Formula B-1 or B-2 or B-3 to B-7, in some embodiments, R 7 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-4 In some embodiments, R 7 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0301] For any relevant structural diagram of Formula B-1 or B-2 or B-3 to B-7, in some embodiments, R 8 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-4 In some embodiments, R 8 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0302] For any relevant structural diagram of Formula B-1 or B-2 or B-3 to B-7, in some embodiments, R 9 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-4 In some embodiments, R 9 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0303] For any relevant structural diagram of Formula B-1 or B-2 or B-3 to B-7, in some embodiments, R 10 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-4 In some embodiments, R 10 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0304] For any relevant structural diagram of Formula B-1 or B-2 or B-3 to B-7, in some embodiments, R 11 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-4 In some embodiments, R 11 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0305] For any relevant structural diagram of Formula B-1 or B-2 or B-3 to B-7, in some embodiments, R 12 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-4 In some embodiments, R 12 For the embodiments listed in this paragraph, in some embodiments, R 1-18The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0306] For any relevant structural diagram of Formula B-1 or B-2 or B-3 to B-7, in some embodiments, R 13 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-4 In some embodiments, R 13 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0307] For any relevant structural diagram of Formula B-1 or B-2 or B-3 to B-7, in some embodiments, R 14 For H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl or C 1-4 In some embodiments, R 14 is H. In some embodiments, R 14 For the embodiments listed in this paragraph, in some embodiments, R 1-18 The remaining groups may independently be R A 、F、Cl、Br、CN、OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , COR A 、CO2R A ,OCOR A NR A COR B ,CONR A R B In some embodiments, R 1-18 The remaining groups can be H, F, Cl, Br, CN, C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 Hydroxyalkyl.

[0308] In some embodiments of the invention, one or more hydrogen atoms are replaced with deuterium. It is well established that deuteration of physiologically active compounds provides the advantage of retaining the pharmacological characteristics of their hydrogen counterparts while positively affecting their metabolic consequences. Selective replacement of one or more hydrogens with deuterium in the compounds of the invention can improve the safety, tolerability and efficacy of the compound relative to its all hydrogen counterparts.

[0309] Methods for incorporating deuterium into compounds are well established. Using established metabolic studies in the art, the compounds of the invention can be tested to identify sites for selective placement of deuterium isotopes where the isotopes will not be metabolized. In addition, these studies identify metabolic sites as locations where deuterium atoms are placed.

[0310] Some embodiments of Formula B-1 may include compounds represented by Formula B-3: in D is optionally substituted cyclobutyl; A is a C4 alkyl group; X is CF3; Y is H; R 1 is C3 hydroxyalkyl; R 2 and R 4 is H; and R 3 is F; or a pharmaceutically acceptable salt thereof.

[0311] Some embodiments of Formula B-1 may include compounds represented by Formula B-4: in D is optionally substituted cyclobutyl; A is a C4 alkyl group; X is CF3; Y is H; R 1 is a C3 hydroxyalkyl group; and R 2 , R 3 and R 4 is H; or a pharmaceutically acceptable salt thereof.

[0312] Some embodiments of Formula B-1 may include compounds represented by Formula B-5: in D is tert-butyl; A is a C5 alkyl group; X is H; Y is H; R 1 is CN; R 2 and R 4 is H; and R 3 is F; or a pharmaceutically acceptable salt thereof.

[0313] Some embodiments of Formula B-1 may include compounds represented by Formula B-6: in D is tert-butyl; A is a C4 alkyl group; X is CF3; Y is H; R 1 is CN; R 2 and R 4 is H; and R 3 is F; or a pharmaceutically acceptable salt thereof.

[0314] Some embodiments of Formula B-1 may include compounds represented by Formula B-7: in D is tert-butyl; A is a C5 alkyl group; X is H; Y is H; R 1 is CN; R 2 and R 3 is F; and R 4 is H; or a pharmaceutically acceptable salt thereof.

[0315] Some embodiments of Formula B-1 include compounds represented by the following structures or pharmaceutically acceptable salts thereof:

[0316] The compounds disclosed herein can be synthesized by the methods disclosed in US Pat. Nos. 9,650,376 and 9,481,653, which are incorporated herein by reference.

[0317] In the embodiments described herein, the therapeutically effective amount of a compound of Formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, can be from about 0.1 mg / day to about 3,000 mg / day. In such embodiments of various methods, a pharmaceutical composition suitable for oral administration can include at least about 50 mg of a compound of Formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, and in some embodiments, such a pharmaceutical composition can include at least about 75 mg of a compound of Formula A-1 to A-44 or B-1, at least about 100 mg of a compound of Formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, at least about 150 mg of a compound of Formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, at least about 200 mg of a compound of Formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, at least about 25 0 mg of a compound having formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, at least about 300 mg of a compound having formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, at least about 500 mg of a compound having formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, at least about 600 mg of a compound having formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, at least about 750 mg of a compound having formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, or at least about 1000 mg of a compound having formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof.

[0318] In an embodiment, there is a compound of formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof can be applied in a pharmaceutical composition. The pharmaceutical composition of various methods can be prepared, packaged, sold in bulk as a single unit dose or as multiple unit doses and can be applied in a conventional manner by any route that they have activity. For example, the composition can be administered orally, intraocularly, intravenously, intramuscularly, intraarterially, intramedullary, intrathecal, intraventricularly, transdermally, subcutaneously, intraperitoneally, intracapsularly, intranasally, intestinally, locally, sublingually, rectum, by suction, by reservoir injection or by implantation, or by using vaginal cream, suppository, pessary, vaginal ring, rectal suppository, intrauterine contraceptive device and transdermal form (such as patch and cream). Specific mode of administration will depend on indications. The selection of specific route of administration and dosage regimen can be adjusted or adjusted by clinicians according to known methods to obtain the best clinical response. All methods described herein can be performed by administering a compound of Formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof by any such route of administration described herein. In addition, a compound of Formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof can be delivered by using any such route of administration for the entire dosing regimen described herein.

[0319] Pharmaceutical compositions comprising a compound of Formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof in solid dosage form may include, but are not limited to, tablets, capsules, cachets, pellets, pills, powders and granules; topical dosage forms, which include, but are not limited to, solutions, powders, fluid emulsions, fluid suspensions, semisolids, ointments, pastes, creams, gels and jellies, and foams; and parenteral dosage forms, which include, but are not limited to, solutions, suspensions, emulsions and dry powders; the pharmaceutical composition comprises an effective amount of a polymer or copolymer. It is also known in the art that the active ingredient may be included in such formulations together with a pharmaceutically acceptable diluent, filler, disintegrant, binder, lubricant, surfactant, hydrophobic vehicle, water-soluble vehicle, emulsifier, buffer, wetting agent, humectant, solubilizer, preservative, and the like. Devices and methods for administration are known in the art and the skilled artisan may refer to various pharmacological references for guidance. See, for example, Modern Pharmaceutics, Banker and Rhodes, Marcel Dekker, Inc. (1979); and Goodman and Gilman, The Pharmaceutical Basis of Therapeutics, 6th ed., MacMillan Publishing Co., New York (1980).

[0320] For oral administration, there is a compound of formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof can be easily prepared by combining a compound of formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier well known in the art. Such carriers enable the compound of various methods to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by the subject to be treated. Pharmaceutical preparations for oral use can be obtained in the following manner: solid excipients are added (optionally grinding the resulting mixture), and after adding suitable adjuvants (if desired) the granular mixture is processed to obtain tablets or dragee cores. Suitable excipients include, but are not limited to, fillers, such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; cellulose preparations, including, but not limited to, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP). If desired, disintegrants may be added, such as, but not limited to, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (such as sodium alginate).

[0321] In some embodiments of various methods, the pharmaceutical composition can be suitable for oral administration, such as solid oral dosage forms or capsules, and in certain embodiments, the composition can be a tablet. Such tablets may include any number of additional medicaments, such as one or more adhesives, one or more lubricants, one or more diluents, one or more lubricants, one or more surfactants, one or more dispersants, one or more coloring agents, etc. Such tablets can be prepared by any method known in the art, such as by compression or molding. Compressed tablets can be prepared by compressing the ingredients of the composition in a free-flowing form (such as powder or granules) in a suitable machine, and molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. The tablets of some embodiments can be uncoated, and in other embodiments, they can be coated by known techniques.

[0322] In other embodiments of the various methods for preparing oral administration, the pharmaceutical composition of the various methods can be provided in a dragee core with a suitable coating. In such embodiments, concentrated sugar solutions can be used to prepare dragee cores, and these concentrated sugar solutions can optionally include gum arabic, talcum, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvents or solvent mixtures. In certain embodiments, dyes or pigments can be added to tablets or dragee coatings to identify or characterize the different combinations of active compound dosages. In other embodiments, the pharmaceutical composition prepared for oral administration, comprising an effective amount of a compound with formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof, can include but is not limited to a plug-in capsule (push-fit capsule) made of gelatin, and a soft sealed capsule made of gelatin and a plasticizer (such as glycerol or sorbitol). The plug-in capsules may contain active ingredients mixed with fillers (e.g., such as lactose), binders (e.g., such as starch) and / or lubricants (e.g., such as talc or magnesium stearate) and optionally stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid (e.g., fatty oil, liquid paraffin or liquid polyethylene glycol). In addition, stabilizers may be added. The dosage of all formulations for oral administration should be suitable for such administration.

[0323] In the embodiment of various methods in which tablets and dragee cores are coated, coating can delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action in a longer period of time. In addition, such coating can be suitable for releasing compounds or pharmaceutically acceptable salts thereof with formula A-1 to A-44 or B-1 to B-7 in a predetermined mode, for example to realize controlled release formulations, or it can be adapted to release active compounds until passing through the stomach by including, for example, enteric coatings. Suitable coatings covered by such embodiments may include, but are not limited to, sugar coatings, film coatings such as hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, acrylate copolymers, polyethylene glycol and / or polyvinyl pyrrolidone, or enteric coatings such as methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac and / or ethyl cellulose. In addition, time-delay materials (such as, for example, glyceryl monostearate or glyceryl distearate) may be incorporated into the coating of some embodiments. In still other embodiments, the solid tablet composition may include a coating suitable for protecting the composition from undesirable chemical changes, such as reducing chemical degradation prior to release of the active drug substance.

[0324] Pharmaceutical compositions suitable for oral administration encompassed in embodiments of the various methods may comprise a therapeutically effective amount of a compound having Formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, and may further comprise one or more diluents, one or more disintegrants, one or more lubricants, one or more pigments or colorants, one or more gelatins, one or more plasticizers, and the like. For example, in some embodiments, the tablet may contain an effective amount of a compound having Formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, about 20% to about 50% by weight of a diluent, about 10% to about 30% by weight of a second diluent, about 2% to about 6% by weight of a disintegrant, and about 0.01% to about 2% by weight of a lubricant, and in specific embodiments, such tablets may contain an effective amount of a compound having Formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, about 20% to about 50% by weight of microcrystalline cellulose, about 10% to about 30% by weight of mannitol, about 2% to about 6% by weight of cross-linked polyvinylpyrrolidone or cross-linked carboxymethyl cellulose, and about 0.01% to about 2% by weight of magnesium stearate. In further embodiments, the pharmaceutical composition may include any amount or combination of microcrystalline cellulose, mannitol, sodium, crospovidone, croscarmellose, magnesium stearate, or any combination thereof.

[0325] In some embodiments of various methods, a pharmaceutical composition comprising a compound with formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof can be made into a suspension, solution or emulsion in an oily or aqueous vehicle suitable for injection. In such embodiments, such liquid preparations may further include preparations formulated for parenteral administration, such as suspending agents, stabilizers and / or dispersants. These injectable preparations can be administered by any route, including but not limited to, for example, subcutaneous, intravenous, intramuscular, intra-arterial, bolus injection or continuous infusion, and in the embodiment of injectable preparations administered by continuous infusion, this infusion can be performed for about fifteen minutes to about twenty-four hours. In certain embodiments, injection preparations can exist in unit dosage form, such as in an ampoule or a multi-dose container, and a preservative is added.

[0326] In other embodiments of various methods, the compound of formula A-1 to A-44 or B-1 to B-7 or its pharmaceutically acceptable salt can be formulated into a depot preparation, and such long-acting preparations can be administered by implantation (e.g., as subcutaneous implantation or intramuscular implantation) or by intramuscular injection. Depot injection can be administered at intervals of about 1 to about 6 months or longer. Therefore, for example, the compound can be formulated with suitable polymerization or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a slightly soluble derivative (e.g., as a slightly soluble salt).

[0327] In still other embodiments, a pharmaceutical composition comprising a compound of Formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof can be formulated for buccal or sublingual administration. In such embodiments, the pharmaceutical composition can be prepared as chewable tablets, flash melts or lozenges formulated in any conventional manner known in the art.

[0328] In yet other embodiments, a pharmaceutical composition comprising a compound of Formula A-1 to A-44 or B-1 to B-7, or a pharmaceutically acceptable salt thereof, can be formulated for administration by inhalation. In such embodiments, the pharmaceutical composition according to the various methods can be delivered in an aerosol spray form from a pressurized package or nebulizer using a suitable propellant such as, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol package, the dosage unit can be determined by providing a valve to deliver a metered amount. Gelatin capsules or cartridges, for example for use in an inhaler or insufflator, can be formulated containing a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0329] In further embodiments, the pharmaceutical compositions containing the compounds of Formulae A-1 to A-44 or B-1 to B-7, or pharmaceutically acceptable salts thereof, can be formulated as rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

[0330] In some embodiments, a pharmaceutical composition comprising a compound of formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof can be formulated for transdermal administration. Such pharmaceutical compositions can be made into, for example, plasters or applied by a transdermal therapeutic system provided to a subject. In other embodiments, medicines and therapeutic compositions for transdermal administration, comprising a compound of formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof, can include suitable solid or gel phase carriers or excipients, such as, but not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers (such as, for example, polyethylene glycol).

[0331] In some embodiments, a pharmaceutical composition comprising a compound of formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof can be administered alone as a monotherapy. In other embodiments, a pharmaceutical composition comprising a compound of formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof can be administered in combination with one or more other active ingredients (e.g., such as adjuvants, protease inhibitors or other compatible drugs or compounds), wherein such a combination is considered to be desirable or advantageous for achieving the desired effects of the methods described herein.

[0332] In an embodiment, the method further comprises administering one or more active agents simultaneously or concurrently with administering a compound of formula A-1 to A-44 or B-1 to B-7 or a pharmaceutically acceptable salt thereof. In an embodiment, the one or more active agents are dextrorotatory pramipexole, riluzole, baclofen, tizanidine or edaravone. Riluzole is a neuroprotectant that blocks sodium channels in an inactivated state. Riluzole has been shown to prolong the survival of ALS patients. In an embodiment, riluzole is administered once or twice a day at 50 mg. In an embodiment, dextrorotatory pramipexole is administered at a total daily dose of 150 mg or 300 mg or 600 mg. In an embodiment, baclofen is administered at 0.05 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg or 20 mg. In an embodiment, tizanidine is administered at 2 mg, 4 mg or 6 mg. In an embodiment, edaravone is administered at 30 mg. In an embodiment, the one or more active agents are dextrorotatory pramipexole. In an embodiment, the one or more active agents are riluzole.

[0333] In an embodiment, one or more active agents are anti-glutamatergic or ion channel blockers, such as, but not limited to, FP-0011, memantine, N-acetylated-α-linked acid dipeptidase (NAALADase) inhibitors, nimodipine, or a combination thereof. Excessive levels of glutamate have been shown to be toxic to neurons, and evidence suggests that both direct and indirect glutamate toxicity may lead to the pathogenesis of motor neuron degeneration in diseases such as ALS. FP0011 is an anti-glutamatergic compound that can reduce presynaptic glutamate levels and show powerful neuroprotective properties. Memantine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist that has been shown to protect neurons from NMDA or glutamate-induced toxicity in vitro and in animal models of neurodegenerative diseases. In an embodiment, memantine is administered at 2 mg, 5 mg, 7 mg, 10 mg, 14 mg, 21 mg, or 28 mg. N-acetylated-α-linked acid dipeptidase (NAALADase) converts N-acetyl-aspartyl-glutamate into glutamate during neuronal damage and may represent a new method to block excess glutamate release in the treatment of neurodegenerative disorders without interfering with normal brain function. Nimodipine is a dihydropyridine calcium channel blocker that can antagonize excitatory amino acid receptor activation to reduce calcium entry into damaged neurons and may help slow or reverse ALS. In an embodiment, nimodipine is administered at 30 mg or 60 mg.

[0334] In an embodiment, one or more active agents are mitochondrial energy promoters, such as but not limited to resveratrol, creatine, erythropoietin, cholest-4-ene-3-one oxime (TRO-19622) and combinations thereof. Resveratrol is a powerful antioxidant found in red grape skins, and has been found to inhibit calcium influx into cells associated with glutamate-induced cytotoxicity. In an embodiment, resveratrol is administered at 100mg, 500mg, 1000mg or 1500mg. Creatine contributes to the formation of ATP (the main source of cellular energy in the body), and has been shown to provide a protective mechanism against neurodegenerative diseases by stabilizing cell membranes and mitochondrial energy transfer complexes (which can reduce motor neuron death by improving mitochondrial function). Creatine can also reduce oxidative stress and increase glutamate uptake, and can help reduce muscle strength loss in ALS patients. In an embodiment, creatine is administered at about 750mg to about 5 grams. Erythropoietin (EPO) is a glycoprotein hormone that controls erythropoiesis, red blood cell production, and has recently been identified as a cytokine with a variety of neuroprotective effects (including, for example, reducing inflammation, enhancing survival signals, and preventing neuronal cell death). Cholesterol-4-ene-3-one oxime (TRO-19622) is a low molecular weight compound that enhances motor neuron survival and growth by interacting with protein components of the mitochondrial permeability transition pore, and can rescue motor neuron cell bodies from axonomy-induced cell death in vivo. In an embodiment, one or more active agents are creatine.

Claims

1. A compound having the formula: or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating Kv7-related disorders.

4. The use according to claim 3, wherein the Kv7-related disorder is selected from epilepsy, neonatal spasms, pain, neurotransmitter release disorders, smooth muscle contraction disorders, movement disorders, dystonia, mania, hearing disorders, anxiety, drug abuse, schizophrenia, bladder disorders, vascular system disorders, tinnitus, frontotemporal dementia and amyotrophic lateral sclerosis.

5. The use according to claim 4, wherein the pain is selected from neuropathic pain, inflammatory pain, persistent pain, cancer pain, migraine and postoperative pain.

6. The use according to claim 4, wherein the frontotemporal dementia is familial frontotemporal dementia.

7. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disorder associated with KCNQ2 mutation.

8. The method of claim 7, wherein the disorder associated with a KCNQ2 mutation is selected from the group consisting of neonatal spasms, epilepsy, benign familial neonatal convulsions type 1 (BFNC), epileptic spasms, epileptic encephalopathy, generalized tonic seizures, globus pallidus morphologic abnormalities, apnea, cerebral edema, dystonia, facial erythema, hypotonia, corpus callosum agenesis, hyperrhythmia, spastic quadriplegia, and myokymia.

9. The method of claim 7, wherein the disorder associated with KCNQ2 mutation is selected from the group consisting of neonatal seizures, focal clonic seizures, generalized tonic-clonic seizures, and febrile seizures.

10. The use according to claim 7, wherein the disorder associated with KCNQ2 mutation is selected from benign familial neonatal seizures 1 (BFNS1), early infantile epileptic encephalopathy 7 (EIEE7), benign familial neonatal epilepsy (KCNQ2-BFNE), neonatal seizures associated with hypoxic-ischemic injury, epileptic encephalopathy (KCNQ2-NEE) and early infantile epileptic encephalopathy with psychomotor retardation.

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