Controlled delivery cromakalim prodrugs

Abstract

The present invention relates to cromakalim prodrugs, compositions, and therapeutic ATP-sensitive potassium (K ATP ) provides their use for modulation of channels.

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 947,342, filed December 12, 2019, which is incorporated by reference herein for all purposes. [Background technology]

[0002] Potassium channels are membrane proteins that regulate the selective flow of potassium ions across cell membranes, which in turn generates an electrical signal within the cell to set or reset the cell's resting membrane potential.

[0003] ATP-sensitive potassium (K ATP ) channels play an important role in controlling and regulating cellular functions in response to metabolic state. These channels are gated by the intracellular nucleotides ATP and ADP and are expressed on the plasma membrane of cells in multiple organs, including the brain, lung, heart, pancreas, pituitary gland, skeletal and smooth muscles, vascular tissue, central nervous system, hair follicles, and eye tissue. ATP Inhibition of the channel by intracellular ATP allows the cell to couple the metabolic state of the cell to the electrical activity of the cell membrane.

[0004] K ATP Pharmacological agents that activate (open) or inhibit (close) the channel may have important clinical applications. Channel openers are drugs that release K + This, in turn, causes the closure of voltage-dependent calcium channels in the cell membrane and relaxation of vascular muscles (vasodilation). Conversely, the increase in vascular K + Inhibition (closing) of the channel is K + It reduces efflux and opens calcium channels, thereby increasing intracellular calcium levels, resulting in depolarization and vasoconstriction.

[0005] K ATPThe K channel was first discovered in the heart (Non-Patent Document 1). ATP It has been found that the K channel plays an important role in managing cardiac stress, including ischemic stroke. ATP Channels are also abundant in vascular smooth muscle, where they help maintain and regulate vascular tone. ATP Inhibition of the channel ultimately leads to a decrease in vessel diameter and an increase in vascular resistance. Activation of the channel leads to the opposite: an increase in vessel diameter and a decrease in vascular resistance. Thus, K ATP Channels play an important role in regulating vasodilation and vasoconstriction in response to endogenous factors and pharmaceutical products.

[0006] K ATP Patent applications describing channel openers and their uses include US Pat. No. 5,393,663; US Pat. No. 5,493,326; US Pat. No. 5,523,362; US Pat. No. 5,631,633; US Pat. No. 5,711,366; and US Pat. No. 5,711,366. Cromakalim and diazoxide were reported to lower blood pressure in Non-Patent Document 2. Publications by Chowdhury et al. describe the use of diazoxide and nicorandil (Non-Patent Document 3 and Non-Patent Document 4). Cromakalim placed in membrane patches from rabbit mesenteric artery smooth muscle cells reduces the single K channel in the presence of ATP. ATP The channel open state probability (P open ) by more than nine-fold (Non-Patent Document 5). Other potassium channel openers include pinacidil and minoxidil sulfate, which act as vasodilators in vitro and in vivo.

[0007] Cromakalim exists as a mixture of diastereomers in the trans configuration (a mixture of the (3R,4S) diastereomer and the (3S,4R) diastereomer, where the (3R,4S) diastereomer and the (3S,4R) diastereomer are enantiomers of each other).

[0008] [ka]

[0009] The (3S,4R)-enantiomer is also called (-)-cromakalim or levcromakalim, and the (3R,4S)-enantiomer is also called (+)-cromakalim or dexcromakalim.

[0010] [ka]

[0011] Most of the reported activity of cromakalim comes from its (3S,4R)-enantiomer, levcromakalim (Non-Patent Document 6 and Non-Patent Document 7).

[0012] Cromakalim and its use as an antihypertensive agent was first described in U.S. Patent No. 5,393,633, assigned to Beecham Group, Inc. Further disclosures regarding the effects of cromakalim on intraocular pressure and glaucoma include U.S. Patent No. 5,393,633, ... and U.S. Patent No. 5,393,633.

[0013] While cromakalim has established activity as a potassium channel opener and vasodilator, it is virtually insoluble in water. Cromakalim's lipophilicity limits its usefulness for certain in vivo applications. Cromakalim is often solubilized with DMSO or cremophor, which is also used for the water-insoluble drug taxol. Cremophor in particular has toxic side effects.

[0014] In response to the need to generate a formulation of levcromakalim with suitable properties for administration to an aqueous environment in vivo, the Mayo Foundation for Medical Education and Research and Reagents at the University of Minnesota generated a phosphate ester prodrug, CKLP1, which may be in the form of a disodium salt (see U.S. Patent No. 5,313,633).

[0015] [ka]

[0016] CKLP1, in combination with the normally rapid in vivo hydrolysis to parent levcromakalim (depending on the concentration of alkaline phosphatase enzyme), provides improved water solubility enhancement that facilitates administration. Thus, CKLP1 overcomes one of the challenges of levcromakalim therapy without compromising the efficiency or timing of dosing. See also Non-Patent Document 10.

[0017] CKLP1 is a prodrug of levcromakalim. Its phosphate ester prodrug is more water soluble than levcromakalim and has been reported to reduce intraocular pressure (IOP) in normotensive mouse models with once-daily dosing. The effect of CKLP1 on episcleral venous pressure and distal outflow resistance was described in Non-Patent Document 11, and pharmacokinetic parameters in rabbits after topical and intravenous administration were described in Non-Patent Document 12. The synthesis of CKLP1 and the corresponding (3R,4S)-enantiomer is described by Roy Chowdhury et al. in Non-Patent Document 10.

[0018] Although progress has been made in the field of therapeutic potassium channel openers, it would be beneficial to provide additional compounds with different properties for different therapeutic applications, methods for their use, and advantageous formulations that can modify metabolic signaling via the potassium channel pathway to treat responsiveness disorders in patients in need of such treatment. [Prior art documents] [Patent documents]

[0019] [Patent Document 1] U.S. Patent No. 2,986,573 [Patent Document 2] U.S. Patent No. 3,361,816 [Patent Document 3] U.S. Patent No. 4,200,640

Patent document 4

Patent document 5

Patent document 6

Patent document 7

Patent document 8

Patent document 9

Patent document 10

Non-licensed literature

[0020] [Non-licensed document 1] Noma, A. Nature, 1983, 305, 147

Non-licensed Document 2

Non-licensed Document 4

Non-licensed Document 5

[0021] It has been found that cromakalim, and in one embodiment, levcromakalim, can be administered in a unique controlled delivery mode by administering it as a dimeric or trimeric prodrug or their pharma- ceutically acceptable salts linked via one or more phosphate ester moieties. In one embodiment, the novel dimeric and trimeric prodrugs allow for tunable kinetics in which two or three levcromakalim moieties are converted at different rates depending on the phosphate ester linkage, e.g., one moiety is released more quickly than the other one or two moieties. The remaining second moiety can be converted slowly over time. This allows for a controlled drug delivery mode with dual capabilities to provide multiple release rates over an extended period of time.

[0022] The compounds of the present invention are more lipophilic than the previously disclosed CKLP1, allowing for a more complex release of the active moiety over time, rather than an almost immediate hydrolysis to the parent cromakalim. The compounds can in some embodiments be administered in formulations that are more lipophilic than CKLP1, making them advantageous for administration to the outside as well as inside lipophilic tissues more easily than cromakalim itself.

[0023] The dimeric or trimeric cromakalim prodrugs or pharma- ceutically acceptable salts thereof may contain a cromakalim moiety that is either the (-)(3S,4R)-enantiomer (levcromakalim) or the (+)(3R,4S)-enantiomer ((+)-cromakalim), or any mixture thereof. It may be used as the free acid, if present in the molecule, or the fully or partially neutralized acid. In one embodiment, the pH of pharmaceutical formulations containing the novel dimeric or trimeric cromakalim prodrugs is adjusted to a pH level desired for pharmaceutical administration, often between about 5.5 or 6.5 and 8.5, more typically between 6.5 and 8, using a pharma- ceutically acceptable base.

[0024] At physiological pH, the compounds of the invention having free acids will exist in equilibrium with the fully ionized form, or in one embodiment, the partially ionized form. For example, the pH of the eye is approximately 7.4-7.6, which is composed mostly of water. Thus, the free hydroxyl of the compounds of the invention will exist in the body as the corresponding ionized form (due to natural equilibrium in a slightly basic solution). This ionized form will then decompose to cromakalim, and in one embodiment, levcromakalim.

[0025] The disclosed compounds or pharma- ceutical acceptable salts thereof can be used to treat disorders including ATP-sensitive potassium (K), including disorders that are treated via increased vasodilation and blood flow and / or decreased vascular resistance and / or fluid resistance. ATP) channel can be used to treat disorders that respond to modulation. In one embodiment, the treatment is achieved without substantial hyperemia. Selected compounds of the present invention can be used to increase tissue perfusion and thus achieve cytoprotective activity. As an example, this treatment can be used to protect neurons by reducing cerebral ischemic damage during stroke and cerebral hypoxia. Selected compounds of the present invention can also be used to generally reduce blood pressure.

[0026] Disorders that can be treated by the compounds of the present invention include, but are not limited to, intraocular pressure regulation (leading to the treatment of glaucoma), retinal cell protection, regulation of insulin secretion from the pancreas, glucose homeostasis in the hypothalamus, cardioprotection and neuroprotection, neurotransmitter release, cellular adaptation to stress, hair loss, alopecia, diabetes, hyperinsulinemia, asthma, urinary incontinence, epilepsy, hypertension, hypoglycemia, and disorders related to metabolic stress, including general hypoxia and ischemia.Compounds of the present invention can also be used to reduce venous resistance, such as episcleral venous pressure (EVP), and / or improve ocular distal outflow in subjects in need of reduction and / or improvement, for example, in subjects with normal tension glaucoma.In particular, selected compounds of the present invention can be used to treat EVP in diseased hosts as well as otherwise normal hosts.

[0027] In certain embodiments, the compounds of the present invention provide peripheral vasodilation, which is useful for the treatment of a range of disorders that can benefit from such peripheral vasodilation, including, but not limited to, Raynaud's disease, peripheral arterial disease, peripheral vascular disease, lower limb ischemia, and erectile dysfunction.

[0028] More generally, the selected compound may be administered via systemic, topical, inhalation, transmucosal (mist, bronchial inhaler and / or nebulizer, and / or nasal spray), parenteral, intravenous, subcutaneous, intramuscular, vaginal, suppository, transdermal, buccal, or sublingual delivery. Ocular delivery is suitably achieved using topical drops, gels, emulsions, liposomes, suspensions, punctal plugs, and / or syrups. Intraocular and more posterior routes of administration include intravitreal, intrastromal, intracameral, sub-Tenon, subretinal, retrobulbar, peribulbar, suprachoroidal, choroidal, subchoroidal, conjunctival, episcleral, posterior juxtascleral, or perilimbal routes of administration.

[0029] Novel dimeric and trimeric cromakalim compounds and their salts In certain embodiments, the dimeric or trimeric compounds of the present invention are provided that metabolize via controlled delivery of cromakalim with two-step or multi-step kinetics. In certain non-limiting embodiments, the first cromakalim moiety is hydrolyzed from the dimer to generate CKLP1 with the stereochemical variation shown below, which then hydrolyzes to generate the second cromakalim molecule. The rate of hydrolysis will depend on the level of alkaline phosphatase in the compound's surroundings. The rate of hydrolysis is also correlated with the ability of the enzyme to hydrolyze the compound based on steric hindrance. Steric hindrance is used to control hydrolysis even more dramatically in trimeric compounds. These complex metabolic patterns contribute to the sustained release properties of the disclosed cromakalim prodrugs, and in one embodiment, the levcromakalim prodrugs.

[0030] In one embodiment, the present invention provides compound 1: [ka] and / or a pharma- ceutically acceptable equivalent thereof.

[0031] In one embodiment, compound 1 has the (3S,4R) or (4S,3R) stereochemistry shown below.

[0032] [ka]

[0033] Non-limiting examples of alternatives to compound 1 include other trans- or cis-diastereomers of cromakalim: [ka] may be mentioned.

[0034] Alternative isomers include: [ka] Examples include:

[0035] In one embodiment, compound 1 has the formula I: [ka] (In the formula, X + is administered as a compound of cation (which can be any pharma- ceutically acceptable cation that achieves the desired result). In certain embodiments, the cation is selected from sodium, potassium, aluminum, calcium, magnesium, lithium, iron, zinc, arginine, chloroprocaine, choline, diethanolamine, ethanolamine, lysine, histidine, meglumine, procaine, hydroxyethylpyrrolidine, ammonium, tetrapropylammonium, tetrabutylphosphonium, methyldiethanamine, and triethylamine.

[0036] Non-limiting examples of compounds of formula I include: [ka] TIFF0007636742000010.tif112170 is an example.

[0037] In one embodiment, X + is Na + Or K + In one embodiment, X + Li + In one embodiment, X + is Cs + In one embodiment, X + is an ammonium ion having a net positive charge of 1. In an alternative embodiment, the ammonium ion having a net positive charge of 1 has the following formula: [ka] (In the formula, R 1 is C1-C6 alkyl, such as, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, sec-butyl, isobutyl, -CH2C(CH3)3, -CH(CH2CH3)2, and -CH2CH(CH2CH3)2, cyclopropyl, CH2-cyclopropyl, cyclobutyl, and CH2-cyclobutyl, or aryl, such as phenyl or naphthyl.

[0038] Non-limiting examples of ammonium ions having a net positive charge of 1 include: [ka] Examples include:

[0039] In another embodiment, X + is a pharma- ceutically acceptable quaternary amine, such as benzalkonium, particularly in topical formulations.

[0040] In an alternative embodiment, X + are tetraalkylammonium compounds including, but not limited to, tetramethylammonium.

[0041] In another embodiment, compound 1 has formula II with a divalent cation: [ka] (In the formula, M 2+ is administered as a compound of a divalent cation, including, but not limited to, an alkaline earth metal cation (magnesium, calcium, or strontium), a metal cation having an oxidation state of +2 (e.g., zinc or iron), or an ammonium ion having a net positive charge of 2 (e.g., benzathine, hexamethyldiammonium, and ethylenediamine).

[0042] Non-limiting examples of compounds of formula II include: [ka] TIFF0007636742000015.tif54170 is an example.

[0043] Additional non-limiting examples of compounds of formula II include: [ka] Examples include:

[0044] In one embodiment, M 2+ is Mg 2+ In one embodiment, M 2+ Ca 2+ In one embodiment, M 2+ is Sr 2+ In one embodiment, M 2+ Zn 2+ In one embodiment, M 2+ is Fe 2+ In one embodiment, M 2+ is an ammonium ion having a net positive charge of 2. Non-limiting examples of ammonium ions having a net positive charge of 2 include: [ka] Examples include:

[0045] In an alternative embodiment, the ammonium ion having a net positive charge of two has the formula: [ka] (In the formula, R 1 is C1-C6 alkyl, such as, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, sec-butyl, isobutyl, -CH2C(CH3)3, -CH(CH2CH3)2, and -CH2CH(CH2CH3)2, cyclopropyl, CH2-cyclopropyl, cyclobutyl, and CH2-cyclobutyl, or aryl, such as phenyl or naphthyl; and a is an integer selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0046] In another embodiment, the present invention provides a compound of formula III: [ka] or a pharma- ceutically acceptable salt thereof.

[0047] Non-limiting examples of compounds of formula III include: [ka] Examples include:

[0048] In another embodiment, the present invention provides a compound of formula IV: [ka] or a pharma- ceutically acceptable salt thereof.

[0049] Non-limiting examples of compounds of formula IV include: [ka] Examples include:

[0050] Other non-limiting examples of formula IV include: [ka] Examples include:

[0051] In another embodiment, the present invention provides a compound of formula V or formula VI, in which the negative charge is neutralized: [ka] (In the formula, x, y, + , and M 2+ is a therapeutically active compound as defined herein.

[0052] Non-limiting examples of compounds of formula V and formula VI include: [ka] Examples include:

[0053] In another embodiment, the present invention provides a compound of formula VII or formula VIII, in which the negative charge is neutralized: [ka] (In the formula, m, n, + , and M 2+ is an active compound of the formula (as defined herein).

[0054] In another embodiment, the present invention provides a compound having the structure shown below as Compound 2 or a pharma- ceutically acceptable salt thereof: [ka] or a pharma- ceutically acceptable salt thereof.

[0055] In another embodiment, the active compound or a pharma- ceutically acceptable salt is Compound 3 or Compound 4: [ka] or a pharma- ceutically acceptable salt thereof.

[0056] In another embodiment, the present invention relates to a compound of formula IX or formula X: [ka] (In the formula, x, y, and z are independently selected from 1, 2, 3, 4, and 5, or in alternative embodiments, x, y, and z are independently selected from 1, 2, 3, 4, 5, 6, 7, and 8; and m, n, and o are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, or in alternative embodiments, m, n, and o are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10), or a pharma- ceutically acceptable salt thereof.

[0057] In another embodiment, the present invention relates to a compound of formula XI or formula XII: [ka] (In the formula, X + and M 2+ is an active compound or a pharma- ceutically acceptable salt of the structure:

[0058] In another embodiment, the present invention provides an active compound or a pharma- ceutically acceptable salt of the structure of formula XIII, or a compound of formula XIV or formula XV in which the negative charge is neutralized: [ka] (In the formula, x, + , and M 2+ is defined herein).

[0059] In one embodiment, x is selected from 2, 3, 4, 5, 6, 7, and 8.

[0060] In another embodiment, the present invention relates to a compound of formula XVI or formula XVII: [ka] wherein x and y are defined herein, or a pharma- ceutically acceptable salt thereof.

[0061] In another embodiment, the present invention relates to a compound of formula XVIII or formula XIX: [ka] wherein x and m are defined herein, or a pharma- ceutically acceptable salt thereof.

[0062] In one embodiment, x is selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0063] In another embodiment, the present invention provides a compound of formula XX or formula XXI, in which the negative charge is neutralized: [ka] (Wherein, x, m, and X + is a compound of formula (I) (as defined herein).

[0064] In one embodiment, x is selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0065] In another embodiment, the present invention provides a compound of formula XXII or formula XXIII, in which the negative charge is neutralized: [ka] (Wherein, x, m, and M 2+ is a compound of formula (I) (as defined herein).

[0066] In one embodiment, x is independently selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0067] In another embodiment, the present invention relates to a compound of formula XXIV or formula XXV: [ka] (In the formula, p is selected from 0 and 1; R is independently in each occurrence H and X + and X + , x, and m are defined herein as an active compound or a pharma- ceutically acceptable salt thereof.

[0068] In one embodiment, x is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In another embodiment, m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0069] In another embodiment, the present invention relates to a compound of formula XXVI or formula XXVII: [ka] wherein m and n are defined herein, or a pharma- ceutically acceptable salt thereof.

[0070] In certain embodiments, the compounds of the invention are [ka] Selected from TIFF0007636742000039.tif168170TIFF0007636742000040.tif224170TIFF0007636742000041.tif82170.

[0071] The disclosed compounds and compositions are useful for therapeutically inhibiting ATP-sensitive potassium (K ATP In one embodiment, the compounds and compositions can be used to modulate vascular smooth muscle to treat certain cardiovascular, vascular, muscular, endocrine, pulmonary, urological, dermatological, lymphatic, and neurological disorders. ATP In one embodiment, the compounds and compositions of the present invention provide peripheral vasodilation to treat, for example, Raynaud's disease, peripheral arterial disease, peripheral vascular disease, lower limb ischemia, and erectile dysfunction.

[0072] These compounds may also be used in topical formulations for a range of disorders where increased blood flow is therapeutic, including vascular disorders, muscular disorders, dermatological disorders, and ocular disorders. For example, in one embodiment, the compounds of the present invention are formulated for topical administration and used to improve peripheral vasodilation or treat vascular disorders such as Raynaud's disease, peripheral vascular disease, and hypoperfusion or hyperperfusion in a host in need of such improvement or treatment.

[0073] In one embodiment, the compounds and compositions of the present invention are used to improve K+ metabolism for ophthalmic purposes, including reducing intraocular pressure (e.g., for the treatment of glaucoma), reducing episcleral venous pressure (EVP), and / or improving distal outflow capacity in a subject in need of such reduction and / or improvement. ATP The compounds of the present invention are modulators of the EVP channel. In particular, the selected compounds of the present invention can be used to treat EVP in diseased hosts as well as in otherwise normal hosts. The selected compounds of the present invention can also be used to treat ophthalmic and retinal diseases by improving perfusion and oxygenation.

[0074] In one embodiment, any of the compounds of the present invention can be formulated for topical administration and used to treat dermatological disorders, such as hair loss or alopecia, in a host in need of such treatment, hi one embodiment, the compounds of the present invention are formulated for topical administration in dosage forms such as lotions, gels, ointments, patches, creams, mists, or sprays.

[0075] In one aspect, compounds of formula I-XXVII or pharma- ceutically acceptable salts or compositions thereof are provided as a method for relaxing vascular smooth muscle to treat certain diseases and disorders, including cardiovascular, vascular, ophthalmic, muscular, endocrine, pulmonary, urological, dermatological, lymphatic, and neurological disorders or diseases. In one embodiment, the compound is selected from Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof.

[0076] In one aspect, the compounds of formula I-XXVII or pharma- ceutically acceptable salts or compositions thereof are provided as a method of treating a cardiovascular or vascular disorder or disease, including hypertension, high blood pressure, congestive heart failure, transient ischemic attacks, heart attack, acute myocardial infarction, acute and chronic myocardial ischemia, unstable angina and associated chest pain, arrhythmias, pulmonary arterial hypertension (PAH), vasoconstrictive disorders, vasospastic disorders, Raynaud's disease, or peripheral vascular disease (PVD). In one embodiment, the compound is selected from Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof.

[0077] In one aspect, a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof is provided as a method for treating an endocrine metabolic disorder or disease, including hypoglycemia, hyperinsulinemia, diabetes, or prediabetes. In one embodiment, the compound is selected from Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof.

[0078] In one aspect, a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof is provided as a method for treating skeletal myopathy. In one embodiment, the compound is selected from Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof.

[0079] In one aspect, a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof is provided as a method for treating a pulmonary disease or disorder, such as asthma, nocturnal asthma, or airway hyperresponsiveness. In one embodiment, the compound is selected from Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof.

[0080] In one aspect, the compounds of formula I-XXVII or their pharma- ceutically acceptable salts or compositions are provided as a method for treating urological disorders or diseases, such as urinary incontinence or erectile dysfunction. In one embodiment, the compounds of formula I-XXVII or their pharma- ceutically acceptable salts or compositions are used to treat female sexual arousal disorder due to blood flow. In one embodiment, the compound is selected from Compound 1-Compound 21 or their pharma- ceutically acceptable salts.

[0081] In one aspect, a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof is provided as a method for treating a dermatological disorder or disease, such as hair loss or hypotrichosis. In one embodiment, the compound is selected from Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof.

[0082] In one aspect, a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof is provided as a method for treating a neurological disorder or disease, such as epilepsy, ischemic multifocal disease, neuropathic pain, or neurodegeneration. In one embodiment, the compound is selected from Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof.

[0083] In one aspect, a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof is provided as a method of treating a lymphatic disorder such as lymphadenopathy, lymphedema, lymphangitis, lymphadenitis, lymphangiomatosis, Castleman's disease, or a cancer of the lymphatic system, including Hodgkin's lymphoma, non-Hodgkin's lymphoma, or lymphangiomatosis. In one embodiment, the compound is selected from Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof.

[0084] In one aspect, the compounds of Formula I-XXVII or pharma- ceutically acceptable salts or compositions thereof are provided as a method for treating ophthalmic disorders including elevated episcleral venous pressure (EVP), glaucoma, normal tension glaucoma, ocular hypertension, Graves' ophthalmopathy, Graves' orbitopathy (GO), retrobulbar tumors, cavernous sinus thrombosis, orbital vein thrombosis, episcleral / orbital venous vasculitis, superior vena cava occlusion, superior vena cava thrombosis, carotid cavernous fistula, dural cavernous shunt, orbital varicose veins, and Sturge-Weber syndrome. In one embodiment, the compound is selected from Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof. In one embodiment, the ocular hypertension is the result of trauma or surgery.

[0085] In another aspect, the compounds of formula I-XXVII or pharma- ceutically acceptable salts or compositions thereof are provided as a method for preventing or treating ocular damage due to ischemic conditions, for example by improving perfusion and oxygenation. In one embodiment, the compound is selected from Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof.

[0086] In one aspect, compounds of formula I-XXVII or pharma- ceutically acceptable salts or compositions thereof are provided for treating hypertensive or vascular occlusive and / or ischemic retinopathy, central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), arterial occlusive / embolic disease and / or hypoperfusion disease, diabetic retinopathy, optic nerve damage due to ischemia (posterior and anterior ischemic optic neuropathy (NAION)), and acute and chronic angle-closure glaucoma-induced damage to the optic nerve and retina nerve fiber layer (retinal ganglion layer). In one embodiment, the compound is selected from Compound 1-Compound 21 or a pharma-ceutically acceptable salt thereof.

[0087] In one embodiment, the compound of formula I-formula XXVII or a pharma- ceutically acceptable salt or composition thereof is administered to treat an ocular disorder caused by elevated episcleral venous pressure in a host in need of treatment, selected from normal tension glaucoma, primary open angle glaucoma, juvenile and congenital glaucoma, neovascular glaucoma, pseudoexfoliation glaucoma, and steroid-induced open angle glaucoma. In one embodiment, the glaucoma is selected from primary open angle glaucoma (POAG), primary angle-closure glaucoma, normal tension glaucoma (NTG), pediatric glaucoma, pseudoexfoliation glaucoma, pigmentary glaucoma, traumatic glaucoma, neovascular glaucoma, and iridocorneal endothelial glaucoma. Primary open angle glaucoma is also known as chronic open angle glaucoma, chronic simple glaucoma, and simple glaucoma.

[0088] Thus, the present invention includes the following features: (a) Compound 1, or a pharma- ceutically acceptable salt thereof; (b) Compound 2, Compound 3, or Compound 4, or a pharma- ceutically acceptable salt thereof; (c) Compound 5 to Compound 21, or a pharma- ceutically acceptable salt thereof; (d) a compound of formula I, formula V, formula VII, formula XII, formula XIV, formula XX, or formula XXI; (e) a compound of formula II, formula VI, formula VIII, formula XI, formula XV, formula XXII, or formula XXIII; (f) a compound of formula III, formula IV, formula IX, formula X, formula XIII, formula XVI, formula XVII, formula XVIII, formula XIX, formula XXV, or formula XXVII, or a pharma- ceutically acceptable salt thereof; (g) a compound of formula XXIV or formula XXV, or a pharma- ceutically acceptable salt thereof; (h)X + is sodium, potassium, aluminum, calcium, magnesium, lithium, iron, zinc, arginine, chloroprocaine, choline, diethanolamine, ethanolamine, lysine, histidine, meglumine, procaine, hydroxyethylpyrrolidine, ammonium, tetrapropylammonium, tetrabutylphosphonium, methyldiethanamine, or triethylamine; (i) M 2+ is magnesium, calcium, or strontium, zinc, iron, benzathine, hexamethyldiammonium, or ethylenediamine; (j) a pharmaceutical composition comprising any of embodiments (a)-(i), optionally in a pharma- ceutically acceptable carrier; (k) a pharmaceutical composition of (j) administered as a dosage form; (l) a pharmaceutical composition (k) having a dosage form suitable for ocular administration; (m) the pharmaceutical composition of (k) or (l), whose dosage form is a solution, emulsion, or suspension; (n) a pharmaceutical composition of (k) to (m) having a dosage form suitable for topical administration; (o) the pharmaceutical composition of (k) or (n), the dosage form of which is a gel, mist, spray, ointment, cream, lotion, or transdermal patch; (p) a pharmaceutical composition (k) having a dosage form suitable for systemic administration; (q) the pharmaceutical composition of (p), whose dosage form is an inhaler, tablet, capsule, liquid, suspension, ointment, or suppository; (r) a pharmaceutical composition (k) having a dosage form suitable for parenteral administration; (s) the pharmaceutical composition of (j) or (l) administered as topical drops, nanoparticles, or a gel; and (t) pharmaceutical compositions of (k) administered orally, intraocularly, intravenously, subcutaneously, intramuscularly, intrathecally, intranasally, mucosally, by inhalation, transdermally, intradermally, and vaginally; (u) a method of reducing episcleral venous pressure (EVP) and / or improving distal outflow in a host with elevated EVP, comprising administering Compound 1 to Compound 21 or a pharma- ceutically acceptable salt thereof; (v) a method of reducing episcleral venous pressure (EVP) and / or improving distal outflow or venous congestion in a host with elevated EVP comprising administering a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt thereof; (w) method (u) or (v) for treating an ophthalmic disorder selected from elevated episcleral venous pressure (EVP), glaucoma, acute glaucoma due to inflammatory cataract, ocular hypertension, Graves' ophthalmopathy, Graves' orbitopathy (GO), retrobulbar tumors, cavernous sinus thrombosis, orbital vein thrombosis, episcleral / orbital venous vasculitis, superior vena cava occlusion, superior vena cava thrombosis, carotid-cavernous fistula, dural cavernous shunt, orbital varicose veins, and Sturge-Weber syndrome by reducing EVP and / or improving distal outflow or venous congestion; (x) a method for preventing or treating eye damage due to an ischemic condition in a host in need of such treatment, comprising administering to the host any one of Compounds 1 to 21 or a pharma- ceutically acceptable salt thereof; (y) a method for preventing or treating ocular damage due to an ischemic condition in a host in need thereof, comprising administering a compound of Formula I to Formula XXVII or a pharma- ceutically acceptable salt thereof; (z) A method for preventing or treating hypertensive retinopathy, central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), arterial occlusive / embolic disease and / or hypoperfusion disease, diabetic retinopathy, optic nerve damage due to ischemia and / or hypoperfusion (posterior and anterior ischemic optic neuropathy (NAION)), and acute and chronic angle-closure glaucoma-induced damage to the optic nerve and retina nerve fiber layer (retinal ganglion layer) in a host in need of such prevention or treatment, comprising administering Compound 1 to Compound 21 or a pharma- ceutically acceptable salt thereof to the host in need of such prevention or treatment; (aa) a method for preventing or treating hypertensive retinopathy, central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), arterial occlusive / embolic disease and / or hypoperfusion disease, diabetic retinopathy, optic nerve damage due to ischemia (posterior and anterior ischemic optic neuropathy (NAION)), and acute and chronic angle-closure glaucoma-induced damage to the optic nerve and retina nerve fiber layer (retinal ganglion layer) in a host in need of such prevention or treatment, comprising administering a compound of Formula I to Formula XXVII or a pharma-ceutically acceptable salt thereof; (bb) A method for treating hypertension, congestive heart failure, acute and chronic myocardial ischemia, unstable angina and associated chest pain, arrhythmia, the occurrence of ventricular fibrillation associated with acute myocardial infarction, pulmonary arterial hypertension, persistent pulmonary hypertension of the newborn, peripheral arterial disease, peripheral vascular disease, and critical limb ischemia in a host in need of treatment, comprising administering to the host in need of treatment Compound 1 to Compound 21 or a pharma- ceutically acceptable salt thereof; (cc) a method for treating hypertension, congestive heart failure, acute and chronic myocardial ischemia, unstable angina and associated chest pain, arrhythmias, the occurrence of ventricular fibrillation associated with acute myocardial infarction, pulmonary arterial hypertension, persistent pulmonary hypertension of the newborn, peripheral arterial disease, peripheral vascular disease, and critical limb ischemia in a host in need of such treatment comprising administering a compound of Formula I-Formula XXVII or a pharma-ceutically acceptable salt thereof; (dd) a method for treating hypoglycemia, hyperinsulinism, diabetes, or prediabetes in a host in need of treatment, comprising administering to the host in need of treatment Compound 1 to Compound 21 or a pharma- ceutically acceptable salt thereof; (ee) a method for treating hypoglycemia, hyperinsulinism, diabetes, or prediabetes comprising administering a compound of Formula I to Formula XXVII or a pharma- ceutically acceptable salt thereof; (ff) a method for treating skeletal muscle myopathy, urinary incontinence, alopecia, hypotrichosis, airway hyperresponsiveness, asthma and nocturnal asthma, erectile dysfunction, and blood flow-related female sexual arousal disorder in a host in need of treatment, comprising administering to the host in need of treatment Compound 1 to Compound 21 or a pharma- ceutically acceptable salt thereof; (gg) a method for treating skeletal muscle myopathy, urinary incontinence, hair loss, hypotrichosis, airway hyperresponsiveness, asthma and nocturnal asthma, erectile dysfunction, and blood flow female sexual arousal disorder in a host in need of such treatment comprising administering a compound of Formula I to Formula XXVII or a pharma- ceutically acceptable salt thereof; (hh) a method of treating a lymphatic disorder, such as lymphadenopathy, lymphedema, lymphangitis, lymphadenitis, lymphangiomatosis, Castleman's disease, or cancer of the lymphatic system, including Hodgkin's lymphoma, non-Hodgkin's lymphoma, or lymphangiomatosis, in a host in need of such treatment comprising administering a compound of Formula I-Formula XXVII; (ii) A method for treating a lymphatic disease, such as lymphadenopathy, lymphedema, lymphangitis, lymphadenitis, lymphangiomatosis, Castleman's disease, or cancer of the lymphatic system, including Hodgkin's lymphoma, non-Hodgkin's lymphoma, or lymphangiomatosis, in a host in need of treatment, comprising administering to the host in need of treatment Compound 1 to Compound 21 or a pharma- ceutically acceptable salt thereof; (jj) a method for improving peripheral vasodilation or treating vascular disorders such as Raynaud's disease, peripheral vascular disease, and hypoperfusion or hyperperfusion in a host in need of such treatment, comprising administering to the host in need of such treatment Compounds 1 to 21 or a pharma- ceutically acceptable salt thereof; (kk) A method for improving peripheral vasodilation or treating vascular disorders such as Raynaud's disease, peripheral vascular disease, and hypoperfusion or hyperperfusion in a host in need of such improvement or treatment, comprising administering a compound of Formula I to Formula XXVII or a pharma- ceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0089] Detailed Description of the Invention The present invention relates to dimeric and trimeric cromakalim prodrugs, compositions, and therapeutic ATP-sensitive potassium (K ATPThe present invention provides a method for the regulation of the IL-18 receptor agonist (IL-18 receptor agonist) and their use for the modulation of the IL-18 receptor agonist (IL-18 receptor agonist) channel. The prodrugs of the present invention may, in one embodiment, be administered in a delivery system that allows for controlled delivery over time, unlike previous prodrugs of cromakalim or levcromakalim that are rapidly hydrolyzed to the parent compound. These compounds are also advantageous because they can be formulated into lipophilic formulations that are useful for administration to lipophilic tissues.

[0090] In one embodiment, the compounds and compositions of the present invention relax vascular smooth muscle to treat certain cardiovascular, vascular, muscular, endocrine, pulmonary, urological, dermatological, ophthalmic, and neurological disorders described herein. ATP This is the channel modulator.

[0091] In one embodiment, the compounds and compositions of the invention are useful in the treatment of ophthalmic conditions, including reducing episcleral venous pressure (EVP) and improving distal outflow capacity in subjects with elevated EVP. ATP This is the channel modulator.

[0092] In one embodiment, the active compound or a pharma- ceutically acceptable salt is Compound 1: [ka] or a pharma- ceutical acceptable version thereof.

[0093] In one embodiment, the active compound has the formula I: [ka] (In the formula, X +is a compound of formula (III) which can be any pharma- ceutically acceptable cation that achieves the desired result. In certain embodiments, the cation is selected from sodium, potassium, aluminum, calcium, magnesium, lithium, iron, zinc, arginine, chloroprocaine, choline, diethanolamine, ethanolamine, lysine, histidine, meglumine, procaine, hydroxyethylpyrrolidine, ammonium, tetrapropylammonium, tetrabutylphosphonium, methyldiethanamine, and triethylamine.

[0094] In certain embodiments, the cation is a quaternary ammonium compound. In certain embodiments, the cation is a tetraalkylammonium. In certain embodiments, the cation is a tetramethylammonium. In an alternative embodiment, the ammonium ion having a net positive charge of one has the formula: [ka] (In the formula, R 1 is C1-C6 alkyl, such as, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, sec-butyl, isobutyl, -CH2C(CH3)3, -CH(CH2CH3)2, and -CH2CH(CH2CH3)2, cyclopropyl, CH2-cyclopropyl, cyclobutyl, and CH2-cyclobutyl, or aryl, such as phenyl or naphthyl.

[0095] Non-limiting examples of compounds of formula I include: [ka] Examples include:

[0096] Additional non-limiting examples of compounds of formula I are: [ka] The file is TIFF0007636742000047.tif148170.

[0097] In another embodiment, the active compound has a neutralized negative charge of formula II: [ka] (In the formula, M 2+ are compounds of divalent cations including, but not limited to, alkaline earth metal cations (magnesium, calcium, or strontium), metal cations having an oxidation state of +2 (e.g., zinc or iron), or ammonium ions having a net positive charge of two (e.g., benzathine, hexamethyldiammonium, and ethylenediamine).

[0098] In an alternative embodiment, the ammonium ion having a net positive charge of two has the formula: [ka] (In the formula, R 1 is C1-C6 alkyl, such as, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, sec-butyl, isobutyl, -CH2C(CH3)3, -CH(CH2CH3)2, and -CH2CH(CH2CH3)2, cyclopropyl, CH2-cyclopropyl, cyclobutyl, and CH2-cyclobutyl, or aryl, such as phenyl or naphthyl; and a is an integer selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0099] Non-limiting examples of compounds of formula II include: [ka] Examples include:

[0100] Additional non-limiting examples of compounds of formula II include: [ka] Examples include:

[0101] In another embodiment, the present invention provides a compound of formula III: [ka] or a pharma- ceutically acceptable salt thereof.

[0102] In one embodiment of Formula III, x and y are 1. In one embodiment of Formula III, x and y are 2. In one embodiment of Formula III, x and y are 3. In one embodiment of Formula III, x and y are 4. In one embodiment of Formula III, x and y are 5. In one embodiment of Formula III, x is 1 and y is selected from 1, 2, 3, 4, and 5. In one embodiment of Formula III, x is 2 and y is selected from 1, 2, 3, 4, and 5. In one embodiment of Formula III, x is 3 and y is 1, 2, 3, 4, and 5. In one embodiment of Formula III, x is 4 and y is selected from 1, 2, 3, 4, and 5. In one embodiment of Formula III, x is 5 and y is selected from 1, 2, 3, 4, and 5.

[0103] In one embodiment of Formula III, x is 2 and y is selected from 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula III, x is 3 and y is selected from 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula III, x is 4 and y is selected from 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula III, x is 5 and y is selected from 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula III, x is 6 and y is selected from 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula III, x is 7 and y is selected from 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula III, x is 8 and y is selected from 2, 3, 4, 5, 6, 7, and 8.

[0104] Non-limiting examples of compounds of formula III include: [ka] TIFF0007636742000054.tif203170TIFF0007636742000055.tif58170 are examples.

[0105] In one embodiment, y is 1. In one embodiment, y is 2. In one embodiment, y is 3. In one embodiment, y is 4. In one embodiment, y is 5. In one embodiment, y is 6. In one embodiment, y is 7. In one embodiment, y is 8.

[0106] In another embodiment, the present invention provides a compound of formula IV: [ka] or a pharma- ceutically acceptable salt thereof, wherein m and n are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; in alternative embodiments, m and n are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0107] In one embodiment of Formula IV, m and n are 1. In one embodiment of Formula IV, m and n are 2. In one embodiment of Formula IV, m and n are 3. In one embodiment of Formula IV, m and n are 4. In one embodiment of Formula IV, m and n are 5. In one embodiment of Formula IV, m and n are 6. In one embodiment of Formula IV, m and n are 7. In one embodiment of Formula IV, m and n are 8. In one embodiment of Formula IV, m and n are 9. In one embodiment of Formula IV, m and n are 10. In one embodiment of Formula IV, m is 1 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 2 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 3 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 4 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 5 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 6 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 7 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 8 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one Formula IV embodiment, m is 9 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one Formula IV embodiment, m is 10 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0108] In one embodiment, m and n are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 0 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 1 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 2 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 3 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 4 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 5 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 6 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 7 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 8 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 9 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula IV, m is 10 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0109] Non-limiting examples of compounds of formula IV include: [ka] TIFF0007636742000058.tif206170TIFF0007636742000059.tif116170 are examples.

[0110] In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3. In one embodiment, n is 4. In one embodiment, n is 5. In one embodiment, n is 6. In one embodiment, n is 7. In one embodiment, n is 8.

[0111] Additional non-limiting examples of compounds of formula IV include: [ka] Examples include:

[0112] In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3. In one embodiment, n is 4. In one embodiment, n is 5. In one embodiment, n is 6. In one embodiment, n is 7. In one embodiment, n is 8.

[0113] In another embodiment, the present invention provides a compound of formula V or formula VI, in which the negative charge is neutralized: [ka] (In the formula, x, y, + , and M 2+ is an active compound of the formula (as defined herein).

[0114] Non-limiting examples of compounds of formula V include: [ka] TIFF0007636742000063.tif45170 is an example.

[0115] Non-limiting examples of compounds of formula VI include: [ka] TIFF0007636742000065.tif140170 is an example.

[0116] In one embodiment of Formula V or Formula VI, x and y are 1. In one embodiment of Formula V or Formula VI, x and y are 2. In one embodiment of Formula V or Formula VI, x and y are 3. In one embodiment of Formula V or Formula VI, x and y are 4. In one embodiment of Formula V or Formula VI, x and y are 5. In one embodiment of Formula V or Formula VI, x is 1 and y is selected from 1, 2, 3, 4, and 5. In one embodiment of Formula V or Formula VI, x is 2 and y is selected from 1, 2, 3, 4, and 5. In one embodiment of Formula V or Formula VI, x is 3 and y is 1, 2, 3, 4, and 5. In one embodiment of Formula V or Formula VI, x is 4 and y is selected from 1, 2, 3, 4, and 5. In one embodiment of Formula V or Formula VI, x is 5 and y is selected from 1, 2, 3, 4, and 5.

[0117] In one embodiment of Formula V or Formula VI, x is 2 and y is selected from 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula V or Formula VI, x is 3 and y is selected from 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula V or Formula VI, x is 4 and y is selected from 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula V or Formula VI, x is 5 and y is selected from 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula V or Formula VI, x is 6 and y is selected from 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula V or Formula VI, x is 7 and y is selected from 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula V or Formula VI, x is 8 and y is selected from 2, 3, 4, 5, 6, 7, and 8.

[0118] In another embodiment, the present invention provides a compound of formula VII or formula VIII, in which the negative charge is neutralized: [ka] (In the formula, m, n,+ , and M 2+ is an active compound of the formula (as defined herein).

[0119] Non-limiting examples of compounds of formula VII or formula VIII include: [ka] TIFF0007636742000068.tif223170 is an example.

[0120] In one embodiment of Formula VII or Formula VIII, m and n are 1. In one embodiment of Formula VII or Formula VIII, m and n are 2. In one embodiment of Formula VII or Formula VIII, m and n are 3. In one embodiment of Formula VII or Formula VIII, m and n are 4. In one embodiment of Formula VII or Formula VIII, m and n are 5. In one embodiment of Formula VII or Formula VIII, m and n are 6. In one embodiment of Formula VII or Formula VIII, m and n are 7. In one embodiment of Formula VII or Formula VIII, m and n are 8. In one embodiment of Formula VII or Formula VIII, m and n are 9. In one embodiment of Formula VII or Formula VIII, m and n are 10. In one embodiment of Formula VII or Formula VIII, m is 1 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 2 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 3 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 4 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 5 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 6 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 7 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 8 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 9 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 10 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0121] In one embodiment, m and n are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 0 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 1 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 2 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 3 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 4 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 5 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 6 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 7 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 8 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 9 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula VII or Formula VIII, m is 10 and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0122] Additional non-limiting examples of compounds of formula VII or formula VIII include: [ka] Examples include:

[0123] In another embodiment, the present invention relates to a compound of formula IX or formula X: [ka] (In the formula, x, y, and z are independently selected from 1, 2, 3, 4, and 5, or in alternative embodiments, x, y, and z are independently selected from 1, 2, 3, 4, 5, 6, 7, and 8; and m, n, and o are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, or in alternative embodiments, m, n, and o are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10), or a pharma- ceutically acceptable salt thereof.

[0124] In one Formula IX embodiment, x, y, and z are 1. In one Formula IX embodiment, x, y, and z are 2. In one Formula IX embodiment, x, y, and z are 3. In one Formula IX embodiment, x, y, and z are 4. In one Formula IX embodiment, x, y, and z are 5.

[0125] In another embodiment, x, y, and z are independently selected from 1, 2, 3, 4, 5, 6, 7, or 8. In another embodiment, x, y, and z are each different values. In one embodiment, x is 2, y is 2, and z is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment, x is 3, y is 3, and z is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment, x is 4, y is 4, and z is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment, x is 5, y is 5, and z is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment, x is 6, y is 6, and z is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment, x is 7, y is 7, and z is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment, x is 8, y is 8, and z is selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0126] In one embodiment of Formula X, m, n, and o are 1. In one embodiment of Formula X, m, n, and o are 2. In one embodiment of Formula X, m, n, and o are 3. In one embodiment of Formula X, m, n, and o are 4. In one embodiment of Formula X, m, n, and o are 5. In one embodiment of Formula X, m, n, and o are 6. In one embodiment of Formula X, m, n, and o are 7. In one embodiment of Formula X, m, n, and o are 8. In one embodiment of Formula X, m, n, and o are 9. In one embodiment of Formula X, m, n, and o are 10.

[0127] In another embodiment, m, n, and o are selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In another embodiment, m, n, and o are each different values. In another embodiment, m and n are 0 and o is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In another embodiment, m and n are 1 and o is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In another embodiment, m and n are 2 and o is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In another embodiment, m and n are 3 and o is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In another embodiment, m and n are 4 and o is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In another embodiment, m and n are 5 and o is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In another embodiment, m and n are 6 and o is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In another embodiment, m and n are 7 and o is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In another embodiment, m and n are 8 and o is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In another embodiment, m and n are 9 and o is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In another embodiment, m and n are 10 and o is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0128] Non-limiting examples of compounds of formula IX include: [ka] TIFF0007636742000072.tif178170 is an example.

[0129] Non-limiting examples of compounds of formula X include: [ka] TIFF0007636742000074.tif153170TIFF0007636742000075.tif154170 are examples.

[0130] In one embodiment, the active compound or a pharma- ceutically acceptable salt is Compound 2: [ka] or a pharma- ceutical acceptable version thereof.

[0131] In another embodiment, the active compound or pharma- ceutically acceptable salt is Compound 3 and Compound 4: [ka] or a pharma- ceutically acceptable salt thereof.

[0132] In another embodiment, the present invention provides a compound of formula XI or formula XII, in which the negative charge is neutralized: [ka] (In the formula, X + and M 2+ is a compound of formula (I) (as defined herein).

[0133] Non-limiting examples of compounds of formula XI and formula XII include: [ka] Examples include:

[0134] In an alternative embodiment, the present invention provides a compound of formula XIA: [ka] It is a compound of the formula:

[0135] Non-limiting examples of compounds of formula XIA include: [ka] Examples include:

[0136] In another embodiment, the present invention provides an active compound or a pharma- ceutically acceptable salt of the structure of formula XIII, or a compound of formula XIV or formula XV in which the negative charge is neutralized: [ka] (In the formula, x, + , and M 2+ is defined herein).

[0137] In one embodiment of Formula XIII, Formula XIV, or Formula XV, x is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XIII, Formula XIV, or Formula XV, x is 1. In one embodiment of Formula XIII, Formula XIV, or Formula XV, x is 2. In one embodiment of Formula XIII, Formula XIV, or Formula XV, x is 3. In one embodiment of Formula XIII, Formula XIV, or Formula XV, x is 4. In one embodiment of Formula XIII, Formula XIV, or Formula XV, x is 5. In one embodiment of Formula XIII, Formula XIV, or Formula XV, x is 6. In one embodiment of Formula XIII, Formula XIV, or Formula XV, x is 7. In one embodiment of Formula XIII, Formula XIV, or Formula XV, x is 8.

[0138] Non-limiting examples of compounds of formula XIII, formula XIV, and formula XV include: [ka] TIFF0007636742000084.tif226170 is an example.

[0139] In another embodiment, the present invention relates to a compound of formula XVI or formula XVII: [ka] wherein x and y are defined herein, or a pharma- ceutically acceptable salt thereof.

[0140] In one Formula XVI embodiment, x is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one Formula XVI embodiment, x is 1. In one Formula XVI embodiment, x is 2. In one Formula XVI embodiment, x is 3. In one Formula XVI embodiment, x is 4. In one Formula XVI embodiment, x is 5. In one Formula XVI embodiment, x is 6. In one Formula XVI embodiment, x is 7. In one Formula XVI embodiment, x is 8.

[0141] In one embodiment of Formula XVI or Formula XVII, x is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XVII, y is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XVI or Formula XVII, x and y are selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XVI or Formula XVII, x and y are 1. In one embodiment of Formula XVI or Formula XVII, x and y are 2. In one embodiment of Formula XVI or Formula XVII, x and y are 3. In one embodiment of Formula XVI or Formula XVII, x and y are 4. In one embodiment of Formula XVI or Formula XVII, x and y are 5. In one embodiment of Formula XVI or Formula XVII, x and y are 6. In one embodiment of Formula XVI or Formula XVII, x and y are 7. In one embodiment of Formula XVI or Formula XVII, x and y are 8. In another embodiment of Formula XVI or Formula XVII, x and y are different values. In one embodiment of Formula XVII, x is 1 and y is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XVII, x is 2 and y is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XVII, x is 3 and y is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XVII, x is 4 and y is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XVII, x is 5 and y is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XVII, x is 6 and y is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XVII, x is 7 and y is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XVII, x is 8 and y is selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0142] Non-limiting examples of compounds of formula XVI include: [ka] Examples include:

[0143] Non-limiting examples of compounds of formula XVII include: [ka] Examples include:

[0144] In another embodiment, the present invention relates to a compound of formula XVIII or formula XIX: [ka] wherein m and x are defined herein, or a pharma- ceutically acceptable salt thereof.

[0145] Non-limiting examples of compounds of formula XVIII include: [ka] Examples include:

[0146] Non-limiting examples of compounds of formula XIX include: [ka] Examples include:

[0147] In one Formula XVIII embodiment, x is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one Formula XVIII embodiment, x is 1. In one Formula XVIII embodiment, x is 2. In one Formula XVIII embodiment, x is 3. In one Formula XVIII embodiment, x is 4. In one Formula XVIII embodiment, x is 5. In one Formula XVIII embodiment, x is 6. In one Formula XVIII embodiment, x is 7. In one Formula XVIII embodiment, x is 8.

[0148] In one embodiment of Formula XIX, m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula XIX, m is 0. In one embodiment of Formula XIX, m is 1. In one embodiment of Formula XIX, m is 2. In one embodiment of Formula XIX, m is 3. In one embodiment of Formula XIX, m is 4. In one embodiment of Formula XIX, m is 5. In one embodiment of Formula XIX, m is 6. In one embodiment of Formula XIX, m is 7. In one embodiment of Formula XIX, m is 8. In one embodiment of Formula XIX, m is 9. In one embodiment of Formula XIX, m is 10.

[0149] Additional non-limiting examples of compounds of formula XVIII or formula XIX include: [ka] TIFF0007636742000092.tif134170 is an example.

[0150] In another embodiment, the present invention provides a compound of formula XX or formula XXI, in which the negative charge is neutralized: [ka] (Wherein, m, x, and X + is a compound of formula (I) (as defined herein).

[0151] Non-limiting examples of compounds of formula XX include: [ka] Examples include:

[0152] Non-limiting examples of compounds of formula XXI include: [ka] Examples include:

[0153] In one embodiment of Formula XX, x is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XX, x is 1. In one embodiment of Formula XX, x is 2. In one embodiment of Formula XX, x is 3. In one embodiment of Formula XX, x is 4. In one embodiment of Formula XX, x is 5. In one embodiment of Formula XX, x is 6. In one embodiment of Formula XX, x is 7. In one embodiment of Formula XX, x is 8.

[0154] In one embodiment of Formula XXI, m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula XXI, m is 0. In one embodiment of Formula XXI, m is 1. In one embodiment of Formula XXI, m is 2. In one embodiment of Formula XXI, m is 3. In one embodiment of Formula XXI, m is 4. In one embodiment of Formula XXI, m is 5. In one embodiment of Formula XXI, m is 6. In one embodiment of Formula XXI, m is 7. In one embodiment of Formula XXI, m is 8. In one embodiment of Formula XXI, m is 9. In one embodiment of Formula XXI, m is 10.

[0155] Additional non-limiting examples of compounds of formula XXI include: [ka] Examples include:

[0156] In another embodiment, the present invention provides a compound of formula XXII or formula XXIII, in which the negative charge is neutralized: [ka] (Wherein, m, x, and M 2+ is a compound of formula (I) (as defined herein).

[0157] In one embodiment of Formula XXII, x is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XXII, x is 1. In one embodiment of Formula XXII, x is 2. In one embodiment of Formula XXII, x is 3. In one embodiment of Formula XXII, x is 4. In one embodiment of Formula XXII, x is 5. In one embodiment of Formula XXII, x is 6. In one embodiment of Formula XXII, x is 7. In one embodiment of Formula XXII, x is 8.

[0158] In one embodiment of Formula XXIII, m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of Formula XXIII, m is 0. In one embodiment of Formula XXIII, m is 1. In one embodiment of Formula XXIII, m is 2. In one embodiment of Formula XXIII, m is 3. In one embodiment of Formula XXIII, m is 4. In one embodiment of Formula XXIII, m is 5. In one embodiment of Formula XXIII, m is 6. In one embodiment of Formula XXIII, m is 7. In one embodiment of Formula XXIII, m is 8. In one embodiment of Formula XXIII, m is 9. In one embodiment of Formula XXIII, m is 10.

[0159] Non-limiting examples of compounds of formula XXII and formula XXIII include: [ka] Examples include:

[0160] In another embodiment, the present invention relates to a compound of formula XXIV or formula XXV: [ka] (In the formula, p is selected from 0 and 1; R is independently in each occurrence H and X + and X + wherein x, m, and n are as defined herein, and are an active compound of the structure or a pharma- ceutically acceptable salt thereof.

[0161] In one embodiment, x is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In another embodiment, m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0162] Non-limiting examples of compounds of formula XXIV and formula XXV include: [ka] Examples include:

[0163] In certain embodiments, the compound of formula XXIV is [ka] is selected from.

[0164] In certain embodiments, the compound of formula XXIV is [ka] is selected from.

[0165] In certain embodiments, the compound of formula XXIV is [ka] is selected from.

[0166] In certain embodiments, the compound of formula XXIV is [ka] is selected from.

[0167] In certain embodiments, the compound of formula XXIV is [ka] is selected from.

[0168] In certain embodiments, the compound of formula XXIV is [ka] is selected from.

[0169] In certain embodiments, the compound of formula XXIV is [ka] is selected from.

[0170] In certain embodiments, the compound of formula XXIV is [ka] is selected from.

[0171] In certain embodiments, the compound of formula XXIV is [ka] is selected from.

[0172] In certain embodiments, the compound of formula XXV is [ka] is selected from.

[0173] In certain embodiments, the compound of formula XXV is [ka] is selected from.

[0174] In certain embodiments, the compound of formula XXV is [ka] is selected from.

[0175] In certain embodiments, the compound of formula XXV is [ka] is selected from.

[0176] In certain embodiments, the compound of formula XXV is [ka] is selected from.

[0177] In certain embodiments, the compound of formula XXV is [ka] is selected from.

[0178] In certain embodiments, the compound of formula XXV is [ka] is selected from.

[0179] In another embodiment, the present invention relates to a compound of formula XXVI or formula XXVII: [ka] wherein x and y are defined herein, or a pharma- ceutically acceptable salt thereof.

[0180] In one Formula XXVI embodiment, m is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one Formula XXVI embodiment, m is 1. In one Formula XXVI embodiment, m is 2. In one Formula XXVI embodiment, m is 3. In one Formula XXVI embodiment, m is 4. In one Formula XXVI embodiment, m is 5. In one Formula XXVI embodiment, m is 6. In one Formula XXVI embodiment, m is 7. In one Formula XXVI embodiment, m is 8.

[0181] In one embodiment of Formula XXVI or Formula XXVII, m is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XXVII, m is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XXVII, m and n are selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XXVII, m and n are 1. In one embodiment of Formula XXVII, m and n are 2. In one embodiment of Formula XXVII, m and n are 3. In one embodiment of Formula XXVII, m and n are 4. In one embodiment of Formula XXVII, m and n are 5. In one embodiment of Formula XXVII, m and n are 6. In one embodiment of Formula XXVII, m and n are 7. In one embodiment of Formula XXVII, m and n are 8. In another embodiment of Formula XXVII, m and n are different values.

[0182] In one embodiment of Formula XXVII, m is 1 and n is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XXVII, m is 2 and n is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XXVII, m is 3 and n is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XXVII, m is 4 and n is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XXVII, m is 5 and n is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XXVII, m is 6 and n is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XXVII, m is 7 and n is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In one embodiment of Formula XXVII, m is 8 and n is selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0183] Non-limiting examples of compounds of formula XXVI and formula XXVII include: [ka] TIFF0007636742000119.tif216170TIFF0007636742000120.tif65170 are examples.

[0184] Additional embodiments of the present invention include:

[0185] Specific embodiments of formula I and formula XII of the present invention include (a) In formula I or formula XII, + Na + That is, (b) In formula I or formula XII, + K + That is, (c) In formula I or formula XII, + Li + That is, (d) In formula I or formula XII,+ NH4 + and (e) In formula I or formula XII, + N(Me)4 + That is, Examples include:

[0186] Specific embodiments of formula II and formula XI of the present invention include: (a) In Formula II and Formula XI, M 2+ Ca 2+ That is, (b) In Formula II and Formula XI, M 2+ Mg 2+ That is, (c) In Formula II and Formula XI, M 2+ Zn 2+ That is, Examples include:

[0187] Specific embodiments of formula XIII, formula XVI, and formula XVIII of the present invention include: (a) in formula XIII, formula XVI, and formula XVIII, x is 1; (b) in formula XIII, formula XVI, and formula XVIII, x is 2; (c) in formula XIII, formula XVI, and formula XVIII, x is 3; (d) in formula XIII, formula XVI, and formula XVIII, x is 4; (e) in formula XIII, formula XVI, and formula XVIII, x is 5; (f) in formula XIII, formula XVI, and formula XVIII, x is 6; (g) in formula XIII, formula XVI, and formula XVIII, x is 7; and (h) in formula XIII, formula XVI, and formula XVIII, x is 8; Examples include:

[0188] Specific embodiments of formula XIX and formula XXVI of the present invention include (a) in formula XIX and formula XXVI, m is 1; (b) in formula XIX and formula XXVI, m is 2; (c) in formula XIX and formula XXVI, m is 3; (d) in formula XIX and formula XXVI, m is 4; (e) in formula XIX and formula XXVI, m is 5; (f) in formula XIX and formula XXVI, m is 6; (g) In formula XIX and formula XXVI, m is 7; (h) in formula XIX and formula XXVI, m is 8; (i) in formula XIX and formula XXVI, m is 9; and (j) in formula XIX and formula XXVI, m is 10; Examples include:

[0189] Specific embodiments of formula III, formula XVII, and formula IX of the present invention include: (a) in formula III, formula XVII, and formula IX, x is 1; (b) in formula III, formula XVII, and formula IX, x is 2; (c) in formula III, formula XVII, and formula IX, x is 3; (d) in formula III, formula XVII, and formula IX, x is 4; (e) in formula III, formula XVII, and formula IX, x is 5; (f) in formula III, formula XVII, and formula IX, x is 6; (g) in formula III, formula XVII, and formula IX, x is 7; (h) in formula III, formula XVII, and formula IX, x is 8; (i) In (a) to (h), y is 1; (j) In (a) to (h), y is 2; (k) In (a) through (hh), y is 3; (l) In (aa) to (h), y is 4; (m) In (a) to (h), y is 5; (n) In (a) to (h), y is 6; (o) In (a) to (h), y is 7; (p) In (a) to (h), y is 8; (q) In (a) through (p), z is 1; (r) In (a) through (p), z is 2; (s) In (a) through (p), z is 3; (t) In (a) through (p), z is 4; (u) In (a) through (p), z is 5; (v) In (a) to (p), z is 6; (w) In (a) to (p), z is 7; and (x) In (a) to (p), z is 8; Examples include:

[0190] Specific embodiments of formula IV, formula XXVII, and formula X of the present invention include: (a) in formula IV and formula XXVII, m is 0; (b) in formula IV and formula XXVII, m is 1; (c) in formula IV and formula XXVII, m is 2; (d) in formula IV and formula XXVII, m is 3; (e) in formula IV and formula XXVII, m is 4; (f) in formula IV and formula XXVII, m is 5; (g) In formula IV and formula XXVII, m is 6; (h) in formula IV and formula XXVII, m is 7; (i) In formula IV and formula XXVII, m is 8; (j) in formula IV and formula XXVII, m is 9; (k) in formula IV and formula XXVII, m is 10; (l) In (a) to (k), n is 0; (m) In (a) to (k), n is 1; (n) In (a) to (k), n is 2; (o) In (a) to (k), n is 3; (p) In (a) through (k), n is 4; (q) In (a) to (k), n is 5; (r) In (a) to (k), n is 6; (s) In (a) through (k), n is 7; (t) In (a) through (k), n is 8; (u) In (a) to (k), n is 9; (v) In (a) to (k), n is 10; (w) In (a) to (v), o is 0; (x) In (a) to (v), o is 1; (y) In (a) to (v), o is 2; (z) In (a) to (v), o is 3; (aa) In (a) to (v), o is 4; (bb) In (a) to (v), o is 5; (cc) In (a) to (v), o is 6; (dd) In (a) to (v), o is 7; (ee) In (a) to (v), o is 8; (ff) In (a) to (v), o is 9; and (gg) In (a) to (v), o is 10; Examples include:

[0191] Specific embodiments of the present invention include: (a) In formula V, formula VII, formula XIV, formula XX, formula XXI, formula XXIV, and formula XXV, X + Na + That is, (b) In the formula V, formula VII, formula XIV, formula XX, formula XXI, formula XXIV, and formula XXV, X + K + That is, (c) In formula V, formula VII, formula XIV, formula XX, formula XXI, formula XXIV, and formula XXV, X + Li + That is, (d) In the formula V, formula VII, formula XIV, formula XX, formula XXI, formula XXIV, and formula XXV, X + NH4 + That is, (e) In the formula V, formula VII, formula XIV, formula XX, formula XXI, formula XXIV, and formula XXV, X + N(Me)4 + That is, (f) In (a) to (e), x is 1; (g) In (a) to (e), x is 2; (h) In (a) to (e), x is 3; (i) In (a) to (e), x is 4; (j) In (a) to (e), x is 5; (k) In (a) to (e), x is 6; (l) In (a) to (e), x is 7; (m) In (a) to (e), x is 8; (n) In (a) to (m), y is 1; (o) In (a) to (m), y is 2; (p) In (a) through (m), y is 3; (q) In (a) to (m), y is 4; (r) In (a) to (m), y is 5; (s) In (a) through (m), y is 6; (t) In (a) through (m), y is 7; (u) In (a) to (m), y is 8; (v) In (a) to (e), m is 0; (w) In (a) to (e), m is 1; (x) In (a) to (e), m is 2; (y) In (a) to (e), m is 3; (z) In (a) to (e), m is 4; (aa) In (a) to (e), m is 5; (bb) In (a) to (e), m is 6; (cc) In (a) to (e), m is 7; (dd) In (a) to (e), m is 8; (ee) In (a) to (e), m is 9; (ff) In (a) to (e), m is 10; (gg) In (v) through (ff), n is 0. (hh) In (v) to (ff), n is 1; (ii) In (v) to (ff), n is 2; (jj) In (v) to (ff), n is 3; In (kk)(v) through (ff), n is 4. (ll) In (v) to (ff), n is 5; In (mm)(v) to (ff), n is 6; (nn) In (v) through (ff), n is 7; In (oo)(v)~(ff), n is 8. In (pp)(v)~(ff), n is 9. (qq) In (v) through (ff), n is 10. (rr) In (a) to (m), p is 0; (ss) In (a) through (m), p is 1; (tt) In (a) to (e) and (v) to (ff), p is 0; and (uu) In (a) to (e) and (v) to (ff), p is 1; Examples include:

[0192] Specific embodiments of formula VI, formula VIII, formula XV, formula XXII, and formula XXIII of the present invention include: (a) In the formulas VI, VIII, XV, XXII, and XXIII, M 2+ Ca 2+ That is, (b) In formula VI, formula VIII, formula XV, formula XXII, and formula XXIII, M 2+ Mg 2+ That is, (c) In the formulas VI, VIII, XV, XXII, and XXIII, M 2+ Zn 2+ That is, (d) In (a) to (c), x is 1; (e) In (a) to (c), x is 2; (f) In (a) to (c), x is 3; (g) In (a) to (c), x is 4; (h) In (a) to (c), x is 5; (i) In (a) to (c), x is 6; (j) In (a) to (c), x is 7; (k) In (a) to (c), x is 8; (l) In (a) to (k), y is 1; (m) In (a) through (k), y is 2; (n) In (a) to (k), y is 3; (o) In (a) to (k), y is 4; (p) In (a) through (k), y is 5; (q) In (a) to (k), y is 6; (r) In (a) to (k), y is 7; (s) In (a) to (k), y is 8; (t) In (a) to (c), m is 0; (u) In (a) to (c), m is 1; (v) In (a) to (c), m is 2; (w) In (a) to (c), m is 3; (x) In (a) to (c), m is 4; (y) In (a) to (c), m is 5; (z) In (a) to (c), m is 6; (aa) In (a) to (c), m is 7; (bb) In (a) to (c), m is 8; (cc) In (a) to (c), m is 9; (dd) In (a) to (c), m is 10; (ee) In (t) through (dd), n is 0. (ff) In (t) through (dd), n is 1; (gg) In (t) through (dd), n is 2. In (hh)(t) through (dd), n is 3; (ii) In (t) to (dd), n is 4; In (jj)(t) through (dd), n is 5. In (kk)(t)~(dd), n is 6. (ll) In (t) through (dd), n is 7; In (mm)(t)~(dd), n is 8. In (nn)(t) through (dd), n is 9; and In (oo)(t)~(dd), n is 10. Examples include:

[0193] In one aspect, compounds 1-21 or pharma- ceutically acceptable salts or compositions thereof, or compounds of formula I-XXVII or pharma- ceutically acceptable salts or compositions thereof, are provided as a method for treating certain diseases and disorders, including cardiovascular, vascular, metabolic, ophthalmic, and neurodegenerative disorders and diseases, by increasing blood flow by relaxing vascular smooth muscle. In one embodiment, compounds of formula I-XXVII are administered to improve peripheral vasodilation, for example, to treat Raynaud's disease or erectile dysfunction.

[0194] In one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt or composition thereof, or a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof, is provided as a method of treating cardiovascular or vascular disorders, including hypertension, high blood pressure, congestive heart failure, heart attack, acute myocardial infarction, acute and chronic myocardial ischemia, unstable angina and associated chest pain, arrhythmias, pulmonary arterial hypertension (PAH), peripheral vascular disease, vasoconstrictive disease, vasospastic disease, Raynaud's disease, or peripheral arterial disease.

[0195] In one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt or composition thereof, or a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof is provided as a method for treating an endocrine disorder, including hypoglycemia, hyperinsulinism, diabetes, or prediabetes.

[0196] In one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt or composition thereof, or compounds of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof, are provided as a method for treating smooth muscle myopathy and / or skeletal muscle myopathy, urinary incontinence, hair loss, hypotrichosis, airway hyperresponsiveness, asthma and nocturnal asthma, erectile dysfunction, and female sexual arousal disorder due to blood flow.

[0197] In one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt or composition thereof, or a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof, is provided as a method of reducing intraocular pressure, reducing episcleral venous pressure (EVP), decreasing vascular resistance, and / or improving distal outflow in a host in need thereof. Non-limiting examples of ophthalmic disorders that cause or lead to elevated EVP include elevated episcleral venous pressure (EVP), glaucoma, ocular hypertension, normal tension glaucoma, Graves' ophthalmopathy, Graves' orbitopathy (GO), retrobulbar tumors, cavernous sinus thrombosis, orbital vein thrombosis, episcleral / orbital venous vasculitis, superior vena cava occlusion, superior vena cava thrombosis, carotid cavernous sinus fistula, dural cavernous sinus shunt, orbital varicose veins, and Sturge-Weber syndrome.

[0198] In another aspect, Compound 1-Compound 21 or a pharma- ceutically acceptable salt or composition thereof, or a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof, are provided as a method for preventing or treating ocular damage, for example, due to ischemic conditions. In one embodiment, Compound 1 or Compound 2 or a pharma- ceutically acceptable salt thereof, or a compound of Formula I-Formula XXVII are provided for treating hypertensive retinopathy, normal tension glaucoma, central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), arterial occlusive / embolic disease and / or hypoperfusion disease, diabetic retinopathy, retinopathy of immature optic nerve damage due to ischemia (posterior and anterior ischemic optic neuropathy (NAION)), and acute and chronic angle-closure glaucoma-induced damage to the optic nerve and nerve fiber layer of the retina (retinal ganglion layer).

[0199] I. Detailed Description of the Compounds of the Invention The compounds of formula I-XXVII, including compounds 1-21, are prodrugs of cromakalim, and in some embodiments, of levcromakalim. Unless the stereochemistry of a chiral carbon is specifically specified in any of compounds 1-21 or in any of the formulae described herein (formula I-XXVII), any stereochemical configuration that achieves the desired result can be used. The carbon can be in either the R or S configuration, or a mixture thereof, including a racemic mixture. Also, since there are two chiral carbons in the cromakalim moiety, this moiety can exhibit one of four diastereomeric configurations, namely two trans and two cis. For example, in one embodiment, compound 1: [ka] The structure: [ka] The compound is selected from the group consisting of

[0200] Furthermore, in one embodiment, the compounds of the present invention exist as mixtures of diastereomers and / or racemates. [ka] The composition also comprises [ka] The molecule may include

[0201] In another example, compound 2: [ka] The structure: [ka] The compound is selected from TIFF0007636742000127.tif243170.

[0202] In one embodiment, compounds 1 to 21 or compounds of formulae I to XXVII can be used in the form of any desired ratio of (3S,4R) and (3R,4S) enantiomers, including up to pure enantiomers. In some embodiments, compounds 1 to 21 or compounds of formulae I to XXVII are used in a form that is at least 90% free of the opposite enantiomer, and may not be at least 98%, 99%, or even 100% free of the opposite enantiomer. Unless otherwise specified, enantiomerically enriched compounds of compounds 1 to 21 or compounds of formulae I to XXVII are at least 90% free of the opposite enantiomer.

[0203] Isotope Substitution The present invention includes compounds and uses of compounds of Compound 1-Compound 21 or compounds of Formula I-Formula XXVII with desired isotopic substitution of atoms above natural abundance, i.e., enriched isotope amounts. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but different numbers of neutrons. Common examples include, but are not limited to, isotopes of hydrogen, e.g., deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in the depicted structures. Alternatively or additionally, isotopes of carbon, such as 13 C and 14 C can be used. A preferred isotope substitution is deuterium in place of hydrogen at one or more positions on a molecule to improve drug performance. Deuterium can be attached at the position of bond cleavage during metabolism (α-deuterium kinetic isotope effect) or at a position next to or near the site of bond cleavage (β-deuterium kinetic isotope effect).

[0204] Substitution with isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, for example, increased half-life in vivo or reduced dosage requirements. Substitution of hydrogen with deuterium at a metabolic degradation site can slow or eliminate metabolism at that bond. At any position in a compound where a hydrogen atom can be present, the hydrogen atom can be substituted with protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H. Thus, references herein to compounds include all possible isotopic forms, unless the context clearly dictates otherwise.

[0205] The term "isotopically labeled" analogues includes "deuterated analogues," 13 C-labeled analogues” or “deuterated / 13 The term "deuterated analog" refers to an analog that is a "C labeled analog". 1 H) is the H isotope, namely deuterium ( 2 H). Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium. In certain embodiments, the isotope is 90%, 95%, or 99% or more enriched in the isotope at any location of interest. In some embodiments, the isotope is 90%, 95%, or 99% enriched in deuterium at the desired location. Unless indicated to the contrary, deuteration is at least 80% at the selected location.

[0206] II. Definition Compounds are described using their proper names. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0207] The terms "a" and "an" do not denote a limitation of quantity, but rather the presence of at least one of the referenced items. The term "or" means "and / or." The recitation of ranges of values, unless otherwise specified herein, is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein by reference as if it were individually recited herein. All range endpoints are included within the range and are independently combinable. All methods described herein can be performed in any suitable order unless otherwise specified herein or clearly contradicted by context. The use of examples or exemplary language (e.g., "such as") is intended merely to better illustrate the invention and does not dictate a limitation of the scope of the invention unless otherwise asserted.

[0208] "Dosage form" refers to a unitary administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal dosage forms, sublingual dosage forms, topical dosage forms, gels, mucosal dosage forms, etc. "Dosage form" can also include implants, such as optical implants.

[0209] As used herein, "effective amount" means an amount that provides a therapeutic or prophylactic benefit.

[0210] "Parenteral" administration of pharmaceutical compositions includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im), intrasternal injection, or infusion techniques.

[0211] "Treating" a disease, as that term is used herein, means reducing the frequency or severity of at least one sign or symptom of the disease or disorder experienced by a subject (i.e., palliative treatment), or reducing the cause or effect of the disease or disorder (i.e., disease-modifying treatment).

[0212] As used herein, a "pharmaceutical composition" is a composition that includes at least one active agent and at least one other agent, such as a carrier. "Pharmaceutical combinations" are combinations of at least two active agents that can be combined in a single dosage form or given together in separate dosage forms, where the active agents are indicated for use in combination to treat any of the disorders described herein.

[0213] The term "carrier" applied to pharmaceutical compositions / combinations of the invention refers to a diluent, excipient, or vehicle provided with an active compound.

[0214] "Pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise unsuitable for administration to a host, typically a human, useful in the preparation of a pharmaceutical composition / combination. In one embodiment, an excipient acceptable for veterinary use is used.

[0215] A "patient" or "host" or "subject" is a human or non-human animal in need of treatment or prevention of any of the disorders specifically described herein. Typically, the host is a human. "Host" may alternatively refer to, for example, mammals, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.

[0216] A "therapeutically effective amount" of a pharmaceutical composition / combination of the present invention means an amount effective to bring about a therapeutic effect, such as amelioration of symptoms or reduction or diminishment of the disease itself, when administered to a host.

[0217] "Pharmaceutically acceptable salts" include derivatives of the disclosed compounds in which the parent compound is modified by making its inorganic and organic salts, non-toxic salts, acid addition salts or base addition salts. The salts of the compounds can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of an appropriate base (such as hydroxide, carbonate, bicarbonate of (Li, Na, Ca, Mg or K)) or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent or a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are typical when practicable.

[0218] Examples of pharma- ceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include conventional non-toxic salts and ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as those derived from acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) n Examples of the salts include salts prepared from organic acids such as --COOH (wherein n is 0 to 4).

[0219] Further non-limiting examples of salts include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, adipic acid, aspartic acid, benzenesulfonic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, and the like. Examples of suitable salts include carboxylic acid, formic acid, mucic acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutaric acid, glycerophosphoric acid, hippuric acid, isobutyric acid, lactobionic acid, lauric acid, malonic acid, mandelic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, palmitic acid, pyroglutamic acid, sebacic acid, thiocyanic acid, and undecylenic acid. Further lists of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0220] Exemplary acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate salts.

[0221] Certain compounds of the present invention are cation-neutralized phosphate prodrugs of cromakalim and, in some embodiments, levcromakalim. Exemplary inorganic base addition salts of potassium channels include those containing benzathine, chloroprocaine, choline, diethylaminoethanol, hydroxyethylpyrrolidine, ammonium, tetrapropylammonium, tetrabutylphosphonium, hexamethyldiammonium, methyldiethanamine, triethylamine, meglumine, and procaine. In one embodiment, the compounds of formulas I-XXVII are neutralized with an inorganic base addition salt selected from benzathine, chloroprocaine, choline, diethylaminoethanol, hydroxyethylpyrrolidine, ammonium, tetrapropylammonium, tetrabutylphosphonium, hexamethyldiammonium, methyldiethanamine, triethylamine, meglumine, and procaine.

[0222] III. Pharmaceutical Compositions and Dosage Forms The compounds of the invention described herein may be administered as neat chemicals to a host in need of administration, but are more typically administered as pharmaceutical compositions comprising an effective amount of Compound 1-21 or a pharma- ceutically acceptable salt or composition thereof, or a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof, to a host in need of such treatment, typically a human. Thus, in one embodiment, the present disclosure provides a pharmaceutical composition comprising an effective amount of the compound or a pharma- ceutically acceptable salt thereof together with at least one pharma- ceutically acceptable carrier for any of the uses described herein. The pharmaceutical composition may comprise the compound or salt as the only active agent, or in alternative embodiments, may comprise the compound and at least one additional active agent.

[0223] The exact amount of an active compound or pharmaceutical composition described herein delivered to a host, typically a human, in need of delivery will be determined by a healthcare provider to achieve the desired clinical benefit.

[0224] In certain non-limiting embodiments, the pharmaceutical composition is present in a dosage form containing from about 0.005 mg to about 5 mg, from about 0.003 mg to about 3 mg, from about 0.001 mg to about 1 mg, from about 0.05 mg to about 0.5 mg, from about 0.03 mg to about 0.3 mg, or from about 0.01 mg to about 0.1 mg, or from about 0.01 mg to about 0.05 mg.

[0225] In one embodiment, the pharmaceutical composition is present in a dosage form comprising from about 0.1 mg to about 1500 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of active compound, and optionally from about 0.01 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples are dosage forms containing at least about 0.005 mg, 0.01 mg, 0.1 mg, 0.2 mg, 0.25 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1250 mg, 1300 mg, 1400 mg, 1500 mg, or 1600 mg of the active compound or salt thereof. In one embodiment, the dosage form has at least about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 200 mg, 400 mg, 500 mg, 600 mg, 1000 mg, 1200 mg, or 1600 mg of active compound or its salt. The amount of active compound in the dosage form is calculated without reference to salt. The dosage form can be administered, for example, once a day (qd), twice a day (bid), three times a day (tid), four times a day (qid), once every two days (Q2d), once every three days (Q3d), or any dosing schedule that provides treatment of the disorders described herein, as needed.

[0226] Pharmaceutical compositions can contain, for example, any molar ratio of active compound and additional active agents that achieve the desired result.

[0227] The compounds or their pharmaceutically acceptable salts disclosed or used herein can be delivered by any method known for therapeutic delivery, including but not limited to conventional methods (solutions, suspensions, emulsions, ointments, inserts, and gels), vesicles (liposomes, niosomes, discomes, and pharmacosomes), particulates (microparticles and nanoparticles), advanced materials (scleral plugs, gene delivery, siRNA, and stem cells), and controlled release systems (implants, hydrogels, dendrimers, collagen shields, polymer solutions, therapeutic contact lenses, cyclodextrin carriers, microneedles, and microemulsions).

[0228] Pharmaceutical carriers should have sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the patient being treated. Carriers may be inert or may have pharmaceutical benefits of their own. The amount of carrier used in combination with the compound is sufficient to provide a practical amount of material to be administered per unit dose of the compound. Representative carriers include solvents, diluents, pH adjusters, preservatives, antioxidants, suspending agents, wetting agents, viscosity agents, tonicity agents, stabilizers, and combinations thereof. In some embodiments, the carrier is an aqueous carrier. Examples of aqueous carriers include, but are not limited to, aqueous solutions or suspensions, such as saline, plasma, bone marrow aspirate, buffers such as Hank's Buffered Salt Solution (HBSS), HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), Ringer's buffer, ProVisc™, diluted ProVisc™, ProVisc™ diluted in PBS, Krebs buffer, Dulbecco's PBS, standard PBS, sodium hyaluronate solution (HA, 5 mg / mL in PBS), citrate buffer, simulated body fluids including simulated tears, platelet-rich plasma and tissue culture media, or aqueous solutions or suspensions containing organic solvents. Pharmaceutical formulations for ocular administration are preferably in the form of sterile aqueous solutions. Acceptable solutions include, for example, water, Ringer's solution, phosphate buffered saline (PBS), and isotonic sodium chloride solution. The formulations can also be sterile solutions, suspensions, or emulsions in non-toxic diluents or solvents such as 1,3-butanediol.

[0229] If desired, a thickening agent can be added to the pharmaceutical composition to increase the viscosity of the composition.Examples of useful thickening agents include, but are not limited to, hyaluronic acid, sodium hyaluronate, carbomer, polyacrylic acid, cellulose derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextin, polysaccharides, polyacrylamides, polyvinyl alcohol (including partially hydrolyzed polyvinyl acetate), polyvinyl acetate, derivatives thereof, and mixtures thereof.In one embodiment, the thickening agent is hyaluronic acid, and the hyaluronic acid is crosslinked.In one embodiment, the thickening agent is hyaluronic acid, and the hyaluronic acid is linear.

[0230] The administered solution, suspension, or emulsion may be buffered with an effective amount of buffer necessary to maintain a suitable pH for the selected administration. Suitable buffers are well known by those skilled in the art. Some examples of useful buffers are acetate buffer, borate buffer, carbonate buffer, citrate buffer, and phosphate buffer. The administered solution, suspension, or emulsion may also contain one or more tonicity agents to adjust the isotonic range of the formulation. Suitable tonicity agents are well known in the art. Some examples include glycerin, mannitol, sorbitol, sodium chloride, and other electrolytes.

[0231] Pharmaceutical compositions suitable for topical application to the skin can take the form of a gel, ointment, cream, lotion, paste, spray, aerosol, or oil, and may optionally contain petroleum jelly, lanolin, polyethylene glycol, alcohol, or combinations thereof.

[0232] Pharmaceutical compositions suitable for transdermal administration may be provided as separate patches adapted to remain in intimate contact with the epidermis of the recipient for extended periods of time. Pharmaceutical compositions suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)), typically taking the form of an optionally buffered aqueous solution of active compound. In one embodiment, a microneedle patch or device is provided for drug delivery across or into biological tissue, particularly the skin. The microneedle patch or device allows drug delivery across or into the skin or other tissue barrier at clinically relevant rates with minimal or no damage, pain, or irritation to the tissue.

[0233] Other forms of administration include oral, rectal, sublingual, sublabial, or buccal, and typical dosage forms for these routes include pills, tablets, capsules, liquids, suspensions, emulsions, and suppositories. Enteric-coated oral tablets can also be used to enhance the bioavailability of the compound for oral administration routes. The most effective dosage form will depend on the bioavailability / pharmacokinetics of the particular agent selected, as well as the severity of the disease in the patient. Oral dosage forms are particularly preferred due to their ease of administration and the potential for favorable patient compliance. In one embodiment, the compound is administered vaginally via suppository, cream, gel, lotion, or ointment.

[0234] In another embodiment, the compound of the present invention is administered via parenteral administration, including intravenous, subcutaneous, intramuscular, intrathecal, intradermal, or intranasal, in a dosage suitable for parenteral administration, including liquid, suspension, emulsion, or lyophilized powder.In some cases, the composition is distributed or packaged in liquid form.Alternatively, the formulation can be packaged as a solid, for example, obtained by lyophilization of a suitable liquid formulation.The solid can be reconstituted with a suitable carrier or diluent before administration.

[0235] In one embodiment, the compounds of the present invention are administered via inhalation pulmonary route. Pharmaceutical compositions suitable for pulmonary administration can be delivered by a wide range of passive respiratory and active powered single / multi-dose dry powder inhalers (DPIs). The most commonly used devices for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of suitable pulmonary delivery device depends on parameters such as the nature of the drug and its formulation, the site of action, and the pathophysiology of the lungs.

[0236] Additional non-limiting examples of inhalation drug delivery devices and methods include, for example, U.S. Pat. No. 7,383,837, entitled "Inhalation device" (SmithKline Beecham Corporation); WO 2006 / 033584, entitled "Powder inhaler" (Glaxo SmithKline Pharmaceuticals SA); WO 2005 / 044186, entitled "Inhalable pharmaceutical formulations employing desiccating agents and methods of administering the same" (Glaxo Group Ltd and SmithKline Beecham Corporation); U.S. Pat. No. 9,095,670, entitled "Inhalation device and method of dispensing medicament," and U.S. Pat. No. 8,205,611, entitled "Dry powder inhaler" (Astrazeneca Pharmaceuticals SA). AB; International Publication No. WO 2013 / 038170 entitled "Inhaler" (Astrazeneca AB and Astrazeneca UK Ltd.); U.S. Patent Application Publication No. 2014 / 0352690 entitled "Inhalation Device with Feedback System", U.S. Patent No. 8,910,625 and U.S. Patent Application Publication No. 2015 / 0165137 entitled "Inhalation Device for Use in Aerosol Therapy" (Vectura GmbH); U.S. Patent No. 6,948,No. 496, U.S. Patent Application Publication No. 2005 / 0152849, entitled "Powders comprising anti-adherent materials for use in dry powder inhalers", U.S. Patent No. 6,582,678, U.S. Patent No. 8,137,657, U.S. Patent Application Publication No. 2003 / 0202944 and U.S. Patent Application Publication No. 2010 / 0330188, entitled "Carrier particles for use in dry powder inhalers", U.S. Patent No. 6,221,338, entitled "Method of producing particles for use in dry powder inhalers", U.S. Patent No. 6,989,155, entitled "Powders", and U.S. Patent No. 6,989,155, entitled "Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation". No. 7,845,349 entitled "Inhaler", U.S. Patent Application Publication No. 2012 / 0114709 and U.S. Patent No. 8,101,160 entitled "Formulations for Use in Inhaler Devices", U.S. Patent Application Publication No. 2013 / 0287854 entitled "Compositions and Uses", U.S. Patent Application Publication No. 2014 / 0037737 entitled "Particles for Use in a Pharmaceutical Composition" and U.S. Patent No. 8,580,306, U.S. Patent Application Publication No. 2015 / 0174343 entitled "Mixing Channel for an Inhalation Device," U.S. Patent No. 7,744,855 and U.S. Patent Application Publication No. 2010 / 0285142 entitled "Method of making particles for use in a pharmaceutical composition," U.S. Patent No. 7,541,022 entitled "Pharmaceutical formulations for dry powder inhalers," U.S. Patent Application Publication No. 2009 / 0269412, and U.S. Patent Application Publication No. 2015 / 0050350 (Vectura Limited).

[0237] A pharma-ceutically acceptable excipient should have a high enough purity and low enough toxicity to make it suitable for administration to the patient being treated. The excipient may be inert or may have its own pharmaceutical benefit. The amount of excipient used in combination with the compound is sufficient to provide a practical amount of material administered per unit dose of the compound. Classes of excipients include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, fillers, flavorings, glidants, lubricants, pH adjusters, preservatives, stabilizers, surfactants, solubilizers, tableting agents, and wetting agents. Exemplary pharma-ceutically acceptable excipients include sugars, starches, cellulose, powdered tragacanth, malt, gelatin, talc, and vegetable oils. Examples of other matrix materials, fillers, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch. Examples of surface active agents include sodium lauryl sulfate and polysorbate 80. Examples of drug complexing agents or solubilizers include polyethylene glycol, caffeine, xanthene, gentisic acid, and cyclodextrin. Examples of disintegrants include sodium starch glycolate, sodium alginate, sodium carboxymethylcellulose, methylcellulose, colloidal silicon dioxide, and croscarmellose sodium. Examples of binders include methylcellulose, microcrystalline cellulose, starch, gum, and tragacanth. Examples of lubricants include magnesium stearate and calcium stearate. Examples of pH adjusters include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, and the like; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, and buffers generally including mixtures of acids and salts of the acids. Optionally, other active agents may be included in the pharmaceutical composition as long as they do not substantially interfere with the activity of the compound of the present invention.

[0238] In certain embodiments, the excipient is selected from the group consisting of phosphoglycerides; phosphatidylcholine; dipalmitoylphosphatidylcholine (DPPC); dioleylphosphatidylethanolamine (DOPE); dioleyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine; cholesterol; cholesterol esters; diacylglycerol; diacylglycerol succinate; diphosphatidylglycerol (DPPG); hexanedecanol; fatty alcohols; polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; surfactant fatty acids such as palmitic acid or oleic acid; fatty acids; fatty acid monoglycerides; fatty acid diglycerides; fatty acid amides; sorbitan trioleate (Span™ 85); glycocholate; sorbitan monolaurate (Span™ 20); polysorbate 20 (Tween™ 20); polysorbate 60 (Tween™ 60); polysorbate 65 (Tween™ 65); Polysorbate 80 (Tween 80); Polysorbate 85 (Tween 85); Polyoxyethylene monostearate; Surfactin; Poloxamer; Sorbitan fatty acid esters such as sorbitan trioleate; Lecithin; Lysolecithin; Phosphatidylserine; Phosphatidylinositol; Sphingomyelin; Phosphatidylethanolamine (cephalin); Cardiolipin; Phosphatidic acid; Cerebroside; Dicetyl phosphate; Dipalmitoyl phosphatase Phatidylglycerol;stearylamine;dodecylamine;hexadecylamine;acetyl palmitate;glycerol ricinoleate;hexadecyl stearate;isopropyl myristate;tyloxapol;poly(ethylene glycol) 5000-phosphatidylethanolamine;poly(ethylene glycol) 400-monostearate;phospholipids;synthetic and / or natural detergents with high surface active properties;deoxycholate;cyclodextrins;chaotropic salts;ion pairing agents;Glucose, fructose, galactose, ribose, lactose, sucrose, maltose, trehalose, cellobiose, mannose, xylose, arabinose, glucuronic acid, galacturonic acid, mannuronic acid, glucosamine, galactosamine and neuraminic acid;Pullulan, cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextran, glycogen, hydroxyethyl starch, carrageenan, glycon, amylose, chitosan, N,O-carboxymethyl chitosan, algin and alginic acid, starch, chitin, inulin, konjac, glucomannan, pustulan, heparin, hyaluronic acid, curdlan and xanthan, mannitol, sorbitol, xylitol, erythritol, maltitol and lactitol, pluronic polymers, polyethylene, polycarbonates (e.g., poly(1,3-dioxane-2-one) )), polyanhydrides (e.g. poly(sebacic anhydride)), polypropyl fumarate, polyamides (e.g. polycaprolactam), polyacetals, polyethers, polyesters (e.g. polylactides, polyglycolides, polylactide-co-glycolides, polycaprolactones, polyhydroxy acids (e.g. poly(β-hydroxyalkanoates)), poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polyureas, polystyrenes and polyamines, polylysine, polylysine-PEG copolymers and poly(ethyleneimine), poly(ethyleneimine)-PEG copolymers, glycerol monocaprylocaprate, propylene glycol, vitamin E selected from TPGS (also known as d-α-tocopheryl polyethylene glycol 1000 succinate), gelatin, titanium dioxide, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO / PPO), polyethylene glycol (PEG), sodium carboxymethylcellulose (NaCMC), or hydroxypropyl methylcellulose acetate succinate (HPMCAS);

[0239] In some embodiments, the compounds of the present invention may be provided as lyophilized powder formulations. Lyophilized powder formulations may be prepared, for example, by low temperature dehydration methods that remove residual solvents by sublimation rather than boiling. Lyophilization is the preferred method for formulating sensitive solid materials, as it typically maintains the integrity of the product due to the low temperatures used in processing. In addition, the lyophilized solids are more quickly and easily reconstituted due to the presence of microscopic pores formed by this method. The high vacuum used during lyophilization ensures thorough removal of any undesirable volatile components, such as methanol, ethanol, or other volatile organic substances. In one embodiment, the lyophilized powder formulations of the compounds and products described herein contain less than about 5%, about 4%, about 3%, about 2%, about 1%, about 0.5%, or about 0.01% methanol by weight. Methods for lyophilization of solids used in pharmaceutical applications, especially sensitive materials, are known in the art. Lyophilization can be performed using any commercially available equipment, such as shelf / cabinet, contact, radiant, or microwave-assisted freeze dryers.

[0240] A typical freeze-drying procedure consists of four steps. In the first step (pre-processing), the compound is dissolved in a suitable solvent, and additional excipients are optionally added, if necessary, to improve stability, preserve appearance, or improve downstream processing. Furthermore, the solution of the active compound can be concentrated as appropriate to aid in the freezing and downstream sublimation process. Furthermore, the components can be initially flash frozen individually to ensure that a free-flowing solid is formed upon completion of freeze-drying.

[0241] In the second step (freezing), a solution of the active compound is frozen in a container below the triple point of the solution to ensure that sublimation occurs rather than melting. Optionally, the material can be subjected to cycles of temperature up and down in a process called annealing. If the compound to be freeze-dried is an amorphous solid, the compound may not have a triple point, but instead a critical point. Amorphous solids must be kept below their critical point throughout the freeze-drying process to prevent the solid from remelting or collapsing during the subsequent drying step. For sensitive materials, the freezing step is often performed quickly by lowering the material temperature to about -50°C to -80°C. This prevents the formation of large solvent crystals that can reduce the structural integrity of the freeze-dried material and lead to poor structure.

[0242] In the third step (primary drying), the pressure in the vessel is reduced (typically to the range of a few millibars) and minimal heat is applied to the material to sublime the solvent. The pressure is typically controlled by application of a partial vacuum. A small amount of heat can be applied to promote sublimation of the solvent molecules. Due to the low air density in the vessel, this heat is typically applied via conduction or radiation.

[0243] In the fourth step (secondary drying), the temperature is increased to a higher temperature than in the primary drying stage in order to remove any remaining anti-freezing solvent molecules. The increased temperature is necessary to break down any physicochemical interactions that may have formed between the solvent molecules and the frozen material. Additionally, the pressure is typically reduced compared to the primary drying step in order to facilitate desorption.

[0244] Upon completion of the freeze-drying process, the vacuum is typically released with an inert gas, such as nitrogen, and the container is sealed. A typical container includes a sealed ampoule, which includes a sealed glass that is broken open at the time of desired use. The active material can then be reconstituted at the time of use with a suitable carrier, such as those described herein, such as sterile water or glycerin.

[0245] In one aspect, the compound of Formula I-XXVII is administered as an implant formulation, which in one embodiment provides controlled release. The implant may be of any desired shape, and in one embodiment, the implant is a rod, cylinder, or pellet. In one embodiment, the invention includes a sustained release amorphous solid glass formulation comprising a prodrug of Formula I-XXVII. In one embodiment, a composition comprising a prodrug of Formula I-XXVII is machined, molded, emulsion processed, electrospun, electrosprayed, blow molded, or extruded to form a fiber, fiber mesh, woven fabric, nonwoven fabric, pellet, cylinder, microsphere, nanosphere, or any other type of shaped article from which the compound is released in a vitreous state, thereby allowing for controlled release, for example, at body temperature (approximately 37° C.). In one embodiment, the vitreous nature of the state enhances the controlled release of cromakalim, or in one embodiment, levcromakalim. In one embodiment, the article having a vitreous state does not include controlled release excipients, excipients that enhance mechanical integrity, and / or binding excipients.

[0246] The term "glassy state" as used herein refers to an amorphous solid comprising more than 70% (wt / wt), 80% (wt / wt), 90% (wt / wt), 95% (wt / wt), 98% (wt / wt), or 99% (wt / wt) of one or more compounds of Formula I-Formula XXVII and exhibiting a glass transition temperature in the range of 38°C to 150°C. In the glassy state, the level of crystallinity is low, ranging from 0% to 15%, e.g., 0% to 1%, 0% to 3%, 0% to 5%, 0% to 7%, 0% to 9%, 0% to 10%, or 0% to 13%, as measured by DSC or XRD. Glass formulations of the present disclosure may be formed using heat or solvent treatment of one or more compounds of Formula I-Formula XXVII.

[0247] In some embodiments, the sustained release amorphous solid glass formulation releases the prodrug of Formula I-Formula XXVII through surface erosion following injection, e.g., ocular injection, at a temperature in the range of approximately 37° C., e.g., 35° C. to 38° C. In some embodiments, surface erosion releases less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, or less than about 5% of the compound of Formula I-Formula XXVII as a percentage of the total compound of Formula I-Formula XXVII, followed by release of cromakalim, or in some embodiments, levcromakalim.

[0248] In some embodiments, the compounds of formula I-XXVII are machined, molded, emulsion processed, electrospun, electrosprayed, blow molded, or extruded to form fibers, fiber meshes, woven fabrics, nonwoven fabrics, pellets, cylinders, microspheres, nanospheres, thus forming a glassy solid. The glassy solid is then heated above its glass transition temperature Tg and heat treated. In alternative embodiments, microparticles or nanoparticles, or other shaped articles such as rods, cones, or cylinders, are made by melting the compounds of formula I-XXVII to form glassy pellets of other shapes, crushing the glassy articles into coarse or irregularly shaped particles, filtering the particles through a sieve, heating the particles above Tg, and rolling them into smooth articles, such as microparticles, nanoparticles, or spheres.

[0249] ocular delivery When used in ocular therapy, the compounds disclosed herein or used as described herein are typically administered, for example, as a solution, suspension, or other formulation, intraocularly, intravitreally, intrastromal, intracameral, sub-Tenon, subretinal, retrobulbar, periocular, suprachoroidal, subchoroidal, choroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, pericorneally, within the lacrimal punctal and / or intracanalicular system, or through a mucus, mucin, or mucosal barrier, in an immediate or controlled release manner, or via an ocular device, injection, or topical formulation, e.g., a solution, suspension, or emulsion provided as drops.

[0250] Suitable non-aqueous pharma- ceutically acceptable carriers include, but are not limited to, oleoyl polyethylene glycol glyceride, linoleoyl polyethylene glycol glyceride, lauroyl polyethylene glycol glyceride, liquid paraffin (Paraffinum liquidum, mineral oil), light liquid paraffin (low viscosity paraffin, Paraffinum perliquidum, light mineral oil), soft paraffin (petrolatum), hard paraffin, vegetable fatty oils such as castor oil, arachis oil, or sesame oil, medium chain triglycerides (MCT, triglycerides with saturated fatty acids, preferably octanoic and decanoic acids), synthetic fatty oils such as isopropyl myristate, caprylocaproyl macrogol-8 glyceride, caprylocaproyl polyoxyl-8 glyceride, wool alcohols such as cetylstearyl alcohol, wool fat, glycerol, propylene glycol, propylene glycol diesters of caprylic / capric acid, polyethylene glycol (PEG), semifluorinated alkanes (e.g. as described in WO 2011 / 113855), or mixtures thereof. Preferably, the non-aqueous pharma- ceutically acceptable vehicle used in the solution is hydrophobic.

[0251] Pharmaceutically acceptable excipients used in topical ophthalmic pharmaceutical compositions according to the present invention include, but are not limited to, stabilizers, surfactants, polymer-based carriers such as gelling agents, organic co-solvents, pH active ingredients, osmotically active ingredients, and preservatives.

[0252] Surfactants for use in the topical ophthalmic pharmaceutical compositions according to the present invention include, but are not limited to, lipids such as phospholipids, phosphatidylcholines, lecithins, cardiolipins, fatty acids, phosphatidylethanolamines, phosphatides, tyloxapol, polyethylene glycols and derivatives such as PEG 400, PEG 1500, PEG 2000, poloxamer 407, poloxamer 188, polysorbate 80, polysorbate 20, sorbitan laurate, sorbitan stearate, sorbitan palmitate, or mixtures thereof, preferably polysorbate 80. Suitable polymer-based carriers such as gelling agents for use in the topical ophthalmic pharmaceutical compositions according to the present invention include, but are not limited to, cellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), methylcellulose (MC), hydroxyethylcellulose (HEC), amylase and derivatives, amylopectin and derivatives, dextran and derivatives, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and acrylic polymers such as HEMA, polyacrylic acid or polymethacrylic acid derivatives such as carbopol, and derivatives of the above, or mixtures thereof.

[0253] Suitable pH active ingredients, such as buffers or pH adjusters, for use in pharmaceutical compositions according to the invention include, but are not limited to, acetate buffers, borate buffers, carbonate buffers, citrate buffers, and phosphate buffers, including disodium phosphate, monosodium phosphate, boric acid, sodium borate, sodium citrate, hydrochloric acid, sodium hydroxide. The pH active ingredients are selected based on the target pH for the composition, which is generally in the range of pH 4 to 9. In one embodiment, the formulation comprising a compound of Formula I-III or a pharma- ceutically acceptable salt thereof has a pH of approximately between 5 and 8, between 5.5 and 7.4, between 6 and 7.5, or between 6.5 and 7. In one embodiment, the formulation comprises a citrate buffer at a pH of approximately 6.5 to 7. In another embodiment, the formulation comprises a phosphate buffer at a pH of approximately 6.5 to 7. Suitable osmotically active ingredients for use in pharmaceutical compositions according to the invention include, but are not limited to, sodium chloride, mannitol, and glycerol.

[0254] Organic co-solvents for use in the pharmaceutical compositions according to the present invention include, but are not limited to, ethylene glycol, propylene glycol, N-methylpyrrolidone, 2-pyrrolidone, 3-pyrrolidinol, 1,4-butanediol, dimethyl glycol monomethyl ether, diethylene glycol monomethyl ether, solketal, glycerol, polyethylene glycol, polypropylene glycol.

[0255] Preservatives used in pharmaceutical compositions according to the present invention include, but are not limited to, benzalkonium chloride, alkyldimethylbenzylammonium chloride, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzethonium chloride, thiomersal, chlorobutanol, benzyl alcohol, phenoxyethanol, phenylethyl alcohol, sorbic acid, methyl and propylparaben, chlorhexidine digluconate, EDTA, or mixtures thereof.

[0256] In certain embodiments, the ophthalmic solution contains approximately 0.1% to 5.0% of a compound of Formula I to Formula XXVII or a pharma- ceutically acceptable salt thereof, measured in mg / mL. In certain embodiments, the ophthalmic solution contains approximately 5% to 30% of a compound of Formula I to Formula XXVII, measured in mg / mL. In one embodiment, the solution contains approximately 0.2% to 4.5%, 0.3% to 3.0%, 0.4% to 2.0%, or 0.5% to 1.5% of a compound of Formula I to Formula XXVII, measured in mg / mL. In one embodiment, the solution contains at least 10%, at least 8%, at least 5%, at least 4%, at least 3%, at least 2%, at least 1%, at least 0.9%, at least 0.7%, at least 0.5%, at least 0.3%, or at least 0.1% of a compound of Formula I to Formula XXVII. In another embodiment, the solution contains at least 30%, at least 25%, at least 20%, or at least 15% of a compound of Formula I-XXVII. In one embodiment, the solution contains approximately 0.2%, 0.4%, or 0.8% of a compound of Formula I-XXVII or a salt thereof. In one embodiment, the solution contains approximately 0.5%, 1%, or 2% of a compound of Formula I-XXVII or a salt thereof.

[0257] In another embodiment, the solution has a concentration of a compound of Formula I-XXVII or a pharma- ceutically acceptable salt thereof in the range of about 2.5 mM to 500 mM. In one embodiment, the concentration is no more than about 550 mM, 500 mM, 450 mM, 400 mM, 350 mM, 300 mM, 250 mM, 200 mM, 150 mM, 100 mM, 50 mM, 45 mM, 40 mM, 35 mM, 30 mM, 25 mM, 20 mM, 15 mM, 10 mM, 8 mM, 6 mM, 5 mM, 4 mM, 3 mM, 2.5 mM, 2.0 mM, 1.5 mM, or 1.0 mM.

[0258] In one embodiment, the concentration of the compound of Formula I to Formula XXVII or a pharma- ceutically acceptable salt thereof is in the range of about 0.2% to 2% (corresponding to a 5 mM to 52 mM solution). In one embodiment, the concentration is at least 0.2% (corresponding to 5 M), at least 0.4% (corresponding to 10 mM), at least 0.5% (corresponding to 12.5 mM), at least 0.8% (corresponding to 20 mM), at least 1% (corresponding to approximately 25 mM), or at least 2% (corresponding to approximately 50 mM).

[0259] The compounds of Formula I-Formula XXVII or pharma- ceutically acceptable salts thereof may also be used in ocular therapy using alternative routes, i.e., intravitreal, intrastromal, intracameral, subtenon, subretinal, retrobulbar, periocular, suprachoroidal, subchoroidal, choroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, posterior juxtascleral, pericornal, or lacrimal injections, or through mucus, mucin, or mucosal barriers, in an immediate or controlled release manner, or via an ocular device, or injection.

[0260] In one embodiment, the compound of formula I to formula XXVII is administered via suprachoroidal injection.Suprachoroidal delivery is described in US Patent No. 9,636,332, US Patent No. 9,539,139, US Patent No. 10,188,550, US Patent No. 9,956,114, US Patent No. 8,197,435, US Patent No. 7,918,814, and International Publication No. WO 2012 / 051575, WO 2015 / 095772, WO 2018 / 031913, WO 2017 / 192565, WO 2017 / 190142, WO 2017 / 120601, and WO 2017 / 120600.

[0261] A device for minimally invasive delivery of drugs to the suprachoroidal space may include a needle that directly injects drugs or drug-containing materials into the suprachoroidal space. The device may also include an element that advances the needle through the conjunctiva and scleral tissue into the suprachoroidal space or immediately adjacent to the suprachoroidal space without puncturing or trauma to the inner choroidal layer. The location of the tip of the delivery device may be confirmed by non-invasive imaging such as ultrasound or optical coherence tomography, external depth markers or stops on the tissue contacting portion of the device, depth or position sensors built into the device, or a combination of such sensors. For example, the delivery device may include a sensor at the tip, such as a light guide or ultrasound sensor, that measures choroidal depth and position, or a pressure transducer that measures the change in local fluid pressure due to entry into the suprachoroidal space. In one embodiment, the suprachoroidal injection is performed using a 26 gauge, 27 gauge, 28 gauge, 29 gauge, or 30 gauge thin-walled or regular-walled needle. In alternative embodiments, suprachoroidal injections are performed using a 31 gauge, 32 gauge, or 33 gauge thin-walled or regular-walled needle.

[0262] Many methods and devices for ocular drug delivery are known in the art, non-limiting examples of which are described in the following patents and patent applications, which are incorporated herein by reference in their entirety: Examples include U.S. Patent No. 8,192,408 (Psivida U.S., Inc.), entitled "Ocular trocar assembly"; U.S. Patent No. 7,585,517 (Macusight, Inc.), entitled "Transcleral delivery"; U.S. Patent Nos. 5,710,182 and 5,795,913 (Santen OY), entitled "Ophthalmic composition"; U.S. Patent No. 8,663,639, entitled "Formulations for treating ocular diseases and conditions," U.S. Patent No. 8,486,960, entitled "Formulations and methods for vascular permeability-related diseases or conditions," and U.S. Patent No. 8,510,913, entitled "Liquid formulations for treatment of diseases or conditions." No. 8,367,097 and U.S. Patent No. 8,927,005, entitled "Delivery substance and drug delivery system using the same" (Santen Pharmaceutical Co., Ltd.); WO 2011 / 050365, entitled "Conformable Therapeutic Shield For Vision and Pain," and WO 2009 / 145842, entitled "Therapeutic Device for Pain Management and Vision" (Forsight Labs,LLC; U.S. Patent No. 9,066,779 and U.S. Patent No. 8,623,395, entitled "Implantable therapeutic device," International Publication No. WO 2014 / 160884, entitled "Ophthalmic Implant for Delivering Therapeutic Substances," U.S. Patent No. 8,399,006, U.S. Patent No. 8,277,830, U.S. Patent No. 8,795,712, U.S. Patent No. 8,808,727, U.S. Patent No. 8,298,578, and International Publication No. WO 2010 / 088548, entitled "Systems for Sustained Intraocular Delivery of Low Solubility Compounds from a Port Delivery System Implant," Nos. 8,905,963 and 9,033,911, both entitled "Injector apparatus and method for drug delivery," WO 2015 / 057554, "Formulations and Methods for Increasing or Reducing Mucus," U.S. Pat. Nos. 8,715,712 and 8,939,948, both entitled "Ocular insert apparatus and methods," WO 2013 / 116061, "Insertion and Removal Methods and Apparatus for Therapeutic Devices," and "Ophthalmic System for Sustained Release of Drugs to the Eye," all of which are incorporated herein by reference. Sustained Release of Drug to theNo. WO 2014 / 066775 entitled "Implantable Therapeutic Device", WO 2015 / 085234 and WO 2012 / 019176 entitled "Methods and Apparatus to Determine Porous Structures for Drug Delivery", WO 2012 / 065006 entitled "Methods and Apparatus to Determine Porous Structures for Drug Delivery", WO 2010 / 141729 entitled "Anterior Segment Drug Delivery", WO 2011 / 050327 entitled "Corneal Denervation for Treatment of Ocular Pain", and WO 2012 / 050327 entitled "Small Molecule Delivery with Implantable Therapeutic Device". No. 2013 / 022801 entitled "Subconjunctival Implant for Posterior Segment Drug Delivery", No. 2012 / 019047 entitled "Therapeutic Agent Formulations for Implanted Devices", No. 2012 / 068549 entitled "Therapeutic Agent Formulations for Implanted Devices", No. 2012 / 019139 entitled "Combined Delivery Methods and Apparatus", No. 2013 / 040426 entitled "Ocular Insert Apparatus and Methods", No. 2012 / 019136 entitled "Injector Apparatus and Method for Drug Delivery", No. 2012 / 019136 entitled "Fluid Exchange Apparatus and Methodand WO 2013 / 040247 (ForSight Vision4, Inc.) entitled "Methods for Promoting Mucus-Penetrating Cells in the Presence of Mucus in the Presence of Vascular Cells." Kala Pharmaceuticals describes the use of mucus-penetrating polymers in U.S. Pat. Nos. 9,056,057, 9,393,213, 9,532,955, 9,737,419, 9,827,191, and 10,058,511.

[0263] Additional non-limiting examples of methods of delivering active compounds are described in WO 2015 / 085251 (Envisia Therapeutics, Inc.), entitled "Intracameral Implant for Treatment of an Ocular Condition"; WO 2011 / 008737 (Engineered Aerosol Particles, and Associated Methods), entitled "Engineered Aerosol Particles, and Associated Methods," WO 2013 / 082111 (Geometrically Engineered Particles and Methods for Modulating Macrophage or Immune Responses), and WO 2014 / 082112 (Degradable compounds and methods of use thereof, particularly with particle replication in non-wetting molds). WO 2009 / 132265 entitled "Interventional drug delivery systems and associated methods," WO 2010 / 099321 entitled "Interventional drug delivery systems and associated methods," WO 2008 / 100304 entitled "Polymer particle composite having high fidelity order, size, and shape particles," WO 2007 / 024323 entitled "Nanoparticle fabrication methods, systems, and materials" (Liquidia Technologies, Inc.and the University of North Carolina at Chapel Hill; WO 2010 / 009087 (Liquidia Technologies, Inc. and Eyegate Pharmaceuticals, Inc.) entitled "Iontophoretic Delivery of a Controlled-Release Formulation in the Eye" and WO 2009 / 132206 entitled "Compositions and Methods for Intracellular Delivery and Release of Cargo", WO 2007 / 133808 entitled "Nano-particles for cosmetic applications", WO 2007 / 056561 entitled "Medical device, materials, and methods" and WO 2007 / 056561 entitled "Method for producing patterned materials" These techniques are presented in WO 2010 / 065748 entitled "Nanostructured surfaces for biomedical / biomaterial applications and processes thereof" (Liquidia Technologies, Inc.) and WO 2007 / 081876 entitled "Nanostructured surfaces for biomedical / biomaterial applications and processes thereof" (Liquidia Technologies, Inc.).

[0264] Local or transdermal delivery Administration of the compounds of formula I-XXVII or pharma-ceutically acceptable salts can also include topical or transdermal administration. Pharmaceutical compositions suitable for topical application to the skin can take the form of gels, ointments, creams, lotions, pastes, sprays, aerosols, or oils, and can optionally contain petroleum jelly, lanolin, polyethylene glycol, alcohol, or combinations thereof.

[0265] Pharmaceutical compositions suitable for transdermal administration may be provided as separate patches adapted to remain in intimate contact with the epidermis of the recipient for extended periods of time. Pharmaceutical compositions suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)), typically taking the form of an optionally buffered aqueous solution of active compound. In one embodiment, a microneedle patch or device is provided for drug delivery across or into biological tissue, particularly the skin. The microneedle patch or device allows drug delivery across or into the skin or other tissue barrier at clinically relevant rates with minimal or no damage, pain, or irritation to the tissue.

[0266] Advantageously, the composition may contain, but is not limited to, conditioning agents, skin protectants, other antioxidants, UV absorbers, sunscreen actives, cleansing agents, viscosity modifiers, film formers, emollients, surfactants, solubilizers, preservatives, fragrances, chelating agents, foaming or defoaming agents, opacifiers, stabilizers, pH adjusters, absorbents, anti-caking agents, slip improvers, various solvents, solubilizers, denaturants, abrasives, weighting agents, emulsion stabilizers, suspending agents, colorants, binders, conditioning agents-emollients, surfactant emulsifiers, biological materials, anti-acne actives, anti-wrinkle and anti-skin atrophy actives, skin barrier repair aids, cosmetic soothing ... A wide variety of skin care actives and inactive ingredients may be combined with the compounds according to the present invention, including topical anesthetics, artificial tanning agents and accelerators, skin lightening actives, antimicrobial and antifungal actives, sebum stimulators, sebum inhibitors, moisturizers, and / or combinations thereof.

[0267] In general, conditioning agents can be used to improve the appearance and / or feel of the skin through moisturizing, hydrating, plasticizing, lubricating, and occlusive, or combinations thereof, during and after topical application. Non-limiting examples of conditioning ingredients include, but are not limited to, mineral oil, petrolatum, C7-C40 Branched chain hydrocarbons, C1-C 30 Carboxylic Acid C1-C 30 Alcohol esters, C2-C 30 Dicarboxylic acids C1-C 30 Alcohol esters, C1-C 30 Monoglycerides of carboxylic acids, C1-C 30 Diglycerides of carboxylic acids, C1-C 30 Triglycerides of carboxylic acids, C1-C 30 Ethylene glycol monoesters of carboxylic acids, C1-C 30 Ethylene glycol diesters of carboxylic acids, C1-C 30 Propylene glycol monoesters of carboxylic acids, C1-C 30 Propylene glycol diesters of carboxylic acids, C1-C sugars 30 Carboxylic acid monoesters and polyesters, polydialkylsiloxanes, polydiarylsiloxanes, polyalkarylsiloxanes, cyclomethicones with 3 to 9 silicon atoms, vegetable oils, hydrogenated vegetable oils, polypropylene glycols C4 to C 20 Alkyl ether, diC8~C 30 Non-limiting examples of linear and branched chain hydrocarbons having from about 7 to about 40 carbon atoms include, but are not limited to, dodecane, isododecane, squalane, cholesterol, hydrogenated polyisobutylene, docosane, hexadecane, isohexadecane, C7-C8 alkyl ethers, and mixtures thereof. 40 Isoparaffin, C1-C 30 Monoglycerides of carboxylic acids, C1-C 30 Diglycerides of carboxylic acids, C1-C 30 Triglycerides of carboxylic acids, C1-C 30 Ethylene glycol monoesters of carboxylic acids, C1-C 30 Ethylene glycol diesters of carboxylic acids, C1-C 30 Propylene glycol monoesters of carboxylic acids, and C1-C 30Included are propylene glycol diesters of carboxylic acids, including linear, branched, and aryl carboxylic acids, as well as the propoxylated and ethoxylated derivatives of these materials.

[0268] Non-limiting examples of sunscreens useful in the composition include 4-N,N-(2-ethylhexyl)methylaminobenzoic acid esters of 2,4-dihydroxybenzophenone, 4-N,N-(2-ethylhexyl)methylaminobenzoic acid esters with 4-hydroxydibenzoylmethane, 4-N,N-(2-ethylhexyl)-methylaminobenzoic acid esters of 2-hydroxy-4-(2-hydroxyethoxy)benzophenone, 4-N,N-(2-ethylhexyl)-methylaminobenzoic acid esters of 4-(2-hydroxyethoxy)dibenzoylmethane, acid esters, 2-ethylhexyl p-methoxycinnamate, 2-ethylhexyl N,N-dimethyl-p-aminobenzoate, p-aminobenzoic acid, 2-phenylbenzimidazole-5-sulfonic acid, octocrylene, oxybenzone, homomenthyl salicylate, octyl salicylate, 4,4'-methoxy-t-butyldibenzoylmethane, 4-isopropyldibenzoylmethane, 3-benzylidene camphor, 3-(4-methylbenzylidene) camphor, titanium dioxide, zinc oxide, silica, iron oxide, and mixtures thereof. Other useful sunscreens include aminobenzoic acid (PABA), benzylidene camphor, butyl methoxydibenzoylmethane, diethanolamine p-methoxycinnamate, 5 dioxybenzone, ethyl dihydroxypropyl (PABA), glyceryl aminobenzoate, homomenthyl salicylate, isopropyl dibenzoylmethane, lawsone and dihydroxyacetone, menthyl anthranilate, methyl anthranilate, methyl benzylidene camphor, octocrylene, octyl dimethyl (PABA), octyl methoxycinnamate, oxybenzone, 2-phenylbenzimidazole-5-sulfonic acid, red petrolatum, sulisobenzone, titanium dioxide, triethanolamine salicylate, zinc oxide, and mixtures thereof.

[0269] The exact amount of sunscreen that can be used will vary depending on the sunscreen chosen and the sun protection factor (SPF) desired to be achieved.

[0270] If desired, thickeners can be added to topical formulations to increase the viscosity of the composition.Examples of useful thickeners include, but are not limited to, water-soluble polyacrylic resins and hydrophobically modified polyacrylic resins such as Carbopol and Pemulen, starches such as corn starch, potato starch and tapioca, gums such as guar gum and gum arabic, and cellulose ethers such as hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose.

[0271] A wide variety of emulsifiers are also useful, including, but not limited to, sorbitan esters, glyceryl esters, polyglyceryl esters, methyl glucose esters, sucrose esters, ethoxylated fatty alcohols, hydrogenated castor oil ethoxylates, sorbitan ester ethoxylates, polymeric emulsifiers, silicone emulsifiers, glyceryl monoesters, preferably C 16 ~C 22 Glyceryl monoesters of saturated, unsaturated, and branched chain fatty acids, such as glyceryl oleate, glyceryl monostearate, glyceryl monopalmitate, glyceryl monobehenate, and mixtures thereof; 16 ~C 22 Polyglyceryl esters of saturated, unsaturated and branched fatty acids, such as polyglyceryl-4 isostearate, polyglyceryl-3 oleate, diglycerol monooleate, tetraglycerol monooleate and mixtures thereof, methyl glucose esters, preferably C 16 ~C 22 Methyl glucose esters of saturated, unsaturated and branched fatty acids, such as methyl glucose dioleate, methyl glucose sesquiisostearate and mixtures thereof, sucrose fatty acid esters, preferably C 12 ~C 22Sucrose esters of saturated, unsaturated, and branched fatty acids, such as sucrose stearate, sucrose laurate, sucrose distearate (e.g., CRODESTA® F10), and mixtures thereof; 12 ~C 22 Ethoxylated fatty 5 alcohols such as oleth-2, oleth-3, steareth-2, and mixtures thereof, hydrogenated castor oil ethoxylates such as PEG-7 hydrogenated castor oil, sorbitan ester ethoxylates such as PEG-40 sorbitan peroleate, polysorbate-80, and mixtures thereof, polymeric emulsifiers such as ethoxylated dodecyl glycol copolymers, and silicone emulsifiers such as lauryl methicone copolyol, cetyl dimethicone, dimethicone copolyol, and mixtures thereof.

[0272] systemic delivery In another embodiment, the compound of formula I-formula XXVII or its pharma-ceutically acceptable salt is administered via any systemic route that achieves the desired effect in an effective amount. Examples are enteral or parenteral administration, including oral, buccal, sublingual, intravenous, subcutaneous, intramuscular, intrathecal, or intranasal delivery, including solutions, suspensions, emulsions, or lyophilized powders. In some cases, the composition is dispensed or packaged in liquid form. Alternatively, the formulation can be packaged as a solid, for example obtained by lyophilization of a suitable liquid formulation. The solid can be reconstituted with a suitable carrier or diluent before administration. In one embodiment, the compound is administered vaginally via a suppository, cream, gel, lotion, or ointment.

[0273] Other modes of administration include oral, rectal, sublingual, sublabial, or buccal, and typical dosage forms for these routes include pills, tablets, capsules, solutions, suspensions, emulsions, and suppositories.

[0274] In one embodiment, the compounds of formula I to formula XXVII, or their pharma- ceutically acceptable salts, are administered via the pulmonary route of inhalation.Dosage forms for pulmonary drug delivery include propellants, non-aqueous inhalers, dry powder inhalers, and jet or ultrasonic nebulizers.

[0275] Oral Delivery In one aspect, the compounds of Formula I-XXVII or their pharma- ceutically acceptable salts are administered orally. The compounds can be formulated using any desired technique, including formulating the prodrug as a solvent-free chemical (e.g., powder, amorphous, non-crystalline form, or oil) or mixing the prodrug with a pharma- ceutically acceptable excipient. The resulting pharma- ceutically acceptable composition for oral delivery comprises an effective amount of the prodrug or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients.

[0276] Typical dosage forms for oral administration include pills, tablets, capsules, gel capsules, liquids, suspensions, or emulsions. Dosage forms may also feature compartmentalization. For example, when the dosage form is a pill, tablet, or capsule, it may have layers of different materials with different excipients or excipients at different concentrations. For example, enteric-coated oral tablets may be used to enhance the bioavailability of the compound for oral administration routes. The enteric coating will be a layer of excipients that allows the tablet to withstand gastric acid. The most effective dosage form will depend on the bioavailability / pharmacokinetics of the particular agent selected, as well as the severity of the disease in the patient. Oral dosage forms are particularly preferred due to their ease of administration and the potential for favorable patient compliance.

[0277] In certain embodiments, the oral dosage form comprises one or more additional active agents described herein. In certain embodiments, the second active agent is administered separately from the compound of the invention.

[0278] In another embodiment, one dosage form can be converted into another dosage form to advantageously improve properties. For example, a suitable liquid formulation can be lyophilized to produce a solid pharma- ceutically acceptable composition. A solid can be reconstituted with a suitable carrier or diluent prior to administration.

[0279] Oral pharmaceutical compositions may contain any amount of active compound that achieves the desired result, e.g., from 0.1% to 99% by weight of the compound, usually at least about 5% by weight of the compound. Some embodiments contain at least about 10%, 15%, 20%, 25% to about 50% by weight, or about 5% to about 75% by weight of the compound.

[0280] Oral dosage forms can be administered, for example, as needed, once daily (qd), twice daily (bid), three times daily (tid), four times daily (qid), once every two days (Q2d), once every three days (Q3d), or any dosing schedule that results in treatment of the disorders described herein.

[0281] IV. Methods for Treating Systemic Diseases and Disorders Cardiovascular Diseases and Disorders Potassium channel activity is a major regulator of vascular myocyte membrane potential, and potassium channel activity is often altered during cardiovascular disease, including hypertension, atherosclerosis, myocardial ischemia, and chronic heart failure. Impaired vasoconstriction and arterial dilation capacity are likely the result of defective and / or dysfunctional potassium channel function in blood vessels. Potassium channel openers, which activate (i.e., open) potassium channels, act as vasodilators that dilate or relax blood vessels, preventing arterial walls and veins from narrowing.

[0282] In one embodiment, a compound of Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof is administered to treat hypertension in a host in need of treatment. In one embodiment, a compound of Formula I-Formula XXVII is administered to treat hypertension in a host in need of treatment. In one embodiment, the hypertension is systemic hypertension and / or treatment-resistant hypertension. In one embodiment, the hypertension is stage 1 hypertension, stage 2 hypertension, stage 3 hypertension, or stage 4 hypertension. In one embodiment, the hypertension is acute. In one embodiment, the hypertension is chronic. In one embodiment, the hypertension is primary or essential. In one embodiment, the hypertension is secondary. In one embodiment, the hypertension is pulmonary arterial hypertension. In one embodiment, the hypertension is persistent pulmonary hypertension of the newborn.

[0283] Studies have shown that potassium channel openers act directly on the myocardium to prevent myocardial dysfunction under ischemic and heart failure conditions (Grover GJ, Garlid KD. ATP-sensitive potassium channels: a review of their cardioprotective pharmacology. J Mol Cell Cardiol 2000; 32: 677-95). Thus, in one embodiment, a compound of Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof is administered to treat acute and / or chronic heart failure in a host in need of treatment. In one embodiment, a compound of Formula I-Formula XXVII is administered to treat heart failure in a host in need of treatment. In one embodiment, the heart failure is stage 1, stage 2, stage 3, or stage 4. In one embodiment, the heart failure is congestive heart failure. In one embodiment, the heart failure is low output heart failure. In one embodiment, the heart failure is left ventricular failure after acute myocardial infarction (AMI) or heart attack. In one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof, or a compound selected from Formula I-Formula XXVII is provided in an amount effective to reduce capillary wedge pressure. In one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof, or a compound selected from Formula I-Formula XXVII is provided in an amount effective to treat or prevent arrhythmias and / or ventricular fibrillation associated with AMI in a host in need of such treatment or prevention. In one embodiment, the host has undergone an ablation procedure.

[0284] In one embodiment, a compound of Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof or a composition thereof is administered to treat acute, transient, and / or chronic myocardial ischemia in a host in need of treatment. In one embodiment, a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt thereof or a composition thereof is administered to treat myocardial ischemia in a host in need of treatment. In one embodiment, the myocardial ischemia is acute. In one embodiment, the myocardial ischemia is chronic.

[0285] Evidence has been shown that potassium channel openers exhibit cardioprotective properties. For example, potassium channel openers such as nicorandil, aprikalim, and pinacidil have shown cardioprotective effects in several experimental models of surgical ischemia and cardiopulmonary bypass. It has also been shown that the use of potassium channel openers prior to storage results in the preservation of cardiac function after prolonged cold storage (Kevelaitis E, et al. Circulation, 1999: 100: 345). Thus, in one embodiment, a compound of Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof is administered as a cardioprotectant in a host in need thereof. In one embodiment, a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt thereof or a composition thereof is administered as a cardioprotectant in a host in need thereof. In one embodiment, a compound of Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof, or a compound selected from Formula I-Formula XXVII is used as a cardioprotectant in a host experiencing a heart attack. In one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof, or a compound selected from Formula I-Formula XXVII is used as a cardioprotectant in a host undergoing cardiac surgery. In one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof, or a compound selected from Formula I-Formula XXVII is provided in an amount effective for preserving the heart prior to organ donation.

[0286] Potassium channel openers such as nicorandil have been found to be useful in treating stable and unstable angina with minimal side effects (Simpson D, Wellington K. Drugs 2004, 641941). In one study, nicorandil reduced transient myocardial ischemia, non-sustained ventricular arrhythmias, and supraventricular arrhythmias compared to placebo when added to active antianginal therapy for unstable angina (Patel, DJ, et al. Eur Heart J. 1999, 20, 51). Thus, in one embodiment, a compound of Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof is administered to treat angina in a host in need of treatment. In one embodiment, a compound of Formula I-Formula XXVII is administered to treat angina in a host in need of treatment. In one embodiment, the angina is stable angina. In one embodiment, the angina is unstable angina. In one embodiment, the angina is variant angina and / or paroxysmal angina, hi one embodiment, the angina is microvascular angina.

[0287] Vascular endothelium is a thin layer of cells that lines blood vessels, and disorders that impair the function of the endothelium are called endothelial dysfunction. This is often a precursor to cardiovascular disease, AMI, volatile hypertension and hypoperfusion, nocturnal hypotension, migraine headaches, Raynaud's disease, and atherosclerosis. Thus, in one embodiment, a compound of Compound 1 to Compound 21 or a pharma- ceutically acceptable salt thereof is administered to treat endothelial dysfunction in a host in need of treatment. In one embodiment, a compound of Formula I to Formula XXVII or a pharma- ceutically acceptable salt thereof or a composition thereof is administered to treat endothelial dysfunction in a host in need of treatment.

[0288] Microvascular dysfunction (or coronary microvascular disease) is a type of non-obstructive coronary artery disease that causes the small blood vessels that supply the heart muscle to fail. Patients with microvascular dysfunction do not have plaque buildup in their coronary blood vessels, but have damage to the inner walls of the blood vessels, which can cause spasms and reduce blood flow to the heart muscle. In an alternative embodiment of the present invention, a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt is provided in an amount effective for treating microvascular dysfunction.

[0289] Vascular Diseases and Disorders Potassium channel activity is a major regulator of vascular myocyte membrane potential, and thus potassium channel activity has a major impact on vascular diameter, blood flow, perfusion pressure, vascular resistance, and blood pressure. Vasospastic diseases are peripheral vascular disorders caused by reversible localized or diffuse vasoconstriction of arteries or smaller blood vessels. Vasospastic syndromes include Raynaud's disease, acrocystis acrocephalus, and livedo reticularis. In one embodiment, Compound 1-Compound 21 or a pharmacologic acceptable salt thereof, or a compound selected from Formulae I-XXVII, is administered to treat Raynaud's disease.

[0290] In another embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof, or a compound selected from Formula I-Formula XXVII, is used to treat peripheral arterial disease or peripheral vascular disease, including lower limb ischemia. In one embodiment, the lower limb ischemia is acute. In one embodiment, the lower limb ischemia is chronic.

[0291] Excessive vasoconstriction and endothelial dysfunction in response to various triggers in the brain may also cause migraine headaches, particularly migraines believed to be caused by endothelial dysfunction. In one embodiment, a compound of Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof is administered to treat migraine headaches in a host in need of treatment. In one embodiment, a compound of Formula I-Formula XXVII is administered to treat migraine headaches in a host in need of treatment.

[0292] Skeletal and smooth muscle diseases and disorders Potassium channels are found in skeletal and smooth muscles (Quasthoff et al. Neuroscience Letters 1990, 119:191). Myopathy is a muscle disease in which muscle fibers do not function properly, causing muscle weakness. In one embodiment, a compound of Compound 1-21 or a pharma- ceutically acceptable salt thereof or a composition thereof is administered to treat a myopathy in a host in need of treatment. In one embodiment, a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt thereof or a composition thereof is administered to treat a myopathy in a host in need of treatment.

[0293] In one embodiment, the myopathy is acquired. Acquired myopathy can be further subclassified as inflammatory myopathy, toxic myopathy, and myopathy associated with a general condition. In one embodiment, the inflammatory myopathy is selected from polymyositis, dermatomyositis, and inclusion body myositis (IBM). Toxic myopathy is a drug-induced myopathy, a side effect observed with the use of cholesterol-lowering drugs, HIV therapy drugs, antiviral therapy drugs, rheumatic drugs, and antifungal agents (Valiyil et al. Curr Rheumatol Rep. 2010, 12, 213). Thus, in one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof, or a compound selected from Formulae I-XXVII, is administered to treat toxic myopathy induced by a drug. Non-limiting examples of drugs that induce toxic myopathy include steroids, cholesterol-lowering drugs (e.g., statins, fibrates, niacin, and ezetimibe), propofol, amiodarone, colchicine, chloroquine, antiviral drugs and protease inhibitors, omeprazole, and tryptophan.

[0294] In an alternative embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof, or a compound selected from Formula I-Formula XXVII is administered to treat a myopathy associated with a systemic condition. Non-limiting examples of systemic diseases include endocrine disorders, systemic inflammatory diseases, electrolyte imbalances, critical illness myopathies, and amyloid myopathies.

[0295] In one embodiment, the myopathy is hereditary. Hereditary myopathy may be further subclassified as muscular dystrophies, congenital myopathies, mitochondrial myopathies, and metabolic myopathies. In one embodiment, Compound 1-Compound 21 or a pharmaceutically acceptable salt thereof, or a compound selected from Formulae I-XXVII, is administered to treat muscular dystrophies, including dystrophinopathies (Duchenne muscular dystrophy), myotonic dystrophy type 1 and myotonic dystrophy type 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, and limb-girdle muscular dystrophy. In one embodiment, Compound 1-Compound 21 or a pharmaceutically acceptable salt thereof, or a compound selected from Formulae I-XXVII, is administered to treat congenital myopathies, including nemaline myopathy or central core myopathy. In one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof, or a compound selected from Formula I-Formula XXVII is administered to treat metabolic myopathies, including acid maltase deficiency or acid alpha-1,4-glucosidase deficiency (Pompe disease), glycogen storage diseases types 3-11, carnitine deficiency, fatty acid oxidation disorders, and carnitine palmitoyltransferase deficiency. In one embodiment, a compound of Formula I-X is administered to treat mitochondrial myopathies, including Kearns-Sayre syndrome (KSS), mitochondrial DNA depletion syndrome (MDS), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited deafness and diabetes mellitus (MIDD), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with ragged-red fibers (MERRF), neuropathy, ataxia, and retinitis pigmentosa (NARP), and Pearson syndrome.

[0296] Diseases and disorders of the endocrine system One endocrine disorder associated with altered potassium channel activity is diabetes mellitus. Potassium channels found in the pancreas function as modulators of insulin release and thus affect glucose metabolism. A channel opener, namely diazoxide, has been used to treat hypoglycemia due to hyperinsulinism (Dunne MJ, et al. N Engl J Med, 1997, 336:703).

[0297] Thus, in one embodiment, a compound of Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof is administered to treat diabetes in a host in need of such treatment. In one embodiment, a compound of Formula I-Formula XXVII is administered to treat diabetes in a host in need of such treatment. In one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof, or a compound selected from Formula I-Formula XXVII is provided in an amount effective to treat hypoglycemia.

[0298] Lung Diseases and Disorders Bronchial smooth muscle excitability is one of the causes of bronchial hyperresponsiveness, a hallmark of asthma. Potassium channel openers that can induce smooth muscle hyperpolarization are useful in the treatment of bronchial asthma (Fozard, JR.; Manley, PW. Potassium channel openers: agents for the treatment of airways hyperreactivity. New drugs for asthma, allergy and COPD. In: Hansel, TT.; Barnes, PJ., editors. Prog Respir Res. 2001. p. 77-80.p. 31). Nicorandil has been shown to have bronchodilatory properties in humans (Wajima Z, et al. Crit Care Med, 2003, 31, 485), and cromakalim is useful in the treatment of nocturnal asthma (Williams, AJ et al. Lancet, 1990, 336, 334).

[0299] In one embodiment, Compound 1 to Compound 21 or a pharma- ceutically acceptable salt thereof, or a compound selected from Formula I to Formula XXVII, is provided in an amount effective for treating airway hyperresponsiveness. In one embodiment, a compound of Compound 1 to Compound 21 or a pharma- ceutically acceptable salt thereof is administered to treat an obstructive airway disease in a host in need of treatment. In one embodiment, a compound of Formula I to Formula XXVII or a pharma- ceutically acceptable salt thereof or a composition thereof is administered to treat an obstructive airway disease in a host in need of treatment. In one embodiment, the obstructive airway disease is asthma or nocturnal asthma. In one embodiment, the obstructive airway disease is selected from chronic bronchitis, emphysema, cystic fibrosis, and bronchiolitis.

[0300] Urinary problems, erectile dysfunction, and premature labor Urinary incontinence is caused by muscle hypersensitivity and involuntary contraction of the bladder and is very common, especially in the elderly. The use of cromakalim in preliminary clinical trials resulted in improvement in the symptom of frequent urination (Nurse, DE et al. Br J Urol, 1991, 68, 27-31). In one embodiment, a compound of Compound 1 to Compound 21 or a pharma- ceutically acceptable salt thereof or a composition thereof is administered to treat urinary incontinence in a host in need of treatment. In one embodiment, a compound of Formula I to Formula XXVII or a pharma- ceutically acceptable salt thereof or a composition thereof is administered to treat urinary incontinence in a host in need of treatment.

[0301] Vasodilators have also been found to be useful in the treatment of erectile dysfunction, helping to relax constricting blood vessels and improving blood flow. Potassium channel openers, which relax smooth muscles, can help cause an erection. In one study, minoxidil applied as a lubricating gel was more effective than placebo or nitroglycerin in promoting erections (Cavallini, G. J Urol 1991, 146, 50-53). Thus, in one embodiment, a compound of Compound 1-21 or a pharma- ceutically acceptable salt thereof or a composition thereof is administered to treat erectile dysfunction in a host in need of treatment. In one embodiment, a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt thereof or a composition thereof is administered to treat erectile dysfunction in a host in need of treatment. In an alternative embodiment, a compound of Formula I-Formula XXVII is used in an amount effective to increase blood flow in the treatment of female sexual arousal disorder.

[0302] In one embodiment, a compound of Formula I-XXVII or a pharma- ceutically acceptable salt or composition thereof is used to relax uterine smooth muscle as a therapeutic agent for preterm labor.

[0303] Dermatological diseases and disorders Potassium channel openers improve blood supply to hair follicles and help promote hair growth. One example of a channel opener that improves hair growth is the use of topically and / or orally administered minoxidil as a treatment for hair loss in men with androgenetic alopecia and women with female pattern hair loss (Lucky, AW et al. J Am Acad Dermatol, 2004, 50, 541 and Olsen, EA et al. J Am Acad Dermatol, 2002, 47, 377). Minoxidil also helped to reduce the period of baldness from maximum hair loss to the first regrowth after chemotherapy. Thus, in one embodiment, an effective amount of Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof is administered to promote hair loss in a host in need of promotion. In one embodiment, an effective amount of a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt thereof or a composition thereof is administered to promote hair loss in a host in need of promotion. Non-limiting examples of types of hair loss include male pattern hair loss, female pattern hair loss, alopecia, and hypotrichosis.

[0304] Neurological diseases and disorders ATP-sensitive potassium channels are expressed in the substantia nigra, neocortex, hippocampus, hypothalamus, and microglia of the brain (Rodriguez, MJ et al. Oxidative Medicine and Cellular Longevity, 2013, 2013, 194546). By hyperpolarizing the membrane, channel openers reduce neuronal excitability and are therefore potential therapeutic agents for many neurological disorders, including epilepsy, neuropathic pain, ischemia and stroke, and neurodegeneration. Cromakalim has also been shown to induce neuroprotective effects when injected before an epileptic seizure (Blondeau, et al. Neurosci, 2000, 100, 465) and to exhibit protective effects against β-amyloid toxicity, the cause of cerebrovascular amyloidosis, a hallmark of Alzheimer's disease (Chi, X. et al. Neurosci Lett, 2000, 290, 9).

[0305] Thus, in one embodiment, a compound of Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof is administered to treat epilepsy in a host in need of treatment. In one embodiment, a compound of Formula I-Formula XXVII is administered to treat epilepsy in a host in need of treatment. In one embodiment, the epilepsy is generalized epilepsy. In one embodiment, the epilepsy is focal epilepsy.

[0306] Neurodegeneration is the loss and death of neurons. This cellular process includes a neuroinflammatory response accompanied by activation of glial cells, including microglia and astrocytes. Since ATP-sensitive potassium channels are found in microglia, microglia represent a drug target for neurodegeneration and disorders resulting from neurodegeneration, including normal tension glaucoma, primary open angle glaucoma, Alzheimer's disease, Parkinson's disease, Huntington's disease, motor neuron disease, spinocerebellar ataxia, and spinal muscular atrophy. In one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof, or a compound selected from Formulae I-XXVII, is administered to treat neurodegeneration in a host in need of treatment. In one embodiment, the neurodegenerative disease is selected from Alzheimer's disease, glaucoma, Parkinson's disease, Huntington's disease, motor neuron disease, spinocerebellar ataxia, and spinal muscular atrophy.

[0307] Tumor hypoperfusion and hypoxia In one aspect, an effective amount of a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt thereof is administered to a patient to treat tumor hypoperfusion or tumor hypoxia. Tumor hypoperfusion refers to reduced blood flow within a tumor. Tumor hypoxia refers to reduced oxygen levels within tumor cells. There may be overlap between the two.

[0308] When a tumor is in a state of hypoperfusion, perhaps because the tumor is growing rapidly, it does not have sufficient blood flow to allow tumor therapeutics to reach the tumor cells. This may result in resistance to treatment with chemotherapeutic drugs. In one embodiment, the compounds of Formula I-Formula XXVII or their pharma- ceutically acceptable salts are administered to a patient with tumor hypoperfusion, thus making the tumor more easily treatable with antitumor drugs, such as chemotherapeutic drugs.

[0309] In another embodiment, a compound of Formula I-XXVII is administered to a patient with hypoperfusion of non-tumor tissue, for example as a result of trauma.

[0310] When tumors are hypoxic, they are hypoxic because of lack of oxygen in cells. Tumors that are hypoxic may be more likely to exhibit metastatic behavior. Thus, in one embodiment, an effective amount of a compound of formula I-formula XXVII or a pharma- ceutically acceptable salt thereof is administered to a patient, optionally in combination with or alternating with a chemotherapeutic agent or other antitumor therapeutic agent, to treat tumor hypoxia.

[0311] In another embodiment, an effective amount of a compound of the invention, or a pharma- ceutically acceptable salt thereof, is administered, optionally in combination with a VEFG therapeutic, to treat hypoxia or hypoperfusion.

[0312] In alternative embodiments, an effective amount of a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt thereof is used in combination or alternation with oxygen therapy (e.g., an oxygen mask or a small tube placed under the nose to give oxygen) or an asthma medication (e.g., fluticasone, budesonide, mometasone, beclomethasone, ciclesonide, montelukast, zafirlukast, zileuton, salmeterol, formoterol, vilanterol, albuterol, levalbuterol, prednisone, methylprednisone, omalizumab, mepolizumab, benralizumab, or reslizumab).

[0313] Lymphatic disorders The lymphatic system helps remove toxins and waste from the body, and its main function is to carry lymph, a fluid that contains white blood cells, throughout the body and fight infections. The system is primarily made up of lymphatic vessels connected to lymph nodes, which filter the lymph. ATP The channel is expressed by lymphatic muscle cells and expresses a specific K ATP Studies have shown that channel openers dilate lymphatic vessels.

[0314] For example, as discussed in a recent study by Garner et al. ("KATP Channel Openers Inhibit Lymphatic Contractions and Lymph Flow as a Possible Mechanism of Peripheral Edema", Journal of Pharmacology and Experimental Therapeutics, October 25, 2020), rhythmic contractions of isolated rat mesenteric lymphatic vessels were induced by KATP channel openers such as cromakalim, minoxidil sulfate, and diazoxide. ATP This gradually abates with exposure to channel openers. Increasing concentrations of cromakalim attenuated the frequency and amplitude of contractions, eventually eliminating vascular constriction and compromising flow through the vessels. Similar effects were observed with minoxidil sulfate and diazoxide when administered at clinically relevant concentrations.

[0315] The most common disorders of the lymphatic system include lymphadenopathy, which is an enlargement of lymph nodes, and lymphedema, which is swelling of lymph nodes due to blockage. Thus, in one embodiment, an effective amount of a compound of Formula I to Formula XXVII or a pharma- ceutically acceptable salt thereof is administered to treat lymphadenopathy or lymphedema. In one embodiment, an effective amount of Compound 1 to Compound 21 or a pharma- ceutically acceptable salt thereof is administered to treat lymphadenopathy or lymphedema.

[0316] Inflammation of lymphatic vessels is known as lymphangitis, and symptoms typically include swelling, redness, and / or pain at the site of infection. In one embodiment, an effective amount of a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt thereof is administered to treat lymphangitis. In one embodiment, an effective amount of Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof is administered to treat lymphangitis.

[0317] Lymph nodes may also be infected with viruses, bacteria, and / or fungi, which is called lymphadenitis. Symptoms of lymphadenitis also include redness or swelling around the lymph node. In one embodiment, an effective amount of a compound of Formula I-Formula III or a pharma- ceutically acceptable salt thereof is administered to treat lymphangitis, in one embodiment, a compound of Formula I-Formula XXVII is administered in combination with an antibiotic or antifungal agent. In one embodiment, Compound 1-Compound 21 are administered in combination with an antibiotic or antifungal agent.

[0318] A common cancer of the lymphatic system is Hodgkin's lymphoma, a cancer that originates from the lymphocytes of white blood cells. This cancer can occur in any part of the body, and symptoms include painless enlargement of lymph nodes in the neck, armpits, or groin. There are two major types of Hodgkin's lymphoma: classical Hodgkin's lymphoma and nodal lymphocyte-predominant Hodgkin's lymphoma. Treatments for Hodgkin's lymphoma include chemotherapy and / or radiation, the most common treatment being the monoclonal antibody Rituximab (Rituxan). In one embodiment, an effective amount of a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt thereof is administered in combination with chemotherapy and / or radiation to treat Hodgkin's lymphoma. In one embodiment, an effective amount of Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof is administered in combination with chemotherapy and / or radiation to treat Hodgkin's lymphoma. In one embodiment, an effective amount of Compound 21 or a pharma- ceutically acceptable salt thereof is administered in combination with chemotherapy and / or radiation to treat Hodgkin's lymphoma. In one embodiment, the chemotherapy agent is Rituximab.

[0319] Non-Hodgkin's lymphoma occurs when the body produces too many abnormal white blood cells called lymphocytes, which lead to tumors. A common subtype of non-Hodgkin's lymphoma is B-cell non-Hodgkin's lymphoma. Symptoms include swollen lymph nodes, fever, and / or chest pain. Non-Hodgkin's lymphoma is treated with chemotherapy and / or radiation. A common treatment is a regimen known as R-CHOP, which consists of the monoclonal antibody rituximab (Rituxan) in addition to cyclophosphamide, doxorubicin, vincristine, and prednisone. In one embodiment, an effective amount of a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt thereof is administered in combination with chemotherapy and / or radiation to treat non-Hodgkin's lymphoma. In one embodiment, an effective amount of a compound of Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof is administered in combination with chemotherapy and / or radiation to treat non-Hodgkin's lymphoma. In one embodiment, the chemotherapy drugs consist of cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab.

[0320] Castleman disease is a group of lymphoproliferative disorders characterized by lymphadenopathy and has at least three distinct subtypes: monocentric Castleman disease (UCD), human herpesvirus 8-associated multicentric Castleman disease (HHV-8-associated MCD), and idiopathic multicentric Castleman disease (iMCD). In UCD, a single area of ​​lymph node enlargement is seen, whereas in iMCD, multiple areas of lymph node enlargement are seen. HHV-8-associated MCD is similar to iMCD in that multiple areas of lymph node enlargement are seen, but the patient is also infected with human herpesvirus 8.

[0321] In one embodiment, an effective amount of a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt thereof is administered to treat Castleman's disease, including monocentric Castleman's disease (UCD), human herpesvirus 8-associated multicentric Castleman's disease (HHV-8-associated MCD), and idiopathic multicentric Castleman's disease (iMCD). In one embodiment, an effective amount of Compound 1-Compound 21 or a pharma- ceutically acceptable salt thereof is administered to treat Castleman's disease, including monocentric Castleman's disease (UCD), human herpesvirus 8-associated multicentric Castleman's disease (HHV-8-associated MCD), and idiopathic multicentric Castleman's disease (iMCD).

[0322] Lymphangiomatosis is a disease in which cysts and / or lesions form from lymphatic vessels. The masses are widespread rather than present as a single localized mass. Lymphangiomatosis is a multisystem disorder in which abnormally proliferating lymphatic channels expand over time and invade surrounding tissues, bones, and organs. Lymphangiomatosis is a rare disease that is most prevalent in children and teenagers. There is no standard treatment, and treatments are often aimed only at alleviating symptoms. In one embodiment, an effective amount of a compound of Formula I-Formula XXVII or a pharmaceutically acceptable salt thereof is administered to treat or alleviate symptoms associated with lymphangiomatosis. In one embodiment, an effective amount of a compound 1-Compound 21 or a pharmaceutically acceptable salt thereof is administered to treat or alleviate symptoms associated with lymphangiomatosis.

[0323] V. Methods of Treating Eye Diseases and Disorders Reduced episcleral venous pressure (EVP) and improved distal outflow pathway In a healthy eye, aqueous humor is produced by the ciliary body and then flows through the pupil to fill the anterior chamber of the eye. It then drains from the anterior chamber through the trabecular meshwork (TM) into Schlemm's canal. From there, a collecting duct carries the aqueous humor to the episcleral veins and finally into the distal venous system. The episcleral vasculature consists of arteriovenous anastomoses and a muscular venous network innervated by vasodilator and vasoconstrictor nerve fibers. When aqueous humor comes into contact within the episcleral veins, it creates a retrograde pressure that can slow the outflow of aqueous humor, called episcleral venous pressure (EVP).

[0324] This system of aqueous humor production and outflow is simply driven by pressure gradients across the tissue. The difference in pressure between inside (IOP) and outside (epicleral venous pressure (EVP)) drives aqueous humor along pathways, and IOP is directly related to EVP as expressed by Goldmann's modified model of aqueous humor dynamics: IOP = ((aqueous inflow - uveoscleral outflow) / conventional aqueous outflow rate) + EVP.

[0325] Normal EVP ranges from 8mmHg to 12mmHg, and it is estimated that for every 1mmHg increase in EVP, there is a 1mmHg increase in mean IOP. EVP can be affected by a variety of factors, including body position, vascular pathology, volume overload, Valsalva maneuver, and systemic disease. Causes of EVP can be classified into three categories: 1) venous congestion (thyroid-associated ophthalmopathy, superior vena cava syndrome, retrobulbar tumors, cavernous sinus thrombosis, and orbital amyloidosis), 2) arteriovenous fistula (carotid-cavernous fistula, dural arteriovenous shunt, orbital varicose veins, and Sturge-Weber syndrome), and 3) idiopathic.

[0326] Ocular disorders caused and / or exacerbated by episcleral venous pressure (EVP) include normal tension glaucoma, primary open angle glaucoma, juvenile and congenital glaucoma, steroid-induced open angle glaucoma, steroid-induced elevated intraocular pressure, ocular hypertension, neovascular glaucoma, Graves' ophthalmopathy (or thyroid eye disease (TED)), thyroid-associated orbitopathy (TAO), Graves' orbitopathy (GO), retrobulbar tumors, cavernous sinus thrombosis, orbital vein thrombosis, episcleral / orbital venous vasculitis, superior vena cava obstruction, superior vena cava thrombosis, carotid-cavernous (CC) sinus fistula, dural cavernous sinus shunt, orbital varicose veins, Sturge-Weber syndrome, and idiopathic elevated episcleral venous pressure.

[0327] In one aspect, Compound 1 to Compound 21 or a pharma- ceutically acceptable salt thereof, or a compound selected from Formula I to Formula XXVII, or a composition thereof, is provided for treating elevated episcleral venous pressure (EVP) in a subject with elevated EVP.

[0328] In one embodiment, Compound 1 to Compound 21 or a pharma- ceutically acceptable salt thereof, or a compound selected from Formula I to Formula XXVII, or a composition thereof, is provided for treating an ocular disorder caused by elevated episcleral venous pressure (EVP). In one embodiment, the elevated episcleral venous pressure is idiopathic. In one embodiment, the elevated episcleral venous pressure is caused by venous congestion. In one embodiment, the elevated episcleral venous pressure is caused by arteriovenous fistula and / or CC sinus fistula.

[0329] In one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt or composition thereof is administered to treat an ocular disorder selected from normal tension glaucoma, primary open angle glaucoma, juvenile and congenital glaucoma, neovascular glaucoma, and steroid-induced open angle glaucoma, caused by elevated episcleral venous pressure in a host in need of treatment.

[0330] In one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt or composition thereof is administered to treat an ocular disorder caused by elevated episcleral venous pressure in a host in need of treatment, selected from steroid-induced elevated intraocular pressure, normal tension glaucoma, ocular hypertension, Sturge-Weber syndrome, and idiopathic elevated episcleral venous pressure.

[0331] In one aspect, Compound 1 to Compound 21 or a pharma- ceutically acceptable salt thereof, or a compound selected from Formula I to Formula XXVII, or a composition thereof, is provided for treating age-related macular degeneration (AMD), including wet AMD or dry AMD.

[0332] In one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt or composition thereof is administered to treat an ophthalmic disorder caused by elevated episcleral venous pressure in a host in need of treatment, selected from Graves' ophthalmopathy, thyroid eye disease (TED), thyroid-associated orbitopathy (TAO), Graves' orbitopathy (GO), retrobulbar tumors, cavernous sinus thrombosis, and orbital vein thrombosis.

[0333] In one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt or composition thereof is administered to treat an ocular disorder caused by elevated episcleral venous pressure in a host in need of treatment, selected from episcleral / orbital venous vasculitis, superior vena cava occlusion, superior vena cava thrombosis, carotid-cavernous fistula, dural cavernous shunt, and orbital varicose veins.

[0334] In one embodiment, the compound of formula I-formula XXVII or a pharma- ceutically acceptable salt or composition thereof is administered to treat an ocular disorder caused by elevated episcleral venous pressure in a host in need of treatment, selected from normal tension glaucoma, primary open angle glaucoma, juvenile and congenital glaucoma, neovascular glaucoma, pseudoexfoliation glaucoma, and steroid-induced open angle glaucoma. In one embodiment, the glaucoma is selected from primary open angle glaucoma (POAG), primary angle-closure glaucoma, normal tension glaucoma (NTG), pediatric glaucoma, pseudoexfoliation glaucoma, pigmentary glaucoma, traumatic glaucoma, neovascular glaucoma, and iridocorneal endothelial glaucoma. Primary open angle glaucoma is also known as chronic open angle glaucoma, chronic simple glaucoma, and simple glaucoma.

[0335] In one embodiment, a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof is administered to treat an ocular disorder caused by elevated episcleral venous pressure in a host in need of treatment, selected from steroid-induced elevated intraocular pressure, ocular hypertension, Sturge-Weber syndrome, pseudoexfoliation glaucoma, and idiopathic elevated episcleral venous pressure.

[0336] In one embodiment, a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof is administered to treat an ophthalmic disorder caused by elevated episcleral venous pressure in a host in need of treatment, selected from Graves' ophthalmopathy, thyroid eye disease (TED), thyroid-associated orbitopathy (TAO), Graves' orbitopathy (GO), retrobulbar tumors, cavernous sinus thrombosis, and orbital vein thrombosis.

[0337] In one embodiment, a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof is administered to treat an ophthalmic disorder caused by elevated episcleral venous pressure in a host in need of treatment, selected from episcleral / orbital venous vasculitis, superior vena cava occlusion, superior vena cava thrombosis, carotid-cavernous fistula, dural cavernous shunt, and orbital varicose veins.

[0338] In one aspect, a method for reducing intraocular pressure is provided, comprising administering Compound 1 to Compound 21, or a pharma- ceutically acceptable salt or composition thereof, in an amount effective to reduce episcleral venous pressure (EVP) in a host in need thereof.

[0339] In one aspect, a method of reducing intraocular pressure is provided, comprising administering a compound of Formula I-Formula XXVII or a pharma-ceutically acceptable salt or composition thereof in an amount effective to reduce episcleral venous pressure (EVP) in a host in need thereof.

[0340] In one aspect, a method for reducing intraocular pressure is provided, comprising administering Compound 1 to Compound 21, or a pharma- ceutically acceptable salt or composition thereof, in an amount effective to increase distal outflow capacity in a host in need thereof.

[0341] In one aspect, a method of reducing intraocular pressure is provided, comprising administering a compound of Formula I-Formula XXVII or a pharma-ceutically acceptable salt or composition thereof in an amount effective to increase distal outflow capacity in a host in need thereof.

[0342] In another aspect, a method is provided for reducing synthesis and / or deposition of extracellular matrix (ECM) proteins in the trabecular meshwork (TM). The TM is a specialized tissue located at the iridocorneal angle of the eye and is responsible for regulating aqueous humor outflow resistance. ATP The channels are present in TM and Schlemm's canal, and it has been shown that when these channels are activated by channel openers, the channels enhance outflow capacity (Chowdhury et al., Non-Patent Document 4).

[0343] Thus, in one embodiment, there is provided a method of reducing intraocular pressure comprising administering a compound 1-21 or a pharma- ceutically acceptable salt or composition thereof in an amount effective to reduce extracellular matrix (ECM) protein synthesis and / or deposition in the trabecular meshwork (TM). In one embodiment, there is provided a method of reducing intraocular pressure comprising administering a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof in an amount effective to reduce extracellular matrix (ECM) protein synthesis and / or deposition in the trabecular meshwork (TM).

[0344] Prevention or treatment of eye injuries Retinal ischemia is a condition in which blood flow, and therefore oxygen and necessary nutrients, is cut off from the retina. When the retina does not have the necessary amount of oxygen, cells begin to die. ATP-sensitive potassium channels are present in the retina and act as a barrier to the release of potassium. ATP Channel openers have been shown to have neuroprotective effects, indeed levcromakalim has been shown to mimic the effects of ischemic preconditioning (Ettaiche, M. et al. Brain Research, 2001, 890, 118).

[0345] Thus, in one embodiment, Compound 1-Compound 21 or a pharma- ceutically acceptable salt or composition thereof is administered to treat or prevent ischemic ocular damage in a host in need thereof. In one embodiment, a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt or composition thereof is administered to treat or prevent ischemic ocular damage in a host in need thereof.

[0346] Non-limiting examples of eye diseases that are the result of eye damage due to ischemic conditions are hypertensive retinopathy, central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), retinal artery occlusion that may be caused by an embolism, hypoperfusion retinopathy, diabetic retinopathy, retinopathy of prematurity, posterior ischemic optic neuropathy (PION), anterior ischemic optic neuropathy (AION), non-arteritic anterior ischemic optic neuropathy (NAION), and acute and chronic angle-closure glaucoma.

[0347] In some embodiments, Compound 1-Compound 21, or a compound of Formula I-Formula XXVII, is administered to a subject in need thereof, e.g., (1) prostaglandins (latanoprost (Xalatan), bimatoprost (Lumigan), travoprost (Travatan or Travatan Z), tafluprost (Zioptan), or latanoprost bunod (Vyzulta)), (2) alpha2 adrenergic agonists (brimonidine or apraclonidine), (3) β-blockers (timolol, betaxolol, levobunolol, metipranolol, or carteolol), (4) rho kinase inhibitors or ROCK inhibitors (Ripasudil or Netarsudil (Rhopressa)), (5) a second potassium channel opener (minoxidil, diazoxide, nicorandil, or pinacidil), or (6) Carbonic anhydrase inhibitors (dorzolamide, brinzolamide, acetazolamide, dichlorphenamide, pilocarpine, or methazolamide), (7) PI3K inhibitors, such as wortmannin, demethoxyviridin, perifosine, idelalisib, pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (taselisib), (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-phenoxy-2-butanyl hydrogen ( or methyl(oxo){[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide), d) (omipalisib), TGX-221 ((±)-7-methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9 -yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-1-one), GS-1101 (5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4 methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz), AS 252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), buparlisib (5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl ]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl) -8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholin-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-oate), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-( 4,6-di-4-morpholinyl-1,3,5-triazin-2-yl]phenyl]urea) (gedatorisib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide) and GSK1059615 (5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl) ethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib), LY294002, AZD8186, PF-4989216, piraralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, Apitolisib (GDC-0980; RG7422), (8) BTK inhibitors, such as ibrutinib (also known as PCI-32765) (Imbruvica™) (1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), dianilinopyrimidine inhibitors, such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics (U.S. Patent Application Publication No. 2011 / 0117073, which is incorporated herein by reference in its entirety), dasatinib (N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide), LFM-A13 (α-cyano-β-hydroxybutyric acid roxy-β-methyl-N-(2,5-dibromophenyl)propenamide), GDC-0834 (RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), CGI-560 4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746 (4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774 (4-(4- ((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide), CTA056 (7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one) and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one), or, (9) Syk inhibitors, such as cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxysilyl)phenyl]pyrazine-1-yl)phenyl) ... phenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate), BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide), imatinib (Gleevac;4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1-(tert -butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), PRT-060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S )-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5-fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348 (3-ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl It may be useful to administer in combination with an effective amount of a compound selected from: 1-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one), piceatannol (3-hydroxyresveratrol), YM193306, 7-azaindole, piceatannol, ER-27319, PRT060318, luteolin, apigenin, quercetin, fisetin, myricetin, morin;

[0348] Long-term therapy without significant tachyphylaxis or resistance In one embodiment, the present invention includes long-term (i.e., at least 6 weeks, 7 weeks, or at least 2 months, 3 months, 4 months, 5 months, or 6 months, or indefinitely during the course of therapy) medical therapy, including ocular treatment, using a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt thereof in a manner that does not result in significant tachyphylaxis (i.e., loss of activity over time) or resistance, including, but not limited to, normal tension glaucoma. Tachyphylaxis is a decrease in response to a drug that can be acute or sudden. Tachyphylaxis can occur after an initial dose or after a series of doses. Resistance is the need to increase the dose of a drug to produce a given response.

[0349] The present invention provides a method for using the compounds of formula I-XXVII of the present invention or pharma- ceutically acceptable salts thereof for long-term therapy in a manner that does not induce significant tachyphylaxis or alternatively tolerance. Loss of activity over time has been noted with many drugs, including ocular therapeutics. For example, tachyphylaxis is a common effect of over-the-counter ocular allergy medications, and is also observed with some drugs for other ocular conditions, including glaucoma. Tachyphylaxis has many causes, including increased or decreased expression of receptors or enzymes. This phenomenon has been noted particularly with beta-adrenergic antagonists and histamine.

[0350] The dose may be once a day or several times a day, at the physician's best judgment and as further described herein. In one embodiment, the dose is delivered as a topical drop for glaucoma, including normal tension glaucoma, or any form of high pressure glaucoma, including those described herein as examples elsewhere. It is advantageous for patients to be able to take a stable dose of drug for an extended period of time without having to change the drug or dosage strength. Although no two patients are the same and patients may show different results based on genetics or disease, in general, long-term therapy using an effective amount of a compound of formula I-formula XXVII or a pharma- ceutically acceptable salt thereof in a delivery system appropriate for the disorder being treated can be achieved according to the present invention.

[0351] Once-daily dosing In another embodiment, a once-daily (QD) human dose is provided to treat high-pressure glaucoma, including but not limited to primary open-angle glaucoma (POAG), primary angle-closure glaucoma, pediatric glaucoma, pseudoexfoliation glaucoma, pigmentary glaucoma, traumatic glaucoma, neovascular glaucoma, iridocorneal endothelial glaucoma (primary open-angle glaucoma is also known as chronic open-angle glaucoma, chronic simple glaucoma, and simple glaucoma). In an alternative embodiment, a once-daily (QD) human dose is used to treat acute high-pressure glaucoma due to cataracts. One aspect of the present invention is the ability to treat glaucoma in humans with a once-daily dose without (or alternatively with) a controlled release formulation (e.g., gel or micro- or nanoparticle formulation). In typical embodiments, it is administered without a controlled release formulation, but rather in a simple formulation such as, for example, phosphate buffered saline or citrate buffer, optionally with an ophthalmic excipient including, but not limited to, mannitol or another osmotic agent.

[0352] Patient compliance is a serious issue, and the fewer times a day dosing is required, the more likely compliance will be achieved. A once-daily human dosing for glaucoma is advantageous in maintaining intraocular pressure in a desirable range to minimize optic nerve damage while also optimizing compliance. Many therapeutic drugs for glaucoma must be used multiple times a day for effective therapy, or must be formulated in gels or controlled delivery materials to achieve once-daily dosing. However, the compound of formula I-formula XXVII of the present invention or its pharma-ceutically acceptable salt can be administered once a day in topical drops or other convenient manners at a selected effective dosage.

[0353] Hyperemia In yet another embodiment, an ocular therapy is provided using an effective amount of a compound of Formula I-Formula XXVII or a pharma- ceutically acceptable salt thereof that does not result in significant hyperemia. Hyperemia is excess blood in the blood vessels supplying an organ. Ocular hyperemia, also called "red eye", can include or cause blood vessel congestion, small hemorrhages, small pinpoint hemorrhages, and / or microhemorrhages. Ocular hypertension can have a variety of causes, including, but not limited to, exogenous irritants, conjunctivitis (including infectious or allergic), trauma, endogenous ocular injury, subconjunctival hemorrhage, blepharitis, anterior uveitis, glaucoma, or irritating drugs.

[0354] Certain ocular drugs either do not address redness or actually cause redness. According to the present invention, the use of the compound of formula I-formula XXVII of the present invention or its pharma- ceutically acceptable salts does not cause significant redness in patients when used during therapy, even when used over the long-term therapy described herein. Significant redness in one embodiment is redness that causes sufficient discoloration or discomfort in the patient that the patient considers it an adverse effect of treatment. As a result, technology advances can be achieved by supporting patient compliance and comfort.

[0355] Another aspect of the present invention is the treatment of glaucoma associated with Sturge-Weber syndrome, a congenital disorder that affects the skin, nervous system, and sometimes the eyes. Sturge-Weber syndrome is sometimes referred to as a neurocutaneous disorder. Sturge-Weber syndrome can cause Sturge-Weber syndrome-induced glaucoma, which affects 30% to 70% of patients. Management of Sturge-Weber syndrome-induced glaucoma can be complicated, and many patients require surgery or drainage devices. In accordance with the present invention, Sturge-Weber syndrome-induced glaucoma can be treated by administering an effective amount of a compound of Formula I-Formula XXVII of the present invention or a pharma- ceutically acceptable salt thereof, optionally in a pharma- ceutically acceptable carrier as described herein. The patient can continue long-term therapy under the care of a physician.

[0356] Integrated or supplemental therapy with MIGS (Microinvasive Glaucoma Surgery) Minimally (or minimally) invasive glaucoma surgery (MIGS) has become an innovative technique in the evolution of glaucoma surgery. Since glaucoma is a disease in which the optic nerve is damaged primarily due to increased intraocular pressure, the goal of glaucoma surgery is to prevent or reduce damage to the optic nerve by lowering intraocular pressure.

[0357] Standard glaucoma surgery is still considered major surgery and involves trabeculectomy, ExPRESS shunts, or external tube shunts such as Ahmed-style and Baerveldt-style valve implants. Although such procedures are often effective in lowering intraocular pressure and halting the progression of glaucoma, they are associated with many potential complications, including double vision, severe eye infections, exposure of the drainage implant, corneal swelling, and excessively low intraocular pressure.

[0358] According to Saheb and Ahmed, the term MIGS has five favorable properties: 1. The ab interno approach via a clear corneal incision, which eliminates the need for a conjunctival incision 2. Minimally traumatic procedure to the target tissue, 3. IOP-lowering effect that justifies the approach, 4. A high safety profile that avoids serious complications compared to other glaucoma surgeries; and 5. Rapid recovery with minimal impact on the patient's quality of life; Refers to a group of surgical procedures that share a common theme.

[0359] The MIGS group of surgeries have been developed recently to alleviate some of the complications of most standard glaucoma surgeries. Thus, in one embodiment, the prodrugs of Formula I-XXVII are used as adjuncts in combination with minimally invasive glaucoma surgery (MIGS).

[0360] MIGS aims to achieve lower intraocular pressure in patients with glaucoma with shorter surgery times and ideally, medication-sparing effects. MIGS procedures work by using microscopic instruments and small incisions. MIGS procedures reduce complication rates, but some efficacy comes at the expense of increased safety (Pillunat, LE, et al., Clin Ophthalmol. 2017; 11: 1583-1600).

[0361] MIGS surgery falls into several categories: 1. Trabecular meshwork bypass surgery, 2. Microtrabeculectomies (a miniaturized form of trabeculectomy), 3. Complete internal or suprachoroidal shunt, and 4. A kinder, gentler form of laser photocoagulation, It is classified as follows.

[0362] Trabecular meshwork surgery (trabeculectomy) involves the use of special contact lenses on the eye to cut open the trabecular meshwork with small devices under high-powered microscopic control without damaging other tissues in the intraocular drainage pathway. The trabecular meshwork may be destroyed (Trabectome or Trab360) or bypassed using small snorkel-like devices (iStent) or plug-shaped stent devices (iStent Inject). Both techniques are FDA approved, but are most useful in the early to moderate stages of glaucoma, as they generally do not reduce intraocular pressure as much. With these devices, the resistance of the trabecular meshwork is obviated, leaving mainly distal outflow capacity and episcleral venous pressure as limitations to further aqueous humor drainage. In certain embodiments, a compound of Formula I-XXVII or a pharma- ceutically acceptable salt thereof, or another compound of the invention or a salt thereof, is used as an additive in combination with Trabectome or Trab360 and / or iStent / iStent Inject to treat glaucoma by additively lowering IOP via increasing distal outflow or lowering episcleral venous pressure before or after treatment in an acute or chronic use setting. In certain embodiments, a compound of Formula I-XXVII or a pharma- ceutically acceptable salt thereof, or another compound of the invention or a salt thereof, is used as an additive in combination with Trabectome or Trab360 and / or iStent / iStent Inject to treat glaucoma by additively lowering IOP via increasing distal outflow or lowering episcleral venous pressure before or after treatment in an acute or chronic use setting.

[0363] Micro trabeculectomy works by inserting a small microscopic tube into the eye and draining from inside the eye under the outer membrane of the eye (conjunctiva). Xen Gel Stent and PRESERFLO are two new devices that can make trabeculectomy surgery safer. Results have shown superior pressure reduction with improved safety over trabeculectomy in studies conducted outside the United States. In certain embodiments, the compounds of the present invention are used as part of a protocol with Xen Gel Stent and / or Preserflo to treat glaucoma by additively lowering IOP via increasing distal outflow or reducing episcleral venous pressure before or after treatment in acute or chronic use settings.

[0364] Suprachoroidal shunts, including Gold Micro shunt, iStent Supra, Cypass Micro stent, Aquashunt, and STARflo, work by using a small tube with a very small internal opening to connect the anterior segment of the eye to the suprachoroidal space between the retina and the eye wall to increase drainage from the eye. This procedure has relatively few serious complications and reduces pressure enough to be useful even in moderate glaucoma. In certain embodiments, the compounds of Formula I-Formula XXVII or pharma- ceutically acceptable salts of the present invention are used in combination with a suprachoroidal shunt procedure to treat glaucoma by additively lowering IOP via increasing distal outflow or reducing episcleral venous pressure before or after treatment in acute or chronic use settings.

[0365] Trabecular meshwork bypass stents and shunts are investigational devices that function to dilate Schlemm's canal. These procedures promote the inflow of aqueous humor into Schlemm's canal by inserting a shunt (Eyepasse Glaucoma Implant, GMP Companies, Inc., Fort Lauderdale, FL) or by inserting a stent into Schlemm's canal itself (iStent, Glaukos Corp., Laguna Hills, CA). Other devices, such as the Solx Gold Micro-Shunt (OccuLogix, Inc., Mississauga, Ontario, Canada), divert aqueous humor into the suprachoroidal space. In certain embodiments, the compounds of Formula I-Formula XXVII or pharma- ceutically acceptable salts of the present invention are used in combination with trabecular meshwork bypass stent or shunt procedures to treat glaucoma by additively lowering IOP via increasing distal outflow or reducing episcleral venous pressure before or after the procedure in an acute or chronic use setting.

[0366] Laser photocoagulation was previously limited to advanced glaucoma that could not be controlled despite trabeculectomy or tube shunt. Endoscopic cyclophotocoagulation and micropulse cyclophotocoagulation are two recent advances in the use of laser photocoagulation and have proven useful in cases where glaucoma has not yet progressed. In certain embodiments, the compounds of formulas I-XXVII of the present invention or pharma- ceutically acceptable salts are used in endoscopic cyclophotocoagulation and micropulse cyclophotocoagulation protocols to treat glaucoma by additively lowering IOP via increasing distal outflow / reducing episcleral venous pressure before or after treatment in acute or chronic use settings.

[0367] In recent years, endoscopic cyclophotocoagulation (ECP) has become a widely accepted and popular treatment for refractory glaucoma, pediatric glaucoma, in combination with phacoemulsification with intraocular lens placement, as an adjunct to cataract surgery in both medically controlled and uncontrolled glaucoma. ECP is performed by inserting an endolaser unit through the cataract incision, across the anterior segment, and into the posterior chamber on the nasal side of the eye, followed by lens removal and intraocular lens implantation. Laser energy is applied to the ciliary processes to destroy the ciliary epithelial cells that produce aqueous humor. In certain embodiments, the compounds of Formula I-XXVII or pharma- ceutically acceptable salts of the present invention are used in ECP protocols to treat glaucoma by additively lowering IOP via increasing distal outflow / reducing episcleral venous pressure before or after treatment in acute or chronic use settings.

[0368] Micropulse cyclophotocoagulation delivers the laser in short bursts, allowing the surgeon to target specific areas of the ciliary body while allowing the tissue time to cool between bursts, minimizing damage. Both the MicroPulse P3 probe and the new Cyclo G6 glaucoma laser system (Iridex) have been successfully used in retinal diseases, showing excellent safety and efficacy rates. In certain embodiments, the compounds of formulas I-XXVII or pharma- ceutically acceptable salts of the present invention are used in micropulse cyclophotocoagulation surgical protocols to treat glaucoma by additively lowering IOP via increasing distal outflow or reducing episcleral venous pressure before or after the procedure in acute or chronic use settings.

[0369] Other devices include Gonioscopy-assisted transluminal trabeculotomy (GATT), Kafuk Dual Blade, Ab interno tubular grafting and Hydrus Microstent, CyPass Micro-Stent, iStent Supra, Xen Glaucoma Treatment System, and InnFocus MicroShunt. In certain embodiments, the compounds of formula I to formula XXVII of the present invention or pharma- ceutically acceptable salts are used in the surgical protocols of these devices to treat the above-mentioned glaucoma.

[0370] Laser trabeculoplasty, including selective laser trabeculoplasty (SLT), argon laser trabeculoplasty (ALT), and micropulse laser trabeculoplasty (MLT), is a surgical laser procedure that serves to reduce resistance at the trabecular meshwork by ablating cells of the trabecular meshwork and improving outflow in a manner similar to other forms of trabeculoplasty and certain MIGS devices. In certain embodiments, the compounds of Formulas I-XXVII of the present invention or pharma- ceutical acceptable salts are used as additives in combination with selective laser trabeculoplasty to treat glaucoma by additively lowering IOP via increasing distal outflow or reducing episcleral venous pressure before or after treatment in acute or chronic use settings.

[0371] In one embodiment, the compounds of Formula I-XXVII are used as second-line therapeutic agents to prostaglandin analogs such as latanoprost, bimatoprost (Lumigan), travoprost (Travatan or Travatan Z), or tafluprost (Zioptan), and as additives to the MIGS therapies described herein.

[0372] In one embodiment, the compounds of Formula I-XXVII are used as second line therapeutic agents to latanoprost and as adjuncts to the MIGS therapies described herein.

[0373] In one embodiment, the compounds of Formula I through Formula XXVII are used as second-line therapy to alpha 2 adrenergic agonists such as brimonidine (Alphagan™), epinephrine, dipivefrin (Propine™), or apraclonidine (Lopidine™), and as an additive to the MIGS therapies described herein.

[0374] In one embodiment, the compounds of Formula I-XXVII are used as second line therapy to beta blockers such as timolol, levobunolol, metipranolol, or carteolol, and as additives to the MIGS therapies described herein.

[0375] In one embodiment, the compounds of Formula I-XXVII are used as second line therapeutics to ROCK inhibitors such as Ripasudil, Netarsudil (Rhopressa), Fasudil, RKI-1447, GSK429286A, or Y-30141, and as additives to the MIGS therapies described herein.

[0376] In one embodiment, the compounds of Formula I-XXVII are used as second line therapeutics to ROCK inhibitors such as Ripasudil, Netarsudil (Rhopressa), Fasudil, RKI-1447, GSK429286A, or Y-30141, and as additives to the MIGS therapies described herein.

[0377] In one embodiment, the compounds of Formula I-XXVII are used as second-line therapeutic agents to a second potassium channel opener, such as minoxidil, diazoxide, nicorandil, or pinacidil, and as additives to the MIGS therapies described herein.

[0378] In one embodiment, the compounds of Formula I through Formula XXVII are used as second-line therapy to carbonic anhydrase inhibitors such as dorzolamide (Trusopt™), brinzolamide (Azopt™), acetazolamide (Diamox™), or methazolamide (Neptazane™), and as additives to the MIGS therapies described herein. The present disclosure includes embodiments described in the following sections. [Section 1] formula: TIFF0007636742000128.tif36128 or a pharma- ceutically acceptable salt thereof. [Section 2] formula: TIFF0007636742000129.tif36128 Item 1. The compound according to item 1, or a pharma- ceutically acceptable salt thereof. [Section 3] formula: TIFF0007636742000130.tif36128 Item 1. The compound according to item 1, or a pharma- ceutically acceptable salt thereof. [Section 4] formula: TIFF0007636742000131.tif81128 Item 1. The compound according to item 1, or a pharma- ceutically acceptable salt thereof. [Section 5] formula: TIFF0007636742000132.tif80128 Item 1. The compound according to item 1, or a pharma- ceutically acceptable salt thereof. [Section 6] Formula I: TIFF0007636742000133.tif53128 (In the formula, X + is optionally a pharma- ceutically acceptable counterbalancing cation selected from an alkali metal cation or an ammonium ion. [Section 7] X + is Na + 、K + , Li+ , and Cs + Item 7. The compound of formula I according to item 6, selected from: [Section 8] X + teeth, TIFF0007636742000134.tif39128 Item 7. The compound of formula I according to item 6, selected from: [Section 9] structure: TIFF0007636742000135.tif52128 The compound of formula I according to any one of items 6 to 8. [Section 10] structure: TIFF0007636742000136.tif51128 The compound of formula I according to any one of items 6 to 8. [Section 11] structure: TIFF0007636742000137.tif107131 The compound of formula I according to any one of items 6 to 8. [Section 12] structure: TIFF0007636742000138.tif114131 The compound of formula I according to any one of items 6 to 8. [Section 13] Formula II: TIFF0007636742000139.tif51128 (In the formula, M 2+ is a pharma- ceutically acceptable divalent cation optionally selected from an alkaline earth metal cation, a metal cation having an oxidation state of +2, or an ammonium ion having a net positive charge of two. [Section 14] M 2+ is Mg 2+ , Ca 2+ 、Sr 2+ , Zn 2+ , and Fe 2+ Item 14. The compound of formula II according to item 13, selected from: [Section 15] M 2+ teeth, TIFF0007636742000140.tif18128 Item 14. The compound of formula II according to item 13, selected from: [Section 16] structure: TIFF0007636742000141.tif51128 16. The compound of formula II according to any one of items 12 to 15. [Section 17] structure: TIFF0007636742000142.tif54128 16. The compound of formula II according to any one of items 12 to 15. [Section 18] structure: TIFF0007636742000143.tif112134 16. The compound of formula II according to any one of items 12 to 15. [Section 19] structure: TIFF0007636742000144.tif114134 16. The compound of formula II according to any one of items 12 to 15. [Section 20] Formula III or Formula IV: TIFF0007636742000145.tif73128 (In the formula, x and y are independently selected from 1, 2, 3, 4, and 5; m and n are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, or a pharma- ceutically acceptable salt thereof. [Section 21] Formula V, Formula VI, Formula VII, Formula VIII, Formula XI, or Formula XII: TIFF0007636742000146.tif168141TIFF0007636742000147.tif201147 (In the formula, X + is an alkali metal cation or an ammonium ion having a net positive charge of 1, M 2+ is an alkaline earth metal cation, a metal cation having an oxidation state of +2, or an ammonium ion having a net positive charge of 2; x and y are independently selected from 1, 2, 3, 4, and 5; m and n are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. [Section 22] Formula IX or Formula X: TIFF0007636742000148.tif152128 (In the formula, x, y, and z are independently selected from 1, 2, 3, 4, and 5; and m, n, and o are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, or a pharma- ceutically acceptable salt thereof. [Section 23] formula: TIFF0007636742000149.tif159128 or a pharma- ceutically acceptable salt thereof. [Section 24] structure: TIFF0007636742000150.tif35128 or a pharma- ceutically acceptable salt thereof, optionally in a pharma- ceutically acceptable carrier. [Section 25] structure: TIFF0007636742000151.tif40128 Item 25. A pharmaceutical composition according to item 24, comprising the compound of formula (I) or a pharma- ceutically acceptable salt thereof, optionally in a pharma- ceutically acceptable carrier. [Section 26] structure: TIFF0007636742000152.tif36128 Item 25. A pharmaceutical composition according to item 24, comprising the compound of formula (I) or a pharma- ceutically acceptable salt thereof, optionally in a pharma- ceutically acceptable carrier. [Section 27] A pharmaceutical composition comprising the compound according to any one of items 4 to 5, 20, and 22 to 26 or a pharma- ceutically acceptable salt thereof, optionally in a pharma- ceutically acceptable carrier. [Section 28] A pharmaceutical composition comprising a compound according to any one of items 6 to 19 and 21, optionally in a pharma- ceutically acceptable carrier. [Section 29] Item 29. The pharmaceutical composition according to any one of items 24 to 28, wherein the pharma- ceutically acceptable carrier is suitable for local delivery. [Section 30] Item 30. The pharmaceutical composition according to item 29, wherein the carrier is in the form of aqueous drops, a lotion, a cream, a gel, a mist, an ointment, a skin patch, or a spray. [Section 31] Item 29. The pharmaceutical composition according to any one of items 24 to 28, wherein the pharma- ceutically acceptable carrier is suitable for oral delivery. [Section 32] Item 32. The pharmaceutical composition according to item 31, wherein the pharma- ceutically acceptable carrier is in the form of a pill, tablet, or capsule. [Section 33] Item 29. The pharmaceutical composition according to any one of Items 24 to 28, wherein the pharma- ceutically acceptable carrier is suitable for parenteral administration. [Section 34] Item 34. The pharmaceutical composition according to item 29 or 33, wherein the pharma- ceutical acceptable carrier is in the form of a solution, suspension, or emulsion. [Section 35] 29. The pharmaceutical composition according to any one of items 24 to 28, wherein the pharma- ceutically acceptable carrier is suitable for inhalation pulmonary route. [Section 36] Item 36. The pharmaceutical composition according to item 35, wherein the pharma- ceutically acceptable carrier is in the form of a nebulizer, a metered dose inhaler, or a dry powder inhaler. [Section 37] Item 29. The pharmaceutical composition according to any one of items 24 to 28, wherein the pharma- ceutically acceptable carrier is suitable for ocular delivery. [Section 38] Item 38. The pharmaceutical composition according to item 37, wherein the pharma- ceutically acceptable carrier is in the form of a solution, suspension, or emulsion. [Section 39] 1. A method for treating a disorder treatable with a vasodilator comprising administering to a subject an effective amount of a compound of the formula: TIFF0007636742000153.tif36128 or a pharma- ceutically acceptable salt thereof. [Section 40] formula: TIFF0007636742000154.tif36128 or a pharma- ceutically acceptable salt thereof. [Section 41] formula: TIFF0007636742000155.tif36128 or a pharma- ceutically acceptable salt thereof. [Section 42] A method for treating a disorder treatable with a vasodilator, comprising administering an effective amount of a compound according to any one of claims 1 to 23, optionally in a pharma- ceutically acceptable carrier. [Section 43] Item 43. The method according to any one of Items 39 to 42, wherein the disorder is an ophthalmic, cardiovascular, vascular, skeletal muscle, endocrine system, pulmonary, urological, dermatological, or neurological disease or disorder. [Section 44] Item 44. The method according to any one of items 39 to 43, wherein the disorder is glaucoma. [Section 45] 44. The method of any one of paragraphs 39 to 43, wherein the disorder is EVP in an otherwise affected patient. [Section 46] Item 44. The method of any one of items 39 to 43, wherein the disorder is EVP in an otherwise normal patient. [Section 47] Item 44. The method according to any one of items 39 to 43, wherein the disorder is hair loss or alopecia. [Section 48] 44. The method according to any one of items 39 to 43, wherein the disorder is Raynaud's disease. [Section 49] Item 44. The method according to any one of items 39 to 43, wherein the disorder is a cardiovascular disease selected from hypertension, heart failure, myocardial ischemia, angina pectoris, acute myocardial infarction (AMI), arrhythmia, and endothelial dysfunction. [Section 50] Item 50. The method of item 49, wherein the heart failure is congestive heart failure. [Section 51] Item 44. The method according to any one of Items 39 to 43, wherein the disorder is urinary incontinence or erectile dysfunction. [Section 52] Item 44. The method according to any one of Items 39 to 43, wherein the disorder is a pulmonary disease selected from asthma, nocturnal asthma, and airway hyperresponsiveness. [Section 53] Item 44. The method according to any one of items 39 to 43, wherein the disorder is hypertension. [Section 54] 44. The method according to any one of items 39 to 43, wherein the disorder is selected from elevated episcleral venous pressure (EVP), normal tension glaucoma, open angle glaucoma, ocular hypertension, Graves' ophthalmopathy, Graves' orbitopathy (GO), retrobulbar tumors, cavernous sinus thrombosis, orbital vein thrombosis, episcleral / orbital venous vasculitis, superior vena cava occlusion, superior vena cava thrombosis, carotid cavernous fistula, dural cavernous shunt, orbital varicose veins, and Sturge-Weber syndrome. [Section 55] Item 44. The method according to any one of items 39 to 43, wherein the disorder is treated by peripheral vasodilation. [Section 56] Item 56. The method according to any one of Items 39 to 55, wherein the host is a human. [Section 57] 24. An effective amount of a compound according to any one of paragraphs 1 to 23, optionally in a pharma- ceutically acceptable carrier, for treating a disorder treatable with a vasodilator. [Section 58] 58. The compound according to clause 57, wherein the disorder is an ophthalmic, cardiovascular, vascular, musculoskeletal, endocrine, pulmonary, urological, dermatological, or neurological disease or disorder. [Section 59] 24. Use of an effective amount of a compound according to any one of paragraphs 1 to 23, optionally in a pharma- ceutically acceptable carrier, in the manufacture of a medicament for treating a disorder treatable with a vasodilator. [Section 60] 60. The use according to paragraph 59, wherein the disorder is an ophthalmic, cardiovascular, vascular, musculoskeletal, endocrine, pulmonary, urological, dermatological, or neurological disease or disorder. [Section 61] Formula XIII, Formula XVI, Formula XVII, Formula XXIV, or Formula XXV: TIFF0007636742000156.tif253128TIFF0007636742000157.tif208128 (In the formula, x and y are independently selected from 1, 2, 3, 4, 5, 6, 7, and 8; m and n are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; p is selected from 0 and 1, and R is independently in each occurrence H and X + or a pharma- ceutically acceptable salt thereof. [Section 62] Formula XIV or Formula XV: TIFF0007636742000158.tif103128 (In the formula, X + is optionally a pharma- ceutically acceptable counterbalancing cation selected from an alkali metal cation or an ammonium ion having a net positive charge of one. [Section 63] Formula XX or Formula XXI: TIFF0007636742000159.tif87128 (In the formula, X+ is optionally a pharma- ceutically acceptable counterbalancing cation selected from an alkali metal cation or an ammonium ion having a net positive charge of one. [Section 64] Formula XXII or Formula XXIII: TIFF0007636742000160.tif89128 (In the formula, M 2+ is optionally a pharma- ceutically acceptable divalent cation selected from an alkaline earth metal cation, a metal cation having an oxidation state of +2, or an ammonium ion having a net positive charge of 2. [Section 65] X + is Na + 、K + , Li + , and Cs + Item 64. The compound according to item 62 or 63, selected from: [Section 66] X + teeth, TIFF0007636742000161.tif76145 Item 66. The compound according to item 65, selected from: [Section 67] M 2+ is Mg 2+ , Ca 2+ 、Sr 2+ , Zn 2+ , and Fe 2+ Item 65. The compound according to item 64, selected from: [Section 68] M 2+ teeth, TIFF0007636742000162.tif19128 Item 68. The compound according to item 67, selected from: [Section 69] TIFF0007636742000163.tif218128 62. The compound according to claim 61, having a formula selected from the following: or a pharma- ceutically acceptable salt thereof. [Section 70] 70. A pharmaceutical composition comprising a compound according to any one of paragraphs 61 to 69, optionally in a pharma- ceutically acceptable carrier. [Section 71] 71. The pharmaceutical composition of claim 70, wherein the pharma- ceutical acceptable carrier is suitable for localized delivery. [Section 72] Item 72. The pharmaceutical composition of item 71, wherein the carrier is in the form of aqueous drops, a lotion, a cream, a gel, a mist, an ointment, a skin patch, or a spray. [Section 73] 71. The pharmaceutical composition of claim 70, wherein the pharma- ceutically acceptable carrier is suitable for oral delivery. [Section 74] 74. The pharmaceutical composition of claim 73, wherein the carrier is in the form of a pill, tablet, or capsule. [Section 75] 71. The pharmaceutical composition of claim 70, wherein the pharma- ceutically acceptable carrier is suitable for parenteral administration. [Section 76] Item 71. The pharmaceutical composition according to item 70, wherein the carrier is in the form of a solution, suspension, or emulsion. [Section 77] 71. The pharmaceutical composition according to paragraph 70, wherein the pharma- ceutical acceptable carrier is suitable for the inhaled pulmonary route. [Section 78] 78. The pharmaceutical composition according to claim 77, wherein the pharma- ceutically acceptable carrier is in the form of a nebulizer, a metered dose inhaler, or a dry powder inhaler. [Section 79] 71. The pharmaceutical composition of claim 70, wherein the pharma- ceutically acceptable carrier is suitable for ocular delivery. [Section 80] Item 80. The pharmaceutical composition according to item 79, wherein the pharma- ceutically acceptable carrier is in the form of a solution, suspension, or emulsion. [Section 81] A method for treating a disorder treatable with a vasodilator, comprising administering an effective amount of a compound according to any one of claims 61 to 69, optionally in a pharma- ceutically acceptable carrier. [Section 82] 82. The method of claim 81, wherein the disorder is an ophthalmic, cardiovascular, vascular, musculoskeletal, endocrine, pulmonary, urological, dermatological, or neurological disease or disorder. [Section 83] 83. The method of claim 82, wherein the disorder is glaucoma. [Section 84] 83. The method of claim 82, wherein the disorder is EVP in an otherwise affected patient. [Section 85] 83. The method of claim 82, wherein the disorder is EVP in an otherwise normal patient. [Section 86] 83. The method of claim 82, wherein the disorder is hair loss or alopecia. [Section 87] 83. The method of claim 82, wherein the disorder is Raynaud's disease. [Section 88] 83. The method of claim 82, wherein the disorder is ischemia. [Section 89] 83. The method of claim 82, wherein the disorder is a cardiovascular disease selected from hypertension, heart failure, myocardial ischemia, angina pectoris, acute myocardial infarction (AMI), arrhythmia, and endothelial dysfunction. [Section 90] 90. The method of claim 89, wherein the heart failure is congestive heart failure. [Section 91] 83. The method of claim 82, wherein the disorder is urinary incontinence or erectile dysfunction. [Section 92] 83. The method of claim 82, wherein the disorder is a pulmonary disease selected from asthma, nocturnal asthma, and airway hyperresponsiveness. [Section 93] 83. The method of claim 82, wherein the disorder is hypertension. [Section 94] 83. The method of claim 82, wherein the disorder is selected from elevated episcleral venous pressure (EVP), normal tension glaucoma, open angle glaucoma, ocular hypertension, Graves' ophthalmopathy, Graves' orbitopathy (GO), retrobulbar tumors, cavernous sinus thrombosis, orbital vein thrombosis, episcleral / orbital venous vasculitis, superior vena cava occlusion, superior vena cava thrombosis, carotid cavernous fistula, dural cavernous shunt, orbital varicose veins, and Sturge-Weber syndrome. [Section 95] 95. The method of claim 94, wherein the disorder is normal tension glaucoma. [Section 96] 83. The method of claim 82, wherein the disorder is treated by peripheral vasodilation. [Section 97] Item 97. The method according to any one of Items 82 to 96, wherein the host is a human. [Section 98] 70. An effective amount of a compound according to any one of paragraphs 61 to 69, optionally in a pharma- ceutically acceptable carrier, for treating a disorder treatable with a vasodilator. [Section 99] 99. The compound according to paragraph 98, wherein the disorder is an ophthalmic, cardiovascular, vascular, musculoskeletal, endocrine, pulmonary, urological, dermatological, or neurological disease or disorder. [Section 100] 70. Use of an effective amount of a compound according to any one of paragraphs 61 to 69, optionally in a pharma- ceutically acceptable carrier, in the manufacture of a medicament for treating a disorder treatable with a vasodilator. [Section 101] 101. The use according to claim 100, wherein the disorder is an ophthalmic, cardiovascular, vascular, musculoskeletal, endocrine, pulmonary, urological, dermatological, or neurological disease or disorder. EXAMPLES

[0379] Experimental Example General chemical synthesis methods All oxygen and / or moisture sensitive reactions were carried out under a N2 atmosphere. All reagents and solvents were purchased from commercial suppliers and used as received. HPLC conditions for all reported LCMS: Column: XBridge C18, 3.5 μm, 4.6 mm×30 mm at 25° C.; gradient for 3 min run: 5%→100% B in 2.0 min, hold 100% B for 0.7 min, run time=2.7 min. Gradient for 7 min run: 5% B for 0.5 min, 5%→100% B in 5 min, hold 100% B for 1.5 min, flow rate: 3 mL / min. Eluent A: 10 mM ammonium formate in water (pH=3.8); Eluent B: acetonitrile (no additives).

[0380] List of abbreviations ACN Acetonitrile DCM Dichloromethane DIPEA Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide EDCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide EtOH Ethanol HCl Hydrochloric acid HPLC High Performance Liquid Chromatography I2 Iodine LCMS Liquid Chromatography-Mass Spectrometry mCPBA meta-chloroperoxybenzoic acid MeCN Acetonitrile MEK Methyl ethyl ketone MeOH Methanol NaH Sodium hydride NaOH Sodium hydroxide Na2S2O3 Sodium Thiosulfate Na2SO4 Sodium Sulfate NMO N-Methylmorpholine N-oxide PCl3 Phosphorus Trichloride POCl3 Phosphoryl Trichloride PTFE Polytetrafluoroethylene Py Pyridine RT Hold time or room temperature TBAF Tetrabutylammonium fluoride TBS tert-Butyldimethylsilyl THF Tetrahydrofuran UPLC Ultra-high performance liquid chromatography.

[0381] Example 1 Method A for synthesizing compound 1 Process 1 [ka]

[0382] To a solution of 2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1.00 g, 5.24 mmol) in DCM (40.0 mL) was added (S,S)-(+)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride ((S,S)-Jacobsen catalyst) (166 mg, 262 μmol). The solution was cooled to −78° C. NMO (3.16 g, 26.2 mmol) was then added in one portion, followed by 3-chloroperbenzoic acid (2.41 g, 10.5 mmol) in several portions. Once the olefin was consumed (TLC or LCMS monitored, ca. 90 min), the reaction was quenched by the addition of a solution of Na2S2O3 (20 mL). A solution of 2N NaOH (40 mL) was then added and the organic layer was separated. The aqueous phase was further extracted with 2×50 mL of DCM. The combined organic layers were washed with 2N HCl (50 mL), washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The organic residue was purified by normal phase column chromatography using 0%→20% ethyl acetate in hexanes, with the product eluting at 20%. The fractions were concentrated to give compound 1-1-2 (1.05 g, quantitative yield) as a white solid. LCMS RT = 1.27 min; MS calculated: 201.28; Found: [M]+: N / A. 1 H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 2.0 Hz, 1H), 7.55 - 7.51 (m, 1H), 6.87 (dd, J = 8.5, 4.5 Hz, 1H), 3.91 (dd, J = 4.4, 0.4 Hz, 1H), 3.54 (d, J = 4.4 Hz, 1H), 1.60 (s, 3H), 1.30 (s, 3H).

[0383] Process 2 [ka]

[0384] A solution of 2-pyrrolidinone (713 μL, 6.29 mmol) and compound 1-1-2 (1.05 g, 5.24 mmol) in DMSO (26.2 mL) was treated with sodium hydride (60% dispersion in mineral oil, 151 mg, 6.29 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were combined, washed with brine, dried, filtered, and concentrated. 5 mL of DCM and a few drops of EtOH were added to the crude residue, which was then sonicated and filtered to give levcromakalim (0.93 g, 62% yield) as a white solid. LCMS RT = 1.08 min; MS calculated: 286.13; Found: [M+H] + : 287.2. 1 H NMR (400 MHz, CDCl3) δ 7.51 - 7.41 (m, 1H), 7.25 - 7.24 (m, 1H), 6.89 (d, J = 8.5 Hz, 1H), 5.28 (d, J = 10.4 Hz, 1H), 3.75 (d, J = 10.4 Hz, 1H), 3.33 (dd, J = 16.9, 7.8 Hz, 1H), 3.10 - 3.02 (m, 1H), 2.67 - 2.48 (m, 2H), 2.22 - 2.02 (m, 2H), 1.54 (s, 3H), 1.28 (s, 3H). Levcromakalim ee analysis: Analytical column: ChiralPak IA, 250 mm x 4.6 mm (inner diameter), 5 μm; Mobile phase: 8:8:84 MeOH:DCM:Hexane; Isocratic flow: 1 mL / min; (pressure was 49.5 bar); Column temperature: approx. 26°C; Run time: 12 min; Wavelength: 254 nm RT of peak number 1 = RT1 = 9.3 min (width at mid-height = W1 = 0.1546 min) RT of peak number 2 = RT2 = 10.0 min (width at mid-height = W2 = 0.1696 min) Enantiomeric excess >99%.

[0385] Process 3 [ka]

[0386] To a suspension of levcromakalim (300 mg, 1.05 mmol) and imidazole (89.2 mg, 1.31 mmol) in THF (5.24 mL) was added phosphorus trichloride (46.2 μL, 524 μmol). The reaction was stirred overnight at 50° C. After fairly complete conversion to the product, the reaction was concentrated and used directly in the subsequent step without further purification.

[0387] LCMS RT = 1.45 min; MS calculated: 618.22; Found: [M+H] + : 619.4.

[0388] Process 4 [ka]

[0389] Compound 1-3-2 (324 mg, 524 μmol) was dissolved in pyridine / water (10:1) (5.24 mL), and then iodine (400 mg, 1.57 mmol) was added to the solution and stirred at room temperature for 1 h. The reaction was concentrated and acidified to pH=1 with 1N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness. The residue was purified by reverse phase column chromatography (60 g) using 0%→20%→40% ACN in water. The product was eluted with 35% ACN in water. The fractions were concentrated to give compound 1 (252 mg, 76% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.66 (dd, J = 8.4, 1.8 Hz, 2H), 7.47 (s, 2H), 7.02 (d, J = 8.5 Hz, 2H), 5.19 (d, J = 8.1 Hz, 2H), 4.45 (t, J = 9.7 Hz, 2H), 3.52 - 3.38 (m, 2H), 3.01 - 2.85 (m, 2H), 2.41 (dd, J = 16.3, 7.6 Hz, 2H), 2.30 - 2.20 (m, 2H), 2.03 - 1.88 (m, 4H), 1.53 (s, 6H), 1.22 (s, 6H). LCMS RT = 2.26 min (7 min run); MS calculated: 634.22; Found: [M] + : 635.4. LCMS showed compound 1 as a single enantiomer. Compound 1 LCMS RT = 2.26 min (7 min run) The diastereomers of compound 1 were made according to the procedure described above. LCMS RT of compound 1 diastereomer = 2.07 min (7 min run).

[0390] Method B for synthesizing compound 1 Process 3 [ka]

[0391] The vessel was charged with levcromakalim (1.0 wt) followed by MEK (20 vol) at 18°C-23°C. Pyridine (6 eq, 1.3 vol) was then added and the resulting slurry was cooled to 0°C-5°C before adding POCl3 (4 eq, 1.7 vol) while maintaining the temperature between 0°C and 5°C. The temperature of the reaction mixture was then adjusted to 18°C-23°C and the mixture was stirred for 18 hours. Analysis by HPLC indicated 98.1% conversion to compound 1-4-1. Additional POCl3 (1 eq) was added and the reaction was stirred for an additional 3 hours. HPLC analysis indicated 98.3% conversion to compound 1. The mixture was stirred for an additional 18 hours before being quenched with 2M HCl (8.0 vol). The mixture was heated to 60°C-65°C and stirred at this temperature for 2 hours before being cooled to 18°C-23°C. The organic and aqueous layers were separated and the acidic phase was back extracted with MEK (5.0 vol). The combined organic layers were washed with brine (13% w / w, 5 vol) and the aqueous phase was back extracted with MEK (2×2.5 vol). The organic layer was allowed to stand overnight at which point a yellow solid precipitated. The mixture was concentrated under reduced pressure at 40° C. to give a residue. The residue was dissolved in MEK (5.0 vol) and the mixture was concentrated under reduced pressure at 40° C. to give a residue. The crude product (63% uncorrected yield) was analyzed by HPLC and LCMS. The crude mixture contained product as analyzed by LCMS ([MH] + =635.40).

[0392] The crude product was transferred to a second vessel and the slurry was washed with MeCN (5.0 vol) for 20 min at ambient temperature. The product was isolated by filtration through a filter paper and the cake was washed with MeCN (1.0 vol). The product was dried on the filter paper under vacuum with a nitrogen bleed for 2 h. The isolated product (26% uncorrected yield) showed high purity (96.78% area purity by HPLC).

[0393] Example 2 Formation of the calcium salt of compound 1 [ka]

[0394] To a 4-dram vial was added compound 1 (4.20 mg, 6.62 μmol) in a 1:1 mixture of THF (200 μL):HO (200 μL). To this solution was added a 0.0216 M solution of calcium hydroxide (95%) (306 μL, 6.62 μmol). The solution was sonicated, directly freeze-dried, and lyophilized to give compound 5 as a solid.

[0395] UPLC: Waters Acquity UPLC CSH C18, 1.8 μm, 2.1 mm × 30 mm, at 40 °C; 5% → 100% B in 2.0 min, hold 100% B for 0.7 min, run time = 2.7 min, eluent: A = Milli-Q HO 10 mM ammonium formate (pH = 3.8), B = MeCN. m / z [ESI + ]=635.3, Rt=1.14 minutes.

[0396] HNMR: 1H NMR (400 MHz, dmso) δ 7.62 (dd, J = 8.5, 1.8 Hz, 1H), 7.34 (s, 1H), 6.96 (d, J = 8.5 Hz, 1H), 5.03 (d, J = 10.3 Hz, 1H), 4.41 (t, J = 10.4 Hz, 1H), 3.73 (dd, J = 14.0, 8.1 Hz, 1H), 2.89 (d, J = 5.5 Hz, 1H), 2.43 - 2.25 (m, 2H), 2.04 - 1.81 (m, 2H), 1.54 (s, 3H), 1.20 (s, 3H).

[0397] Example 3 Formation of the sodium salt of compound 1 [ka]

[0398] To a 4-dram vial was added compound 1 (4.20 mg, 6.62 μmol) in a 1:1 mixture of THF (200 μL):HO (200 μL). To this solution was added a 0.25 M solution of sodium hydroxide (26.5 μL, 6.62 μmol). The solution was sonicated, directly freeze-dried, and lyophilized to give compound 6 as a solid.

[0399] UPLC: Waters Acquity UPLC CSH C18, 1.8 μm, 2.1 mm × 30 mm, at 40 °C; 5% → 100% B in 2 min, hold 100% B for 0.7 min, run time = 2.7 min, eluent: A = Milli-Q HO 10 mM ammonium formate (pH = 3.8), B = MeCN. m / z [ESI + ]=635.3, Rt=1.14 minutes.

[0400] HNMR: 1H NMR (400 MHz, dmso) δ 7.61 (dd, J = 8.5, 1.8 Hz, 1H), 7.31 (s, 1H), 6.96 (d, J = 8.5 Hz, 1H), 5.01 (d, J = 10.5 Hz, 1H), 4.40 (t, J = 10.5 Hz, 1H), 3.76 (dd, J = 14.0, 8.2 Hz, 1H), 2.88 (d, J = 6.0 Hz, 1H), 2.41 - 2.25 (m, 2H), 2.02 - 1.83 (m, 2H), 1.53 (s, 3H), 1.19 (s, 3H).

[0401] Example 4 Formation of the potassium salt of compound 1 [ka]

[0402] To a 4 dram vial was added compound 1 (4.20 mg, 6.62 μmol) in a 1:1 mixture of THF (200 μL):HO (200 μL). To this solution was added a 0.25 M solution of potassium hydroxide (26.5 μL, 6.62 μmol). The solution was sonicated, directly freeze-dried, and lyophilized to give compound 7 as a solid.

[0403] UPLC: Waters Acquity UPLC CSH C18, 1.8 μm, 2.1 mm × 30 mm, at 40 °C; 5% → 100% B in 2 min, hold 100% B for 0.7 min, run time = 2.7 min, eluent: A = Milli-Q HO 10 mM ammonium formate (pH = 3.8), B = MeCN. m / z [ESI + ]=635.3, Rt=1.14 minutes.

[0404] HNMR: 1H NMR (400 MHz, dmso) δ 7.61 (dd, J = 8.5, 2.0 Hz, 1H), 7.31 (d, J = 1.1 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 5.01 (d, J = 10.5 Hz, 1H), 4.40 (t, J = 10.5 Hz, 1H), 3.77 (dd, J = 14.18.3 Hz, 1H), 2.87 (d, J = 5.8 Hz, 1H), 2.39 - 2.24 (m, 2H), 2.02 - 1.82 (m, 2H), 1.53 (s, 3H), 1.19 (s, 3H).

[0405] Example 5 Formation of the tetramethylammonium salt of compound 1 [ka]

[0406] To a 4 dram vial was added compound 1 (4.00 mg, 6.30 μmol) in a 1:1 mixture of THF (200 μL):HO (200 μL). To this solution was added a 2.5% solution of tetramethylammonium hydroxide (10% in water) (23.0 μL, 6.30 μmol). The solution was sonicated, directly freeze-dried, and placed in lyo to give compound 8 as a solid.

[0407] UPLC: Waters Acquity UPLC CSH C18, 1.8 μm, 2.1 mm × 30 mm, at 40 °C; 5% → 100% B in 2 min, hold 100% B for 0.7 min, run time = 2.7 min, eluent: A = Milli-Q HO 10 mM ammonium formate (pH = 3.8), B = MeCN. m / z [ESI + ]=635.3, Rt(A05)=1.14 minutes.

[0408] HNMR: 1H NMR (400 MHz, dmso) δ 7.60 (dd, J = 8.4, 1.9 Hz, 1H), 7.30 (d, J = 1.1 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 5.01 (d, J = 10.6 Hz, 1H), 4.40 (t, J = 10.5 Hz, 1H), 3.78 (dd, J = 14.1, 8.3 Hz, 1H), 3.09 (s, 9H), 2.95 - 2.76 (m, 1H), 2.03 - 1.82 (m, 2H), 1.53 (s, 3H), 1.19 (s, 3H). NOTE: The peak at 3.09 should be the 12H for the salt.

[0409] Example 6 Synthesis of compound 9 General method All oxygen and / or moisture sensitive reactions were carried out under a N2 atmosphere. All reagents and solvents were purchased from commercial suppliers and used as received. HPLC conditions for all reported LCMS: Waters Acquity UPLC CSH C18, 1.8 μm, 2.1 mm x 30 mm, at 40 °C; 5% → 100% B in 2 min, hold 100% B for 0.7 min, run time = 2.7 min, eluent: A = Milli-Q H2O + 10 mM ammonium formate (pH = 3.8), B = MeCN. Waters Acquity H-Class UPLC system. UV detector = Waters Acquity PDA, 195 nm to 360 nm. MS detector = Acquity QDa Performance ESI.

[0410] Process 1 [ka]

[0411] To a solution of levcromakalim (50.0 mg, 0.175 mmol) in DMF (2.00 mL) under a nitrogen balloon at room temperature was added sodium hydride (60% dispersion in mineral oil) (48.9 mg, 1.22 mmol). The solution was stirred for 3 minutes before sodium iodide (10.0 mg, 66.7 μmol) was added. Finally, (2-bromoethoxy)-tert-butyldimethylsilane (262 μL, 1.22 mmol) was added dropwise and the reaction was stirred for 20 minutes before quenching the reaction by adding 3 mL of water. The reaction mixture was concentrated under vacuum to remove methanol and DMF. Water was then added again and the product was extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified by flash column chromatography (silica, eluent gradient: 0% to 100% ethyl acetate in heptane) to afford compound 9-1-2 (65.0 mg, 84%) as a yellow viscous oil.

[0412] NOTE: Reactions carried out for longer, such as 1 hour or overnight, will produce dehydration by-products and must be quenched shortly. Compound 9-1-2: LCMS RT = 1.94 min; MS calculated value: 444.64; Found value: [M+H] + : 445.3.

[0413] Process 2 [ka]

[0414] Compound 9-1-2 (64.0 mg, 0.144 mmol) was dissolved in THF (1.44 mL) in a 4 mL vial. To this solution was added tetrabutylammonium fluoride (1.0 M in THF) (45.0 μL, 0.288 mmol) at room temperature. The reaction was stirred at room temperature for 20 min, after which LCMS showed complete conversion to the desired product. The reaction mixture was concentrated in vacuo, dissolved in EtOAc, and the crude solution was passed through a silica pad to remove TBAF. The filtrate was concentrated to give compound 9-2-2 (40.0 mg, 84%) as an amorphous white solid.

[0415] NOTE: Purification should be performed on the same day, as approximately 10% dehydration byproduct was observed overnight. Compound 9-2-2: LCMS RT = 1.08 min; MS calculated: 330.38; Found: [M+H] + : 331.1.

[0416] Process 3 [ka]

[0417] To a suspension of levcromakalim (20 mg, 0.07 mmol) in DCM (0.80 mL) was added DIPEA (12.12 μL, 0.07 mmol). The suspension was slowly added to a solution of PCl3 (18.28 μL, 0.210 mmol) in DCM (0.80 mL). The reaction was stirred at room temperature for 1 h until the reaction was judged complete. The reaction was then concentrated in vacuo to give crude compound 9-3-2, which was dried under high vacuum and used in the subsequent step without further purification.

[0418] Compound 9-3-2 was dissolved in DCM (1.00 mL). To this solution was added a solution of compound 9-2-2 (22 mg, 0.070 mmol) and DIPEA (12.12 μL, 0.07 mmol) in DCM (0.50 mL). The reaction mixture was stirred at room temperature for 16 h to give the crude disubstituted intermediate. The crude was concentrated in vacuo and dissolved in pyridine / water (10:1) (0.30 mL) before adding iodine (23 mg, 0.091 mmol) to the solution. The resulting solution was stirred at room temperature for 15 min. LCMS showed complete conversion to the desired product. The reaction was concentrated and acidified to pH=1 with HCl (1N) before being extracted three times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified by preparative HPLC using the method shown below to give compound 9 (9.00 mg, 39% yield) as a white solid.

[0419] NOTE: Ammonium formate (pH 3.8) is ideal for purification as the LCMS method shows decomposition in the final compound when ammonium bicarbonate is used.

[0420] 1H NMR (400 MHz, DMSO-d6) δ 7.65 - 7.61 (m, 1H), 7.61 - 7.58 (m, 1H), 7.39 (s, 1H), 7.30 (s, 1H), 6.97 (d, J = 3.6 Hz, 1H), 6.95 (d, J = 3.5 Hz, 1H), 5.07 (d, J = 10.5 Hz, 1H), 5.05 - 4.97 (m, 1H), 4.35 (t, J = 10.4 Hz, 1H), 3.82 - 3.56 (m, 6H), 3.52 - 3.40 (m, 1H), 3.09 - 2.91 (m, 1H), 2.84 - 2.73 (m, 1H), 2.48 - 2.36 (m, 3H), 2.34 - 2.21 (m, 1H), 2.09 - 1.85 (m, 4H), 1.52 (s, 3H), 1.50 (s, 3H), 1.18 (s, 6H) (no exchangeable OH was observed, this contains 2.3 wt% formic acid). LCMS RT = 1.16 min (2.7 min run); MS calculated: 678.67; Found: [M+H] + : 679.4. Purification method: PPIMS03 Prep-QDa.

[0421] overview Instrumentation: Waters Prep LC-MS LC: Automated purification LC-MS (2545 Quaternary, Solvent heater, 2767, SFO, 515, 515, 2998, QDa Performance) MassLynx 4.1 SCN 947 / 961 / FractionLynx UV detection: Waters PDA 2998 (198nm~360nm) MS detection: Waters QDa Performance, ESI (ES(+ / -), 100amu~1200amu) Mobile phase at 40°C Eluent A: 10 mM ammonium formate in Milli-Q H2O (pH = 3.8) Eluent B: Acetonitrile Precolumn: XBridge Prep C18, 5μm 19mm×10mm Column: CSH Prep C18 OBD, 5 μm, 30 mm x 75 mm Gradient: 0 min = 10% B, 1 min = 10% B, 12 min = 30% B, 12.1 min = 100% B, 15 min = 100% Flow rate: 45mL / min Run Time: 15 minutes Trigger used: MS (mass A = 678.67).

[0422] Example 7 Synthesis of compound 10 General method All oxygen and / or moisture sensitive reactions were carried out under a N2 atmosphere. All reagents and solvents were purchased from commercial suppliers and used as received. HPLC conditions for all reported LCMS: Column: XBridge C18, 3.5 μm, 4.6 mm×30 mm at 25° C.; gradient for 3 min run: 5%→100% B in 2.0 min; hold 100% B for 0.7 min, run time=2.7 min. Gradient for 7 min run: 5% B for 0.5 min, 5%→100% B in 5 min, hold 100% B for 1.5 min, flow rate: 3 mL / min. Eluent A: 10 mM ammonium formate in water (pH=3.8); Eluent B: acetonitrile (no additives).

[0423] Process 1 [ka]

[0424] Sodium hydride (60% dispersion in mineral oil) (21.0 mg, 524 μmol) was added to a solution of levcromakalim (50.0 mg, 175 μmol) in DMF (1.00 mL) at room temperature, resulting in the formation of bubbles. After 5 min, sodium iodide (5.29 mg, 34.9 μmol) was added, followed by (2-bromoethoxy)-tert-butyldimethylsilane (116 μL, 524 μmol). Upon completion (approximately 30 min, as monitored by TLC or LCMS), the reaction was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The organic layers were combined, dried, and concentrated. The resulting residue was purified on a 24 g normal phase column using 0%→40% ethyl acetate in hexanes, and the product eluted with 36% ethyl acetate in hexanes. The fractions were concentrated to give compound 9-1-2 (75.2 mg, 97% yield) as a colorless oil. Compound 9-1-2: LCMS R T = 2.00 min; MS calculated: 444.24; Found: [M] + : 445.3.

[0425] Process 2 [ka]

[0426] To compound 9-1-2 (75.2 mg, 169 μmol) in THF (1 mL) was added tetrabutylammonium fluoride (1.0 M in THF) (338 μL, 338 μmol). After stirring at room temperature for 20 min, the reaction was judged complete. The reaction mixture was concentrated under vacuum and directly purified on normal phase on a 24 g column using 60%→100% ethyl acetate in hexanes, and the product compound 2-2 eluted with 100% ethyl acetate to give 52 mg of a colorless solid.

[0427] NOTE: Purification should be done on the same day. Dehydration products were observed in the crude mixture over time. Compound 9-2-2: LCMS RT = 1.10 min; MS calculated: 330.16; Found: [M+H] +: 331.1.

[0428] Process 3 [ka]

[0429] To a suspension of compound 9-2-2 (52.0 mg, 157 μmol) and imidazole (13.4 mg, 197 μmol) in THF (1 mL) was added phosphorus trichloride (6.94 μL, 78.7 μmol). The reaction was stirred overnight at 50° C. The reaction was concentrated and used directly in the subsequent step without further purification.

[0430] Process 4 [ka]

[0431] To a crude mixture of compound 10-3-2 (55.6 mg, 78.7 μmol) in pyridine / water (10:1) (787 μL) was added iodine (60.0 mg, 236 μmol). After 0.5 h, the reaction was judged complete. The reaction solution was concentrated and acidified with a few drops of 6N HCl before loading onto a reverse phase column and purification with 0%→20%→40% ACN in water. The product eluted with 35% ACN in water. The fractions were concentrated to give compound 10 (25.1 mg, 44% yield) as a white solid.

[0432] 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (dd, J = 8.5, 1.9 Hz, 2H), 7.40 (s, 2H), 6.97 (d, J = 8.5 Hz, 2H), 5.03 (s, 2H), 3.91 - 3.69 (m, 10H), 3.34 (s, 1H), 3.01 (s, 2H), 2.40 (ddd, J = 32.2, 16.4, 7.8 Hz, 4H), 2.06 - 1.93 (m, 4H), 1.51 (s, 6H), 1.17 (s, 6H). LCMS RT = 1.25 min; MS calculated: 722.27; Found: [M] + : 723.4.

[0433] Example 8 Synthesis of compound 11 Process 1 [ka]

[0434] Sodium hydride (60% dispersion in mineral oil) is added to a solution of levcromakalim in DMF at room temperature, resulting in the formation of bubbles. After 5 minutes, sodium iodide is added, followed by (2-bromoethoxy)-tert-butyldimethylsilane. Upon completion (approximately 30 minutes, as monitored by TLC or LCMS), the reaction is diluted with water and extracted with ethyl acetate. The organic layers are combined, dried, and concentrated. The resulting residue is purified by normal phase column using ethyl acetate in hexane. The fractions are concentrated to give compound 11-1-2.

[0435] Process 2 [ka]

[0436] To compound 11-1-2 in THF is added tetrabutylammonium fluoride (1.0 M in THF). The reaction is stirred until judged complete. The reaction mixture is concentrated in vacuo and purified on a normal phase column using ethyl acetate in hexanes to give compound 11-2-2.

[0437] Process 3 [ka]

[0438] To a suspension of levcromakalim in DCM, DIPEA is added. The suspension is slowly added to a solution of PCl3 in DCM. The reaction is stirred at room temperature for 1 hour until the reaction is judged complete. The reaction is then concentrated in vacuo to give a crude mixture that is dried under high vacuum and used in the subsequent step without further purification.

[0439] The crude mixture from the previous step is dissolved in DCM. To this solution is added a solution of compound 11-2-2 and DIPEA in DCM. The reaction mixture is stirred at room temperature for 16 hours to give crude compound 11-3-3. The crude was concentrated in vacuo and carried on to the next step without further purification.

[0440] Process 4 [ka]

[0441] Iodine is added to a crude mixture of compound 11-3-3 in pyridine / water (10:1). After approximately 0.5 hours or when the reaction is deemed complete, the reaction solution is concentrated and acidified with a few drops of 6N HCl before loading onto a reverse phase column and purifying with ACN in water. The product fractions are concentrated to give compound 11.

[0442] Alternatively, the product from step 2 can be converted to a pharma- ceutically acceptable salt: [ka]

[0443] To a 4 dram vial is added compound 11-2-2 in a 1:1 mixture of THF:H2O. To this solution is added a 0.25 M solution of sodium hydroxide. The solution is sonicated, directly freeze-dried, and lyophilized to give compound 11-5-1 as a solid. Alternative salts including potassium and tetramethylammonium can be synthesized by similar procedures.

[0444] Example 9 Synthesis of compound 12 Process 1 [ka]

[0445] Sodium hydride (60% dispersion in mineral oil) is added to a solution of levcromakalim in DMF at room temperature, resulting in the formation of bubbles. After 5 minutes, sodium iodide is added, followed by (2-bromoethoxy)-tert-butyldimethylsilane. Upon completion (approximately 30 minutes, as monitored by TLC or LCMS), the reaction is diluted with water and extracted with ethyl acetate. The organic layers are combined, dried, and concentrated. The resulting residue is purified by normal phase column using ethyl acetate in hexane. The fractions are concentrated to give compound 12-1-2.

[0446] Process 2 [ka]

[0447] To compound 12-1-2 in THF is added tetrabutylammonium fluoride (1.0 M in THF). The reaction is stirred until judged complete. The reaction mixture is concentrated in vacuo and purified on a normal phase column using ethyl acetate in hexanes to give compound 12-2-2.

[0448] Process 3 [ka]

[0449] To a suspension of compound 12-2-2 in DCM, DIPEA is added. The suspension is slowly added to a solution of PCl3 in DCM. The reaction is stirred at room temperature for 1 hour until the reaction is judged complete. The reaction is then concentrated in vacuo to give a crude mixture that is dried under high vacuum and used in the subsequent step without further purification.

[0450] Process 4 [ka]

[0451] Iodine is added to a crude mixture of compound 12-3-2 in pyridine / water (10:1). After approximately 0.5 hours or when the reaction is deemed complete, the reaction solution is concentrated and acidified with a few drops of 6N HCl before loading onto a reverse phase column and purifying with ACN in water. The product fractions are concentrated to give compound 12.

[0452] Example 10 Synthesis of compound 13 Process 1 [ka]

[0453] To a suspension of compound 12-3-2 and imidazole in THF is added levcromakalim. The reaction is stirred overnight at 50° C. The reaction is concentrated and used directly in the next step without further purification.

[0454] Process 2 [ka]

[0455] Iodine is added to a crude mixture of compound 13-1-2 in pyridine / water (10:1). After approximately 0.5 hours or when the reaction is deemed complete, the reaction solution is concentrated and acidified with a few drops of 6N HCl before loading onto a reverse phase column and purifying with ACN in water. The product fractions are concentrated to give compound 13.

[0456] Example 11 Synthesis of compound 14 Process 1 [ka]

[0457] Sodium hydride (60% dispersion in mineral oil) is added to a solution of levcromakalim in DMF at room temperature, resulting in the formation of bubbles. After 5 minutes, sodium iodide is added, followed by (2-bromoethoxy)-tert-butyldimethylsilane. Upon completion (approximately 30 minutes, as monitored by TLC or LCMS), the reaction is diluted with water and extracted with ethyl acetate. The organic layers are combined, dried, and concentrated. The resulting residue is purified by normal phase column using ethyl acetate in hexane. The fractions are concentrated to give compound 14-1-2.

[0458] Process 2 [ka]

[0459] To compound 14-1-2 in THF is added tetrabutylammonium fluoride (1.0 M in THF). The reaction is stirred until judged complete. The reaction mixture is concentrated in vacuo and purified on a normal phase column using ethyl acetate in hexanes to give compound 14-2-2.

[0460] Process 3 [ka]

[0461] To a suspension of compound 14-2-2 in DCM, DIPEA is added. The suspension is slowly added to a solution of PCl3 in DCM. The reaction is stirred at room temperature for 1 hour until the reaction is judged complete. The reaction is then concentrated in vacuo to give a crude mixture that is dried under high vacuum and used in the subsequent step without further purification.

[0462] Process 4 [ka]

[0463] Iodine is added to a crude mixture of compound 14-3-2 in pyridine / water (10:1). After approximately 0.5 hours or when the reaction is deemed complete, the reaction solution is concentrated and acidified with a few drops of 6N HCl before loading onto a reverse phase column and purifying with ACN in water. The product fractions are concentrated to give compound 14.

[0464] Alternatively, the product from step 2 can be converted to a pharma- ceutically acceptable salt: [ka]

[0465] To a 4 dram vial is added compound 14-2-2 in a 1:1 mixture of THF:H2O. To this solution is added a 0.25 M solution of sodium hydroxide. The solution is sonicated, directly freeze-dried, and lyophilized to give compound 14-5-1 as a solid.

[0466] Example 12 Synthesis of compound 15 Process 1 [ka]

[0467] To a suspension of compound 1-3-2 and imidazole in THF is added 12-2-2. The reaction is stirred overnight at 50° C. The reaction is concentrated and used directly in the next step without further purification.

[0468] Process 2 [ka]

[0469] Iodine is added to a crude mixture of compound 15-1-3 in pyridine / water (10:1). After approximately 0.5 hours or when the reaction is deemed complete, the reaction solution is concentrated and acidified with a few drops of 6N HCl before loading onto a reverse phase column and purifying with ACN in water. The product fractions are concentrated to give compound 15.

[0470] Example 13 Synthesis of compound 16 Process 1 [ka]

[0471] To a suspension of compound 1-3-2 and imidazole in THF is added 14-2-2. The reaction is stirred overnight at 50° C. The reaction is concentrated and used directly in the next step without further purification.

[0472] Process 2 [ka]

[0473] Iodine is added to a crude mixture of compound 16-1-3 in pyridine / water (10:1). After approximately 0.5 hours or when the reaction is deemed complete, the reaction solution is concentrated and acidified with a few drops of 6N HCl before loading onto a reverse phase column and purifying with ACN in water. The product fractions are concentrated to give compound 16.

[0474] Example 14 Synthesis of compound 17 [ka]

[0475] A 5 mL microwave vial was charged with compound 1-4-1 (50 mg, 0.13 mmol, 1 equiv), 1,6-hexanediol (8.0 mg, 0.07 mmol, 0.5 equiv), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (30 mg, 0.15 mmol, 1.1 equiv). Pyridine (3 mL) was added to the mixture and the vial was sealed. The reaction was stirred at room temperature for 16 h. The reaction was judged complete by HPLC analysis. The crude reaction mixture was diluted with diethyl ether (5 mL) and allowed to stand to form a film. The diethyl ether was decanted and the residue was washed with diethyl ether (5 mL), decanted, the residue was dissolved in ethanol, 10 drops of 2M HCl in diethyl ether was added, and the mixture was evaporated to dryness to give an amber film (56 mg, 77%). 1H NMR (MeOD): δ 1.22 (4H, tt, J = 7.5, 7.0 Hz), 1.31 (6H, s), 1.57 (4H, tt, 7.5, 7.0 Hz), 1.66 (6H, s), 2.06-2.14 (4H, m), 2.51-2.57 (4H, m), 3.55-3.63 (4H, m), 4.12 (4H, m), 4.66 (2H, d, J = 7.9 Hz), 5.36 (2H, J = 7.9 Hz), 6.96 (2H, dd, J = 8.4), 7.35 (2H, s), 7.58 (2H, dd, J = 8.4, 1.9 Hz).

[0476] Example 15 Synthesis of compound 18 [ka]

[0477] A 5 mL microwave vial was charged with compound 1-4-1 (50 mg, 0.13 mmol, 1 equiv), triethylene glycol (10.2 mg, 0.07 mmol, 0.5 equiv), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (29 mg, 0.15 mmol, 1.1 equiv). Pyridine (0.5 mL) was added to the mixture and the vial was sealed. The reaction was stirred at room temperature for 16 hours. The reaction was judged complete by HPLC analysis. The crude reaction mixture was evaporated to dryness to give an amber film. A few drops of 2N HCl in diethyl ether were added, followed by 1 mL of ethyl acetate. The mixture was then filtered through a 0.45 μm PTFE syringe filter and evaporated to give an amber film (22 mg, 37%). 1H NMR (MeOD): δ 1.31 (6H, s), 1.52 (6H, s), 2.12-2.16 (4H, m), 2.54-2.60 (4H, m), 3.52-3.66 (12H, m), 4.22 (4H, m), 4.72 (2H, d, J = 7.9 Hz), 5.38 (2H, J = 7.9 Hz), 6.98 (2H, dd, J = 8.4), 7.37 (2H, s), 7.54 (2H, dd, J = 8.4, 1.9 Hz).

[0478] Example 16 Synthesis of compound 19 [ka]

[0479] A microwave vial was charged with compound 1-4-1 (50 mg, 0.13 mmol, 1 equiv), 1,6-hexanediol (34 mg, 0.29 mmol, 2.1 equiv), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (131 mg, 0.68 mmol, 5 equiv). Pyridine (0.5 mL) was added to the mixture and the vial was sealed. The reaction was stirred at room temperature for 16 h. The reaction was judged complete by HPLC analysis. The crude reaction mixture was evaporated to dryness to give an amber residue (66 mg). The crude material was diluted with 0.5 mL of 1N HCl, extracted with ethyl acetate (1 mL), the layers were separated, and the organic layer was evaporated to dryness to give a slightly yellow film (23 mg, 38%). 1H NMR (MeOD): δ 1.27 (4H, m), 1.37 (3H, s), 1.57 (4H, m), 1.60 (3H, s), 2.06-2.14 (2H, m), 2.51-2.57 (2H, m), 3.55-3.63 (4H, m), 4.12 (2H, m), 4.66 (1H, d, J = 7.9 Hz), 5.36 (1H, d, J = 7.9 Hz), 6.96 (1H, dd, J = 8.4), 7.35 (1H, s), 7.58 (1H, dd, J = 8.4, 1.9 Hz).

[0480] Example 17 Synthesis of compound 20 [ka]

[0481] A microwave vial was charged with compound 1-4-1 (50 mg, 0.13 mmol, 1 equiv), triethylene glycol (43 mg, 0.29 mmol, 2.1 equiv), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (131 mg, 0.68 mmol, 5 equiv). Pyridine (0.5 mL) was added to the mixture and the vial was sealed. The reaction was stirred at room temperature for 16 h. The reaction was judged complete by HPLC analysis. The crude reaction mixture was evaporated to dryness to give an amber residue (64 mg). The crude material was diluted with 0.5 mL of 1N HCl, extracted with ethyl acetate (1 mL), the layers were separated, and the organic layer was evaporated to dryness to give a slightly yellow film (7 mg, 10%). 1H NMR (MeOD): δ 1.32 (3H, s), 1.58 (3H, s), 2.03-2.10 (2H, m), 2.52-2.58 (2H, m), 3.48-3.52 (2H, m), 3.68-3.74 (10H, m), 4.34 (2H, m), 4.75 (1H, d, J = 7.9 Hz), 5.30 (1H, d, J = 7.9 Hz), 6.97 (1H, dd, J = 8.4), 7.38 (1H, s), 7.54 (1H, dd, J = 8.4, 1.9 Hz).

[0482] Example 18 Synthesis of compound 21 [ka]

[0483] Compound 1, compound 19, and EDCI are added to pyridine in a reaction tube. The reaction is stirred at room temperature for 48 hours. When the reaction is judged complete by HPLC analysis, the crude reaction mixture is evaporated to dryness. The crude material is diluted with 1N HCl, extracted with ethyl acetate, the layers are separated, and the organic layer is evaporated to dryness to give compound 21.

[0484] The present specification has been described with reference to embodiments of the present invention. However, it will be understood by those skilled in the art that various modifications and changes can be made without departing from the scope of the present invention as described herein. Accordingly, the present specification is to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of the present invention.

Claims

1. formula: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof.

2. formula: 【Chemistry 2】 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

3. formula: 【Chemistry 3】 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

4. formula: 【Chemistry 4】 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

5. formula: 【Chemistry 5】 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

6. Formula I: 【Chemistry 6】 (In the formula, X ＋ is optionally a pharma- ceutically acceptable counterbalancing cation selected from an alkali metal cation or an ammonium ion.

7. X ＋ is Na ＋ , K ＋ , Li ＋ , and Cs ＋ 7. The compound of formula I according to claim 6, selected from:

8. X ＋ teeth, 【Chemistry 7】 7. The compound of formula I according to claim 6, selected from:

9. Formula II: 【Chemistry 8】 (In the formula, M ２＋ is a pharma- ceutically acceptable divalent cation optionally selected from an alkaline earth metal cation, a metal cation having an oxidation state of +2, or an ammonium ion having a net positive charge of two.

10. M ２＋ is Mg ２＋ , Ca ２＋ , Sr ２＋ , Zn ２＋ , and Fe ２＋ 10. The compound of formula II according to claim 9, selected from:

11. M ２＋ teeth, 【Chemistry 9】 10. The compound of formula II according to claim 9, selected from:

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof, optionally in a pharma- ceutically acceptable carrier.

13. A pharmaceutical composition comprising a compound according to any one of claims 6 to 11, optionally in a pharma- ceutically acceptable carrier.

14. 14. The pharmaceutical composition of claim 12 or 13, wherein the pharma- ceutically acceptable carrier is suitable for local delivery.

15. 15. The pharmaceutical composition of claim 14, wherein the carrier is in the form of aqueous drops, a lotion, a cream, a gel, a mist, an ointment, a skin patch, or a spray.

16. 14. The pharmaceutical composition of claim 12 or 13, wherein the pharma- ceutically acceptable carrier is in the form of a solution, suspension, or emulsion.

17. 14. The pharmaceutical composition of claim 12 or 13, wherein the pharma- ceutically acceptable carrier is suitable for ocular delivery.

18. 14. The pharmaceutical composition of claim 12 or 13, wherein the pharma- ceutically acceptable carrier is in the form of a solution, suspension, or emulsion.

19. A pharmaceutical composition for treating a disorder in a host that can be treated with a vasodilator, comprising a compound according to any one of claims 1 to 11, optionally in a pharma- ceutical acceptable carrier.

20. 20. The pharmaceutical composition of claim 19, wherein the disorder is an ophthalmic, cardiovascular, vascular, musculoskeletal, endocrine, pulmonary, urological, dermatological, or neurological disease or disorder.

21. 21. The pharmaceutical composition of claim 19 or 20, wherein the disorder is glaucoma.

22. 21. The pharmaceutical composition of claim 19 or 20, wherein the disorder is selected from elevated episcleral venous pressure (EVP), normal tension glaucoma, open angle glaucoma, ocular hypertension, Graves' ophthalmopathy, Graves' orbitopathy (GO), retrobulbar tumors, cavernous sinus thrombosis, orbital vein thrombosis, episcleral / orbital venous vasculitis, superior vena cava occlusion, superior vena cava thrombosis, carotid cavernous fistula, dural cavernous shunt, orbital varicose veins, and Sturge-Weber syndrome.

23. The pharmaceutical composition according to any one of claims 19 to 22, wherein the host is a human.

24. 12. Use of a compound according to any one of claims 1 to 11, optionally in a pharma- ceutically acceptable carrier, in the manufacture of a medicament for the treatment of a disorder treatable with a vasodilator.

25. 25. The use according to claim 24, wherein the disorder is an ophthalmic, cardiovascular, vascular, musculoskeletal, endocrine, pulmonary, urological, dermatological, or neurological disease or disorder.

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