Kv7 channel activator composition and use method

Abstract

To provide a compound for treating Kv7-related diseases such as epilepsy, amyotrophic lateral sclerosis, various types of pain, hyperexcitability, dyskinesia, dystonia, mania and tinnitus.SOLUTION: Provided are an optionally substituted benzimidazol-1,2-yl amide represented by formula 11, and a pharmaceutical composition having a therapeutically effective amount of said compound and a pharmaceutically acceptable excipient.SELECTED DRAWING: None

Description

[Technical field]

[0001] This invention was made with United States Government support under Grant No. U44NS093160 awarded by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. The United States Government has certain rights in this invention. [Background technology]

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 644,902, filed March 19, 2018, U.S. Provisional Application No. 62 / 644,932, filed March 19, 2018, U.S. Provisional Application No. 62 / 663,438, filed April 27, 2018, and U.S. Provisional Application No. 62 / 697,198, filed July 12, 2018. The disclosures of each of these applications are incorporated herein by reference. Summary of the Invention

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

[0004] Native M channels, and the corresponding macroscopic M currents, were first characterized in amphibian sympathetic neurons. M channels activate and deactivate slowly, are active at or near the resting membrane potential of the neuron, muscarinic cholinergic agonists reduce M currents, and interact with G protein-coupled receptors (GPCRs) and physiological K currents. + It was not until the cloning of this gene subfamily that the pharmacological and biophysical identity between Kv7.2 / 7.3 (and possibly Kv7.5 / 7.3) heteromultimers and the elusive "M" channels was established, providing important new evidence for their importance in neuronal control.

[0005] The distribution of these channels, both regionally and developmentally, as well as their biophysical properties, support their role in providing durable resistance to depolarizing excitatory influences. Under physiological conditions, as demonstrated for native M channels, they are highly effective in regulating the subthreshold excitability of certain neuronal populations and play a key role in regulating the frequency and final pattern of action potential discharge in many types of neurons. Their importance in regulating neurons was interrupted by the discovery that neuronal Kv7 mutations lead to benign familial neonatal convulsions (BFNC), indicating that reduction or elimination of the influence of Kv7.2 and Kv7.3 channels can dramatically alter neuronal excitability. Mutational analysis demonstrated their involvement in BFNC, suggesting their usefulness as targets for antiepileptic drugs (AEDs).

[0006] Unlike the established pharmacological terminology for GPCRs, K +The mechanism of action of channel modulators, especially compounds that activate channels, is still being refined. The application of voltage clamp techniques to the study of ion channel pharmacology has enabled detailed biophysical studies of whole-cell currents or single channels, allowing characterization of the nature of compound-channel interactions, but has not prevented continuing confusion regarding terminology. The terms openers or activators are commonly used throughout the literature, but do not adequately describe the mechanism of action of all these “positive modulator” compounds. In general, openers or activators are expected to increase the open probability of the channel or increase the macroscopic current amplitude, but this nomenclature is actually too simplistic. For example, retigabine, the first published Kv7 opener, has a complex and intriguing profile in that it has inhibitory activity at higher membrane potentials. Neuronal Kv7 channel openers work in concert with the activity of the channel in the “normal” activation voltage range, enhancing current without significantly affecting the activation threshold, while others can significantly alter the activation threshold. Furthermore, some openers appear to completely remove the voltage dependence of activation. Whether these effects represent any continuum is currently unclear, as they are often concentration-dependent. Clearly, the mode of interaction of compounds that may increase channel currents is complex and in most cases not well understood, and the impact of these profiles on neuronal responsiveness and system physiology is also unclear. Retigabine is a moderately potent, but not highly specific, highly effective opener of Kv7.2, Kv7.5, and heteromultimeric Kv7 channels. Its effect is characterized by a large increase in channel current over a narrow voltage range. As mentioned above, the opener is less effective at more positive voltages, and under certain conditions, the channel current is significantly reduced at more positive voltages compared to the control current (this "crossover" voltage dependence of the opener's action is characteristic of many neuronal Kv7 channel openers). This effect is also concentration dependent, becoming more pronounced at higher concentrations.

[0007] Provided herein are compounds that are potent and / or at least can be biased towards Kv7.2 / 7.3 heteromultimers over Kv7.4 homomultimers, which may have reduced adverse side effects compared to retigabine. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Before the compositions and methods of the present invention are described, it should be understood that any invention is not limited to the specific processes, compositions, or methodologies described. Moreover, the processes, compositions, and methodologies described in a particular embodiment are interchangeable. Thus, for example, a composition, dosing regimen, route of administration, etc. described in a particular embodiment can be used in any of the methods described in other particular embodiments. It should also be understood that the terms used in the description are only for the purpose of describing the particular versions or embodiments, and are not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless expressly defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one 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, the preferred methods are described herein. All publications and references described herein are incorporated by reference. Nothing herein should be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0009] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references 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 with which it is used. Thus, about 50% means a range of 45% to 55%. Unless otherwise indicated, all numbers expressing properties such as amounts of ingredients, molecular weights, reaction conditions, and the like used in the specification and claims should be understood in all instances to be modified by the term "about". Thus, unless indicated to the contrary, the numerical parameters set forth in the specification and the appended claims are approximations that may vary depending on the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed at least in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0011] "Administering," when used in conjunction with a therapeutic agent, means administering the therapeutic agent directly into or onto a target tissue, or administering the therapeutic agent to a subject, whereby the therapeutic agent positively affects the tissue to which it is targeted. "Administering" a composition can be accomplished by oral administration, injection, infusion, absorption, or any method in combination with other known techniques. "Administering" can include the act of self-administration, or administration by another person, such as a health care 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 a composition or method includes only those elements, steps, or ingredients specifically recited in a particular embodiment or claim.

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

[0015] The term "improve" is used to convey that the present invention refers to the overall physical condition of an individual to whom an active agent is administered. For example, an individual's overall physical condition may be "improved" if one or more symptoms of a condition, disease, or disorder, such as a neurodegenerative disorder, are alleviated by administration of an active agent. "Improve" may also refer to a change in the appearance, morphology, characteristics, and / or physical attributes of the tissue, or any combination thereof, to which it is provided, applied, or administered.

[0016] The terms "inhibit," "suppress," "reduce," "interfere," and / or "reduce" (and similar terms) generally refer to the act of directly or indirectly diminishing a function, activity, or behavior compared to what is naturally expected, or the average, or compared to the current state.

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

[0018] Examples of Kv7-related disorders associated with mutations in the KCNQ2 gene include, but are not limited to, benign familial neonatal seizures (BFNS) or KCNQ2 encephalopathy (also known as KCNQ2 neonatal epileptic encephalopathy). Examples of Kv7-related disorders associated with mutations in the KCNQ3 gene include, but are not limited to, BFNS or KCNQ3-related developmental disorders. Examples of Kv7-related disorders associated with mutations in the KCNQ4 gene include, but are not limited to, autosomal dominant nonsyndromic hearing loss. Examples of Kv7-related disorders associated with mutations in the KCNQ5 gene include, but are not limited to, nonsyndromic intellectual disability or epileptic encephalopathy. Examples of disorders associated with cellular hyperexcitability that are 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 disorder, or a combination thereof.

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

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

[0021] As used herein, the terms "patient" and "subject" are interchangeable and may be taken to mean any organism that may be treated with the compounds of the present invention. Thus, the terms "patient" and "subject" may include, but are not limited to, non-human mammals, primates, or humans. 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, cow, sheep, horse, primate, or human.

[0022] As used herein, the terms "therapeutically effective amount" or "therapeutic dose" are interchangeable and can refer to an amount of an active agent or pharmaceutical compound that induces a clinical, biological or medical response in a tissue, system, animal, individual or human as desired by a researcher, veterinarian, physician or other clinical professional. The clinical, biological or medical response can include, for example, one or more of the following: (1) preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but has not yet experienced or exhibited a pathology or symptom of the disease, condition or disorder; (2) inhibiting a disease, condition or disorder in an individual who is experiencing or exhibiting a pathology or symptom of the disease, condition or disorder or preventing further progression of the pathology and / or symptom of the disease, condition or disorder; and (3) improving a disease, condition or disorder in an individual who is experiencing or exhibiting a pathology or symptom of the disease, condition or disorder or reversing the pathology and / or symptom experienced or exhibited by the individual.

[0023] The terms "treat," "treated," or "treating" may be interpreted to mean prevention of a particular disorder, disease, or condition, alleviation of symptoms associated with a particular disorder, disease, or condition, and / or prevention of symptoms associated with a particular disorder, disease, or condition. In some embodiments, the term refers to slowing the progression of a disorder, disease, or condition, or reducing 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 functionality that has been impaired or lost due to a particular disorder, disorder, or condition.

[0024] By "pharmaceutically acceptable salt" is meant a salt that is suitable for use in contact with the tissues of a patient, within the scope of sound medical judgment, without undue toxicity, irritation, allergic reaction, etc., and 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 describes pharmaceutically acceptable salts in detail. A pharma- ceutically acceptable "salt" is any acid addition salt, preferably a pharma- ceutically acceptable acid addition salt, including, but not limited to, halogen acid salts such as hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, etc.; inorganic acid salts such as, for example, nitrates, perchlorates, sulfates, and phosphates; organic acid salts such as, for example, sulfonates (methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates or p-toluenesulfonates, acetates, malates, fumarates, succinates, citrates, benzoates, gluconates, lactates, mandelates, mucates, pamoates, pantothenates, oxalates, maleates); and amino acid salts such as aspartates and glutamates. The acid addition salt may be a mono- or di-acid addition salt, such as a dihydrohalogen acid salt, a di-sulfate salt, a di-phosphate salt, or a di-organo acid salt. In all cases, the acid addition salts used as achiral reagents are not selected on the basis of any anticipated or known preference for interaction with or precipitation of a particular optical isomer of the products of the present disclosure.

[0025] Unless otherwise indicated, when a compound or chemical structural feature, such as an aryl, is referred to as "optionally substituted," it is meant to include a feature that does not have a substituent (i.e., unsubstituted) or a feature that is "substituted," i.e., a feature that has one or more substituents. The term "substituent" has its broadest meaning known to those of skill in the art and includes a moiety that replaces one or more hydrogen atoms attached to a parent compound or structural feature. In some embodiments, the substituent may be a conventional organic moiety known in the art and may have a molecular weight (e.g., the sum of the atomic weights of the atoms of the substituent) in the range of 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, a substituent has 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, each of which may independently be N, O, S, Si, F, Cl, Br, or I, with the proviso that the substituent contains one C, N, O, S, Si, F, Cl, Br, or I atom. Examples of substituents include, but are not limited to, alkyl, alkenyl, alkynyl, heteroalkynyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanate, isothiocyanate, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, and the like.

[0026] For convenience, the term "molecular weight" is used in reference to a portion or region of a molecule, rather than a complete molecule, to indicate the sum of the atomic weights of the atoms in the portion or region of the molecule.

[0027] Below are shown structures associated with some of the chemical names mentioned herein. As shown below, these structures may be unsubstituted, or, if the structures are unsubstituted, a substituent may be present independently at any position normally occupied by a hydrogen atom. [ka] Unless indicated otherwise, attachment may 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 a moiety composed of carbon and hydrogen without double or triple bonds. An alkyl may be a straight chain alkyl, branched alkyl, cycloalkyl, or combinations thereof, and in some embodiments, may contain 1 to 35 carbon atoms. In some embodiments, an alkyl may be a C alkyl group 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. 1-10 Straight chain alkyl; C3H7 (e.g. isopropyl), C4H9 (e.g. branched butyl isomers), C5H 11 (e.g. branched pentyl isomers), C6H 13 (e.g. branched hexyl isomers), C7H 15 (e.g. branched heptyl isomers) 3-10 Branched alkyl; 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. 3-10 cycloalkyl, and the like.

[0029] With respect to an optionally substituted moiety, such as an optionally substituted alkyl, the term "optionally substituted C 1-12 Phrases such as "alkyl" and "alkyl" refer to C alkyl groups which may be unsubstituted or may have one or more substituents. 1-12 The term "alkyl" refers to an alkyl group and does not limit the number of carbon atoms in the substituent. Thus, for example, the parent alkyl group has 12 carbon atoms, so CH2(CH2) 11 OCH3 is an optionally substituted C 1-12 It is an alkyl group. 1-12 The phrases "optionally substituted alkyl" and the like refer to unsubstituted C 1-12 It refers to an alkyl, or substituted alkyl, in which the alkyl parent and all substituents taken together have 1 to 12 carbon atoms. For example, CH2CH2OCH3 is a C alkyl group because the alkyl group (e.g., ethyl) and the substituents (e.g., methoxy) together contain 3 carbon atoms. 1-12 and optionally substituted alkyl. Similar rules can be applied to other optionally substituted moieties such as aryl and heterocyclyl.

[0030] The substituents on the alkyl can be the same as those generally described above. In some embodiments, the substituents on the alkyl can be independently selected from F, Cl, Br, I, CN, CO2H, -O-alkyl, ester groups, acyl, amine groups, amide groups, phenyl (including fused phenyl, where the phenyl substituent is fused to the parent alkyl moiety, resulting in an optionally substituted alkyl such as indenyl), and can have a molecular weight of about 15 to about 100, or about 500.

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

[0032] The term "heterocyclyl" includes any ring or ring system containing a heteroatom, such as N, O, S, P. 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, oxatanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxalanyl, dithiolanyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino, and the like.

[0033] The term "heteroaryl" also has the meaning understood by one of ordinary skill in the art and includes "aryls" having one or more heteroatoms in the ring or ring system, such as pyridinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, oxadiazolyl, isoxazolyl, indolyl, quinolinyl, 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 cycloalkyls, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; cycloalkenyls, e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.; cycloalkynyls, e.g., cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl, etc.; bridged cycloalkyls, e.g., bicyclo[1.1.1]pentane, norbornane, etc.; and rings that do not contain heteroatoms, such as aryl rings that do not contain heteroatoms.

[0035] Where stereochemistry is not indicated, the name or structural representation includes any stereoisomer or mixture of any stereoisomers, and applicants reserve the right to specifically identify and claim compounds as single stereoisomers or mixtures of any particular stereoisomers.

[0036] The 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 further exist as diastereomers. The embodiments herein include all possible stereoisomers, such as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers. In some embodiments, the formulas are shown without a definite stereochemistry at a particular position. The embodiments herein include all stereoisomers of such formulas and pharma- ceutically acceptable salts thereof. Diastereoisomeric pairs of enantiomers may be separated, for example, by fractional crystallization from a suitable solvent, and the enantiomeric pairs thus obtained may be separated into individual stereoisomers by conventional means, for example, by the use of optically active acids or bases as resolving agents or on a chiral HPLC column. Additionally, any enantiomer or diastereomer of a compound of the general formula may be obtained by stereospecific or stereoselective synthesis using optically pure or enantioenriched starting materials or reagents of known configuration. The scope of the embodiments described and claimed herein includes racemic forms of the compounds, as well as individual enantiomer-, diastereomer-, and stereoisomer-enriched mixtures, and applicants reserve the right to specifically identify and claim the compounds in such forms.

[0037] The compounds disclosed herein can exist as all stereoisomers, conformational isomers, and mixtures thereof in all ratios, as well as isotopic forms, such as deuterated compounds, and therefore applicants reserve the right to specifically identify and claim such forms of the compounds.

[0038] Disclosed herein are examples of developments in Kv7.2 / 7.3 structure-activity relationships that have resulted in a significant increase in potency against this ion channel target. The EC 50is 1.1 μM as characterized in the Kv7.2 / 7.3 FluxOR potassium ion channel assay (Invitrogen, F20015). Species described in US2017 / 0114022, US2018 / 0148419, and WO2018 / 081825, tested in the thallium flux assay, are EC 50 Kv7.2 / 7.3 have a range of potencies as indicated by their EC 50 Only a few (11%) had values ​​below 0.30 μM. The genera and species described herein distinguish themselves from previous chemical entities as Kv7 activators, as shown by their superior activity against Kv7.2 / 7.3. The thallium flux EC 50 Values ​​range from ≦1 μM to ≦0.3 μM, with EC 50 Some of these new examples have a value of ≦0.05 μM. In certain preferred embodiments, the compounds of the present application have R 2 and having small non-hydrogen substituents at positions 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14. [ka] In combination with increasing substitution at the beta position to the carbonyl of an optionally substituted hydrophobic alkyl group, Kv7.2 / 7.3 EC 50 yields <1 μM.

[0039] Some embodiments include a compound represented by formula 1C: [ka]

[0040] With respect to Formula 1C, Bz can be an optionally substituted benzimidazol-1,2-yl. When the benzimidazol-1,2-yl is substituted, it can have 1, 2, 3, or 4 substituents. The benzimidazol-1,2-yl can include any substituent. In some embodiments, some or all of the substituents on the benzimidazol-1,2-yl can have 0-10 carbon atoms and 0-10 heteroatoms, where each heteroatom is independently: O, N, S, F, Cl, Br, or I (provided that at least one non-hydrogen atom is present), and / or has a molecular weight of 15 g / mol to 500 g / mol. In some embodiments, some or all of the substituents can have a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to 50 Da, respectively, and consist of 2 to 5 chemical elements, which 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, with respect to Formula 1C, the substituents of Bz are CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H 11 , cyclic C5H9, C6H 13 , cyclic CH 11 C etc. 1-10 It may be an optionally substituted alkyl, such as OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 , Cyclic OC5H9, OC6H 13 , cyclic OC6H 11 C etc. 1-10 Optionally substituted alkoxy; halo, such as F, Cl, Br, I; OH; CN; NO2; C, such as CF3, CF2H, C2F5 1-6 Fluoroalkyl; C such as OCF3, OCF2H, OC2F5 1-6Fluoroalkoxy; C such as -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl 1-10 Esters; -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc. 1-10 Ketones; or C, such as NH2, NH(CH3), N(CH3)2, and N(CH3)C2H5 1-10 In some embodiments, the substituents of Bz are 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, COH, C 1-4 CO2-alkyl, NH2, or C 1-4 It may be alkylamino.

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

[0043] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, where D is an optionally substituted C 3-6 Carbocyclyl or C 2-5D is heterocyclyl. When D is substituted cyclobutyl, it can have 1, 2, 3, 4, 5, 6, or 7 substituents. When D is substituted phenyl, it can have 1, 2, 3, 4, or 5 substituents. When D is substituted isoxazolyl, it can have 1 or 2 substituents. D can include any substituent. In some embodiments, some or all of the substituents of D can have 0-10 carbon atoms and 0-10 heteroatoms, where each heteroatom is independently: O, N, S, F, Cl, Br, or I (provided that at least one non-hydrogen atom is present), and / or have a molecular weight of 15 g / mol to 500 g / mol. In some embodiments, some or all of the substituents may have a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to 50 Da, respectively, and consist of 2 to 5 chemical elements, where the chemical elements are independently C, H, O, N, S, F, Cl, or Br.

[0044] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, where the substituents of D are optionally substituted CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H 11 , cyclic C5H9, C6H 13 , cyclic CH 11 , bicyclo[1.1.1]pentane, norbornane, etc. 1-10 Optionally substituted alkyl; OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 , Cyclic OC5H9, OC6H 13 , cyclic OC6H 11 C etc. 1-10 Optionally substituted alkoxy; halo, such as F, Cl, Br, I; OH; CN; NO2; C, such as CF3, CF2H, C2F5 1-6 Fluoroalkyl; C such as OCF3, OCF2H, OC2F5 1-6 Fluoroalkoxy; C such as -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl1-10 Esters; -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc. 1-10 Ketones; or C, such as NH2, NH(CH3), N(CH3)2, and N(CH3)C2H5 1-10 In some embodiments, the substituents of D are F, Cl, Br, I, CN, NO, C 1-4 Alkyl, C 1-4 Alkyl-OH, C 1-3 O-Alkyl, CF3, COH, C 1-4 CO-Alkyl, COH, C 1-4 CO2-alkyl, NH2, or C 1-4 It may be alkylamino.

[0045] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, and in some embodiments, D is [ka] or any substituted C 2-4 It is an alkyl.

[0046] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, where in some embodiments, D is an optionally substituted cyclobutyl, an optionally substituted phenyl, an optionally substituted isoxazolyl, a bicyclo[1.1.1]pentane, a norbornane, or an isopropyl.

[0047] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, in some embodiments, D is an optionally substituted cyclobutyl. In some embodiments, D is a cyclobutyl. In some embodiments, D is [ka] It is.

[0048] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, in some embodiments, D is isopropyl.

[0049] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, in some embodiments, D is t-butyl, or tert-butyl.

[0050] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, where in some embodiments, D is bicyclo[1.1.1]pentane.

[0051] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, where in some embodiments, D is an optionally substituted phenyl. In some embodiments, D is [ka] It is.

[0052] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, where in some embodiments, D is an optionally substituted pyridinyl, such as an optionally substituted pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl. [ka] It is.

[0053] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, where in some embodiments, D is an optionally substituted isoxazolyl. [ka] It is.

[0054] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, where A is [ka] C etc. 1-8 It is an alkyl.

[0055] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, where X is H, F, CH3, SCF3, CF3, optionally substituted C 2-10 In some embodiments, X is H. In some embodiments, X is CH. In some embodiments, X is F. In some embodiments, X is CF.

[0056] In any relevant embodiment or structural representation of formula 1C or 2C herein, when X is a substituted phenyl, it may have 1, 2, 3, 4, or 5 substituents. When X is a substituted pyridinyl, it may have 1, 2, 3, or 4 substituents. In some embodiments, some or all of the substituents of X may have 0-10 carbon atoms and 0-10 heteroatoms, where each heteroatom is independently: O, N, S, F, Cl, Br, or I (provided that at least one non-hydrogen atom is present), and / or have a molecular weight of 15 g / mol to 500 g / mol. In some embodiments, some or all of the substituents may have a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to 50 Da, respectively, and consist of 2 to 5 chemical elements, where the chemical elements are independently C, H, O, N, S, F, Cl, or Br.

[0057] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, where the X substituent is CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H 11 , cyclic C5H9, C6H13 , cyclic CH 11 C etc. 1-10 It may be an optionally substituted alkyl, such as OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, cyclic OC5H 11 , Cyclic OC5H9, OC6H 13 , cyclic OC6H 11 C etc. 1-10 Optionally substituted alkoxy; halo, such as F, Cl, Br, I; OH; CN; NO2; C, such as CF3, CF2H, C2F5 1-6 Fluoroalkyl; C such as OCF3, OCF2H, OC2F5 1-6 Fluoroalkoxy; C such as -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl 1-10 Esters; -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc. 1-10 Ketones; or C, such as NH2, NH(CH3), N(CH3)2, and N(CH3)C2H5 1-10 In some embodiments, the substituents of X are F, Cl, Br, I, CN, NO, C 1-4 Alkyl, C 1-4 Alkyl-OH, C 1-3 O-Alkyl, CF3, COH, C 1-4 CO-Alkyl, COH, C 1-4 CO2-alkyl, NH2, SCF3, or C 1-4 It may be alkylamino.

[0058] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, where 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, where the 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 C0-6 In some embodiments, Y is H, F, CF, OH, C 1-5 O-Alkyl, C 0-6 Amino, or C 0-6 In some embodiments, Y is fluoroamino. In some embodiments, Y is H. In some embodiments, Y is OH. In some embodiments, Y is F. In some embodiments, Y is CF. In some embodiments, Y is a C alkyl group such as -OCH, OC, OC, H, etc. 1-3 In some embodiments, Y is C 0-6 In some embodiments, Y is [ka] In some embodiments, Y is an optionally substituted tetrahydropyranyl such as one or two C 3-6 C, which may contain a carbocyclyl ring 1-8 In some embodiments where Y includes at least one carbocyclyl ring, the 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 [ka] (or methyl(2,2,2-trifluoroethyl)amino). In some embodiments, Y is dimethylamino.

[0059] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, and in some embodiments: [ka] teeth, [ka] C etc.2-8 It is an alkyl.

[0060] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, and in some embodiments: [ka] teeth, [ka] C etc. 2-8 It is a hydroxyalkyl.

[0061] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, and in some embodiments: [ka] teeth, [ka] C etc. 2-8 It is a fluoroalkyl.

[0062] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, and in some embodiments: [ka] teeth, [ka] C etc. 2-8 It is an alkoxyalkyl.

[0063] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, and in some embodiments: [ka] teeth, [ka] C etc. 2-8 It is a hydroxyfluoroalkyl.

[0064] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, and in some embodiments: [ka] teeth, [ka] In some embodiments, the 2-hydroxy-2-phenylethyl group is an optionally substituted 2-hydroxy-2-phenylethyl group, such as [ka] teeth, [ka] It is.

[0065] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, and in some embodiments: [ka] teeth, [ka] and the like.

[0066] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein, and in some embodiments: [ka] teeth, [ka] Any substitution of C such as 2-8 It is a fluoroaminoalkyl.

[0067] The following applies to any relevant embodiment or structural representation of formula 1C or 2C herein. 1-18 can be H or any substituent, for example, a substituent having 0-12 atoms or 0-6 carbon atoms and 0-5 heteroatoms, where each heteroatom is independently O, N, S, F, Cl, Br, or I, and / or has a molecular weight of 15 g / mole to 300 g / mole. 1-18 may have a) one or more optionally substituted or optionally attached alkyl moieties, 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, or substituents that do not have an alkyl moiety, such as F, Cl, Br, I, NO2, CN, NH2, OH, COH, CO2H. In some embodiments, R 1-18 each of 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 consists of 2 to 5 chemical elements, and the chemical elements are independently C, H, O, N, S, F, Cl, or Br.

[0068] For any relevant structural representation of formula 1C or 2C, R 1-18 Some non-limiting examples of A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R Betc. In some embodiments, R 1-18 is H; F; Cl; Br; CN; C such as methyl, ethyl, propyl isomers (e.g., n-propyl and isopropyl), cyclopropyl, butyl isomers, cyclobutyl isomers (e.g., cyclobutyl and methylcyclopropyl), pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 Alkyl; optionally substituted C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl, -O-benzyl, etc. 1-7 Alkoxy; -CHOH, -CH-OH, -CH-OH, C 1-4 Hydroxyalkyl; C such as -CO2-CH3, -CO2-C2H5, -CO2-C3H7, -CO2-C4H9 2-5 It can be -CO2-alkyl. [ka]

[0069] For any relevant structural representation of formula 1C or 2C, R A Each of is independently H or a group of formula C a H 2a+1 or a linear or branched alkyl group having the formula C a H 2a-1 Cycloalkyl having C 1-12 alkyl, where a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as those of the formula: CH3, C2H5, C3H7, C4H9, C5H 11 , C6H 13 , C7H 15 , C8H 17 , C9H 19 , C 10 H 21 or linear or branched alkyl such as C3H5, C4H7, C5H9, C6H 11 , C7H 13 , C8H15 , C9H 17 , C 10 H 19 In some embodiments, R A is H or optionally substituted C 1-6 In some embodiments, R A is H or optionally substituted C 1-3 R can be alkyl. A may be H or CH. In some embodiments, R A can be H.

[0070] For any relevant structural representation of formula 1C or 2C, R B Each of is independently H or a group of formula C a H 2a+1 or a linear or branched alkyl group having the formula C a H 2a-1 Cycloalkyl having C 1-12 alkyl, where a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as those of the formula: CH3, C2H5, C3H7, C4H9, C5H 11 , C6H 13 , C7H 15 , C8H 17 , C9H 19 , C 10 H 21 or linear or branched alkyl such as C3H5, C4H7, C5H9, C6H 11 , C7H 13 , C8H 15 , C9H 17 , C 10 H 19 In some embodiments, R B is H or optionally substituted C 1-3 R can be alkyl. B may be H or CH. In some embodiments, R B can be H.

[0071] With respect to any related structural representation of Formula 1C or 2C, such as Formula 2C, in some embodiments, R 1 are 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 are H, Cl, Br, CN, OCH3, OCHF2, CHF2, CF3, -CO2CH2CH3, -CH2OH, [ka] In some embodiments, R 1 is H. In some embodiments, R 1 is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br. In some embodiments, R 1 is CN. In some embodiments, R 1 is OCH. In some embodiments, R 1 is CF3. In some embodiments, R 1 is -COCHCH. In some embodiments, R 1 is -CHOH. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is -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. With respect to the embodiments described in this paragraph, in some embodiments, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are independently 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 It may be a hydroxyalkyl.

[0072] With respect to any relevant structural representation of formula 1C or 2C, in some embodiments, R 2 are 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, R2 is F. In some embodiments, R 2 is CHOH. In some embodiments, R 2 is -CO2CH3. With respect to the embodiments described in this paragraph, in some embodiments, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and 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 is -CH2OH, -CO2Me, or -C(CH3)2OH.

[0073] With respect to any relevant structural representation of formula 1C or 2C, in some embodiments, R 3 are H, F, Cl, Br, CN, OCH3, OCHF2, 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 is F. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A, C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and 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 It may be a hydroxyalkyl.

[0074] With respect to any relevant structural representation of formula 1C or 2C, in some embodiments, R 4 are 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 With respect to the embodiments described in this paragraph, in some embodiments, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONRA R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0075] With respect to any relevant structural representation of formula 1C or 2C, in some embodiments, R 5 are 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 5 is CH3. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0076] With respect to any relevant structural representation of formula 1C or 2C, in some embodiments, R 6 are 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 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0077] With respect to any relevant structural representation of formula 1C or 2C, in some embodiments, R 7 are 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 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0078] With respect to any relevant structural representation of formula 1C or 2C, in some embodiments, R 8 are 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 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0079] With respect to any relevant structural representation of formula 1C or 2C, in some embodiments, R 9 are 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 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0080] With respect to any relevant structural representation of formula 1C or 2C, in some embodiments, R 10 are H, F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-Alkyl, C 1-4 Alkyl or C 1-5 In some embodiments, R10 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0081] With respect to any relevant structural representation of formula 1C or 2C, in some embodiments, R 11 are 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 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR AR B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0082] With respect to any relevant structural representation of formula 1C or 2C, in some embodiments, R 12 are 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 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0083] With respect to any relevant structural representation of formula 1C or 2C, in some embodiments, R 13are 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 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0084] With respect to any relevant structural representation of formula 1C or 2C, in some embodiments, R 14 are 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 is F. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C1-5 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0085] In some embodiments of the present invention, one or more hydrogen atoms are replaced by deuterium.It is well established that deuteration of physiologically active compounds provides the advantage of retaining the pharmacological profile of their hydrogen counterparts while positively affecting their metabolic results.In the compounds of the present invention, selectively replacing one or more hydrogen atoms with deuterium can improve the safety, tolerability and efficacy of the compound when compared with its all hydrogen counterparts.

[0086] The method of incorporating deuterium into a compound is well established.Using metabolic studies established in the art, the compound of the present invention can be tested to identify the site for selective placement of deuterium isotope, where the isotope is not metabolized.Furthermore, these studies identify metabolic site as the place where deuterium atom is placed.

[0087] In certain embodiments, the embodiments described herein do not include compounds explicitly disclosed in U.S. Patent No. 9,481,653, WO2016 / 040952, U.S. Provisional Application No. 62 / 579,770, U.S. Provisional Application No. 62 / 663,427, or U.S. Provisional Application No. 62 / 644,932.

[0088] In certain embodiments, the compound of formula 1C has a Kv7.2 / 7.3 thallium flux EC of 10 μM or less. 50 In certain embodiments, the compound of formula 1C has a Kv7.2 / 7.3 thallium flux EC 50 In certain embodiments, the compound of formula 1C has a Kv7.2 / 7.3 thallium flux EC of 0.3 μM or less. 50 has.

[0089] Some embodiments of Formula 1C include compounds represented by formula 8a: [ka] During the ceremony, D is optionally substituted cyclobutyl or t-butyl; A is a C alkyl; X is a substituted cyclobutyl, the substituent being 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 with two fluorine atoms, the fluorine atoms are not geminal, and the compounds represented by formula 8a, or a pharma- ceutically acceptable salt thereof, may be included.

[0090] Some embodiments of Formula 1C include compounds represented by formula 8b: [ka] During the ceremony, D is optionally substituted cyclobutyl or t-butyl, the optional substituents being selected from CH3 and F; A is a C alkyl; X is a substituted cyclobutyl, the substituent being F; Y is H, R 1 is selected from C3 hydroxyalkyl, CN, or F; R 2 is selected from H, F, or -OCF3; R 3 is selected from H, F, or -OCH3; R 4 is H or F, and When X is substituted with two fluorine atoms, the fluorine atoms are not geminal. It may include a compound represented by formula 8b, or a pharma- ceutically acceptable salt thereof.

[0091] Some embodiments of Formula 1C include compounds represented by formula 8c: [ka] During the ceremony, D is optionally substituted cyclobutyl, optionally substituted phenyl, or t-butyl, the optional substituents being selected from -CH3 and F; A is a C alkyl; X is a substituted cyclobutyl, the substituent being F; Y is H, R 1 is selected from H, C3 hydroxyalkyl, CN, F, or Cl; R 2 is selected from H, CN, F, Br, or -OCF3; R 3 is selected from H, F, or -OCH3; R 4 is H or F, and When X is substituted with two fluorine atoms, the fluorine atoms are not geminal. It may include a compound represented by formula 8c, or a pharma- ceutically acceptable salt thereof.

[0092] Some embodiments of Formula 1C include compounds represented by formula 9: [ka] During the ceremony, D is cyclobutyl; A is a C alkyl; X is optionally substituted cyclobutyl, the substituent being F; Y is H, R 1 is a C3 hydroxyalkyl; R 2 and R 4 is H, R 3 is F, and When X is substituted with two fluorine atoms, the fluorine atoms are not geminal. The compound may include a compound represented by formula 9, or a pharma- ceutically acceptable salt thereof.

[0093] Some embodiments of Formula 1C include compounds represented by Formula 10: [ka] During the ceremony, D is an optionally substituted C 2-5 alkyl, the optional substituents being selected from -CH3 and F; A is C 1-6 is alkyl, X is H, F, -CH3, -CF3, -SCF3, pyridinyl, optionally substituted C 1-3 alkyl, optionally substituted phenyl, or optionally substituted cyclobutyl, each of which 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 Heterocyclyl, optionally substituted C 1-5 Alkyl, optionally substituted C1-7 Alkoxy, -NR A R B or halogen, the optional substituents being selected from -OH and F; R 2 is H, halogen, -CN, -OCH3, -COR A , -CF3, -OCF3, optionally substituted C1 alkyl, where R 2 The optional substituents are -OCH3 and -COR A is selected from R 3 is H, halogen, -CF3, -OCHF2, -OCF3, or -OCH3, R 4 is H, halogen, or C3 hydroxyalkyl; R A and R B is CH3, The compound may include a compound represented by formula 10, or a pharma- ceutically acceptable salt thereof.

[0094] Some embodiments of Formula 1C include compounds represented by formula 11: [ka] During the ceremony, D is an optionally substituted C 2-5 alkyl or optionally substituted phenyl, the optional substituents being selected from -CH3 and F; A is C 1-6 is alkyl, X is H, F, -CH3, -CF3, -SCF3, pyridinyl, optionally substituted C 1-3 alkyl, optionally substituted phenyl, or optionally substituted cyclobutyl, each of which is F; Y is H, F, -OH, or -CH3; R 1 , H, C 3-4 Hydroxyalkyl, -CN, -OH, -CF3, -OCHF2, optionally substituted C 3-5Heterocyclyl, optionally substituted C 1-5 Alkyl, optionally substituted C 1-7 Alkoxy, -NR A R B or halogen, the optional substituents being selected from -OH and F; R 2 is H, halogen, -CN, -OCH3, -COR A , -CF3, -OCF3, optionally substituted C 1-2 Alkyl, R 2 The optional substituents are -OCH3 and -COR A is selected from R 3 is H, halogen, -CF3, -OCHF2, -OCF3, or -OCH3, R 4 is H, halogen, or C3 hydroxyalkyl; R A and R B is CH3, The compound may include a compound represented by formula 11, or a pharma- ceutically acceptable salt thereof.

[0095] Some embodiments of Formula 1C include compounds represented by Formula 12: [ka] During the ceremony, D is an optionally substituted cyclobutyl, where the optional substituent is -CH; A is a C alkyl; X is -CH3, Y is -CH3, R 1 is -CN, R 2 and R 3 is F, R 4 is H, The compound may include a compound represented by formula 12, or a pharma- ceutically acceptable salt thereof.

[0096] Some embodiments of Formula 1C include compounds represented by Formula 13: [ka] During the ceremony, D is t-butyl; A is a C alkyl; X is optionally substituted cyclobutyl, where 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 with two fluorine atoms, the fluorine atoms are not geminal. The compound may include a compound represented by formula 13, or a pharma- ceutically acceptable salt thereof.

[0097] Some embodiments of Formula 1C include compounds represented by Formula 14: [ka] where D is an optionally substituted C 2-5 alkyl, the optional substituents being selected from -CH3; A is C 1-6 is alkyl, X is H, F, -CH3, -CF3, optionally substituted C 1-3 alkyl, optionally substituted phenyl, or optionally substituted cyclobutyl, each of which 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 Heterocyclyl, optionally substituted C 1-5 Alkyl, optionally substituted C 1-7 Alkoxy, -NR A RB , F or Cl, the optional substituents being 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, The compound may include a compound represented by formula 14, or a pharma- ceutically acceptable salt thereof.

[0098] In some embodiments of formula 11, when X is substituted with two fluorine atoms, the 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 pharma- ceutically acceptable salts thereof.

[0100] In some embodiments, provided herein is any one of the following compounds of Group I, or a pharma- ceutically acceptable salt thereof. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0101] In some embodiments, provided herein is any one of the following compounds of Group II, or a pharma- ceutically acceptable salt thereof. [ka] [ka] [ka]

[0102] In some embodiments, provided herein is any one of the following compounds of Group III, or a pharma- ceutically acceptable salt thereof. [ka] [ka] [ka]

[0103] How to use An embodiment of the present invention relates to a method of treating a Kv7-associated disorder, 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, Group I, Group II, Group III, or Table 1, or a pharma- ceutically acceptable salt thereof. Disorders include epilepsy, neonatal convulsions, pain, migraine, neurotransmitter release disorders, smooth muscle contraction disorders, dyskinesia, dystonia, mania, hearing disorders, neuropathic pain, inflammatory pain, persistent pain, cancer pain, postoperative pain, anxiety, substance abuse, schizophrenia, bladder disorders, vascular disorders, tinnitus, benign familial neonatal seizures, epilepsy, neurological disorders (and subsequent neuronal hyperexcitability) mediated by reduced basal M currents, sensorineural hearing loss, intellectual disability, epileptic encephalopathy, treatment-resistant epilepsy, cortical atrophy, neuropathy, infantile spasms with hypsarrhythmia, myoclonic-tonic-clonic seizures, myoclonic seizures, tonic-clonic seizures, absence and focal seizures with impaired consciousness, congenital neurological disorders with intellectual disability or epileptic encephalopathy. The compound is selected from the group consisting of: encephalopathy, benign familial neonatal convulsions, severe epileptic encephalopathy, congenital neurodevelopmental disorders with nonsyndromic intellectual disability or epileptic encephalopathy phenotype, epileptic encephalopathy, neonatal seizures, benign familial neonatal convulsions type 1, benign familial neonatal seizures type 1, neonatal seizures associated with hypoxic-ischemic injury, epileptic convulsions, epileptic encephalopathy, early infantile epileptic encephalopathy 7, early infantile epileptic encephalopathy with delayed psychomotor development, abnormal globus pallidus morphology, apnea, cerebral edema, dystonia, facial erythema, muscular hypotonia, febrile convulsions, hypoplasia of the corpus callosum, hypsarrhythmia, focal clonic seizures, generalized tonic-clonic seizures, myokymia, spastic quadriplegia, gynecological disorders, and combinations thereof. In an embodiment, such a compound may be administered in a pharmaceutical composition as described herein.

[0104] In some embodiments, the gynecological disorder is selected from the group consisting of preterm labor, postpartum hemorrhage, uterine tone, uterine perforation, uterine hyperstimulation, menorrhagia, menorrhagia, dysmenorrhea, and endometriosis.

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

[0106] An embodiment of the present invention relates to a method of treating a KCNQ subunit associated disorder, 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 pharma- ceutically acceptable salt thereof. An embodiment of the present invention relates to a method of treating a KCNQ2 subunit associated disorder, 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 pharma- ceutically acceptable salt thereof. An embodiment of the present invention relates to a method of treating a KCNQ3 subunit associated disorder, 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 pharma- ceutically acceptable salt thereof.An embodiment of the present invention relates to a method of treating a KCNQ4 subunit associated disorder, 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 pharma- ceutically acceptable salt thereof. An embodiment of the present invention relates to a method of treating a KCNQ5 subunit associated disorder, 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, Group I, Group II, Group III, or Table 1, or a pharma- ceutically acceptable salt thereof.

[0107] An embodiment of the present invention relates to a method of treating a disorder associated with a mutation in a KCNQ subunit, 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 pharma- ceutically acceptable salt thereof. An embodiment of the present invention relates to a method of treating a disorder associated with a mutation in a KCNQ2 subunit, 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 pharma- ceutically acceptable salt thereof. An embodiment of the present invention relates to a method of treating a disorder associated with a mutation in the KCNQ3 subunit, 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 pharma- ceutically acceptable salt thereof. An embodiment of the present invention relates to a method of treating a disorder associated with a mutation in the KCNQ4 subunit, 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 pharma- ceutically acceptable salt thereof. An embodiment of the present invention relates to a method of treating a disorder associated with a mutation in the KCNQ5 subunit, 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, Group I, Group II, Group III, or Table 1, or a pharma- ceutically acceptable salt thereof.

[0108] The compounds described herein have been shown to activate Kv7 potassium channel. Mutations in the gene KCNQ3 that encodes Kv7 potassium channel cause various disorders. An embodiment of the present invention relates to a method for treating disorders associated with KCNQ3 mutations, 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, group I, group II, group III, or table 1, or a pharma- ceutically acceptable salt thereof. Disorders associated with KCNQ3 mutations are selected from the group consisting of benign familial neonatal seizures, epilepsy, neurological disorders (and subsequent neuronal hyperexcitability) mediated by reduced basal M current, and any combination thereof.

[0109] The compounds described herein have been shown to activate Kv7 potassium channel.Mutations in the gene KCNQ4 that codes for Kv7 potassium channel cause various disorders.An embodiment of the present invention relates to a method for treating disorders associated with KCNQ4 mutation, 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, group I, group II, group III, or table 1, or a pharma- ceutically acceptable salt thereof.The disorder associated with KCNQ4 mutation is sensorineural hearing loss.

[0110] The compounds described herein have been shown to activate Kv7 potassium channel.Mutations in the gene KCNQ5, which encodes Kv7 potassium channel, cause various disorders.Embodiments of the present invention relate to a method for treating disorders associated with KCNQ5 mutations, 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 a compound of table 1, or a pharma- ceutically acceptable salt thereof. The disorder associated with a KCNQ5 mutation is selected from the group consisting of intellectual disability, epileptic encephalopathy, treatment-resistant epilepsy, cortical atrophy, neuropathy, infantile spasms with hypsarrhythmia, myoclonic-tonic-clonic seizures, myoclonic seizures, tonic-clonic seizures, absence and focal seizures with impaired consciousness, congenital neurological disorders with intellectual disability or epileptic encephalopathy, benign familial neonatal convulsions, severe epileptic encephalopathy, congenital neurodevelopmental disorders with nonsyndromic intellectual disability or epileptic encephalopathy phenotype, and combinations thereof.

[0111] The compounds described herein have been shown to activate Kv7 potassium channel.Mutations in the gene KCNQ2, which encodes Kv7 potassium channel, cause various disorders.Embodiments of the present invention relate to a method for treating disorders associated with KCNQ2 mutations, 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 a compound of table 1, or a pharma- ceutically acceptable salt thereof. The disorder associated with KCNQ2 mutation is selected from the group consisting of neonatal convulsions, neonatal seizures, benign familial neonatal epilepsy (KCNQ2-BFNE), epileptic encephalopathy (KCNQ2-NEE), benign familial neonatal convulsions type 1 (BFNC), benign familial neonatal seizures type 1 (BFNS1), neonatal seizures associated with hypoxic-ischemic injury, epileptic convulsions, epileptic encephalopathy, early infantile epileptic encephalopathy 7, early infantile epileptic encephalopathy with delayed psychomotor development, abnormal globus pallidus morphology, apnea, cerebral edema, dystonia, facial erythema, muscular hypotonia, febrile convulsions, hypoplasia of the corpus callosum, hypsarrhythmia, focal clonic seizures, generalized tonic-clonic seizures, myokymia, spastic quadriplegia, myokymia and combinations thereof.In an embodiment, such compounds can be administered in a pharmaceutical composition as described herein.

[0112] An embodiment relates to a method for treating a condition associated with cellular hyperexcitation in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharma- ceutically acceptable salt thereof, wherein the hyperexcitation is treated.

[0113] An embodiment relates to a method for treating a Kv7-associated disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharma- ceutically acceptable salt thereof, wherein a symptom of the disorder is alleviated or ameliorated by activation of the Kv7 potassium channel.

[0114] An embodiment relates to a method for treating a neurodegenerative disease in a subject comprising administering to the subject a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharma- ceutically acceptable salt thereof, wherein the neurodegenerative disease is treated. The compound of Group I, Group II, Group III, or Table 1, a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14 can be administered to any individual exhibiting symptoms of a neurodegenerative disease or an individual predisposed 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, a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14 include amyotrophic lateral sclerosis (ALS), Huntington's disease, metabolically induced neuronal damage, Alzheimer's disease, Pick's disease, senile dementia, age-related cognitive impairment, vascular dementia, multi-infarct dementia, dementia with Lewy bodies, neurodegenerative dementia, frontotemporal dementia (FTD), familial FTD, neurodegenerative movement disorder, 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 a combination thereof.

[0115] An embodiment relates to a method for treating a neurodegenerative disease, such as amyotrophic lateral sclerosis, in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharma- ceutically acceptable salt thereof, wherein the neurodegenerative disease is treated. In an embodiment, the subject has well-defined ALS, has a duration of onset of symptoms of amyotrophic lateral sclerosis of less than about 18 months, a plasma creatinine level of about 72 μM / L or greater, co-administration of riluzole, co-administration of dexpramipexole, and combinations thereof.

[0116] An embodiment relates to a method for treating amyotrophic lateral sclerosis in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharma- ceutically acceptable salt thereof, wherein amyotrophic lateral sclerosis is treated.

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

[0118] An embodiment relates to a method for treating amyotrophic lateral sclerosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharma- ceutically acceptable salt thereof, wherein the subject is selected from a subject with well-defined amyotrophic lateral sclerosis, a subject with limb-onset amyotrophic lateral sclerosis, a subject with bulbar-onset amyotrophic lateral sclerosis, a subject with less than about 18 months onset of symptoms of amyotrophic lateral sclerosis, a subject with high serum creatinine levels, a subject with low bicarbonate levels, a subject with concomitant administration of riluzole, a subject with concomitant administration of dexpramipexole, and combinations thereof, and amyotrophic lateral sclerosis is treated. In certain embodiments, the method further comprises monitoring the subject for clinical features associated with amyotrophic lateral sclerosis. In certain embodiments, the method further comprises initiating treatment with a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharma- ceutically 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 amyotrophic lateral sclerosis, possible amyotrophic lateral sclerosis, possible amyotrophic lateral sclerosis, or suspected amyotrophic lateral sclerosis.

[0119] An embodiment relates to a method for treating amyotrophic lateral sclerosis in a subject diagnosed with definite amyotrophic lateral sclerosis comprising administering to the subject a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharma- ceutically acceptable salt thereof, wherein the amyotrophic lateral sclerosis is treated. In some embodiments, definite amyotrophic lateral sclerosis is characterized by the presence of El Escorial diagnostic criteria, duration of onset of amyotrophic lateral sclerosis symptoms of less than about 18 months, limb-onset amyotrophic lateral sclerosis, plasma creatinine level of about 72 μM / L or greater, concomitant administration of riluzole, concomitant administration of dexpramipexole, ALSFRS-R score of greater than 36.0, pre-study progression rate of 0.8 points or greater per month, percentage of predicted relaxed (slow) vital capacity (SVC) of 102.0 or less, ALSFRS-R fine motor domain score of greater than 10.0 points, ALSFRS-R score of greater than 36.0, A score of greater than 9 ... LSFRS-R bulbar domain score, ALSFRS-R gross motor domain score greater than 8.0 points, abnormal neurological examination of tongue, abnormal neurological examination of pharynx, larynx, and swallowing, abnormal neurological examination of lower extremities, abnormal neurological examination of upper extremities, abnormal neurological examination of triceps, abnormal neurological examination of muscle mass or muscle bulk, abnormal neurological examination of biceps, abnormal neurological examination, pulse rate greater than 81.0 beats per minute, diastolic blood pressure greater than 82.0 mmHg, systolic blood pressure less than 117.0 mmHg, creatinine greater than 72.0 μmol / L, phosphorus less than 1.090 μmol / L, and ≥248.0 × 10 9 These are: platelet count below 300 cells / L, cholesterol level below 5.3 mmol / L, lactate dehydrogenase level below 161.0 U / L, creatine phosphokinase level below 184.0 U / L, bicarbonate level below 21.6 mmol / L, triglyceride level below 1.4 mmol / L, uric acid level above 320.0 μmol / L, gamma glutamyl transferase (GGT) level above 37.0 U / L, total bilirubin level below 6.0 μmol / L, urine pH below 5.5, or any combination thereof.

[0120] An embodiment relates to a method for treating amyotrophic lateral sclerosis in a subject exhibiting symptoms of amyotrophic lateral sclerosis, comprising administering to the subject a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharma- ceutically acceptable salt thereof, wherein the symptoms of amyotrophic lateral sclerosis are treated. In some embodiments, the subject has definite amyotrophic lateral sclerosis, duration of onset of amyotrophic lateral sclerosis symptoms of less than about 18 months, limb-onset amyotrophic lateral sclerosis, a plasma creatinine level of about 72 μM / L or greater, concomitant administration of riluzole, concomitant administration of dexpramipexole, an ALSFRS-R score of greater than 36.0, a repeat study progression rate of 0.8 points or greater per month, a percentage of predicted relieved (slow) vital capacity (SVC) of 102.0 or less, an ALSFRS-R fine motor domain score of greater than 10.0 points, an ALSFRS-R bulbar domain score of greater than 9.0 points, ALSFRS-R gross motor domain score greater than 8.0 points; abnormal neurological examination of the tongue; abnormal neurological examination of the pharynx, larynx, and swallowing; abnormal neurological examination of the lower extremities; abnormal neurological examination of the upper extremities; abnormal neurological examination of the triceps; abnormal neurological examination of muscle mass or muscle bulk; abnormal neurological examination of the biceps; abnormal neurological examination; pulse rate greater than 81.0 beats per minute; diastolic blood pressure greater than 82.0 mmHg; systolic blood pressure less than 117.0 mmHg; creatinine greater than 72.0 μmol / L; phosphorus less than 1.090 μmol / L; and 248.0 × 10 9 and clinical features selected from a platelet count of 0.1 cells / L or less, a cholesterol level of 0.5 mmol / L or less, a lactate dehydrogenase level of 0.161 U / L or less, a creatine phosphokinase level of 0.184 U / L or less, a bicarbonate level of 0.2 mmol / L or less, a triglyceride level of 0.1 mmol / L or less, a uric acid level of 0.2 mmol / L or less, a gamma glutamyl transferase (GGT) level of 0.2 mmol / L or less, a total bilirubin level of 0.2 mmol / L or less, a urine pH of 0.5 or less, or any combination thereof.

[0121] In some embodiments, the step of administering a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1, a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharma- ceutically acceptable salt thereof, is from 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 1 The method may include administering a daily dose of 75 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 1200 mg to about 1,500 mg.

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

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

[0124] Pharmaceutical Compositions The embodiments herein relate to 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, or Table 1, a compound of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharma- ceutically acceptable salt thereof. Pharmaceutical formulations containing such compounds and a suitable carrier may be in various forms, including, but not limited to, solids, solutions, powders, fluid emulsions, fluid suspensions, semi-solids, and dry powders, containing an effective amount of the compound of the present invention. It is also known in the art that the active ingredient may be included in such formulations together with pharma- ceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, antioxidants, preservatives, and the like. Means and methods of administration are known in the art, and the artisan may refer to various pharmacological references for guidance. See, e.g., Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979) and Goodman & Gilman's, The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980), both of which are incorporated by reference in their entireties.

[0125] In some embodiments, a single unit dose of a compound of Group I, Group II, Group III, or Table 1 or Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharma- ceutically acceptable salt thereof, is 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 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 1200 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 Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharma- ceutically acceptable salt thereof, is from about 25 mg to about 5,000 mg, from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000 mg, from about 150 mg to about 5,000 mg, from about 200 mg to about 5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg to about 5,000 mg, from about 400 mg to about 5,000 mg, from about 450 mg to about 5,000 mg, from about 100 mg to about 3,000 mg, The amount of the active ingredient is selected from the group consisting of about 0 mg, about 150 mg to about 3,000 mg, about 200 mg to about 3,000 mg, about 250 mg to about 3,000 mg, about 300 mg to about 3,000 mg, about 400 mg to about 3,000 mg, 450 mg to about 3,000 mg, about 100 mg to about 1,000 mg, about 150 mg to about 1,000 mg, about 200 mg to about 1,000 mg, about 250 mg to about 1,000 mg, about 300 mg to about 1,000 mg, about 400 mg to about 1,000 mg, about 450 mg to about 1,000 mg, about 500 mg to about 1,000 mg, and about 600 mg to about 1,000 mg. In some embodiments, 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 a single unit dose can be administered once a day or multiple times a day, for example, twice a day or three times a day.

[0127] In some embodiments, the single unit dose further comprises a pharma- ceutically acceptable carrier.

[0128] The compound can be formulated for parenteral or intravenous administration by injection, for example, by bolus injection or continuous infusion.The preparation for injection can be presented in a unit dosage form, for example, in ampoules or multi-dose containers, with preservative added.The composition can take the form of suspension, solution, or emulsion in oily or aqueous vehicle, and can contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents.

[0129] Injectable preparations can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents.Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol.Vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution.

[0130] Other embodiments include the compound prepared as above, which is formulated as a solid dosage form 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.Such dosage forms can also contain additional substances other than inert diluents, such as lubricants, such as magnesium stearate, as is common practice.In the case of capsules, tablets, and pills, dosage forms can also contain buffers and can be further prepared with enteric coatings.

[0131] The preparation of the compound of the present invention in solid dosage form can vary.For example, in one embodiment, liquid or gelatin preparations can be prepared by combining compounds such as those described above and adding thickeners to the liquid mixture to form gelatin.The gelatin can then be encapsulated to form capsules in unit dosage form.In another exemplary embodiment, the oily preparation of the compound prepared as described above can be lyophilized to form a solid that can be mixed with one or more pharma-ceutically acceptable excipients, carriers or diluents to form tablets.

[0132] Further embodiments that may be useful for oral administration of the compounds of the present invention include liquid dosage forms.In such embodiments, liquid dosages may include pharma-ceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs that contain inert diluents commonly used in the art, such as water.Such compositions may also have auxiliary agents, such as wetting agents, emulsifying agents and suspending agents, and sweeteners, flavoring agents, and aromatic agents.

[0133] In yet further embodiments, the compounds described herein can be formulated as depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Depot injections can be administered at intervals of about 1 to about 6 months or more. Thus, for example, the compounds can be formulated as suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

[0134] Experimental Section [ka] Scheme 1 shows the general methodology for the synthesis of 1H-benzo[d]imidazol-2-ylamides 1.5. Appropriately substituted 1-fluoro-2-nitrobenzenes 1.1 are reacted with primary amines to give 1-amino-2-nitrobenzenes 1.2. Alternatively, 1-chloro-2-nitrobenzenes are reacted with primary amines under palladium catalysis to provide the desired 1-amino-2-nitrobenzenes 1.2. The nitro group can be reduced to the corresponding amine by a variety of established methods to provide 1,2-diaminobenzenes 1.3. Reaction of 1.3 with cyanogen bromide gives 1H-benzo[d]imidazol-2-amines 1.4. Amide coupling with appropriate carboxylic acids or acyl chlorides can give 1H-benzo[d]imidazol-2-ylamides such as 1.5. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

[0135] Biological Assays Kv7.2 / 7.3 activation assay

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

[0137] Cell Lines: The hKv7.2 / 7.3 cell line was obtained from Chantest (Cleveland, Ohio 44128) catalog number CT6147. These HEK cells are induced to express the Kv7.2 / 7.3 ion channel.

[0138] Cell culture: Cells were maintained in medium containing DMEM / F12; 50 / 50 (GIBCO catalog no. 11330), 10% fetal bovine serum (FBS) (GIBCO catalog no. 26140), 100 units / mL penicillin-streptomycin (GIBCO catalog no. 15140), 0.005 mg / mL blasticidin (INVIVOGEN catalog no. ant-bl-1), 0.5 mg / mL geneticin (GIBCO catalog no. 10131), 0.1 mg / mL zeocin (GIBCO catalog no. R25001). Cells used in electrophysiological assays were maintained in medium without blasticidin, geneticin, or zeocin for 2 days and channel expression was induced by adding tetracycline (BIOLINE catalog no. BIO-87030) at a final concentration of 1 mg / mL. Cells were grown to approximately 75% confluency in T-175 flasks. Currents were recorded 24 hours after channel induction.

[0139] Compound Plate: Test compounds were plated on a Biomek NX P The external recording solution was prepared by performing serial dilutions in a BECKMAN COULTER filter. Final dilutions were made in the external recording solution with a final DMSO concentration of 0.1% DMSO. For the single concentration screen, each plate contained 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 No. 14175) and collected in a triplicate (GIBCO Catalog No. 12604). Cells were then centrifuged at 2000 rpm for 5 min and transferred to CHO-S-SFM (GIBCO Catalog No. 12052) at approximately 3 × 10 6The cells were resuspended at 100 cells / mL. The cells were stirred for 30 min before starting the experiment. External recording solution contained (in mM): NaCl (145), KCl (4), CaCl2 (2), MgCl2 (1), HEPES (10), and glucose (10); if necessary, pH was adjusted to 7.4 with NaOH and osmolarity was adjusted to 300-305 mOsM with sucrose. Internal solution contained (in mM): KCl (125), KF (10), EGTA (5), Na2ATP (5), MgCl2 (3.2), HEPES (5); pH was adjusted to 7.2 with KOH and osmolarity was adjusted to 298-302 mOsM with sucrose.

[0141] Potassium channel activity was measured on a QPatch HTX (Sofion Biosciences) using a QP rate with 48 wells / plate. Each cell was taken as an independent experiment and only one compound was tested per well. Potassium channel activity was evoked by holding at -80mV and stepping to -30mV for 2s followed by a 100ms pulse to -120mV.

[0142] Single concentration screen: Baseline conditions were obtained by recording five sweeps with external solution alone, which were repeated for three applications of external solution. The effect of test compound on the evoked current was then assessed by recording five sweeps in the presence of 3 μM compound solution. Steady-state currents at the end of a 2 s pulse to -30 mV were measured to determine the fold increase from baseline.

[0143] Data from the Kv7.2 / 7.3 activation assay are summarized in Table 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

[0144] The thallium flux assay is used as a surrogate indicator of potassium channel activity.

[0145] The experimental protocol was adapted from the FluxORTM II 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: The hKV7.2 / 7.3 cell line was obtained from Chantest (Cleveland, Ohio 44128) catalog number CT6147.

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

[0148] Compound plate: Test compounds are diluted in a mixture of 0.1% DMSO / extracellular solution with an 8-point concentration range from 0.014 μM to 30 μM. Serial dilutions were performed on a Biomek NXP (BECKMAN COULTER).

[0149] Measurements and Data Analysis: A plate reader (Empire, Perkin Elmer) is used to characterize the ion channel modulating properties of novel compounds using an excitation wavelength of 475 nm and an emission wavelength of 530 nm. After a 15 s baseline measurement, a stimulation buffer containing thallium and potassium is injected. A final endpoint measurement is taken after 90 s. Responses are normalized to a positive control (retigabine, up to 30 μM). The mean normalized responses at each concentration tested are fit to the standard Hill equation to generate EC50 and maximum responses.

[0150] The thallium flux assay data are summarized in Table 3. [Table 3-1] [Table 3-2] [Table 3-3]

[0151] Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When such inclusion or deletion occurs, the specification is deemed to include the modified group and thus fulfills the written description of all Markush groups used in the appended claims.

[0152] Certain embodiments have been described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations of these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect such variations to be utilized by those of ordinary skill in the art as appropriate, and the inventors intend to practice the invention otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or clearly contradicted by context.

[0153] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Thus, the claims are not limited to the embodiments precisely shown and described.

[0154] KV7 activators and methods for treating ALS In embodiments, the present disclosure relates to a method for treating a neurodegenerative disease, such as, for example, amyotrophic lateral sclerosis, in a subject in need thereof, comprising the steps of: administering to the subject a therapeutically effective amount of a compound of Formulae A-1 to A-44 or B-1 to B-7, or a pharma- ceutically acceptable salt thereof, wherein the neurodegenerative disease is treated.

[0155] In embodiments, the subject has definite ALS, duration of onset of amyotrophic lateral sclerosis symptoms of less than about 18 months, plasma creatinine levels of about 72 μM / L or greater, concomitant administration of riluzole, concomitant administration of dexpramipexole, and combinations thereof.

[0156] Motor neurons from ALS patients have been demonstrated to have reduced delayed rectifier potassium current amplitude, which may contribute to the hyperexcitation seen in neurons from ALS patients. Embodiments described herein relate to compounds of Formulae A-1 through A-44, or Formulae B-1 through B-7, or pharma- ceutically acceptable salts thereof, that activate Kv7 channels to block ALS-associated hyperexcitation and improve motor neuron function and / or survival.

[0157] An embodiment relates to a method for treating a neurodegenerative disease in a subject comprising administering to the subject a therapeutically effective amount of a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt thereof, wherein the neurodegenerative disease is treated. The compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically 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 a compound of Formula A-1 through A-44 or B-1 through B-7, or a pharma- ceutically acceptable salt, include amyotrophic lateral sclerosis (ALS), Huntington's disease, metabolically induced neuronal damage, Alzheimer's disease, Pick's disease, senile dementia, age-related cognitive impairment, vascular dementia, multi-infarct dementia, Lewy body dementia, neurodegenerative dementia, frontotemporal dementia (FTD), familial FTD, neurodegenerative movement disorder, 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 combinations thereof.

[0158] An embodiment relates to a method for treating a neurodegenerative disease such as amyotrophic lateral sclerosis in a subject in need thereof, comprising the steps of: administering to the subject a therapeutically effective amount of a compound of Formulae A-1 to A-44 or B-1 to B-7, or a pharma- ceutically acceptable salt thereof, wherein the neurodegenerative disease is treated. In an embodiment, the subject is a subject with well-defined ALS, having a duration of onset of symptoms of amyotrophic lateral sclerosis of less than about 18 months, a plasma creatinine level of about 72 μM / L or greater, co-administration of riluzole, co-administration of dexpramipexole, and combinations thereof.

[0159] An embodiment relates to a method for treating amyotrophic lateral sclerosis in a subject in need thereof, comprising the steps of: administering to the subject a therapeutically effective amount of a compound of Formulae A-1 to A-44 or B-1 to B-7, or a pharma- ceutically acceptable salt thereof, wherein amyotrophic lateral sclerosis is treated.

[0160] An embodiment relates to a method for treating amyotrophic lateral sclerosis in a subject diagnosed with definite amyotrophic lateral sclerosis, comprising administering to the subject a therapeutically effective amount of a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt, wherein the amyotrophic lateral sclerosis is treated. In an embodiment, the definite amyotrophic lateral sclerosis is as defined by the El Escorial diagnostic criteria. In an embodiment, the subject is a subject with definite ALS, duration of onset of amyotrophic lateral sclerosis symptoms of less than about 18 months, plasma creatinine levels of about 72 μM / L or greater, concomitant administration of riluzole, concomitant administration of 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 universally fatal, but the rate of disease progression may not be linear.

[0162] According to embodiments described herein, the El Escorial World Federation of Neurology's Criteria for the Diagnosis of ALS 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 1(5): 293-9, which is incorporated by reference in its entirety): As used in the El Escorial World Neurological Union criteria for the diagnosis of ALS, the term "definite" means that certain 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 progressive deterioration of certain cognitive functions; the term "onset" means the time of subjective symptoms first noticed by the patient and later confirmed by examination; the term "possible" is intended to mean that certain clinical and exclusion criteria are met; the term "probable" is intended to mean certain clinical and exclusion criteria; the term "worsening" is intended to mean increasing muscle weakness in previously affected segments or new weakness in previously unaffected segments.

[0163] The diagnosis of ALS requires the presence of the following: 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) the absence of electrophysiological evidence of other disease processes that might explain the signs of LMN and / or UMN degeneration and the absence of neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs, along with progressive spread of signs within or to other regions.

[0164] Furthermore, the El Escorial World Federation of Neurological Association criteria for the diagnosis of ALS prescribe the following steps in the diagnosis of amyotrophic lateral sclerosis: A diagnosis of ALS is made by: 1) history, physical and appropriate neurological examination to confirm clinical findings that may suggest suspicious, possible, probable or definite ALS; 2) electrophysiological testing to confirm LMN degeneration in clinically involved areas and to identify LMN degeneration in clinically uninvolved areas and to confirm findings that may exclude other disorders; 3) neuroimaging to confirm findings that may exclude other disease processes; 4) laboratory tests as determined by laboratory tests to confirm possible ALS-related syndromes; 5) neuropathological tests as necessary to confirm findings that may confirm or exclude sporadic ALS, coexisting sporadic ALS, ALS-related syndromes or ALS variants; and 6) repeat clinical and electrophysiological tests at least 6-month intervals to confirm evidence of progression.

[0165] Definite ALS is defined on clinical grounds only by the presence of UMN and LMN signs in the bulbar region and at least two other spinal cord regions, or the presence of UMN and LMN signs in three spinal cord regions. In the absence of electrophysiological, neuroimaging, and clinical testing, the key determinant for the diagnosis of definite ALS is the presence of UMN and LMN signs together in multiple regions.

[0166] Probable ALS is defined on clinical grounds alone by UMN and LMN signs in at least two regions. The regions may vary, but some UMN signs must be rostral (above) the LMN signs. Several different combinations of UMN and LMN signs may be present in patients with probable ALS.

[0167] Possible ALS is defined on clinical grounds alone when UMN and LMN signs are present in only one region, or when UMN signs are present in two or more regions, or when LMN signs are rostral to UMN signs (the latter distribution of signs needs to be distinguished from multiple non-ALS processes). Monomeric ALS, progressive bulbar palsy without spinal UMN and / or LMN signs, progressive primary lateral sclerosis without spinal LMN signs, and progressive primary lateral sclerosis without spinal LMN signs are special cases that develop LMN or UMN signs and meet the criteria for probable ALS over time or are confirmed by specific LMN and UMN neuropathological findings at subsequent autopsy.

[0168] Suspected ALS reveals only LMN signs in two or more regions, while UNN pathology may be demonstrated at autopsy, however, at the time of diagnostic evaluation, only clinical signs are considered relevant for this classification.

[0169] The clinical manifestations of progressive LMN and UMN degeneration seen in ALS may occur 1) alone (sporadic ALS), 2) coincidentally with other pre-existing disease processes not occurring in parallel with ALS (concomitant sporadic ALS), 3) in association with laboratory-defined or epidemiologically-defined abnormalities temporally linked to ALS (ALS-related syndromes), or 4) in association with clinical, genetic, or epidemiological features occurring in parallel with ALS (ALS variants).

[0170] While physical and neurological examinations allow for a clinical diagnosis of ALS with a certain degree of certainty as defined above, clinical examination should incorporate disease history, toxic exposure, past medical history, injury history, family history, and geographic location when determining whether an individual has an ALS-related syndrome or ALS variant.

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

[0172] ALS-related syndromes include: 1) monoclonal gammopathy (monoclonal gammopathy of undetermined significance, Waldenströms macroglobulinemia, osteosclerosing myeloma, etc.), 2) motor system degeneration of immunodeficiency (autoimmunity; high titer GMI ganglioside antibodies, etc.), 3) non-malignant endocrine abnormalities (hyperthyroidism, hyperparathyroidism, hypogonadism, etc.), 4) lymphoma (Hodgkin lymphoma and non-Hodgkin lymphoma), 5) infections (HIV-1, HTLV-I, lethargy, etc.), 6) pulmonary fibrosis (pulmonary fibrosis, pulmonary fibrosis, etc.), 7) pulmonary fibrosis (pulmonary fibrosis, pulmonary fibrosis, etc.), 8) pulmonary fibrosis (pulmonary fibrosis, pulmonary fibrosis, etc.), 9) pulmonary fibrosis (pulmonary fibrosis, pulmonary fibrosis, etc.), 10) pulmonary fibrosis (pulmonary fibrosis, pulmonary fibrosis, etc.), 11) pulmonary fibrosis (pulmonary fibrosis, pulmonary fibrosis, etc.), 12) pulmonary fibrosis (pulmonary fibrosis, pulmonary fibrosis, etc.), 13) pulmonary fibrosis (pulmonary fibrosis, pulmonary fibrosis, etc.), 14) pulmonary fibrosis (pulmonary fibrosis, ... encephalitis, varicella zoster, brucellosis, cat scratch disease, Creutzfeldt-Jakob disease, syphilis, post-polio syndrome, etc.), 6) acquired enzyme deficiencies (detoxification enzymes, etc.), 7) exogenous toxins (lead, mercury, arsenic, thallium, cadmium, manganese, aluminum, organic pesticides, lupine seeds, etc.), 8) physical injuries (electrical shock, radiation therapy, etc.), 9) vascular (vasculitis; ischemic (Dejerine anterior ophthalmic artery syndrome, etc.), 10) spondylotic myelopathy (painless myelopathy without sensory signs, stabilization or postoperative progression).

[0173] ALS variants must meet clinical, electrophysiological and neuroimaging criteria for possible, probable or definite ALS. The predominant symptoms are those seen in sporadic ALS, but multiple phenotypes exist, each characterized by age at onset, site of onset, survival time and presumed type of inheritance.

[0174] Familial ALS variants in genetic linkage studies should be characterized by an established pattern of inheritance over at least two generations and at least one clinically definite or autopsy-confirmed case and compelling evidence to exclude other possible causes. Affected subpairs occurring in only one generation may not be attributable to 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 (chromosome 21-related familial ALS or chromosome 2-related early-onset familial ALS); c) ALS with defined inheritance and no known linkage or gene product (most cases or familial ALS); d) geographic clustering (disorders seen in the Western Pacific, Guam, Kii Peninsula, North Africa, Madras, etc. e) signs of bradykinesia (bradykinesia, cogwheel rigidity, tremor, clinically significant onset of supranuclear ophthalmic signs (tracking 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 (reduced vibration; sharp and dull discrimination; blunted cold sensation; familial or sporadic); j) Electrophysiological features in the diagnosis of ALS.

[0176] An embodiment relates to a method for treating amyotrophic lateral sclerosis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt, wherein the subject is selected from subjects with well-defined amyotrophic lateral sclerosis, subjects with limb-onset amyotrophic lateral sclerosis, subjects with bulbar-onset amyotrophic lateral sclerosis, subjects with amyotrophic lateral sclerosis symptoms of less than about 18 months duration, subjects with high levels of serum creatinine, subjects with low bicarbonate levels, subjects taking riluzole, subjects taking dexpramipexole, and combinations thereof, wherein amyotrophic lateral sclerosis is treated. In certain embodiments, the method further comprises monitoring the subject for clinical features associated with amyotrophic lateral sclerosis. In certain embodiments, the method further comprises initiating treatment with a therapeutically effective amount of a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically 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 amyotrophic lateral sclerosis, probable amyotrophic lateral sclerosis, possible amyotrophic lateral sclerosis, or suspected amyotrophic lateral sclerosis.

[0177] In certain embodiments, the subject has upper motor neuron degeneration and lower motor neuron degeneration in bulbar region and other two 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 the subject whose symptom duration is less than about 18 months, the subject with high serum creatinine level, the subject with low bicarbonate level, the subject who is taking riluzole concomitantly, the subject who is taking dexpramipexole concomitantly, and combinations thereof.In certain embodiments, the subject with high serum creatinine level is the subject who has serum creatinine of more than about 72 μmol / L.

[0178] In an embodiment, a subject with definite amyotrophic lateral sclerosis is a subject diagnosed with definite ALS as defined by the El Escorial criteria. In a particular embodiment, a subject with definite amyotrophic lateral sclerosis is a subject with upper motor neuron degeneration and lower motor neuron degeneration in the bulbar region and two other spinal regions. In a particular embodiment, a subject with definite amyotrophic lateral sclerosis is a subject with upper motor neuron degeneration and lower motor neuron degeneration in three spinal regions.

[0179] An embodiment relates to a method for treating amyotrophic lateral sclerosis in a subject diagnosed with definite amyotrophic lateral sclerosis, 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 pharma- ceutically acceptable salt, wherein amyotrophic lateral sclerosis is treated. In some embodiments, definite amyotrophic lateral sclerosis is characterized by the presence of El Escorial diagnostic criteria, 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, concomitant administration of riluzole, concomitant administration of dexpramipexole, ALSFRS-R score of greater than 36.0, prestudy progression rate of 0.8 points or greater per month, percentage of predicted relieved (slow) vital capacity (SVC) of 102.0 or less, ALSFRS-R fine motor domain score of greater than 10.0 points, ALSFRS-R bulbar palsy of greater than 9.0 points. Abnormal neurological examination of the tongue; abnormal neurological examination of the pharynx, larynx, and swallowing; abnormal neurological examination of the lower extremities; abnormal neurological examination of the upper extremities; abnormal neurological examination of the triceps; abnormal neurological examination of muscle mass or bulk; abnormal neurological examination of the biceps; abnormal neurological 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 greater than 72.0 μmol / L; phosphorus less than or equal to 1.090 μmol / L; and a mean blood pressure of 248.0 × 10 9These are: platelet count below 300 cells / L, cholesterol level below 5.3 mmol / L, lactate dehydrogenase level below 161.0 U / L, creatine phosphokinase level below 184.0 U / L, bicarbonate level below 21.6 mmol / L, triglyceride level below 1.4 mmol / L, uric acid level above 320.0 μmol / L, gamma glutamyl transferase (GGT) level above 37.0 U / L, total bilirubin level below 6.0 μmol / L, urine pH below 5.5, or any combination thereof.

[0180] Embodiments relate to a method for treating amyotrophic lateral sclerosis in a subject exhibiting symptoms of amyotrophic lateral sclerosis, 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 pharma- ceutically acceptable salt, wherein the symptoms of amyotrophic lateral sclerosis are treated. In some embodiments, the subject has definite amyotrophic lateral sclerosis, duration of onset of symptoms of amyotrophic lateral sclerosis of less than about 18 months, limb-onset amyotrophic lateral sclerosis, plasma creatinine level of about 72 μM / L or greater, concomitant administration of riluzole, concomitant administration of dexpramipexole, ALSFRS-R score of greater than 36.0, restudy progression rate of 0.8 points or greater per month, percentage of predicted relieved (slow) vital capacity (SVC) of 102.0 or less, ALSFRS-R fine motor domain score of greater than 10.0 points, ALSFRS-R bulbar domain score of greater than 9.0 points, ALSFRS-R gross motor domain score greater than 8.0 points; abnormal neurological examination of the tongue; abnormal neurological examination of the pharynx, larynx, and swallowing; abnormal neurological examination of the lower extremities; abnormal neurological examination of the upper extremities; abnormal neurological examination of the triceps; abnormal neurological examination of muscle mass or muscle bulk; abnormal neurological examination of the biceps; abnormal neurological examination; pulse rate greater than 81.0 beats per minute; diastolic blood pressure greater than 82.0 mmHg; systolic blood pressure less than 117.0 mmHg; creatinine greater than 72.0 μmol / L; phosphorus less than 1.090 μmol / L; and 248.0 × 10 9and clinical features selected from the following: a platelet count of 0.1 cells / L or less, a cholesterol level of 0.5 mmol / L or less, a lactate dehydrogenase level of 0.161 U / L or less, a creatine phosphokinase level of 0.184 U / L or less, a bicarbonate level of 0.2 mmol / L or less, a triglyceride level of 0.1 mmol / L or less, a uric acid level of 0.2 mmol / L or less, a gamma glutamyl transferase (GGT) level of 0.2 mmol / L or less, a total bilirubin level of 0.2 mmol / L or less, a urine pH of 0.5 or less, or any combination thereof.

[0181] In certain embodiments, a subject with a duration of onset of symptoms of myotrophic lateral sclerosis of less than about 18 months is a subject with a duration of onset of symptoms selected from less than about 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, or less than about 1 month.

[0182] In certain embodiments, a subject with a high level of serum creatinine is a subject with a 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, and greater than about 72 μmol / L. In certain embodiments, a subject with a high level of serum creatinine is a subject with a 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, and about 72 μmol / L of serum creatinine.

[0183] In certain embodiments, the subject co-administered with riluzole is a subject on a stable dosage regimen of riluzole. In certain embodiments, the subject co-administered with riluzole is a subject who is administered about 50 milligrams of riluzole twice a day. In certain embodiments, the subject co-administered with riluzole is a subject who has been administered riluzole for more than about 30 days. In certain embodiments, the subject co-administered with riluzole is a subject who has been administered riluzole for more than about 60 days. In certain embodiments, the subject co-administered with dexpramipexole is a subject on a stable dosage regimen of dexpramipexole. In certain embodiments, the subject co-administered with dexpramipexole is a subject who is administered about 75 milligrams of dexpramipexole twice a day. In certain embodiments, the subject co-administered with dexpramipexole is a subject who is administered about 150 milligrams of dexpramipexole twice a day. In certain embodiments, the subject co-administered with dexpramipexole is a subject receiving about 300 milligrams of dexpramipexole twice daily.

[0184] In certain embodiments, the treatment of amyotrophic lateral sclerosis in the subject is selected from improved ALSFRS-R score, improved CAFS rank, decreased mortality, increased life expectancy, and combinations thereof. In some embodiments, the subject shows more than 20% improvement in the ALS Functional Rating Scale Revised score (ALSFRS-R) when compared to baseline. In certain embodiments, the subject shows more than 30% improvement in the ALS Functional Rating Scale Revised score (ALSFRS-R) when compared to baseline. The ALSFRS-R measures four domains: pulmonary function, bulbar function, and gross and fine motor skills. There are a total of 12 questions, each scored from 0 to 4, for a total of 48 possible scores. The 12 questions and the rating scale are described in Cederbaum, et al., 169 J. NEUROL. SCI., 13-21 (1999), which is incorporated herein by reference 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 certain embodiments, symptoms associated with ALS may include, for example, reduced fine motor function, reduced gross motor function, reduced bulbar function, reduced respiratory function, and combinations thereof. Additionally, in other embodiments, symptoms associated with ALS may include difficulty with daily activities, such as, for example, walking, speaking, eating, swallowing, writing, climbing stairs, cutting food, turning over in bed, dressing, difficulty maintaining hygiene, and combinations thereof, and may experience other symptoms, such as, for example, dyspnea, difficulty breathing, orthopnea, respiratory failure, increased salivation, and combinations thereof. In certain embodiments of the various methods, a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt thereof, may be used to treat ALS. For example, in some embodiments, an individual diagnosed with ALS within the past two years is treated with a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt thereof, to abolish or slow the progression of ALS or to eliminate symptoms associated with ALS (e.g., loss of fine motor function, loss of gross motor function, loss of bulbar function, loss of respiratory function, etc.). In other embodiments, a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically 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 ability to write, loss of ability to move or roll, loss of speech, difficulty swallowing, difficulty breathing, etc. In other embodiments, individuals with advanced symptoms or individuals diagnosed with ALS more than two years prior to initiating treatment may be treated with a compound of Formulae A-1 through A-44 or B-1 through B-7, or a pharma- ceutically acceptable salt thereof, and such individuals may respond to treatment by exhibiting a reduction or elimination of one or more symptoms associated with ALS, or in certain embodiments, may experience a reduction in the rate of onset or progression of symptoms, for example, the rate of loss of motor function, the rate of loss of language, and and / or the rate of dysphagia may be slowed and / or reduced.

[0186] In embodiments, a subject is administered a therapeutically effective amount of a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt thereof, and the reduction in muscle loss is reduced. In embodiments, a subject is administered a therapeutically effective amount of a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt thereof, and the reduction in serum creatinine is reduced. In additional embodiments of the various methods, a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically 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 rapid weight loss, which is a primary symptom of ALS, may be associated with increased energy expenditure, hypermetabolism of skeletal muscle, and the systematic wasting of muscle tissue known as cachexia.

[0187] In some embodiments, the method is performed for a period selected from at least about 12 months, at least about 18 months, at least about 2 years, at least about 4 years, at least about 6 years, at least about 8 years, at least about 10 years, at least about 20 years, and until the subject dies. In other embodiments, the method is performed at least daily indefinitely.

[0188] The present application provides a method for identifying a patient who will respond to treatment with a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt thereof, comprising diagnosing a patient with EEC-confirmed ALS, measuring the patient's serum creatinine level, and identifying the patient as a responder if the serum creatinine level is greater than about 72 μmol / L.Some embodiments include methods for identifying a subject who is likely to respond to a treatment described herein. In some embodiments, the subject exhibits one or more of the following features: definite ALS as defined by El Escorial diagnostic criteria, 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, concomitant administration of riluzole, concomitant administration of dexpramipexole, ALSFRS-R score of greater than 36.0, restudy progression rate of 0.8 points or greater per month, percentage of predicted relaxed (slow) vital capacity (SVC) of 102.0 or less, ALSFRS-R differential of greater than 10.0 points, or ALSFRS-R differential of greater than 10.0 points. Fine motor domain score, ALSFRS-R bulbar domain score greater than 9.0 points, ALSFRS-R gross motor domain score greater than 8.0 points, abnormal neurological examination of tongue, abnormal neurological examination of pharynx, larynx, and swallowing, abnormal neurological examination of lower limbs, abnormal neurological examination of upper limbs, abnormal neurological examination of triceps, abnormal neurological examination of muscle mass or bulk, abnormal neurological examination of biceps, abnormal neurological examination, pulse rate greater than 81.0 beats per minute, diastolic blood pressure greater than 82.0 mmHg, systolic blood pressure less than 117.0 mmHg, creatinine greater than 72.0 μmol / L, phosphorus less than 1.090 μmol / L, and 248.0 × 10 9A platelet count of 0.01 to 0.01 cells / L or less, a cholesterol level of 0.01 to 0.05 mmol / L or less, a lactate dehydrogenase level of 0.01 to 0.05 U / L or less, a creatine phosphokinase level of 0.01 to 0.05 U / L or less, a bicarbonate level of 0.01 to 0.05 mmol / L or less, a triglyceride level of 0.01 to 0.05 mmol / L or less, a uric acid level of 0.01 to 0.05 mmol / L or less, a gamma glutamyl transferase (GGT) level of 0.01 to 0.05 U / L or less, a total bilirubin level of 0.01 to 0.05 μmol / L or less, a urine pH of 0.01 to 0.05 μmol / L or less, 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 two or more of the above characteristics. In embodiments, the method further comprises monitoring the subject for clinical characteristics associated with amyotrophic lateral sclerosis. In an embodiment, the method further comprises initiating treatment with a therapeutically effective amount of (6R)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole or a pharma- ceutically 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 amyotrophic lateral sclerosis, probable amyotrophic lateral sclerosis, possible amyotrophic lateral sclerosis, or suspected amyotrophic lateral sclerosis.

[0189] Below are shown structures associated with some of the chemical names mentioned herein. As shown below, these structures may be unsubstituted, or, if the structures are unsubstituted, a substituent may be present independently at any position normally occupied by a hydrogen atom. [ka] Unless indicated otherwise, attachment may occur at any position normally occupied by a hydrogen atom. [ka]

[0190] Formulas A and B

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

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

[0193] In some embodiments, some 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 can be: [ka]

[0195] Some embodiments of formula A-1 can include compounds represented by one or more of formulas A-2 through A-42, or a pharma- ceutically acceptable salt thereof. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0196] With respect to any relevant embodiment or structural representation of formula A-1 herein, such as formulas A-1 through A-42, 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, CHO, C2H4O (e.g., OCH2CH2 (the O atom may be on either side of CH2CH2), CHOCH2, OCH(CH3), etc.), or C3H6O.

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

[0198] In some embodiments of Formula A-1, such as Formulas A-1 through A-42, L is CH2.

[0199] In some embodiments of Formula A-1, such as Formulas A-1 through A-42, L is CH2CH2.

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

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

[0202] With respect to any related embodiment or structural representation of formula A-1 herein, such as formulas A-1 through A-42, R 1is 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 CH 11 , optionally substituted bicyclo[2.2.1]heptan-2-yl, optionally substituted bicyclo[3.1.1]heptan-2-yl, etc. 1-12 Optionally substituted alkyl; 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-CH 11 , optionally substituted (2,3-dihydro-1H-inden-1-yl)oxy, etc. 1-12 Optionally substituted C such as optionally substituted -O-alkyl, optionally substituted phenyl, etc. 6-10 Optionally substituted C such as aryl, optionally substituted -O-phenyl 6-10 or optionally substituted C such as optionally substituted isoxazole, optionally substituted tetrahydropyranyl, and optionally substituted tetrahydrofuranyl. 2-9 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 It is a heterocyclyl.

[0203] With respect to any related embodiment or structural representation of formula A-1 herein, such as formulas A-1 to A-42, in some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is C 3-4 In some embodiments, R 1 is optionally substituted bicyclo[2.2.1]heptan-2-yl. In some embodiments, R 1 is an optionally substituted isoxazol-3-yl. In some embodiments, R 1 is CF3. In some embodiments, R 1 is an optionally substituted cyclopentyl. In some embodiments, R 1 is an optionally substituted cyclohexyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is optionally substituted bicyclo[3.1.1]heptan-2-yl. In some embodiments, R 1 is an optionally substituted -O-phenyl. In some embodiments, R 1 is optionally substituted CH(CF). In some embodiments, R 1 is C 2-4 In some embodiments, R 1 is an optionally substituted adamantan-1-yl. In some embodiments, R 1 is optionally substituted tetrahydro-2H-pyranyl. In some embodiments, R 1 is optionally substituted (2,3-dihydro-1H-inden-1-yl)oxy. In some embodiments, R 1 is optionally substituted tetrahydrofuranyl.

[0204] With respect to any related embodiment or structural representation of formula A-1 herein, such as formulas A-1 to A-42, in some embodiments, R 1 can be one of the following: : [ka]

[0205] With respect to any related embodiment or structural representation of formula A-1 herein, such as formulas A-2 and A-42 to A-42, R 2 -R α -Cy. R α are CH2, C2H4, C3H6, C4H8, and C5H 10 , C6H 12 , cyclic C3H5, cyclic C4H7, cyclic C5H9, cyclic C6H 11 Bonds such as C 1-12 Cy is H; optionally substituted C such as optionally substituted phenyl. 6-10 aryl; or optionally substituted C such as optionally substituted azetidinyl, optionally substituted oxetanyl, and optionally substituted thietanyl. 2-9 In some embodiments, R 2 is an optionally substituted cyclobutyl or an optionally substituted 2-methylpropyl. In some embodiments, R 2 teeth, [ka] It is.

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

[0207] The following applies to any relevant embodiment or structural representation of formulae A-1 to A-44 herein. 3 -R 52R may have H or any substituent, for example, 0-12 atoms or 0-6 carbon atoms and 0-5 heteroatoms, where each heteroatom is independently: O, N, S, F, Cl, Br, or I, and / or has a molecular weight of 15 g / mol to 300 g / mol. 3 -R 52 Any of the may have a) one or more optionally substituted or optionally attached alkyl moieties, or 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, or substituents that do not have an alkyl moiety, such as F, Cl, Br, I, NO2, CN, NH2, OH, COH, CO2H.

[0208] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 3 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 3 is H; F; Cl; CN; CF3; OH; NH2; C isomers such as methyl, ethyl, propyl isomers (e.g., n-propyl and isopropyl), cyclopropyl, butyl isomers, cyclobutyl isomers (e.g., cyclobutyl and methylcyclopropyl), pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R3 are H, F, Cl, Br, I, CN, and C. 1-12 Optionally substituted alkyl, C 1-12 optionally substituted -O-alkyl, optionally substituted C 2-9 Heterocyclyl, 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 Aminoalkyl (or alkyl with an amino substituent). In some embodiments, R 3 can be H, CH, OH, OCH, NH, NHCH, N(CH), COH, COCH, CF, Cl, CN, or OCH. In some embodiments, R 3 can be H, CF, Cl, CN, or OCH. In some embodiments, R 3 is H. In some embodiments, R 3 is CF3. In some embodiments, R 3 is Cl. In some embodiments, R 3 is CN. In some embodiments, R 3 is OCH3. [ka]

[0209] The following applies to any relevant embodiment or structural representation of formulae A-1 through A-44 herein: A each of which is independently H, or C 1-12 Alkyl: Formula C a H a+1 or a linear or branched alkyl group having the formula C a H a-1 where a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, for example, cycloalkyl having the formula: CH3, C2H5, C3H7, C4H9, C5H11 , C6H 13 , C7H 15 , C8H 17 , C9H 19 , C 10 H 21 or linear or branched alkyl such as C3H5, C4H7, C5H9, C6H 11 , C7H 13 , C8H 15 , C9H 17 , C 10 H 19 In some embodiments, R A is H or C 1-6 In some embodiments, R A is H or C 1-3 In some embodiments, R A may be H or CH. In some embodiments, R A can be H.

[0210] The following applies to any relevant embodiment or structural representation of formulae A-1 through A-44 herein: B Each of is independently H or C 1-12 Alkyl: Formula C a H a+1 or a linear or branched alkyl group having the formula C a H a-1 where a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, for example, cycloalkyl having the formula: CH3, C2H5, C3H7, C4H9, C5H 11 , C6H 13 , C8H 17 , C7H 15 , C9H 19 , C 10 H 21 or linear or branched alkyl such as C3H5, C4H7, C5H9, C6H 11 , C7H 13 , C8H 15 , C9H 17 , C 10 H 19In some embodiments, R B is H or C 1-3 In some embodiments, R B may be H or CH. In some embodiments, R B can be H.

[0211] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 4 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 4 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 4 are H, F, Cl, Br, I, CN, and C. 1-12 Optionally substituted alkyl, C 1-12 optionally substituted -O-alkyl, optionally substituted C 2-9 Heterocyclyl, 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, C1-12 Optionally substituted aminoacyl or optionally substituted C 1-12 In some embodiments, R 4 can be H, CF, or Cl. In some embodiments, R 4 is H. In some embodiments, R 4 is CF3. In some embodiments, R 4 is Cl.

[0212] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 5 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 5 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 5 are H, F, Cl, Br, I, CN, and C. 1-12 Optionally substituted alkyl, C 1-12 optionally substituted -O-alkyl, optionally substituted C 2-9 Heterocyclyl, 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 can be H, F, Cl, CN, CF, OH; NH, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 5 can be H.

[0213] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 6 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 6 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 6can be H, F, Cl, CN, CF, OH; NH, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 6 can be H.

[0214] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 7 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 7 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 7 can be H, F, Cl, CN, CF, OH; NH, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 7 can be H.

[0215] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 8Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 8 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 8 can be H, F, Cl, CN, CF, OH; NH, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 8 is H. In some embodiments, R 8 is F.

[0216] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 9 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A RB etc. In some embodiments, R 9 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 9 can be H, F, Cl, CN, CF, OH; NH, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 9 can be H.

[0217] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 10 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 10 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 10 can be H, F, Cl, CN, CF, OH; NH, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 10 can be H.

[0218] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 11 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 11 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 11 is H, CH, F, Cl, or CF. In some embodiments, R 11can be H.

[0219] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 12 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 12 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 12 is H, CH, F, Cl, or CF. In some embodiments, R 12 can be H.

[0220] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 13 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A RB etc. In some embodiments, R 13 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 13 is H, CH, F, Cl, or CF. In some embodiments, R 13 can be H.

[0221] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 14 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 14 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6In some embodiments, R 14 is H, CH, F, Cl, or CF. In some embodiments, R 14 can be H.

[0222] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 15 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 15 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 15 is H, CH, F, Cl, or CF. In some embodiments, R 15 can be H.

[0223] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 16 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2RA , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 16 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 16 is H, CH, F, Cl, or CF. In some embodiments, R 16 can be H.

[0224] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 17 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 17 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 17 is H, CH, F, Cl, or CF. In some embodiments, R 17 can be H.

[0225] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 18 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 18 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 18 can be H, F, Cl, OH, CN, CF, CH, CHCH, -OCH, or -OCHCH. In some embodiments, R 18 can be H.

[0226] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 19 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 19 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 19 can be H, OH, CN, CF, CH, CHCH, -OCH, or -OCHCH. In some embodiments, R 19 can be H.

[0227] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 20 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R Betc. In some embodiments, R 20 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 20 can be H, F, Cl, OH, CN, CF, CH, CHCH, -OCH, or -OCHCH. In some embodiments, R 20 can be H.

[0228] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 21 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 21 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 21 can be H, OH, CN, CF, CH, CHCH, -OCH, or -OCHCH. In some embodiments, R 21 can be H.

[0229] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 22 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 22 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 22 can be H, F, Cl, OH, CN, CF, CH, CHCH, -OCH, or -OCHCH. In some embodiments, R 22 can be H.

[0230] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 23 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 23 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 23 can be H, OH, CN, CF, CH, CHCH, -OCH, or -OCHCH. In some embodiments, R 23 is H. In some embodiments, R 23 is CH3.

[0231] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 24 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A CORB ,CONR A R B etc. In some embodiments, R 24 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 24 can be H, F, Cl, OH, CN, CF, CH, CHCH, -OCH, or -OCHCH. In some embodiments, R 24 is H. In some embodiments, R 24 is CH3.

[0232] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 25 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 25 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 25 can be H, OH, CN, CF, CH, CHCH, -OCH, or -OCHCH. In some embodiments, R 25 can be H.

[0233] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 26 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 26 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 26 can be H, F, Cl, OH, CN, CF, CH, or -OCH. In some embodiments, R 26 can be H.

[0234] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 27 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 27 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 27 can be H, F, Cl, OH, CN, CF, CH, or -OCH. In some embodiments, R 27 can be H.

[0235] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 28 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R Betc. In some embodiments, R 28 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 28 can be H, F, CN, CF, or CH. In some embodiments, R 28 can be H.

[0236] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 29 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 29 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6In some embodiments, R 29 can be H, F, Cl, OH, CN, CF, CH, or -OCH. In some embodiments, R 29 can be H.

[0237] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 30 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 30 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 30 can be H, F, Cl, OH, CN, CF, CH, CHCH, -OCH, or -OCHCH. In some embodiments, R 30 can be H.

[0238] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 31 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NRA R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 31 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 31 can be H, OH, CN, CF, CH, CHCH, -OCH, or -OCHCH. In some embodiments, R 31 can be H.

[0239] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 32 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 32 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers.1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 32 can be H, F, Cl, CN, CF, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 32 can be H.

[0240] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 33 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 33 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 33can be H, F, Cl, CN, CF, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 33 is H. In some embodiments, R 33 is CH3.

[0241] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 34 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 34 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 34 can be H, F, Cl, OH, CN, CF, CH, NH, NHCH, N(CH), or -OCH. In some embodiments, R 34 can be H.

[0242] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 35 Some non-limiting examples ofA , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 35 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 35 can be H, F, CN, CF, CH, CHCH, CHCHCH, or CH(CH). In some embodiments, R 35 is H. In some embodiments, R 35 is CH3.

[0243] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 36 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 36are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 36 can be H, F, CN, CF, CH, CHCH, CHCHCH, or CH(CH). In some embodiments, R 36 is H. In some embodiments, R 36 is CH3.

[0244] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 37 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 37 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl.1-6 In some embodiments, R 37 can be H, F, CN, CF, CH, CHCH, CHCHCH, or CH(CH). In some embodiments, R 37 is H. In some embodiments, R 37 is CH3.

[0245] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 38 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 38 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 38 can be H, F, CN, CF, CH, CHCH, CHCHCH, or CH(CH). In some embodiments, R 38 is H. In some embodiments, R 38 is CH3.

[0246] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 39 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 39 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 39 can be H, F, CN, CF, CH, CHCH, CHCHCH, or CH(CH). In some embodiments, R 39 can be H.

[0247] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 40 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R Betc. In some embodiments, R 40 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 40 can be H, F, CN, CF, CH, CHCH, CHCHCH, or CH(CH). In some embodiments, R 40 can be H.

[0248] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 41 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 41 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl.1-6 In some embodiments, R 41 can be H, F, CN, CF, CH, CHCH, CHCHCH, or CH(CH). In some embodiments, R 41 is H. In some embodiments, R 41 is CH3.

[0249] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 42 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 42 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 42 can be H, CN, CF, CH, CHCH, CHCHCH, or CH(CH). In some embodiments, R 42 is H. In some embodiments, R 42 is CH3.

[0250] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 43 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 43 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 43 can be H, F, Cl, CN, CF, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 43 can be H.

[0251] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 44 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONRA R B etc. In some embodiments, R 44 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 44 can be H, F, Cl, CN, CF, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 44 can be H.

[0252] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 45 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 45 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 45 can be H, F, Cl, CN, CF, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 45 can be H.

[0253] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 46 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 46 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 46can be H, F, Cl, CN, CF, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 46 can be H.

[0254] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 47 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 47 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 47 can be H, F, Cl, CN, CF, OH; NH, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 47 can be H.

[0255] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 48Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 48 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 48 can be H, F, Cl, CN, CF, OH; NH, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 48 can be H.

[0256] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 49 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R49 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 49 can be H, F, Cl, CN, CF, OH; NH, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 49 can be H.

[0257] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 50 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 50 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 50 can be H, F, Cl, CN, CF, OH; NH, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 50 can be H.

[0258] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 51 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 51 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 51can be H, F, Cl, CN, CF, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 51 can be H.

[0259] With respect to any relevant embodiment or structural representation of formulae A-1 to A-44 herein, R 52 Some non-limiting examples of A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 52 are H; F; Cl; CN; CF3; OH; NH2; C such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 alkyl; or C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl. 1-6 In some embodiments, R 52 can be H, F, Cl, CN, CF, CH, CHCH, CHCHCH, CH(CH), -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). 52 can be H.

[0260] Some embodiments of formula A-1 include compounds represented by formula A-43: [ka] During the ceremony, L is CH2, R 1 is an optionally substituted cyclic C3H5; R 1 an optional substituent is CF3; R 2 is optionally substituted cyclobutyl; R 3 is an optionally substituted C alkyl; R 3 an optional substituent of is OH; R 4 is H, R 5 is H, or a pharma- ceutically acceptable salt thereof.

[0261] Some embodiments of formula A-1 include compounds represented by formula A-44: [ka] During the ceremony, L is CH2, R 1 is an optionally substituted C alkyl; R 1 each optional substituent is independently CF3 or CH3; R 2 is optionally substituted cyclobutyl; R 3 is an optionally substituted C alkyl; R 3 an optional substituent of is OH; R 4 is H, R 5 is H, or a pharma- ceutically acceptable salt thereof.

[0262] Some embodiments of formula A-1 include compounds represented by the following structure, or a pharma- ceutically acceptable salt thereof: [ka]

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[0263] Some embodiments include a compound represented by formula B-1: [ka]

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

[0265] For example, with respect to formula B-1, or in any embodiment of formula B-1, the substituents of Bz are CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H 11 , cyclic C5H9, C6H 13 , cyclic CH 11 C etc. 1-10 It may be an optionally substituted alkyl, such as OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 , Cyclic OC5H9, OC6H 13 , cyclic OC6H 11 C etc. 1-10 Optionally substituted alkoxy; halo, such as F, Cl, Br, I; OH; CN; NO2; C, such as CF3, CF2H, C2F5 1-6 Fluoroalkyl; C such as OCF3, OCF2H, OC2F5 1-6Fluoroalkoxy; C such as -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl 1-10 Esters; -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc. 1-10 Ketones; or C, such as NH2, NH(CH3), N(CH3)2, and N(CH3)C2H5 1-10 In some embodiments, the substituents of Bz are 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, COH, C 1-4 CO2-alkyl, NH2, or C 1-4 It may be alkylamino.

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

[0267] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, where D is an optionally substituted C 3-6 Carbocyclyl or C 2-5D is heterocyclyl. When D is substituted cyclobutyl, it can have 1, 2, 3, 4, 5, 6, or 7 substituents. When D is substituted phenyl, it can have 1, 2, 3, 4, or 5 substituents. When D is substituted isoxazolyl, it can have 1 or 2 substituents. D can include any substituent. In some embodiments, some or all of the substituents of D can have 0-10 carbon atoms and 0-10 heteroatoms, where each heteroatom is independently: O, N, S, F, Cl, Br, or I (provided that at least one non-hydrogen atom is present), and / or have a molecular weight of 15 g / mol to 500 g / mol. In some embodiments, some or all of the substituents may have a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to 50 Da, respectively, and consist of 2 to 5 chemical elements, where the chemical elements are independently C, H, O, N, S, F, Cl, or Br.

[0268] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 to B-7 herein, where the substituents of D are CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H 11 , cyclic C5H9, C6H 13 , cyclic CH 11 C etc. 1-10 C, such as optionally substituted alkyl 1-10 It may be an optionally substituted alkyl, such as OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 , Cyclic OC5H9, OC6H 13 , cyclic OC6H 11 C etc. 1-10 Optionally substituted alkoxy; halo, such as F, Cl, Br, I; OH; CN; NO2; C, such as CF3, CF2H, C2F5 1-6 Fluoroalkyl; C such as OCF3, OCF2H, OC2F5 1-6Fluoroalkoxy; C such as -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl 1-10 Esters; -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc. 1-10 Ketones; or C, such as NH2, NH(CH3), N(CH3)2, and N(CH3)C2H5 1-10 In some embodiments, the substituents of D are F, Cl, Br, I, CN, NO, C 1-4 Alkyl, C 1-4 Alkyl-OH, C 1-3 O-Alkyl, CF3, COH, C 1-4 CO-Alkyl, COH, C 1-4 CO2-alkyl, NH2, or C 1-4 It may be alkylamino.

[0269] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, and in some embodiments D is [ka] or any substituted C 2-4 It is an alkyl.

[0270] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, where in some embodiments, D is an optionally substituted cyclobutyl, an optionally substituted phenyl, an optionally substituted isoxazolyl, or an isopropyl.

[0271] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, in which in some embodiments, D is an optionally substituted cyclobutyl. In some embodiments, D is a cyclobutyl. In some embodiments, D is [ka] It is.

[0272] To any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, the following applies, in some embodiments, D is isopropyl.

[0273] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, where in some embodiments, D is t-butyl or tert-butyl.

[0274] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, in some embodiments, D is an optionally substituted phenyl. In some embodiments, D is [ka] It is.

[0275] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, where in some embodiments D is an optionally substituted pyridinyl, such as an optionally substituted pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl. [ka] It is.

[0276] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, in some embodiments, D is an optionally substituted isoxazolyl. [ka] It is.

[0277] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, where A is [ka] C etc. 2-8 It is an alkyl.

[0278] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, where X is H, F, CH3, CF3, optionally substituted phenyl, or optionally substituted pyridinyl. In some embodiments, X is H. In some embodiments, X is F. In some embodiments, X is CF3.

[0279] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein: when X is a substituted phenyl, it may have 1, 2, 3, 4, or 5 substituents. When X is a substituted pyridinyl, it may have 1, 2, 3, or 4 substituents. In some embodiments, some or all of the substituents of X may have 0-10 carbon atoms and 0-10 heteroatoms, where each heteroatom is independently: O, N, S, F, Cl, Br, or I (provided that at least one non-hydrogen atom is present), and / or have a molecular weight of 15 g / mol to 500 g / mol. In some embodiments, some or all of the substituents may have a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to 50 Da, respectively, and consist of 2 to 5 chemical elements, where the chemical elements are independently C, H, O, N, S, F, Cl, or Br.

[0280] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, where the X substituent is CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H 11 , cyclic C5H9, C6H 13 , cyclic CH 11 C etc. 1-10 It may be an optionally substituted alkyl, such as OCH3, OC2H5, OC3H7, cyclic OC3H5, OC4H9, cyclic OC4H7, OC5H 11 , Cyclic OC5H9, OC6H 13 , cyclic OC6H 11 C etc. 1-10 Optionally substituted alkoxy; halo, such as F, Cl, Br, I; OH; CN; NO2; C, such as CF3, CF2H, C2F5 1-6 Fluoroalkyl; C such as OCF3, OCF2H, OC2F5 1-6 Fluoroalkoxy; C such as -O2CCH3, -CO2CH3, -O2CC2H5, -CO2C2H5, -O2C-phenyl, -CO2-phenyl 1-10 Esters; -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc. 1-10 Ketones; or C, such as NH2, NH(CH3), N(CH3)2, and N(CH3)C2H5 1-10 In some embodiments, the substituents of X are F, Cl, Br, I, CN, NO, C 1-4 Alkyl, C 1-4 Alkyl-OH, C 1-3 O-Alkyl, CF3, COH, C 1-4 CO-Alkyl, COH, C 1-4 CO2-alkyl, NH2, or C 1-4 It may be alkylamino.

[0281] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, where 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, where the 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, CF, OH, C 1-5 O-Alkyl, C 0-6 Amino, or C 0-6 In some embodiments, Y is fluoroamino. In some embodiments, Y is H. In some embodiments, Y is OH. In some embodiments, Y is F. In some embodiments, Y is CF. In some embodiments, Y is a C alkyl group such as -OCH, OC, OC, H, etc. 1-3 In some embodiments, Y is C 0-6 In some embodiments, Y is [ka] In some embodiments, Y is an optionally substituted tetrahydropyranyl such as one or two C 3-6 C, which may contain a carbocyclyl ring 1-8 In some embodiments where Y includes at least one carbocyclyl ring, the 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 [ka] (or methyl(2,2,2-trifluoroethyl)amino). In some embodiments, Y is dimethylamino.

[0282] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, and in some embodiments: [ka] teeth, [ka] C etc. 2-8 It is an alkyl.

[0283] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, and in some embodiments: [ka] teeth, [ka] C etc. 2-8 It is a hydroxyalkyl.

[0284] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, and in some embodiments: [ka] teeth, [ka] C etc. 2-8 It is a fluoroalkyl.

[0285] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, and in some embodiments: [ka] teeth, [ka] C etc. 2-8 It is an alkoxyalkyl.

[0286] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, and in some embodiments: [ka] teeth, [ka] C etc. 2-8 It is a hydroxyfluoroalkyl.

[0287] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, and in some embodiments: [ka] teeth, [ka] and optionally substituted 2-hydroxy-2-phenylethyl.

[0288] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, and in some embodiments: [ka] teeth, [ka] and the like.

[0289] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 through B-7 herein, and in some embodiments: [ka] teeth, [ka] Any substitution of C such as 2-8 It is a fluoroaminoalkyl.

[0290] The following applies to any relevant embodiment or structural representation of formula B-1, or B-2, or B-3 to B-7 herein. 1-18 can be H or any substituent, for example, a substituent having 0-12 atoms or 0-6 carbon atoms and 0-5 heteroatoms, where each heteroatom is independently O, N, S, F, Cl, Br, or I, and / or has a molecular weight of 15 g / mole to 300 g / mole. 1-18 may have a) one or more optionally substituted or optionally connected alkyl moieties, or 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, or substituents that do not have an alkyl moiety, such as F, Cl, Br, I, NO2, CN, NH2, OH, COH, CO2H. In some embodiments, each R 1-18 are 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, the chemical elements being independently C, H, O, N, S, F, Cl, or Br.

[0291] For any related structural representation of formula B-1, or B-2, or B-3 to B-7, R 1-18 Some non-limiting examples of A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-5 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 is H; F; Cl; Br; CN; CHF2, CF3, etc. 1-3 Fluoroalkyl; OH; NH; C such as methyl, ethyl, propyl isomers (e.g., n-propyl and isopropyl), cyclopropyl, butyl isomers, cyclobutyl isomers (e.g., cyclobutyl and methylcyclopropyl), pentyl isomers, cyclopentyl isomers, hexyl isomers, and cyclohexyl isomers. 1-6 Alkyl; C such as -O-methyl, -O-ethyl, the isomers of -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl 1-6 Alkoxy; -CHOH, -CH-OH, -CH-OH, C 1-4 Hydroxyalkyl; C such as -CO2-CH3, -CO2-C2H5, -CO2-C3H7, -CO2-C4H9 2-5 It can be -CO2-alkyl. [ka]

[0292] For any related structural representation of formula B-1, or B-2, or B-3 to B-7, RA Each of is independently H or a group of formula C a H a+1 or a linear or branched alkyl group having the formula C a H a-1 Cycloalkyl having C 1-12 alkyl, where a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as those of the formula: CH3, C2H5, C3H7, C4H9, C5H 11 , C6H 13 , C7H 15 , C8H 17 , C9H 19 , C 10 H 21 or linear or branched alkyl such as C3H5, C4H7, C5H9, C6H 11 , C7H 13 , C8H 15 , C9H 17 , C 10 H 19 In some embodiments, R A is H or C 1-6 In some embodiments, R A is H or C 1-3 R can be alkyl. A may be H or CH. In some embodiments, R A can be H.

[0293] For any related structural representation of formula B-1, or B-2, or B-3 to B-7, R B Each of is independently H or a group of formula C a H a+1 or a linear or branched alkyl group having the formula C a H a-1 Cycloalkyl having C 1-12 alkyl, where a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as those of the formula: CH3, C2H5, C3H7, C4H9, C5H 11 , C6H 13 , C7H 15 , C8H 17, C9H 19 , C 10 H 21 or linear or branched alkyl such as C3H5, C4H7, C5H9, C6H 11 , C7H 13 , C8H 15 , C9H 17 , C 10 H 19 In some embodiments, R B is H or C 1-3 R can be alkyl. B may be H or CH. In some embodiments, R B can be H.

[0294] With respect to any related structural representation of formula B-1, or B-2, or B-3 through B-7, such as formula 2C, in some embodiments, R 1 are H, F, Cl, Br, CN, OCH3, OH, CHF2, CF3, C 1-4 -CO2-Alkyl, C 1-4 Alkyl or C 1-4 In some embodiments, R 1 are H, Cl, Br, CN, OCH3, CHF2, CF3, -CO2CH2CH3, -CH2OH, [ka] In some embodiments, R 1 is H. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br. In some embodiments, R 1 is CN. In some embodiments, R 1 is OCH. In some embodiments, R 1 is CHF2. In some embodiments, R 1 is CF3. In some embodiments, R 1 is -COCHCH. In some embodiments, R1 is -CHOH. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is -OCH3, -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. With respect to the embodiments described in this paragraph, in some embodiments, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-5 It may be a hydroxyalkyl.

[0295] With respect to any of the related structural representations of formulae B-1, B-2, or B-3 through B-7, in some embodiments, R 2 are 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 CHOH. In some embodiments, R 2 is -CO2CH3. With respect to the embodiments described in this paragraph, in some embodiments, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and 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 is -CH2OH, -CO2Me, or -C(CH3)2OH.

[0296] With respect to any of the related structural representations of formulae B-1, B-2, or B-3 through B-7, in some embodiments, R 3 are 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 is H. In some embodiments, R 3 is F. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0297] With respect to any of the related structural representations of formulae B-1, B-2, or B-3 through B-7, in some embodiments, R 4 are 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 4is CH3. In some embodiments, R 4 With respect to the embodiments described in this paragraph, in some embodiments, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0298] With respect to any of the related structural representations of formulae B-1, B-2, or B-3 through B-7, in some embodiments, R 5 are 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 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R.A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0299] With respect to any of the related structural representations of formulae B-1, B-2, or B-3 through B-7, in some embodiments, R 6 are 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 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0300] With respect to any of the related structural representations of formulae B-1, B-2, or B-3 through B-7, in some embodiments, R 7 are 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 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0301] With respect to any of the related structural representations of formulae B-1, B-2, or B-3 through B-7, in some embodiments, R 8 are 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 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A, F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0302] With respect to any of the related structural representations of formulae B-1, B-2, or B-3 through B-7, in some embodiments, R 9 are 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 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0303] With respect to any of the related structural representations of formulae B-1, B-2, or B-3 through B-7, in some embodiments, R 10 are 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 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0304] With respect to any of the related structural representations of formulae B-1, B-2, or B-3 through B-7, in some embodiments, R 11 are 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 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0305] With respect to any of the related structural representations of formulae B-1, B-2, or B-3 through B-7, in some embodiments, R 12 are 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 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , C.O.R.A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0306] With respect to any of the related structural representations of formulae B-1, B-2, or B-3 through B-7, in some embodiments, R 13 are 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 is H. In some embodiments of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4It may be a hydroxyalkyl.

[0307] With respect to any of the related structural representations of formulae B-1, B-2, or B-3 through B-7, in some embodiments, R 14 are 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 of the embodiments described in this paragraph, R 1-18 The remaining groups are independently R A , F, Cl, Br, CN, OR A , C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B etc. In some embodiments, R 1-18 The remaining groups are H, F, Cl, Br, CN, and C 1-3 Fluoroalkyl, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 -CO2-alkyl or C 1-4 It may be a hydroxyalkyl.

[0308] In some embodiments of the present invention, one or more hydrogen atoms are replaced by deuterium.It is well established that deuteration of physiologically active compounds provides the advantage of retaining the pharmacological profile of their hydrogen counterparts while positively affecting their metabolic results.In the compounds of the present invention, selectively replacing one or more hydrogen atoms with deuterium can improve the safety, tolerability and efficacy of the compound when compared with its all hydrogen counterparts.

[0309] The method of incorporating deuterium into a compound is well established.Using metabolic studies established in the art, the compound of the present invention can be tested to identify the site for selective placement of deuterium isotope, where the isotope is not metabolized.Furthermore, these studies identify metabolic site as the place where deuterium atom is placed.

[0310] Some embodiments of formula B-1 include compounds represented by formula B-3: [ka] During the ceremony, D is an optionally substituted cyclobutyl; A is a C4 alkyl; X is CF3, Y is H, R 1 is a C3 hydroxyalkyl; R 2 and R 4 is H, and R 3 is F, It may include a compound represented by formula B-3, or a pharma- ceutically acceptable salt thereof.

[0311] Some embodiments of formula B-1 include compounds represented by formula B-4: [ka] During the ceremony, D is an optionally substituted cyclobutyl; A is a C4 alkyl; X is CF3, Y is H, R 1 is a C3 hydroxyalkyl, and R 2 , R 3 and R 4 is H, It may include a compound represented by formula B-4, or a pharma- ceutically acceptable salt thereof.

[0312] Some embodiments of formula B-1 include compounds represented by formula B-5: [ka] During the ceremony, D is t-butyl; A is a C5 alkyl; X is H, Y is H, R 1 is CN, R 2 and R 4 is H, and R 3 is F, It may include a compound represented by formula B-5, or a pharma- ceutically acceptable salt thereof.

[0313] Some embodiments of formula B-1 include compounds represented by formula B-6: [ka] During the ceremony, D is t-butyl; A is a C4 alkyl; X is CF3, Y is H, R 1 is CN, R 2 and R 4 is H, and R 3 is F, It may include a compound represented by formula B-6, or a pharma- ceutically acceptable salt thereof.

[0314] Some embodiments of formula B-1 include compounds represented by formula B-7: [ka] During the ceremony, D is t-butyl; A is a C5 alkyl; X is H, Y is H, R 1 is CN, R 2 and R 3 is F, and R 4 is H, It may include a compound represented by formula B-7, or a pharma- ceutically acceptable salt thereof.

[0315] Some embodiments of formula B-1 include compounds represented by the following structure, or a pharma- ceutically acceptable salt thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[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, a therapeutically effective amount of a compound of Formula A-1 through A-44 or B-1 through B-7, or a pharma- ceutically 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 may contain at least about 50 milligrams of a compound of formula A-1 through A-44 or B-1 through B-7, or a pharma- ceutically acceptable salt thereof, and in some embodiments such a pharmaceutical composition may contain at least about 75 milligrams of a compound of formula A-1 through A-44 or B-1 through B-7, or a pharma- ceutically acceptable salt thereof, at least about 100 milligrams of a compound of formula A-1 through A-44 or B-1 through B-7, or a pharma- ceutically acceptable salt thereof, at least about 150 milligrams of a compound of formula A-1 through A-44 or B-1 through B-7, or a pharma- ceutically acceptable salt thereof, at least about 200 milligrams of a compound of formula A-1 through A-44 or B-1 through B-7, or a pharma- ceutically acceptable salt thereof. The composition may comprise at least about 100 milligrams of a compound of formula A-1 through A-44 or B-1 through B-7, or a pharma- ceutically acceptable salt thereof, at least about 250 milligrams of a compound of formula A-1 through A-44 or B-1 through B-7, or a pharma- ceutically acceptable salt thereof, at least about 300 milligrams of a compound of formula A-1 through A-44 or B-1 through B-7, or a pharma- ceutically acceptable salt thereof, at least about 500 milligrams of a compound of formula A-1 through A-44 or B-1 through B-7, or a pharma- ceutically acceptable salt thereof, at least about 600 milligrams of a compound of formula A-1 through A-44 or B-1 through B-7, or a pharma- ceutically acceptable salt thereof, at least about 750 milligrams of a compound of formula A-1 through A-44 or B-1 through B-7, or a pharma- ceutically acceptable salt thereof, at least about 1000 milligrams of a compound of formula A-1 through A-44 or B-1 through B-7, or a pharma- ceutically acceptable salt thereof.

[0318] In embodiments, the compounds of formulae A-1 to A-44 or B-1 to B-7, or pharma- ceutically acceptable salts thereof, may be administered in a pharmaceutical composition. The pharmaceutical compositions of various methods may be prepared, packaged, and sold in bulk, either as a single unit dose or as multiple unit doses, and may be administered in a conventional manner by any route in which they are active. For example, the compositions may be administered orally, ophthalmically, intravenously, intramuscularly, intraarterially, intramedullary, intrathecally, intracerebroventricularly, transdermally, subcutaneously, intraperitoneally, intravesically, intranasally, intestinal, topically, sublingually, intrarectally, by depot injection, or by implant, or by the use of vaginal creams, suppositories, pessaries, vaginal rings, rectal suppositories, intrauterine devices, and transdermal forms such as patches and creams. The particular method of administration will vary depending on the indication. The selection of the particular route of administration and dosing regimen may be adjusted or titrated by the clinician according to known methods to obtain the optimal clinical response. All of the methods described herein can be practiced by administering a compound of formula A-1 through A-44 or B-1 through B-7, or a pharma- ceutically acceptable salt thereof, by any such route of administration described herein. Additionally, a compound of formula A-1 through A-44 or B-1 through B-7, or a pharma- ceutically acceptable salt thereof, can be delivered by using such routes of administration for the entire dosing regimen described herein.

[0319] Pharmaceutical compositions containing a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt thereof, in solid dosage forms may include, but are not limited to, tablets, capsules, cachets, pellets, pills, powders, and granules; topical dosage forms including, but are not limited to, solutions, powders, liquid emulsions, liquid suspensions, semisolids, ointments, pastes, creams, gels and jellies, and foams; and parenteral dosage forms including, but are not limited to, solutions, suspensions, emulsions, and dry powders, and have an effective amount of polymer or copolymer. It is also known in the art that the active ingredient may be included in such formulations together with pharma- ceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives, and the like. Means and methods of administration are known in the art, and the artisan may refer to various pharmacological references for guidance. See, for example, Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman & Gilman's The Pharmaceutica Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980).

[0320] For oral administration, the compounds of formula A-1-A-44 or B-1-B-7, or pharma- ceutically acceptable salts thereof, can be easily formulated by combining the compounds of formula A-1-A-44 or B-1-B-7, or pharma- ceutically acceptable salts thereof with pharma- ceutically acceptable carriers well known in the art. Such carriers allow the compounds of various methods to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by the subject to be treated. Pharmaceutical preparations for oral use can be obtained by adding solid excipients, grinding the resulting mixture as necessary, adding suitable auxiliaries as necessary, and then processing the mixture of granules to obtain tablets or dragee cores. Suitable excipients include sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; fillers, such as, but not limited to, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and cellulose preparations, including polyvinylpyrrolidone (PVP). If desired, disintegrating agents, such as, but not limited to, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, can be added.

[0321] In some embodiments of the various methods, the pharmaceutical composition may be suitable for oral administration, such as, for example, a solid oral dosage form or a capsule, and in certain embodiments, the composition may be a tablet. Such tablets may contain any number of additional agents, such as, for example, one or more binders, one or more lubricants, one or more diluents, one or more lubricants, one or more surface active agents, one or more dispersants, one or more colorants, etc. Such tablets may be prepared by any method known in the art, such as compression or molding. Compressed tablets may be prepared by compressing the components of the composition in a free-flowing form, such as powder or granules, in a suitable machine, and molded tablets may be produced by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. The tablets in some embodiments may be uncoated, while in other embodiments, they may be coated by known techniques.

[0322] In other embodiments of the various methods prepared for oral administration, the pharmaceutical compositions of the various methods may be provided in dragee cores with suitable coatings. In such embodiments, dragee cores may be prepared using gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and concentrated sugar solutions that may optionally contain suitable organic solvents or solvent mixtures. In some embodiments, dyes or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. In still other embodiments, the pharmaceutical compositions containing an effective amount of a compound of formula A-1-A-44 or B-1-B-7 or a pharma-ceutically acceptable salt thereof prepared for oral administration may include, but are not limited to, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Additionally, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.

[0323] In various embodiments of how tablets and dragee cores are coated, the coating may delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. Moreover, such coatings may be adapted to release the compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt thereof, in a predetermined pattern, for example to achieve a controlled release formulation, or may be adapted not to release the active compound until after stomach passage, for example by including an enteric coating. Suitable coatings included in such embodiments may include, but are not limited to, sugar coatings, film coatings such as hydroxypropylmethylcellulose, methylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycol, and / or polyvinylpyrrolidone, or enteric coatings such as methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and / or ethylcellulose. Additionally, a time delay material, such as, for example, glyceryl monostearate or glyceryl distearate, can be incorporated into the coating of some embodiments. In yet other embodiments, the solid tablet compositions may include a coating adapted to protect the composition from undesired chemical changes, for example, to reduce chemical degradation prior to the release of the active pharmaceutical ingredient.

[0324] Pharmaceutical compositions suitable for oral administration within the various method embodiments may comprise a therapeutically effective amount of a compound of Formulae A-1 through A-44 or B-1 through B-7, or a pharma- ceutically 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 of formula A-1 to A-44 or B-1 to B-7, or a pharma- ceutically acceptable salt thereof, in an amount of about 20% to about 50% by weight of the 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; in certain embodiments, such a tablet may contain an effective amount of a compound of formula A-1 to A-44 or B-1 to B-7, or a pharma- ceutically 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 crospovidone or croscarmellose, and about 0.01% to about 2% by weight of magnesium stearate. In further embodiments, the pharmaceutical compositions may include any amount or combination of microcrystalline cellulose, mannitol, sodium, crospovidone, croscarmellose magnesium stearate, or any combination thereof.

[0325] In some embodiments of the various methods, pharmaceutical compositions comprising a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt thereof, may be prepared as a suspension, solution, or emulsion in an oily or aqueous vehicle suitable for injection. In such embodiments, such liquid formulations may further include formulating agents, such as suspending, stabilizing, and / or dispersing agents, formulated for parenteral administration. Such injectable formulations may be administered by any route, including, but not limited to, subcutaneous, intravenous, intramuscular, intraarterial, bolus injection, or continuous infusion, and in embodiments in which the injectable formulation is administered by continuous infusion, the infusion may be performed for a period of about 15 minutes to about 24 hours. In certain embodiments, the injectable formulation may be presented in unit dosage form, e.g., in ampoules or multi-dose containers, with the addition of a preservative.

[0326] In other embodiments of the various methods, the compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt thereof, may be formulated as a depot preparation, and such long-acting preparations may be administered by implantation, e.g., subcutaneous or intramuscular injection, or by intramuscular injection. Depot injections may be administered at intervals of about one month to about six months or more. Thus, for example, the compound may be formulated with a suitable polymer or hydrophobic material, e.g., as an emulsion in an acceptable oil, or with an ion exchange resin, or as a sparingly soluble derivative, e.g., as a sparingly soluble salt.

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

[0328] In yet another embodiment, pharmaceutical compositions containing a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt thereof, may be formulated for administration by inhalation. In such an embodiment, pharmaceutical compositions by various methods may be delivered in the form of an aerosol spray presentation from a pressurized pack 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 pack, the dosage unit may be determined by providing a valve to deliver a metered amount. For example, capsules and cartridges of gelatin for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0329] In further embodiments, pharmaceutical compositions containing a compound of Formula A-1-A-44 or B-1-B-7, or a pharma-ceutically acceptable salt thereof, can be formulated into rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0330] In some embodiments, pharmaceutical compositions comprising a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt thereof, may be formulated for transdermal administration. Such pharmaceutical compositions may be prepared, for example, to be applied in a patch or by a transdermal therapeutic system delivered to a subject. In other embodiments, pharmaceutical and therapeutic compositions comprising a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt thereof, for transdermal administration may include suitable solid or gel phase carriers or excipients, such as, for example, 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-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt thereof, may be administered alone as a single therapeutic agent. In other embodiments, a pharmaceutical composition comprising a compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt thereof, may be administered in combination with one or more other active ingredients, such as adjuvants, protease inhibitors, or other compatible drugs or compounds, if such combination is deemed desirable or advantageous to achieve the desired effects of the methods described herein.

[0332] In an embodiment, the method further comprises administering one or more active agents simultaneously or together with administering the compound of formula A-1-A-44 or B-1-B-7, or a pharma- ceutically acceptable salt thereof. In an embodiment, the one or more active agents are dexpramipexole, riluzole, baclofen, tizanidine, or edaravone. Riluzole is a neuroprotective agent that blocks inactivated sodium channels. Riluzole has been shown to prolong survival in subjects with ALS. In an embodiment, riluzole is administered at 50 mg once or twice daily. In an embodiment, dexpramipexole 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 is dexpramipexole. In an embodiment, the one or more active agents is riluzole.

[0333] In embodiments, the one or more active agents are antiglutamate or ion channel blockers, such as, but not limited to, FP-0011, memantine, N-acetylated-a-linked acid dipeptidase (NALADase) inhibitors, nimodipine, or combinations thereof. Excessive glutamate levels have been shown to be toxic to neurons, and evidence suggests that both direct and indirect glutamate toxicity may contribute to the pathogenesis of motor neuron degeneration in diseases such as ALS. FP0011 is an antiglutamatergic compound that may reduce presynaptic glutamate levels and exhibits potent neuroprotective properties. Memantine is a noncompetitive 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 embodiments, memantine is administered at 2 mg, 5 mg, 7 mg, 10 mg, 14 mg, 21 mg, or 28 mg. N-acetylated-alpha-linked-acid-dipeptidase (NAALADase) converts N-acetyl-aspartate-glutamate to glutamate upon neuronal injury and may represent a new approach to block excess glutamate release without interfering with normal brain function in the treatment of neurodegenerative disorders. Nimodipine is a dihydropyridine calcium channel blocker that antagonizes activation of excitatory amino acid receptors to reduce calcium influx into damaged neurons, which may help slow or reverse ALS. In embodiments, nimodipine is administered at 30 mg or 60 mg.

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

Claims

【Request Item 1】 【Chemistry 1】 or a pharmaceutically acceptable salt thereof. 【Request Item 2】 【Chemistry 2】 or a pharmaceutically acceptable salt thereof. 【Request Item 3】 【Chemistry 3】 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. 5. The pharmaceutical composition of claim 4 for use in the treatment of a Kv7-associated disorder.

6. 6. The pharmaceutical composition of claim 5, wherein the Kv7-related disorder is selected from epilepsy, neonatal convulsions, pain, migraine, neurotransmitter release disorders, smooth muscle contraction disorders, dyskinesia, dystonia, mania, hearing disorders, neuropathic pain, inflammatory pain, persistent pain, cancer pain, postoperative pain, anxiety, substance abuse, schizophrenia, bladder disorders, vascular disorders, frontotemporal dementia (FTD), familial FTD, or amyotrophic lateral sclerosis.

7. 5. The pharmaceutical composition of claim 4 for use in the treatment of a disorder associated with a KCNQ2 mutation.

8. 8. The pharmaceutical composition of claim 7, wherein the disorder is selected from neonatal convulsions, neonatal seizures, 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 convulsions, epileptic encephalopathy, early infantile epileptic encephalopathy 7 (EIEE7), early infantile epileptic encephalopathy with psychomotor developmental delay, abnormal globus pallidus morphology, apnea, cerebral edema, dystonia, facial erythema, muscular hypotonia, febrile convulsions, hypoplasia of the corpus callosum, hypsarrhythmia, focal clonic seizures, generalized tonic-clonic seizures, myokymia, spastic quadriplegia, and myokymia.

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