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  • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
  • C07D235/30—Nitrogen atoms not forming part of a nitro radical
  • C07D235/32—Benzimidazole-2-carbamic acids, unsubstituted or substituted; Esters thereof; Thio-analogues thereof
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• K + channels present on the plasma membranes of most cell types, are the most diverse class of all ion channels and are associated with a wide range of physiological functions including the regulation of the electrical properties of excitable cells.
• the primary pore-forming (a) subunits of these highly selective cation channels are divided into three primary structural classes based on the number of transmembrane (TM)-spanning regions and pore (P) regions: currently there are known to be 6TM/1P, 2TM/1P and 4TM/2P K + channels.
• Kv7 genes (originally termed KCNQ, a name assigned by the HUGO Gene Nomenclature Committee (HGNC)) were assigned to a subfamily of voltage-gated K + channels by the International Union of Pharmacology (IUPHAR).
• the Kv7 subfamily consists of five homologous pore-forming a subunits, Kv7.1-7.5, that have a structure typical of voltage-gated K + channels with 6TM-spanning regions (S1-S6) flanked by intracellular N- terminal and C-terminal domains, a typical voltage-sensor domain located in S4 comprised of alternating positively-charged residues and a single P region between S5 and S6 of each subunit.
• the channels are formed as tetramers of the primary a subunits, either as homotetramers or heterotetramers.
• Neurons are known to express Kv7 channels comprised of Kv7.2-7.5 a subunits. Some of these gene products may be exclusively neuronal while others, such as Kv7.4 and Kv7.5, can be found in other tissues such as smooth and skeletal muscle.
• Kv7.4 and Kv7.5 can be found in other tissues such as smooth and skeletal muscle.
• M-channels were notable because they were slowly activating and non-inactivating, active at membrane potentials at or near the resting membrane potential of neurons and muscarinic cholinergic agonists produced a reduction in the M-current, demonstrating a direct and inhibitory link between G-protein coupled receptors (GPCRs) and a physiological K + current. It was not until the cloning of this subfamily of genes that the pharmacological and biophysical identity was established between Kv7.2/7.3 (and likely Kv7.5/7.3) heteromultimers and the elusive‘M’-channel, providing significant new evidence for their importance in neuronal regulation.
• GPCRs G-protein coupled receptors
• opener or activator is commonly used throughout the literature but does not adequately describe the mode 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 macroscopic current amplitude, but this nomenclature is really too simplistic.
• retigabine the first publicly disclosed Kv7 opener
• Neuronal Kv7 channel openers may work in concert with the activity of a channel over the ‘nor enhance currents without activation threshold.
• some openers appear to remove the voltage-dependence of activation entirely. Whether these effects represent some continuum is currently unclear since the effects are often concentration-dependent.
• the modes of interaction of compounds that can increase channel current are complex and in most cases not well understood and the implications of these profiles on neuronal responsiveness and systems physiology are also unclear.
• Retigabine is modestly potent, not highly specific, but it is a very effective opener of Kv7.2, Kv7.5 and heteromultimeric Kv7 channels. Its effects are characterized by a significant increase in channel current over a narrow voltage range. As mentioned above, at more positive voltages the opener is less effective and under some conditions channel current significantly decreases at more positive voltages relative to control currents (this‘crossover’ voltage-dependence of opener action is a characteristic of many neuronal Kv7 channel openers). This effect is also concentration-dependent and is more pronounced at higher concentrations.
• the term“about” means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45%-55%.
• all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon 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 at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
• administering when used in conjunction with a therapeutic, means to administer a therapeutic directly into or onto a target tissue or to administer a therapeutic to a subject whereby the therapeutic positively impacts the tissue to which it is targeted.
• administering a composition may be accomplished by oral administration, injection, infusion, absorption or by any method in combination with other known techniques.
• administering may include the act of self-administration or administration by another person such as a healthcare provider or a device.
• the term“consists of” or“consisting of” means that the composition or method includes only the elements, steps, or ingredients specifically recited in the particular embodiment or claim.
• the term“consisting essentially of” or“consists essentially of” means that the composition or method includes only the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention.
• improves is used to convey that the present invention refers to the overall physical state o agent has been administered. symptoms of a condition, disease or disorder, such as a neurodegenerative disorder, are alleviated by administration of an active agent.“Improves” may also refer to changes in the appearance, form, characteristics, and/or physical attributes of tissue, or any combination thereof, to which it is being provided, applied, or administered.
• the term“inhibit,”“suppress,”“decrease,”“interfere,” and/or“reduce” generally refers to the act of reducing, either directly or indirectly, a function, activity, or behavior relative to the natural, expected, or average or relative to current conditions.
• Kv7 associated diseases is a disease, disorder, or condition: associated with a mutation in the KCNQ2 gene; associated with a mutation in the the KCNQ3 gene; associated with a mutation in the KCNQ4 gene; associated with a mutation in the KCNQ5 gene; associated with genes encoding Kv7 potassium channels; associated with a non-mutated Kv7 potassium channel, but dysfunctional Kv7 potassium channel; associated with the hyperexcitability of cells that are believed to cause the disease, disorder or condition; or a combination thereof. Regardless of causation, these Kv7 associated diseases, disorders or conditions can be treated by the activation of the Kv7 potassium channel, even though the Kv7 potassium channel may not be a direct or indirect cause of the disease, disorder or condition.
• Kv7 associated disorder in relation to a mutation in the KCNQ2 gene examples include but are not limited to benign familial neonatal seizures (BFNS) or KCNQ2 encephalopathy (also known as KCNQ2 neonatal epileptic encephalopathy).
• KCNQ2 encephalopathy also known as KCNQ2 neonatal epileptic encephalopathy
• KCNQ3 gene examples include but are not limited to BFNS or KCNQ3-related developmental disability.
• Kv7 associated disorder in relation to a mutation in the KCNQ4 gene examples include but are not limited to autosomal dominant nonsyndromic hearing loss.
• Kv7 associated disorder in relation to a mutation in the KCNQ5 gene examples include but are not limited to nonsyndromic intellectual disability or epileptic encephalopathy.
• a disorder associated with the hyperexcitability of cells that are believed to cause the disease, disorder or condition include but are not limited to focal clonic seizures, generalized tonic-clonic seizures, neuropathic pain, overactive bladder; or smooth muscle disorders, or a combination thereof.
• compositions and methods may be utilized with or on a subject in need of such treatment, which may also be referred to as“in need ther need thereof” means that the subject has been identified as having a need for the particular method or treatment and that the treatment has been given to the subject for that particular purpose.
• the term“therapeutic” means an agent utilized to treat, combat, ameliorate, or prevent, or any combination thereof, an unwanted condition, disorder or disease of a subject.
• the term“patient” and“subject” are interchangeable and may be taken to mean any living organism, which may be treated with compounds of the present invention.
• the terms“patient” and“subject” may include, but are not limited to, any non-human mammal, primate or human.
• the“patient” or “subject” is an adult, child, infant, or fetus.
• the“patient” or“subject” is a human.
• the“patient” or“subject” is a mammal, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, or humans.
• therapeutically effective amount or“therapeutic dose” as used herein are interchangeable and may refer to the amount of an active agent or pharmaceutical compound or composition that elicits a clinical, biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinical professional.
• a clinical, biological or medical response may include, for example, one or more of the following: (1) preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display pathology or symptoms of the disease, condition or disorder, (2) inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptoms of the disease, condition or disorder or arresting further development of the pathology and/or symptoms of the disease, condition or disorder, and (3) ameliorating a disease, condition or disorder in an individual that is experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder or reversing the pathology and/or symptoms experience or exhibited by the individual.
• the term“treat,”“treated,” or“treating” may be taken to mean prophylaxis of a specific disorder, disease or condition, alleviation of the symptoms associated with a specific disorder, disease or condition and/or prevention of the symptoms associated with a specific disorder, disease or condition.
• the term refers to slowing the progression of the disorder, disease or condition or alleviating the symptoms associated with the specific disorder, disease or condition.
• the term refers to alleviating the symptoms a disease or condition.
• the term refers to restoring function which was impaired or lost due to a specific disorder, disorder or condition.
• “Pharmaceutically acceptable salt” is meant to indicate those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. (1977) J. Pharm. Sciences, Vol.6, 1-19, describes pharmaceutically acceptable salts in detail.
• a pharmaceutically acceptable“salt” is any acid addition salt, preferably a pharmaceutically acceptable acid addition salt, including, but not limited to, halogenic acid salts such as hydrobromic, hydrochloric, hydrofluoric and hydroiodic acid salt; an inorganic acid salt such as, for example, nitric, perchloric, sulfuric and phosphoric acid salt; an organic acid salt such as, for example, sulfonic acid salts (methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, benzenesulfonic or p-toluenesufonic, acetic, malic, fumaric, succinic, citric, benzonic, gluconic, lactic, mandelic, mucic, pamoic, pantothenic, oxalic and maleic acid salts; and an amino acid salt such as aspartic or glutamic acid salt.
• halogenic acid salts such as hydrobromic, hydrochloric
• the acid addition salt may be a mono- or di-acid addition salt, such as a di-hydrohalogic, di-sulfuric, di-phosphoric or di-organic acid salt.
• the acid addition salt is used as an achiral reagent which is not selected on the basis of any expected or known preference for the interaction with or precipitation of a specific optical isomer of the products of this disclosure.
• a compound or chemical structural feature such as aryl when referred to as being“optionally substituted,” it includes a feature that has no substituents (i.e. unsubstituted), or a feature that is“substituted,” meaning that the feature has one or more substituents.
• the term“substituent” has the broadest meaning known to one of ordinary skill in the art, and includes a moiety that replaces one or more hydrogen atoms attached to a parent compound or structural feature.
• a substituent may be an ordinary organic moiety known in the art, which may have a molecular weight (e.g.
• a substituent comprises, or consists of: 0-30, 0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0-10, or 0-5 heteroatoms, wherein each heteroatom may independently be: N, O, S, Si, F, Cl, Br, or I; provided that the substituent includes one C m
• moiety or part of a molecule For convenience, the term“molecular weight” is used with respect to a moiety or part of a molecule to indicate the sum of the atomic masses of the atoms in the moiety or part of a molecule, even though it may not be a complete molecule.
• alkyl has the broadest meaning generally understood in the art, and may include a moiety composed of carbon and hydrogen containing no double or triple bonds.
• Alkyl may be linear alkyl, branched alkyl, cycloalkyl, or a combination thereof, and in some embodiments, may contain from one to thirty-five carbon atoms.
• alkyl may include C 1-10 linear alkyl, such as methyl (- CH 3 ), methylene (-CH 2 -), ethyl (-CH 2 CH 3 ), ethylene (-C 2 H 4 -), n-propyl (-CH 2 CH 2 CH 3 ), propylene (-C 3 H 6 -), n-butyl (-CH 2 CH 2 CH 2 CH 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), n-hexyl (- CH 2 CH 2 CH 2 CH 2 CH 3 ), etc.; C 3-10 branched alkyl, such as C 3 H 7 (e.g. iso-propyl), C 4 H 9 (e.g.
• branched butyl isomers C 5 H 11 (e.g. branched pentyl isomers), C 6 H 13 (e.g. branched hexyl isomers), C 7 H 15 (e.g. branched heptyl isomers), etc.; C 3-10 cycloalkyl, such as C 3 H 5 (e.g. cyclopropyl), C 4 H 7 (e.g. cyclobutyl isomers such as cyclobutyl, methylcyclopropyl, etc.), C 5 H 9 (e.g.
• cyclopentyl isomers such as cyclopentyl, methylcyclobutyl, dimethylcyclopropyl, etc.), C 6 H 11 (e.g. cyclohexyl isomers), C 7 H 13 (e.g. cycloheptyl isomers), bicyclo[1.1.1]pentane, norborane, etc.; and the like.
• a phrase such as“optionally substituted C 1-12 alkyl” refers to a C 1-12 alkyl that may be unsubstituted, or may have 1 or more substituents, and does not limit the number of carbon atoms in any substituent.
• CH 2 (CH 2 ) 11 OCH 3 is optionally substituted C 1-12 alkyl because the parent alkyl group has 12 carbon atoms.
• CH 2 CH 2 OCH 3 is C 1-12 optionally substituted alkyl because the alkyl group (e.g. ethyl) and the substituent (e.g. methoxy) together contain 3 carbon atoms. Similar conventions may be applied to other optionally substituted moieties such as aryl and heterocyclyl.
• Substituents on alkyl may be the same as those described generally above.
• substituents on alkyl are independently selected from F, Cl, Br, I, CN, CO 2 H, -O-alkyl, ester groups, acyl, amine groups, amide groups, phenyl (including fused phenyl resulting optionally substituted alkyl such as indenyl, where the phenyl substituent is fused to the parent alkyl moiety), and may have a molecular weight of about 15 to about 100 or about 500.
• aryl has the broadest meaning generally understood in the art, and may include an aromatic ring or aromatic ring system such as phenyl, naphthyl, etc.
• heterocyclyl includes any ring or ring system containing a heteroatom such as N, O, S, P, etc.
• Heterocyclyl includes heteroaryl rings or ring systems (such as those listed below) and non-aromatic rings or ring systems.
• non- aromatic heterocyclyl examples include azetidinyl, oxatanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxalanyl, dithiolanyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino, etc.
• heteroaryl also has the meaning understood by a person of ordinary skill in the art, and includes an“aryl” which has 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, benzooxazolyl, benzothiazolyl, benzoimidazolyl, etc.
• an“aryl” which has one or more heteroatoms in the ring or ring system, such as pyridinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, oxadiazolyl, isoxazolyl, indolyl, quinolinyl, benzofuranyl, benzothieny
• the term“carbocyclyl” has the broadest meaning generally understood in the art and includes rings free of heteroatoms, such as cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; cycloalkenyl, e.g. cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl; cycloalkynyl, e.g.
• a name or structural representation includes any stereoisomer or any mixture of stereoisomers and Applicant reserves the right to specifically identify and claim a compound as a single stereoisomer or any particular mixture of stereoisomers.
• Compounds described herein may contain an asymmetric center and may thus exist as enantiomers. Where the compounds according to embodiments herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Embodiments herein include all such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers. In some embodiments, the formulas are shown without a definitive stereochemistry at certain positions. Embodiments herein include all stereoisomers of such formulas and pharmaceutically acceptable salts thereof.
• Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid or base as a resolving agent or on a chiral HPLC column. Further, 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 compounds disclosed herein can exist as and therefore include all stereoisomers, conformational isomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds and Applicant reserves the right to specifically identify and claim a compound in any such form.
• Kv7 activator ezogabine has an EC 50 of 1.1 ⁇ M as characterized in the Kv7.2/7.3 FluxOR Potassium Ion Channel Assay (Invitrogen, F20015).
• alkyl group at the Y position as in any of structural formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, often result in a Kv7.2/7.3 EC 50 ⁇ 1 ⁇ M.
• Some embodiments include a compound represented by Formula 1C:
• Bz can be optionally substituted benzoimidazol-1,2-yl. If the benzoimidazol-1,2-yl is substituted, it may have 1, 2, 3, or 4 substituents. Any substituent may be included on the benzoimidazol-1,2-yl. In some embodiments, some or all of the substituents on the benzoimidazol-1,2-yl may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I (provided that there is at least 1 non-hydrogen atom); and/or a molecular weight of 15 g/mol to 500 g/mol.
• some or all of the substituents may each have a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to 50 Da, and consist of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br.
• Bz can be optionally substituted benzoimidazol-1,2-diyl. In some embodiments, Bz can be optionally substituted benzoimidazol-1,2,6-triyl.
• the substituents of Bz may be C 1-10 optionally substituted alkyl, such as CH 3 , C 2 H 5 , C 3 H 7 , cyclic C 3 H 5 , C 4 H 9 , cyclic C 4 H 7 , C 5 H 11 , cyclic C 5 H 9 , C 6 H 13 , cyclic C 6 H 11 , etc., which may be optionally substituted; C 1-10 optionally substituted alkoxy such as OCH 3 , OC 2 H 5 , OC 3 H 7 , cyclic OC 3 H 5 , OC 4 H 9 , cyclic OC 4 H 7 , OC 5 H 11 , cyclic OC 5 H 9 , OC 6 H 13 , cyclic OC 6 H 11 , etc.; halo, such as F, Cl, Br, I; OH; CN; NO 2 ; C 1-6 fluoroalkyl, such as CF 3 , CF
• a substituent of Bz may be F, Cl, Br, I, CN, NO 2 , C 1-4 alkyl, C 1-4 alkyl-OH, C 1- 3 O-alkyl, CF 3 , COH, C 1-4 CO-alkyl, CO 2 H, C 1-4 CO 2 -alkyl, NH 2 , or C 1-4 alkylamino.
• Formula 1C may include a compound represented by Formula 2C:
• D is optionally substituted C 3-6 carbocyclyl or C 2-5 heterocyclyl. If D is substituted cyclobutyl, it may have 1, 2, 3, 4, 5, 6, or 7 substituents. If D is substituted phenyl, it may have 1, 2, 3, 4, or 5 substituents. If D is substituted isoxazolyl, it may have 1 or 2. Substituents. D may include any substituent.
• some or all of the substituents of D may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I (provided that there is at least 1 non-hydrogen atom); and/or a molecular weight of 15 g/mol to 500 g/mol.
• some or all of the substituents may each have a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to 50 Da, and consist of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br.
• the substituents of D may be C 1-10 optionally substituted alkyl, such as CH 3 , C 2 H 5 , C 3 H 7 , cyclic C 3 H 5 , C 4 H 9 , cyclic C 4 H 7 , C 5 H 11 , cyclic C 5 H 9 , C 6 H 13 , cyclic C 6 H 11 , bicyclo[1.1.1]pentane, norborane, etc., which may be optionally substituted; C 1- 10 optionally substituted alkoxy such as OCH 3 , OC 2 H 5 , OC 3 H 7 , cyclic OC 3 H 5 , OC 4 H 9 , cyclic OC 4 H 7 , OC 5 H 11 , cyclic OC 5 H 9 , OC 6 H 13 , cyclic OC 6 H 11 , etc.; halo, such as F, Cl, Br, I; OH;
• D is:
• D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, bicyclo[1.1.1]pentane, norborane, or isopropyl.
• D is optionally substituted
• D is cyclobutyl. In some embodiments, D is .
• D is isopropyl
• D is t-butyl, or tert-butyl.
• D is bicyclo[1.1.1]pentane.
• D is optionally substituted some embodiments D is
• D is optionally substituted pyridinyl, such as optionally substituted pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl.
• pyridinyl such as optionally substituted pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl.
• D is
• D is optionally substituted isoxazolyl.
• D is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
• A is C 1-8 alkyl, such as linear or branched linear or
• X is H, F, CH 3 , SCF 3 , CF 3 , optionally substituted C 2-10 alkyl, optionally substituted phenyl, or optionally substituted pyridinyl.
• X is H.
• X is CH 3 .
• X is F.
• X is CF 3 .
• X is substituted phenyl, it may have 1, 2, 3, 4, or 5, substituents. If X is substituted pyridinyl, it may have 1, 2, 3, or 4 substituents. In some embodiments, some or all of the substituents of X may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I (provided that there is at least 1 non-hydrogen atom); and/or a molecular weight of 15 g/mol to 500 g/mol.
• some or all of the substituents may each have a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to 50 Da, and consist of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br.
• the substituents of X may be C 1-10 optionally substituted alkyl, such as CH 3 , C 2 H 5 , C 3 H 7 , cyclic C 3 H 5 , C 4 H 9 , cyclic C 4 H 7 , C 5 H 11 , cyclic C 5 H 9 , C 6 H 13 , cyclic C 6 H 11 , etc., which may be optionally substituted; C 1-10 optionally substituted alkoxy such as OCH 3 , OC 2 H 5 , OC 3 H 7 , cyclic OC 3 H 5 , OC 4 H 9 , cyclic OC 4 H 7 , cyclic OC 5 H 11 , cyclic OC 5 H 9 , OC 6 H 13 , cyclic OC 6 H 11 , etc.; halo, such as F, Cl, Br, I; OH; CN; NO 2 ; C 1-6 fluoro
• a substituent of X may be F, Cl, Br, I, CN, NO 2 , C 1-4 alkyl, C 1-4 alkyl-OH, C 1-3 O-alkyl, CF 3 , COH, C 1-4 CO-alkyl, CO 2 H lk l ino.
• Y is H, F, Cl, Br, I, or a moiety having a molecular weight of 15 Da to 300 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br.
• Y is H, F, Cl, Br, I, CN, -COH, C 1-6 -CO-alkyl, CF 3 , OH, C 1-5 O-alkyl, C 0-6 amino, or C 0-6 fluoroamino. In some embodiments, Y is H, F, CF 3 , OH, C 1-5 O-alkyl, C 0-6 amino, or C 0-6 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 3 .
• Y is C 1-3 O-alkyl, such as -OCH 3 , OC 2 H 5 , OC 3 H 7 , etc. In some embodiments, Y is C 0-6 fluoroamino. In some embodiments, Y
• Y may include a C 1-8 alkyl that may include one or two C 3-6 carbocyclyl rings. In some embodiments, wherein Y includes at least one carbocyclyl rings, the rings may be connected to each other. In some embodiments, Y is -C(CF 3 ) 2 OH (or 1,1,1,3,3,3-hexafluoro-2- hydroxypropan-2-yl). In some embodiments Y (or methyl(2,2,2- trifluoroethyl)amino). In some embodiments, Y is dimethylamino.
• X 2C herein the following applies, in some embodiments C 2-8 hydroxyalkyl, such as
• X 2C herein the following applies, in some embodiments C 2-8 alkoxyalkyl, such as .
• X 2C herein the following applies, in some embodiments C 2-8 hydroxyfluoroalkyl
• Y is optionally substituted 2-
• Y is optionally substituted C 2-8
• fluoroaminoalkyl such .
• R 1-18 may be H or any substituent, such as a substituent having 0 to 12 atoms or 0 to 6 carbon atoms and 0 to 5 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I, and/or having a molecular weight of 15 g/mol to 300 g/mol.
• each of R 1-18 is independently H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 300 Da, 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to 60 Da, and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br.
• R 1-18 may include R A , F, Cl, Br, CN, OR A , C 1-3 fluoroalkyl, C 1-5 hydroxyalkyl, NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 1-18 may be H; F; Cl; Br; CN; C 1-3 fluoroalkyl, such as CHF 2 , CF 3 , etc; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers (e.g. n-propyl and isopropyl), cyclopropyl, butyl isomers, cyclobutyl isomers (e.g.
• C 1-7 alkoxy such as –O–methyl, –O–ethyl, isomers of –O–propyl, –O– cyclopropyl, isomers of–O–butyl, isomers of–O–cyclobutyl, isomers of–O–pentyl, isomers of–O–cyclopentyl, isomers of–O–hexyl, isomers of–O–cyclohexyl,–O–benzyl, etc.; C 1–4 hydroxyalkyl, such as–CH 2 OH,–C 2 H 4 –OH,–C 3 H 6 –OH, C 4 H 8 –OH, etc.; C 2–5 –CO 2 –alkyl, such as–CO 2 –CH 3 ,–CO 2 –C 2 H
• each R A may independently be H, or C 1-12 alkyl, including: linear or branched alkyl having a formula C a H 2a+1 , or cycloalkyl having a formula C a H 2a-1 , wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl of a formula: CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , C 5 H 11 , C 6 H 13 , C 7 H 15 , C 8 H 17 , C 9 H 19 , C 10 H 21 , etc., or cycloalkyl of a formula: C 3 H 5 , C 4 H 7 , C 5 H 9 , C 6 H 11 , C 7 H 13 , C 8 H 15 , C 9 H 17 , C 10 H 19 , etc.
• R A may be H or optionally substituted C 1-6 alkyl. In some embodiments, R A may be H or optionally substituted C 1-3 alkyl. In some embodiments, R A may be H or CH 3 . In some embodiments, R A may be H.
• each R B may independently be H, or C 1-12 alkyl, including: linear or branched alkyl having a formula C a H 2a+1 , or cycloalkyl having a formula C a H 2a-1 , wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl of a formula: CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , C 5 H 11 , C 6 H 13 , C 7 H 15 , C 8 H 17 , C 9 H 19 , C 10 H 21 , etc., or cycloalkyl of a formula: C 3 H 5 , C 4 H 7 , C 5 H 9 , C 6 H 11 , C 7 H 13 , C 8 H 15 , C 9 H 17 , C 10 H 19 , etc.
• R B may be H or C 1-3 alkyl.
• R B may be H or C 1-3 alkyl.
• R 1 is H, F, Cl, Br, CN, OCH 3 , OH, CHF 2 , CF 3 , C 1-4 -CO 2 -alkyl, C 1–4 alkyl, or C 1-5 hydroxyalkyl.
• R 1 is H, Cl, Br, CN, .
• R 1 is H.
• R 1 is F.
• R 1 is Cl.
• R 1 is Br.
• R 1 is CN.
• R 1 is OCH 3 .
• R 1 is CHF 2 .
• R 1 is CF 3 .
• R 1 is -CO 2 CH 2 CH 3 .
• R 1 is -CH 2 OH.
• R 1 is . In some embodiments, R 1
• R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is -OCH 3 , -OH, -OCHF 2 ,–O–benzyl, -CN, -CF 3 , -CH 2 OH, -COOCH 2 CH 3 , -C(CH 3 ) 2 OH, -CHOHCH 2 CH 3 , -CHOHCH 3 , -CHF 2 , -CH(CH 3 ) 2 , -C(CH 2 CH 3 ) 2 OH, -CH 2 CO OCH 2 CH 3 , -CH 2 C(CH 3 ) 2 OH, -CH 2 COOH, or -CH 2 CON(CH 3 ) 2 .
• the remaining groups of R 1-18 may independently be R A , F, Cl, Br, CN, OR A , C 1-3 fluoroalkyl, C 1-5 hydroxyalkyl, NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• the remaining groups of R 1-18 may be H, F, Cl, Br, CN, C 1-3 fluoroalkyl, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-4 -CO 2 -alkyl, or C 1–5 hydroxyalkyl.
• R 2 is H, F, Cl, Br, CN, OCH 3 , OCF 3 , CHF 2 , CF 3 , C 1-4 -CO 2 -alkyl, C 1–4 alkyl, or C 1-5 hydroxyalkyl.
• R 2 is H.
• R 2 is F.
• R 2 is CH 2 OH.
• R 2 is -CO 2 CH 3 .
• the remaining groups of R 1-18 may independently be R A , F, Cl, Br, CN, OR A , C 1-3 fluoroalkyl, C 1-5 hydroxyalkyl, NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• the remaining groups of R 1-18 may be H, F, Cl, Br, CN, C 1-3 fluoroalkyl, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-4 -CO 2 -alkyl, or C 1–4 hydroxyalkyl.
• R 2 is -CH 2 OH, - CO 2 Me, or -C(CH 3 ) 2 OH.
• R 3 is H.
• R 3 is F.
• the remaining groups of R 1-18 may independently be R A , F, Cl, Br, CN, OR A , C 1-3 fluoroalkyl, C 1- 5 hydroxyalkyl, NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• the remaining groups of R 1-18 may be H, F, Cl, Br, CN, C 1-3 fluoroalkyl, OH, NH 2 , C 1-6 alkyl, optionally substituted C 1-6 alkoxy, C 1-4 -CO 2 -alkyl, or C 1–4 hydroxyalkyl.
• R 4 is H, F, Cl, Br, CN, OCH 3 , CHF 2 , CF 3 , C 1-4 -CO 2 -alkyl, C 1–4 alkyl, or C 1-5 hydroxyalkyl.
• R 4 is H.
• R 4 is F.
• R 4 is CH 3 .
• R 4 is CF 3 .
• the remaining groups of R 1-18 may independently be R A , F, Cl, Br, CN, OR A , C 1-3 fluoroalkyl, C 1-5 hydroxyalkyl, NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• the remaining groups of R 1-18 may be H, F, Cl, Br, CN, C 1-3 fluoroalkyl, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-4 -CO 2 -alkyl, or C 1–4 hydroxyalkyl.
• R 5 is H, F, Cl, Br, CN, OCH 3 , CHF 2 , CF 3 , C 1-4 -CO 2 -alkyl, C 1–4 alkyl, or C 1-5 hydroxyalkyl.
• R 5 is H.
• R 5 is CH 3 .
• the remaining groups of R 1-18 may independently be R A , F, Cl, Br, CN, OR A , C 1-3 fluoroalkyl, C 1-5 hydroxyalkyl, NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• the remaining groups of R 1-18 may be H, F, Cl, Br, CN, C 1-3 fluoroalkyl, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-4 -CO 2 -alkyl, or C 1–4 hydroxyalkyl.
• R 6 is H, F, Cl, Br, CN, OCH 3 , CHF 2 , CF 3 , C 1-4 -CO 2 -alkyl, C 1–4 alkyl, or C 1-5 hydroxyalkyl. In some embodiments, R 6 is H.
• the remaining groups of R 1-18 may independently be R A , F, Cl, Br, CN, OR A , C 1-3 fluoroalkyl, C 1-5 hydroxyalkyl, NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• the remaining groups of R 1-18 may be H, F, Cl, Br, CN, C 1-3 fluoroalkyl, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-4 -CO 2 -alkyl, or C 1–4 hydroxyalkyl.
• R 7 is 3 C 1 4 -CO 2 -alkyl, C 1–4 alkyl, recited in this paragraph, in some embodiments, the remaining groups of R 1-18 may independently be R A , F, Cl, Br, CN, OR A , C 1-3 fluoroalkyl, C 1-5 hydroxyalkyl, NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• the remaining groups of R 1-18 may be H, F, Cl, Br, CN, C 1-3 fluoroalkyl, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-4 -CO 2 -alkyl, or C 1–4 hydroxyalkyl.
• R 8 is H, F, Cl, Br, CN, OCH 3 , CHF 2 , CF 3 , C 1-4 -CO 2 -alkyl, C 1–4 alkyl, or C 1-5 hydroxyalkyl. In some embodiments, R 8 is H.
• the remaining groups of R 1-18 may independently be R A , F, Cl, Br, CN, OR A , C 1-3 fluoroalkyl, C 1-5 hydroxyalkyl, NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• the remaining groups of R 1-18 may be H, F, Cl, Br, CN, C 1-3 fluoroalkyl, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-4 -CO 2 -alkyl, or C 1–4 hydroxyalkyl.
• R 9 is H, F, Cl, Br, CN, OCH 3 , CHF 2 , CF 3 , C 1-4 -CO 2 -alkyl, C 1–4 alkyl, or C 1-5 hydroxyalkyl. In some embodiments, R 9 is H.
• the remaining groups of R 1-18 may independently be R A , F, Cl, Br, CN, OR A , C 1-3 fluoroalkyl, C 1-5 hydroxyalkyl, NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• the remaining groups of R 1-18 may be H, F, Cl, Br, CN, C 1-3 fluoroalkyl, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-4 -CO 2 -alkyl, or C 1–4 hydroxyalkyl.
• R 10 is H, F, Cl, Br, CN, OCH 3 , CHF 2 , CF 3 , C 1-4 -CO 2 -alkyl, C 1–4 alkyl, or C 1-5 hydroxyalkyl. In some embodiments, R 10 is H.
• the remaining groups of R 1-18 may independently be R A , F, Cl, Br, CN, OR A , C 1-3 fluoroalkyl, C 1-5 hydroxyalkyl, NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• the remaining groups of R 1-18 may be H, F, Cl, Br, CN, C 1-3 fluoroalkyl, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-4 -CO 2 -alkyl, or C 1–4 hydroxyalkyl.
• R 11 is H, F, Cl, Br, CN, OCH 3 , CHF 2 , CF 3 , C 1-4 -CO 2 -alkyl, C 1–4 alkyl, or C 1-5 hydroxyalkyl.
• R 11 is H.
• ining groups of R 1-18 may COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• the remaining groups of R 1-18 may be H, F, Cl, Br, CN, C 1-3 fluoroalkyl, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-4 -CO 2 -alkyl, or C 1–4 hydroxyalkyl.
• R 12 is H, F, Cl, Br, CN, OCH 3 , CHF 2 , CF 3 , C 1-4 -CO 2 -alkyl, C 1–4 alkyl, or C 1-5 hydroxyalkyl. In some embodiments, R 12 is H.
• the remaining groups of R 1-18 may independently be R A , F, Cl, Br, CN, OR A , C 1-3 fluoroalkyl, C 1-5 hydroxyalkyl, NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• the remaining groups of R 1-18 may be H, F, Cl, Br, CN, C 1-3 fluoroalkyl, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-4 -CO 2 -alkyl, or C 1–4 hydroxyalkyl.
• R 13 is H, F, Cl, Br, CN, OCH 3 , CHF 2 , CF 3 , C 1-4 -CO 2 -alkyl, C 1–4 alkyl, or C 1-5 hydroxyalkyl. In some embodiments, R 13 is H.
• the remaining groups of R 1-18 may independently be R A , F, Cl, Br, CN, OR A , C 1-3 fluoroalkyl, C 1-5 hydroxyalkyl, NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• the remaining groups of R 1-18 may be H, F, Cl, Br, CN, C 1-3 fluoroalkyl, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-4 -CO 2 -alkyl, or C 1–4 hydroxyalkyl.
• R 14 is H, F, Cl, Br, CN, OCH 3 , CHF 2 , CF 3 , C 1-4 -CO 2 -alkyl, C 1–4 alkyl, or C 1-5 hydroxyalkyl.
• R 14 is H.
• R 14 is F.
• the remaining groups of R 1-18 may independently be R A , F, Cl, Br, CN, OR A , C 1-3 fluoroalkyl, C 1-5 hydroxyalkyl, NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• the remaining groups of R 1-18 may be H, F, Cl, Br, CN, C 1-3 fluoroalkyl, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-4 -CO 2 -alkyl, or C 1–4 hydroxyalkyl.
• one or more hydrogen atoms is replaced by a deuterium. It is well established that deuteration of physiologically active compounds offer the advantage of retaining the pharmacological profile of their hydrogen counterparts while positively impacting their metabolic outcome. Selective replacement of one or more hydrogen with deuterium, in a compound of the present invention, could improve the safety, tolera d when compared to its all [0086] Methods for incorporation of deuterium into compounds are well established. Using metabolic studies established in the art, the compound of the present invention can be tested to identify sites for selective placement of a deuterium isotope, wherein the isotope will not be metabolized. Moreover these studies identify sites of metabolism as the location where a deuterium atom would be placed.
• the embodiments expressed herein do not encompass any compound expressly disclosed in US Patent No. 9,481,653, WO 2016/040952, US Provisional No. 62/579,770, U.S. Provisional No. 62/663,427, or US Provisional No.62/644,932.
• the compounds of Formula 1C have a Kv7.2/7.3 Thallium flux EC 50 of £ 10 ⁇ M. In certain embodiments, the compounds of Formula 1C have a Kv7.2/7.3 Thallium flux EC 50 of £ 1 ⁇ M. In certain embodiments, the compounds of Formula 1C have a Kv7.2/7.3 Thallium flux EC 50 of £ 0.3 ⁇ M.
• Some embodiments of Formula 1C may include a compound represented by Formula 8a:
• D is optionally substituted cyclobutyl or t-butyl
• A is C 1 alkyl
• X is substituted cyclobutyl, wherein the substituent is F;
• Y is H
• R 1 is C 3 hydroxyalkyl or CN
• R 2 and R 4 are H
• R 3 is H or F
• Some embodiments of Formula 1C may include a compound represented by Formula 8b:
• D is optionally substituted cyclobutyl or t-butyl
• A is C 1 alkyl
• X is substituted cyclobutyl, wherein the substituent is F;
• Y is H
• R 1 is selected from C 3 hydroxyalkyl, CN, or F;
• R 2 is selected from H, F, or -OCF 3 ;
• R 3 is selected from H, F, or -OCH 3 ;
• R 4 is H or F
• Some embodiments of Formula 1C may include a compound represented by Formula 8c:
• D is optionally substituted cyclobutyl, optionally
• subst the optional A is C 1 alkyl
• X is substituted cyclobutyl, wherein the substituent is F;
• Y is H
• R 1 is selected from H, C 3 hydroxyalkyl, CN, F, or Cl;
• R 2 is selected from H, CN, F, Br, or -OCF 3 ;
• R 3 is selected from H, F, or -OCH 3 ;
• R 4 is H or F
• Formula 1C may include a compound represented by Formula 9:
• D is cyclobutyl
• A is C 1 alkyl
• X is optionally substituted cyclobutyl, wherein the
• Y is H
• R 1 is C 3 hydroxyalkyl
• R 2 and R 4 are H
• R 3 is F
• Some embodiments of Formula 1C may include a compound represented by Formula 10:
• D is optionally substituted C 2 - 5 alkyl, wherein the
• substituents are selected from -CH 3 and F;
• A is C 1-6 alkyl
• X is H, F, -CH 3 , -CF 3 , -SCF 3 , pyridinyl, optionally
• Y is H, F, -OH, or -CH 3 ;
• R 1 is H, C 3-4 hydroxyalkyl, -CN, -OH, -CF 3 , -OCHF 2 ,
• R 2 is H, halogen, -CN, -OCH 3 , -COR A , -CF 3 , -OCF 3 ,
• substituents of R 2 are selected from -OCH 3 and -COR A ;
• R 3 is H, halogen, -CF 3 , -OCHF 2 , -OCF 3 , or -OCH 3 ;
• R 4 is H, halogen, or C 3 hydroxyalkyl
• R A and R B are CH 3 ;
• Formula 1C may include a compound represented by Formula 11:
• D is optionally substituted C 2-5 alkyl or optionally
• A is C 1-6 alkyl
• X is H, F, -CH 3 , -CF 3 , -SCF 3 , pyridinyl, optionally
• Y is H, F, -OH, or -CH 3 ;
• R 1 is H, C 3-4 hydroxyalkyl, -CN, -OH, -CF 3 , -OCHF 2 ,
• R 2 is H, halogen, -CN, -OCH 3 , -COR A , -CF 3 , -OCF 3 ,
• substituents of R 2 are selected from -OCH 3 and -COR A ;
• R 3 is H, halogen, -CF 3 , -OCHF 2 , -OCF 3 , or -OCH 3 ;
• R 4 is H, halogen, or C 3 hydroxyalkyl
• R A and R B are CH 3 ;
• Formula 1C may include a compound represented by Formula 12:
• D is optionally substituted cyclobutyl, wherein the
• A is C 3 alkyl
• X is -CH 3 ;
• Y is -CH 3 ;
• R 1 is CN
• R 2 and R 3 are F;
• Some embodiments of Formula 1C may include a compound represented by Formula 13:
• A is C 1 alkyl
• X is optionally substituted cyclobutyl, wherein the
• Y is H
• R 1 and R 4 are F
• R 2 and R 3 are H;
• Some embodiments of Formula 1C may include a compound represented b F l 14
• D is optionally substituted C 2-5 alkyl, wherein the
• A is C 1-6 alkyl
• X is H, F, -CH 3 , -CF 3 , optionally substituted C 1-3 alkyl,
• Y is H, F, -OH, or -CH 3 ;
• R 1 is H, C 3-4 hydroxyalkyl, -CN, -CF 3 , -OCH 2 CF 3 , - OCHF 2 , ptionally substituted C 3-5 heterocyclyl,
• substituents are selected from -OH and F;
• R 2 is F, Br, -CN, -OCH 3 , -OCF 3 , or -CF 3 ;
• R 3 is H, halogen, -CF 3 , -OCHF 2 , -OCF 3 , or -OCH 3 ;
• R 4 is H, fluorine, or chlorine
• R A and R B are CH 3 ;
• Embodiments of the present invention relate to a method of treating a Kv7 associated disorder comprising administering a therapeutically effective amount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• the disorder is selected from the group consisting of epilepsy, neonatal spasms, pain, migraine, a disorder of neurotransmitter release, a smooth muscle contractility disorder, a dyskinesia, dystonia, mania, a hearing disorder, neuropathic pain, inflammatory pain, persistent pain, cancer pain, postoperative pain, anxiety, substance abuse, schizophrenia, a bladder disorder, a vasculature disorder, tinnitus, benign familial neonatal seizures, epilepsy, neurological disease via reduced basal M-current (and subsequent neuronal hyperexcitability), sensorineural hearing impairment, intellectual disability, epileptic encephalopathy, treatment-resistant epilepsy, cortical atrophy, neurological impairment, infantile spasms with hypsarrhythmia, myoclonic-tonic seizures, myoclonic seizures, tonic seizures, absence and focal-onset seizures with impaired awareness, congenital neurological disorder with intellectual disability or epileptic encephalopathy, benign familial neonatal convulsions, severe epileptic
• the gynecological system disorders are selected from the group consisting of pre-term labor, post-partum hemorrhage, uterine atony, uterine perforation, uterine hyper-stimulation, menorrhagia, metrorrhagia, menometrorrhagia, dysmenorrhea and endometriosis.
• KCNQ channel subunits (1-5). A subunits arranged as homotetramers or heterotetramers. KCNQ2, KCNQ3, KCNQ4, and KCNQ5 are expressed in the nervous system and have been associated with a range of disorders involving neuronal excitability.
• Embodiments herein are directed to methods of treating a disorder associated with a KCNQ subunit comprising administering a therapeutically effective amount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• Embodiments herein are directed to methods of treating a disorder associated with a KCNQ2 subunit comprising administering a therapeutically effective amount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• Embodiments herein are directed to methods of treating a disorder associated with a KCNQ3 subunit comprising administering a therapeutically effective amount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• Embodiments herein are directed to methods of treating a disorder associated with a KCNQ4 subunit comprising administering a therapeutically effective amount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• Embodiments herein are directed to methods of treating a disorder associated with a KCNQ5 subunit comprising administering a therapeutically effective amount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• Embodiments herein are directed to methods of treating a disorder associated with a mutation in a KCNQ subunit comprising administering a therapeutically effective amount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• Embodiments herein are directed to methods of treating a disorder associated with a mutation in a KCNQ2 subunit comprising administering a therapeutically effective amount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof, to ments herein are directed to administering a therapeutically effective amount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• Embodiments herein are directed to methods of treating a disorder associated with a mutation in a KCNQ4 subunit comprising administering a therapeutically effective amount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• Embodiments herein are directed to methods of treating a disorder associated with a mutation in a KCNQ5 subunit comprising administering a therapeutically effective amount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• KCNQ3 which encodes the Kv7 potassium channel
• Embodiments herein are directed to methods of treating a disorder associated with a KCNQ3 mutation comprising administering a therapeutically effective amount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• the disorder associated with a KCNQ3 mutation is selected from the group consisting of benign familial neonatal seizures, epilepsy, neurological disease via reduced basal M-current (and subsequent neuronal hyperexcitability), and any combination thereof.
• KCNQ4 which encodes the Kv7 potassium channel
• Embodiments herein are directed to methods of treating a disorder associated with a KCNQ4 mutation comprising administering a therapeutically effective amount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• the disorder associated with a KCNQ4 mutation is sensorineural hearing impairment.
• KCNQ5 which encodes the Kv7 potassium channel result in a wide ra n are directed to methods of therapeutically effective amount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• the disorder associated with a KCNQ5 mutation is selected from the group consisting of intellectual disability, epileptic encephalopathy, treatment-resistant epilepsy, cortical atrophy, neurological impairment, infantile spasms with hypsarrhythmia, myoclonic-tonic seizures, myoclonic seizures, tonic seizures, absence and focal-onset seizures with impaired awareness, congenital neurological disorder with intellectual disability or epileptic encephalopathy, benign familial neonatal convulsions, severe epileptic encephalopathies, congenital neurodevelopmental disorder with phenotypes of nonsyndromic intellectual disability or epileptic encephalopathy, and any combination thereof.
• KCNQ2 which encodes the Kv7 potassium channel
• Embodiments herein are directed to methods of treating a disorder associated with a KCNQ2 mutation comprising administering a therapeutically effective amount of a compound of formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, a compound of Group I, Group II, Group III, or Table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• the disorder associated with a KCNQ2 mutation is selected from the group consisting of neonatal spasms, neonatal seizures, epilepsy, benign familial neonatal epilepsy (KCNQ2-BFNE), epileptic encephalopathy (KCNQ2-NEE), benign familial neonatal convulsions type 1 (BFNC), benign familial neonatal seizures 1 (BFNS1), neonatal seizures associated with hypoxic-ischemic injury, epileptic spasms, epileptic encephalopathy, early infantile epileptic encephalopathy 7 (EIEE7), early infantile epileptic encephalopathy with delayed psychomotor development, generalized tonic seizures, abnormal globus pallidus morphology, apnea, cerebral edema, dystonia, facial erythema, muscular hypotonia, febrile seizures, hypoplasia of the corpus callosum, hypsarrhythmia, focal clonic seizure, generalized tonic-clonic seizures, myokymia,
• Embodiments are directed to methods for treating conditions associated with hyperexcitability of cells 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 or Formulas 1C, 2C, 8a, 8b rmaceutically acceptable salt
• Embodiments are directed to methods for treating a Kv7 associated disorder 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 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, wherein the symptoms of the disorder are alleviated or improved due to the activation of Kv7 potassium channel.
• Embodiments are directed to methods for treating 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 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is treated.
• the compound of Group I, Group II, Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, may be administered to any individual exhibiting the symptoms of a neurodegenerative disease or to individuals predisposed to a neurodegenerative disease.
• Non-limiting examples of neurodegenerative diseases that may be treated using a compound of Group I, Group II, Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14,include amyotrophic lateral sclerosis (ALS), Huntington’s disease, metabolically induced neurological damage, Alzheimer’s disease, Pick’s disease, senile dementia, age associated cognitive dysfunction, 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 disorder or disease, inflammatory demyelinating disorder, Parkinson’s disease, hepatic encephalopathy, chronic encephalopathy, chronic encephalitis, or any combination thereof.
• ALS amyotrophic lateral sclerosis
• Huntington’s disease ALS
• Embodiments are directed to methods for treating neurodegenerative disease, such as 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 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is treated.
• a compound of Group I, Group II, Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof wherein the neurodegenerative disease is treated.
• the subject is a subject with definite ALS, has amyotrophic lateral sclerosis symptom onset duration of less than about 18 months, plasma creatinine levels of about 72 mM/L or greater, concomitant riluzole administration, concomitant dexpramipexole administration, and combin [0116]
• Embodiments are directed to methods 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 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, wherein the amyotrophic lateral sclerosis is treated.
• Embodiments are directed to methods 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 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, wherein the amyotrophic lateral sclerosis is treated.
• the definite amyotrophic lateral sclerosis is as defined by the El Escorial diagnosis criteria.
• the subject is a subject with definite ALS, amyotrophic lateral sclerosis symptom onset duration of less than about 18 months, plasma creatinine levels of about 72 mM/L or greater, concomitant riluzole administration, concomitant dexpramipexole administration,, and combinations thereof.
• Embodiments are directed to methods 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 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, wherein the subject is selected from a subject with definite amyotrophic lateral sclerosis, a subject with limb-onset amyotrophic lateral sclerosis, a subject with bulbar-onset amyotrophic lateral sclerosis, a subject with amyotrophic lateral sclerosis symptom onset duration of less than about 18 months, a subject with a high level of serum creatinine, a subject with low bicarbonate levels, a subject with concomitant riluzole administration, a subject with concomitant dexpramipexole administration, and combinations thereof, and wherein the amyotrophic
• the method further comprises monitoring said subject for any clinical features associated with amyotrophic lateral sclerosis.
• the method further comprises initiating therapy with a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof upon diagnosis of amyotrophic lateral sclerosis.
• the subject exhibits symptoms of amyotrophic lateral sclerosis.
• the subject erosis probable amyotrophic lateral sclerosis, possible amyotrophic lateral sclerosis or suspected amyotrophic lateral sclerosis.
• Embodiments are directed to methods 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 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof, wherein the amyotrophic lateral sclerosis is treated.
• amyotrophic lateral sclerosis is the presence of the El Escorial diagnosis criteria, amyotrophic lateral sclerosis symptom onset duration of less than about 18 months, limb-onset amyotrophic lateral sclerosis, plasma creatinine levels of about 72 mM/L or greater, concomitant riluzole administration, concomitant dexpramipexole administration, an ALSFRS-R score of greater than 36.0, a pre-study progression rate greater than or equal to 0.8 points per month, a percentage predicted relaxed (slow) vital capacity (SVC) of less than or equal to 102.0, an ALSFRS-R fine motor domain score of greater than 10.0 points, ALSFRS-R bulbar domain score or greater than 9.0 points, an ALSFRS-R gross motor domain score of greater than 8.0 points, an abnormal neurological exam of the tongue, an abnormal neurological exam of the pharynx, larynx and swallowing, an abnormal neurological exam of the lower extremities
• Embodiments are directed to methods for treating amyotrophic lateral sclerosis in a subject exhibiting symptoms of amyotrophic lateral sclerosis comprising administering to the subjec of a compound of Group I, pharmaceutically acceptable salt thereof, wherein the symptoms of amyotrophic lateral sclerosis are treated.
• the subject exhibits clinical characteristics selected from definite amyotrophic lateral sclerosis, amyotrophic lateral sclerosis symptom onset duration of less than about 18 months, limb-onset amyotrophic lateral sclerosis, plasma creatinine levels of about 72 mM/L or greater, concomitant riluzole administration, concomitant dexpramipexole administration, an ALSFRS-R score of greater than 36.0, a re- study progression rate greater than or equal to 0.8 points per month, a percentage predicted relaxed (slow) vital capacity (SVC) of less than or equal to 102.0, an ALSFRS-R fine motor domain score of greater than 10.0 points, ALSFRS-R bulbar domain score or greater than 9.0 points, an ALSFRS-R gross motor domain score of greater than 8.0 points, an abnormal neurological exam of the tongue, an abnormal neurological exam of the pharynx, larynx and swallowing, an abnormal neurological exam of the lower extremities, an
• administering a therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof may include administering daily doses of about 0.1 mg to about 1,500 mg, about 1 mg to about 1,500 mg, about 10 mg to about 1,500 mg, about 50 mg to about 1,500 mg, about 75 mg to about 1,500 mg, about 100 mg to about 1,500 mg, about 125 mg to about 1,500 mg, about 150 mg to about 1,500 mg, about 175 mg to about 1,500 mg, 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 450 mg to about 1,500 about 1,500 mg, about 800 mg to about 1,500 mg, about 1,000 mg to about 1,500 mg, and about 1,200 mg to about 1,500 mg.
• the therapeutically effective amount of a compound of Group I, Group II, Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or a pharmaceutically acceptable salt thereof is selected from the group consisting of from about 0.1 mg to about 1,000 mg, 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.
• Such therapeutically effective amounts may be administered once a day or in equal, divided doses twice a day, three times a day, or four times a day.
• administering a therapeutically effective amount comprises administering a dose equal to about half of a daily dose twice per day. In some embodiments, the dose is administered every about 12 hours. In some embodiments, administering a therapeutically effective amount comprises administering about 25 mg two times per day, about 75 mg two times per day, about 150 mg two times per day, or about 300 mg two times per day.
• Embodiments herein are directed to pharmaceutical compositions comprising a therapeutically effective amount of a compound described herein or acceptable salts thereof, such as a compound of Group I, Group II, Group III, Table 1, or of Formula 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14, or pharmaceutically acceptable salts thereof.
• Pharmaceutical formulations containing such compounds and a suitable carrier can be in various forms including, but not limited to, solids, solutions, powders, fluid emulsions, fluid suspensions, semi-solids, and dry powders including an effective amount of a compound of the invention.
• the active ingredients can be contained in such formulations with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, antioxidants, preservatives and the like.
• pharmaceutically acceptable diluents fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, antioxidants, preservatives and the like.
• diluents fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, antioxidants, preservatives and the like.
• a single unit dose of a compound of Group I, Group II, Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14 or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 0.1 mg to about 1,500 mg, about 1 mg to about 1,500 mg, about 10 mg to about 1,500 mg, about 50 mg to about 1,500 mg, about 75 mg to about 1,500 mg, about 100 mg to about 1,500 mg, about 125 mg to about 1,500 mg, about 150 mg to about 1,500 mg, about 175 mg to about 1,500 mg, 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
• a single unit dose amount of a compound of Group I, Group II, Group III, or Table 1 or Formulas 1C, 2C, 8a, 8b, 8c, 9, 10, 11, 12, 13, or 14 or a pharmaceutically acceptable salt thereof is selected from group consisting of about 25 mg to about 5,000 mg, about 50 mg to about 5,000 mg, about 100 mg to about 5,000 mg, about 150 mg to about 5,000 mg, about 200 mg to about 5,000 mg, about 250 mg to about 5,000 mg, about 300 mg to about 5,000 mg, about 400 mg to about 5,000 mg, about 450 mg to about 5,000 mg, about 100 mg to about 3,000 mg, 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 3,000 mg, about 400 mg to about
• the single unit dose amount may be 10 mg/day to 1,500 mg/day, or about 100 mg/day to 600 mg/day. In some embodiments, such single unit doses may be administered once per day or multiple times per day, such as twice per day or three times per day.
• the single unit dose further comprises a pharmaceutically acceptable carrier.
• the compounds can be formulated for parenteral or intravenous administration by injection, e.g., by bolus injection or continuous infusion.
• Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative ms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
• Injectable preparations may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• a nontoxic parenterally acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
• acceptable vehicles and solvents that may be employed are water, Ringer’s solution, and isotonic sodium chloride solution.
• compositions include a compound prepared as described above which are formulated as a solid dosage form for oral administration including capsules, tablets, pills, powders, and granules.
• the active compound may be admixed with one or more inert diluent such as sucrose, lactose, or starch.
• Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
• the dosage forms may also comprise buffering agents and can additionally be prepared with enteric coatings.
• Preparation of a compound of the invention in solid dosage form may vary.
• a liquid or gelatin formulation may be prepared by combining a compound, such as those described above, and adding a thickening agent to the liquid mixture to form a gelatin. The gelatin may then be encapsulated in unit dosage form to form a capsule.
• an oily preparation of a compound prepared as described above may be lyophilized to for a solid that may be mixed with one or more pharmaceutically acceptable excipient, carrier or diluent to form a tablet.
• liquid dosage forms which may be useful for oral administration of a compound for the invention include liquid dosage forms.
• a liquid dosage may include a pharmaceutically acceptable emulsion, solution, suspension, syrup, and elixir containing inert diluents commonly used in the art, such as water.
• Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
• the compounds described herein can be formulated as a depot preparation.
• Such long acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Depot injections can be adm hs or longer intervals.
• materials for example, as an emulsion in an acceptable oil
• ion exchange resins for example, as sparingly soluble derivatives, for example, as a sparingly soluble salt.
• Scheme 1 shows a general methodology for the synthesis of 1H- benzo[d]imidazol-2-yl amides 1.5.
• An appropriately substituted 1-fluoro-2-nitrobenzene 1.1 is reacted with a primary amine to afford 1-amino-2-nitrobenzene 1.2.
• a 1- chloro-2-nitrobenzene is reacted with a primary amine under palladium catalysis to provide the desired 1-amino-2-nitrobenzene 1.2.
• the nitro group may be reduced to the corresponding amine by a variety of well-established methods to provide 1,2- diaminobenzenes 1.3.
• Cell Culture Cells were maintained in a media containing DMEM/F12; 50/50 (GIBCO cat.# 11330), 10% Fetal Bovine Serum (FBS) (GIBCO cat.# 26140), 100 units/mL Penicillin-Streptomycin (GIBCO cat.# 15140), 0.005 mg/mL Blasticidin (INVIVOGEN cat.# ant-bl-1), 0.5 mg/mL Geneticin (GIBCO cat.# 10131), 0.1 mg/mL Zeocin (GIBCO cat.# R25001).
• Cells used in the electrophysiology assay were maintained in a media without Blasticidin, Geneticin and Zeocin for 2 days and channel expression was induced by adding tetracycline (BIOLINE cat.# BIO-87030) at a final concentration of 1 mg/mL. Cells were grown in T-175 flask to ⁇ 75% confluency. Currents were recorded 24 hours after channel induction.
• Test compounds were prepared by performing serial dilutions on a Biomek NX P (BECKMAN COULTER). Final dilutions were made in external recording solution with a final DMSO concentration of 0.1% DMSO. For single concentration screens each plate had 10 mM retigabine as a positive control and 0.1% DMSO as a negative control.
• External recording solution contained (in mM): NaCl (145), KCl (4), CaCl 2 (2), MgCl 2 (1), HEPES (10) and Glucose (10); pH was adjusted to 7.4 with NaOH and the osmolarity was adjusted to 300-305 mOsM with sucrose if necessary.
• Internal solution contained (in mM): KCl (125), KF (10), EGTA (5), Na 2 ATP (5), MgCl 2 (3.2), HEPES (5); pH was adjusted to 7.2 with KOH and the osmolarity was adjusted to 298-302 mOsM with sucrose.
• Potassium channel activity was measured on the QPatch HTX (Sophion Bioscience) using QPlates with 48-wells/plate. Each cell was taken as an independent experiment and only one compound was tested per well. Potassium channel activity was elicited by holding at -80 mV and stepping to -30 mV for 2 s followed by a 100 ms pulse to -120 mV.
• the experimental protocol was adapted from the FluxORTM II Green Potassium Ion Channel Assay User Guide (Pub. No. MAN0016084, Invitrogen). Conditions were optimized for the Kv7.2/7.3 cell line.
• Cell Line The hKV7.2/7.3 cell line was obtained from Chantest (Cleveland, OH 44128) cat.# CT6147. [0147] Cell Culture: Kv7.2/7.3 cells were maintained in a media containing DMEM/F12; 50/50 (GIBCO cat.# 11330), 10% Fetal Bovine Serum (FBS) (GIBCO cat.# 26140), 100 units/mL Penicillin-Streptomycin (GIBCO cat.# 15140), 0.005 mg/ml Blasticidin (SIGMA 15205), 0.5 mg/mL Geneticin (GIBCO cat.# 10131), and 0.1 mg/mL Zeocin (GIBCO cat.# R25001).
• test compound is diluted in a mixture of 0.1% DMSO/extracellular solution with an eight-point concentration range from 0.014 ⁇ M to 30 ⁇ M. Serial dilutions were made on a Biomek NXP (BECKMAN COULTER).
• Measurement and data analysis A plate reader (Enspire, 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 sec baseline measurement, the stimulus buffer containing thallium and potassium is injected. A final endpoint measure is taken after 90 sec. Responses are normalized to positive control (retigabine, 30 ⁇ M max). Mean normalized responses at each concentration tested are fit to the standard Hill equation to generate an EC50 and maximal response. [0150] Data of the Thallium Flux Assay is summarized in Table 3
• this disclosure relates to methods for treating neurodegenerative disease, such as 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 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is treated.
• neurodegenerative disease such as amyotrophic lateral sclerosis
• the subject is a subject with definite ALS, has amyotrophic lateral sclerosis symptom onset duration of less than about 18 months, plasma creatinine levels of about 72 mM/L or greater, concomitant riluzole administration, concomitant dexpramipexole administration, and combinations thereof.
• Embodiments described herein are directed to compounds of formula A- 1 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof, which activate Kv7 channels to block the hyperexcitability associated with ALS and improve motor neuron function and/or survival.
• Embodiments are directed to methods for treating neurodegenerative disease in a subject comprising administering to the subject a therapeutically effective amount of a compound of formula A-1 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is treated.
• the compounds of formula A-1 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof may be administered to any individual exhibiting the symptoms of a neurodegenerative disease or to individuals predisposed to a neurodegenerative disease.
• Non-limiting examples of neurodegenerative diseases that may be treated using a compound of formula A-1 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof, include amyotrophic lateral sclerosis (ALS), Huntington’s disease, metabolically induced neurological damage, Alzheimer’s disease, Pick’s disease, senile dementia, age associated cognitive dysfunction, 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 disorder or disease, inflammatory demyelinating disorder, Parkinson’s disease, hepatic encephalopathy, chronic encephalopathy, chronic encephalitis, or any combination thereof.
• ALS amyotrophic lateral sclerosis
• Huntington’s disease ALS
• metabolically induced neurological damage Alzheimer’s disease
• Pick’s disease
• Embodiments are directed to methods for treating neurodegenerative disease, such as 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 through A-44 or B- 1 through B-7, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is treated.
• the subject is a subject with definite ALS, has amyotrophic lateral sclerosis symptom onset duration of less than about 18 months, plasma creatinine levels of about 72 mM/L or greater, concomitant riluzole administration, concomitant dexpramipexole administration, and combinations thereof.
• Embodiments are directed to methods 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 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof, wherein the amyotrophic lateral sclerosis is treated.
• Embodiments are directed to methods 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 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof, wherein the amyotrophic lateral sclerosis is treated.
• the definite amyotrophic lateral sclerosis is as defined by the El Escorial diagnosis criteria.
• the subject is a subject with definite ALS, amyotrophic lateral sclerosis symptom onset duration of less than about 18 months, plasma creatinine levels of about 72 mM/L or greater, concomitant riluzole administration, concomitant dexpramipexole administration,, and combinations thereof.
• ALS Amyotrophic lateral sclerosis
• Lou Gehrig Lou Gehrig’s disease
• ALS is a progressively 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.
• the term“definite” is intended to mean specific clinical exclusionary criteria met, no other diagnosis possible on basis of clinical distribution or laboratory findings;
• the term“dementia” is intended to mean progressive deterioration of specific cognitive functions;
• the term“onset” is intended to mean time of first subjective symptom noticed by patient which later is confirmed by examination;
• the term “possible” is intended to mean specific clinical and exclusionary criteria met;
• the term “probable” is intended to mean specific clinical and exclusionary criteria; and the term “worsening” is intended to mean increased weakness of muscles in a previously affected segment or new weakness in a previously unaffected segment.
• the diagnoses of ALS requires the presence of: 1) signs of lower motor neuron (LMN) degeneration by clinical, electrophysiological or neuropathologic examination, 2) signs of upper motor neuron (UMN) degeneration by clinical examination, and 3) progressive spread of signs within a region or to other regions, together with the absence of electrophysiological evidence of other disease processes that might explain the signs of LMN and/or UMN degenerations; and neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs.
• LDN lower motor neuron
• UPN upper motor neuron
• the El Escorial World Federation of Neurology Criteria for the Diagnosis of ALS set forth the following steps in the diagnosis of Amyotrophic Lateral Sclerosis.
• the diagnoses of ALS is made possible by 1) history, physical and appropriate neurological examinations to ascertain clinical finding which may suggest suspected, possible, probable or definite ALS, 2) electrophysiological examinations to ascertain findings which confirm LMN degeneration in clinically involved regions, identify LMN degeneration in clinically uninvolved regions and exclude other disorders, 3) neuroimaging examinations to ascertain findings which may exclude other disease processes, 4) clinical laboratory examinations, determined by clinical judgment, to ascertain possible ALS-related syndromes, 5) neuropathologic examinations, where appropriate, to ascertain findings which may confirm or exclude sporadic ALS, coexistent sporadic ALS, ALS-related syndromes or ALS variants, 6) repetition of clinical and electrophysiological examinations at least six months apart to ascertain evidence of progression.
• Definite ALS is defined on clinical grounds alone by the presence of UMN as well as LMN signs in the bulbar region and at least two of the other spinal regions or the presence of UMN and LMN signs in three spinal regions.
• the important determinants of diagnosis of definite ALS in the absence of electrophysiological, neuroimaging and laboratory examinations are the presence of UMN and LMN signs together in multiple regions.
• Probable ALS is defined on clinical grounds alone by UMN and LMN signs in at least two regions. While the regions may be different, some UMN signs must be rostral (above) the LMN signs. Multiple different combinations of UMN and LMN signs may be present in patients with probable ALS.
• Possible ALS is defined on clinical grounds alone when the UMN and LMN signs are in only one region or UMN signs alone are present in 2 or more regions or LMN signs are rostral to UMN signs (the latter distribution of signs needs to be differentiated from multiple non-ALS processes).
• Monomelic ALS, progressive bulbar palsy without spinal UMN and/or LMN signs and progressive primary lateral sclerosis without spinal LMN signs and progressive primary lateral sclerosis without spinal LMN signs constitute special cases which may develop LMN or UMN signs to meet the criteria for probable ALS with time or be subsequently confirmed at autopsy by specific LMN and UMN neuropathologic findings.
• Suspected ALS will manifest only LMN signs in 2 or more regions, although UMN pathology might be demonstrated at autopsy. However, only clinical signs are considered pertinent to this classification at the time of diagnostic evaluation.
• the clinical signs of progressive LMN and UMN degeneration seen in ALS may 1) occur alone (sporadic ALS), 2) be present incidentally with other pre-existing disease processes that have not developed in parallel with the ALS (coexistent sporadic ALS), 3) Occur in association with laboratory-defined or epidemiologically defined abnormalities that are time- linked to the ALS (ALS-related syndromes), or 4) Occur in association with clinical, genetic or epidemiological features which develop in parallel with the ALS (ALS variants).
• the physical and neurological examinations will allow for the clinical diagnosis of ALS to a particular degree of certainty as defined above; however, the history of the disease onset, toxic exposures, past medical history, injuries, family history, geographic location, etc., must be incorporated with the clinical examinations in determining whether the patient may have an ALS related syndrome or an ALS variant.
• ALS-related syndromes must meet the clinical, electrophysiological and neuroimaging criteria for possible, probable or definite ALS.
• ALS-related syndromes have unique laboratory-defined or epidemiologically defined features which are time-linked to the development of the ALS phenotype. If correction of the associated laboratory-defined feature does not result in correction of the ALS phenotype, then the patient with an ALS-related syndrome should be considered in the same way as a patient with sporadic ALS.
• ALS-related syndromes include: 1) monoclonal gammopathy (monoclonal gammopathy of unknown significance, Waldenstroms’s macroglobulinemia, osteosclerotic myeloma, etc.), 2) dysimmune motor system degeneration (autoimmune; high-titer GMI ganglioside antibody; etc.), 3) nonmalignant endocrine abnormalities (hyperthyroidism, hyperparathyroidism, hypogonadism, etc.), 4) lymphoma (Hodgkin’s and non-Hodgkin’s lymphoma).
• infection HIV-1, HTLV-I, encephalitis lethargica, varicella-zoster, brucellosis, cat-scratch disease, Creutzfeldt-Jakob disease, syphilis, delayed post-poliomyelitis, etc.
• acquired enzyme defects detoxification enzymes, etc.
• exogenous toxins lead, mercury, arsenic, thallium, cadmium, manganese, aluminum, organic pesticides, lupin seeds, etc.
• physical injury electrical shock, radiation therapy, etc.
• vascular vaculitis
• ischemic Dejerine anterior bulbar artery syndrome, etc.
• spondylotic myelopathy painless myelopathy with no sensory signs, stabilization or progression post-surgery).
• ALS Variants must meet the clinical, electrophysiological and neuroimaging criteria for possible, probable or definite ALS.
• the predominant presentation is that seen in sporadic ALS, but includes one or more features such as: multiple phenotypes characterized by age of onset; site of onset; length of survival; and presumed type of inheritance.
• Familial ALS variants in genetic linkage studies should be characterized by an established genetic mode of inheritance over at least two generations and at least one clinically definite or autopsy confirmed case and compelling evidence excluding other possible causes. Affected sub pairs occurring in one generation alone may not result from a single gene effect.
• ALS with defined inheritance and known gene product hexosaminidase A/B deficiency, superoxide dismutase deficiency
• b) ALS with defined inheritance and chromosome linkage but no gene product chromosome 21 associated familial ALS or chromosome 2 associated juvenile familial ALS
• c) ALS with defined inheritance and no known linkage or gene product d) geographic clustering (including disorders seen in the Western Pacific, Guam, Kii Peninsula, North Africa, Madras, etc.);
• Eetrapyramidal signs (bradykinesia; cogwheel rigidity; tremor; clinically significant onset of supranuclear eye signs (pursuit abnormalities); familial or sporadic);
• f) cerebellar degeneration spikenocerebellar abnormalities; familial or sporadic
• g) dementia progressive cognitive abnormalities; familial or sporadic
• Embodiments are directed to methods 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 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof, wherein the subject is selected from a subject with definite amyotrophic lateral sclerosis, a subject with limb-onset amyotrophic lateral sclerosis, a subject with bulbar-onset amyotrophic lateral sclerosis, a subject with amyotrophic lateral sclerosis symptom onset duration of less than about 18 months, a subject with a high level of serum creatinine, a subject with low bicarbonate levels, a subject with concomitant riluzole administration, a subject with concomitant dexpramipexole administration, and combinations thereof, and wherein the amyotrophic lateral sclerosis is treated.
• the method further comprises monitoring said subject for any clinical features associated with amyotrophic lateral sclerosis. In certain embodiments, the method further comprises initiating therapy with a therapeutically effective amount of a compound of formula A-1 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof upon diagnosis of amyotrophic lateral sclerosis. In certain embodiments, the subject exhibits symptoms of amyotrophic lateral sclerosis. In certain embodiments, the subject has definite amyotrophic lateral sclerosis, probable amyotrophic lateral sclerosis, possible amyotrophic lateral sclerosis or suspected amyotrophic lateral sclerosis.
• the subject has upper motor neuron degeneration and lower motor neuron degeneration in the bulbar region and two other spinal regions. In certain embodiments, the subject has upper motor neuron degeneration and lower motor neuron degeneration in three spinal regions. In certain embodiments, the subject is selected from a subject with symptom onset duration of less than about 18 months, a subject with a high level of serum creatinine, a subject with low levels of serum sodium bicarbonate, a subject with concomitant riluzole administration, a subject concomitant dexpramipexole administration, and combinations thereof. In certain embodiments, a subject with a high level of serum creatinine is a subject with greater than about 72 ⁇ mol/L serum creatinine.
• the subject with definite amyotrophic lateral sclerosis is a subject diagnosed with definite ALS as defined by the El Escorial criteria.
• the 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.
• the subject with definite amyotrophic lateral sclerosis is a subject with upper motor neuron degeneration and lower motor neuron degeneration in three spinal regions.
• Embodiments are directed to methods 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 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof, wherein the amyotrophic lateral sclerosis is treated.
• amyotrophic lateral sclerosis is the presence of the El Escorial diagnosis criteria, amyotrophic lateral sclerosis symptom onset duration of less than about 18 months, limb-onset amyotrophic lateral sclerosis, plasma creatinine levels of about 72 mM/L or greater, concomitant riluzole administration, concomitant dexpramipexole administration, an ALSFRS-R score of greater than 36.0, a pre- study progression rate greater than or equal to 0.8 points per month, a percentage predicted relaxed (slow) vital capacity (SVC) of less than or equal to 102.0, an ALSFRS-R fine motor domain score of greater than 10.0 points, ALSFRS-R bulbar domain score or greater than 9.0 points, an ALSFRS-R gross motor domain score of greater than 8.0 points, an abnormal neurological exam of the tongue, an abnormal neurological exam of the pharynx, larynx and swallowing, an abnormal neurological exam of the lower extremities,
• SVC relaxed
• Embodiments are directed to methods 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 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof, wherein the symptoms of amyotrophic lateral sclerosis are treated.
• the subject exhibits clinical characteristics selected from definite amyotrophic lateral sclerosis, amyotrophic lateral sclerosis symptom onset duration of less than about 18 months, limb-onset amyotrophic lateral sclerosis, plasma creatinine levels of about 72 mM/L or greater, concomitant riluzole administration, concomitant dexpramipexole administration,, an ALSFRS-R score of greater than 36.0, a re-study progression rate greater than or equal to 0.8 points per month, a percentage predicted relaxed (slow) vital capacity (SVC) of less than or equal to 102.0, an ALSFRS-R fine motor domain score of greater than 10.0 points, ALSFRS-R bulbar domain score or greater than 9.0 points, an ALSFRS-R gross motor domain score of greater than 8.0 points, an abnormal neurological exam of the tongue, an abnormal neurological exam of the prharynx, larynx and swallowing, an abnormal neurological exam of the lower extremities
• the subject with amyotrophic lateral sclerosis symptom onset duration of less than about 18 months is a subject with symptom onset selected from less than 18 months, less than about 17 months, less than about 16 months, less than about 15 months, less than about 14 months, less than about 13 months, less than about 12 months, less than about 11 months, less than about 10 months, less than about 9 months, less than about 8 months, less than about 7 months, less than about 6 months, less than about 5 months, less than about 4 months, less than about 3 months, less than about 2 months, and less than about 1 month.
• the subject with amyotrophic lateral sclerosis symptom onset duration of less than about 18 months is a subject with symptom onset selected from about 18 months, about 17 months, about 16 months, about 15 months about 14 months, about 13 months, about 12 months, about 11 months, about 10 months, about 9 months, about 8 months, about 7 months, about 6 months, about 5 months, about 4 months, about 3 months, about 2 months, and about 1 month.
• the subject with a high level of serum creatinine is a subject with serum creatinine level selected from greater than about 40 ⁇ mol/L, greater than about 45 ⁇ mol/L, greater than about 50 ⁇ mol/L, greater than about 55 ⁇ mol/L, greater than about 60 ⁇ mol/L, greater than about 65 ⁇ mol/L, greater than about 70 ⁇ mol/L, greater than about 72 ⁇ mol/L of serum creatinine.
• the subject with a high level of serum creatinine is a subject with serum creatinine level selected from about 40 ⁇ mol/L, about 45 ⁇ mol/L, about 50 ⁇ mol/L, about 55 ⁇ mol/L, about 60 ⁇ mol/L, about 65 ⁇ mol/L, about 70 ⁇ mol/L, about 72 ⁇ mol/L of serum creatinine.
• the subject with concomitant riluzole administration is a subject on a stable dosing regimen of riluzole. In certain embodiments, the subject with concomitant riluzole administration is a subject receiving about 50 milligrams of riluzole twice daily. In certain embodiments, the subject with concomitant riluzole administration is a subject who has been receiving riluzole for more than about thirty days. In certain embodiments, the subject with concomitant riluzole administration is a subject who has been receiving riluzole for about sixty days or more.
• the subject with concomitant dexpramipexole administration is a subject on a stable dosing regimen of dexpramipexole. In certain embodiments, the subject with concomitant dexpramipexole administration is a subject receiving about 75 milligrams of dexpramipexole twice daily. In certain embodiments, the subject with concomitant dexpramipexole administration is a subject receiving about 150 milligrams of dexpramipexole twice daily. In certain embodiments, the subject with concomitant dexpramipexole administration is a subject receiving about 300 milligrams of dexpramipexole twice daily.
• treating amyotrophic lateral sclerosis in said subject is selected from improved ALSFRS-R score, improved CAFS rank, decreased mortality, increased life expectancy, and combinations thereof.
• the subject exhibits a greater than 20 % improvement in ALS Functional Rating Scale, Revised (ALSFRS-R) score when compared to baseline.
• the subject exhibits a greater than 30 % improvement in ALS Functional Rating Scale, Revised (ALSFRS-R) score when compared to baseline.
• the ALSFRS-R measures 4 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 possible score of 48. The twelve questions and rating scale are provided in Cederbaum, et al., 169 J. NEUROL. SCI., 13-21 (1999) which is incorporated herein in its entirety.
• treating ALS can include slowing progression of ALS, reducing intensity of symptoms associated with ALS, reducing onset of symptoms associated with ALS, reducing weight loss associated with ALS, reversing weight loss associated with ALS, delaying mortality, and combinations thereof.
• the symptoms associated with ALS may be, for example, decreases in fine motor function, decreases in gross motor function, decreases in bulbar function, decreases in respiratory function, and combinations thereof.
• the symptoms associated with ALS can include difficulty with daily activities, such as, for example, difficulty with walking, speech, eating, swallowing, writing, climbing stairs, cutting food, turning in bed, dressing, maintaining hygiene, and combinations thereof, and may experience other symptoms, such as, for example, difficulty breathing, dyspnea, orthopnea, respiratory insufficiency, increased salivation and combinations thereof.
• a compound of formula A-1 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof may be used to treat ALS.
• individuals diagnosed with ALS within two years or less may be treated with a compound of formula A-1 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof, to reduce, eliminate, or slow advancement of ALS or symptoms associated with ALS such as, for example, fine motor function loss, gross motor function loss, loss of bulbar function, and loss of respiratory function.
• a compound of formula A-1 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof may be administered to reduce or slow the advancement of symptoms including, but not limited to, trembling, loss of muscle control, loss of ability to write, loss of ability to move or roll over, loss of speech, inability to swallow, difficulty breathing, and so on.
• individuals with advanced symptoms or individuals who were diagnosed with ALS more than two years before beginning treatment may be treated with a compound of formula A-1 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof, and such individuals may respond to treatment by exhibiting a reduction or elimination of one or more symptoms related to ALS, or in certain embodiments, the rate of symptom onset or advancement may be reduced, for example; the rate of motor function loss, the rate of loss of speech, and/or difficulty swallowing may be slowed and/or reduced.
• the subject is administered a therapeutically effective amount of a compound of formula A-1 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof, and the decline of muscle loss is reduced.
• the subject is administered a therapeutically effective amount of a compound of formula A-1 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof, and the decline of serum creatinine is reduced.
• compound of formula A-1 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof may be administered to subjects in need of treatment for excessive weight loss associated with ALS.
• the precipitous weight loss that is a cardinal symptom of ALS may be associated with increased energy expenditure, skeletal muscle hypermetabolism, and the systematic wasting of muscle tissue known as cachexia.
• the method is carried out for a time period selected from at least about twelve months, at least about eighteen months, at least about two years, at least about four years, at least about six years, at least about eight years, at least about ten years, at least about twenty years, and until the subject dies. In other embodiments, the method is carried out at least daily for an indefinite amount of time.
• the present application provides for a method of identifying a patient who will respond to treatment with a compound of formula A-1 through A-44 or B-1 through B-7, or a pharmaceutically acceptable salt thereof, comprising: diagnosing a patient with EEC definite ALS; measuring the serum creatinine levels of the patient; and identifying the patient as a responder if the serum creatinine levels are greater than about 72 ⁇ mol/L.
• Some embodiments include methods of identifying a subject that will likely respond to treatments described herein.
• the subject will exhibit one or more of the following characteristics: definite ALS as defined by the El Escorial diagnosis criteria, amyotrophic lateral sclerosis symptom onset duration of less than about 18 months, limb-onset amyotrophic lateral sclerosis, plasma creatinine levels of about 72 mM/L or greater, concomitant riluzole administration, concomitant dexpramipexole administration, an ALSFRS-R score of greater than 36.0, a re-study progression rate greater than or equal to 0.8 points per month, a percentage predicted relaxed (slow) vital capacity (SVC) of less than or equal to 102.0, an ALSFRS-R fine motor domain score of greater than 10.0 points, ALSFRS-R bulbar domain score or greater than 9.0 points, an ALSFRS-R gross motor domain score of greater than 8.0 points, an abnormal neurological exam of the tongue, an abnormal neurological exam of the prharynx, larynx and swallowing, an abnormal neurological exam
• SVC
• the subject will have at least one of the above characteristics. In some embodiments, the subject will have more than one of the above characteristics. In embodiments, the method further comprises monitoring said subject for any clinical features associated with amyotrophic lateral sclerosis. In embodiments, the method further comprises initiating therapy with a therapeutically effective amount of (6R)-2-amino- 4,5,6,7-tetrahydro-6-(propylamino)benzothiazole or a pharmaceutically acceptable salt thereof 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.
• Some embodiments include a compound represented by Formula A-1:
• A is optionally substituted imidazo[4,5-b]pyridin-2-yl, such as optionally substituted 1H-imidazo[4,5- b]pyridin-2-yl or optionally substituted 3H-imidazo[4,5-b]pyridin-2-yl. If the imidazo[4,5- b]pyridin-2-yl is substituted, it may have 1, 2, 3, or 4 substituents. Any substituent may be included on the imidazo[4,5-b]pyridin-2-yl.
• some or all of the substituents on the imidazo[4,5-b]pyridin-2-yl may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I (provided that there is at least 1 non-hydrogen atom); and/or a molecular weight of 15 g/mol to 500 g/mol.
• the substituents may be C 1-10 optionally substituted alkyl, such as CH 3 , C 2 H 5 , C 3 H 7 , cyclic C 3 H 5 , C 4 H 9 , cyclic C 4 H 7 , C 5 H 11 , cyclic C 5 H 9 , C 6 H 13 , cyclic C 6 H 11 , etc., which may be optionally substituted; C 1-10 optionally substituted alkoxy such as OCH 3 , OC 2 H 5 , OC 3 H 7 , cyclic OC 3 H 5 , OC 4 H 9 , cyclic OC 4 H 7 , OC 5 H 11 , cyclic OC 5 H 9 , OC 6 H 13 , cyclic OC 6 H 11 , etc.; halo, such as F, Cl, Br, I; OH; CN; NO 2 ; C 1-6 fluoroalkyl, such as CF 3 , CF 2 H, C 2 F 5 , etc.; C 1-6 flu
• any or all of the substituents of 1H-imidazo[4,5- b]pyridin-2-yl or 3H-imidazo[4,5-b]pyridin-2-yl are independently CF3, Cl, CN, or OCH3.
• A has a CF3 substituent.
• A has a Cl substituent.
• A has a CN substituent.
• A has an OCH3 substituent.
• A may be:
• L is CH 2 , CF 2 , C 2 H 4 (such as CH 2 CH 2 , CH(CH 3 ), etc.), C 3 H 6 (such as CH 2 CH 2 CH 2 , CH 2 CH(CH 3 ), CH(CH 3 )CH 2 , CH(CH 3 ) 2 , etc.), O, CH 2 O, C 2 H 4 O (such as OCH 2 CH 2 (where the O atom may be on either side of the CH 2 CH 2 ), CH 2 OCH 2 , OCH(CH 3 ), etc.,), or C 3 H 6 O.
• L is CH 2 , CF 2 , CH 2 CH 2 , CH(CH 3 ) 2 , or CH(CH 3 ).
• L is CH 2 .
• L is CH 2 CH 2 .
• L is CH(CH 3 ) 2 .
• L is CH(CH 3 ).
• R 1 may be C 1-12 optionally substituted alkyl, such as optionally substituted CH 3 , optionally substituted C 2 H 5 , optionally substituted C 3 H 7 , optionally substituted cyclic C 3 H 5 , optionally substituted C 4 H 9 , optionally substituted cyclic C 4 H 7 , optionally substituted C 5 H 11 , optionally substituted cyclic C 5 H 9 , optionally substituted C 6 H 13 , optionally substituted cyclic C 6 H 11 , optionally substituted bicyclo[2.2.1]heptan-2-yl, optionally substituted bicyclo[3.1.1]heptan-2-yl, etc.; C 1-12 optionally substituted -O-alkyl, such as optionally substituted -O-CH 3 , optionally substituted -O-C 2 H 5 , optionally substituted -O-C 3 H 7
• R 1 is CH 3 , 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 heterocyclyl.
• R 1 is optionally substituted phenyl.
• R 1 is C 3-4 alkyl.
• R 1 is optionally substituted bicyclo[2.2.1]heptan-2-yl.
• R 1 is optionally substituted isoxazol-3-yl.
• R 1 is CF 3 .
• R 1 is optionally substituted cyclopentyl.
• R 1 is optionally substituted cyclohexyl.
• R 1 is methyl.
• R 1 is optionally substituted bicyclo[3.1.1]heptan-2-yl. In some embodiments, R 1 is optionally substituted–O- phenyl. In some embodiments, R 1 is optionally substituted CH(CF 3 ) 2 . In some embodiments, R 1 is C 2-4 –O-alkyl. In some embodiments, R 1 is 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.
• R 1 can be one of the following: R 7 R 7 20 R 21 R19 R 6 R 8 R 6 R 19 R R 20
• R 2 is–R a -Cy.
• R a is a bond or C 1-12 optionally substituted alkyl, such as CH 2 , C 2 H 4 , C 3 H 6 , C 4 H 8 , C 5 H 10 , C 6 H 12 , cyclic C 3 H 5 , cyclic C 4 H 7 , cyclic C 5 H 9 , cyclic C 6 H 11 , etc.
• Cy is H; optionally substituted C 6-10 aryl, such as optionally substituted phenyl; or optionally substituted C 2-9 heterocyclyl, such as optionally substituted azetidinyl, optionally substituted oxatanyl, optionally substituted thietanyl, etc.
• R 2 is optionally substituted cyclobutyl or optionally substituted 2- methylpropyl.
• R 2 is: R 16 R 17 R 17
• R 2 is cyclobutyl. In some embodiments, R 2 is 2-methylpropyl.
• R 3 -R 52 may be H or any substituent, such as a substituent having 0 to 12 atoms or 0 to 6 carbon atoms and 0 to 5 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I, and/or having a molecular weight of 15 g/mol to 300 g/mol.
• R 3 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 3 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, 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, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of -O-propyl, -O- cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O- cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• R 3 may be H, F, Cl, Br, I, CN, C 1-12 optionally substituted alkyl, C 1-12 optionally substituted–O-alkyl, optionally substituted C 2-9 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).
• R 3 may be H, CH 3 , OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , COH, COCH 3 , CF 3 , Cl, CN, or OCH 3 . In some embodiments, R 3 may be H, CF 3 , Cl, CN, or OCH 3 . In some embodiments, R 3 is H. In some embodiments, R 3 is CF 3 . In some embodiments, R 3 is Cl. In some embodiments, R 3 is CN. In some embodiments, R 3 is OCH 3 .
• Each R A may independently be H, or C 1-12 alkyl, including: linear or branched alkyl having a formula C a H a+1 , or cycloalkyl having a formula C a H a-1 , wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl of a formula: CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , C 5 H 11 , C 6 H 13 , C 7 H 15 , C 8 H 17 , C 9 H 19 , C 10 H 21 , etc., or cycloalkyl of a formula: C 3 H 5 , C 4 H 7 , C 5 H 9 , C 6 H 11 , C 7 H 13 , C 8 H 15 , C 9 H 17 , C 10 H 19 , etc.
• a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12
• Each R B may independently be H, or C 1-12 alkyl, including: linear or branched alkyl having a formula C a H a+1 , or cycloalkyl having a formula C a H a , wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl of a formula: CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , C 5 H 11 , C 6 H 13 , C 8 H 17 , C 7 H 15 , C 9 H 19 , C 10 H 21 , etc., or cycloalkyl of a formula: C 3 H 5 , C 4 H 7 , C 5 H 9 , C 6 H 11 , C 7 H 13 , C 8 H 15 , C 9 H 17 , C 10 H 19 , etc.
• R B may be H or C 1-3 alkyl. In some embodiments, R B may be H or CH 3 . In some embodiments, R B may be H. [0211] With respect to any relevant embodiment or structural representation of Formula A-1 through A-44 herein, some non-limiting examples of R 4 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 4 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.,or–O-C 1-6 alkyl, such as -O-methyl, -O-ethyl, isomers of -O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• R 4 may be H, F, Cl, Br, I, CN, C 1-12 optionally substituted alkyl, C 1-12 optionally substituted–O-alkyl, optionally substituted C 2-9 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.
• R 4 may be H, CF 3 , or Cl.
• R 4 is H.
• R 4 is CF 3 .
• R 4 is Cl.
• R 5 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 5 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 5 may be H, F, Cl, Br, I, CN, C 1-12 optionally substituted alkyl, C 1-12 optionally substituted–O-alkyl, optionally substituted C 2-9 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.
• R 5 may be H, F, Cl, CN, CF 3 , OH; NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 .
• R 5 may be H.
• R 6 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 6 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 6 may be H, F, Cl, CN, CF 3 , OH; NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 .
• R 6 may be H.
• R 7 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 7 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 7 may be H, F, Cl, CN, CF 3 , OH; NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 .
• R 7 may be H.
• R 8 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 8 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 8 may be H, F, Cl, CN, CF 3 , OH; NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 .
• R 8 is H.
• R 8 is F.
• R 9 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 9 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 9 may be H, F, Cl, CN, CF 3 , OH; NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 .
• R 9 may be H.
• R 10 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 10 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 10 may be H, F, Cl, CN, CF 3 , OH; NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 .
• R 10 may be H.
• R 11 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 11 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 12 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 12 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 13 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 13 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 14 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 14 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 15 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 15 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 16 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 16 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 17 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 17 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 18 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 18 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 18 may be H, F, Cl, OH, CN, CF 3 , CH 3 , CH 2 CH 3 , -OCH 3 , or -OCH 2 CH 3 . In some embodiments, R 18 may be H. [0226] With respect to any relevant embodiment or structural representation of Formula A-1 through A-44 herein, some non-limiting examples of R 19 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 19 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 20 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 20 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 20 may be H, F, Cl, OH, CN, CF 3 , CH 3 , CH 2 CH 3 , -OCH 3 , or -OCH 2 CH 3 . In some embodiments, R 20 may be H.
• R 21 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 21 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 21 may be H, OH, CN, CF 3 , CH 3 , CH 2 CH 3 , -OCH 3 , or -OCH 2 CH 3 . In some embodiments, R 21 may be H.
• R 22 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 22 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 22 may be H, F, Cl, OH, CN, CF 3 , CH 3 , CH 2 CH 3 , -OCH 3 , or -OCH 2 CH 3 . In some embodiments, R 22 may be H.
• R 23 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 23 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 23 may be H, OH, CN, CF 3 , CH 3 , CH 2 CH 3 , -OCH 3 , or -OCH 2 CH 3 . In some embodiments, R 23 is H. In some embodiments, R 23 is CH 3 .
• R 24 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 24 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 24 may be H, F, Cl, OH, CN, CF 3 , CH 3 , CH 2 CH 3 , -OCH 3 , or -OCH 2 CH 3 . In some embodiments, R 24 is H. In some embodiments, R 24 is CH 3 .
• some non-limiting examples of R 25 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 25 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 26 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 26 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 27 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 27 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 27 may be H, F, Cl, OH, CN, CF 3 , CH 3 , or -OCH 3 . In some embodiments, R 27 may be H.
• R 28 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 28 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 29 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 29 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 30 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 30 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 30 may be H, F, Cl, OH, CN, CF 3 , CH 3 , CH 2 CH 3 , -OCH 3 , or -OCH 2 CH 3 . In some embodiments, R 30 may be H.
• R 31 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 31 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 32 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 32 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 32 may be H, F, Cl, CN, CF 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 . In some embodiments, R 32 may be H.
• R 33 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 33 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 33 may be H, F, Cl, CN, CF 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 .
• R 33 is H.
• R 33 is CH 3 .
• R 34 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 34 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 34 may be H, F, Cl, OH, CN, CF 3 , CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , or -OCH 3 . In some embodiments, R 34 may be H.
• R 35 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 35 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 35 may be H, F, CN, CF 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 . In some embodiments, R 35 is H. In some embodiments, R 35 is CH 3 .
• R 36 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 36 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 36 may be H, F, CN, CF 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 . In some embodiments, R 36 is H. In some embodiments, R 36 is CH 3 .
• R 37 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 37 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 37 may be H, F, CN, CF 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 . In some embodiments, R 37 is H. In some embodiments, R 37 is CH 3 .
• R 38 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 38 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 38 may be H, F, CN, CF 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 . In some embodiments, R 38 is H. In some embodiments, R 38 is CH 3 .
• R 39 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 39 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 40 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 40 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 41 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 41 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 41 may be H, F, CN, CF 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 . In some embodiments, R 41 is H. In some embodiments, R 41 is CH 3 .
• R 42 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 42 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 42 may be H, CN, CF 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 ,. In some embodiments, R 42 is H. In some embodiments, R 42 is CH 3 .
• R 43 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 43 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 43 may be H, F, Cl, CN, CF 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 . In some embodiments, R 43 may be H.
• R 44 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 44 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 44 may be H, F, Cl, CN, CF 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 . In some embodiments, R 44 may be H.
• R 45 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 45 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 45 may be H, F, Cl, CN, CF 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 . In some embodiments, R 45 may be H.
• R 46 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 46 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 46 may be H, F, Cl, CN, CF 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 . In some embodiments, R 46 may be H.
• R 47 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 47 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 47 may be H, F, Cl, CN, CF 3 , OH; NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 .
• R 47 may be H.
• R 48 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 48 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 48 may be H, F, Cl, CN, CF 3 , OH; NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 .
• R 48 may be H.
• R 49 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 49 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 49 may be H, F, Cl, CN, CF 3 , OH; NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 .
• R 49 may be H.
• R 50 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 50 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 50 may be H, F, Cl, CN, CF 3 , OH; NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 .
• R 50 may be H.
• R 51 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 51 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 51 may be H, F, Cl, CN, CF 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 . In some embodiments, R 51 may be H.
• R 52 may include R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc.
• R 52 may be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of - O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.
• C 1-6 alkyl
• R 52 may be H, F, Cl, CN, CF 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 .
• R 52 may be H.
• Some embodiments of Formula A-1 may include a compound represented by Formula A-43:
• L is CH 2 ;
• R 1 is optionally substituted cyclic C 3 H 5 , wherein the
• R 1 is CF 3 ;
• R 2 is optionally substituted cyclobutyl
• R 3 is optionally substituted C 3 alkyl, wherein the optional
• R 4 is H
• R 5 is H
• Formula A-1 may include a compound represented by Formula A-44: R 5
• L is CH 2 ;
• R 1 is optionally substituted C 2 alkyl, wherein the optional
• R 1 are independently CF 3 or CH 3 ;
• R 2 is optionally substituted cyclobutyl;
• R 3 is optionally substituted C 3 alkyl, wherein the optional
• R 4 is H
• R 5 is H
• Some embodiments of Formula A-1 include a compound represented by the following structures or a pharmaceutically acceptable salt thereof:

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