4-aminopiperidines as selective modulators of potassium channels

Abstract

Selective modulators of Kv7 potassium channels that are useful for the treatment of a range of channelopathies, including epilepsy, developmental and epileptic encephalopathy, pain, tinnitus, cancer, cardiovascular disease, and neurodegeneration.

Description

[0001]8123-112520-02 08 / 07 / 254-AMINOPIPERIDINES AS SELECTIVE MODULATORS OF POTASSIUM CHANNELS CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No.63 / 680,984, filed August 8, 2024, which is herein incorporated by reference in its entirety. BACKGROUND The Kv7 (also referred to as KCNQ) potassium channel family of transmembrane proteins, encoded by KCNQ genes, plays a critical role in cell excitability. They belong to the voltage-gated ion channel super- family, are non-inactivating channels, and contribute both to the maintenance of the resting membrane potential and the control of excitability in cells. The KCNQ gene family is comprised of 5 isoforms, Kv7.1–5, and assembles as either homo- or heterotetramers (i.e. Kv7.2 / 3, Kv7.3 / 5, or Kv7.4 / 5). Each isoform has a specific distribution within the body, and specific mutations within the gene family have been implicated in human diseases. Accordingly, the search for isoform- specific, potent chemical probes aimed at the mechanistic function of Kv7 channels in various tissues remains an area of high interest. Kv7.2 channels are located both in the central and peripheral nervous system, showing a high density in the neocortex and hippocampus. High-current amplitude Kv7.2 / 3 heterotetramers are the most abundant Kv7.2 channel assembly compared to the less abundant low-current amplitude homomeric channels and Kv7.4 or Kv7.5 heterotetramers. Particular attention has been given to Kv7.2 / 3 channels for their M-current contributions in neuronal tissue. Among other functions, the homomeric Kv7.2 isoform has been implicated in the patho-physiology of epilepsy, wherein the heteromeric Kv7.2 / 3 isoform has been associated with the induction and prolongation of tinnitus. SUMMARY Disclosed herein is a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:8123-112520-02 08 / 07 / 25 wherein X is Y is N, C, O or S; Z is N, C, O or S; R1is H; R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -S(O)(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R5is H; R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; and R9is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl,8123-112520-02 08 / 07 / 25where each bond represented by ----- is a single or double bond as needed to satisfy valence requirements. Further disclosed herein is a method comprising administering to a subject in need of treatment for epilepsy, developmental or epileptic encephalopathy, pain, tinnitus, cancer, cardiovascular disease, neurodegeneration, fibromyalgia, arthritis, hyperalgesia, depression, schizophrenia, bipolar disorder, traumatic brain injury, smooth muscle disorders, erectile dysfunction, myotonic congenita, or inflammatory airway diseases, a therapeutically effective amount of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof: Formula I wherein X is N, C, O or S; Y is N, C, O or S; Z is N, C, O or S; R1is H; R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -S(O)(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R5is H;8123-112520-02 08 / 07 / 25R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; and R9is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, where each bond represented by ----- is a single or double bond as needed to satisfy valence requirements. DETAILED DESCRIPTION Terminology The following explanations of terms and methods are provided to better describe the present compounds, compositions and methods, and to guide those of ordinary skill in the art in the practice of the present disclosure. It is also to be understood that the terminology used in the disclosure is for the purpose of describing particular embodiments and examples only and is not intended to be limiting. “Acyl” refers to a group having the structure –C(O)R, where R may be, for example, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. “Lower acyl” groups are those that contain one to six carbon atoms. “Acyloxy” refers to a group having the structure –OC(O)R-, where R may be, for example, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. “Lower acyloxy” groups contain one to six carbon atoms. “Administration” as used herein is inclusive of administration by another person to the subject or self-administration by the subject. The term "aliphatic" is defined as including alkyl, alkenyl, alkynyl, halogenated alkyl and cycloalkyl groups. A "lower aliphatic" group is a branched or unbranched aliphatic group having from 1 to 10 carbon atoms. “Alkanediyl,” “cycloalkanediyl,” “aryldiyl,” “alkanearyldiyl” refers to a divalent radical derived from aliphatic, cycloaliphatic, aryl, and alkanearyl hydrocarbons. “Alkenyl” refers to a cyclic, branched or straight chain group containing only carbon and hydrogen, and contains one or more double bonds that may or may not be conjugated. Alkenyl groups may be unsubstituted or substituted. “Lower alkenyl” groups contain one to six carbon atoms.8123-112520-02 08 / 07 / 25The term “alkoxy” refers to a straight, branched or cyclic hydrocarbon configuration and combinations thereof, including from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms (referred to as a “lower alkoxy”), more preferably from 1 to 4 carbon atoms, that include an oxygen atom at the point of attachment. An example of an “alkoxy group” is represented by the formula – OR, where R can be an alkyl group, optionally substituted with an alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, alkoxy or heterocycloalkyl group. Suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy cyclopropoxy, cyclohexyloxy, and the like. “Alkoxycarbonyl” refers to an alkoxy substituted carbonyl radical, –C(O)OR, wherein R represents an optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl or similar moiety. The term “alkyl” refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. A “lower alkyl” group is a saturated branched or unbranched hydrocarbon having from 1 to 6 carbon atoms. Preferred alkyl groups have 1 to 4 carbon atoms. Alkyl groups may be “substituted alkyls” wherein one or more hydrogen atoms are substituted with a substituent such as halogen, cycloalkyl, alkoxy, amino, hydroxyl, aryl, alkenyl, or carboxyl. For example, a lower alkyl or (C1-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C3-C6)cycloalkyl(C1-C6)alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2- cyclobutylethyl, 2-cyclopentylethyl, or 2-cyclohexylethyl; (C1-C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C2- C6)alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl; (C2- C6)alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl; (C1- C6)alkanoyl can be acetyl, propanoyl or butanoyl; halo(C1-C6)alkyl can be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, or pentafluoroethyl; hydroxy(C1-C6)alkyl can be hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1- hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 4-hydroxybutyl, 1- hydroxypentyl, 5-hydroxypentyl, 1-hydroxyhexyl, or 6-hydroxyhexyl; (C1-C6)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (C1-C6)alkylthio can be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, or hexylthio; (C2-C6)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy. “Alkynyl” refers to a cyclic, branched or straight chain group containing only carbon and hydrogen, and unless otherwise mentioned typically contains one to twelve carbon atoms, and8123-112520-02 08 / 07 / 25contains one or more triple bonds. Alkynyl groups may be unsubstituted or substituted. “Lower alkynyl” groups are those that contain one to six carbon atoms. The term “amine” or “amino” refers to a group of the formula –NRR', where R and R' can be, independently, hydrogen or an alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, heterocycloalkyl, or carboxyl group. For example, an “alkylamino” or “alkylated amino” refers to –NRR', wherein at least one of R or R' is an alkyl. A suitable amine or amino group is acetamido. The term "aminoalkyl" refers to alkyl groups as defined above where at least one hydrogen atom is replaced with an amino group (e.g, -CH2-NH2). “Aminocarbonyl” alone or in combination, means an amino substituted carbonyl (carbamoyl) radical, wherein the amino radical may optionally be mono- or di-substituted, such as, for example, with alkyl, aryl, acyl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like. For example, an aminocarbonyl may be represented by the formula –C(O)NRR', where R and R' independently can be, for example, a hydrogen, alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group. An “analog” is a molecule that differs in chemical structure from a parent compound, for example a homolog (differing by an increment in the chemical structure or mass, such as a difference in the length of an alkyl chain or the inclusion of one of more isotopes), a molecular fragment, a structure that differs by one or more functional groups, or a change in ionization. An analog is not necessarily synthesized from the parent compound. A derivative is a molecule derived from the base structure. An “animal” refers to living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds. The term mammal includes both human and non-human mammals. Similarly, the term “subject” includes both human and non-human subjects, including birds and non- human mammals. Illustrative non-human mammals include animal models (such as mice), non-human primates, companion animals (such as dogs and cats), livestock (such as pigs, sheep, cows), as well as non-domesticated animals, such as the big cats. The term subject applies regardless of the stage in the organism’s life-cycle. Thus, the term subject applies to an organism in utero or in ovo, depending on the organism (that is, whether the organism is a mammal or a bird, such as a domesticated or wild fowl). The term "aralkyl" refers to an alkyl group wherein an aryl group is substituted for a hydrogen of the alkyl group. An example of an aralkyl group is a benzyl group. “Aryl” refers to a monovalent unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which can optionally be unsubstituted or substituted. A “heteroaryl group,” is defined as an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorous. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,8123-112520-02 08 / 07 / 25isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like. The aryl or heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy, or the aryl or heteroaryl group can be unsubstituted. “Aryloxy” or “heteroaryloxy” refers to a group of the formula –OAr, wherein Ar is an aryl group or a heteroaryl group, respectively. "Bicyclic" or "bicyclyl", as used here, in refers to a ring assembly of two rings where the two rings are fused together, linked by a single bond or linked by two bridging atoms. The rings may be a carbocyclyl, a heterocyclyl, or a mixture thereof. A “carbonylamino” group may be –N(R)-C(O)-R (wherein each R is independently a substitution group such as, for example, alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group, or H). A suitable carbonylamino group is acetamido. The term “carboxylate” or “carboxyl” refers to the group -COO- or -COOH. The carboxyl group can form a carboxylic acid. “Substituted carboxyl” refers to -COOR where R is alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group. For example, a substituted carboxyl group could be a carboxylic acid ester or a salt thereof (e.g., a carboxylate). The term “co-administration” or “co-administering” refers to administration of a compound disclosed herein with at least one other therapeutic agent or therapy within the same general time period, and does not require administration at the same exact moment in time (although co- administration is inclusive of administering at the same exact moment in time). Thus, co- administration may be on the same day or on different days, or in the same week or in different weeks. In some embodiments, the co-administration of two or more agents or therapies is concurrent. In other embodiments, a first agent / therapy is administered prior to a second agent / therapy. Those of skill in the art understand that the formulations and / or routes of administration of the various agents or therapies used may vary. The appropriate dosage for co-administration can be readily determined by one skilled in the art. In some embodiments, when agents or therapies are co-administered, the respective agents or therapies are administered at lower dosages than appropriate for their administration alone. Thus, co-administration is especially desirable in embodiments where the co- administration of the agents or therapies lowers the requisite dosage of a potentially harmful (e.g., toxic) agent and / or lowers the frequency of administering the potentially harmful (e.g., toxic) agent. “Co-administration” or “co-administering” encompass administration of two or more active agents to a subject so that both the active agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active agents are present.8123-112520-02 08 / 07 / 25The term “cycloalkyl” refers to a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term “heterocycloalkyl group” is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorous. The term “ester” refers to a carboxyl group-containing moiety having the hydrogen replaced with, for example, a C1-6alkyl group (“carboxylC1-6alkyl” or “alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”) and so on. CO2C1-3alkyl groups are preferred, such as for example, methylester (CO2Me), ethylester (CO2Et) and propylester (CO2Pr) and includes reverse esters thereof (e.g. –OCOMe, -OCOEt and –OCOPr). "Halo" or "halogen", as used herein, refers to fluoro, chloro, bromo, and iodo. The terms "halogenated alkyl" or "haloalkyl group" refer to an alkyl group with one or more hydrogen atoms present on these groups substituted with a halogen (F, Cl, Br, I). The term “heterocyclic” refers to a closed-ring compound, or radical thereof as a substituent bonded to another group, particularly other organic groups, where at least one atom in the ring structure is other than carbon, and typically is oxygen, sulfur and / or nitrogen. The term “hydroxyl” is represented by the formula –OH. The term "hydroxyalkyl" refers to an alkyl group that has at least one hydrogen atom substituted with a hydroxyl group. The term "alkoxyalkyl group" is defined as an alkyl group that has at least one hydrogen atom substituted with an alkoxy group described above. “Inhibiting” refers to inhibiting the full development of a disease or condition. “Inhibiting” also refers to any quantitative or qualitative reduction in biological activity or binding, relative to a control. “N-heterocyclic” refers to mono or bicyclic rings or ring systems that include at least one nitrogen heteroatom. The rings or ring systems generally include 1 to 9 carbon atoms in addition to the heteroatom(s) and may be saturated, unsaturated or aromatic (including pseudoaromatic). The term "pseudoaromatic" refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings. Aromatic includes pseudoaromatic ring systems, such as pyrrolyl rings. Examples of 5-membered monocyclic N-heterocycles include pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4 oxadiazolyls) isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3- and 1,3,4-triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls), and dithiazolyl. Examples of 6-membered monocyclic N-heterocycles include pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and triazinyl. The heterocycles may be optionally substituted with a broad range of substituents, and preferably with C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano8123-112520-02 08 / 07 / 25or mono or di(C1-6alkyl)amino. The N-heterocyclic group may be fused to a carbocyclic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl. Examples of 8, 9 and 10-membered bicyclic heterocycles include 1H thieno[2,3-c]pyrazolyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, and the like. These heterocycles may be optionally substituted, for example with C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(C1-6alkyl)amino. Unless otherwise defined optionally substituted N-heterocyclics includes pyridinium salts and the N-oxide form of suitable ring nitrogens. The term “subject” includes both human and non-human subjects, including birds and non- human mammals, such as non-human primates, companion animals (such as dogs and cats), livestock (such as pigs, sheep, cows), as well as non-domesticated animals, such as the big cats. The term subject applies regardless of the stage in the organism’s life-cycle. Thus, the term subject applies to an organism in utero or in ovo, depending on the organism (that is, whether the organism is a mammal or a bird, such as a domesticated or wild fowl). “Substituted” or “substitution” refers to replacement of a hydrogen atom of a molecule or an R-group with one or more additional R-groups. Unless otherwise defined, the term “optionally- substituted” or “optional substituent” as used herein refers to a group which may or may not be further substituted with 1, 2, 3, 4 or more groups, preferably 1, 2 or 3, more preferably 1 or 2 groups. The substituents may be selected, for example, from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, hydroxyl, oxo, C1-6alkoxy, aryloxy, C1-6alkoxyaryl, halo, C1-6alkylhalo (such as CF3 and CHF2), C1-6alkoxyhalo (such as OCF3and OCHF2), carboxyl, esters, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketones, amides, aminoacyl, substituted amides, disubstituted amides, thiol, alkylthio, thioxo, sulfates, sulfonates, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonylamides, substituted sulfonamides, disubstituted sulfonamides, aryl, arC1-6alkyl, heterocyclyl and heteroaryl wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl and groups containing them may be further optionally substituted. Optional substituents in the case N- heterocycles may also include but are not limited to C1-6alkyl i.e. N-C1-3alkyl, more preferably methyl, particularly N-methyl. A "therapeutically effective amount" refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, a therapeutically effective amount of an agent is an amount sufficient to inhibit or treat the disease or condition without causing a substantial cytotoxic effect in the subject. The therapeutically effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the therapeutic composition. “Treatment” refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop. As used herein, the term8123-112520-02 08 / 07 / 25“ameliorating,” with reference to a disease or pathological condition, refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease. The phrase “treating a disease” refers to inhibiting the full development of a disease, for example, in a subject who is at risk for a disease. A “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing a pathology or condition, or diminishing the severity of a pathology or condition. “Pharmaceutical compositions” are compositions that include an amount (for example, a unit dosage) of one or more of the disclosed compounds together with one or more non-toxic pharmaceutically acceptable additives, including carriers, diluents, and / or adjuvants, and optionally other biologically active ingredients. Such pharmaceutical compositions can be prepared by standard pharmaceutical formulation techniques such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA (19th Edition). The terms “pharmaceutically acceptable salt or ester” refers to salts or esters prepared by conventional means that include salts, e.g., of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. “Pharmaceutically acceptable salts” of the presently disclosed compounds also include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, for example by reacting the free acid with a suitable organic or inorganic base. Any chemical compound recited in this specification may alternatively be administered as a pharmaceutically acceptable salt thereof. “Pharmaceutically acceptable salts” are also inclusive of the free acid, base, and zwitterionic forms. Descriptions of suitable pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH (2002). When compounds disclosed herein include an acidic function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like. Such salts are known to those of skill in the art. For additional examples of “pharmacologically acceptable salts,” see Berge et al., J. Pharm. Sci.66:1 (1977).8123-112520-02 08 / 07 / 25“Pharmaceutically acceptable esters” includes those derived from compounds described herein that are modified to include a carboxyl group. An in vivo hydrolysable ester is an ester, which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Representative esters thus include carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, n- propyl, t-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl, optionally substituted by, for example, halogen, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy) or amino); sulphonate esters, such as alkyl- or aralkylsulphonyl (for example, methanesulphonyl); or amino acid esters (for example, L-valyl or L-isoleucyl). A “pharmaceutically acceptable ester” also includes inorganic esters such as mono-, di-, or tri-phosphate esters. In such esters, unless otherwise specified, any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms. Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group, optionally substituted as shown in the definition of carbocycylyl above. Pharmaceutically acceptable esters thus include C1-C22fatty acid esters, such as acetyl, t-butyl or long chain straight or branched unsaturated or omega-6 monounsaturated fatty acids such as palmoyl, stearoyl and the like. Alternative aryl or heteroaryl esters include benzoyl, pyridylmethyloyl and the like any of which may be substituted, as defined in carbocyclyl above. Additional pharmaceutically acceptable esters include aliphatic L-amino acid esters such as leucyl, isoleucyl and especially valyl. For therapeutic use, salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.8123-112520-02 08 / 07 / 25The compounds containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. The term “addition salt” as used hereinabove also comprises the solvates which the compounds described herein are able to form. Such solvates are for example hydrates, alcoholates and the like. The term “quaternary amine” as used hereinbefore defines the quaternary ammonium salts which the compounds are able to form by reaction between a basic nitrogen of a compound and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p- toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins. Prodrugs of the disclosed compounds also are contemplated herein. A prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into an active compound following administration of the prodrug to a subject. The term “prodrug” as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds described herein. Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo. Prodrugs of a compounds described herein may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. F or a general discussion of prodrugs involving esters see Svensson and Tunek, Drug Metabolism Reviews 165 (1988) and Bundgaard, Design of Prodrugs, Elsevier (1985). The term “prodrug” also is intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when the prodrug is administered to a subject. Since prodrugs often have enhanced properties relative to the active agent pharmaceutical, such as, solubility and bioavailability, the compounds disclosed herein can be delivered in prodrug form. Thus, also contemplated are prodrugs of the presently disclosed compounds, methods of delivering prodrugs and compositions containing such prodrugs. Prodrugs of the disclosed compounds typically are prepared by modifying one or more functional groups present in the compound in such a way that8123-112520-02 08 / 07 / 25the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent compound. Prodrugs may include compounds having a phosphonate, hydroxy, thio and / or amino group functionalized with any group that is cleaved in vivo to yield the corresponding amino, hydroxy, thio and / or phosphonate group, respectively. Examples of prodrugs can include, without limitation, compounds having an acylated amino group and / or a phosphonate ester or phosphonate amide group. Protected derivatives of the disclosed compounds also are contemplated. A variety of suitable protecting groups for use with the disclosed compounds are disclosed in Greene and Wuts, Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999. In general, protecting groups are removed under conditions that will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. One preferred method involves the removal of an ester, such as cleavage of a phosphonate ester using Lewis acidic conditions, such as in TMS-Br mediated ester cleavage to yield the free phosphonate. A second preferred method involves removal of a protecting group, such as removal of a benzyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxy-based group, including t-butoxy carbonyl protecting groups can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as water, dioxane and / or methylene chloride. Another exemplary protecting group, suitable for protecting amino and hydroxy functions amino is trityl. Other conventional protecting groups are known and suitable protecting groups can be selected by those of skill in the art in consultation with Greene and Wuts, Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999. When an amine is deprotected, the resulting salt can readily be neutralized to yield the free amine. Similarly, when an acid moiety, such as a phosphonic acid moiety is unveiled, the compound may be isolated as the acid compound or as a salt thereof. Particular examples of the presently disclosed compounds may include one or more asymmetric centers; thus the compounds described can exist in different stereoisomeric forms. Accordingly, compounds and compositions may be provided as individual pure enantiomers or as stereoisomeric mixtures, including racemic mixtures. In certain embodiments the compounds disclosed herein may be synthesized in or may be purified to be in substantially enantiopure form, such as in a 90% enantiomeric excess, a 95% enantiomeric excess, a 97% enantiomeric excess or even in greater than a 99% enantiomeric excess, such as in enantiopure form. The presently disclosed compounds can have at least one asymmetric center or geometric center, cis-trans center(C=C, C=N). All chiral, diasteromeric, racemic, meso, rotational, conformational and geometric isomers of the structures are intended unless otherwise specified. The compounds can be isolated as a single isomer or as mixture of isomers by methods utilizing specific chiral resolving agents like quinine, Chiral HPLC, SFC (super critical fluid chromatography) etc. All tautomers of the compounds are also considered part of the disclosure. The presently disclosed8123-112520-02 08 / 07 / 25compounds also include all isotopes of atoms present in the compounds, which can include, but are not limited to, deuterium, tritium,13C,18F, stable and radioisotope, etc. Compounds Disclosed herein are novel and selective modulators of Kv7 potassium channels that are useful for the treatment of a range of channelopathies, including epilepsy, developmental and epileptic encephalopathy, pain, tinnitus, cancer, cardiovascular disease, and neurodegeneration. In particular, disclosed herein are Kv7 potassium channel modulators of Formula I, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof: Formula I wherein X is N, C, O or S; Y is N, C, O or S; Z is N, C, O or S; R1is H; R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -S(O)(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R5is H;8123-112520-02 08 / 07 / 25R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; and R9is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, where each bond represented by ----- is a single or double bond as needed to satisfy valence requirements. In certain embodiments, at least one of X, Y, or Z is N, S or O. In certain embodiments, R1is H. In certain embodiments, R3is alkyl. In certain embodiments, R3is (C1-C6) alkyl, particularly methyl. In certain embodiments, R4is alkyl or cycloalkyl. In certain embodiments, R4is (C1-C6) alkyl, particularly propyl. In certain embodiments, R4is (C3-C6) cycloalkyl, particularly cyclopropyl. In certain embodiments, R6is H or alkoxy. In certain embodiments, R7is H or alkoxy. In certain embodiments, R7is (C1-C6) alkoxy, particularly methoxy. In certain embodiments, at least one of R6, R7, or R9is halo. In certain embodiments, at least one of R6, R7, or R9is -C(O)O-R10. In certain embodiments, at least one of R6, R7, or R9is cyano. In certain embodiments, R8is arylalkyl, substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl. In certain embodiments, R8is phenyl-substituted alkyl, particularly benzyl. Illustrative compounds include: , 8123-112520-02 08 / 07 / 25, 8123-112520-02 08 / 07 / 25their stereoisomers. Pharmaceutical Compositions and Methods of Use The compounds disclosed herein may be used for treating Kv7-mediated diseases. For example, the compounds disclosed herein may be used for treating epilepsy, developmental and epileptic encephalopathy, pain (e.g., neuropathic pain, migraine), tinnitus, cancer, cardiovascular disease, neurodegeneration (e.g., Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington’s disease), fibromyalgia, arthritis, hyperalgesia, depression, schizophrenia, bipolar disorder, traumatic brain injury, smooth muscle disorders, erectile dysfunction, myotonic congenita, and inflammatory airway diseases. In some embodiments, the methods disclosed herein involve administering to a subject in need of treatment a pharmaceutical composition, for example a composition that includes a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds disclosed herein. The compounds may be administered orally, parenterally (including subcutaneous injections (SC or depo-SC), intravenous (IV), intramuscular (IM or depo-IM), intrasternal injection or infusion techniques), sublingually, intranasally (inhalation), intrathecally, topically, ophthalmically, or rectally. The pharmaceutical composition may be administered in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and / or vehicles. The compounds are preferably formulated into suitable pharmaceutical preparations such as tablets, capsules, or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. Typically the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art. In some embodiments, one or more of the disclosed compounds are mixed or combined with a suitable pharmaceutically acceptable carrier to prepare a pharmaceutical composition. Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to be suitable for the particular mode of administration. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21stEdition (2005), describes exemplary compositions and formulations suitable for pharmaceutical delivery of the compounds disclosed herein. In addition, the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. Upon mixing or addition of the compound(s) to a pharmaceutically acceptable carrier, the resulting mixture may be a solution, suspension, emulsion, or the like. Liposomal suspensions may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. Where the compounds exhibit insufficient solubility, methods for8123-112520-02 08 / 07 / 25solubilizing may be used. Such methods are known and include, but are not limited to, using cosolvents such as dimethylsulfoxide (DMSO), using surfactants such as Tween®, and dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as salts or prodrugs may also be used in formulating effective pharmaceutical compositions. The disclosed compounds may also be prepared with carriers that protect them against rapid elimination from the body, such as time-release formulations or coatings. Such carriers include controlled release formulations, such as, but not limited to, microencapsulated delivery systems. The disclosed compounds and / or compositions can be enclosed in multiple or single dose containers. The compounds and / or compositions can also be provided in kits, for example, including component parts that can be assembled for use. For example, one or more of the disclosed compounds may be provided in a lyophilized form and a suitable diluent may be provided as separated components for combination prior to use. In some examples, a kit may include a disclosed compound and a second therapeutic agent (such as an anti-retroviral agent) for co-administration. The compound and second therapeutic agent may be provided as separate component parts. A kit may include a plurality of containers, each container holding one or more unit dose of the compound. The containers are preferably adapted for the desired mode of administration, including, but not limited to tablets, gel capsules, sustained-release capsules, and the like for oral administration; depot products, pre-filled syringes, ampoules, vials, and the like for parenteral administration; and patches, medipads, creams, and the like for topical administration. The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the subject treated. A therapeutically effective concentration may be determined empirically by testing the compounds in known in vitro and in vivo model systems for the treated disorder. In some examples, a therapeutically effective amount of the compound is an amount that lessens or ameliorates at least one symptom of the disorder for which the compound is administered. Typically, the compositions are formulated for single dosage administration. The concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the active compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. In some examples, about 0.1 mg to 1000 mg of a disclosed compound, a mixture of such compounds, or a physiologically acceptable salt or ester thereof, is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form. The amount of active substance in those compositions or preparations is such that a suitable dosage in the range indicated is obtained. The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. In some examples, the compositions are8123-112520-02 08 / 07 / 25formulated in a unit dosage form, each dosage containing from about 1 mg to about 1000 mg (for example, about 2 mg to about 500 mg, about 5 mg to 50 mg, about 10 mg to 100 mg, or about 25 mg to 75 mg) of the one or more compounds. In other examples, the unit dosage form includes about 0.1 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, or more of the disclosed compound(s). The disclosed compounds or compositions may be administered as a single dose, or may be divided into a number of smaller doses to be administered at intervals of time. The therapeutic compositions can be administered in a single dose delivery, by continuous delivery over an extended time period, in a repeated administration protocol (for example, by a multi-daily, daily, weekly, or monthly repeated administration protocol). It is understood that the precise dosage, timing, and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. In addition, it is understood that for a specific subject, dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only. When administered orally as a suspension, these compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners / flavoring agents. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants. If oral administration is desired, the compound is typically provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient. Oral compositions will generally include an inert diluent or an edible carrier and may be compressed into tablets or enclosed in gelatin capsules. For the purpose of oral therapeutic administration, the active compound or compounds can be incorporated with excipients and used in the form of tablets, capsules, or troches. Pharmaceutically compatible binding agents and adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches, and the like can contain any of the following ingredients or compounds of a similar nature: a binder such as, but not limited to, gum tragacanth, acacia, corn starch, or gelatin; an excipient such as microcrystalline8123-112520-02 08 / 07 / 25cellulose, starch, or lactose; a disintegrating agent such as, but not limited to, alginic acid and corn starch; a lubricant such as, but not limited to, magnesium stearate; a gildant, such as, but not limited to, colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; and a flavoring agent such as peppermint, methyl salicylate, or fruit flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials, which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors. When administered orally, the compounds can be administered in usual dosage forms for oral administration. These dosage forms include the usual solid unit dosage forms of tablets and capsules as well as liquid dosage forms such as solutions, suspensions, and elixirs. When the solid dosage forms are used, it is preferred that they be of the sustained release type so that the compounds need to be administered only once or twice daily. In some examples, an oral dosage form is administered to the subject 1, 2, 3, 4, or more times daily. In additional examples, the compounds can be administered orally to humans in a dosage range of 1 to 1000 mg / kg body weight in single or divided doses. One illustrative dosage range is 0.1 to 200 mg / kg body weight orally (such as 0.5 to 100 mg / kg body weight orally) in single or divided doses. For oral administration, the compositions may be provided in the form of tablets containing about 1 to 1000 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 milligrams of the active ingredient. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. Injectable solutions or suspensions may also be formulated, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer’s solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil, and the like, or a synthetic fatty vehicle such as ethyl oleate, and the like, polyethylene glycol, glycerine, propylene glycol, or other synthetic solvent; antimicrobial agents such as benzyl alcohol and methyl parabens; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents8123-112520-02 08 / 07 / 25such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, and phosphates; and agents for the adjustment of tonicity such as sodium chloride and dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass, plastic, or other suitable material. Buffers, preservatives, antioxidants, and the like can be incorporated as required. Where administered intravenously, suitable carriers include physiological saline, phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol, polypropyleneglycol, and mixtures thereof. Liposomal suspensions including tissue-targeted liposomes may also be suitable as pharmaceutically acceptable carriers. The compounds can be administered parenterally, for example, by IV, IM, depo-IM, SC, or depo-SC. When administered parenterally, a therapeutically effective amount of about 0.1 to about 500 mg / day (such as about 1 mg / day to about 100 mg / day, or about 5 mg / day to about 50 mg / day) may be delivered. When a depot formulation is used for injection once a month or once every two weeks, the dose may be about 0.1 mg / day to about 100 mg / day, or a monthly dose of from about 3 mg to about 3000 mg. The compounds can also be administered sublingually. When given sublingually, the compounds should be given one to four times daily in the amounts described above for IM administration. The compounds can also be administered intranasally. When given by this route, the appropriate dosage forms are a nasal spray or dry powder. The dosage of the compounds for intranasal administration is the amount described above for IM administration. When administered by nasal aerosol or inhalation, these compositions may be prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents. The compounds can be administered intrathecally. When given by this route, the appropriate dosage form can be a parenteral dosage form. The dosage of the compounds for intrathecal administration is the amount described above for IM administration. The compounds can be administered topically. When given by this route, the appropriate dosage form is a cream, ointment, or patch. When administered topically, an illustrative dosage is from about 0.5 mg / day to about 200 mg / day. Because the amount that can be delivered by a patch is limited, two or more patches may be used. The compounds can be administered rectally by suppository. When administered by suppository, an illustrative therapeutically effective amount may range from about 0.5 mg to about 500 mg. When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic8123-112520-02 08 / 07 / 25glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and / or dissolve in the rectal cavity to release the drug. It should be apparent to one skilled in the art that the exact dosage and frequency of administration will depend on the particular compounds administered, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular subject, and other medication the individual may be taking as is well known to administering physicians or other clinicians who are skilled in therapy of retroviral infections, diseases, and associated disorders. Examples General Procedure A. yl)carbamate. A flame dried round bottom flask under inert atmosphere was charged with isobutyraldehyde (72 µL, 0.78 mmol) and CH2Cl2(2 mL). The solution was treated with 5-chloro-3- aminopyridine (0.10 g, 0.78 mmol) and allowed to stir at room temperature for 4 h. The mixture was then cooled to 0 °C and treated sequentially with diphenyl hydrogen phosphate (0.019 g, 0.08 mmol), and a solution of benzyl (E)-propyl-1-en-1-ylcarbamate (0.15 g, 0.78 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred at 0 °C for 5 min and allowed to slowly warm to room temperature before heating at reflux for 36 h. The solution was then cooled, concentrated, and purified by chromatography on SiO2(30-50% EtOAc in Hexanes) to yield benzyl ((2SR,3SR,4RS)-7-chloro-2- isopropyl-3-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)carbamate (172.3 mg, 59%) as white crystals: m.p.123.9 °C;1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 1.8 Hz, 1H), 7.36 (m, 5H), 6.78 (d, J = 1.8 Hz, 1H), 5.22, 5.14 (AB, J = 12.2 Hz, 2H), 5.22 (brs, 1H), 4.55 (t, J = 9.2 Hz, 1H), 3.84 (brs, 1H), 3.08 (d, J = 8.9 Hz, 1H), 2.14 – 2.02 (m, 1H), 1.92 – 1.73 (m, 1H), 1.10 (d, J = 6.5 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H);13CNMR (101 MHz, CDCl3) 157.7, 141.4, 139.4, 136.8, 136.3, 131.1, 128.6, 128.1, 119.3, 66.9, 61.3, 55.8, 36.0, 28.5, 20.2, 14.8, 14.5; HRMS (ES+) m / z calcd for C20H25N3O2Cl ([M + H]+) 374.1629, found 374.1644; ATR-IR (cm-1) 3371, 2965, 1702, 1683, 1453, 1251, 1029.8123-112520-02 08 / 07 / 25cyclohexyl-6-methyl-4,5,6,7-tetrahydroisoxazolo[4,5-b]pyridin-7- according to General Procedure A with a 2 h pre-stir of isoxazol-4-amine (130 mg, 1.50 mmol) and cyclohexanecarbaldehyde (185 µL, 1.50 mmol). The reaction mixture was warmed to rt over 14 h. Purification by chromatography on SiO2(30% EtOAc in Hexanes) provided benzyl ((2SR,3SR,4RS)-5-cyclohexyl-6-methyl-4,5,6,7-tetrahydroisoxazolo[4,5-b]pyridin-7- yl)carbamate (357.9 mg, 65%) as a white solid: m.p.193.6 °C;1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.49 – 7.31 (m, 5H), 5.23 – 5.08 (m, 2H), 4.94 (app t, 1H), 4.72 (t, J = 8.7 Hz, 1H), 3.06 (brs, 1H), 2.83 (d, J = 8.0 Hz, 1H), 1.95 – 1.55 (m, 8H), 1.42 – 1.08 (m, 5H), 1.05 (d, J = 6.6 Hz, 3H);13CNMR (101 MHz, CDCl3) 156.6, 150.7, 143.0, 136.4, 128.7, 128.3, 128.1, 126.6, 67.2, 63.5, 50.7, 38.4, 37.3, 30.9, 26.8, 26.6, 26.3, 26.0, 14.8; HRMS (ES+) m / z calcd for C21H28N3O3 ([M + H]+) 370.2125, found 370.2117 ATR-IR (cm-1) 3351, 2926, 1685, 1501, 1242, 1039. carbonyl)amino)-5-cyclopentyl-6-methyl-4,5,6,7- tetrahydrothieno[3,2-b]pyridine-2-carboxylate. Synthesized according to General Procedure A with a 30 min pre-stir of methyl 4-aminothiophene-2-carboxylate (0.12 g, 0.78 mmol) and cyclopentanecarbaldehyde (84 μL, 0.78 mmol). The reaction mixture was warmed to rt over 16 h. Purification by chromatography on SiO2(10-20% EtOAc in Hexanes) provided methyl ((5SR,6SR,7RS)-7-(((benzyloxy)carbonyl)amino)-5-cyclopentyl-6-methyl-4,5,6,7- tetrahydrothieno[3,2-b]pyridine-2-carboxylate (85.3 mg, 26%) as a white solid: m.p.159.6 °C;1H NMR (400 MHz, CDCl3) δ 7.43 – 7.29 (m, 5H), 7.13 (s, 1H), 5.18, 5.13 (AB, J = 12.2 Hz, 2H), 4.95 (d, J = 8.8 Hz, 1H), 4.64 (t, J = 7.4 Hz, 1H), 3.83 (s, 4H), 3.03 (t, J = 6.4 Hz, 1H), 2.27 – 2.16 (m, 1H), 1.97 – 1.88 (m, 1H), 1.74 – 1.49 (m, 7H), 1.43 – 1.21 (m, 2H), 1.07 (d, J = 6.8 Hz, 3H).13CNMR (151 MHz, CDCl3) 162.8, 156.2, 143.7, 136.5, 131.0, 128.7, 128.3, 128.2, 124.1, 119.5, 67.1, 60.4, 52.2, 52.0, 41.3, 38.3, 29.4, 27.1, 25.9, 25.6, 16.2; HRMS (ES+) m / z calcd for C23H29N2O4S ([M + H]+) 429.1843, found 429.1843.8123-112520-02 08 / 07 / 25 6-cyclopentyl-5-methyl-4,5,6,7-tetrahydrothieno[2,3-b]pyridin-4- yl)carbamate. Synthesized according to General Procedure A with a 30 min pre-stir of 2-cyano-5- aminothiophene (0.12 g, 0.95 mmol) and cyclopentanecarbaldehyde (.10 mL, 0.95 mmol). The reaction mixture was warmed to rt over 16 h. Purification by chromatography on SiO2 (10-20% EtOAc in Hexanes) provided benzyl ((4SR,5SR,6RS)-2-cyano-6-cyclopentyl-5-methyl-4,5,6,7- tetrahydrothieno[2,3-b]pyridin-4-yl)carbamate (128.7 mg, 34%) as a white solid: m.p.123.5 °C;1H NMR (400 MHz, CDCl3) δ 7.44 – 7.30 (m, 5H), 7.19 (s, 1H), 5.17, 5.13 (AB, J = 12.2 Hz, 2H), 4.78 (d, J = 8.6 Hz, 1H), 4.68 (s, 1H), 4.45 (t, J = 7.1 Hz, 1H), 3.13 (app t, 1H), 2.29 – 2.21 (m, 1H), 1.97 – 1.89 (m, 1H), 1.76 – 1.57 (m, 5H), 1.34 – 1.19 (m, 3H), 1.04 (d, J = 6.8 Hz, 3H);13CNMR (101 MHz, CDCl3) 156.2, 154.0, 138.3, 136.4, 128.7, 128.4, 128.2, 116.0, 114.6, 90.5, 67.1, 61.9, 51.1, 41.6, 36.5, 29.4, 27.6, 25.9, 25.8, 25.5, 16.3; HRMS (ES+) m / z calcd for C22H26N3O2S ([M + H]+) 396.1740, found 396.1742 ATR-IR (cm-1) 3371, 2917, 1706, 1462, 1255, 1041. cyclohexyl-3,6-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7- yl)carbamate. Synthesized according to General Procedure A with a 1 h pre-stir of tert-butyl 4-amino- 1H-pyrazole-1-carboxylate (233 mg, 1.27 mmol) and cyclohexanecarbaldehyde (157 µL, 1.27 mmol). The reaction mixture was warmed to rt over 16 h. Purification by chromatography on SiO2 (40% EtOAc in Hexanes) provided tert-butyl (5SR,6SR,7RS)-7-(((benzyloxy)carbonyl)amino)-5- cyclohexyl-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine-1-carboxylate (429 mg, 72%) as a white solid: m.p.169.7 °C;1H NMR (600 MHz, CDCl3) δ 7.40 – 7.28 (m, 6H), 5.13, 5.11 (AB, J = 12.5 Hz, 2H), 4.89 (d, J = 5.6 Hz, 1H), 4.73 (dd, J = 6.4, 3.0 Hz, 1H) 3.68 (brs, 1H), 2.64 (dd, J = 8.6, 3.2 Hz, 1H), 2.58 (brs, 1H), 1.86 (J = 11.7 Hz, 1H), 1.77 – 1.62 (m, 4 H), 1.55 (s, 9H), 0.98 (d, J = 6.8 Hz, 3H);13CNMR (101 MHz, CDCl3) 115.7, 148.1, 136.8, 133.6, 131.5, 128.6, 128.2, 121.1,8123-112520-02 08 / 07 / 2584.9, 66.6, 61.9, 50.1, 38.5, 32.8, 30.2, 28.0, 26.5, 26.2, 26.1, 17.9; HRMS (ES+) m / z calcd for C26H37N4O4([M + H]+) 469.2809, found 469.2810. A flame dried round bottom flask under inert atmosphere was charged with tert-butyl (5SR,6SR,7RS)- 7-(((benzyloxy)carbonyl)amino)-5-cyclohexyl-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- b]pyridine-1-carboxylate (265 mg, 0.56 mmol) and CH2Cl2 (5 mL). The solution was treated with a solution of trifluoracetic acid (4 mL, 54 mmol) in CH2Cl2 (5 mL). The reaction mixture was concentrated after 3 h. The residue was resuspended in CH2Cl2 (10 mL) and extracted with sat. sodium bicarbonate solution (10 mL). The aqueous layer was extracted with CH2Cl2(10 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated to provide benzyl ((5SR,6SR,7RS)-5-cyclohexyl-3,6-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7- yl)carbamate (154.5 mg, 74%) as a white solid:1H NMR (400 MHz, DMSO-d6) δ 11.95 (brs, 1H), 7.51 – 7.23 (m, 5H), 6.87 (s, 1H), 5.61 – 4.91 (m, 2H), 4.38 (s, 1H), 4.10 (s, 1H), 2.69 (d, J = 9.0 Hz, 1H), 1.81 – 1.03 (m, 14 H), 0.88 (d, J = 6.2 Hz, 3H); HRMS (ES+) m / z calcd for C21H29N2O4 ([M + H]+) 369.2285, found 369.2285. cyclohexyl-3,6-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7- yl)carbamate. Synthesized according to General Procedure A with a 1 h pre-stir of tert-butyl 4-amino- 3-methyl-1H-pyrazole-1-carboxylate (266 mg, 1.35 mmol) and cyclohexanecarbaldehyde (166 µL, 1.35 mmol). The reaction mixture was warmed to rt over 16 h. Purification by chromatography on SiO2(40% EtOAc in Hexanes) provided tert-butyl (5SR,6SR,7RS)-7-(((benzyloxy)carbonyl)amino)-5- cyclohexyl-3,6-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine-1-carboxylate (429 mg, 72%) as a white solid: m.p.172.3 °C;1H NMR (400 MHz, CDCl3) δ 7.40 – 7.28 (m, 5H), 5.13, 5.11 (AB, J = 12.5 Hz, 2H), 4.89 (d, J = 4.2 Hz, 1H), 4.65 (d, J = 5.1 Hz, 1H) 3.47 (brs, 1H), 2.68 – 2.58 (m, 2H), 2.18 (s, 3H), 1.86 (J = 11.7 Hz, 1H), 1.77 – 1.62 (m, 5 H), 1.55 (s, 9H), 0.98 (d, J = 6.8 Hz, 3H);13CNMR (101 MHz, CDCl3) 115.7, 148.1, 136.8, 133.6, 131.5, 128.6, 128.2, 121.1, 84.9, 66.6, 61.9, 50.1, 38.5, 32.8, 30.2, 28.0, 26.5, 26.2, 26.1, 17.9; HRMS (ES+) m / z calcd for C27H39N4O4([M + H]+) 483.2966, found 483.2967. A flame-dried round bottom flask under inert atmosphere was charged with tert-butyl (5SR,6SR,7RS)- 7-(((benzyloxy)carbonyl)amino)-5-cyclohexyl-3,6-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- b]pyridine-1-carboxylate (319 mg, 0.66 mmol) and CH2Cl2 (5 mL). The solution was treated with a8123-112520-02 08 / 07 / 25solution of trifluoracetic acid (3.2 mL, 43 mmol) in CH2Cl2(5 mL). The reaction mixture was concentrated after 3 h. The residue was resuspended in CH2Cl2(10 mL) and extracted with sat. sodium bicarbonate solution (10 mL). The aqueous layer was extracted with CH2Cl2 (10 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated to provide benzyl ((5SR,6SR,7RS)-5-cyclohexyl-3,6-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7- yl)carbamate (180.5 mg, 72%) as a white solid: m.p.184.3 °C;1H NMR (400 MHz, CDCl3) δ 11.66 (s, 1H), 7.37 – 7.29 (m, 5H), 5.21 – 5.01 (m, 3H), 4.55 (t, J = 8.4 Hz, 1H), 2.77 (dd, J = 9.5, 3.0 Hz, 1H), 2.13 (s, 3H), 1.87 – 1.52 ( m, 7H), 1.36 – 1.15 (m, 5H), 1.04 (d, J = 6.7 Hz, 3H); HRMS (ES+) m / z calcd for C26H37N4O4([M + H]+) 469.2809, found 469.2810. carbonyl)amino)-6-cyclopentyl-5-methyl-4,5,6,7- carboxylate. Synthesized according to General Procedure A with a 30 min pre-stir of ethyl 5-aminothiophene-2-carboxylate (163 mg, 0.95 mmol) and cyclopentanecarbaldehyde (0.10 µL, 0.95 mmol). The reaction mixture was warmed to rt over 12 h. Purification by chromatography on SiO2(20% EtOAc in Hexanes) provided ethyl (4SR,5SR,6RS)-4- (((benzyloxy)carbonyl)amino)-6-cyclopentyl-5-methyl-4,5,6,7-tetrahydrothieno[2,3-b]pyridine-2- carboxylate (183.9 mg, 44%) as a colorless solid: m.p.187.9 °C;1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.40 – 7.33 (m, 5H), 5.19, 5.12 (AB, J = 13.7 Hz, 2H), 4.77 (d, J = 8.3 Hz, 1H), 4.59 (s, 1H), 4.46 (dd, J = 8.3, 6.3 Hz, 1H), 3.09 (t, J = 6.2 Hz, 1H), 2.28 – 2.20 (m, 1H), 2.02 – 1.95 (m, 1H), 1.77 – 1.59 (m, 6H), 1.28 – 1.19 (m, 7H, 1.03 (d, J = 6.7 Hz, 3H);13CNMR (101 MHz, CDCl3) 162.8, 156.2, 154.8, 136.6, 134.3, 128.7, 128.3, 128.2, 114.7, 66.9, 61.9, 60.6, 51.3, 41.8, 36.5, 29.4, 28.0, 25.8, 25.5, 16.6, 14.6; HRMS (ES+) m / z calcd for C24H31N2O4S ([M + H]+) 442.1999, found 443.1998. 6-ethyl-5-methyl-4,5,6,7-tetrahydrothieno[2,3-b]pyridin-4- yl)carbamate was isolated as a byproduct from the synthesis of benzyl ((4RS,5SS,6SR)-2-cyano-6- cyclopentyl-5-methyl-4,5,6,7-tetrahydrothieno[2,3-b]pyridin-4-yl)carbamate. Purification by8123-112520-02 08 / 07 / 25chromatography on SiO2(10-20% EtOAc in Hexanes) provided benzyl ((4RS,5RS,6SR)-2-cyano-6- ethyl-5-methyl-4,5,6,7-tetrahydrothieno[2,3-b]pyridin-4-yl)carbamate (72.2 mg, 22%) as a white solid: m.p.149.2 °C;1H NMR (400 MHz, CDCl3) δ 7.42 – 7.38 (m, 5H), 7.16 (s, 1H), 5.16 (s, 2H), 4.76 (d, J = 9.6 Hz, 1H), 4.55 – 4.47 (m, 2H), 3.21 – 3.11 (m, 1H), 1.79 – 1.52 (m, 4H), 1.04 (d, J = 6.2 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H) (;13CNMR (151 MHz, CDCl3) 156.7, 154.1, 137.8, 136.4, 128.8, 128.5, 128.3, 116.5, 116.1, 90.8, 67.3, 59.7, 51.9, 37.8, 25.6, 14.8, 8.9; HRMS (ES+) m / z calcd for C19H22N3O2S ([M + H]+) 356.1472, found 356.1427. In view of the many possible embodiments to which the principles of the disclosed compound and methods may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention.

Claims

8123-112520-02 08 / 07 / 25What is claimed is:

1. A compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:wherein X is N, C, O or S; Y is N, C, O or S; Z is N, C, O or S; R1is H; R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -S(O)(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R5is H; R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl,8123-112520-02 08 / 07 / 25substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; and R9is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, where each bond represented by ----- is a single or double bond as needed to satisfy valence requirements.

2. The compound of claim 1, wherein at least one of X, Y, or Z is N, S or O.

3. The compound of claim 1 or 2, wherein R3is alkyl.

4. The compound of claim 1 or 2, wherein R3is (C1-C6) alkyl.

5. The compound of any one of claims 1 to 4, wherein R4is alkyl or cycloalkyl.

6. The compound of any one of claims 1 to 4, wherein R4is (C1-C6) alkyl.

7. The compound of any one of claims 1 to 4, wherein R4is (C3-C6) cycloalkyl, particularly cyclopropyl.

8. The compound of any one of claims 1 to 7, wherein R6is H or alkoxy.

9. The compound of any one of claims 1 to 8, wherein R7is H or alkoxy.

10. The compound of any one of claims 1 to 8, wherein R7is (C1-C6) alkoxy.

11. The compound of any one of claims 1 to 10, wherein at least one of R6, R7, or R9is halo.

12. The compound of any one of claims 1 to 10, wherein at least one of R6, R7, or R9is - C(O)O-R10.

13. The compound of any one of claims 1 to 10, wherein at least one of R6, R7, or R9is cyano.8123-112520-02 08 / 07 / 2514. The compound of any one of claims 1 to 13, wherein R8is arylalkyl, substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl.

15. The compound of any one of claims 1 to 14, wherein R8is phenyl-substituted alkyl, particularly benzyl.

16. A method comprising administering to a subject in need of treatment for epilepsy, developmental or epileptic encephalopathy, pain, tinnitus, cancer, cardiovascular disease, neurodegeneration, fibromyalgia, arthritis, hyperalgesia, depression, schizophrenia, bipolar disorder, traumatic brain injury, smooth muscle disorders, erectile dysfunction, myotonic congenita, or inflammatory airway diseases, a therapeutically effective amount of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:Formula I wherein X is N, C, O or S; Y is N, C, O or S; Z is N, C, O or S; R1is H; R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -S(O)(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;8123-112520-02 08 / 07 / 25R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R5is H; R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; and R9is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, where each bond represented by ----- is a single or double bond as needed to satisfy valence requirements.

17. A method comprising administering to a subject in need of treatment for a Kv7- mediated disease a therapeutically effective amount of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:wherein X is N, C, O or S; Y is N, C, O or S; Z is N, C, O or S; R1is H;8123-112520-02 08 / 07 / 25R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -S(O)(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R5is H; R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; and R9is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, cyano, or -C(O)O-R10, wherein R10is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, where each bond represented by ----- is a single or double bond as needed to satisfy valence requirements.

18. The method of claim 16 or 17, wherein at least one of X, Y, or Z is N, S or O.

19. The method of any one of claims 16 to 18, wherein R3is alkyl.

20. The method of any one of claims 16 to 18, wherein R3is (C1-C6) alkyl.

21. The method of any one of claims 16 to 20, wherein R4is alkyl or cycloalkyl.

22. The method of any one of claims 16 to 20, wherein R4is (C1-C6) alkyl.

23. The method of any one of claims 16 to 20, wherein R4is (C3-C6) cycloalkyl, particularly cyclopropyl.8123-112520-02 08 / 07 / 2524. The method of any one of claims 16 to 23, wherein R6is H or alkoxy.

25. The method of any one of claims 16 to 24, wherein R7is H or alkoxy.

26. The method of any one of claims 16 to 24, wherein R7is (C1-C6) alkoxy.

27. The method of any one of claims 16 to 26, wherein at least one of R6, R7, or R9is halo.

28. The method of any one of claims 16 to 26, wherein at least one of R6, R7, or R9is - C(O)O-R10.

29. The method of any one of claims 16 to 26, wherein at least one of R6, R7, or R9is cyano.

30. The method of any one of claims 16 to 29, wherein R8is arylalkyl, substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl.

31. The method of any one of claims 16 to 29, wherein R8is phenyl-substituted alkyl, particularly benzyl.

Images