EP3148983A1 - N-hydroxylaminobarbitursäure-derivate als nitroxyldonatoren - Google Patents

N-hydroxylaminobarbitursäure-derivate als nitroxyldonatoren

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Publication number
EP3148983A1
EP3148983A1 EP15729288.9A EP15729288A EP3148983A1 EP 3148983 A1 EP3148983 A1 EP 3148983A1 EP 15729288 A EP15729288 A EP 15729288A EP 3148983 A1 EP3148983 A1 EP 3148983A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
substituted
heteroaryl
heterocycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP15729288.9A
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English (en)
French (fr)
Inventor
Daryl A. GUTHRIE
John P. Toscano
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Johns Hopkins University
Original Assignee
Johns Hopkins University
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Publication date
Application filed by Johns Hopkins University filed Critical Johns Hopkins University
Publication of EP3148983A1 publication Critical patent/EP3148983A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C07D239/62—Barbituric acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • HNO Nitroxyl
  • the present disclosure relates to nitroxyl donating compounds (referred to herein as nitroxyl donors), pharmaceutical compositions comprising such compounds, kits, and methods of using such compounds or pharmaceutical compositions for treating conditions responsive to nitroxyl therapy.
  • the compounds of the present disclosure produce, or are believed to produce, HNO under physiologically relevant conditions.
  • the compounds of the disclosure have, or are believed to have, suitable toxicological profiles.
  • the present disclosure provides HABA type nitroxyl donating compounds that have half-lives of greater than about 10 minutes when measured under the conditions specified in Example 17 or Example 18.
  • the HABA type nitroxyl donating compounds of the present disclosure have half-lives from about 10 minutes to about 4000 minutes when measured under the conditions specified in Example 17.
  • the HABA type nitroxyl donating compounds of the present disclosure have half-lives from about 15 minutes to about 3900 minutes when measured under the conditions specified in Example 17. In particular embodiments, the HABA type nitroxyl donating compounds of the present disclosure have half-lives from about 10 minutes to about 200 minutes when measured under the conditions specified in Example 18. In specific embodiments, the HABA type nitroxyl donating compounds of the present disclosure have half-lives from about 12 minutes to about 190 minutes when measured under the conditions specified in Example 18.
  • the present disclosure provides HABA type nitroxyl donating compounds that produce a percent yield of HNO greater than about 50% when measured under the conditions specified in Example 17.
  • the HABA type nitroxyl donating compounds of the present disclosure produce a percent yield of HNO from about 75% to about 100%> when measured under the conditions specified in Example 17.
  • the HABA type nitroxyl donating compounds of the present disclosure produce a percent yield of HNO from about 85%o to about 100% when measured under the conditions specified in Example 17.
  • the present disclosure provides HABA type nitroxyl donating compounds that have a half- life of greater than about 10 minutes when measured under the conditions described in Example 17 or Example 18 and that produce a percent yield of HNO greater than about 50%) when measured under the conditions described in Example 17.
  • the present disclosure provides HABA type nitroxyl donating compounds that have a half- life from about 10 minutes to about 4000 minutes when measured under the conditions described in Example 17 and that produce a percent yield of HNO from about 75% to about 100%) when measured under the conditions described in Example 17.
  • the present disclosure provides HABA type nitroxyl donating compounds that have a half- life from about 10 minutes to about 200 minutes when measured under the conditions described in Example 18 and that produce a percent yield of HNO from about 75% to about 100%) when measured under the conditions described in Example 17.
  • the present disclosure provides HABA type nitroxyl donating compounds that have a half- life from about 15 minutes to about 3900 minutes when measured under the conditions described in Example 17 and that produce a percent yield of HNO from about 85% to about 100% when measured under the conditions described in Example 17.
  • the present disclosure provides HABA type nitroxyl donating compounds that have a half- life from about 12 minutes to about 190 minutes when measured under the conditions described in Example 18 and that produce a percent yield of HNO from about 85% to about 100%) when measured under the conditions described in Example 17.
  • the HABA type nitroxyl donating compound is not 5-(N-hydroxylamino)-5-ethyl-N,N-dimethylbarbituric acid or 5-(N-hydroxylamino)-5- (acetyl-0-methyloxime)-N,N-dimethylbarbituric acid.
  • the present disclosure provides a nitroxyl donating compound of the formula (1):
  • each R 1 is independently H or (Ci)alkyl
  • R 2 is (Ci-C6)alkyl substituted with a substituent selected from the group consisting of (C6-Ci 4 )aryl, (C3-C6)cycloalkyl, (C 5 -C 7 )heterocycloalkyl, (5- or 6-membered)heteroaryl and (9- or 10-membered)heteroaryl, wherein said aryl, cycloalkyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 6 ;
  • R 7 is H or (C r C 6 )alkyl.
  • the present disclosure provides a nitroxyl donating compound of the formula (2):
  • each R 1 is independently H or (Ci)alkyl
  • R 2 is selected from the group consisting of a branched (C3-Ce)alkyl, a branched (C 3 - Ce)alkenyl, and a branched (C 3 -Ce)alkoxy, wherein said alkyl, alkenyl, and alkoxy are unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 4 ;
  • R 7 is H or (C r C 6 )alkyl.
  • the present disclosure provides a nitroxyl donating compound of the formula (3):
  • each R 1 is H;
  • R 2 is selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl and (Ci-C 6 )alkoxy, wherein said alkyl, alkenyl, alkynyl and alkoxy are unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 4 ;
  • R 7 is H or (Ci-C 6 )alkyl.
  • the present disclosure provides a nitroxyl donating compound of the formula (4):
  • each R 1 is independently H or (Ci)alkyl
  • R 2 is (C 6 -Cio)aryl, (C 3 -C 6 )cycloalkyl, (C 5 -C 7 )heterocycloalkyl and (5- or 6- membered)heteroaryl, wherein said aryl, cycloalkyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 ;
  • R 7 is H or (C C 6 )alkyl.
  • the present disclosure provides a nitroxyl donating compound of the formula (5):
  • R is hydrogen, -(Ci-C 6 )alkyl, -(C 2 -C 4 )alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(C 5 - C 7 )heterocycloalkyl, benzyloxy, -0-(C r C 6 )alkyl, -NH 2 , -NH-(C r C 4 )alkyl, or -N((C r C 4 )alkyl) 2 , wherein said -(Ci-C 6 )alkyl, -(C 2 -C 4 )alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(C 5 - C 7 )heterocycloalkyl, benzyloxy, -0-(C r C 6 )alkyl, -NH-(C r C 4 )al
  • Compounds of the disclosure are or are believed to be nitroxyl donors under physiologically relevant conditions.
  • compounds (l)-(4), (1 1), (12), and (18) undergo the desired HNO producing pathway, quantitatively producing HNO in phosphate buffered saline, pH of 7.4, each measured in Example 17.
  • the compounds of the disclosure have or are believed to have desirable toxicological profiles. It has been discovered that the desirable toxicological profile of the present compounds stem in part from their half-lives, and the discovery of an optimal range of half-lives for nitroxyl donors.
  • compounds (l)-(4), (1 1), (12) and (18) have half-lives from approximately 15 minutes to approximately 3900 minutes, each measured under the conditions of Example 17, and compounds (1)-(10), (14), (16) and (17) have half-lives from approximately 14 minutes to approximately 189 minutes, each measured under the conditions of Example 18.
  • Compounds and/or compositions of the disclosure can be used to treat a variety of conditions that are responsive to nitroxyl therapy.
  • the compounds and/or compositions of the disclosure can be used to treat or prevent the occurrence of cardiovascular diseases, alcoholism, vascular dysfunction and cancer.
  • a nitroxyl donating composition of the disclosure can be used to treat cardiovascular disease, ischemia/reperfusion injury, pulmonary hypertension or another condition responsive to nitroxyl therapy.
  • a nitroxyl donating composition of the disclosure can be used to treat heart failure.
  • a compound and/or composition of the disclosure can be used to treat decompensated heart failure (e.g., acute decompensated heart failure).
  • the compounds and/or compositions of the disclosure can be used to treat systolic heart failure.
  • the compounds and/or compositions of the disclosure can be used to treat diastolic heart failure.
  • FIG. 1 shows nitroxyl production as determined via NMR protocol using added TXPTS.
  • FIG. 1A shows the time course disappearance of a compound of the disclosure (compound (1)) and appearance of its corresponding barbituric acid (compound BA-1 anion) and TXPTS aza-ylide.
  • FIG. IB shows the disappearance of four compounds of the disclosure (compound (1), compound (2), compound (3), and compound (4)) under conditions outlined in Table 2.
  • FIG. 2a shows a plot of UV-vis determined decomposition rates as a function of pH at 25 °C for three compounds of the disclosure (compound (1), compound (2), and compound (3)).
  • FIG. 2c shows the initial UV-vis spectra of compound (4) from pH 5.0 to 9.5 compared with the expected byproduct of HNO release, compound (BA-4), at pH 9.5.
  • the invention includes the following:
  • N-hydroxylaminobarbituric acid type compound wherein said compound has a half- life of greater than about 10 minutes when measured under the conditions described in Example 17 or Example 18, provided that said compound is not 5-(N-hydroxylamino)-5-ethyl-N,N- dimethylbarbituric acid or 5-(N-hydroxylamino)-5-(acetyl-0-methyloxime)-N,N-dimethylbarbituric acid.
  • N-hydroxylaminobarbituric acid type compound wherein said compound produces a percent yield of ⁇ greater than about 50% when measured under the conditions described in Example 17, provided that said compound is not 5-(N-hydroxylamino)-5-ethyl-N,N-dimethylbarbituric acid or 5-(N-hydroxylamino)-5-(acetyl-0-methyloxime)-N,N-dimethylbarbituric acid.
  • N-hydroxylaminobarbituric acid type compound wherein said compound has a half- life of greater than about 10 minutes when measured under the conditions described in Example 17 or Example 18 and said compound produces a percent yield of ⁇ greater than about 50% when measured under the conditions described in Example 17, provided that said compound is not 5-(N- hydroxylamino)-5-ethyl-N,N-dimethylbarbituric acid or 5-(N-hydroxylamino)-5-(acetyl-0- methyloxime) -N,N-dimethylbarbituric acid.
  • each R is independently H or (Ci)alkyl
  • R is (Ci-C6)alkyl substituted with a substituent selected from the group consisting of (C6-Ci 4 )aryl, (C3-C6)cycloalkyl, (C 5 -C 7 )heterocycloalkyl, (5- or 6-membered)heteroaryl and (9- or 10-membered)heteroaryl, wherein said aryl, cycloalkyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 6 ;
  • R 7 is H or (C C 6 )alkyl.
  • R 2 is (Ci-C6)alkyl substituted with (C6-Ci4)aryl, wherein said aryl is unsubstituted or substituted with with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 6 .
  • each R 1 is (Ci)alkyl
  • R 1 is (Ci)alkyl
  • each R 1 is independently H or (Ci)alkyl
  • R 2 is (Ci-C 6 )alkyl substituted with (C 5 -C 7 )heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 6 ; each R 4 is independently selected from the group consisting of halo, -OH, -NH 2 , -C ⁇ N,
  • R is (Ci-C6)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10- membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 6 ;
  • each R 1 is independently H or (Ci)alkyl
  • R 2 is selected from the group consisting of a branched C3-C6 alkyl, a branched C3-C6 alkenyl, and a branched C3-C6 alkoxy, wherein said alkyl, alkenyl, and alkoxy are unsubstituted or substituted with 1, 2 or 3 substituents selected from R 4 ;
  • R 7 is H or (C C 6 )alkyl.
  • each R is H;
  • R is selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl and (Ci-C 6 )alkoxy, wherein said alkyl, alkenyl, alkynyl and alkoxy are unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 4 ;
  • R 7 is H or (Ci-C 6 )alkyl.
  • R 2 is selected from the group consisting of a branched (C 3 -C 6 )alkyl, branched (C 3 -C 6 )alkenyl, and branched (C 3 -C 6 )alkoxy, wherein said alkyl, alkenyl, and alkoxy are unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 4 .
  • (C6)heterocycloalkyl selected from the group consisting of piperidinyl, piperazinyl, tetrahydro- oxazinyl, tetrahydropyran, dioxane, morpholine and thiomorpholine.
  • R' and R" are independently selected from (Ci-C6)alkyl, (C 2 -Ce)alkenyl, (C 2 -Ce)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 - C 7 )heterocycloalkyl; and each R 6 is independently selected from the group consisting of halo and (Ci-C6)alkyl.
  • each R 1 is independently H or (Ci)alkyl
  • R is (C6-Cio)aryl, (C3-C6)cycloalkyl, (C 5 -C 7 )heterocycloalkyl and (5- or 6- membered)heteroaryl, wherein said aryl, cycloalkyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituents selected from R 4 ;
  • R 7 is H or (C r C 6 )alkyl.
  • R is (C6-Cio)aryl, wherein said aryl is unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituents selected from R 4 .
  • R 2 is phenyl unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituents selected from
  • R 2 is unsubstituted phenyl.
  • R 2 is (C 3 -C 6 )cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituents selected from R 4 .
  • R 2 is (C 5 -C 7 )heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 .
  • R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 .
  • R 1 , R 2 and X are as defined in the above (10.)-(122.) ;
  • R is hydrogen, -(Ci-C6)alkyl, -(C2-C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(C 5 -C 7 )heterocycloalkyl, benzyloxy, -0-(Ci-C 6 )alkyl, -NH 2 , -NH-(Ci-C 4 )alkyl, or
  • a pharmaceutical composition comprising the compound of any one of the above (1.)- (128.) and at least one pharmaceutically acceptable excipient.
  • a “pharmaceutically acceptable salt” refers to a salt of any therapeutic agent disclosed herein, which salt can include any of a variety of organic and inorganic counter ions known in the art and which salt is pharmaceutically acceptable.
  • various exemplary embodiments of counter ions are sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like.
  • a pharmaceutically acceptable salt can include as a counter ion, by way of example, an organic or inorganic acid, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like.
  • Illustrative salts include, but are not limited to, sulfate, citrate, acetate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, besylate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,
  • a salt can be prepared from a compound of any one of the formulae disclosed herein having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base.
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl-N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower-alkyl amines), such as mono-, bis-, or tris-(2- hydroxyethyl)amine, 2-hydroxy-fert-butylamine, or tris-(hydroxymethyl)methylamine, NN-di-lower- alkyl-N-(hydroxy-lower-alkyl)-amines, such as NN-dimethyl-N-(
  • a salt can also be prepared from a compound of any one of the formulae disclosed herein having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid.
  • Suitable acids include hydrogen sulfate, citric acid, acetic acid, hydrochloric acid (HQ), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, phosphoric acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • “Pharmaceutically acceptable excipient” refers to any substance, not itself a therapeutic agent, used as a carrier, diluent, adjuvant, binder, and/or vehicle for delivery of a therapeutic agent to a patient, or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a compound or pharmaceutical composition into a unit dosage form for administration.
  • Pharmaceutically acceptable excipients are known in the pharmaceutical arts and are disclosed, for example, in Gennaro, Ed., Remington: The Science and Practice of Pharmacy, 20 th Ed.
  • pharmaceutically acceptable excipients can provide a variety of functions and can be described as wetting agents, buffering agents, suspending agents, lubricating agents, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants, and sweeteners.
  • Examples of pharmaceutically acceptable excipients include without limitation: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropylmethylcellulose, and hydroxypropylcellulose; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes;
  • oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil;
  • glycols such as propylene glycol
  • polyols such as glycerin, sorbitol, mannitol and polyethylene glycol
  • esters such as ethyl oleate and ethyl laurate
  • agar such as agar
  • buffering agents such as magnesium hydroxide and aluminum hydroxide
  • a "patient” refers to an animal, such as a mammal, including but not limited to, a human. Hence, the methods disclosed herein can be useful in human therapy and veterinary applications.
  • the patient is a mammal.
  • the patient is a human.
  • Effective amount refers to such amount of a therapeutic agent or a pharmaceutically acceptable salt thereof, which in combination with its parameters of efficacy and potential for toxicity, as well as based on the knowledge of the practicing specialist, should be effective in a given therapeutic form. As is understood in the art, an effective amount can be administered in one or more doses. “Treatment”, “treating” and the like is an approach for obtaining a beneficial or desired result, including clinical results.
  • beneficial or desired results include but are not limited to inhibiting and/or suppressing the onset and/or development of a condition or reducing the severity of such condition, such as reducing the number and/or severity of symptoms associated with the condition, increasing the quality of life of those suffering from the condition, decreasing the dose of other medications required to treat the condition, enhancing the effect of another medication a patient is taking for the condition, and/or prolonging survival of patients having the condition.
  • Prevent refers to reducing the probability of developing a condition in a patient who does not have, but is at risk of developing a condition.
  • a patient “at risk” may or may not have a detectable condition, and may or may not have displayed a detectable condition prior to the treatment methods disclosed herein.
  • At risk denotes that a patient has one or more so- called risk factors, which are measurable parameters that correlate with development of a condition and are known in the art. A patient having one or more of these risk factors has a higher probability of developing the condition than a patient without such risk factor(s).
  • Perfect inotrope refers to an agent that causes an increase in myocardial contractile function.
  • Exemplary positive inotropes are a beta-adrenergic receptor agonist, an inhibitor of phosphodiesterase activity, and calcium-sensitizers.
  • iteia-adrenergic receptor agonists include, among others, dopamine, dobutamine, terbutaline, and isoproterenol. Analogs and derivatives of such compounds are also intended.
  • U.S. Pat. No. 4,663,351 discloses a dobutamine prodrug that can be administered orally.
  • a condition that is "responsive to nitroxyl therapy” includes any condition in which administration of a compound that donates an effective amount of nitroxyl under physiological conditions treats and/or prevents the condition, as those terms are defined herein.
  • a condition whose symptoms are suppressed or diminished upon administration of nitroxyl donor is a condition responsive to nitroxyl therapy.
  • PH Pulmonary hypertension
  • MPAP mean pulmonary arterial pressure
  • (Ci-C 6 )alkyl refers to saturated linear and branched hydrocarbon structures having 1, 2, 3, 4, 5, or 6 carbon atoms.
  • alkyl residue having a specific number of carbons When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, "propyl” includes n-propyl and iso-propyl and "butyl” includes n-butyl, sec -butyl, iso-butyl and tert- butyl.
  • (Ci-C6)alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-hexyl, and the like.
  • “(C 2 -C6)alkyl” refers to saturated linear and branched hydrocarbon structures having 2, 3, 4, 5, or 6 carbon atoms.
  • alkyl residue having a specific number of carbons When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, "propyl” includes n-propyl and iso-propyl and "butyl” includes n-butyl, sec -butyl, iso-butyl and tert-butyl.
  • Examples of (C 2 -C 6 )alkyl groups include ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-hexyl, and the like.
  • (Ci-C 4 )alkyl refers to saturated linear and branched hydrocarbon structures having 1 , 2, 3, or 4 carbon atoms. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, "propyl” includes n-propyl and iso-propyl and "butyl” includes n-butyl, sec -butyl, iso-butyl and tert-butyl. Examples of (Ci-C4)alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, and the like.
  • (Ci-C 2 )alkyl refers to saturated linear and branched hydrocarbon structures having 1 or 2 carbon atoms. Examples of (Ci-C 2 )alkyl groups include methyl and ethyl.
  • (C3-C6)alkyl refers to saturated linear and branched hydrocarbon structures having 3, 4, 5, or 6 carbon atoms.
  • alkyl residue having a specific number of carbons When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, "propyl” includes n-propyl and z ' o-propyl and "butyl” includes n-butyl, sec-butyl, iso-butyl and tert-butyl.
  • (C3-C 5 )alkyl groups include n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
  • Branched (C 3 -C 6 )alkyl refers to saturated branched hydrocarbon structures having 3, 4, 5, or
  • branched (C 3 -C 6 )alkyl groups include iso-propyl, tert-butyl, 2,3- dimethylbutyl, 2-methylpentyl, 3-methylpentyl, and the like.
  • (C 2 -C 6 )alkenyl refers to a straight-chain or branched unsaturated hydrocarbon radical having 2, 3, 4, 5 or 6 carbon atoms and a double bond in any position, e.g., ethenyl, 1 -propenyl, 2-propenyl (allyl), 1 -butenyl, 2-butenyl, 3-butenyl, 1 -methylethenyl, 1 -methyl- 1 -propenyl, 2-methyl-2-propenyl, 2- methyl- 1 -propenyl, l -methyl-2-propenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 2-methyl-2-pentenyl, 4- methyl-2-pentenyl, 4-methyl-l -pentenyl, 3 -methyl- 1 -pentenyl, and the like.
  • (C 2 -C4)alkenyl refers to a straight-chain or branched unsaturated hydrocarbon radical having 2, 3, or 4 carbon atoms and a double bond in any position, e.g., ethenyl, 1 -propenyl, 2-propenyl (allyl),
  • Branched (C3-C 6 )alkenyl refers to a branched unsaturated hydrocarbon radical having 3, 4, 5 or 6 carbon atoms and a double bond in any position, e.g. , 1 -methylethenyl, 1 -methyl- 1 -propenyl,
  • (C 2 -C 6 )alkynyl refers to a straight chain or branched hydrocarbon having 2, 3, 4, 5 or 6 carbon atoms and including at least one carbon-carbon triple bond.
  • Examples of (C 2 -C 6 )alkynyls include ethynyl, propynyl, 1 -butynyl, 2-butynyl, 1 -pentynyl, 2-pentynyl, 1 -hexynyl, 2-hexynyl, 3- hexynyl, 4-methyl-2-pentynyl and the like.
  • (C 2 -C 3 )alkynyl refers to a straight chain hydrocarbon having 2 or 3 carbon atoms and including at least one carbon-carbon triple bond.
  • Examples of (C 2 -C3)alkynyls include ethynyl and propynyl.
  • (C3-C6)cycloalkyl refers to a saturated cyclic hydrocarbon containing 3, 4, 5 or 6 ring carbon atoms.
  • Examples of (C3-C6)cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • (Ci-C6)alkoxy refers to -0-(Ci-C6)alkyl.
  • Examples of (Ci-C6)alkoxy groups include methoxy, ethoxy, propoxy, n-propoxy, z ' o-propoxy, butoxy, n-butoxy, eobutoxy, teri-butoxy, pentoxy, hexyloxy, and the like.
  • (Ci-C3)alkoxy refers to -0-(Ci-C3)alkyl.
  • Examples of (Ci-C6)alkoxy groups include methoxy, ethoxy, propoxy, n-propoxy and z ' o-propoxy.
  • Branched (C 3 -C 6 )alkoxy refers to -0-(C 3 -C 6 )alkyl, wherein said (C 3 -C 6 )alkyl is branched.
  • Examples of branched (C 3 -C 6 )alkoxy groups include z ' o-propoxy, sec-butoxy, teri-butoxy, 2-methyl-2- butoxy and the like.
  • (C 2 -C 6 )alkenyloxy refers to -0-(C 2 -C6)alkenyl.
  • Examples of (C 2 -C6)alkenyloxy include ethenyloxy, propenyloxy, 1 -propenyloxy, 2-propenyloxy, z ' o-propenyloxy, butenyloxy, 1 -butenyloxy, 2-butenyloxy, 3 -butenyloxy, z ' o-butenyloxy, ec-butenyloxy, feri-butenyloxy, pentenyloxy, 1- pentenyloxy, 2-pentenyloxy, 3 -pentenyloxy, 4-pentenyloxy, z ' o-pentenyloxy, eopentenyloxy, tert- pentenyloxy, hexenyloxy, 1-hexenyloxy, 2-hexenyloxy, 3-hexenyloxy, 4-hexenyloxy, 5-hexenyloxy, z o-hexenyloxy, ec-he
  • (C 2 -C 6 )alkynyloxy refers to -0-(C 2 -C 6 )alkynyl.
  • Examples of (C 2 -C 6 )alkynyloxy include ethynyloxy, propynyloxy, 1 -propynyloxy, 2-propynyloxy, butynyloxy, 1 -butynyloxy, 2-butynyloxy, 3- butynyloxy, pentynyloxy, 1 -pentynyloxy, 2-pentynyloxy, 3-pentynyloxy, 4-pentynyloxy, hexynyloxy, 1 -hexynyloxy, 2-hexynyloxy, 3-hexynyloxy, 4-hexynyloxy, 5-hexynyloxy, and the like.
  • (C5-C 7 )heterocycloalkyl refers to a 5-, 6-, or 7-membered, saturated or partially unsaturated, mono- or bicyclic-heterocycle containing 1, 2, 3, or 4 ring heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein said nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized.
  • a heterocycloalkyl group can be attached to the parent structure through a carbon or a heteroatom.
  • Examples of (C 5 -C 7 )heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, tetrahydro-oxazinyl, tetrahydrofuran, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine,
  • (C6)heterocycloalkyl refers to a 6-membered, saturated or partially unsaturated, bridged, mono- or bicyclic-heterocycle containing 1, 2, 3, or 4 ring heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein said nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized.
  • a heterocycloalkyl group can be attached to the parent structure through a carbon or heteroatom.
  • Examples of (C 6 )heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydro-oxazinyl, tetrahydropyran, dioxane, morpholine, thiomorpholine, and the like.
  • (C 6 -Ci 4 )aryl refers to a monovalent aromatic hydrocarbon group which may be monocyclic, bicyclic or tricyclic, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3, 4, 5, 6 or 7 ring members.
  • Examples of (C 6 -Ci 4 )aryl groups include without limitation phenyl, naphthyl, indanyl, indenyl, tetralinyl, anthryl and phenanthryl. In some
  • the aryl is C 6 aryl. In some embodiments, the aryl is a bicyclic C9-C 10 aryl. In some embodiments, the aryl is a tricyclic C 13-C14 aryl. In some embodiments, the aryl is phenyl. In some embodiments, the aryl is naphthyl.
  • (C6-Cio)aryl refers to a monovalent aromatic hydrocarbon group which may be monocyclic, bicyclic or tricyclic, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3, 4, 5, 6 or 7 ring members.
  • Examples of (C6-Cio)aryl groups include without limitation phenyl, naphthyl, indanyl, indenyl and tetralinyl. In some embodiments, the aryl is C 6 aryl.
  • (Ci 0 -Ci 4 )aryl refers to a monovalent aromatic hydrocarbon group which may be monocyclic, bicyclic or tricyclic, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3, 4, 5, 6 or 7 ring members.
  • Examples of (Ci 0 -Ci 4 )aryl groups include without limitation naphthyl, tetralinyl, anthryl and phenanthryl.
  • (9-or 10-membered)heteroaryl refers to a bicyclic ring of 9 or 10 members in which at least one of rings in the bicyclic ring is aromatic and the bicyclic ring comprises at least one ring heteroatom, e.g. , 1 , 2, 3, or 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur.
  • a (9- or 10-membered)heteroaryl group can be attached to the parent structure through a carbon or heteroatom.
  • Examples of (9-or 10-membered)heteroaryl include without limitation lH-indazolyl, benzo[b]furyl, benzofuryl, benzo[l ,3]dioxole, indolyl, isoindolyl, indolinyl, lH-indolyl, 3H-indolyl, benzo[b]thiophenyl, benzthiazolyl, dihydroindole, indazolyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, cinnolyl, quinazolyl, quinoxalyl, 4H-quinolizyl, benzo-l ,2,5-thiadiazolyl, purinyl, and pteridyl.
  • (5- or 6-membered)heteroaryl refers to a monocyclic aromatic heterocycle ring of 5 or 6 members, i.e. , a monocyclic aromatic ring comprising at least one ring heteroatom, e.g., 1 , 2, 3, or 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur.
  • a (5- or 6- membered)heteroaryl group can be attached to the parent structure through a carbon or heteroatom.
  • Examples of (5- or 6-membered)heteroaryls include pyridyl, pyrrolyl, pyrazolyl, furyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, 1 ,2,3-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,2,3-triazolyl, tetrazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrazyl, pyrazinyl, 1 ,2,3-thiadiazolyl, 1 ,3,4- thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,5-triazinyl, and thiophenyl.
  • (5-membered)heteroaryl refers to a monocyclic aromatic heterocycle ring of 5 members, i.e. , a monocyclic aromatic ring comprising at least one ring heteroatom, e.g., 1 , 2, 3, or 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur.
  • a (5-membered)heteroaryl group can be attached to the parent structure through a carbon or heteroatom.
  • Examples of (5- membered)heteroaryls include pyrrolyl, pyrazolyl, furyl, imidazolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl and 1,2,5-thiadiazolyl.
  • (6-membered)heteroaryl refers to a monocyclic aromatic heterocycle ring of 6 members, i.e., a monocyclic aromatic ring comprising at least one ring heteroatom, e.g., 1, 2, 3, or 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur.
  • a (6-membered)heteroaryl group can be attached to the parent structure through a carbon or heteroatom.
  • (6- membered)heteroaryls include pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,3,5-triazinyl, and thiophenyl.
  • Halo or “halogen” refers to fluoro (-F), chloro (-C1), bromo (-Br) and iodo (-1).
  • a compound of the disclosure can contain one, two, or more asymmetric centers and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • the disclosure encompasses compounds with all such possible forms, as well as their racemic and resolved forms or any mixture thereof, unless specifically otherwise indicated.
  • N-hydroxylamino-barbituric acid type compounds of the disclosure produce nitroxyl under physiologically relevant conditions and do not undergo intramolecular rearrangements.
  • the experiments reported herein suggest that, by tempering the electrophilicity of the R 2 group and/or the nucleophilicity of the hydroxylamine nitrogen, the non-HNO producing rearrangement becomes kinetically unfavorable, thereby allowing HNO production under physiologically relevant conditions.
  • a nitroxyl donating compound of the disclosure is a compound of the formula (1):
  • each R 1 is independently H or (Ci)alkyl
  • R is (Ci-C6)alkyl substituted with a substituent selected from the group consisting of (C6-Ci 4 )aryl, (C3-C6)cycloalkyl, (C 5 -C 7 )heterocycloalkyl, (5- or 6-membered)heteroaryl and (9- or 10-membered)heteroaryl, wherein said aryl, cycloalkyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 6 ;
  • R 7 is H or (C C 6 )alkyl.
  • At least one of R 1 is H. In another, each R 1 is H. In another embodiment, at least one of R 1 is (Ci)alkyl. In another embodiment, each R 1 is (Ci)alkyl.
  • X is S. In other aspects, X is O. In other aspects, X is NH. In other aspects, X is N(Ci-C6)alkyl. In other aspects, X is NCH 3 .
  • At least one R 1 is H and X is S. In another embodiment, at least one R 1 is H and X is O. In another embodiment, at least one R 1 is H and X is NH. In another embodiment, at least one R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is H and X is S. In another embodiment, each R 1 is H and X is O. In another embodiment, each R 1 is H and X is NH. In another embodiment, each R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, each R 1 is H and X is NCH 3 .
  • At least one of R 1 is (Ci)alkyl and X is S. In another embodiment, at least one of R 1 is (Ci)alkyl and X is O. In another embodiment, at least one of R 1 is (Ci)alkyl and X is NH. In another embodiment, at least one R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is (Ci)alkyl and X is S. In another embodiment, each R 1 is (Ci)alkyl and X is O. In another embodiment, each R 1 is (Ci)alkyl and X is NH. In another embodiment, each R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R 1 is H and X is NCH 3 .
  • a nitroxyl donating compound of the disclosure is a compound of the formula (la):
  • each R 1 is independently H or (Ci)alkyl
  • R is (Ci-C6)alkyl substituted with (C6-Ci 4 )aryl, wherein said aryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 6 ;
  • R 7 is H or (C C 6 )alkyl.
  • At least one of R 1 is H. In some aspects, each R 1 is H.
  • At least one of R 1 is (Ci)alkyl. In some aspects, each R 1 is (Ci)alkyl.
  • R 2 is (Ci-C 4 )alkyl substituted with (C6-Ci 4 )aryl. In another embodiment, R 2 is (Ci-C 2 )alkyl substituted with (C6-Ci 4 )aryl. In another embodiment, R 2 is (Ci)alkyl substituted with (C6-Ci 4 )aryl. In each embodiment of this paragraph, the aryl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the aryl is C 6 -Cio aryl. In various embodiments of each of the embodiments in this paragraph, the aryl is C10-C14 aryl. In various embodiments of each of the embodiments in this paragraph, the aryl is selected from the group consisting of phenyl, indanyl, indenyl, tetralinyl and naphthyl. In various embodiments of each of the embodiments in this paragraph, the aryl is phenyl.
  • each R is independently selected from the group consisting of halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 6 -Ci 4 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6- membered)heteroaryl, (C 5 -C 7 )heterocycloalkyl, -C(0)H, -C(0)NH 2 , -C(0)OH, -NH-C(0)-NH 2 , -NH- C(S)-NH 2 , -SC ⁇ N, -S0 2 NH 2 ,
  • each R 4 is independently selected from the group consisting of -OH, - NH 2 , -SH, (C r C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C r C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 - C 6 )alkynyloxy, (C 6 -Ci 4 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl, (C 5 - C 7 )heterocycloalkyl, -NHR', -NR'R", -SR', -OR', wherein R' and R" are independently selected from (C r C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -
  • each R 4 is independently selected from the group consisting of - OH, -NH 2 , -SH, (Ci-C6)alkoxy, (C 2 -C6)alkenyloxy and (C 2 -C6)alkynyloxy.
  • each R 4 is independently selected from the group consisting of (Ci-C6)alkoxy, (C 2 -C6)alkenyloxy and (C 2 - C6)alkynyloxy. In yet other embodiments, R 4 is (Ci-C6)alkoxy. In some embodiments, R 4 is (Cp C 3 )alkoxy. In other embodiments, R 4 is methoxy. In some embodiments, R 4 is -OH.
  • each R 4 is independently selected from the group consisting of halo, - C ⁇ N, -N0 2 , -C(0)H, -C(0)NH 2 , -C(0)OH, -NH-C(0)-NH 2 , -NH-C(S)-NH 2 , -SON, -S0 2 NH 2 , -COR', -C(0)OR', -C(0)NHR', -C(0)NR'R", -S(0)R' and -S(0)OR', wherein R' and R" are independently selected from (C r C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6- membered)heteroaryl, and (C 5 -C 7 )heterocycloalkyl.
  • each R 4 is independently selected from the group consisting of halo, - ON, -N0 2 , -C(0)NH 2 , -C(0)OH, -COR', -C(0)OR', -C(0)NHR', -C(0)NR'R", -S(0)R' and - S(0)OR', wherein R' and R" are independently selected from (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C 6 -Ci 4 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 -C 7 )heterocycloalkyl.
  • R is halo.
  • R is CI.
  • R is S(0)0(C r C 6 )alkyl.
  • R 4 is S(0)0(C
  • R 6 is halo or (Ci-C6)alkyl. In some embodiments, R 6 is halo or In other embodiments, R 6 is halo or (Ci-C2)alkyl. In other embodiments, R 6 is fluoro. In other embodiments, R 6 is methyl.
  • X is S. In other aspects, X is O. In other aspects, X is NH. In other aspects, X is N(Ci-C 6 )alkyl. In other aspects, X is NCH 3 .
  • At least one R 1 is H and X is S. In another embodiment, at least one R 1 is H and X is O. In another embodiment, at least one R 1 is H and X is NH. In another embodiment, at least one R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is H and X is S. In another embodiment, each R 1 is H and X is O. In another embodiment, each R 1 is H and X is NH. In another embodiment, each R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, each R 1 is H and X is NCH 3 .
  • At least one of R 1 is (Ci)alkyl and X is S. In another embodiment, at least one of R 1 is (Ci)alkyl and X is O. In another embodiment, at least one of R 1 is (Ci)alkyl and X is NH. In another embodiment, at least one R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is (Ci)alkyl and X is S. In another embodiment, each R 1 is (Ci)alkyl and X is O. In another embodiment, each R 1 is (Ci)alkyl and X is NH. In another embodiment, each R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R 1 is H and X is NCH 3 .
  • At least one R 1 is H and R 2 is (Ci-C alkyl substituted with (C6-Ci4)aryl. In another embodiment, at least one R 1 is H and R 2 is (Ci-C2)alkyl substituted with (C6-Ci4)aryl. In another embodiment, at least one R 1 is H and R 2 is (Ci)alkyl substituted with (C 6 -Ci 4 )aryl. In each embodiment of this paragraph, the aryl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • each R 1 is H and R 2 is (Ci-C4)alkyl substituted with (C6-Ci 4 )aryl. In another embodiment, each R 1 is H and R 2 is (Ci-C 2 )alkyl substituted with (C6-Ci 4 )aryl. In another embodiment, each R 1 is H and R 2 is (Ci)alkyl substituted with (C6-Ci 4 )aryl.
  • the aryl is unsubstituted in one embodiment, mono -substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri- substituted with three independently selected substituents in a further embodiment.
  • the aryl is phenyl.
  • At least one of R 1 is (Ci)alkyl and R 2 is (Ci-C 4 )alkyl substituted with (C 6 - Ci 4 )aryl. In another embodiment, at least one of R 1 is (Ci)alkyl and R 2 is (Ci-C 2 )alkyl substituted with (C 6 -Ci 4 )aryl. In another embodiment, at least one of R 1 is (Ci)alkyl and R 2 is (Ci)alkyl substituted with (C 6 -Ci 4 )aryl.
  • the aryl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the aryl is phenyl.
  • each R 1 is (Ci)alkyl and R 2 is (Ci-C4)alkyl substituted with (C6-Ci 4 )aryl. In another embodiment, each R 1 is (Ci)alkyl and R 2 is (Ci-C 2 )alkyl substituted with (C6-Ci 4 )aryl. In another embodiment, each R 1 is (Ci)alkyl and R 2 is (Ci)alkyl substituted with (C6-Ci 4 )aryl.
  • the aryl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the aryl is phenyl.
  • a nitroxyl donating compound of the disclosure is a compound of the formula (l a-1):
  • each R 1 is (Ci)alkyl
  • X is O, NR 7 or S; each R 6 is independently selected from the group consisting of H, halo and (Q- C 6 )alkyl; and
  • R 7 is H or (C r C 6 )alkyl.
  • one or more of R 5 is selected from the group consisting of H, -OH, (d-
  • one or more of R 5 is selected from the group consisting of -OH, (Ci-C6)alkoxy, R 4 is-S(0)0(Ci-C6)alkyl and halo. In some aspects, one or more of R 5 is methoxy. In other aspects, one or more of R 5 is CI. In other aspects, one or more of R 5 is R 4 is -S(0)0(Ci-C6)alkyl. In other aspects, one or more of R 5 is -OH. In one embodiment, one R 5 is methoxy and the other R 5 are H. In another embodiment, one R 5 is CI and the other R 5 are H. In another embodiment, one R 5 is
  • R 5 is -S(0)0(Ci-C6)alkyl and the other R 5 are H.
  • one R 5 is -OH and the other R 5 are H.
  • At least one of R 6 is H, halo or (Ci-C 4 )alkyl. In some embodiments, at least one of R 6 is H, halo or (Ci-C 2 )alkyl. In other embodiments, at least one of R 6 is fluoro. In other embodiments, at least one of R 6 is methyl. In other embodiments, at least one of R 6 is H.
  • X is S. In other aspects, X is O. In other aspects, X is NH. In other aspects, X is N(Ci-C 6 )alkyl. In other aspects, X is NCH 3 . In one embodiment, X is S and one R 5 is methoxy and the other R 5 are H. In another embodiment, X is O and one R 5 is methoxy and the other R 5 are H. In another embodiment, X is NH and one R 5 is methoxy and the other R 5 are H. In another embodiment, X is NCH 3 and one R 5 is methoxy and the other R 5 are H.
  • X is S and one R 5 is CI and the other R 5 are H. In another embodiment, X is O and one R 5 is CI and the other R 5 are H. In another embodiment, X is NH and one R 5 is CI and the other R 5 are H. In another embodiment, X is NCH 3 and one R 5 is CI and the other R 5 are H.
  • X is S and one R 5 is -S(0)0(C r C 6 )alkyl and the other R 5 are H.
  • X is O and one R 5 is -S(0)0(C r C 6 )alkyl and the other R 5 are H.
  • X is NH and one R 5 is -S(0)0(C r C 6 )alkyl and the other R 5 are H.
  • X is NCH 3 and one R 5 is -S(0)0(C r C 6 )alkyl and the other R 5 are H.
  • a nitroxyl donating compound of the disclosure is a compound of the formula (l a-2):
  • X is O, NR 7 or S; each R 6 is independently selected from the group consisting of H, halo and (Cr
  • R 7 is H or (C r C 6 )alkyl.
  • one or more of R 5 is selected from the group consisting of H, -OH, (C r C 6 )alkoxy, -S(0)0(Ci-C 6 )alkyl and halo. In some aspects, one or more of R 5 is selected from the group consisting of -OH, (Ci-C 6 )alkoxy, -S(0)0(Ci-C 6 )alkyl and halo. In some aspects, one or more of R 5 is methoxy. In other aspects, one or more of R 5 is CI. In other aspects, one or more of R 5 is - S(0)0(Ci-C6)alkyl. In other aspects, one or more of R 5 is -OH.
  • one R 5 is methoxy and the other R 5 are H. In another embodiment, one R 5 is CI and the other R 5 are H. In another embodiment, one R 5 is
  • R 5 is -S(0)0(Ci-C 6 )alkyl and the other R 5 are H.
  • one R 5 is -OH and the other R 5 are
  • At least one of R 6 is H, halo or In some embodiments, at least one of R 6 is H, halo or (Ci-C2)alkyl. In other embodiments, at least one of R 6 is fluoro. In other embodiments, at least one of R 6 is methyl. In other embodiments, at least one of R 6 is H.
  • X is S. In other aspects, X is O. In other aspects, X is NH. In other aspects, X is N(Ci-C 6 )alkyl. In other aspects, X is NCH 3 .
  • X is S and one R 5 is methoxy and the other R 5 are H. In another embodiment, X is O and one R 5 is methoxy and the other R 5 are H. In another embodiment, X is NH and one R 5 is methoxy and the other R 5 are H. In another embodiment, X is NCH 3 and one R 5 is methoxy and the other R 5 are H. In one embodiment, X is S and one R 5 is CI and the other R 5 are H. In another embodiment, X is O and one R 5 is CI and the other R 5 are H. In another embodiment, X is NH and one R 5 is CI and the other R 5 are H.
  • X is NCH 3 and one R 5 is CI and the other R 5 are H.
  • X is S and one R 5 is -S(0)0(Ci-C 6 )alkyl and the other R 5 are H.
  • X is O and one R 5 is -S(0)0(Ci-C 6 )alkyl and the other R 5 are H.
  • X is NH and one R 5 is -S(0)0(Ci-C 6 )alkyl and the other R 5 are H.
  • X is NCH 3 and one R 5 is -S(0)0(Ci-C 6 )alkyl and the other R 5 are H.
  • X is S and one R 5 is -OH and the other R 5 are H. In another embodiment, X is O and one R 5 is -OH and the other R 5 are H. In another embodiment, X is NH and one R 5 is -OH and the other R 5 are H. In another embodiment, X is NCH 3 and one R 5 is -OH and the other R 5 are H.
  • a nitroxyl donating compound of the disclosure is a compound of the formula (lb):
  • each R 1 is independently H or (Ci)alkyl
  • R 2 is (Ci-C 6 )alkyl substituted with (C 3 -C 6 )cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 6 ;
  • R 7 is H or (C C 6 )alkyl.
  • At least one of R 1 is H. In some aspects, each R 1 is H.
  • At least one of R 1 is (Ci)alkyl. In some aspects, each R 1 is (d)alkyl.
  • R 2 is (Ci-C 4 )alkyl substituted with (C 3 -C 6 )cycloalkyl. In another embodiment, R 2 is (Ci-C 2 )alkyl substituted with (C 3 -C 6 )cycloalkyl. In another embodiment, R 2 is (Ci)alkyl substituted with (C 3 -C 6 )cycloalkyl. In each embodiment of this paragraph, the cycloalkyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the (C 3 -C6)cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cylcohexyl. In various embodiments of each of the embodiments in this paragraph, the (C 3 -C6)cycloalkyl is cyclohexyl.
  • R 6 is halo or (Ci-C6)alkyl. In some embodiments, R 6 is halo or (Ci-C alkyl. In other embodiments, R 6 is halo or (Ci-C2)alkyl. In other embodiments, R 6 is fluoro. In other embodiments, R 6 is methyl.
  • X is S. In other aspects, X is O. In other aspects, X is NH. In other aspects, X is N(Ci-C6)alkyl. In other aspects, X is NCH 3 .
  • At least one R 1 is H and X is S. In another embodiment, at least one R 1 is H and X is O. In another embodiment, at least one R 1 is H and X is NH. In another embodiment, at least one R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is H and X is S. In another embodiment, each R 1 is H and X is O. In another embodiment, each R 1 is H and X is NH. In another embodiment, each R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, each R 1 is H and X is NCH 3 . In one embodiment, at least one of R 1 is (Ci)alkyl and X is S. In another embodiment, at least one of R 1 is (Ci)alkyl and X is O. In another embodiment, at least one of R 1 is (Ci)alkyl and X is NH. In another embodiment, at least one R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 . In another embodiment, each R 1 is (Ci)alkyl and X is S. In another embodiment, each R 1 is each R 1 is H and X is NH. In another embodiment, each R 1 is
  • each R 1 is (Ci)alkyl and X is O. In another embodiment, each R 1 is (Ci)alkyl and X is NH. In another embodiment, each R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, each R 1 is H and X is NCH 3 .
  • At least one R 1 is H and R 2 is (Ci-C 4 )alkyl substituted with (C 3 - C 6 )cycloalkyl. In another embodiment, at least one R 1 is H and R 2 is (Ci-C 2 )alkyl substituted with (C 3 - C 6 )cycloalkyl. In another embodiment, at least one R 1 is H and R 2 is (Ci)alkyl substituted with (C 3 - C 6 )cycloalkyl.
  • the cycloalkyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the cycloalkyl is cyclohexyl.
  • each R 1 is H and R 2 is substituted with (C 3 -C6)cycloalkyl.
  • each R 1 is H and R 2 is (Ci-C2)alkyl substituted with (C 3 -C6)cycloalkyl.
  • each R 1 is H and R 2 is (Ci)alkyl substituted with (C 3 -C6)cycloalkyl.
  • the cycloalkyl is unsubstituted in one embodiment, mono -substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the cycloalkyl is cyclohexyl.
  • At least one of R 1 is (Ci)alkyl and R 2 is (Ci-C 4 )alkyl substituted with (C 3 - C 6 )cycloalkyl. In another embodiment, at least one of R 1 is (Ci)alkyl and R 2 is (Ci-C 2 )alkyl substituted with (C 3 -C 6 )cycloalkyl. In another embodiment, at least one of R 1 is (Ci)alkyl and R 2 is (Ci)alkyl substituted with (C 3 -C 6 )cycloalkyl.
  • the cycloalkyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the cycloalkyl is cyclohexyl.
  • each R 1 is (Ci)alkyl and R 2 is (Ci-C alkyl substituted with (C3- C6)cycloalkyl.
  • each R 1 is (Ci)alkyl and R 2 is (Ci-C 2 )alkyl substituted with (C3- C6)cycloalkyl.
  • each R 1 is (Ci)alkyl and R 2 is (Ci)alkyl substituted with (C3- C6)cycloalkyl.
  • the cycloalkyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the cycloalkyl is cyclohexyl.
  • a nitroxyl donating compound of the disclosure is a compound of the formula (lc):
  • each R 1 is independently H or (Ci)alkyl
  • R 2 is (Ci-C 6 )alkyl substituted with (C 5 -C 7 )heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 6 ;
  • At least one of R 1 is H. In some aspects, each R 1 is H.
  • At least one of R 1 is (Ci)alkyl. In some aspects, each R 1 is (d)alkyl.
  • R 2 is (Ci-C 4 )alkyl substituted with (C 5 -C 7 )heterocycloalkyl. In another embodiment, R 2 is (Ci-C 2 )alkyl substituted with (C 5 -C 7 )heterocycloalkyl. In another embodiment, R 2 is (Ci)alkyl substituted with (C 5 -C 7 )heterocycloalkyl. In each embodiment of this paragraph, the heterocycloalkyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di- substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the heterocycloalkyl is selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, tetrahydro-oxazinyl, tetrahydrofuran, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrahydrofuranone, ⁇ - butyrolactone, 2H-pyran, 4H-pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, piperazine, morpholine, thiomorpholine, oxazine and tetrahydro-oxazinyl.
  • the hetercycloalkyl is a (C6)heterocycloalkyl selected from the group consisting of piperidinyl, piperazinyl, tetrahydro-oxazinyl, tetrahydropyran, dioxane, morpholine and thiomorpholine.
  • R 6 is halo or (Ci-C6)alkyl. In some embodiments, R 6 is halo or (Ci-C 4 )alkyl. In other embodiments, R 6 is halo or (Ci-C 2 )alkyl. In other embodiments, R 6 is fluoro. In other embodiments, R 6 is methyl.
  • X is S. In other aspects, X is O. In other aspects, X is ⁇ . In other aspects, X is N(Ci-C 6 )alkyl. In other aspects, X is NCH 3 . In one embodiment, at least one R 1 is H and X is S. In another embodiment, at least one R 1 is H and X is O. In another embodiment, at least one R 1 is H and X is NH. In another embodiment, at least one R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is H and X is S. In another embodiment, each R 1 is H and X is O. In another embodiment, each R 1 is H and X is NH. In another embodiment, each R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, each R 1 is H and X is NCH 3 .
  • At least one of R 1 is (Ci)alkyl and X is S. In another embodiment, at least one of R 1 is (Ci)alkyl and X is O. In another embodiment, at least one of R 1 is (Ci)alkyl and X is NH. In another embodiment, at least one R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is (Ci)alkyl and X is S. In another embodiment, each R 1 is (Ci)alkyl and X is O. In another embodiment, each R 1 is (Ci)alkyl and X is NH. In another embodiment, each R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, each R 1 is H and X is NCH 3 .
  • At least one R 1 is H and R 2 is (Ci-C alkyl substituted with (C 5 - C 7 )heterocycloalkyl. In another embodiment, at least one R 1 is H and R 2 is (Ci-C2)alkyl substituted with (C 5 -C 7 )heterocycloalkyl. In another embodiment, at least one R 1 is H and R 2 is (Ci)alkyl substituted with (C 5 -C 7 )heterocycloalkyl.
  • the heterocycloalkyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the heterocycloalkyl is (C 5 )heterocycloalkyl.
  • the heterocycloalkyl is (C6)heterocycloalkyl.
  • each R 1 is H and R 2 is (Ci-C 4 )alkyl substituted with (C 5 - C 7 )heterocycloalkyl. In another embodiment, each R 1 is H and R 2 is (Ci-C 2 )alkyl substituted with (C 5 - C 7 )heterocycloalkyl. In another embodiment, each R 1 is H and R 2 is (Ci)alkyl substituted with (C 5 - C 7 )heterocycloalkyl.
  • the heterocycloalkyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the heterocycloalkyl is (C 5 )heterocycloalkyl.
  • the heterocycloalkyl is (C6)heterocycloalkyl.
  • At least one of R 1 is (Ci)alkyl and R 2 is (Ci-C4)alkyl substituted with (C 5 - C 7 )heterocycloalkyl. In another embodiment, at least one of R 1 is (Ci)alkyl and R 2 is (C r C 2 )alkyl substituted with (C 5 -C 7 )heterocycloalkyl. In another embodiment, at least one of R 1 is (Ci)alkyl and R 2 is (Ci)alkyl substituted with (C 5 -C 7 )heterocycloalkyl.
  • the heterocycloalkyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di- substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the heterocycloalkyl is (C 5 )heterocycloalkyl. In various embodiments of each of the embodiments in this paragraph, the heterocycloalkyl is
  • each R 1 is (Ci)alkyl and R 2 is (Ci-C 4 )alkyl substituted with (C 5 - C 7 )heterocycloalkyl. In another embodiment, each R 1 is (Ci)alkyl and R 2 is (Ci-C 2 )alkyl substituted with (C 5 -C 7 )heterocycloalkyl. In another embodiment, each R 1 is (Ci)alkyl and R 2 is (Ci)alkyl substituted with (C 5 -C 7 )heterocycloalkyl.
  • the heterocycloalkyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the heterocycloalkyl is (C 5 )heterocycloalkyl.
  • the heterocycloalkyl is (C6)heterocycloalkyl.
  • a nitroxyl donating compound of the disclosure is a compound of the formula (I d):
  • each R 1 is independently H or (Ci)alkyl
  • R is (Ci-C6)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10- membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 6 ;
  • R 7 is H or (C C 6 )alkyl.
  • At least one of R 1 is H. In some aspects, each R 1 is H. In other aspects of this embodiment, at least one of R 1 is (Ci)alkyl. In some aspects, each R 1 is
  • R 2 is (Ci-C4)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl. In another embodiment, R 2 is (Ci-C 2 )alkyl substituted with (5- or 6- membered)heteroaryl or (9-or 10-membered)heteroaryl. In another embodiment, R 2 is (Ci)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl.
  • the heteroaryl is unsubstituted in one embodiment, mono -substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the heteroaryl is a (5-membered)heteroaryl in one embodiment, a (6-membered)heteroaryl in another embodiment, a (9-membered)heteroaryl in an additional embodiment, and a (l O-membered)heteroaryl in a further embodiment.
  • the heteroaryl is selected from the group consisting of pyridyl, pyrrolyl, pyrazolyl, furyl, thienyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl,
  • the heteroaryl is selected from the group consisting of furyl, thienyl, imidazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1 ,3,5-triazinyl, thiophenyl, lH-indolyl, 3H- indolyl and benzo[d] [l ,3]dioxol.
  • R 6 is halo or (Ci-C 6 )alkyl. In some embodiments, R 6 is halo or (Ci-C 4 )alkyl. In other embodiments, R 6 is halo or (Ci-C 2 )alkyl. In other embodiments, R 6 is fluoro. In other embodiments, R 6 is methyl.
  • X is S. In other aspects, X is O. In other aspects, X is NH. In other aspects, X is N(Ci-C6)alkyl. In other aspects, X is NCH 3 .
  • At least one R 1 is H and X is S. In another embodiment, at least one R 1 is H and X is O. In another embodiment, at least one R 1 is H and X is NH. In another embodiment, at least one R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is H and X is S. In another embodiment, each R 1 is H and X is O. In another embodiment, each R 1 is H and X is NH. In another embodiment, each R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R 1 is H and X is NCH 3 .
  • At least one of R 1 is (Ci)alkyl and X is S. In another embodiment, at least one of R 1 is (Ci)alkyl and X is O. In another embodiment, at least one of R 1 is (Ci)alkyl and X is NH. In another embodiment, at least one R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is (Ci)alkyl and X is S. In another embodiment, each R 1 is (Ci)alkyl and X is O. In another embodiment, each R 1 is (Ci)alkyl and X is NH. In another embodiment, each R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R 1 is H and X is NCH 3 .
  • At least one R 1 is H and R 2 is (Ci-C alkyl substituted with (5- or 6- membered)heteroaryl or (9-or 10-membered)heteroaryl. In another embodiment, at least one R 1 is H and R 2 is (Ci-C2)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl. In another embodiment, at least one R 1 is H and R 2 is (Ci)alkyl substituted with (5- or 6- membered)heteroaryl or (9-or 10-membered)heteroaryl.
  • the heteroaryl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the heteroaryl is furyl.
  • the heteroaryl is thienyl.
  • the heteroaryl is imidazolyl.
  • the heteroaryl is pyridyl.
  • the heteroaryl is lH-indolyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is 3H-indolyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is benzo[d][l,3]dioxolyl.
  • each R 1 is H and R 2 is (Ci-C4)alkyl substituted with (5- or 6- membered)heteroaryl or (9-or 10-membered)heteroaryl.
  • each R 1 is H and R 2 is (Ci-C2)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl.
  • each R 1 is H and R 2 is (Ci)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl.
  • the heteroaryl is
  • the heteroaryl is furyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is thienyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is imidazolyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is pyridyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is lH-indolyl.
  • the heteroaryl is 3H-indolyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is benzo[d][l,3]dioxolyl. In one embodiment, at least one of R 1 is (Ci)alkyl and R 2 is (Ci-C4)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl. In another embodiment, at least one of R 1 is (Ci)alkyl and R 2 is (Ci-C 2 )alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10- membered)heteroaryl.
  • R 1 is (Ci)alkyl and R 2 is (Ci)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl.
  • the heteroaryl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the heteroaryl is furyl.
  • the heteroaryl is thienyl.
  • the heteroaryl is imidazolyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is pyridyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is lH-indolyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is 3H-indolyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is benzo[d] [l ,3]dioxolyl.
  • each R 1 is (Ci)alkyl and R 2 is (Ci-C alkyl substituted with (5- or 6- membered)heteroaryl or (9-or 10-membered)heteroaryl.
  • each R 1 is (Ci)alkyl and R 2 is (Ci-C 2 )alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl.
  • each R 1 is (Ci)alkyl and R 2 is (Ci)alkyl substituted with (5- or 6- membered)heteroaryl or (9-or 10-membered)heteroaryl.
  • the heteroaryl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the heteroaryl is furyl.
  • the heteroaryl is thienyl.
  • the heteroaryl is imidazolyl.
  • the heteroaryl is pyridyl.
  • the heteroaryl is lH-indolyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is 3H-indolyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is benzo[d] [1 ,3]dioxolyl.
  • the compound of formula (1 ) is:
  • the compound of formula (1) is:
  • the compound of formula (1) is:
  • compounds 1, 2 or 3 are utilized as a pharmaeutically acceptable salt thereof.
  • a nitroxyl donating compound of the disclosure is a compound of the formula (2): (2), or a pharmaceutically acceptable salt thereof, wherein: each R 1 is independently H or (Ci)alkyl;
  • R is selected from the group consisting of a branched C3-C6 alkyl, a branched C3-C6 alkenyl, and a branched C3-C6 alkoxy, wherein said alkyl, alkenyl, and alkoxy are unsubstituted or substituted with 1, 2 or 3 substituents selected from R 4 ;
  • R 7 is H or (C C 6 )alkyl.
  • At least one of R 1 is H. In some aspects, each R 1 is H.
  • At least one of R 1 is (Ci)alkyl. In some aspects, each R 1 is (Ci)alkyl.
  • R 2 is a branched C3-C6 alkyl, wherein said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 4 .
  • R 2 is a substituted, branched C 3 -C6 alkyl.
  • R 2 is an unsubstituted, branched C 3 -C6 alkyl.
  • R is selected from the group consisting of z ' o-propyl, sec-butyl, iso-butyl, ieri-butyl, methylbutyl, z ' o-pentyl, methylpentyl, ethylbutyl, dimethylbutyl, and z ' o-propylpropyl.
  • R 2 is selected from the group consisting of sec-butyl, z ' so-butyl, teri-butyl, methylbutyl, z ' so-pentyl, methylpentyl, ethylbutyl, dimethylbutyl, and z ' so-propylpropyl.
  • R 2 is a branched C3-C6 alkenyl, wherein said alkenyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 4 .
  • R 2 is a substituted, branched C 3 -C 6 alkenyl.
  • R 2 is an unsubstituted, branched C 3 -C 6 alkenyl.
  • R 2 is a branched C 3 -C 6 alkoxy, wherein said alkoxy is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 4 .
  • R 2 is a substituted, branched C 3 -C 6 alkoxy.
  • R 2 is an unsubstituted, branched C 3 -C 6 alkoxy.
  • X is S. In other aspects, X is O. In other aspects, X is NH. In other aspects, X is N(Ci-C 6 )alkyl. In other aspects, X is NCH 3 .
  • At least one R 1 is H and X is S. In another embodiment, at least one R 1 is H and X is O. In another embodiment, at least one R 1 is H and X is NH. In another embodiment, at least one R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is H and X is S. In another embodiment, each R 1 is H and X is O. In another embodiment, each R 1 is H and X is NH. In another embodiment, each R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R 1 is H and X is NCH 3 .
  • At least one of R 1 is (Ci)alkyl and X is S. In another embodiment, at least one of R 1 is (Ci)alkyl and X is O. In another embodiment, at least one of R 1 is (Ci)alkyl and X is NH. In another embodiment, at least one R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is (Ci)alkyl and X is S. In another embodiment, each R 1 is (Ci)alkyl and X is O. In another embodiment, each R 1 is (Ci)alkyl and X is NH. In another embodiment, each R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, each R 1 is H and X is NCH 3 . In various embodiments of the first embodiment of the compound of formula (2), at least one R 1 is H in one embodiment, each R 1 is H in another embodiment, at least one of R 1 is (Ci)alkyl m an additional embodiment, and each R 1 is (Ci)alkyl in a further embodiment.
  • At least one R 1 is H in one embodiment, each R 1 is H in another embodiment, at least one of R 1 is (Ci)alkyl m an additional embodiment, and each R 1 is (Ci)alkyl in a further embodiment.
  • At least one R 1 is H in one embodiment, each R 1 is H in another embodiment, at least one of R 1 is (d)alkyl m an additional embodiment, and each R 1 is (Ci)alkyl in a further embodiment.
  • a nitroxyl donating compound of the disclosure is a compound of the formula (3):
  • each R is H;
  • R is selected from the group consisting of (Ci-C6)alkyl, (C 2 -C6)alkenyl, (C 2 - Ce)alkynyl and (Ci-C6)alkoxy, wherein said alkyl, alkenyl, alkynyl and alkoxy are unsubstituted or substituted with 1 , 2 or 3 substituents selected from R ;
  • R 7 is H or (C r C 6 )alkyl.
  • R 2 is (Ci-C 6 )alkyl, wherein said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R 4 .
  • R 2 is unsubstituted (Ci-C 6 )alkyl.
  • R 2 is (Ci-C 4 )alkyl, wherein said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R 4 .
  • R 2 is unsubstituted (Ci-C 4 )alkyl.
  • R 2 is (C 2 -C 6 )alkyl, wherein said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R 4 .
  • R 2 is unsubstituted (C 2 -C 6 )alkyl.
  • R 2 is methyl.
  • R 2 is ethyl.
  • R 2 is propyl.
  • R 2 is butyl.
  • R 2 is pentyl.
  • R 2 is hexyl.
  • R 2 is (Ci-C6)alkyl substituted with 1, 2 or 3 substituents independently selected from R 4 .
  • R 2 is a monosubstituted (Ci-C6)alkyl substituted with a substituent selected from R 4 .
  • R 2 is a disubstituted (Ci-C6)alkyl substituted with 2 substituents independently selected from R 4 .
  • R 2 is a trisubstituted (Cp C6)alkyl substituted with 3 substituents independently selected from R 4 .
  • R 2 is (Cp C6)alkyl substituted 1, 2 or 3 substituents independently selected from halo, SR', -C(0)NH 2 , - C(0)OH, -NH 2 and -NH-C(NH)-NH 2 .
  • R 2 is (C r C 6 )alkyl monsubstituted with halo.
  • R 2 is (Ci-C6)alkyl disubstituted with 2 halos independently selected.
  • R 2 is (Ci-C 6 )alkyl trisubstituted with 3 halos independently selected.
  • R 2 is (Ci-C 6 )alkyl monosubstituted with fluoro.
  • R 2 is (C r C6)alkyl substituted 1, 2 or 3 substituents independently selected from halo, SR', -C(0)NH 2 , - C(0)OH, -NH 2 and -NH-C(NH)-NH 2 .
  • R 2 is (C r C 6 )alky
  • R 2 is (Ci-C 6 )alkyl disubstituted with fluoro.
  • R 2 is (Ci-C 6 )alkyl trisubstituted fluoro.
  • R 2 is (Ci-C 6 )alkyl monosubstituted with SR'.
  • R 2 is (Cp C 6 )alkyl monosubstituted with S(Ci-C 6 )alkyl.
  • R 2 is (Ci-C 6 )alkyl
  • R 2 is (Ci-C 6 )alkyl monosubstituted
  • R 2 is (Ci-C 6 )alkyl monosubstituted with -C(0)OH. In another embodiment, R 2 is (Ci-C 6 )alkyl monosubstituted with -NH 2 . In another embodiment, R 2 is (Ci-C 6 )alkyl monosubstituted with -NH-C(NH)-NH 2 . In one embodiment, R is a (Ci-C alkyl substituted with 1, 2 or 3 substituents independently selected from R 4 . In another embodiment, R 2 is a monosubstituted (Ci-C4)alkyl substituted with a substituent independently selected from R 4 .
  • R 2 is a disubstituted (Ci-C4)alkyl substituted with 2 substituents independently selected from R 4 .
  • R 2 is a trisubstituted (Ci-C4)alkyl substituted with 3 substituents independently selected from R 4 .
  • R 2 is (Ci-C 4 )alkyl substituted 1, 2 or 3 substituents independently selected from halo, SR', -C(0)NH 2 , -C(0)OH, -NH 2 and -NH-C(NH)-NH 2 .
  • R 2 is (C r C 4 )alkyl monsubstituted with halo.
  • R 2 is (Ci-C 4 )alkyl disubstituted with 2 halos independently selected. In another embodiment, R 2 is (Ci-C 4 )alkyl trisubstituted with 3 halos independently selected. In another embodiment, R 2 is (Ci-C 4 )alkyl monosubstituted with fluoro. In another embodiment, R 2 is (Ci-C 4 )alkyl disubstituted with fluoro. In another embodiment, R 2 is (Cp C 4 )alkyl trisubstituted fluoro. In another embodiment, R 2 is (Ci-C 4 )alkyl monosubstituted with SR'.
  • R 2 is (Ci-C 4 )alkyl monosubstituted with S(Ci-C 6 )alkyl. In another embodiment, R 2 is (Ci-C 4 )alkyl monosubstituted with -SCH 3 . In another embodiment, R 2 is (Ci-C 4 )alkyl monosubstituted with -C(0)NH 2 . In another embodiment, R 2 is (Ci-C4)alkyl monosubstituted with -C(0)OH. In another embodiment, R 2 is (Ci-C4)alkyl monosubstituted with -NH 2 . In another embodiment, R 2 is (d-C 4 )alkyl monosubstituted with -NH-C(NH)-NH 2 .
  • R 2 is a (C 2 -C6)alkyl substituted with 1 , 2 or 3 substituents independently selected from R 4 .
  • R 2 is a monosubstituted (C 2 -Ce)alkyl substituted with a substituent independently selected from R 4 .
  • R 2 is a disubstituted (C 2 -C6)alkyl substituted with 2 substituents independently selected from R 4 .
  • R 2 is a trisubstituted (C 2 -Ce)alkyl substituted with 3 substituents independently selected from R 4 .
  • R 2 is (C 2 -Ce)alkyl substituted 1, 2 or 3 substituents independently selected from halo, SR', -C(0)NH 2 , -C(0)OH, -NH 2 and -NH-C(NH)-NH 2 .
  • R 2 is (C 2 -C 6 )alkyl monsubstituted with halo.
  • R 2 is (C 2 -C 6 )alkyl disubstituted with 2 halos independently selected.
  • R 2 is (C 2 -C 6 )alkyl trisubstituted with 3 halos independently selected.
  • R 2 is (C 2 -C 6 )alkyl monosubstituted with fluoro. In another embodiment, R 2 is (C 2 -C 6 )alkyl disubstituted with fluoro. In another embodiment, R 2 is (C 2 - C 6 )alkyl trisubstituted with fluoro. In another embodiment, R 2 is (C 2 -C 6 )alkyl monosubstituted with SR'. In another embodiment, R 2 is (C 2 -C 6 )alkyl monosubstituted with S(Ci-C 6 )alkyl. In another embodiment, R 2 is (C 2 -C 6 )alkyl monosubstituted with -SCH 3 .
  • R 2 is (C 2 - C 6 )alkyl monosubstituted with -C(0)NH 2 . In another embodiment, R 2 is (C 2 -C 6 )alkyl monosubstituted with -C(0)OH. In another embodiment, R is (C2-C6)alkyl monosubstituted with -NH 2 . In another embodiment, R 2 is (C 2 -C 6 )alkyl monosubstituted with -NH-C(NH)-NH 2 .
  • R 2 is a monosubstituted (Ci)alkyl substituted with a substituent selected from R 4 .
  • R 2 is (Ci)alkyl monosubstituted with a substituent selected from halo, SR', -C(0)NH 2 , -C(0)OH, -NH 2 and -NH-C(NH)-NH 2 .
  • R 2 is (Ci)alkyl monsubstituted with halo.
  • R 2 is (Ci)alkyl monosubstituted with fluoro.
  • R 2 is (Ci)alkyl monosubstituted with SR'.
  • R 2 is (Ci)alkyl monosubstituted with S(Ci-C 6 )alkyl. In another embodiment, R 2 is (Ci)alkyl monosubstituted with -SCH 3 . In another embodiment, R 2 is (Ci)alkyl monosubstituted with -C(0)NH 2 . In another embodiment, R 2 is (Ci)alkyl monosubstituted with -C(0)OH. In another embodiment, R 2 is (Ci)alkyl monosubstituted with -NH 2 . In another embodiment, R 2 is (Ci)alkyl monosubstituted with -NH- C(NH)-NH 2 .
  • R 2 is a disubstituted (Ci)alkyl substituted with 2 halos independently selected. In another embodiment, R 2 is (Ci)alkyl disubstituted with fluoro. In another embodiment, R 2 is (Ci)alkyl trisubstituted with 3 halos independently selected. In another
  • R 2 is (Ci)alkyl trisubstituted with fluoro.
  • R 2 is a monosubstituted (C 2 )alkyl substituted with a substituent selected from R 4 .
  • R 2 is (C 2 )alkyl monosubstituted with a substituent selected from halo, SR', -C(0)NH 2 , -C(0)OH, -NH 2 and -NH-C(NH)-NH 2 .
  • R 2 is (C 2 )alkyl monsubstituted with halo.
  • R 2 is (C 2 )alkyl monosubstituted with fluoro.
  • R 2 is (C 2 )alkyl monosubstituted with SR'.
  • R 2 is
  • R 2 is (C 2 )alkyl monosubstituted with S(Ci-C6)alkyl.
  • R 2 is (C 2 )alkyl monosubstituted with -SCH 3 .
  • R 2 is (C 2 )alkyl monosubstituted with -C(0)NH 2 .
  • R 2 is (C 2 )alkyl monosubstituted with -C(0)OH.
  • R 2 is (C 2 )alkyl monosubstituted with -NH 2 .
  • R 2 is (C 2 )alkyl monosubstituted with -NH- C(NH)-NH 2 .
  • R 2 is a disubstituted (C 2 )alkyl substituted with 2 halos independently selected. In another embodiment, R 2 is (C 2 )alkyl disubstituted with fluoro. In another embodiment, R 2 is (C 2 )alkyl trisubstituted with 3 halos independently selected. In another
  • R 2 is (C 2 )alkyl trisubstituted with fluoro.
  • R 2 is a monosubstituted (C 3 )alkyl substituted with a substituent selected from R 4 .
  • R 2 is (C 3 )alkyl monosubstituted with a substituent selected from halo, SR', -C(0)NH 2 , -C(0)OH, -NH 2 and -NH-C(NH)-NH 2 .
  • R 2 is (C 3 )alkyl monsubstituted with halo.
  • R 2 is (C 3 )alkyl monosubstituted with fluoro.
  • R is (C3)alkyl monosubstituted with SR'.
  • R is (C3)alkyl monosubstituted with S(Ci-C6)alkyl.
  • R 2 is (C3)alkyl monosubstituted with -SCH 3 .
  • R 2 is (C3)alkyl monosubstituted with -C(0)NH 2 .
  • R 2 is (C3)alkyl monosubstituted with -C(0)OH.
  • R 2 is (C3)alkyl monosubstituted with -NH 2 .
  • R 2 is (C3)alkyl monosubstituted with -NH- C(NH)-NH 2 .
  • R 2 is a disubstituted (C 3 )alkyl substituted with 2 halos independently selected. In another embodiment, R 2 is (C 3 )alkyl disubstituted with fluoro. In another embodiment, R 2 is (C 3 )alkyl trisubstituted with 3 halos independently selected. In another
  • R 2 is (C 3 )alkyl trisubstituted with fluoro.
  • R 2 is a monosubstituted (C 4 )alkyl substituted with a substituent selected from R 4 .
  • R 2 is (C 4 )alkyl monosubstituted with a substituent selected from halo, SR', -C(0)NH 2 , -C(0)OH, -NH 2 and -NH-C(NH)-NH 2 .
  • R 2 is (C 4 )alkyl monsubstituted with halo.
  • R 2 is (C 4 )alkyl monosubstituted with fluoro.
  • R 2 is (C )alkyl monosubstituted with SR'. In another embodiment, R 2 is (C 4 )alkyl monosubstituted with S(Ci-C6)alkyl. In another embodiment, R 2 is (C 4 )alkyl monosubstituted with -SCH 3 . In another embodiment, R 2 is (C 4 )alkyl monosubstituted with -C(0)NH 2 . In another embodiment, R 2 is (C 4 )alkyl monosubstituted with -C(0)OH. In another embodiment, R 2 is (C 4 )alkyl monosubstituted with -NH 2 .
  • R 2 is (C 4 )alkyl monosubstituted with -NH- C(NH)-NH 2 .
  • R 2 is a disubstituted (C 4 )alkyl substituted with 2 halos independently selected.
  • R 2 is (C 4 )alkyl disubstituted with fluoro.
  • R 2 is (C 4 )alkyl trisubstituted with 3 halos independently selected.
  • R 2 is (C 4 )alkyl trisubstituted with fluoro.
  • R 2 is a branched (C3-Ce)alkyl, wherein said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 4 .
  • R 2 is a substituted, branched C 3 -C 6 alkyl.
  • R 2 is an unsubstituted, branched C 3 -C 6 alkyl.
  • R 2 is selected from the group consisting of z ' o-propyl, sec-butyl, iso-butyl, teri-butyl, methylpentyl, ethylbutyl, dimethylbutyl, and z ' o-propylpropyl.
  • R 2 is selected from the group consisting of sec-butyl, iso-butyl, tert-butyl, methylpentyl, ethylbutyl, dimethylbutyl, and z ' o-propylpropyl.
  • R 2 is (C 2 -C 6 )alkenyl, wherein said alkenyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 4 .
  • R 2 is a substituted (C 2 - C 6 )alkenyl.
  • R 2 is an unsubstituted (C 2 -C 6 )alkenyl.
  • R 2 is an unsubstituted (C3-C6)alkenyl.
  • R is an unsubstituted (C3)alkenyl.
  • R 2 is an unsubstituted (C 4 )alkenyl.
  • R 2 is an unsubstituted (C 5 )alkenyl. In another embodiment, R 2 is an unsubstituted (C6)alkenyl. In one embodiment, R 2 is a substituted (C3-C6)alkenyl. In another embodiment, R 2 is a substituted (C3)alkenyl. In another embodiment, R 2 is a substituted (C4)alkenyl. In another embodiment, R 2 is a substituted (C 5 )alkenyl. In another embodiment, R 2 is a substituted (C 6 )alkenyl.
  • R 2 is a branched (C 3 -C 6 )alkenyl, wherein said alkenyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 4 .
  • R 2 is a substituted, branched (C 3 -C 6 )alkenyl.
  • R 2 is an unsubstituted, branched (C 3 - C 6 )alkenyl.
  • R 2 is an unsubstituted, branched (C 3 -C 6 )alkenyl.
  • R 2 is an unsubstituted, branched (C 3 )alkenyl.
  • R 2 is an unsubstituted, branched (C 4 )alkenyl. In another embodiment, R 2 is an unsubstituted, branched (C 5 )alkenyl. In another embodiment, R 2 is an unsubstituted, branched (C 6 )alkenyl. In one
  • R 2 is a substituted, branched (C 3 -C 6 )alkenyl. In another embodiment, R 2 is a substituted, branched (C3)alkenyl. In another embodiment, R 2 is a substituted, branched (C ⁇ alkenyl. In another embodiment, R 2 is a substituted, branched (C 5 )alkenyl. In another embodiment, R 2 is a substituted, branched (C6)alkenyl.
  • R 2 is (C 2 -Ce)alkynyl, wherein said alkynyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 4 .
  • R 2 is a substituted (C 2 - C6)alkynyl.
  • R 2 is an unsubstituted (C 2 -C6)alkynyl.
  • R 2 is an unsubstituted, branched (C3-C6)alkynyl.
  • R 2 is an unsubstituted, branched (C 3 ) alkynyl.
  • R 2 is an unsubstituted, branched (C 4 ) alkynyl. In another embodiment, R 2 is an unsubstituted, branched (C 5 ) alkynyl. In another embodiment, R 2 is an unsubstituted, branched (C 6 )alkynyl. In one embodiment, R 2 is a substituted, branched (C 3 -C 6 )alkynyl. In another embodiment, R 2 is a substituted, branched (C 3 )alkynyl. In another embodiment, R 2 is a substituted, branched (C 4 )alkynyl. In another embodiment, R 2 is a substituted, branched (C 5 )alkynyl. In another embodiment, R 2 is a substituted, branched (C 6 )alkynyl.
  • R 2 is (Ci-C 6 )alkoxy, wherein said alkoxy is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 4 .
  • R 2 is a substituted (Q- C 6 )alkoxy.
  • R 2 is an unsubstituted (Ci-C 6 )alkoxy.
  • R 2 is methoxy.
  • R 2 is ethoxy.
  • R 2 is propoxy.
  • R is a branched (C3-C6)alkoxy, wherein said alkoxy is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 4 .
  • R 2 is a substituted, branched (C 3 -Ce)alkoxy.
  • R 2 is an unsubstituted, branched (C 3 - Ce) alkoxy.
  • X is S. In other aspects, X is O. In other aspects, X is NH. In other aspects, X is N(Ci-C 6 )alkyl. In other aspects, X is NCH 3 .
  • X is S in one embodiment, X is O in another embodiment, X is NH in an additional embodiment and X is NCH 3 in a further embodiment.
  • X is S in one embodiment, X is O in another embodiment, X is NH in an additional embodiment and X is NCH 3 in a further embodiment.
  • X is S in one embodiment, X is O in another embodiment, X is NH in an additional embodiment and X is NCH 3 in a further embodiment.
  • X is S in one embodiment, X is O in another embodiment, X is NH in an additional embodiment and X is NCH 3 in a further embodiment.
  • X is S in one embodiment, X is O in another embodiment, X is NH in an additional embodiment and X is NCH 3 in a further embodiment.
  • X is S in one embodiment, X is O in another embodiment, X is NH in an additional embodiment and X is NCH 3 in a further embodiment.
  • a nitroxyl donating compound of the disclosure is a compound of the formula (3 a):
  • each R 1 is H;
  • R 2 is (Ci-C 4 )alkyl substituted with phenyl, wherein said phenyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 6 ;
  • R 7 is H or (C C 6 )alkyl.
  • R 2 is (Ci-C 4 )alkyl substituted with phenyl. In another embodiment, R 2 is (Ci-C 2 )alkyl substituted with phenyl. In another embodiment, R 2 is (Ci)alkyl substituted with phenyl. In each embodiment of this paragraph, the phenyl is unsubstituted in one embodiment, mono- substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment. In embodiments in which said (Ci-C alkyl is substituted with R 6 , R 6 is halo or (Ci-C6)alkyl.
  • halo or (Ci-C 4 )alkyl In some embodiments, halo or (Ci-C 4 )alkyl. In other embodiments, R 6 is halo or (Ci-C 2 )alkyl. In other embodiments, R 6 is fluoro. In other embodiments, R 6 is methyl.
  • each R 4 is independently selected from the group consisting of halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 6 -Ci 4 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6- membered)heteroaryl, (C 5 -C 7 )heterocycloalkyl, -C(0)H, -C(0)NH 2 , -C(0)OH, -NH-C(0)-NH 2 , -NH- C(S)-NH 2 , -SC ⁇ N, -S0 2
  • each R 4 is independently selected from the group consisting of -OH, - NH 2 , -SH, (C r C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C r C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 - C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6-membered)heteroaryl, (C 5 - C 7 )heterocycloalkyl, -NHR', -NR'R", -SR', -OR', wherein R' and R" are independently selected from (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -Ci 4 )aryl,
  • each R 4 is independently selected from the group consisting of -OH, - NH 2 , -SH, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C r C 6 )alkoxy, (C 2 -C 6 )alkenyloxy and (C 2 - C 6 )alkynyloxy.
  • each R 4 is independently selected from the group consisting of - OH, -NH 2 , -SH, (Ci-C 6 )alkoxy, (C 2 -C 6 )alkenyloxy and (C 2 -C 6 )alkynyloxy.
  • each R 4 is independently selected from the group consisting of (Ci-C 6 )alkoxy, (C 2 -C 6 )alkenyloxy and (C 2 - C 6 )alkynyloxy. In yet other embodiments, R 4 is (Ci-C 6 )alkoxy. In some embodiments, R 4 is selected (Ci-C 3 )alkoxy. In other embodiments, R 4 is methoxy. In other embodiments, R 4 is -OH.
  • each R 4 is independently selected from the group consisting of halo, - C ⁇ N, -N0 2 , -C(0)H, -C(0)NH 2 , -C(0)OH, -NH-C(0)-NH 2 , -NH-C(S)-NH 2 , -SON, -S0 2 NH 2 , -COR', -C(0)OR', -C(0)NHR', -C(0)NR'R", -S(0)R' and -S(0)OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C 2 -C6)alkenyl, (C 2 -Ce)alkynyl, (C6-Ci 4 )aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, and (C 5 -C 7 )heterocycloalkyl.
  • each R is independently selected from the group consisting of halo, - C ⁇ N, -N0 2 , -C(0)NH 2 , -C(0)OH, -COR', -C(0)OR', -C(0)NHR', and -C(0)NR'R", wherein R' and R" are independently selected from (Ci-C6)alkyl, (C 2 -C6)alkenyl, (C 2 -Ce)alkynyl, (C6-Ci 4 )aryl, (C 3 - C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 -C 7 )heterocycloalkyl.
  • R 4 is halo.
  • R 4 is CI.
  • X is S. In other aspects, X is O. In other aspects, X is NH. In other aspects, X is N(Ci-C 6 )alkyl. In other aspects, X is NCH 3 .
  • R 2 is (Ci-C 4 )alkyl substituted with phenyl and X is S. In another embodiment, R 2 is (Ci-C 4 )alkyl substituted with phenyl and X is O. In another embodiment, R 2 is (Q- C 4 )alkyl substituted with phenyl and X is NH. In another embodiment, R 2 is (Ci-C 4 )alkyl substituted with phenyl and X is NCH 3 .
  • the phenyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the substituent is methoxy, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, halo, and methylsulfonyl.
  • R 2 is (Ci-C 2 )alkyl substituted with phenyl and X is S. In another embodiment, R 2 is (Ci-C 2 )alkyl substituted with phenyl and X is O. In another embodiment, R 2 is (Cr C 2 )alkyl substituted with phenyl and X is NH. In another embodiment, R 2 is (Ci-C 2 )alkyl substituted with phenyl and X is NCH 3 .
  • the phenyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the substituent is -OH, methoxy, halo, or methylsulfonyl, or the substituents are independently selected from -OH, methoxy, halo, and methylsulfonyl.
  • R 2 is (Ci)alkyl substituted with phenyl and X is S.
  • R 2 is (Ci)alkyl substituted with phenyl and X is O. In another embodiment, R 2 is (Ci)alkyl substituted with phenyl and X is NH. In another embodiment, R 2 is (Ci)alkyl substituted with phenyl and X is NCH 3 . In each embodiment of this paragraph, the phenyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the substituent is -OH, methoxy, halo, or methylsulfonyl, or the substituents are independently selected from -OH, methoxy, halo, and methylsulfonyl.
  • a nitroxyl donating compound of the disclosure is a compound of the formula (3a-l):
  • X is O, NR 7 or S; each R 6 is independently selected from the group consisting of H, halo and (Cr C6)alkyl; and
  • R 7 is H or (C C 6 )alkyl.
  • one or more of R 5 is selected from the group consisting of H, -OH, (d- Ce)alkoxy, S(0)0(Ci-C6)alkyl and halo.
  • one or more of R 5 is selected from the group consisting of -OH, (Ci-C6)alkoxy, S(0)0(Ci-C6)alkyl and halo.
  • one or more of R 5 is methoxy.
  • one or more of R 5 is CI.
  • one or more of R 5 is S(0)0(Cr C6)alkyl.
  • one or more of R 5 is -OH.
  • one R 5 is methoxy and the other R 5 are H. In other aspects, one R 5 is CI and the other R 5 are H. In some aspects, one R 5 is S(0)0(Ci-C 6 )alkyl and the other R 5 are H. In another embodiment, one R 5 is -OH and the other R 5 are H.
  • At least one of R 6 is H, halo or (Ci-C 4 )alkyl. In other embodiments, at least one of R 6 is H, halo or (Ci-C 2 )alkyl. In other embodiments, at least one of R 6 is fluoro. In other embodiments, at least one of R 6 is methyl. In other embodiments, at least one of R 6 is H.
  • X is S. In other aspects, X is O. In other aspects, X is NH. In other aspects, X is N(Ci-C 6 )alkyl. In other aspects, X is NCH 3 .
  • a nitroxyl donating compound of the disclosure is a compound of the formula (3b):
  • X is O, NR 7 or S; each R 6 is independently selected from the group consisting of halo and (Ci-C 6 )alkyl; and
  • R 7 is H or (C r C 6 )alkyl.
  • R is (Ci-C 4 )alkyl substituted with (C 3 -C 6 )cycloalkyl.
  • R 2 is (Ci-C 2 )alkyl substituted with (C 3 -C 6 )cycloalkyl.
  • R 2 is (Ci)alkyl substituted with (C 3 -C6)cycloalkyl.
  • the (C 3 - C6)cycloalkyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di- substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the (C 3 -C6)cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cylcohexyl. In various embodiments of each of the embodiments in this paragraph, the (C 3 -C6)cycloalkyl is cyclohexyl.
  • R 6 is halo or (Ci-C6)alkyl. In some embodiments, halo or (Ci-C 4 )alkyl. In other embodiments, R 6 is halo or (Ci-C 2 )alkyl. In other embodiments, R 6 is fluoro. In other embodiments, R 6 is methyl.
  • X is S. In other aspects, X is O. In other aspects, X is NH. In other aspects, X is N(Ci-C 6 )alkyl. In other aspects, X is NCH 3 .
  • R 2 is (Ci-C 4 )alkyl substituted with (C 3 -C 6 )cycloalkyl and X is S. In another embodiment, R 2 is (Ci-C 4 )alkyl substituted with (C 3 -C 6 )cycloalkyl and X is O. In another embodiment, R 2 is (Ci-C 4 )alkyl substituted with (C 3 -C 6 )cycloalkyl and X is NH. In another embodiment, R 2 is (Ci-C 4 )alkyl substituted with (C 3 -C 6 )cycloalkyl and X is NCH 3 .
  • the cycloalkyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the substituent is methoxy, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, halo, and
  • R 2 is (Ci-C 2 )alkyl substituted with (C 3 -C 6 )cycloalkyl and X is S. In another embodiment, R 2 is (Ci-C 2 )alkyl substituted with (C 3 -C 6 )cycloalkyl and X is O. In another embodiment, R 2 is (Ci-C 2 )alkyl substituted with (C 3 -C 6 )cycloalkyl and X is NH. In another embodiment, R 2 is (Ci-C 2 )alkyl substituted with (C 3 -C 6 )cycloalkyl and X is NCH 3 .
  • the cycloalkyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the substituent is methoxy, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, halo, and
  • R 2 is (Ci)alkyl substituted with (C 3 -C6)cycloalkyl and X is S. In another embodiment, R 2 is (Ci)alkyl substituted with (C 3 -C6)cycloalkyl and X is O. In another embodiment, R 2 is (Ci)alkyl substituted with (C 3 -C6)cycloalkyl and X is NH. In another embodiment, R 2 is (Ci)alkyl substituted with (C 3 -C6)cycloalkyl and X is NCH 3 .
  • the cycloalkyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the substituent is methoxy, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, halo, and methylsulfonyl.
  • a nitroxyl donating compound of the disclosure is a compound of the formula (3c):
  • each R 1 is H;
  • R 2 is (Ci-C4)alkyl substituted with (C 5 -C 7 )heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R 6 ;
  • R 7 is H or (C C 6 )alkyl.
  • R 2 is (Ci-C4)alkyl substituted with (C 5 -C 7 )heterocycloalkyl. In another embodiment, R 2 is (Ci-C 2 )alkyl substituted with (C 5 -C 7 )heterocycloalkyl. In another embodiment, R 2 is (Ci)alkyl substituted with (C 5 -C 7 )heterocycloalkyl. In each embodiment of this paragraph, the heterocycloalkyl is unsubstituted in one embodiment, mono-substituted in another embodiment, di- substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the heterocycloalkyl is selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, tetrahydro-oxazinyl, tetrahydrofuran, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrahydrofuranone, ⁇ - butyrolactone, 2H-pyran, 4H-pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, piperazine, morpholine, thiomorpholine, oxazine and tetrahydro-oxazinyl.
  • the hetercycloalkyl is a (C 6 )heterocycloalkyl selected from the group consisting of piperidinyl, piperazinyl, tetrahydro-oxazinyl, tetrahydropyran, dioxane, morpholine and thiomorpholine.
  • R 6 is halo or (Ci-C 6 )alkyl.
  • halo or (Ci-C 4 )alkyl In some embodiments, halo or (Ci-C 4 )alkyl. In other embodiments, R 6 is halo or (Ci-C 2 )alkyl. In other embodiments, R 6 is fluoro. In other embodiments, R 6 is methyl.
  • X is S. In other aspects, X is O. In other aspects, X is ⁇ . In other aspects, X is N(Ci-C 6 )alkyl. In other aspects, X is NCH 3 .
  • R 2 is (Ci-C alkyl substituted with (C 5 -C 7 )heterocycloalkyl and X is S. In another embodiment, R 2 is (Ci-C 4 )alkyl substituted with (C 5 -C 7 )heterocycloalkyl and X is O. In another embodiment, R 2 is substituted with (C 5 -C 7 )heterocycloalkyl and X is NH.
  • R 2 is substituted with (C 5 -C 7 )heterocycloalkyl and X is NCH 3 .
  • the heterocycloalkyl is unsubstituted in one embodiment, mono- substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the substituent is methoxy, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, halo, and methylsulfonyl.
  • R 2 is (Ci-C 2 )alkyl substituted with (C 5 -C 7 )heterocycloalkyl and X is S. In another embodiment, R 2 is (Ci-C 2 )alkyl substituted with (C 5 -C 7 )heterocycloalkyl and X is O. In another embodiment, R 2 is (Ci-C 2 )alkyl substituted with (C 5 -C 7 )heterocycloalkyl and X is NH. In another embodiment, R 2 is (C r C 2 )alkyl substituted with (C 5 -C 7 )heterocycloalkyl and X is NCH 3 .
  • the heterocycloalkyl is unsubstituted in one embodiment, mono- substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the substituent is methoxy, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, halo, and methylsulfonyl.
  • R 2 is (Ci)alkyl substituted with (C 5 -C 7 )heterocycloalkyl and X is S. In another embodiment, R 2 is (Ci)alkyl substituted with (C 5 -C 7 )heterocycloalkyl and X is O. In another embodiment, R 2 is (Ci)alkyl substituted with (C 5 -C 7 )heterocycloalkyl and X is NH. In another embodiment, R 2 is (Ci)alkyl substituted with (C 5 -C 7 )heterocycloalkyl and X is NCH 3 .
  • the heterocycloalkyl is unsubstituted in one embodiment, mono- substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the substituent is methoxy, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, halo, and methylsulfonyl.
  • a nitroxyl donating compound of the disclosure is a compound of the formula (3d):
  • R is (Ci-C 4 )alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10- membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R 6 ;
  • R' and R" are independently selected from (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -Ci 4 )aryl, (C 3 -C 6 )cycloalkyl, (5- or 6-membered)heteroaryl and (C 5 - C 7 )heterocycloalkyl; each R 6 is independently selected from the group consisting of halo and (Ci-C 6 )alkyl; and
  • R 7 is H or (C r C 6 )alkyl.
  • R is (Ci-C 4 )alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl.
  • R 2 is (Ci-C 2 )alkyl substituted with (5- or 6- membered)heteroaryl (9-or 10-membered)heteroaryl.
  • R 2 is (Ci)alkyl substituted with (5- or 6-membered)heteroaryl (9-or 10-membered)heteroaryl.
  • the heteroaryl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the heteroaryl is a (5-membered)heteroaryl in one embodiment, a (6-membered)heteroaryl in another embodiment, a (9-membered)heteroaryl in an additional embodiment, and a (lO-membered)heteroaryl in a further embodiment.
  • the heteroaryl is selected from the group consisting of pyridyl, pyrrolyl, pyrazolyl, furyl, thienyl, imidazolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,
  • the heteroaryl is selected from the group consisting of furyl, thienyl, imidazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,3,5-triazinyl, thiophenyl, indolyl, lH-indolyl, 3-H-indolyl and benzo[d][l,3]dioxolyl.
  • the heteroaryl is furyl.
  • the heteroaryl is thienyl.
  • the heteroaryl is imidazolyl.
  • the heteroaryl is pyridyl.
  • the heteroaryl is lH-indolyl. In another embodiment, the heteroaryl is 3H-indolyl. In another embodiment, the heteroaryl is benzo[d] [l ,3]dioxolyl.
  • R 6 is halo or (Ci-C6)alkyl. In some embodiments, halo or (Ci-C 4 )alkyl. In other embodiments, R 6 is halo or (Ci-C2)alkyl. In other embodiments, R 6 is fluoro. In other embodiments, R 6 is methyl.
  • X is S. In other aspects, X is O. In other aspects, X is NH. In other aspects, X is N(Ci-C 6 )alkyl. In other aspects, X is NCH 3 .
  • R 2 is (Ci-C 4 )alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is S. In another embodiment, R 2 is (Ci-C 4 )alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is O. In another embodiment, R 2 is (Ci-C 4 )alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is NH.
  • R 2 is (Ci-C 4 )alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is NCH 3 .
  • the heteroaryl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the substituent is methoxy, -CH 2 OH, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, -CH 2 OH, halo, and methylsulfonyl.
  • the heteroaryl is furyl.
  • the heteroaryl is thienyl.
  • the heteroaryl is imidazolyl.
  • the heteroaryl is pyridyl.
  • the heteroaryl is lH-indolyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is 3H-indolyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is benzo[d] [l ,3]dioxolyl.
  • R 2 is (Ci-C 2 )alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is S. In another embodiment, R 2 is (Ci-C 2 )alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is O. In another embodiment, R 2 is (Ci-C 2 )alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is NH.
  • R 2 is (Ci-C 2 )alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is NCH 3 .
  • the heteroaryl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the substituent is methoxy, -CH 2 OH, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, -CH 2 OH, halo, and methylsulfonyl.
  • the heteroaryl is furyl.
  • the heteroaryl is thienyl.
  • the heteroaryl is imidazolyl.
  • the heteroaryl is pyridyl.
  • the heteroaryl is lH-indolyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is 3H-indolyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is benzo[d] [l ,3]dioxolyl.
  • R 2 is (Ci)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10- membered)heteroaryl and X is S. In another embodiment, R 2 is (Ci)alkyl substituted with (5- or 6- membered)heteroaryl or (9-or 10-membered)heteroaryl and X is O. In another embodiment, R 2 is (Ci)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is NH.
  • R 2 is (Ci)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10- membered)heteroaryl and X is NCH 3 .
  • the heteroaryl is unsubstituted in one embodiment, mono-substituted in another embodiment, di-substituted with two independently selected substituents in an additional embodiment, or tri-substituted with three independently selected substituents in a further embodiment.
  • the substituent is methoxy, -CH 2 OH, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, -CH 2 OH, halo, and methylsulfonyl.
  • the heteroaryl is furyl.
  • the heteroaryl is thienyl.
  • the heteroaryl is imidazolyl.
  • the heteroaryl is pyridyl.
  • the heteroaryl is lH-indolyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is 3H-indolyl. In various embodiments of each of the embodiments in this paragraph, the heteroaryl is benzo[d] [l ,3]dioxolyl.
  • the compound of formula (3) is:
  • the compound of formula (3) is:
  • the compound of formula (3) is:
  • the compound of formula (3) is:
  • compounds 4, 5, 6 or 7 are utilized as a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a nitroxyl donating compound of the formula (4):
  • each R 1 is independently H or (Ci)alkyl
  • R is (C6-Cio)aryl, (C3-C6)cycloalkyl, (C 5 -C 7 )heterocycloalkyl and (5- or 6- membered)heteroaryl, wherein said aryl, cycloalkyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituents selected from R 4 ;
  • At least one of R 1 is H. In another, each R 1 is H.
  • At least one of R 1 is (Ci)alkyl. In another embodiment, each R 1 is (d)alkyl.
  • X is S. In other aspects, X is O. In other aspects, X is NH. In other aspects, X is N(C r C 6 )alkyl. In other aspects, X is NCH 3 .
  • At least one R 1 is H and X is S. In another embodiment, at least one R 1 is H and X is O. In another embodiment, at least one R 1 is H and X is NH. In another embodiment, at least one R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is H and X is S. In another embodiment, each R 1 is H and X is O. In another embodiment, each R 1 is H and X is NH. In another embodiment, each R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R 1 is H and X is NCH 3 .
  • At least one of R 1 is (Ci)alkyl and X is S. In another embodiment, at least one of R 1 is (Ci)alkyl and X is O. In another embodiment, at least one of R 1 is (Ci)alkyl and X is NH. In another embodiment, at least one R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is (Ci)alkyl and X is S. In another embodiment, each R 1 is (Ci)alkyl and X is O. In another embodiment, each R 1 is (Ci)alkyl and X is NH. In another embodiment, each R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R 1 is H and X is NCH 3 . In another embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (4a):
  • each R 1 is independently H or (Ci)alkyl
  • X is O, NR 7 or S
  • R 7 is H or (C C 6 )alkyl.
  • At least one of R 1 is H. In other aspects, each R 1 is H.
  • At least one of R 1 is (Ci)alkyl. In other aspects, each R 1 is (Ci)alkyl.
  • X is O. In other aspects, X is NH. In other aspects, X is S. In other aspects, X is N(Ci-C6)alkyl. In other aspects, X is NCH 3 . In some aspects of this embodiment, R is (C6-Cio)aryl, wherein said aryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R 4 .
  • R 2 is (C6-Cio)aryl, wherein said aryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C C 6 )alkyl or (C C 6 )alkoxy.
  • R 2 is (C6-Cio)aryl, wherein said aryl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • R 2 is (C 6 -Ci 0 )aryl, wherein said aryl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • R 2 is unsubstituted (C 6 -Ci 0 )aryl.
  • R 2 is (C 6 -Ci 0 )aryl substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • R 2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • R 2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C r
  • R 2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (d-C 6 )alkyl or (C r Ce)alkoxy. In another embodiment, R 2 is unsubstituted phenyl.
  • R 2 is phenyl substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (d-C 6 )alkyl or (C r C 6 )alkoxy.
  • R 1 is H and R 2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , - C ⁇ N, -N0 2 , -SH, (Ci-C6)alkyl or (Ci-C6)alkoxy.
  • At least one of R 1 is H and R 2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • At least one of R 1 is H and R 2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • at least one of R 1 is H and R 2 is unsubstituted phenyl.
  • At least one of R 1 is H and R 2 is phenyl substituted with 1 substituent selected from halo, - OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • each R 1 is H and R 2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -N0 2 , - SH, (Ci-C6)alkyl or (Ci-C6)alkoxy.
  • each R 1 is H and R 2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -NO 2 , -SH, (C C 6 )alkyl or (C C 6 )alkoxy.
  • each R 1 is H and R 2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C C 6 )alkyl or (C C 6 )alkoxy.
  • each R 1 is H and R 2 is unsubstituted phenyl.
  • each R 1 is H and R 2 is phenyl substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • R 1 is (Ci)alkyl and R 2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , - C ⁇ N, -NO 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • R 1 is (d)alkyl and R 2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • At least one of R 1 is (Ci)alkyl and R 2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (Q- Ce)alkyl or (Ci-C6)alkoxy.
  • at least one of R 1 is (Ci)alkyl and R 2 is unsubstituted phenyl.
  • At least one of R 1 is (Ci)alkyl and R 2 is phenyl substituted with 1 substituent selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (d-C 6 )alkyl or (C r Ce)alkoxy.
  • each R 1 is (Ci)alkyl and R 2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , - ON, -NO 2 , -SH, (Ci-C 6 )alkyl or (d-C 6 )alkoxy.
  • each R 1 is (Ci)alkyl and R 2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C C 6 )alkyl or (C C 6 )alkoxy.
  • each R 1 is (Ci)alkyl and R 2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • each R 1 is (Ci)alkyl and R 2 is unsubstituted phenyl.
  • each R 1 is (Ci)alkyl and R 2 is phenyl substituted with 1 substituent selected from halo, -OH, -NH 2 , -ON, - N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • At least one of R 1 is H and X is S. In another embodiment, at least one of R 1 is H and X is NH. In another embodiment, at least one of R 1 is H and X is O. In another embodiment, at least one R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 . In some embodiments, each R 1 is H and X is S. In another embodiment, each R 1 is H and X is NH. In another embodiment, each R 1 is H and X is O. In another embodiment, each R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R 1 is H and X is NCH 3 .
  • At least one of R 1 is (Ci)alkyl and X is S. In another embodiment, at least one of R 1 is (Ci)alkyl and X is NH. In another embodiment, at least one of R 1 is (Ci)alkyl and X is O. In another embodiment, at least one R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is (Ci)alkyl and X is S. In another embodiment, each R 1 is (Ci)alkyl and X is NH. In another embodiment, each R 1 is (Ci)alkyl and X is O. In another embodiment, each R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, each R 1 is H and X is
  • a nitroxyl donating compound of the disclosure is a compound of the formula (4b):
  • each R is independently H or (Ci)alkyl
  • X is O, NR 7 or S
  • R 7 is H or (C r C 6 )alkyl.
  • At least one of R 1 is H. In other aspects, each R 1 is H.
  • At least one of R 1 is (Ci)alkyl. In other aspects, each R 1 is (C alkyl. In some aspects of this embodiment, X is O. In other aspects, X is NH. In other aspects, X is
  • X is N(Ci-C 6 )alkyl. In other aspects, X is NCH 3 .
  • R 2 is (C 3 -C 6 )cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R 4 .
  • R 2 is (C 3 -C 6 )cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (Ci-C 6 )alkyl or (Ci-C6)alkoxy.
  • R 2 is (C 3 -C6)cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , - C ⁇ N, -N0 2 , -SH, (C C 6 )alkyl or (C r C 6 )alkoxy.
  • R 2 is (C 3 -C 6 )cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1 substituent selected from halo, - OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • R 2 is unsubstituted (C 3 -C6)cycloalkyl.
  • R 2 is (C 3 -C6)cycloalkyl substituted with 1 substituent selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C C 6 )alkyl or (C r C 6 )alkoxy.
  • R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from R 4 . In some aspects, R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R 4 .
  • R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -N0 2 , - SH, (Ci-C 6 )alkyl or (Ci-C 6 )alkoxy.
  • R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -NO 2 , -SH, (Ci-C6)alkyl or (Ci-C6)alkoxy.
  • R 2 is unsubstituted cyclohexyl.
  • R 2 is cyclohexyl substituted with 1 substituent selected from halo, -OH, -NH 2 , - C ⁇ N, -NO 2 , -SH, (Ci-C 6 )alkyl or (C r C 6 )alkoxy.
  • at least one of R 1 is H and R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R 4 .
  • At least one of R 1 is H and R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , - SH, (Ci-C 6 )alkyl or (Ci-C 6 )alkoxy.
  • At least one of R 1 is H and R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • At least one of R 1 is H and R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (Q- C 6 )alkyl or (Ci-C 6 )alkoxy.
  • at least one of R 1 is H and R 2 is unsubstituted cyclohexyl.
  • At least one of R 1 is H and R 2 is cyclohexyl substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C C 6 )alkyl or (C r C 6 )alkoxy.
  • each R 1 is H and R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R 4 .
  • each R 1 is H and R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -
  • each R 1 is H and R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C C 6 )alkyl or (C C 6 )alkoxy.
  • each R 1 is H and R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • each R 1 is H and R 2 is unsubstituted cyclohexyl.
  • each R 1 is H and R 2 is cyclohexyl substituted with 1 substituent selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • At least one of R 1 is (Ci)alkyl and R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from R 4 .
  • At least one of R 1 is (Ci)alkyl and R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C C 6 )alkyl or (C C 6 )alkoxy.
  • At least one of R 1 is (Ci)alkyl and R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -NO 2 , -SH, (d- C 6 )alkyl or (Ci-C 6 )alkoxy.
  • at least one of R 1 is (Ci)alkyl and R 2 is unsubstituted cyclohexyl.
  • R 1 is (Ci)alkyl and R 2 is cyclohexyl substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • each R 1 is (Ci)alkyl and R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R 4 .
  • each R 1 is (Ci)alkyl and R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , - SH, (Ci-C 6 )alkyl or (Ci-C 6 )alkoxy.
  • each R 1 is (Ci)alkyl and R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C C 6 )alkyl or (C C 6 )alkoxy.
  • each R 1 is (Ci)alkyl and R 2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (d-C 6 )alkyl or (C r Ce)alkoxy.
  • each R 1 is (Ci)alkyl and R 2 is unsubstituted cyclohexyl.
  • each R 1 is (Ci)alkyl and R 2 is cyclohexyl substituted with 1 substituent selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C C 6 )alkyl or (C C 6 )alkoxy.
  • At least one of R 1 is H and X is S. In another embodiment, at least one of R 1 is H and X is NH. In another embodiment, at least one of R 1 is H and X is O. In another embodiment, at least one R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is H and X is S. In another embodiment, each R 1 is H and X is NH. In another embodiment, each R 1 is H and X is O. In another embodiment, each R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, each R 1 is H and X is NCH 3 .
  • At least one of R 1 is (Ci)alkyl and X is S. In another embodiment, at least one of R 1 is (Ci)alkyl and X is NH. In another embodiment, at least one of R 1 is (Ci)alkyl and X is O. In another embodiment, at least one R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is (Ci)alkyl and X is S. In another embodiment, each R 1 is (Ci)alkyl and X is NH. In another embodiment, each R 1 is (Ci)alkyl and X is O. In another embodiment, each R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R 1 is H and X is
  • a nitroxyl donating compound of the disclosure is a compound of the formula (4c):
  • each R 1 is independently H or (Ci)alkyl
  • X is O, NR 7 or S
  • At least one of R 1 is H. In other aspects, each R 1 is H.
  • At least one of R 1 is (Ci)alkyl. In other aspects, each R 1 is (Ci)alkyl. In some aspects of this embodiment, X is O. In other aspects, X is NH. In other aspects, X is
  • X is N(Ci-C 6 )alkyl. In other aspects, X is NCH 3 .
  • R 2 is (C 5 -C 7 )heterocycloalkyl, wherein said
  • heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R 4 .
  • R 2 is (C 5 -C 7 )heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , - C ⁇ N, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • R 2 is (C 5 - C 7 )heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • R 2 is (C 5 -C 7 )heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (d- C6)alkyl or (Ci-C6)alkoxy.
  • R 2 is unsubstituted (C 5 -C 7 )heterocycloalkyl.
  • R 2 is (C 5 -C 7 )heterocycloalkyl substituted with 1 substituent selected from halo, - OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • R 2 is (C6)heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R 4 .
  • R 2 is (C6)heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (d-C 6 )alkyl or (C r Ce)alkoxy.
  • R 2 is (C6)heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , - C ⁇ N, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • R 2 is (C 6 )heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1 substituent selected from halo, - OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • R 2 is unsubstituted (C 6 )heterocycloalkyl.
  • R 2 is (C 6 )heterocycloalkyl substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • at least one of R 1 is H and R 2 is (C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R 4 .
  • R 1 is H and R 2 is (C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (d-C 6 )alkyl or (d-C 6 )alkoxy.
  • At least one of R 1 is H and R 2 is (C 6 )heterocycloalkyl, wherein said (C 6 )heterocycloalkyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , - SH, (Ci-C 6 )alkyl or (Ci-C 6 )alkoxy.
  • at least one of R 1 is H and R 2 is (C 6 )heterocycloalkyl, wherein said (C 6 )heterocycloalkyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , - SH, (Ci-C 6 )alkyl or (Ci-C 6 )alkoxy.
  • at least one of R 1 is H and R 2 is
  • (C 6 )heterocycloalkyl wherein said (C 6 )heterocycloalkyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • at least one of R 1 is H and R 2 is unsubstituted (C 6 )heterocycloalkyl.
  • At least one of R 1 is H and R 2 is (C 6 )heterocycloalkyl substituted with 1 substituent selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • each R 1 is H and R 2 is (C 6 )heterocycloalkyl, wherein
  • each R 1 is H and R 2 is (C6)heterocycloalkyl, wherein said
  • (C6)heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (d-C 6 )alkyl or (Ci-C 6 )alkoxy.
  • each R 1 is H and R 2 is (C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (Ci-C6)alkyl or (Ci-C6)alkoxy.
  • each R 1 is H and R 2 is (C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C C 6 )alkyl or (C C 6 )alkoxy.
  • each R 1 is H and R 2 is unsubstituted (C 6 )heterocycloalkyl.
  • each R 1 is H and R 2 is
  • R 1 is (Ci)alkyl and R 2 is (C 6 )heterocycloalkyl, wherein said (C 6 )heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R 4 .
  • R 1 is (Ci)alkyl and R 2 is (C 6 )heterocycloalkyl, wherein said (C 6 )heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • R 1 is (Ci)alkyl and R 2 is (C 6 )heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (d-C 6 )alkyl or (Ci-C 6 )alkoxy.
  • At least one of R 1 is (Ci)alkyl and R 2 is (C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (d- Ce)alkyl or (Ci-C6)alkoxy.
  • at least one of R 1 is (Ci)alkyl and R 2 is unsubstituted (C6)heterocycloalkyl.
  • At least one of R 1 is (Ci)alkyl and R 2 is (C 6 )heterocycloalkyl substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • each R 1 is (Ci)alkyl and R 2 is (C 6 )heterocycloalkyl, wherein
  • each R 1 is (Ci)alkyl and R 2 is (C 6 )heterocycloalkyl, wherein said (C 6 )heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • each R 1 is (Ci)alkyl and R 2 is (C 6 )heterocycloalkyl, wherein said (C 6 )heterocycloalkyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (Ci-C6)alkyl or (Ci-C6)alkoxy.
  • each R 1 is (Ci)alkyl and R 2 is
  • each R 1 is (Ci)alkyl and R 2 is unsubstituted (C6)heterocycloalkyl.
  • each R 1 is (Ci)alkyl and R 2 is (C6)heterocycloalkyl substituted with 1 substituent selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C C 6 )alkyl or (C r C 6 )alkoxy.
  • At least one of R 1 is H and X is S. In another embodiment, at least one of R 1 is H and X is NH. In another embodiment, at least one of R 1 is H and X is O. In another embodiment, at least one R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is H and X is S. In another embodiment, each R 1 is H and X is NH. In another embodiment, each R 1 is H and X is O. In another embodiment, each R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, each R 1 is H and X is NCH 3 .
  • At least one of R 1 is (Ci)alkyl and X is S. In another embodiment, at least one of R 1 is (Ci)alkyl and X is NH. In another embodiment, at least one of R 1 is (Ci)alkyl and X is O. In another embodiment, at least one R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 . In some embodiments, each R 1 is (Ci)alkyl and X is S. In another embodiment, each R 1 is (Ci)alkyl and X is NH. In another embodiment, each R 1 is (Ci)alkyl and X is O. In another embodiment, each R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R 1 is H and X is H and X is H and X is
  • a nitroxyl donating compound of the disclosure is a compound of the formula (4d):
  • each R 1 is independently H or (Ci)alkyl;
  • X is O, NR 7 or S;
  • R 7 is H or (C C 6 )alkyl.
  • At least one of R 1 is H. In other aspects, each R 1 is H. In some aspects of this embodiment, at least one of R 1 is (Ci)alkyl. In other aspects, each R 1 is (Ci)alkyl.
  • X is O. In other aspects, X is NH. In other aspects, X is S. In other aspects, X is N(Ci-C6)alkyl. In other aspects, X is NCH 3 . In some aspects of this embodiment, R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R 4 .
  • R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , - SH, (Ci-C 6 )alkyl or (Ci-C 6 )alkoxy.
  • R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • R 2 is unsubstituted (5- or 6-membered)heteroaryl.
  • R 2 is (5- or 6- membered)heteroaryl substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (Ci-C 6 )alkyl or (C r C 6 )alkoxy.
  • At least one of R 1 is H and R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R 4 .
  • at least one of R 1 is H and R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (d-C 6 )alkyl or (d-C 6 )alkoxy.
  • At least one of R 1 is H and R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (d- C 6 )alkyl or (Ci-C 6 )alkoxy.
  • At least one of R 1 is H and R 2 is (5- or 6- membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • at least one of R 1 is H and R 2 is unsubstituted (5- or 6-membered)heteroaryl.
  • R 1 is H and R 2 is (5- or 6-membered)heteroaryl substituted with 1 substituent selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • each R 1 is H and R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R 4 .
  • each R 1 is H and R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , - C ⁇ N, -N0 2 , -SH, (Ci-C 6 )alkyl or (d-C 6 )alkoxy.
  • each R 1 is H and R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 or 2
  • substituent(s) independently selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (d-C 6 )alkyl or (C r
  • each R 1 is H and R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, - N0 2 , -SH, (Ci-C 6 )alkyl or (Ci-C 6 )alkoxy.
  • each R 1 is H and R 2 is unsubstituted (5- or 6-membered)heteroaryl.
  • each R 1 is H and R 2 is (5- or 6- membered)heteroaryl substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • At least one of R 1 is (Ci)alkyl and R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R 4 .
  • at least one of R 1 is (Ci)alkyl and R 2 is (5- or 6- membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 , 2 or 3
  • R 1 is (Ci)alkyl and R 2 is (5- or 6- membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C C 6 )alkyl or (C C 6 )alkoxy.
  • At least one of R 1 is (Ci)alkyl and R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (Ci-C6)alkyl or (Ci-C6)alkoxy.
  • at least one of R 1 is (Ci)alkyl and R 2 is unsubstituted (5- or 6-membered)heteroaryl.
  • At least one of R 1 is (Ci)alkyl and R 2 is (5- or 6-membered)heteroaryl substituted with 1 substituent selected from halo, - OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • each R 1 is (Ci)alkyl and R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R 4 .
  • each R 1 is (Ci)alkyl and R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • each R 1 is (Ci)alkyl and R 2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH 2 , -ON, -N0 2 , -SH, (Ci-C6)alkyl or (Ci-C6)alkoxy.
  • each R 1 is (Ci)alkyl and R 2 is (5- or 6- membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH 2 , -C ⁇ N, -N0 2 , -SH, (Ci-C 6 )alkyl or (d-C 6 )alkoxy.
  • each R 1 is (Ci)alkyl and R 2 is unsubstituted (5- or 6-membered)heteroaryl.
  • each R 1 is (Ci)alkyl and R 2 is ((5- or 6-membered)heteroaryl substituted with 1 substituent selected from halo, - OH, -NH 2 , -ON, -N0 2 , -SH, (C r C 6 )alkyl or (C r C 6 )alkoxy.
  • At least one of R 1 is H and X is S. In another embodiment, at least one of R 1 is H and X is NH. In another embodiment, at least one of R 1 is H and X is O. In another embodiment, at least one R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is H and X is S. In another embodiment, each R 1 is H and X is NH. In another embodiment, each R 1 is H and X is O. In another embodiment, each R 1 is H and X is N(Ci-C 6 )alkyl. In another embodiment, each R 1 is H and X is NCH 3 .
  • At least one of R 1 is (Ci)alkyl and X is S. In another embodiment, at least one of R 1 is (Ci)alkyl and X is NH. In another embodiment, at least one of R 1 is (Ci)alkyl and X is O. In another embodiment, at least one R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R 1 is H and X is NCH 3 .
  • each R 1 is (Ci)alkyl and X is S. In another embodiment, each R 1 is (Ci)alkyl and X is NH. In another embodiment, each R 1 is (Ci)alkyl and X is O. In another embodiment, each R 1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R 1 is H and X is NCH 3 .
  • the present disclosure provides prodrugs thereof.
  • the present disclosure provides compound of formula (5):
  • R 1 , R 2 and X together are as defined herein for each of compounds of formulae (1), (la), (la- 1), (la-2), (lb), (lc), (Id), (2), (3), (3a), (3a-l), (3b), (3c), (3d), (4), (4a), (4b), (4c) and (4d); and
  • R is hydrogen, -(Ci-C6)alkyl, -(C2-C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(C 5 - C 7 )heterocycloalkyl, benzyloxy, -0-(C C 6 )alkyl, -NH 2 , -NH-(C C 4 )alkyl, or -N((Ci-C 4 )alkyl) 2 , wherein said -(Ci-C 6 )alkyl, -(C 2 -C 4 )alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(C 5 - C 7 )heterocycloalkyl, benzyloxy, -0-(C r C 6 )alkyl, -NH-(C r C 4 )alkyl, or -N((C
  • R is methyl, ethyl, benzyl, or phenyl. In particular embodiments, R is methyl or ethyl. In particular embodiments, R is methyl. In particular embodiments, R is ethyl. In particular embodiments, R is benzyl or phenyl. In particular embodiments, R is benzyl. In particular embodiments, R is phenyl.
  • Table 1 provides representative compounds of the disclosure.
  • the compound of interest can be placed in solution, for example in phosphate buffered saline ("PBS") or in a phosphate buffered solution at a pH of about 7.4, in a sealed container.
  • PBS phosphate buffered saline
  • the headspace gas is withdrawn and analyzed to determine its composition, such as by gas chromatography and/or mass spectrometry. If the gas N 2 0 is formed (which occurs by HNO dimerization), the test is positive for nitroxyl donation and the compound is deemed to be a nitroxyl donor.
  • the compound of interest can be placed in a solution of tris(4,6-dimethyl-3- sulfanatophenyl)phosphine trisodium salt (TXPTS) in e.g., a phosphate buffered solution at a pH of about 7.4.
  • TXPTS tris(4,6-dimethyl-3- sulfanatophenyl)phosphine trisodium salt
  • the amount of nitroxyl released from the compound of interest can be detected by monitoring the formation of TXPTS aza-ylide by l H NMR. See Reisz et al. , Org. Lett. 11 :2719-2721 (2009), Reisz et al., J. Am. Chem. Soc. 133: 11675-11685 (2011) and Guthrie et al., J. Org. Chem. 80: 1338-1348 (2015). Accordingly, if TXPTS aza-ylide is formed, the test is positive
  • nitroxyl donation also can be detected by exposing the test compound to metmyoglobin ("Mb 3+ ").
  • Mb 3+ metmyoglobin
  • Nitroxyl reacts with Mb 3+ to form a Mb 2+ -NO complex, which can be detected by changes in the ultraviolet/visible spectrum or by electron paramagnetic resonance ("EPR").
  • the Mb 2+ -NO complex has an EPR signal centered around a g-value of about 2.
  • Nitric oxide reacts with Mb 3+ to form an Mb 3+ -NO complex that has a negligible, if any, EPR signal. Accordingly, if a compound reacts with Mb 3+ to form a complex detectable by common methods, such as
  • the level of nitroxyl donating ability can be expressed as a percentage of a compound's theoretical stoichiometric maximum.
  • a compound that donates a "significant level of nitroxyl" means, in various embodiments, a compound that donates about 40% or more, about 50%> or more, about 60%> or more, about 70%> or more, about 80%> or more, about 90%> or more, or about 95%> or more of its theoretical maximum amount of nitroxyl.
  • a compound donates from about 70% to about 90%) of its theoretical maximum amount of nitroxyl.
  • a compound donates from about 85% to about 95% of its theoretical maximum amount of nitroxyl.
  • a compound donates from about 90%> to about 95% of its theoretical maximum amount of nitroxyl.
  • Compounds that donate less than about 40%>, or less than about 50%, of their theoretical maximum amount of nitroxyl are still nitroxyl donors and can be used in the methods disclosed.
  • a compound that donates less than about 50% of its theoretical amount of nitroxyl can be used in the methods disclosed, but may require higher dosing levels as compared to a compound that donates a higher level of nitroxyl.
  • Testing for nitroxyl donation can be performed at a physiologically relevant pH.
  • a compound of the disclosure is capable of donating nitroxyl at physiological pH (i.e., a pH of about 7.4) and physiological temperature (i.e., a temperature of about 37°C) (together,
  • a compound of the disclosure can donate about 40%) or more of its theoretical maximum (i.e., 100%) amount of nitroxyl under physiological conditions. In particular embodiments, a compound of the disclosure can donate about 50% or more of its theoretical maximum amount of nitroxyl under physiological conditions. In particular
  • a compound of the disclosure can donate about 60% or more of its theoretical maximum amount of nitroxyl under physiological conditions. In particular embodiments, a compound of the disclosure can donate about 70% or more of its theoretical maximum amount of nitroxyl under physiological conditions. In particular embodiments, a compound of the disclosure can donate about 80%) or more of its theoretical maximum amount of nitroxyl under physiological conditions. In particular embodiments, a compound of the disclosure can donate about 90% or more of its theoretical maximum amount of nitroxyl under physiological conditions.
  • a compound of the disclosure might also donate a limited amount of nitric oxide, so long as the amount of nitroxyl donation exceeds the amount of nitric oxide donation.
  • a compound of the disclosure can donate about 25 mole%> or less of nitric oxide under physiological conditions.
  • a compound of the disclosure can donate about 20 mole%> or less of nitric oxide under physiological conditions.
  • a compound of the disclosure can donate about 15 mole% or less of nitric oxide under physiological conditions.
  • a compound of the disclosure can donate about 10 mole%> or less of nitric oxide under physiological conditions.
  • a compound of the disclosure can donates about 5 mole% or less of nitric oxide under physiological conditions. In particular embodiments, a compound of the disclosure can donate about 2 mole% or less of nitric oxide under physiological conditions. In particular embodiments, a compound of the disclosure can donate an insignificant amount (e.g., about 1 mole % or less) of nitric oxide under physiological conditions.
  • compositions comprising a nitroxyl donor at least one pharmaceutically acceptable excipient.
  • pharmaceutically acceptable excipients include those described above, such as carriers, surface active agents, thickening or emulsifying agents, solid binders, dispersion or suspension aids, solubilizers, colorants, flavoring agents, coatings, disintegrating agents, lubricants, sweeteners, preservatives, isotonic agents, and any combination thereof.
  • pharmaceutically acceptable excipients is taught, e.g., in Troy, Ed., Remington: The Science and Practice of Pharmacy, 21 st Ed. (Lippincott Williams & Wilkins,
  • the pharmaceutical compositions can be formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, as drenches (for example, aqueous or non-aqueous solutions or suspensions), tablets (for example, those targeted for buccal, sublingual and systemic absorption), caplets, boluses, powders, granules, pastes for application to the tongue, hard gelatin capsules, soft gelatin capsules, mouth sprays, troches, lozenges, pellets, syrups, suspensions, elixirs, liquids, emulsions and microemulsions; or (2) parenteral administration by, for example, subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension.
  • the pharmaceutical compositions can be for immediate, sustained or controlled release.
  • compositions disclosed herein can be prepared as any appropriate unit dosage form, such as capsules, sachets, tablets, powder, granules, solution, suspension in an aqueous liquid, suspension in a non-aqueous liquid, oil-in-water liquid emulsion, water-in-oil liquid emulsion, liposomes or bolus.
  • unit dosage form such as capsules, sachets, tablets, powder, granules, solution, suspension in an aqueous liquid, suspension in a non-aqueous liquid, oil-in-water liquid emulsion, water-in-oil liquid emulsion, liposomes or bolus.
  • compositions for parenteral e.g., intravenous
  • parenteral e.g., intravenous
  • the pharmaceutical composition is formulated for intravenous administration by continuous infusion.
  • compositions suitable for parenteral administration include, without limitation, either aqueous sterile injection solutions or non-aqueous sterile injection solutions, each containing, for example, anti-oxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous sterile suspensions and nonaqueous sterile suspensions, each containing, for example, suspending agents and thickening agents.
  • the formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampules or vials, and can be stored in a freeze dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, such as water, immediately prior to use. Alternately, the formulation can be in the form of a liquid.
  • compositions administered parenterally can be administered in an acidic, neutral or basic solution.
  • pharmaceutical compositions comprising a nitroxyl donor can be formulated in an acidic solution having a pH of from about 4 to about 5, for instance, a pH of about 4, about 4.5, about 4.8, or about 5, including values there between.
  • an N-hydroxylamino-barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure is formulated for parenteral injection at a pH of from about 5 to about 6.5 in some embodiments, from about 5 to about 6 in some embodiments, from about 5.5 to about 6 in some embodiments, from about 5 to about 5.5 in some embodiments, from about 5.2 to about 6.2 in some embodiments, from about 5.5 to about 6.2 in some embodiments, from about 5.8 to about 6.2 in some embodiments, and at a pH of about 6 in particular embodiments.
  • composition of the disclosure is formulated for parenteral injection at a pH of about 5.
  • an N-hydroxylamino-barbituric acid type nitroxyl donor can be formulated in an aqueous buffer.
  • an N-hydroxylamino- barbituric acid type nitroxyl donor can be formulated in a phosphate or acetate buffer.
  • an N-hydroxylamino-barbituric acid type nitroxyl donor is formulated in a potassium phosphate or sodium phosphate buffer.
  • an N-hydroxylamino-barbituric acid type nitroxyl donor is formulated in a potassium phosphate buffer or sodium phosphate buffer.
  • an N-hydroxylamino-barbituric acid type nitroxyl donor is formulated in a potassium citrate buffer or sodium citrate buffer.
  • the aqueous buffer can also include an appropriate sugar in order to maintain an appropriate osmolality.
  • the pharmaceutical composition can include an appropriate amount of dextrose.
  • the pharmaceutical compositions can generally prepared by diluting a concentrate comprising an N-hydroxylamino-barbituric acid type nitroxyl donor, optionally a cyclodextrin (see Section 4.3.3) and an appropriate buffer into an aqueous solution comprising 5% dextrose (D5W) or 2.5% dextrose (D2.5W).
  • compositions comprising an N-hydroxylamino-barbituric acid type nitroxyl donors can be formulated for oral administration.
  • Compounds for oral administration can be formulated as liquid or solid dosage forms.
  • polyethylene glycol e.g., polyethylene glycol 300 (PEG300) or polyethylene glycol 400 (PEG400)
  • PEG300 polyethylene glycol 300
  • PEG400 polyethylene glycol 400
  • Tablets for oral administration can be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the therapeutic agent or agents in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets can be optionally coated or scored and can be formulated so as to provide slow or controlled release of the active ingredient therein.
  • the disclosure provides a method of increasing in vivo nitroxyl levels, comprising administering to a patient in need thereof an effective amount of a compound or a pharmaceutical composition as disclosed herein.
  • the patient has, is suspected of having, or is at risk of having or developing a condition that is responsive to nitroxyl therapy.
  • the disclosure provides a method of treating, preventing or delaying the onset and/or development of a condition, comprising administering to a patient (including a patient identified as in need of such treatment, prevention or delay) an effective amount of a compound or a pharmaceutical composition as disclosed herein. Identifying a patient in need thereof can be in the judgment of a physician, clinical staff, emergency response personnel or other health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).
  • cardiovascular diseases include, without limitation, cardiovascular diseases, ischemia/reperfusion injury, pulmonary hypertension (PH), alcoholism, vascular dysfunction, and cancer.
  • PH pulmonary hypertension
  • alcoholism vascular dysfunction
  • cancer vascular dysfunction
  • the disclosure provides a method of treating a cardiovascular disease, comprising administering an effective amount of a compound or a pharmaceutical composition as disclosed herein to a patient in need thereof.
  • cardiovascular diseases and symptoms that can usefully be treated with the compounds and compositions disclosed herein include cardiovascular diseases that are responsive to nitroxyl therapy, coronary obstructions, coronary artery disease (CAD), angina, heart attack, myocardial infarction, high blood pressure, ischemic cardiomyopathy and infarction, pulmonary congestion, pulmonary edema, cardiac fibrosis, valvular heart disease, pericardial disease, circulatory congestive states, peripheral edema, ascites, Chagas' disease, ventricular hypertrophy, heart valve disease, heart failure, diastolic heart failure, systolic heart failure, congestive heart failure, acute congestive heart failure, acute decompensated heart failure, and cardiac hypertrophy.
  • CAD coronary artery disease
  • the nitroxyl donating compositions of the disclosure can be used to treat patients suffering from heart failure.
  • the heart failure can be of any type or form, including any of the heart failures disclosed herein.
  • Nonlimiting examples of heart failure include early stage heart failure, Class I, II, III and IV heart failure, acute heart failure, congestive heart failure (CHF) and acute congestive heart failure.
  • the compounds and compositions of the disclosure can be used to treat acute decompensated heart failure.
  • nitroxyl donating compositions of the disclosure are used to treat patients suffering from heart failure
  • another active agent that treats heart failure can also be administered.
  • the nitroxyl donor can be administered in conjunction with a positive inotrope such as a beta-agonist.
  • beta-agonists include, without limitation, dopamine, dobutamine, isoproterenol, analogs of such compounds and derivatives of such compounds.
  • nitroxyl donor can be administered in conjunction with a ⁇ eia-adrenergic receptor antagonist (also referred to herein as ⁇ eia-antagonist or beta -blocker).
  • beta- antagonists include, without limitation, propranolol, metoprolol, bisoprolol, bucindolol, and carvedilol.
  • the disclosure provides a method of treating, preventing or delaying the onset and/or development of ischemia/reperfusion injury, comprising administering an effective amount of a compound or pharmaceutical composition as disclosed herein to a subject in need thereof.
  • the method is for preventing ischemia/reperfusion injury.
  • a pharmaceutical composition of the disclosure is administered prior to the onset of ischemia.
  • a pharmaceutical composition of the disclosure is administered prior to procedures in which myocardial ischemia can occur, for example an angioplasty or surgery, such as a coronary artery bypass graft surgery.
  • a coronary artery bypass graft surgery such as a coronary artery bypass graft surgery.
  • composition of the disclosure is administered after ischemia but before reperfusion.
  • a pharmaceutical composition of the disclosure is administered after ischemia and reperfusion.
  • a pharmaceutical composition of the disclosure can be administered to a patient who is at risk for an ischemic event.
  • a pharmaceutical composition of the disclosure is administered to a patient at risk for a future ischemic event, but who has no present evidence of ischemia.
  • the determination of whether a patient is at risk for an ischemic event can be performed by any method known in the art, such as by examining the patient or the patient's medical history.
  • the patient has had a prior ischemic event.
  • the patient can be at risk of a first or subsequent ischemic event.
  • Examples of patients at risk for an ischemic event include patients with known hypercholesterolemia, EKG changes associated with ischemia ⁇ e.g., peaked or inverted T-waves or ST segment elevations or depression in an appropriate clinical context), abnormal EKG not associated with active ischemia, elevated CKMB, clinical evidence of ischemia ⁇ e.g., crushing sub-sternal chest pain or arm pain, shortness of breath and/or diaphoresis), prior history of myocardial infarction, elevated serum cholesterol, sedentary lifestyle, angiographic evidence of partial coronary artery obstruction, echocardiographic evidence of myocardial damage, or any other evidence of a risk for a future ischemic event.
  • Examples of ischemic events include, without limitation, myocardial infarction (MI) and neurovascular ischemia, such as a cerebrovascular accident (CVA).
  • MI myocardial infarction
  • CVA cerebrovascular accident
  • the subject of treatment is an organ that is to be transplanted.
  • a pharmaceutical composition of the disclosure can be administered prior to reperfusion of the organ in a transplant recipient.
  • a pharmaceutical composition of the disclosure can be administered prior to removal of the organ from the donor, for example through the perfusion cannulas used in the organ removal process.
  • the organ donor is a live donor, for example a kidney donor
  • the compounds or pharmaceutical compositions of the disclosure can be administered to the organ donor.
  • the compounds or pharmaceutical compositions of the disclosure are administered by storing the organ in a solution comprising the compound or pharmaceutical composition.
  • a compound or pharmaceutical composition of the disclosure can be included in the organ preservation solution, such as the University of
  • a pharmaceutical composition of the disclosure that is administered is such that ischemia/reperfusion injury to the tissues of the organ is reduced upon reperfusion in the recipient of transplanted organ.
  • the method reduces tissue necrosis (the size of infarct) in at-risk tissues.
  • Ischemia/reperfusion injury can damage tissues other than those of the myocardium and the disclosed subject matter embraces methods of treating or preventing such damage.
  • the ischemia/reperfusion injury is non-myocardial.
  • the method reduces injury from ischemia/reperfusion in the tissue of the brain, liver, gut, kidney, bowel, or any part of the body other than the myocardium.
  • the patient is at risk for such injury. Selecting a person at risk for non-myocardial ischemia could include a determination of the indicators used to assess risk for myocardial ischemia. However, other factors can indicate a risk for ischemia/reperfusion in other tissues. For example, surgery patients often experience surgery related ischemia. Thus, patients scheduled for surgery could be considered at risk for an ischemic event.
  • risk factors for stroke could demonstrate a patient's risk for ischemia of brain tissue: hypertension, cigarette smoking, carotid artery stenosis, physical inactivity, diabetes mellitus, hyperlipidemia, transient ischemic attack, atrial fibrillation, coronary artery disease, congestive heart failure, past myocardial infarction, left ventricular dysfunction with mural thrombus, and mitral stenosis.
  • hypertension cigarette smoking, carotid artery stenosis, physical inactivity
  • diabetes mellitus hyperlipidemia
  • transient ischemic attack atrial fibrillation
  • coronary artery disease congestive heart failure
  • past myocardial infarction left ventricular dysfunction with mural thrombus
  • mitral stenosis CAD
  • complications of untreated infectious diarrhea in the elderly can include myocardial, renal, cerebrovascular and intestinal ischemia.
  • patients could be selected based on risk factors for ischemic bowel, kidney and/or liver disease. For example, treatment would be initiated in elderly patients at risk of hypotensive episodes (such as surgical blood loss). Thus, patients presenting with such an indication would be considered at risk for an ischemic event.
  • the patient has any one or more of the conditions listed herein, such as diabetes mellitus and hypertension. Other conditions that can result in ischemia, such as cerebral arteriovenous malformation, could demonstrate a patient's risk for an ischemic event.
  • a pharmaceutical composition of the disclosure can be used to prevent or delay the onset and/or development of pulmonary hypertension.
  • a pharmaceutical composition of the disclosure can be used to prevent or delay the onset and/or development of pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • the disclosure provides a method of reducing mean pulmonary arterial pressure (MPAP), comprising administering an effective amount of a compound or a pharmaceutical composition disclosed herein to a patient in need thereof.
  • MPAP mean pulmonary arterial pressure
  • the MPAP is reduced by up to about 50%.
  • the MPAP is reduced by up to about 25%.
  • the MPAP is reduced by up to about 20%.
  • the MPAP is reduced by up to about 15%.
  • the MPAP is reduced by up to 10%.
  • the MPAP is reduced by up to about 5%.
  • the MPAP is reduced to be from about 12 mmHg to about 16 mmHg.
  • the MPAP is reduced to be about 15 mmHg.
  • the compounds and pharmaceutical compositions of the disclosure can be administered via parenteral ⁇ e.g. , subcutaneous, intramuscular, intravenous or intradermal) administration.
  • the N-hydroxylamino-barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure is administered by intravenous infusion.
  • the compounds and pharmaceutical compositions of the disclosure can be administered by oral administration.
  • dosages are expressed based on the amount of active pharmaceutical ingredient, i.e., the amount of nitroxyl donor compound(s) of the disclosure present in the pharmaceutical composition.
  • the dose can usefully be expressed per unit time, either as a fixed amount per unit time or as a weight-based amount per unit time.
  • a N-hydroxylamino-barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure is administered intravenously in an amount of at least about 0.1 ⁇ g/kg/min, at least about 0.2 ⁇ g/kg/min, at least about 0.3 ⁇ g/kg/min, at least about 0.4 ⁇ g/kg/min, at least about 0.5 ⁇ g/kg/min, at least about 1 ⁇ g/kg/min, at least about 2.5 ⁇ g/kg/min, at least about 5 ⁇ g/kg/min, at least about 7.5 ⁇ g/kg/min, at least about 10 ⁇ g/kg/min, at least about 11 ⁇ g/kg/min, at least about 12 ⁇ g/kg/min, at least about 13 ⁇ g/kg/min, at least about 14 ⁇ g/kg/min, at least about 15 ⁇ g/kg/min, at least about 16 ⁇ g/kg/min, at least about 17 ⁇ g/kg/min, at
  • the N-hydroxylamino-barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure is administered intravenously in an amount of no more than about 100 ⁇ g/kg/min, no more than about 90 ⁇ g/kg/min, no more than about 80 ⁇ g/kg/min, no more than about 70 ⁇ g/kg/min, no more than about 60 ⁇ g/kg/min, no more than about 50 ⁇ g/kg/min, no more than about 49 ⁇ g/kg/min, no more than about 48 ⁇ g/kg/min, no more than about 47 ⁇ g/kg/min, no more than about 46 ⁇ g/kg/min, no more than about 45 ⁇ g/kg/min, no more than about 44 ⁇ g/kg/min, no more than about 43 ⁇ g/kg/min, no more than about 42 ⁇ g/kg/min, no more than about 41 ⁇ g/kg/min, no more than about 40 ⁇ g/kg/min, no more than about
  • the N-hydroxylamino-barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure is administered intravenously in an amount ranging from about 10 ⁇ g/kg/min to about 50 ⁇ g/kg/min, about 20 ⁇ g/kg/min to about 40 ⁇ g/kg/min, about 25 ⁇ g/kg/min to about 35 ⁇ g/kg/min, or about 30 ⁇ g/kg/min to about 40 ⁇ g/kg/min.
  • an N-hydroxylamino barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure is administered intravenously in an amount of from about 20 ⁇ g/kg/min to about 30 ⁇ g/kg/min.
  • the compounds or pharmaceutical compositions of the disclosure are administered according to a weight- based daily dosing regimen, either as a single daily dose (QD) or in multiple divided doses administered, e.g., twice a day (BID), three times a day (TID), or four times a day (QID).
  • QD single daily dose
  • BID twice a day
  • TID three times a day
  • QID four times a day
  • the N-hydroxylamino-barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure is administered in a dose of at least about 0.5 mg/kg/d, at least about 0.75 mg/kg/d, at least about 1.0 mg/kg/d, at least about 1.5 mg/kg/d, at least about 2 mg/kg/d, at least about 2.5 mg/kg/d, at least about 3 mg/kg/d, at least about 4 mg/kg/d, at least about 5 mg/kg/d, at least about 7.5 mg/kg/d, at least about 10 mg/kg/d, at least about 12.5 mg/kg/d, at least about 15 mg/kg/d, at least about 17.5 mg/kg/d, at least about 20 mg/kg/d, at least about 25 mg/kg/d, at least about 30 mg/kg/d, at least about 35 mg/kg/d, at least about 40 mg/kg/d, at least about 45 mg/kg/d, at least about 50 mg/kg/
  • the N-hydroxylamino-barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure is administered at a dose of no more than about 100 mg/kg/d, no more than about 100 mg/kg/d, no more than about 90 mg/kg/d, no more than about 80 mg/kg/d, no more than about 80 mg/kg/d, no more than about 75 mg/kg/d, no more than about 70 mg/kg/d, no more than about 60 mg/kg/d, no more than about 50 mg/kg/d, no more than about 45 mg/kg/d, no more than about 40 mg/kg/d, no more than about 35 mg/kg/d, no more than about 30 mg/kg/d.
  • the dose is from about 0.001 mg/kg/d to about 10,000 mg/kg/d. In certain embodiments, the dose is from about 0.01 mg/kg/d to about 1,000 mg/kg/d. In certain embodiments, the dose is from about 0.01 mg/kg/d to about 100 mg/kg/d. In certain embodiments, the dose is from about 0.01 mg/kg/d to about 10 mg/kg/d. In certain embodiments, the dose is from about 0.1 mg/kg/d to about 1 mg/kg/d. In certain embodiments, the dose is less than about 1 g/kg/d.
  • the N-hydroxylamino4oarbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure is administered in a dose range in which the low end of the range is any amount from about 0.1 mg/kg/day to about 90 mg/kg/day and the high end of the range is any amount from about 1 mg/kg/day to about 100 mg/kg/day (e.g., from about 0.5 mg/kg/day to about 2 mg/kg/day in one series of embodiments and from about 5 mg/kg/day to about 20 mg/kg/day in another series of embodiment).
  • the N-hydroxylamino4oarbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure is administered in a dose amount from about 3 to about 30 mg/kg, administered from once a day (QD) to three times a day (TID).
  • compounds or pharmaceutical compositions of the disclosure are administered according to a flat (i.e., non-weiglrt-based) dosing regimen, either as a single daily dose (QD) or in multiple divided doses administered, e.g. , twice a day (BID), three times a day (TID), or four times a day (QID).
  • a flat dosing regimen either as a single daily dose (QD) or in multiple divided doses administered, e.g. , twice a day (BID), three times a day (TID), or four times a day (QID).
  • the N-hydroxylamino4oarbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure is administered at a dose of at least about 0.01 grams/day (g/d), at least about 0.05 g/d, at least about 0.1 g/d, at least about 0.5 g/d, at least about 1 g/d, at least about 1.5 g/d, at least about 2.0 g/d, at least about 2.5 g/d, at least about 3.0 g/d, or at least about 3.5 g/d.
  • the N-hydroxylamino-barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure is administered at a dose of no more than about 5 g/d, no more than about 4.5 g/d, no more than about 4 g/d, no more than about 3.5 g/d, no more than about 3 g/d, no more than about 2.5 g/d, or no more than about 2 g/d.
  • the N-hydroxylamino-barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure is administered in a dose of about 0.01 grams per day to about 4.0 grams per day.
  • the N-hydroxylamino-barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure can be administered at a dose in which the low end of the range is any amount from about 0.1 mg/day to about 400 mg/day and the high end of the range is any amount from about 1 mg/day to about 4000 mg/day.
  • the N- hydroxylamino-barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure is administered in a dose of about 5 mg/day to about 100 mg/day.
  • the N-hydroxylamino-barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure is administered at a dose of from about 150 mg/day to about 500 mg/day.
  • the dosing interval for parenteral or oral administration can be adjusted according to the needs of the patient. For longer intervals between administrations, extended release or depot formulations can be used.
  • N-hydroxylamino-barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure as disclosed herein can be administered prior to, at substantially the same time with, or after administration of an additional therapeutic agent.
  • the administration regimen can include pretreatment and/or co -administration with the additional therapeutic agent.
  • the N-hydroxylamino-barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure and the additional therapeutic agent can be administered simultaneously, separately, or sequentially.
  • administration regimens include without limitation: administration of each compound, pharmaceutical composition or therapeutic agent in a sequential manner; and coadministration of each compound, pharmaceutical composition or therapeutic agent in a substantially simultaneous manner (e.g., as in a single unit dosage form) or in multiple, separate unit dosage forms for each compound, pharmaceutical composition or therapeutic agent.
  • dose level will depend on various factors such as the particular administration mode, administration regimen, compound, and pharmaceutical composition selected, as well as the particular condition and patient being treated.
  • dose level can vary depending upon the activity, rate of excretion and potential for toxicity of the specific N-hydroxylamino-barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure employed; the age, body weight, general health, gender and diet of the patient being treated; the frequency of administration; the other therapeutic agent(s) being co-administered; and the type and severity of the condition.
  • kits comprising a compound or a pharmaceutical composition disclosed herein.
  • the kit comprises a compound or a pharmaceutical composition disclosed herein, each in dry form, and a pharmaceutically acceptable liquid diluent.
  • Either a compound in dry form or a pharmaceutical composition in dry form contains about 2.0% or less water by weight, about 1.5% or less water by weight, about 1.0% or less water by weight, about 0.5% or less water by weight, about 0.3% or less water by weight, about 0.2% or less water by weight, about 0.1% or less water by weight, about 0.05% or less water by weight, about 0.03% or less water by weight, or about 0.01% or less water by weight.
  • liquid diluents include but are not limited to sterile water, saline solutions, aqueous dextrose, glycerol, glycerol solutions, and the like.
  • suitable liquid diluents are disclosed by Nairn, "Solutions, Emulsions, Suspensions and Extracts," pp. 721-752 in Gennaro, Ed., Remington: The Science and Practice of Pharmacy, 20th Ed. (Lippincott Williams & Wilkins, Baltimore, MD, 2000).
  • the kit further comprises instructions for using the compound or pharmaceutical composition.
  • the instructions can be in any appropriate form, such as written or electronic form.
  • the instructions can be written instructions.
  • the instructions are contained in an electronic storage medium ⁇ e.g. , magnetic diskette or optical disk).
  • the instructions include information as to the compound or pharmaceutical composition and the manner of administering the compound or pharmaceutical composition to a patient.
  • the instructions relate to a method of use disclosed herein ⁇ e.g., treating, preventing and/or delaying onset and/or development of a condition selected from cardiovascular diseases, ischemia/reperfusion injury, pulmonary hypertension and other conditions responsive to nitroxyl therapy).
  • the kit further comprises suitable packaging. Where the kit comprises more than one compound or pharmaceutical composition, the compounds or pharmaceutical compositions can be packaged patiently in separate containers, or combined in one container when cross-reactivity and shelf life permit.
  • Scheme 2 depicts a general method for making compounds of formula (1).
  • the compounds disclosed herein can be made according to the methods disclosed below or by procedures known in the art.
  • Starting materials for the reactions can be commercially available or can be prepared by known procedures or obvious modifications thereof.
  • some of the starting materials are available from commercial suppliers such as Sigma-Aldrich (St. Louis, MO).
  • Others can be prepared by procedures or obvious modifications thereof disclosed in standard reference texts such as March's Advanced Organic Chemistry (John Wiley and Sons) and Larock's Comprehensive Organic Transformations (VCH Publishers).
  • the resultant material dissolved in 50 mL of saturated ammonium chloride, extracted with diethyl ether (200 mL), washed with water and saturated sodium chloride, dried over magnesium sulfate, and concentrated to dryness in vacuo to give 5-(N-teri-butoxycarbonyl-hydroxylamino)-5-phenyl-barbituric acid as a white solid.
  • the 5-(N-teri-butoxycarbonyl-hydroxylamino)-5-phenyl-barbituric acid was dissolved in a solution of ethanol (25 mL) to which concentrated hydrochloric acid (10 mL) was added.
  • the resultant material dissolved in 50 mL of saturated ammonium chloride, extracted with diethyl ether (200 mL), washed with water and saturated sodium chloride, dried over magnesium sulfate, and concentrated to dryness in vacuo to give 5-(N-ter/-butoxycarbonyl-hydroxylamino)-5-(2-propen-l -yl)-barbituric acid as a white solid.
  • the 5-(N-ter/-butoxycarbonyl-hydroxylamino)-5-(2-propen-l -yl)-barbituric acid was dissolved in a solution of ethanol (25 mL) to which concentrated hydrochloric acid (10 mL) was added.
  • the resultant material was dissolved in water (20 mL) and washed with dichloromethane (150 mL). Sodium acetate (2.6 g) was added to the remaining aqueous solution and the mixture was extracted by ethyl acetate (200 mL) and the solution was washed with water and saturated sodium chloride, dried over magnesium sulfate, and concentrated to dryness in vacuo. The resulting material was triturated with ether and petroleum ether and filtered to give 10 as a white solid (0.847 g, 39% over two steps).
  • a procedure for determining the amount of HNO released from the compounds of the present disclosure is as follows.
  • the barbituric acid corresponding to a compound is referred to as "BA” followed by the compound number.
  • the barbituric acid corresponding to Compound 1 is referred to as BA1.
  • TXPTS Tris(4,6- dimethyl-3-sulfanatophenyl)phosphine trisodium salt
  • Synthetic TXPTS aza-ylide was obtained through the amidation of TXPTS using hydroxylamine O-sulfonic acid in water (Armstrong, A.; Jones, L. H.; Knight, J. D.; Kelsey, R. D. Org. Lett., 2005, 7, 713-716). All other materials were of reagent grade and used without further purification.
  • each free induction decay was Fourier transformed, phased, baseline corrected, and integral areas measured for the N-methyl groups of compounds 1-3 and BA1-BA3, the upfield alkyl groups of 4, 11, 12, and 16 and BA4, BA11, BA12, and BA16, and the downfield methyl group of TXPTS aza-ylide.
  • the l H NMR spectrum of the HNO derived TXPTS aza-ylide product matched that of synthetic TXPTS aza-ylide.
  • the HNO yield from compounds 1-4, 11, 12, and 16 was determined from the final TXPTS aza-ylide yield.
  • FIG. la The complete decomposition of 1 to give BA1 and HNO-derived TXPTS aza-ylide under physiologically relevant conditions following the l H NMR assay is shown in FIG. la.
  • FIG. lb shows the decompositions of 1, 2, 3, and 4.
  • a procedure for determining the rate and half-life of the compounds of the present disclosure is as follows. To an argon-purged pH 7.4, phosphate buffered saline solution (0.1 M, 4.00 mL) at 37 °C containing glutatione (ca. 120 ⁇ ) was added 1-5, 7, 9, and 11-16 (50 ⁇ . of 1 mM in methanol) to give ca. 12 ⁇ as the initial concentration of 1-5, 7, 9, and 11-16. The solution was briefly mixed and UV-vis spectra were collected at regular time intervals until the reaction was complete as indicated by the appearance of the barbituric acid (BA) byproduct.
  • BA barbituric acid
  • Table 3 shows the incubation of 1-5, 7, 9, and 11-16 in pH 7.4 phosphate buffered saline at 37 °C under argon with added glutathione.
  • Table 4 shows the pKa determination for the BA compounds following the graphical titration method. Table 4.
  • the acidity of the benzyl barbituric acid, BA1 is comparable to benzoic acid.
  • the substituents on benzyl barbituric acid affect the acidity; that is, their acidities are increased by electron-withdrawing groups and decreased by electron-donating groups.
  • This substituent effect has been demonstrated to obey Hammett's equation on a series of 5-substituted-benzyl-l,3-unsubtituted- barbituric acid derivatives (Tate, J. V.; Tinnerman II, W. N.; Jurevics, V.; Jeskey, H.; Biehl, E. R. J. Heterocyclic Chem. 1986, 23, 9-11.)
  • the rate of decomposition of 1, 2 and 3 correlate with the pKa values of their respective BA byproducts.
  • the pKa of the resultant byproducts, BA1 - BA3 also affects the pKa of the corresponding HABA donors as well (FIG. 2a), where the sharp increases in observed rate reflect rapid BA formation as a result of HABA deprotonation.
  • a 1 mM solution of compound 4 is prepared in acetonitrile.
  • To a cuvette containing 3.0 mL of 0.10 M phosphate buffer of the desired pH at 25 °C is added 50 ⁇ of the compound 4 solution.
  • the solution is mixed quickly by rapidly drawing up and dispensing the solution with a pipette.
  • the ring nitrogen proton of 4 is mildly acidic.
  • the pKa of 4 as a whole is more acidic than compounds 1-3.
  • FIG. 2c shows the initial spectra of 4 in a variety of phosphate buffers from pH 5.0 to pH 9.5. As the pH of the buffer increases, a new starting absorbance at 242 nm is observed, which is consistent with other mono-anion 5,5-disubstituted barbituric acids. For example, the max of the mono-anion of 5,5-diethylbarbituric acid, barbital, is 238 nm (Meusel,

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