WO2015183838A1 - N-hydroxylamino-barbituric acid derivatives as nitroxyl donors - Google Patents

N-hydroxylamino-barbituric acid derivatives as nitroxyl donors Download PDF

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Publication number
WO2015183838A1
WO2015183838A1 PCT/US2015/032493 US2015032493W WO2015183838A1 WO 2015183838 A1 WO2015183838 A1 WO 2015183838A1 US 2015032493 W US2015032493 W US 2015032493W WO 2015183838 A1 WO2015183838 A1 WO 2015183838A1
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alkyl
compound
substituted
heteroaryl
heterocycloalkyl
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PCT/US2015/032493
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French (fr)
Inventor
Daryl A. GUTHRIE
John P. Toscano
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The Johns Hopkins University
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Priority to EP15729288.9A priority Critical patent/EP3148983A1/en
Priority to US14/926,607 priority patent/US9464061B2/en
Publication of WO2015183838A1 publication Critical patent/WO2015183838A1/en

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    • 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,

Abstract

The present disclosure provides N-hydroxylamino-barbituric acid compounds of formulae (1)- (4), pharmaceutical compositions and kits comprising them, and methods of using such compounds or pharmaceutical compositions. The present disclosure provides methods of using such compounds or pharmaceutical compositions for treating heart failure.

Description

N-HYDROXYLAMINO-BARBITURIC ACID DERIVATIVES AS NITROXYL DONORS
1. BACKGROUND
Nitroxyl (HNO) has been shown to have positive cardiovascular effects in in vitro and in vivo models of failing hearts. However, at physiological pH, HNO dimerizes to hyponitrous acid, which subsequently dehydrates to nitrous oxide. Because of this metastability, HNO for therapeutic use is generated in situ from donor compounds. A variety of compounds capable of donating nitroxyl have been described and proposed for use in treating disorders known or suspected to be responsive to nitroxyl. See, e.g., U.S. Pat. Nos. 6,936,639; 7,696,373; 8,030,356; 8,268,890; 8,227,639; and
8,318,705; U.S. pre-grant publication nos. 2009/0281067; 2009/0298795; 2011/0136827; and
2011/0144067; International PCT Publication No. WO 2013/059194 and Paolocci et al, "The pharmacology of nitroxyl (HNO) and its therapeutic potential: Not just the janus face of NO,"
Pharmacol. Ther. 113 (2007) 442^158. Although all of these compounds are disclosed to be capable of donating nitroxyl, they differ in various physicochemical properties, and there remains a need to identify nitroxyl donors that have physicochemical properties best suited for treating specific clinical conditions via specific routes of administration.
International PCT Publication No. WO 2013/059194 describes N-hydroxylamino-barbituric acid (HABA) type compounds that are capable of donating nitroxyl. One such compound, 5-(N- hydroxylamine)-5-ethyl-NN-dimethylbarbituric acid (5-ethyl HABA), however, was reported to produce less than the desired amount of ΗΝΟ. Further studies showed that this compound undergoes a competitive intramolecular rearrangement mechanism rather than the desired ΗΝΟ producing mechanism. It was found that, by exchanging the 5-ethyl group with an O-methyloxime group, the non- ΗΝΟ producing mechanism was avoided. Scheme 1 shows the major reaction pathways for the 5-ethyl HABA compound (intramolecular rearrangement pathway) and for the corresponding 5-0- methyloxime HABA compound (desired ΗΝΟ producing pathway).
Figure imgf000004_0001
Accordingly, there is a need to provide new HABA type nitroxyl donating compounds that have a suitable toxicological profile and that undergo the desired HNO producing pathway under physiologically relevant conditions. Development of such compounds requires an understanding of the pharmacokinetic profile associated with nitroxyl donation and the factors influencing the toxicological profile and HNO production. Failure to understand these factors has hampered the development of nitroxyl donors for clinical use.
Citation of any reference in Section 1 of this application is not to be construed as an admission that such reference is prior art to the present application.
2. SUMMARY OF THE DISCLOSURE
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. In addition, the compounds of the disclosure have, or are believed to have, suitable toxicological profiles. In a first embodiment, 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. In particular embodiments, 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. In specific embodiments, 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.
In a second embodiment, 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. In particular embodiments, 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. In specific embodiments, 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.
In a third embodiment, 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.
In a fourth embodiment, 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.
In a fifth embodiment, 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. In a sixth embodiment, 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.
In a seventh embodiment, 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.
Provided that, in each of the seven preceding embodiments, 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.
In a particular embodiment, the present disclosure provides a nitroxyl donating compound of the formula (1):
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
R2 is (Ci-C6)alkyl substituted with a substituent selected from the group consisting of (C6-Ci4)aryl, (C3-C6)cycloalkyl, (C5-C7)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 R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6;
X is O, NR7 or S; each R is independently selected from the group consisting of halo, -OH, -NH2, -C=N, -NO2, -SH, =0, =S, =N-(Ci-C4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr Ce)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl; and
R7 is H or (CrC6)alkyl.
In another particular embodiment, the present disclosure provides a nitroxyl donating compound of the formula (2):
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
R2 is selected from the group consisting of a branched (C3-Ce)alkyl, a branched (C3- Ce)alkenyl, and a branched (C3-Ce)alkoxy, wherein said alkyl, alkenyl, and alkoxy are unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -NO2, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr Ce)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and
R7 is H or (CrC6)alkyl.
In another particular embodiment, the present disclosure provides a nitroxyl donating compound of the formula (3):
Figure imgf000008_0001
or a pharmaceutically acceptable salt thereof, wherein: each R1 is H;
R2 is selected from the group consisting of (Ci-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl and (Ci-C6)alkoxy, wherein said alkyl, alkenyl, alkynyl and alkoxy are unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, - CH2OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (Ci-C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3- C6)cycloalkyl, (5- or 6-membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, - C(0)OH, -NH-C(0)-NH2, -NH-C(NH)-NH2, -NH-C(S)-NH2, -SON, -S02NH2, - COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6-membered)heteroaryl and (C5- C7)heterocycloalkyl; and
R7 is H or (Ci-C6)alkyl.
In another particular embodiment, the present disclosure provides a nitroxyl donating compound of the formula (4):
Figure imgf000009_0001
(4), or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
R2 is (C6-Cio)aryl, (C3-C6)cycloalkyl, (C5-C7)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 R4;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr Ce)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and
R7 is H or (C C6)alkyl. In another particular embodiment, the present disclosure provides a nitroxyl donating compound of the formula (5):
Figure imgf000010_0001
(5), or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000010_0002
R is hydrogen, -(Ci-C6)alkyl, -(C2-C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(C5- C7)heterocycloalkyl, benzyloxy, -0-(CrC6)alkyl, -NH2, -NH-(CrC4)alkyl, or -N((CrC4)alkyl)2, wherein said -(Ci-C6)alkyl, -(C2-C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(C5- C7)heterocycloalkyl, benzyloxy, -0-(CrC6)alkyl, -NH-(CrC4)alkyl, or -N((CrC4)alkyl)2 can be unsubstituted or substituted with 1 , 2 or 3 substituents selected from halo, -(Ci-C6)alkyl, -(C2- C4)alkenyl, -(C2-C3)alkynyl, -(5- or 6-membered)heteroaryl, -0-(Ci-C6)alkyl, -S-(Ci-C6)alkyl, - C(halo)3, -CH(halo)2, -CH2(halo), -CN, -N02, -NH2, -NH-(CrC4)alkyl, -N(-(CrC4)alkyl)2, -C(0)(Cr C4)alkyl, -C(0)0(CrC4)alkyl, -OC(0)(CrC4)alkyl, -OC(0)NH2, -S(0)(CrC4)alkyl, or -S(0)2(Cr C4)alkyl.
Compounds of the disclosure are or are believed to be nitroxyl donors under physiologically relevant conditions. For example, 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. In addition, 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. For example, 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. For instance, 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. In certain embodiments, 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. In particular embodiments, a nitroxyl donating composition of the disclosure can be used to treat heart failure. In a particular embodiment, a compound and/or composition of the disclosure can be used to treat decompensated heart failure (e.g., acute decompensated heart failure). In certain embodiments, the compounds and/or compositions of the disclosure can be used to treat systolic heart failure. In particular embodiments, the compounds and/or compositions of the disclosure can be used to treat diastolic heart failure.
3. BRIEF DESCRIPTION OF FIGURES 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. The solid curves are calculated best fits to a single exponential function of the integrated NMR data (k = 3.1 x 10"4 s"1 for each fit) (see Example 17). 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. 2b shows a plot of the concentration of compound (4) anion k ax = 242 nm) as a function of pH. 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.
4. DETAILED DESCRIPTION
The invention includes the following:
(1.) An 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.
(2.) The N-hydroxylaminobarbituric acid type compound of the above (1.), wherein said compound has a half-life from about 10 minutes to about 200 minutes when measured under the conditions described in Example 18.
(3.) The N-hydroxylaminobarbituric acid type compound of the above (1.), wherein said compound has a half-life from about 12 minutes to about 190 minutes when measured under the conditions described in Example 18.
(4.) The N-hydroxylaminobarbituric acid type compound of the above (1.), wherein said compound has a half-life from about 10 minutes to about 4000 minutes when measured under the conditions described in Example 17.
(5.) The N-hydroxylaminobarbituric acid type compound of the above (1.), wherein said compound has a half-life from about 15 minutes to about 3900 minutes when measured under the conditions described in Example 17.
(6.) An N-hydroxylaminobarbituric acid type compound, wherein said compound produces a percent yield of ΗΝΟ 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.
(7.) The N-hydroxylaminobarbituric acid type compound of the above (6.), wherein said compound produces a percent yield of ΗΝΟ from about 75% to about 100%) when measured under the conditions described in Example 17.
(8.) The N-hydroxylaminobarbituric acid type compound of the above (6.), wherein said compound produces a percent yield of ΗΝΟ from about 85% to about 100%) when measured under the conditions described in Example 17.
(9.) An 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 ΗΝΟ 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.
(10.) The N-hydroxylaminobarbituric acid type compound of the above (9.), wherein said compound has a half-life from about 10 minutes to about 200 minutes when measured under the conditions described in Example 18 and said compound produces a percent yield of HNO from about 75% to about 100% when measured under the conditions described in Example 17.
(1 1.) The N-hydroxylaminobarbituric acid type compound of the above (9.), wherein said compound has a half-life from about 12 minutes to about 190 minutes when measured under the conditions described in Example 18 and wherein said compound produces a percent yield of ΗΝΟ from about 85%o to about 100% when measured under the conditions described in Example 17.
(12.) The N-hydroxylaminobarbituric acid type compound of the above (9.), wherein said compound has a half-life from about 10 minutes to about 4000 minutes when measured under the conditions described in Example 17 and said compound produces a percent yield of ΗΝΟ from about 75%) to about 100% when measured under the conditions described in Example 17.
(13.) The N-hydroxylaminobarbituric acid type compound of the above (9.), wherein said compound has a half-life from about 15 minutes to about 3900 minutes when measured under the conditions described in Example 17 and wherein said compound produces a percent yield of ΗΝΟ from about 85%o to about 100% when measured under the conditions described in Example 17.
(14.) A compound of formula (1):
Figure imgf000013_0001
(1), or a pharmaceutically acceptable salt thereof, wherein: each R is independently H or (Ci)alkyl; R is (Ci-C6)alkyl substituted with a substituent selected from the group consisting of (C6-Ci4)aryl, (C3-C6)cycloalkyl, (C5-C7)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 R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl; and
R7 is H or (C C6)alkyl. (15.) The compound of the above (14.), wherein X is O or S; (16.) The compound of the above (14.) or (15.), wherein at least one of R1 is H. (17.) The compound of the above (14.) or (15), wherein at least one of R1 is (Ci)alkyl. (18.) The compound of any one of the above (14.)-(17.), wherein each R1 is (Ci)alkyl. (19.) The compound of any one of the above (14.) or (16.)-(18.), wherein X is O. (20.) The compound of any one of the above (14.) or (16.)-(18.), wherein X is S. (21.) The compound of any one of the above (14.) or (16.)-(18.), wherein X is NH.
(22.) The compound of any one of the above (14.)-(21.), wherein said compound has formula (la):
Figure imgf000015_0001
or a pharmaceutically acceptable salt thereof, wherein:
R2 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 R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6.
(23.) The compound of the above (22.), wherein R2 is (Ci)alkyl substituted with (C6- Ci4)aryl, wherein said aryl is unsubstituted or substituted with with 1, 2, 3, 4 or 5 substituents selected from R4.
(24.) The compound of the above (22.) or (23.), wherein said aryl is phenyl.
(25.) The compound of any one of the above (22.)-(24.), wherein R4 is (Ci-C6)alkyl, -OH, (CrC3)alkoxy, -S(0)0(CrC6)alkyl or halo.
(26.) The compound of the above (14.) or (15.), wherein said compound has formula (la-1):
Figure imgf000015_0002
(l a-l ). or a pharmaceutically acceptable salt thereof, wherein: each R1 is (Ci)alkyl; each R5 is independently selected from the group consisting of H, halo, -OH, -NH2, - C≡N, -NO2, -SH, =0, =S,
Figure imgf000016_0001
(CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr Ce)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of H, halo and (Cr C6)alkyl.
(27.) The compound of the above (26.), wherein one or more of R5 is selected from the group consisting of H, -OH, (Ci-C3)alkoxy, S(0)0(Ci-C6)alkyl and halo.
(28.) The compound of the above (26.) or (27.), wherein one or more of R5 is methoxy.
(29.) The compound of the above (26.) or (27.), wherein one or more of R5 is CI.
(30.) The compound of any one of the above (26.)-(29.), wherein at least one of R6 is H.
(31.) The compound of any one of the above (26.)-(29.), wherein at least one of R6 is halo.
(32.) The compound of any one of the above (26.)-(29.), wherein at least one of R6 is methyl.
(33.) The compound of any one of the above (26.)-(32.), wherein X is O.
(34.) The compound of any one of the above (26.)-(32.), wherein X is S.
(35.) The compound of any one of the above (26.)-(32.), wherein X is NH.
(36.) The compound of the above (14.) or (15.), wherein said compound has formula (la-2)
Figure imgf000017_0001
or a pharmaceutically acceptable salt thereof, wherein: R1 is (Ci)alkyl; each R5 is independently selected from the group consisting of H, halo, -OH, -NH2, - C≡N, -NO2, -SH, =0, =S,
Figure imgf000017_0002
(CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr Ce)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of H, halo and (Cr C6)alkyl.
(37.) The compound of the above (36.), wherein one or more of R5 is selected from the group consisting of H, -OH, (Ci-C3)alkoxy, S(0)0(Ci-C6)alkyl and halo.
(38.) The compound of the above (36.) or (37.), wherein one or more of R5 is methoxy.
(39.) The compound of the above (36.) or (37.), wherein one or more of R5 is CI.
(40.) The compound of any one of the above (36.)-(39.), wherein at least one of R6 is H.
(41.) The compound of any one of the above (36.)-(39.), wherein at least one of R6 is halo.
(42.) The compound of any one of the above (36.)-(39.), wherein at least one of R6 is (43.) The compound of any one of the above (36.)-(42.), wherein X is O.
(44.) The compound of any one of the above (36.)-(42.), wherein X is S.
(45.) The compound of any one of the above (36.)-(42.), wherein X is NH.
(46.) The compound of any one of the above (14.)-(21.), wherein said compound has formula (lb)
Figure imgf000018_0001
(lb), or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
R2 is (Ci-C6)alkyl substituted with (C3-C6)cycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl. (47.) The compound of the above (46.), wherein R is (Ci)alkyl substituted with (C3- C6)cycloalkyl.
(48.) The compound of the above (46.) or (47.), wherein said (C3-C6)cycloalkyl is cyclohexyl.
(49.) The compound of any one of the above (14.)-(21.), wherein said compound has formula (lc):
Figure imgf000019_0001
(lc), or a pharmaceutically acceptable salt thereof, wherein:
R2 is (Ci-C6)alkyl substituted with (C5-C7)heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R6; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N,
-N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr
C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl.
(50.) The compound of the above (49.), wherein R2 is (Ci)alkyl substituted with (C5- C7)heterocycloalkyl. (51.) The compound of any one of the above (14.)-(21.), wherein said compound has formula (Id):
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof, wherein: 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 R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Q-
C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl.
(52.) The compound of the above (51.), wherein R2 is (Ci)alkyl substituted with (5- or 6- membered)heteroaryl or (9-or 10-membered)heteroaryl. (53.) The compound of the above (51.) or (52.), wherein said heteroaryl is selected from the group consisting of furyl, thienyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,3,5-triazinyl, thiophenyl, and benzo[d][l,3]dioxolyl.
(54.) The compound of the above (14.) having the formula:
Figure imgf000021_0001
or a pharmaceutically acceptable salt thereof.
The compound of the above (14.) having the formula:
Figure imgf000021_0002
or a pharmaceutically acceptable salt thereof.
The compound of the above (14.) having the formula:
Figure imgf000021_0003
or a pharmaceutically acceptable salt thereof.
(57.) A compound of formula (2):
Figure imgf000022_0001
or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
R2 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 R4;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and
R7 is H or (C C6)alkyl.
(58.) The compound of the above (57.), wherein X is O or S.
(59.) The compound of the above (57.) or (58.), wherein at least one of R1 is H.
(60.) The compound of the above (57.) or (58.), wherein at least one of R1 is (Ci)alkyl.
(61.) The compound of any one of the above (57.)-(60.), wherein each R1 is methyl. (62.) The compound of any one of the above (57.)-(61.), wherein R is selected from the group consisting of z' o -propyl, methylpropyl, sec-butyl, z o-butyl, teri-butyl, methylbutyl, z o-pentyl, methylpentyl, ethylbutyl, dimethylbutyl, and z' o-propylpropyl.
(63.) The compound of any one of the above (57.) or (59.)-(62.), wherein X is O.
(64.) The compound of any one of the above (57.) or (59.)-(62.), wherein X is S.
(65.) The compound of any one of the above (57.) or (59.)-(62.), wherein X is NH.
(66.) A compound of formula (3):
Figure imgf000023_0001
(3), or a pharmaceutically acceptable salt thereof, wherein: each R is H;
R is selected from the group consisting of (Ci-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl and (Ci-C6)alkoxy, wherein said alkyl, alkenyl, alkynyl and alkoxy are unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, - CH2OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (Ci-C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3- C6)cycloalkyl, (5- or 6-membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, - C(0)OH, -NH-C(0)-NH2, -NH-C(NH)-NH2, -NH-C(S)-NH2, -SC≡N, -S02NH2, - COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-Ce)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6-membered)heteroaryl and (C5- C7)heterocycloalkyl; and
R7 is H or (Ci-C6)alkyl.
(67.) The compound of the above (66.), wherein X is O or S.
(68.) The compound of the above (66.) or (67.), wherein R2 is (Ci-C6)alkyl, wherein said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R4.
(69.) The compound of the above (66.)-(68.), wherein R2 is methyl, ethyl, propylene, iso- propyl, methylbutyl, methylpropyl, z o-pentyl or trifluoroethyl.
(70.) The compound of the above (66.) or (67.), wherein R2 is selected from the group consisting of a branched (C3-C6)alkyl, branched (C3-C6)alkenyl, and branched (C3-C6)alkoxy, wherein said alkyl, alkenyl, and alkoxy are unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4.
(71.) The compound of any one of the above (66.) or (68.)-(70.), wherein X is O. (72.) The compound of any one of the above (66.) or (68.)-(70.), wherein X is S. (73.) The compound of any one of the above (66.) or (68.)-(70.), wherein X is NH. (74.) The compound of the above (66.) or (67.), wherein said compound has formula (3a):
Figure imgf000024_0001
or a pharmaceutically acceptable salt thereof, wherein: R is (Ci-C4)alkyl substituted with phenyl, wherein said phenyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of halo, -S(0)0(Cr C6)alkyl and (CrC6)alkyl.
(75.) The compound of the above (74.), wherein R2 is (Ci)alkyl substituted with phenyl. (76.) The compound of the above (74.) or (75.), wherein R4 is (Ci-C3)alkoxy or halo. (77.) The compound of any one of the above (74.)-(76.), wherein X is O. (78.) The compound of any one of the above (74.)-(76.), wherein X is S. (79.) The compound of any one of the above (74.)-(76.), wherein X is NH.
(80.) The compound of the above (66.) or (67.), wherein said compound has formula (3a-l):
Figure imgf000025_0001
or a pharmaceutically acceptable salt thereof, wherein: each R5 is selected from the group consisting of H, halo, -OH, -NH2, -C=N, -NO2, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (CrC6)alkoxy, (C2- C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of H, halo and (Cr
C6)alkyl.
(81.) The compound of the above (80), wherein one or more of R5 is selected from the group consisting ofH, -OH, (CrC3)alkoxy, -S(0)0(CrC6)alkyl and halo.
(82.) The compound of the above (80.) or (81.), wherein one or more of R5 is methoxy.
(83.) The compound of the above (80.) or (81.), wherein one or more of R5 is CI.
(84.) The compound of any one of the above (80.)-(83.), wherein at least one of R6 is H.
(85.) The compound of any one of the above (80.)-(83.), wherein at least one of R6 is halo.
(86.) The compound of any one of the above (80.)-(83.), wherein at least one of R6 is methyl.
(87.) The compound of any one of the above (80.)-(86.), wherein X is O.
(88.) The compound of any one of the above (80.)-(86.), wherein X is S.
(89.) The compound of any one of the above (80.)-(86.), wherein X is NH. (90.) The compound of the above (66.) or (67.), wherein said compound has formula (3b):
Figure imgf000027_0001
(3b), or a pharmaceutically acceptable salt thereof, wherein:
R is (Ci-C4)alkyl substituted with (C3-C6)cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl.
(91.) The compound of the above (90.), wherein R2 is (Ci)alkyl substituted with (C3-
C6)cycloalkyl.
(92.) The compound of the above (90.) or (91.), wherein said (C3-C6)cycloalkyl is cyclohexyl.
(93.) The compound of any one of the above (90.)-(92.), wherein X is O.
(94.) The compound of any one of the above (90.)-(92.), wherein X is S. (95.) The compound of any one of the above (90.)-(92.), wherein X is NH.
(96.) The compound of the above (66.) or (67.), wherein said compound has formula (3c):
Figure imgf000028_0001
(3c), or a pharmaceutically acceptable salt thereof, wherein:
R2 is (Ci-C4)alkyl substituted with (C5-C7)heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R6; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl.
(97.) The compound of the above (96.), wherein R2 is (Ci)alkyl substituted with (C5- C7)heterocycloalkyl.
(98.) The compound of the above (96.) or (97.), wherein said hetercycloalkyl is a
(C6)heterocycloalkyl selected from the group consisting of piperidinyl, piperazinyl, tetrahydro- oxazinyl, tetrahydropyran, dioxane, morpholine and thiomorpholine.
(99.) The compound of any one of the above (96.)-(98.), wherein X is O. (100.) The compound of any one of the above (96.)-(98.), wherein X is S.
(101.) The compound of any one of the above (96.)-(98.), wherein X is NH.
(102.) The compound of the above (66.) or (67.), wherein said compound has formula (3d):
Figure imgf000029_0001
(3d), or a pharmaceutically acceptable salt thereof, wherein:
R2 is (Ci-C4)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 substituents selected from R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6; each R4 is independently selected from the group consisting of halo, -OH, - CH2OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (Ci-C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3- C6)cycloalkyl, (5- or 6-membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, - C(0)OH, -NH-C(0)-NH2, -NH-C(S)-NH2, -SC≡N, -S02NH2, -
COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-Ce)alkenyl, (C2-Ce)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6-membered)heteroaryl and (C5- C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl.
(103.) The compound of the above (102.), wherein R2 is (Ci)alkyl substituted with (5- or 6- membered)heteroaryl or (9-or 10-membered)heteroaryl. (104.) The compound of the above (102.) or (103.), wherein said 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]dioxolyl.
(105.) The compound of any one of the above (102.)-(104.), wherein X is O.
(106.) The compound of any one of the above (102.)-(104.), wherein X is S.
(107.) The compound of any one of the above (102.)-(104.), wherein X is NH.
(108.) The compound of the above (66.) having the formula:
Figure imgf000030_0001
4 or a pharmaceutically acceptable salt thereof.
(109.) The compound of the above (66.) having the formula:
Figure imgf000030_0002
5 or a pharmaceutically acceptable salt thereof.
(110.) The compound of the above (66.) having the formula:
Figure imgf000031_0001
or a pharmaceutically acceptable salt thereof.
(1 1 1.) The compound of the above (66.) having the formula:
Figure imgf000031_0002
or a pharmaceutically acceptable salt thereof.
(1 12.) A compound of formula (4):
Figure imgf000031_0003
(4), or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
R is (C6-Cio)aryl, (C3-C6)cycloalkyl, (C5-C7)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 R4; X is O, NR7 or S; each R is independently selected from the group consisting of halo, -OH, -NH2, -C=N, -NO2, -SH, =0, =S, =N-(Ci-C4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr Ce)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and
R7 is H or (CrC6)alkyl.
(113.) The compound of the above (112.), wherein at least one of R1 is H.
(114.) The compound of the above (112.), wherein at least one of R1 is (d)alkyl.
(115.) The compound of the above (112.), wherein each R1 is (Ci)alkyl.
(116.) The compound of any one of the above (112.)-(115.), wherein X is O.
(117.) The compound of any one of the above (112.)-(115.), wherein X is S.
(118.) The compound of any one of the above (112.)-(115.), wherein X is NH.
(119.) The compound of any one of the above (112.)-(118.), wherein said compound has formula (4a):
Figure imgf000032_0001
(4a), or a pharmaceutically acceptable salt thereof, wherein: R is (C6-Cio)aryl, wherein said aryl is unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituents selected from R4.
(120). The compound of the above (1 19.), wherein:
R2 is phenyl unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituents selected from
R4.
(121.) The compound of the above (120.), wherein:
R2 is unsubstituted phenyl.
(122.) The compound of any one of the above (1 12.)-(1 18.), wherein said compound has formula (4b):
Figure imgf000033_0001
(4b), or a pharmaceutically acceptable salt thereof, wherein:
R2 is (C3-C6)cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituents selected from R4.
(123.) The compound of the above (122.), wherein R2 is cyclohexyl.
(124.) The compound of any one of the above (1 12.)-(1 18.), wherein said compound has formula (4c):
Figure imgf000034_0001
(4c), or a pharmaceutically acceptable salt thereof, wherein:
R2 is (C5-C7)heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4.
(125.) The compound of the above (124.), wherein R2 is (C6)heterocycloalkyl.
(126.) The compound of any one of the above (112.)-(118.), wherein said compound has formula (4d):
Figure imgf000034_0002
(4d), or a pharmaceutically acceptable salt thereof, wherein:
R2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4.
(127.) A compound of formula (5):
Figure imgf000035_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1, R2 and X are as defined in the above (10.)-(122.) ; and
R is hydrogen, -(Ci-C6)alkyl, -(C2-C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(C5-C7)heterocycloalkyl, benzyloxy, -0-(Ci-C6)alkyl, -NH2, -NH-(Ci-C4)alkyl, or
-N((Ci-C4)alkyl)2, wherein said -(Ci-C6)alkyl, -(C2-C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(C5-C7)heterocycloalkyl, benzyloxy, -0-(Ci-C6)alkyl, -NH-(Ci-C4)alkyl, or -N((Ci-C4)alkyl)2 can be unsubstituted or substituted with 1 , 2 or 3 substituents selected from halo, -(Ci-C6)alkyl, -(C2-C4)alkenyl, -(C2-C3)alkynyl, -(5- or 6-membered)heteroaryl, -O- (CrC6)alkyl, -S-(CrC6)alkyl, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -N02, -NH2, -NH-(Cr
C4)alkyl, -N(-(CrC4)alkyl)2, -C(0)(CrC4)alkyl, -C(0)0(CrC4)alkyl, -OC(0)(CrC4)alkyl, - OC(0)NH2, -S(0)(CrC4)alkyl, or -S(0)2(CrC4)alkyl.
(128.) A compound selected from:
5-(N-hydroxylamino)-5-benzyl-N,N-dimethylbarbituric acid; 5-(N-hydroxylamino)-5-(4-methoxybenzyl)-N,N-dimethylbarbituric acid;
5-(N-hydroxylamino)-5-(4-chlorobenzyl)-N,N-dimethylbarbituric acid; 5-(N-hydroxylamino)-5-ethyl-barbituric acid; 5-(N-hydroxylamino)-5-benzyl-barbituric acid; 5 -(N-hydroxylamino)-5 -(4 -methoxyb enzyl) -b arbituric acid;
5-(N-hydroxylamino)-5-(4-chlorobenzyl)-barbituric acid; 5-(N-hydroxylamino)-5-phenyl-barbituric acid;
5-(N-hydroxylamino)-5-(2-propen-l -yl)-barbituric acid;
5-(N-hydroxylamino)-5-(2-methylpropyl)-barbituric acid;
5-(N-hydroxylamino)-5-(l -methylethyl)-barbituric acid; 5-(N-hydroxylamino)-5-(l -methylbutyl)-barbituric acid;
5-(N-hydroxylamino)-5-phenyl-thiobarbituric acid;
5-(N-hydroxylamino)-5-(2-chlorobenzyl)-barbituric acid;
5-(N-hydroxylamino)-5-(2-furylmethyl)-barbituric acid;
5-(N-hydroxylamino)-5-(2-thienylmethyl)-barbituric acid; 5-(N-hydroxylamino)-5-methyl-barbituric acid;
5-(N-hydroxylamino)-5-(l -methylpropyl)-barbituric acid;
5-(hydroxylamino)-5-(3-methylbutyl) barbituric acid;
5-(hydroxyamino)-2-imino-5-phenyldihydropyrimidine-4,6(lH,5H)-dione;
5-(hydroxylamino)-5-(2,2,2-trifluoroethyl)barbituric acid; 5-(hydroxylamino)-5-(4-(methylsulfonyl)benzyl)barbituric acid
5-(hydroxylamino)-5-(benzo[d] [1 ,3]dioxol-5-ylmethyl)barbituric acid;
5-(hydroxylamino)-5-(pyridin-4-ylmethyl)barbituric acid;
5-(hydroxylamino)-5-(3-ethyl-5-hydroxy-6-methylpyridin-4-ylmethyl)barbituric acid; 5-(hydroxylamino)-5-(34 ydroxy-5-(hydroxylmethyl)-2-methylpyridin-4-ylmethyl)barbituric acid;
5-(hydroxylamino)5-(2-(methylthio)ethyl)barbituric acid; 5-(hydroxyamino)-5-(4-hydroxybenzyl)barbituric acid;
5-((lH-indol-2-yl)methyl)-5-(hydroxyamino)barbituric acid;
2- (5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)acetic acid;
3- (5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propanoic acid
2- (5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)acetamide;
3- (5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propanamide;
5-((lH-imidazol-5-yl)methyl)-5-(hydroxyamino)barbituric acid;
5-(4-aminobutyl)-5-(hydroxyamino)barbituric acid;
1- (3-(5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propyl)guanidine; 5-(hydroxylamino)5-(2-(methylthio)ethyl)barbituric acid;
5-(hydroxyamino)-5-(4-hydroxybenzyl)barbituric acid;
5-((lH-indol-2-yl)methyl)-5-(hydroxyamino)barbituric acid;
2- (5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)acetic acid;
3- (5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propanoic acid
2- (5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)acetamide;
3- (5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propanamide;
5-((lH-imidazol-5-yl)methyl)-5-(hydroxyamino)barbituric acid;
5-(4-aminobutyl)-5-(hydroxyamino)barbituric acid; and
l-(3-(5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propyl)guanidine. (129.) A pharmaceutical composition comprising the compound of any one of the above (1.)- (128.) and at least one pharmaceutically acceptable excipient.
(130.) The pharmaceutical composition of the above (129.), wherein said pharmaceutical composition is suitable for intravenous administration. ( 131.) A method of treating a cardiovascular disease, comprising administering an effective amount of the compound of any one of the above (l.)-(128.) or the pharmaceutical composition of the above (129.) or (130.) to a patient in need thereof.
(132.) The method of the above (131.), wherein said cardiovascular disease is heart failure.
(133.) The method of the above (131.), wherein said cardiovascular disease is acute decompensated heart failure.
(134.) The method of any one of the above (131.)-(133.), wherein said compound is administered intravenously.
(135.) Use of a pharmaceutical composition of the above (129.) or (130.) for the manufacture of a medicament useful for treating a cardiovascular disease. (136.) Use of a pharmaceutical composition of the above (129.) or (130.) for the manufacture of a medicament useful for treating heart failure.
(137.) Use of a pharmaceutical composition of the above (129.) or (130.) for the manufacture of a medicament useful for treating acute decompensated heart failure.
(138.) The pharmaceutical composition of the above (129.) or (130.) for use in the treatment of heart failure.
(139.) The pharmaceutical composition of the above (129.) or (130.) for use in the treatment of acute decompensated heart failure.
4.1 Definitions
In order that the present disclosure may be more readily understood, certain terms are first defined. Additional terms are defined throughout the detailed description. 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. When the therapeutic agent contains an acidic functionality, various exemplary embodiments of counter ions are sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like. When the therapeutic agent contains a basic functionality, 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,
benzenesulfonate, and p-toluenesulfonate salts. Accordingly, 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-(2-hydroxyethyl) amine, or tri-(2- hydroxy ethyl) amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. 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, 20th Ed. (Lippincott Williams & Wilkins, Baltimore, MD, 2000) and Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington, D.C., (e.g., 1st, 2nd and 3rd Eds., 1986, 1994 and 2000, respectively). As will be known to those in the art, 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;
(9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil;
(10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. "Unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for a human or an animal. Each unit dosage form can contain a predetermined amount of a therapeutic agent calculated to produce a desired effect.
Unless clearly indicated otherwise, 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. In particular embodiments, the patient is a mammal. In certain embodiments, 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. For purposes of this disclosure, 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", "preventing" and the like 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). "Positive 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. For example, 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.
"Pulmonary hypertension" or "PH" refers to a condition in which the pulmonary arterial pressure is elevated. The current hemodynamic definition of PH is a mean pulmonary arterial pressure (MPAP) at rest of greater than or equal to 25 mmHg. Badesch et al., J. Amer. Coll. Cardiol.
54(Suppl.):S55-S66 (2009).
"(Ci-C6)alkyl" refers to saturated linear and branched hydrocarbon structures having 1, 2, 3, 4, 5, or 6 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-C6)alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-hexyl, and the like. "(C2-C6)alkyl" refers to saturated linear and branched hydrocarbon structures having 2, 3, 4, 5, or 6 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 (C2-C6)alkyl groups include ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-hexyl, and the like.
"(Ci-C4)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-C2)alkyl" refers to saturated linear and branched hydrocarbon structures having 1 or 2 carbon atoms. Examples of (Ci-C2)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. 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. Examples of (C3-C5)alkyl groups include n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, n-hexyl and the like. "Branched (C3-C6)alkyl" refers to saturated branched hydrocarbon structures having 3, 4, 5, or
6 carbon atoms. Examples of branched (C3-C6)alkyl groups include iso-propyl, tert-butyl, 2,3- dimethylbutyl, 2-methylpentyl, 3-methylpentyl, and the like.
"(C2-C6)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.
"(C2-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),
1 - butenyl, 2-butenyl, 3-butenyl, 1 -methylethenyl, 1 -methyl- 1 -propenyl, 2-methyl-2-propenyl, 2- methyl- 1 -propenyl, l -methyl-2-propenyl, and the like.
"Branched (C3-C6)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,
2- methyl-2-propenyl, 2 -methyl- 1 -propenyl, 1 -methyl-2-propenyl, and the like.
"(C2-C6)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 (C2-C6)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.
"(C2-C3)alkynyl" refers to a straight chain hydrocarbon having 2 or 3 carbon atoms and including at least one carbon-carbon triple bond. Examples of (C2-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 (C3-C6)alkoxy" refers to -0-(C3-C6)alkyl, wherein said (C3-C6)alkyl is branched. Examples of branched (C3-C6)alkoxy groups include z' o-propoxy, sec-butoxy, teri-butoxy, 2-methyl-2- butoxy and the like. "(C2-C6)alkenyloxy" refers to -0-(C2-C6)alkenyl. Examples of (C2-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-hexenyloxy, fert-hexenyloxy and the like.
"(C2-C6)alkynyloxy" refers to -0-(C2-C6)alkynyl. Examples of (C2-C6)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-C7)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 (C5-C7)heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, tetrahydro-oxazinyl, tetrahydrofuran, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine,
tetrahydrofuranone, γ-butyrolactone, 2H-pyran, 4H-pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, piperazine, morpholine, thiomorpholine, oxazine, tetrahydro-oxazinyl, and the like.
(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 (C6)heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydro-oxazinyl, tetrahydropyran, dioxane, morpholine, thiomorpholine, and the like.
"(C6-Ci4)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-Ci4)aryl groups include without limitation phenyl, naphthyl, indanyl, indenyl, tetralinyl, anthryl and phenanthryl. In some
embodiments, the aryl is C6 aryl. In some embodiments, the aryl is a bicyclic C9-C10 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 C6 aryl.
"(Ci0-Ci4)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 (Ci0-Ci4)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. Examples of (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. When a compound of the disclosure contains an olefinic double bond, a C=N double bond, or any other center of geometric asymmetry, it is intended to include all "geometric isomers", e.g., both Z and E geometric isomers, unless specifically otherwise indicated. All "tautomers", e.g., amine -imine, enamine-enimine, enamine-imine, urea-isourea, ketone - enol, amide-imidic acid, lactam-lactim, are intended to be encompassed by the disclosure as well unless specifically otherwise indicated. 4.2 A^Hydroxylamino-Barbituric Acid Type Nitroxyl Donors
It has been discovered the N-hydroxylamino-barbituric acid type compounds of the disclosure produce nitroxyl under physiologically relevant conditions and do not undergo intramolecular rearrangements. Without being bound by theory, the experiments reported herein suggest that, by tempering the electrophilicity of the R2 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.
In a particular embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (1):
Figure imgf000047_0001
or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
R is (Ci-C6)alkyl substituted with a substituent selected from the group consisting of (C6-Ci4)aryl, (C3-C6)cycloalkyl, (C5-C7)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 R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl; and
R7 is H or (C C6)alkyl.
In one embodiment, at least one of R1 is H. In another, each R1 is H. In another embodiment, at least one of R1 is (Ci)alkyl. In another embodiment, each R1 is (Ci)alkyl.
In some aspects of this embodiment, 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 NCH3.
In one embodiment, at least one R1 is H and X is S. In another embodiment, at least one R1 is H and X is O. In another embodiment, at least one R1 is H and X is NH. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In another embodiment, each R1 is H and X is S. In another embodiment, each R1 is H and X is O. In another embodiment, each R1 is H and X is NH. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3.
In one embodiment, at least one of R1 is (Ci)alkyl and X is S. In another embodiment, at least one of R1 is (Ci)alkyl and X is O. In another embodiment, at least one of R1 is (Ci)alkyl and X is NH. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In another embodiment, each R1 is (Ci)alkyl and X is S. In another embodiment, each R1 is (Ci)alkyl and X is O. In another embodiment, each R1 is (Ci)alkyl and X is NH. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3.
In another embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (la):
Figure imgf000048_0001
or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
R is (Ci-C6)alkyl substituted with (C6-Ci4)aryl, wherein said aryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl; and
R7 is H or (C C6)alkyl.
In some aspects of this embodiment, at least one of R1 is H. In some aspects, each R1 is H.
In other aspects of this embodiment, at least one of R1 is (Ci)alkyl. In some aspects, each R1 is (Ci)alkyl.
In one embodiment, R2 is (Ci-C4)alkyl substituted with (C6-Ci4)aryl. In another embodiment, R2 is (Ci-C2)alkyl substituted with (C6-Ci4)aryl. In another embodiment, R2 is (Ci)alkyl substituted with (C6-Ci4)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. In various embodiments of each of the embodiments in this paragraph, the aryl is C6-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. In embodiments in which the aryl is substituted, each R is independently selected from the group consisting of halo, -OH, -NH2, -ON, -N02, -SH, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(0)-NH2, -NH- C(S)-NH2, -SC≡N, -S02NH2, -COR', -C(0)OR', -C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', - S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6-membered)heteroaryl and (C5- C7)heterocycloalkyl.
In some embodiments, each R4 is independently selected from the group consisting of -OH, - NH2, -SH, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (CrC6)alkoxy, (C2-C6)alkenyloxy, (C2- C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6-membered)heteroaryl, (C5- C7)heterocycloalkyl, -NHR', -NR'R", -SR', -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl. In another embodiment, each R4 is independently selected from the group consisting of -OH, -
NH2, -SH, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (CrC6)alkoxy, (C2-C6)alkenyloxy and (C2- C6)alkynyloxy. In some embodiments, each R4 is independently selected from the group consisting of - OH, -NH2, -SH, (Ci-C6)alkoxy, (C2-C6)alkenyloxy and (C2-C6)alkynyloxy. In other embodiments, each R4 is independently selected from the group consisting of (Ci-C6)alkoxy, (C2-C6)alkenyloxy and (C2- C6)alkynyloxy. In yet other embodiments, R4 is (Ci-C6)alkoxy. In some embodiments, R4 is (Cp C3)alkoxy. In other embodiments, R4 is methoxy. In some embodiments, R4 is -OH.
In some embodiments, each R4 is independently selected from the group consisting of halo, - C≡N, -N02, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(0)-NH2, -NH-C(S)-NH2, -SON, -S02NH2, -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 (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, and (C5-C7)heterocycloalkyl.
In another embodiment, each R4 is independently selected from the group consisting of halo, - ON, -N02, -C(0)NH2, -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-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6-membered)heteroaryl and (C5-C7)heterocycloalkyl. In some embodiments, R is halo. In some embodiments, R is CI. In some embodiments R is S(0)0(CrC6)alkyl. In some embodiments, R4 is S(0)0(Ci)alkyl.
In embodiments in which said (Ci-C6)alkyl is substituted with R6, R6 is halo or (Ci-C6)alkyl. In some embodiments, R6 is halo or
Figure imgf000051_0001
In other embodiments, R6 is halo or (Ci-C2)alkyl. In other embodiments, R6 is fluoro. In other embodiments, R6 is methyl.
In some aspects of this embodiment, 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 NCH3.
In one embodiment, at least one R1 is H and X is S. In another embodiment, at least one R1 is H and X is O. In another embodiment, at least one R1 is H and X is NH. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In another embodiment, each R1 is H and X is S. In another embodiment, each R1 is H and X is O. In another embodiment, each R1 is H and X is NH. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3.
In one embodiment, at least one of R1 is (Ci)alkyl and X is S. In another embodiment, at least one of R1 is (Ci)alkyl and X is O. In another embodiment, at least one of R1 is (Ci)alkyl and X is NH. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In another embodiment, each R1 is (Ci)alkyl and X is S. In another embodiment, each R1 is (Ci)alkyl and X is O. In another embodiment, each R1 is (Ci)alkyl and X is NH. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3.
In one embodiment, at least one R1 is H and R2 is (Ci-C alkyl substituted with (C6-Ci4)aryl. In another embodiment, at least one R1 is H and R2 is (Ci-C2)alkyl substituted with (C6-Ci4)aryl. In another embodiment, at least one R1 is H and R2 is (Ci)alkyl substituted with (C6-Ci4)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. In various embodiments of each of the embodiments in this paragraph, the aryl is phenyl. In one embodiment, each R1 is H and R2 is (Ci-C4)alkyl substituted with (C6-Ci4)aryl. In another embodiment, each R1 is H and R2 is (Ci-C2)alkyl substituted with (C6-Ci4)aryl. In another embodiment, each R1 is H and R2 is (Ci)alkyl substituted with (C6-Ci4)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. In various embodiments of each of the embodiments in this paragraph, the aryl is phenyl.
In one embodiment, at least one of R1 is (Ci)alkyl and R2 is (Ci-C4)alkyl substituted with (C6- Ci4)aryl. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is (Ci-C2)alkyl substituted with (C6-Ci4)aryl. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is (Ci)alkyl substituted with (C6-Ci4)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. In various embodiments of each of the embodiments in this paragraph, the aryl is phenyl.
In one embodiment, each R1 is (Ci)alkyl and R2 is (Ci-C4)alkyl substituted with (C6-Ci4)aryl. In another embodiment, each R1 is (Ci)alkyl and R2 is (Ci-C2)alkyl substituted with (C6-Ci4)aryl. In another embodiment, each R1 is (Ci)alkyl and R2 is (Ci)alkyl substituted with (C6-Ci4)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. In various embodiments of each of the embodiments in this paragraph, the aryl is phenyl.
In another embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (l a-1):
Figure imgf000052_0001
or a pharmaceutically acceptable salt thereof, wherein: each R1 is (Ci)alkyl; each R5 is selected from the group consisting of H, halo, -OH, -NH2, -C≡N, -NO2, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (CrC6)alkoxy, (C2- C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl;
X is O, NR7 or S; each R6 is independently selected from the group consisting of H, halo and (Q- C6)alkyl; and
R7 is H or (CrC6)alkyl. In some embodiments, one or more of R5 is selected from the group consisting of H, -OH, (d-
Ce)alkoxy, -S(0)0(Ci-C6)alkyl and halo. In some aspects, one or more of R5 is selected from the group consisting of -OH, (Ci-C6)alkoxy, R4 is-S(0)0(Ci-C6)alkyl and halo. In some aspects, one or more of R5 is methoxy. In other aspects, one or more of R5 is CI. In other aspects, one or more of R5 is R4 is -S(0)0(Ci-C6)alkyl. In other aspects, one or more of R5 is -OH. In one embodiment, one R5 is methoxy and the other R5 are H. In another embodiment, one R5 is CI and the other R5 are H. In another embodiment, one R5 is
-S(0)0(Ci-C6)alkyl and the other R5 are H. In another embodiment, one R5 is -OH and the other R5 are H.
In some embodiments, at least one of R6 is H, halo or (Ci-C4)alkyl. In some embodiments, at least one of R6 is H, halo or (Ci-C2)alkyl. In other embodiments, at least one of R6 is fluoro. In other embodiments, at least one of R6 is methyl. In other embodiments, at least one of R6 is H.
In some aspects of this embodiment, 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 NCH3. In one embodiment, X is S and one R5 is methoxy and the other R5 are H. In another embodiment, X is O and one R5 is methoxy and the other R5 are H. In another embodiment, X is NH and one R5 is methoxy and the other R5 are H. In another embodiment, X is NCH3 and one R5 is methoxy and the other R5 are H.
In one embodiment, X is S and one R5 is CI and the other R5 are H. In another embodiment, X is O and one R5 is CI and the other R5 are H. In another embodiment, X is NH and one R5 is CI and the other R5 are H. In another embodiment, X is NCH3 and one R5 is CI and the other R5 are H.
In one embodiment, X is S and one R5 is -S(0)0(CrC6)alkyl and the other R5 are H. In another embodiment, X is O and one R5 is -S(0)0(CrC6)alkyl and the other R5 are H. In another embodiment, X is NH and one R5 is -S(0)0(CrC6)alkyl and the other R5 are H. In another embodiment, X is NCH3 and one R5 is -S(0)0(CrC6)alkyl and the other R5 are H.
In another embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (l a-2):
Figure imgf000054_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1 is (Ci)alkyl; each R5 is selected from the group consisting of H, halo, -OH, -NH2, -C=N, -NO2, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (CrC6)alkoxy, (C2- C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl;
X is O, NR7 or S; each R6 is independently selected from the group consisting of H, halo and (Cr
C6)alkyl; and
R7 is H or (CrC6)alkyl.
In some embodiments, one or more of R5 is selected from the group consisting of H, -OH, (Cr C6)alkoxy, -S(0)0(Ci-C6)alkyl and halo. In some aspects, one or more of R5 is selected from the group consisting of -OH, (Ci-C6)alkoxy, -S(0)0(Ci-C6)alkyl and halo. In some aspects, one or more of R5 is methoxy. In other aspects, one or more of R5 is CI. In other aspects, one or more of R5 is - S(0)0(Ci-C6)alkyl. In other aspects, one or more of R5 is -OH.
In one embodiment, one R5 is methoxy and the other R5 are H. In another embodiment, one R5 is CI and the other R5 are H. In another embodiment, one R5 is
-S(0)0(Ci-C6)alkyl and the other R5 are H. In another embodiment, one R5 is -OH and the other R5 are
H.
In some embodiments, at least one of R6 is H, halo or
Figure imgf000055_0001
In some embodiments, at least one of R6 is H, halo or (Ci-C2)alkyl. In other embodiments, at least one of R6 is fluoro. In other embodiments, at least one of R6 is methyl. In other embodiments, at least one of R6 is H.
In some aspects of this embodiment, 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 NCH3.
In one embodiment, X is S and one R5 is methoxy and the other R5 are H. In another embodiment, X is O and one R5 is methoxy and the other R5 are H. In another embodiment, X is NH and one R5 is methoxy and the other R5 are H. In another embodiment, X is NCH3 and one R5 is methoxy and the other R5 are H. In one embodiment, X is S and one R5 is CI and the other R5 are H. In another embodiment, X is O and one R5 is CI and the other R5 are H. In another embodiment, X is NH and one R5 is CI and the other R5 are H. In another embodiment, X is NCH3 and one R5 is CI and the other R5 are H. In one embodiment, X is S and one R5 is -S(0)0(Ci-C6)alkyl and the other R5 are H. In another embodiment, X is O and one R5 is -S(0)0(Ci-C6)alkyl and the other R5 are H. In another embodiment, X is NH and one R5 is -S(0)0(Ci-C6)alkyl and the other R5 are H. In another embodiment, X is NCH3 and one R5 is -S(0)0(Ci-C6)alkyl and the other R5 are H.
In one embodiment, X is S and one R5 is -OH and the other R5 are H. In another embodiment, X is O and one R5 is -OH and the other R5 are H. In another embodiment, X is NH and one R5 is -OH and the other R5 are H. In another embodiment, X is NCH3 and one R5 is -OH and the other R5 are H.
In another embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (lb):
Figure imgf000056_0001
(lb), or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
R2 is (Ci-C6)alkyl substituted with (C3-C6)cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr Ce)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; each R6 is independently selected from halo the group consisting of and (Ci-C6)alkyl; and
R7 is H or (C C6)alkyl.
In some aspects of this embodiment, at least one of R1 is H. In some aspects, each R1 is H.
In other aspects of this embodiment, at least one of R1 is (Ci)alkyl. In some aspects, each R1 is (d)alkyl.
In one embodiment, R2 is (Ci-C4)alkyl substituted with (C3-C6)cycloalkyl. In another embodiment, R2 is (Ci-C2)alkyl substituted with (C3-C6)cycloalkyl. In another embodiment, R2 is (Ci)alkyl substituted with (C3-C6)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. In various embodiments of each of the embodiments in this paragraph, the (C3-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 (C3-C6)cycloalkyl is cyclohexyl.
In embodiments in which said (Ci-C6)alkyl is substituted with R6, R6 is halo or (Ci-C6)alkyl. In some embodiments, R6 is halo or (Ci-C alkyl. In other embodiments, R6 is halo or (Ci-C2)alkyl. In other embodiments, R6 is fluoro. In other embodiments, R6 is methyl.
In some aspects of this embodiment, 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 NCH3.
In one embodiment, at least one R1 is H and X is S. In another embodiment, at least one R1 is H and X is O. In another embodiment, at least one R1 is H and X is NH. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In another embodiment, each R1 is H and X is S. In another embodiment, each R1 is H and X is O. In another embodiment, each R1 is H and X is NH. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3. In one embodiment, at least one of R1 is (Ci)alkyl and X is S. In another embodiment, at least one of R1 is (Ci)alkyl and X is O. In another embodiment, at least one of R1 is (Ci)alkyl and X is NH. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3. In another embodiment, each R1 is (Ci)alkyl and X is S. In another embodiment, each R1 is
(Ci)alkyl and X is O. In another embodiment, each R1 is (Ci)alkyl and X is NH. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3.
In one embodiment, at least one R1 is H and R2 is (Ci-C4)alkyl substituted with (C3- C6)cycloalkyl. In another embodiment, at least one R1 is H and R2 is (Ci-C2)alkyl substituted with (C3- C6)cycloalkyl. In another embodiment, at least one R1 is H and R2 is (Ci)alkyl substituted with (C3- C6)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. In various embodiments of each of the embodiments in this paragraph, the cycloalkyl is cyclohexyl.
In one embodiment, each R1 is H and R2 is
Figure imgf000058_0001
substituted with (C3-C6)cycloalkyl. In another embodiment, each R1 is H and R2 is (Ci-C2)alkyl substituted with (C3-C6)cycloalkyl. In another embodiment, each R1 is H and R2 is (Ci)alkyl substituted with (C3-C6)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. In various embodiments of each of the embodiments in this paragraph, the cycloalkyl is cyclohexyl.
In one embodiment, at least one of R1 is (Ci)alkyl and R2 is (Ci-C4)alkyl substituted with (C3- C6)cycloalkyl. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is (Ci-C2)alkyl substituted with (C3-C6)cycloalkyl. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is (Ci)alkyl substituted with (C3-C6)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. In various embodiments of each of the embodiments in this paragraph, the cycloalkyl is cyclohexyl. In one embodiment, each R1 is (Ci)alkyl and R2 is (Ci-C alkyl substituted with (C3- C6)cycloalkyl. In another embodiment, each R1 is (Ci)alkyl and R2 is (Ci-C2)alkyl substituted with (C3- C6)cycloalkyl. In another embodiment, each R1 is (Ci)alkyl and R2 is (Ci)alkyl substituted with (C3- C6)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. In various embodiments of each of the embodiments in this paragraph, the cycloalkyl is cyclohexyl.
In another embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (lc):
Figure imgf000059_0001
(lc), or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
R2 is (Ci-C6)alkyl substituted with (C5-C7)heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R6;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -NO2, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr Ce)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl; and R7 is H or (C C6)alkyl.
In some aspects of this embodiment, at least one of R1 is H. In some aspects, each R1 is H.
In other aspects of this embodiment, at least one of R1 is (Ci)alkyl. In some aspects, each R1 is (d)alkyl.
In one embodiment, R2 is (Ci-C4)alkyl substituted with (C5-C7)heterocycloalkyl. In another embodiment, R2 is (Ci-C2)alkyl substituted with (C5-C7)heterocycloalkyl. In another embodiment, R2 is (Ci)alkyl substituted with (C5-C7)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. In some aspects of this 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, γ- butyrolactone, 2H-pyran, 4H-pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, piperazine, morpholine, thiomorpholine, oxazine and tetrahydro-oxazinyl. In some aspects of this embodiment, the hetercycloalkyl is a (C6)heterocycloalkyl selected from the group consisting of piperidinyl, piperazinyl, tetrahydro-oxazinyl, tetrahydropyran, dioxane, morpholine and thiomorpholine.
In embodiments in which said (Ci-C6)alkyl is substituted with R6, R6 is halo or (Ci-C6)alkyl. In some embodiments, R6 is halo or (Ci-C4)alkyl. In other embodiments, R6 is halo or (Ci-C2)alkyl. In other embodiments, R6 is fluoro. In other embodiments, R6 is methyl.
In some aspects of this embodiment, X is S. In other aspects, X is O. In other aspects, X is ΝΗ. In other aspects, X is N(Ci-C6)alkyl. In other aspects, X is NCH3. In one embodiment, at least one R1 is H and X is S. In another embodiment, at least one R1 is H and X is O. In another embodiment, at least one R1 is H and X is NH. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In another embodiment, each R1 is H and X is S. In another embodiment, each R1 is H and X is O. In another embodiment, each R1 is H and X is NH. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3.
In one embodiment, at least one of R1 is (Ci)alkyl and X is S. In another embodiment, at least one of R1 is (Ci)alkyl and X is O. In another embodiment, at least one of R1 is (Ci)alkyl and X is NH. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In another embodiment, each R1 is (Ci)alkyl and X is S. In another embodiment, each R1 is (Ci)alkyl and X is O. In another embodiment, each R1 is (Ci)alkyl and X is NH. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3.
In one embodiment, at least one R1 is H and R2 is (Ci-C alkyl substituted with (C5- C7)heterocycloalkyl. In another embodiment, at least one R1 is H and R2 is (Ci-C2)alkyl substituted with (C5-C7)heterocycloalkyl. In another embodiment, at least one R1 is H and R2 is (Ci)alkyl substituted with (C5-C7)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. In various embodiments of each of the embodiments in this paragraph, the heterocycloalkyl is (C5)heterocycloalkyl. In various embodiments of each of the embodiments in this paragraph, the heterocycloalkyl is (C6)heterocycloalkyl.
In one embodiment, each R1 is H and R2 is (Ci-C4)alkyl substituted with (C5- C7)heterocycloalkyl. In another embodiment, each R1 is H and R2 is (Ci-C2)alkyl substituted with (C5- C7)heterocycloalkyl. In another embodiment, each R1 is H and R2 is (Ci)alkyl substituted with (C5- C7)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. In various embodiments of each of the embodiments in this paragraph, the heterocycloalkyl is (C5)heterocycloalkyl. In various embodiments of each of the embodiments in this paragraph, the heterocycloalkyl is (C6)heterocycloalkyl.
In one embodiment, at least one of R1 is (Ci)alkyl and R2 is (Ci-C4)alkyl substituted with (C5- C7)heterocycloalkyl. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is (CrC2)alkyl substituted with (C5-C7)heterocycloalkyl. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is (Ci)alkyl substituted with (C5-C7)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. In various embodiments of each of the embodiments in this paragraph, the heterocycloalkyl is (C5)heterocycloalkyl. In various embodiments of each of the embodiments in this paragraph, the heterocycloalkyl is
(C6)heterocycloalkyl.
In one embodiment, each R1 is (Ci)alkyl and R2 is (Ci-C4)alkyl substituted with (C5- C7)heterocycloalkyl. In another embodiment, each R1 is (Ci)alkyl and R2 is (Ci-C2)alkyl substituted with (C5-C7)heterocycloalkyl. In another embodiment, each R1 is (Ci)alkyl and R2 is (Ci)alkyl substituted with (C5-C7)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. In various embodiments of each of the embodiments in this paragraph, the heterocycloalkyl is (C5)heterocycloalkyl. In various embodiments of each of the embodiments in this paragraph, the heterocycloalkyl is (C6)heterocycloalkyl.
In another embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (I d):
Figure imgf000062_0001
(I d), or a pharmaceutically acceptable salt thereof, wherein: each R1 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 R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl; and
R7 is H or (C C6)alkyl.
In some aspects of this embodiment, at least one of R1 is H. In some aspects, each R1 is H. In other aspects of this embodiment, at least one of R1 is (Ci)alkyl. In some aspects, each R1 is
(Ci)alkyl.
In one embodiment, R2 is (Ci-C4)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl. In another embodiment, R2 is (Ci-C2)alkyl substituted with (5- or 6- membered)heteroaryl or (9-or 10-membered)heteroaryl. In another embodiment, R2 is (Ci)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl. In each embodiment of this paragraph, 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. In various embodiments of each of the embodiments in this paragraph, 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.
In some aspects of this embodiment, the heteroaryl is selected from the group consisting of pyridyl, pyrrolyl, pyrazolyl, furyl, thienyl, 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,
1 ,3,5-triazinyl, thiophenyl, lH-indolyl, 3H-indolyl and benzo[d] [l ,3]dioxol.
In some embodiments, 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.
In embodiments in which said (Ci-C6)alkyl is substituted with R6, R6 is halo or (Ci-C6)alkyl. In some embodiments, R6 is halo or (Ci-C4)alkyl. In other embodiments, R6 is halo or (Ci-C2)alkyl. In other embodiments, R6 is fluoro. In other embodiments, R6 is methyl.
In some aspects of this embodiment, 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 NCH3.
In one embodiment, at least one R1 is H and X is S. In another embodiment, at least one R1 is H and X is O. In another embodiment, at least one R1 is H and X is NH. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In another embodiment, each R1 is H and X is S. In another embodiment, each R1 is H and X is O. In another embodiment, each R1 is H and X is NH. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3.
In one embodiment, at least one of R1 is (Ci)alkyl and X is S. In another embodiment, at least one of R1 is (Ci)alkyl and X is O. In another embodiment, at least one of R1 is (Ci)alkyl and X is NH. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In another embodiment, each R1 is (Ci)alkyl and X is S. In another embodiment, each R1 is (Ci)alkyl and X is O. In another embodiment, each R1 is (Ci)alkyl and X is NH. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3.
In one embodiment, at least one R1 is H and R2 is (Ci-C alkyl substituted with (5- or 6- membered)heteroaryl or (9-or 10-membered)heteroaryl. In another embodiment, at least one R1 is H and R2 is (Ci-C2)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl. In another embodiment, at least one R1 is H and R2 is (Ci)alkyl substituted with (5- or 6- membered)heteroaryl or (9-or 10-membered)heteroaryl. In each embodiment of this paragraph, 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. In various embodiments of each of the embodiments in this paragraph, 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. 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.
In one embodiment, each R1 is H and R2 is (Ci-C4)alkyl substituted with (5- or 6- membered)heteroaryl or (9-or 10-membered)heteroaryl. In another embodiment, each R1 is H and R2 is (Ci-C2)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl. In another embodiment, each R1 is H and R2 is (Ci)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl. In each embodiment of this paragraph, 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. In various embodiments of each of the embodiments in this paragraph, 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. 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. In one embodiment, at least one of R1 is (Ci)alkyl and R2 is (Ci-C4)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is (Ci-C2)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10- membered)heteroaryl. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is (Ci)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl. In each embodiment of this paragraph, 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. In various embodiments of each of the embodiments in this paragraph, 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. 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.
In one embodiment, each R1 is (Ci)alkyl and R2 is (Ci-C alkyl substituted with (5- or 6- membered)heteroaryl or (9-or 10-membered)heteroaryl. In another embodiment, each R1 is (Ci)alkyl and R2 is (Ci-C2)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl. In another embodiment, each R1 is (Ci)alkyl and R2 is (Ci)alkyl substituted with (5- or 6- membered)heteroaryl or (9-or 10-membered)heteroaryl. In each embodiment of this paragraph, 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. In various embodiments of each of the embodiments in this paragraph, 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. 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.
According to one embodiment, the compound of formula (1 ) is:
Figure imgf000067_0001
According to one embodiment, the compound of formula (1) is:
Figure imgf000067_0002
According to one embodiment, the compound of formula (1) is:
Figure imgf000067_0003
In particular embodiments, compounds 1, 2 or 3 are utilized as a pharmaeutically acceptable salt thereof.
In another embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (2):
Figure imgf000068_0001
(2), or a pharmaceutically acceptable salt thereof, wherein: each R1 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 R4;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and
R7 is H or (C C6)alkyl.
In some aspects of this embodiment, at least one of R1 is H. In some aspects, each R1 is H.
In other aspects of this embodiment, at least one of R1 is (Ci)alkyl. In some aspects, each R1 is (Ci)alkyl.
According to a first embodiment, R2 is a branched C3-C6 alkyl, wherein said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4. In one embodiment, R2 is a substituted, branched C3-C6 alkyl. In another embodiment, R2 is an unsubstituted, branched C3-C6 alkyl. In one embodiment, 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. In other embodiments, R2 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.
According to a second embodiment, R2 is a branched C3-C6 alkenyl, wherein said alkenyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4. In one embodiment, R2 is a substituted, branched C3-C6 alkenyl. In another embodiment, R2 is an unsubstituted, branched C3-C6 alkenyl.
According to a third embodiment, R2 is a branched C3-C6 alkoxy, wherein said alkoxy is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4. In one embodiment, R2 is a substituted, branched C3-C6 alkoxy. In another embodiment, R2 is an unsubstituted, branched C3-C6 alkoxy.
In some aspects of this embodiment, 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 NCH3.
In one embodiment, at least one R1 is H and X is S. In another embodiment, at least one R1 is H and X is O. In another embodiment, at least one R1 is H and X is NH. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In another embodiment, each R1 is H and X is S. In another embodiment, each R1 is H and X is O. In another embodiment, each R1 is H and X is NH. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3.
In one embodiment, at least one of R1 is (Ci)alkyl and X is S. In another embodiment, at least one of R1 is (Ci)alkyl and X is O. In another embodiment, at least one of R1 is (Ci)alkyl and X is NH. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In another embodiment, each R1 is (Ci)alkyl and X is S. In another embodiment, each R1 is (Ci)alkyl and X is O. In another embodiment, each R1 is (Ci)alkyl and X is NH. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3. In various embodiments of the first embodiment of the compound of formula (2), at least one R1 is H in one embodiment, each R1 is H in another embodiment, at least one of R1 is (Ci)alkyl m an additional embodiment, and each R1 is (Ci)alkyl in a further embodiment.
In various embodiments of the second embodiment of the compound of formula (2), at least one R1 is H in one embodiment, each R1 is H in another embodiment, at least one of R1 is (Ci)alkyl m an additional embodiment, and each R1 is (Ci)alkyl in a further embodiment.
In various embodiments of the third embodiment of the compound of formula (2), at least one R1 is H in one embodiment, each R1 is H in another embodiment, at least one of R1 is (d)alkyl m an additional embodiment, and each R1 is (Ci)alkyl in a further embodiment.
In another embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (3):
Figure imgf000070_0001
(3), or a pharmaceutically acceptable salt thereof, wherein: each R is H;
R is selected from the group consisting of (Ci-C6)alkyl, (C2-C6)alkenyl, (C2- 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 ;
X is O, NR7 or S; each R is independently selected from the group consisting of halo, -OH, - CH2OH, -NH2, -C≡N, -NO2, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (Ci-Ce) alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3- C6)cycloalkyl, (5- or 6-membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, - C(0)OH, -NH-C(0)-NH2, -NH-C(NH)-NH2,-NH-C(S)-NH2, -SON, -S02NH2, - COR', -C(0)0R',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-Ce)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6-membered)heteroaryl and (C5- C7)heterocycloalkyl; and
R7 is H or (CrC6)alkyl.
According to one embodiment, R2 is (Ci-C6)alkyl, wherein said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R4. In one embodiment, R2 is unsubstituted (Ci-C6)alkyl. In another embodiment, R2 is (Ci-C4)alkyl, wherein said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R4. In another embodiment, R2 is unsubstituted (Ci-C4)alkyl. In another embodiment, R2 is (C2-C6)alkyl, wherein said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R4. In another embodiment, R2 is unsubstituted (C2-C6)alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl. In another embodiment, R2 is propyl. In another embodiment, R2 is butyl. In another embodiment, R2 is pentyl. In another embodiment, R2 is hexyl.
In one embodiment, R2 is (Ci-C6)alkyl substituted with 1, 2 or 3 substituents independently selected from R4. In another embodiment, R2 is a monosubstituted (Ci-C6)alkyl substituted with a substituent selected from R4. In another embodiments, R2 is a disubstituted (Ci-C6)alkyl substituted with 2 substituents independently selected from R4. In another embodiments, R2 is a trisubstituted (Cp C6)alkyl substituted with 3 substituents independently selected from R4. In one embodiment, R2 is (Cp C6)alkyl substituted 1, 2 or 3 substituents independently selected from halo, SR', -C(0)NH2, - C(0)OH, -NH2 and -NH-C(NH)-NH2. In another embodiment, R2 is (CrC6)alkyl monsubstituted with halo. In another embodiment, R2 is (Ci-C6)alkyl disubstituted with 2 halos independently selected. In another embodiment, R2 is (Ci-C6)alkyl trisubstituted with 3 halos independently selected. In another embodiment, R2 is (Ci-C6)alkyl monosubstituted with fluoro. In another embodiment, R2 is (Cr
C6)alkyl disubstituted with fluoro. In another embodiment, R2 is (Ci-C6)alkyl trisubstituted fluoro. In another embodiment, R2 is (Ci-C6)alkyl monosubstituted with SR'. In another embodiment, R2 is (Cp C6)alkyl monosubstituted with S(Ci-C6)alkyl. In another embodiment, R2 is (Ci-C6)alkyl
monosubstituted with -SCH3. In another embodiment, R2 is (Ci-C6)alkyl monosubstituted
with -C(0)NH2. In another embodiment, R2 is (Ci-C6)alkyl monosubstituted with -C(0)OH. In another embodiment, R2 is (Ci-C6)alkyl monosubstituted with -NH2. In another embodiment, R2 is (Ci-C6)alkyl monosubstituted with -NH-C(NH)-NH2. In one embodiment, R is a (Ci-C alkyl substituted with 1, 2 or 3 substituents independently selected from R4. In another embodiment, R2 is a monosubstituted (Ci-C4)alkyl substituted with a substituent independently selected from R4. In another embodiments, R2 is a disubstituted (Ci-C4)alkyl substituted with 2 substituents independently selected from R4. In another embodiments, R2 is a trisubstituted (Ci-C4)alkyl substituted with 3 substituents independently selected from R4. In one embodiment, R2 is (Ci-C4)alkyl substituted 1, 2 or 3 substituents independently selected from halo, SR', -C(0)NH2, -C(0)OH, -NH2 and -NH-C(NH)-NH2. In another embodiment, R2 is (CrC4)alkyl monsubstituted with halo. In another embodiment, R2 is (Ci-C4)alkyl disubstituted with 2 halos independently selected. In another embodiment, R2 is (Ci-C4)alkyl trisubstituted with 3 halos independently selected. In another embodiment, R2 is (Ci-C4)alkyl monosubstituted with fluoro. In another embodiment, R2 is (Ci-C4)alkyl disubstituted with fluoro. In another embodiment, R2 is (Cp C4)alkyl trisubstituted fluoro. In another embodiment, R2 is (Ci-C4)alkyl monosubstituted with SR'. In another embodiment, R2 is (Ci-C4)alkyl monosubstituted with S(Ci-C6)alkyl. In another embodiment, R2 is (Ci-C4)alkyl monosubstituted with -SCH3. In another embodiment, R2 is (Ci-C4)alkyl monosubstituted with -C(0)NH2. In another embodiment, R2 is (Ci-C4)alkyl monosubstituted with -C(0)OH. In another embodiment, R2 is (Ci-C4)alkyl monosubstituted with -NH2. In another embodiment, R2 is (d-C4)alkyl monosubstituted with -NH-C(NH)-NH2.
In one embodiment, R2 is a (C2-C6)alkyl substituted with 1 , 2 or 3 substituents independently selected from R4. In another embodiment, R2 is a monosubstituted (C2-Ce)alkyl substituted with a substituent independently selected from R4. In another embodiments, R2 is a disubstituted (C2-C6)alkyl substituted with 2 substituents independently selected from R4. In another embodiments, R2 is a trisubstituted (C2-Ce)alkyl substituted with 3 substituents independently selected from R4. In one embodiment, R2 is (C2-Ce)alkyl substituted 1, 2 or 3 substituents independently selected from halo, SR', -C(0)NH2, -C(0)OH, -NH2 and -NH-C(NH)-NH2. In another embodiment, R2 is (C2-C6)alkyl monsubstituted with halo. In another embodiment, R2 is (C2-C6)alkyl disubstituted with 2 halos independently selected. In another embodiment, R2 is (C2-C6)alkyl trisubstituted with 3 halos independently selected. In another embodiment, R2 is (C2-C6)alkyl monosubstituted with fluoro. In another embodiment, R2 is (C2-C6)alkyl disubstituted with fluoro. In another embodiment, R2 is (C2- C6)alkyl trisubstituted with fluoro. In another embodiment, R2 is (C2-C6)alkyl monosubstituted with SR'. In another embodiment, R2 is (C2-C6)alkyl monosubstituted with S(Ci-C6)alkyl. In another embodiment, R2 is (C2-C6)alkyl monosubstituted with -SCH3. In another embodiment, R2 is (C2- C6)alkyl monosubstituted with -C(0)NH2. In another embodiment, R2 is (C2-C6)alkyl monosubstituted with -C(0)OH. In another embodiment, R is (C2-C6)alkyl monosubstituted with -NH2. In another embodiment, R2 is (C2-C6)alkyl monosubstituted with -NH-C(NH)-NH2.
In one embodiment, R2 is a monosubstituted (Ci)alkyl substituted with a substituent selected from R4. In another embodiment, R2 is (Ci)alkyl monosubstituted with a substituent selected from halo, SR', -C(0)NH2, -C(0)OH, -NH2 and -NH-C(NH)-NH2. In another embodiment, R2 is (Ci)alkyl monsubstituted with halo. In another embodiment, R2 is (Ci)alkyl monosubstituted with fluoro. In another embodiment, R2 is (Ci)alkyl monosubstituted with SR'. In another embodiment, R2 is (Ci)alkyl monosubstituted with S(Ci-C6)alkyl. In another embodiment, R2 is (Ci)alkyl monosubstituted with -SCH3. In another embodiment, R2 is (Ci)alkyl monosubstituted with -C(0)NH2. In another embodiment, R2 is (Ci)alkyl monosubstituted with -C(0)OH. In another embodiment, R2 is (Ci)alkyl monosubstituted with -NH2. In another embodiment, R2 is (Ci)alkyl monosubstituted with -NH- C(NH)-NH2. In another embodiments, R2 is a disubstituted (Ci)alkyl substituted with 2 halos independently selected. In another embodiment, R2 is (Ci)alkyl disubstituted with fluoro. In another embodiment, R2 is (Ci)alkyl trisubstituted with 3 halos independently selected. In another
embodiment, R2 is (Ci)alkyl trisubstituted with fluoro.
In one embodiment, R2 is a monosubstituted (C2)alkyl substituted with a substituent selected from R4. In another embodiment, R2 is (C2)alkyl monosubstituted with a substituent selected from halo, SR', -C(0)NH2, -C(0)OH, -NH2 and -NH-C(NH)-NH2. In another embodiment, R2 is (C2)alkyl monsubstituted with halo. In another embodiment, R2 is (C2)alkyl monosubstituted with fluoro. In another embodiment, R2 is (C2)alkyl monosubstituted with SR'. In another embodiment, R2 is
(C2)alkyl monosubstituted with S(Ci-C6)alkyl. In another embodiment, R2 is (C2)alkyl monosubstituted with -SCH3. In another embodiment, R2 is (C2)alkyl monosubstituted with -C(0)NH2. In another embodiment, R2 is (C2)alkyl monosubstituted with -C(0)OH. In another embodiment, R2 is (C2)alkyl monosubstituted with -NH2. In another embodiment, R2 is (C2)alkyl monosubstituted with -NH- C(NH)-NH2. In another embodiments, R2 is a disubstituted (C2)alkyl substituted with 2 halos independently selected. In another embodiment, R2 is (C2)alkyl disubstituted with fluoro. In another embodiment, R2 is (C2)alkyl trisubstituted with 3 halos independently selected. In another
embodiment, R2 is (C2)alkyl trisubstituted with fluoro.
In one embodiment, R2 is a monosubstituted (C3)alkyl substituted with a substituent selected from R4. In another embodiment, R2 is (C3)alkyl monosubstituted with a substituent selected from halo, SR', -C(0)NH2, -C(0)OH, -NH2 and -NH-C(NH)-NH2. In another embodiment, R2 is (C3)alkyl monsubstituted with halo. In another embodiment, R2 is (C3)alkyl monosubstituted with fluoro. In another embodiment, R is (C3)alkyl monosubstituted with SR'. In another embodiment, R is (C3)alkyl monosubstituted with S(Ci-C6)alkyl. In another embodiment, R2 is (C3)alkyl monosubstituted with -SCH3. In another embodiment, R2 is (C3)alkyl monosubstituted with -C(0)NH2. In another embodiment, R2 is (C3)alkyl monosubstituted with -C(0)OH. In another embodiment, R2 is (C3)alkyl monosubstituted with -NH2. In another embodiment, R2 is (C3)alkyl monosubstituted with -NH- C(NH)-NH2. In another embodiments, R2 is a disubstituted (C3)alkyl substituted with 2 halos independently selected. In another embodiment, R2 is (C3)alkyl disubstituted with fluoro. In another embodiment, R2 is (C3)alkyl trisubstituted with 3 halos independently selected. In another
embodiment, R2 is (C3)alkyl trisubstituted with fluoro. In one embodiment, R2 is a monosubstituted (C4)alkyl substituted with a substituent selected from R4. In another embodiment, R2 is (C4)alkyl monosubstituted with a substituent selected from halo, SR', -C(0)NH2, -C(0)OH, -NH2 and -NH-C(NH)-NH2. In another embodiment, R2 is (C4)alkyl monsubstituted with halo. In another embodiment, R2 is (C4)alkyl monosubstituted with fluoro. In another embodiment, R2 is (C )alkyl monosubstituted with SR'. In another embodiment, R2 is (C4)alkyl monosubstituted with S(Ci-C6)alkyl. In another embodiment, R2 is (C4)alkyl monosubstituted with -SCH3. In another embodiment, R2 is (C4)alkyl monosubstituted with -C(0)NH2. In another embodiment, R2 is (C4)alkyl monosubstituted with -C(0)OH. In another embodiment, R2 is (C4)alkyl monosubstituted with -NH2. In another embodiment, R2 is (C4)alkyl monosubstituted with -NH- C(NH)-NH2. In another embodiments, R2 is a disubstituted (C4)alkyl substituted with 2 halos independently selected. In another embodiment, R2 is (C4)alkyl disubstituted with fluoro. In another embodiment, R2 is (C4)alkyl trisubstituted with 3 halos independently selected. In another
embodiment, R2 is (C4)alkyl trisubstituted with fluoro.
According to a second embodiment, R2 is a branched (C3-Ce)alkyl, wherein said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4. In one embodiment, R2 is a substituted, branched C3-C6 alkyl. In another embodiment, R2 is an unsubstituted, branched C3-C6 alkyl. In one embodiment, R2 is selected from the group consisting of z' o-propyl, sec-butyl, iso-butyl, teri-butyl, methylpentyl, ethylbutyl, dimethylbutyl, and z' o-propylpropyl. In other embodiments, R2 is selected from the group consisting of sec-butyl, iso-butyl, tert-butyl, methylpentyl, ethylbutyl, dimethylbutyl, and z' o-propylpropyl. According to a third embodiment, R2 is (C2-C6)alkenyl, wherein said alkenyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4. In some embodiments, R2 is a substituted (C2- C6)alkenyl. In other embodiments, R2 is an unsubstituted (C2-C6)alkenyl. In one embodiment, R2 is an unsubstituted (C3-C6)alkenyl. In another embodiment, R is an unsubstituted (C3)alkenyl. In another embodiment, R2 is an unsubstituted (C4)alkenyl. In another embodiment, R2 is an unsubstituted (C5)alkenyl. In another embodiment, R2 is an unsubstituted (C6)alkenyl. In one embodiment, R2 is a substituted (C3-C6)alkenyl. In another embodiment, R2 is a substituted (C3)alkenyl. In another embodiment, R2 is a substituted (C4)alkenyl. In another embodiment, R2 is a substituted (C5)alkenyl. In another embodiment, R2 is a substituted (C6)alkenyl.
According to a fourth embodiment, R2 is a branched (C3-C6)alkenyl, wherein said alkenyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4. In one embodiment, R2 is a substituted, branched (C3-C6)alkenyl. In another embodiment, R2 is an unsubstituted, branched (C3- C6)alkenyl. In one embodiment, R2 is an unsubstituted, branched (C3-C6)alkenyl. In another embodiment, R2 is an unsubstituted, branched (C3)alkenyl. In another embodiment, R2 is an unsubstituted, branched (C4)alkenyl. In another embodiment, R2 is an unsubstituted, branched (C5)alkenyl. In another embodiment, R2 is an unsubstituted, branched (C6)alkenyl. In one
embodiment, R2 is a substituted, branched (C3-C6)alkenyl. In another embodiment, R2 is a substituted, branched (C3)alkenyl. In another embodiment, R2 is a substituted, branched (C^alkenyl. In another embodiment, R2 is a substituted, branched (C5)alkenyl. In another embodiment, R2 is a substituted, branched (C6)alkenyl.
According to a fifth embodiment, R2 is (C2-Ce)alkynyl, wherein said alkynyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R4. In some embodiments, R2 is a substituted (C2- C6)alkynyl. In other embodiments, R2 is an unsubstituted (C2-C6)alkynyl. In one embodiment, R2 is an unsubstituted, branched (C3-C6)alkynyl. In another embodiment, R2 is an unsubstituted, branched (C3) alkynyl. In another embodiment, R2 is an unsubstituted, branched (C4) alkynyl. In another embodiment, R2 is an unsubstituted, branched (C5) alkynyl. In another embodiment, R2 is an unsubstituted, branched (C6)alkynyl. In one embodiment, R2 is a substituted, branched (C3-C6)alkynyl. In another embodiment, R2 is a substituted, branched (C3)alkynyl. In another embodiment, R2 is a substituted, branched (C4)alkynyl. In another embodiment, R2 is a substituted, branched (C5)alkynyl. In another embodiment, R2 is a substituted, branched (C6)alkynyl.
According to sixth embodiment, R2 is (Ci-C6)alkoxy, wherein said alkoxy is unsubstituted or substituted with 1, 2 or 3 substituents selected from R4. In some embodiments, R2 is a substituted (Q- C6)alkoxy. In other embodiments, R2 is an unsubstituted (Ci-C6)alkoxy. In one embodiment, R2 is methoxy. In another embodiment, R2 is ethoxy. In another embodiment, R2 is propoxy. According to an seventh embodiment, R is a branched (C3-C6)alkoxy, wherein said alkoxy is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4. In one embodiment, R2 is a substituted, branched (C3-Ce)alkoxy. In another embodiment, R2 is an unsubstituted, branched (C3- Ce) alkoxy.
In some aspects of this embodiment, 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 NCH3.
In various embodiments of the first embodiment of the compound of formula (3), X is S in one embodiment, X is O in another embodiment, X is NH in an additional embodiment and X is NCH3 in a further embodiment.
In various embodiments of the second embodiment of the compound of formula (3), X is S in one embodiment, X is O in another embodiment, X is NH in an additional embodiment and X is NCH3 in a further embodiment.
In various embodiments of the third embodiment of the compound of formula (3), X is S in one embodiment, X is O in another embodiment, X is NH in an additional embodiment and X is NCH3 in a further embodiment.
In various embodiments of the fourth embodiment of the compound of formula (3), X is S in one embodiment, X is O in another embodiment, X is NH in an additional embodiment and X is NCH3 in a further embodiment.
In various embodiments of the fifth embodiment of the compound of formula (3), X is S in one embodiment, X is O in another embodiment, X is NH in an additional embodiment and X is NCH3 in a further embodiment.
In various embodiments of the sixth embodiment of the compound of formula (3), X is S in one embodiment, X is O in another embodiment, X is NH in an additional embodiment and X is NCH3 in a further embodiment.
In various embodiments of the seventh embodiment of the compound of formula (3), X is S in one embodiment, X is O in another embodiment, X is NH in an additional embodiment and X is NCH3 in a further embodiment. According to one aspect of this embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (3 a):
Figure imgf000077_0001
or a pharmaceutically acceptable salt thereof, wherein: each R1 is H;
R2 is (Ci-C4)alkyl substituted with phenyl, wherein said phenyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl; and
R7 is H or (C C6)alkyl.
In one embodiment, R2 is (Ci-C4)alkyl substituted with phenyl. In another embodiment, R2 is (Ci-C2)alkyl substituted with phenyl. In another embodiment, R2 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 R6, R6 is halo or (Ci-C6)alkyl.
In some embodiments, halo or (Ci-C4)alkyl. In other embodiments, R6 is halo or (Ci-C2)alkyl. In other embodiments, R6 is fluoro. In other embodiments, R6 is methyl.
In embodiments in which said phenyl is substituted, each R4 is independently selected from the group consisting of halo, -OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(0)-NH2, -NH- C(S)-NH2, -SC≡N, -S02NH2, -COR', -C(0)OR', -C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', - S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6-membered)heteroaryl and (C5- C7)heterocycloalkyl.
In some embodiments, each R4 is independently selected from the group consisting of -OH, - NH2, -SH, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (CrC6)alkoxy, (C2-C6)alkenyloxy, (C2- C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6-membered)heteroaryl, (C5- C7)heterocycloalkyl, -NHR', -NR'R", -SR', -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl.
In another embodiment, each R4 is independently selected from the group consisting of -OH, - NH2, -SH, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (CrC6)alkoxy, (C2-C6)alkenyloxy and (C2- C6)alkynyloxy. In some embodiments, each R4 is independently selected from the group consisting of - OH, -NH2, -SH, (Ci-C6)alkoxy, (C2-C6)alkenyloxy and (C2-C6)alkynyloxy. In other embodiments, each R4 is independently selected from the group consisting of (Ci-C6)alkoxy, (C2-C6)alkenyloxy and (C2- C6)alkynyloxy. In yet other embodiments, R4 is (Ci-C6)alkoxy. In some embodiments, R4 is selected (Ci-C3)alkoxy. In other embodiments, R4 is methoxy. In other embodiments, R4 is -OH.
In some embodiments, each R4 is independently selected from the group consisting of halo, - C≡N, -N02, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(0)-NH2, -NH-C(S)-NH2, -SON, -S02NH2, -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, (C2-C6)alkenyl, (C2-Ce)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, and (C5-C7)heterocycloalkyl.
In another embodiment, each R is independently selected from the group consisting of halo, - C≡N, -N02, -C(0)NH2, -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, (C2-C6)alkenyl, (C2-Ce)alkynyl, (C6-Ci4)aryl, (C3- C6)cycloalkyl, (5- or 6-membered)heteroaryl and (C5-C7)heterocycloalkyl. In some embodiments, R4 is halo. In some embodiments, R4 is CI.
In some aspects of this embodiment, 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 NCH3.
In one embodiment, R2 is (Ci-C4)alkyl substituted with phenyl and X is S. In another embodiment, R2 is (Ci-C4)alkyl substituted with phenyl and X is O. In another embodiment, R2 is (Q- C4)alkyl substituted with phenyl and X is NH. In another embodiment, R2 is (Ci-C4)alkyl substituted with phenyl and X is NCH3. 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 various embodiments of each of the embodiments in this paragraph, the substituent is methoxy, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, halo, and methylsulfonyl.
In one embodiment, R2 is (Ci-C2)alkyl substituted with phenyl and X is S. In another embodiment, R2 is (Ci-C2)alkyl substituted with phenyl and X is O. In another embodiment, R2 is (Cr C2)alkyl substituted with phenyl and X is NH. In another embodiment, R2 is (Ci-C2)alkyl substituted with phenyl and X is NCH3. 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 various embodiments of each of the embodiments in this paragraph, the substituent is -OH, methoxy, halo, or methylsulfonyl, or the substituents are independently selected from -OH, methoxy, halo, and methylsulfonyl.
In one embodiment, R2 is (Ci)alkyl substituted with phenyl and X is S. In another
embodiment, R2 is (Ci)alkyl substituted with phenyl and X is O. In another embodiment, R2 is (Ci)alkyl substituted with phenyl and X is NH. In another embodiment, R2 is (Ci)alkyl substituted with phenyl and X is NCH3. 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 various embodiments of each of the embodiments in this paragraph, the substituent is -OH, methoxy, halo, or methylsulfonyl, or the substituents are independently selected from -OH, methoxy, halo, and methylsulfonyl.
In another embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (3a-l):
Figure imgf000080_0001
or a pharmaceutically acceptable salt thereof, wherein: each R5 is selected from the group consisting of H, halo, -OH, -NH2, -C=N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (CrC6)alkoxy, (C2- C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl;
X is O, NR7 or S; each R6 is independently selected from the group consisting of H, halo and (Cr C6)alkyl; and
R7 is H or (C C6)alkyl. In some embodiments, one or more of R5 is selected from the group consisting of H, -OH, (d- Ce)alkoxy, S(0)0(Ci-C6)alkyl and halo. In some aspects, one or more of R5 is selected from the group consisting of -OH, (Ci-C6)alkoxy, S(0)0(Ci-C6)alkyl and halo. In some aspects, one or more of R5 is methoxy. In other aspects, one or more of R5 is CI. In some aspects, one or more of R5 is S(0)0(Cr C6)alkyl. In another embodiment, one or more of R5 is -OH.
In some aspects, one R5 is methoxy and the other R5 are H. In other aspects, one R5 is CI and the other R5 are H. In some aspects, one R5 is S(0)0(Ci-C6)alkyl and the other R5 are H. In another embodiment, one R5 is -OH and the other R5 are H.
In some embodiments, at least one of R6 is H, halo or (Ci-C4)alkyl. In other embodiments, at least one of R6 is H, halo or (Ci-C2)alkyl. In other embodiments, at least one of R6 is fluoro. In other embodiments, at least one of R6 is methyl. In other embodiments, at least one of R6 is H.
In some aspects of this embodiment, 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 NCH3.
According to one aspect of this embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (3b):
Figure imgf000081_0001
(3b), or a pharmaceutically acceptable salt thereof, wherein: each R is H;
R is (Ci-C4)alkyl substituted with (C3-C6)cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6; each R is independently selected from the group consisting of halo, -OH, -NH2, -C=N,
-NO2, -SH, =0, =S, =N-(Ci-C4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr
Ce)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl;
X is O, NR7 or S; each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl; and
R7 is H or (CrC6)alkyl.
In one embodiment, R is (Ci-C4)alkyl substituted with (C3-C6)cycloalkyl. In another embodiment, R2 is (Ci-C2)alkyl substituted with (C3-C6)cycloalkyl. In another embodiment, R2 is (Ci)alkyl substituted with (C3-C6)cycloalkyl. In each embodiment of this paragraph, the (C3- 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. In various embodiments of each of the embodiments in this paragraph, the (C3-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 (C3-C6)cycloalkyl is cyclohexyl.
In embodiments in which said (Ci-C4)alkyl is substituted with R6, R6 is halo or (Ci-C6)alkyl. In some embodiments, halo or (Ci-C4)alkyl. In other embodiments, R6 is halo or (Ci-C2)alkyl. In other embodiments, R6 is fluoro. In other embodiments, R6 is methyl.
In some aspects of this embodiment, 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 NCH3.
In one embodiment, R2 is (Ci-C4)alkyl substituted with (C3-C6)cycloalkyl and X is S. In another embodiment, R2 is (Ci-C4)alkyl substituted with (C3-C6)cycloalkyl and X is O. In another embodiment, R2 is (Ci-C4)alkyl substituted with (C3-C6)cycloalkyl and X is NH. In another embodiment, R2 is (Ci-C4)alkyl substituted with (C3-C6)cycloalkyl and X is NCH3. 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. In various embodiments of each of the embodiments in this paragraph, the substituent is methoxy, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, halo, and
methylsulfonyl.
In one embodiment, R2 is (Ci-C2)alkyl substituted with (C3-C6)cycloalkyl and X is S. In another embodiment, R2 is (Ci-C2)alkyl substituted with (C3-C6)cycloalkyl and X is O. In another embodiment, R2 is (Ci-C2)alkyl substituted with (C3-C6)cycloalkyl and X is NH. In another embodiment, R2 is (Ci-C2)alkyl substituted with (C3-C6)cycloalkyl and X is NCH3. 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. In various embodiments of each of the embodiments in this paragraph, the substituent is methoxy, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, halo, and
methylsulfonyl.
In one embodiment, R2 is (Ci)alkyl substituted with (C3-C6)cycloalkyl and X is S. In another embodiment, R2 is (Ci)alkyl substituted with (C3-C6)cycloalkyl and X is O. In another embodiment, R2 is (Ci)alkyl substituted with (C3-C6)cycloalkyl and X is NH. In another embodiment, R2 is (Ci)alkyl substituted with (C3-C6)cycloalkyl and X is NCH3. 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. In various embodiments of each of the embodiments in this paragraph, the substituent is methoxy, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, halo, and methylsulfonyl.
According to one aspect of this embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (3c):
Figure imgf000084_0001
or a pharmaceutically acceptable salt thereof, wherein: each R1 is H;
R2 is (Ci-C4)alkyl substituted with (C5-C7)heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R6;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl; and
R7 is H or (C C6)alkyl.
In one embodiment, R2 is (Ci-C4)alkyl substituted with (C5-C7)heterocycloalkyl. In another embodiment, R2 is (Ci-C2)alkyl substituted with (C5-C7)heterocycloalkyl. In another embodiment, R2 is (Ci)alkyl substituted with (C5-C7)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. In various embodiments of each of the embodiments in this paragraph, the heterocycloalkyl is selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, tetrahydro-oxazinyl, tetrahydrofuran, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrahydrofuranone, γ- butyrolactone, 2H-pyran, 4H-pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, piperazine, morpholine, thiomorpholine, oxazine and tetrahydro-oxazinyl.
In one embodiment, the hetercycloalkyl is a (C6)heterocycloalkyl selected from the group consisting of piperidinyl, piperazinyl, tetrahydro-oxazinyl, tetrahydropyran, dioxane, morpholine and thiomorpholine. In embodiments in which said (Ci-C4)alkyl is substituted with R6, R6 is halo or (Ci-C6)alkyl.
In some embodiments, halo or (Ci-C4)alkyl. In other embodiments, R6 is halo or (Ci-C2)alkyl. In other embodiments, R6 is fluoro. In other embodiments, R6 is methyl.
In some aspects of this embodiment, X is S. In other aspects, X is O. In other aspects, X is ΝΗ. In other aspects, X is N(Ci-C6)alkyl. In other aspects, X is NCH3. In one embodiment, R2 is (Ci-C alkyl substituted with (C5-C7)heterocycloalkyl and X is S. In another embodiment, R2 is (Ci-C4)alkyl substituted with (C5-C7)heterocycloalkyl and X is O. In another embodiment, R2 is substituted with (C5-C7)heterocycloalkyl and X is NH. In another embodiment, R2 is
Figure imgf000085_0001
substituted with (C5-C7)heterocycloalkyl and X is NCH3. 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. In various embodiments of each of the embodiments in this paragraph, the substituent is methoxy, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, halo, and methylsulfonyl. In one embodiment, R2 is (Ci-C2)alkyl substituted with (C5-C7)heterocycloalkyl and X is S. In another embodiment, R2 is (Ci-C2)alkyl substituted with (C5-C7)heterocycloalkyl and X is O. In another embodiment, R2 is (Ci-C2)alkyl substituted with (C5-C7)heterocycloalkyl and X is NH. In another embodiment, R2 is (CrC2)alkyl substituted with (C5-C7)heterocycloalkyl and X is NCH3. 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. In various embodiments of each of the embodiments in this paragraph, the substituent is methoxy, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, halo, and methylsulfonyl.
In one embodiment, R2 is (Ci)alkyl substituted with (C5-C7)heterocycloalkyl and X is S. In another embodiment, R2 is (Ci)alkyl substituted with (C5-C7)heterocycloalkyl and X is O. In another embodiment, R2 is (Ci)alkyl substituted with (C5-C7)heterocycloalkyl and X is NH. In another embodiment, R2 is (Ci)alkyl substituted with (C5-C7)heterocycloalkyl and X is NCH3. 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. In various embodiments of each of the embodiments in this paragraph, the substituent is methoxy, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, halo, and methylsulfonyl.
According to one aspect of this embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (3d):
Figure imgf000086_0001
(3d), or a pharmaceutically acceptable salt thereof, wherein: each R is H;
R is (Ci-C4)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 R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6;
X is O, NR7 or S; each R is independently selected from the group consisting of halo, -OH, - CH2OH, -NH2, -C≡N, -NO2, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (Ci-C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3- C6)cycloalkyl, (5- or 6-membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, - C(0)OH, -NH-C(0)-NH2, -NH-C(S)-NH2, -SC≡N, -S02NH2, -
COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6-membered)heteroaryl and (C5- C7)heterocycloalkyl; each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl; and
R7 is H or (CrC6)alkyl.
In one embodiment, R is (Ci-C4)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl. In another embodiment, R2 is (Ci-C2)alkyl substituted with (5- or 6- membered)heteroaryl (9-or 10-membered)heteroaryl. In another embodiment, R2 is (Ci)alkyl substituted with (5- or 6-membered)heteroaryl (9-or 10-membered)heteroaryl. In each embodiment of this paragraph, 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. In various embodiments of each of the embodiments in this paragraph, 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.
In some aspects of this 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,
1,3,5-triazinyl, thiophenyl, indolyl, lH-indolyl, 3-H-indolyl and benzo[d][l,3]dioxolyl.
In some embodiments, 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. In one embodiment, the heteroaryl is furyl. In another embodiment, the heteroaryl is thienyl. In another embodiment, the heteroaryl is imidazolyl. In another embodiment, the heteroaryl is pyridyl. In another embodiment, the heteroaryl is lH-indolyl. In another embodiment, the heteroaryl is 3H-indolyl. In another embodiment, the heteroaryl is benzo[d] [l ,3]dioxolyl.
In embodiments in which said (Ci-C4)alkyl is substituted with R6, R6 is halo or (Ci-C6)alkyl. In some embodiments, halo or (Ci-C4)alkyl. In other embodiments, R6 is halo or (Ci-C2)alkyl. In other embodiments, R6 is fluoro. In other embodiments, R6 is methyl.
In some aspects of this embodiment, 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 NCH3.
In one embodiment, R2 is (Ci-C4)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is S. In another embodiment, R2 is (Ci-C4)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is O. In another embodiment, R2 is (Ci-C4)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is NH. In another embodiment, R2 is (Ci-C4)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is NCH3. In each embodiment of this paragraph, 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. In various embodiments of each of the embodiments in this paragraph, the substituent is methoxy, -CH2OH, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, -CH2OH, halo, and methylsulfonyl. In various embodiments of each of the embodiments in this paragraph, 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. 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.
In one embodiment, R2 is (Ci-C2)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is S. In another embodiment, R2 is (Ci-C2)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is O. In another embodiment, R2 is (Ci-C2)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is NH. In another embodiment, R2 is (Ci-C2)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is NCH3. In each embodiment of this paragraph, 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. In various embodiments of each of the embodiments in this paragraph, the substituent is methoxy, -CH2OH, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, -CH2OH, halo, and methylsulfonyl. In various embodiments of each of the embodiments in this paragraph, 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. 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.
In one embodiment, R2 is (Ci)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10- membered)heteroaryl and X is S. In another embodiment, R2 is (Ci)alkyl substituted with (5- or 6- membered)heteroaryl or (9-or 10-membered)heteroaryl and X is O. In another embodiment, R2 is (Ci)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10-membered)heteroaryl and X is NH. In another embodiment, R2 is (Ci)alkyl substituted with (5- or 6-membered)heteroaryl or (9-or 10- membered)heteroaryl and X is NCH3. In each embodiment of this paragraph, 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. In various embodiments of each of the embodiments in this paragraph, the substituent is methoxy, -CH2OH, halo, or methylsulfonyl, or the substituents are independently selected from methoxy, -CH2OH, halo, and methylsulfonyl. In various embodiments of each of the embodiments in this paragraph, 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. 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.
According to one embodiment, the compound of formula (3) is:
Figure imgf000090_0001
4
According to one embodiment, the compound of formula (3) is:
Figure imgf000090_0002
5
According to one embodiment, the compound of formula (3) is:
Figure imgf000090_0003
According to one embodiment, the compound of formula (3) is:
Figure imgf000091_0001
In particular embodiments, compounds 4, 5, 6 or 7 are utilized as a pharmaceutically acceptable salt thereof.
In another particular embodiment, the present disclosure provides a nitroxyl donating compound of the formula (4):
Figure imgf000091_0002
or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
R is (C6-Cio)aryl, (C3-C6)cycloalkyl, (C5-C7)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 R4;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)0R',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and R7 is H or (C C6)alkyl.
In one embodiment, at least one of R1 is H. In another, each R1 is H.
In another embodiment, at least one of R1 is (Ci)alkyl. In another embodiment, each R1 is (d)alkyl.
In some aspects of this embodiment, X is S. In other aspects, X is O. In other aspects, X is NH. In other aspects, X is N(CrC6)alkyl. In other aspects, X is NCH3.
In one embodiment, at least one R1 is H and X is S. In another embodiment, at least one R1 is H and X is O. In another embodiment, at least one R1 is H and X is NH. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In another embodiment, each R1 is H and X is S. In another embodiment, each R1 is H and X is O. In another embodiment, each R1 is H and X is NH. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3.
In one embodiment, at least one of R1 is (Ci)alkyl and X is S. In another embodiment, at least one of R1 is (Ci)alkyl and X is O. In another embodiment, at least one of R1 is (Ci)alkyl and X is NH. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In another embodiment, each R1 is (Ci)alkyl and X is S. In another embodiment, each R1 is (Ci)alkyl and X is O. In another embodiment, each R1 is (Ci)alkyl and X is NH. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3. In another embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (4a):
Figure imgf000093_0001
or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
X is O, NR7 or S;
R2 is (C6-Cio)aryl, wherein said aryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and
R7 is H or (C C6)alkyl.
In some aspects of this embodiment, at least one of R1 is H. In other aspects, each R1 is H.
In some aspects of this embodiment, at least one of R1 is (Ci)alkyl. In other aspects, each R1 is (Ci)alkyl.
In some aspects of this embodiment, 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 NCH3. 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 R4. In some embodiments, R2 is (C6-Cio)aryl, wherein said aryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, -ON, -N02, -SH, (C C6)alkyl or (C C6)alkoxy. In another embodiment, R2 is (C6-Cio)aryl, wherein said aryl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (CrC6)alkyl or (Cr C6)alkoxy. In another embodiment, R2 is (C6-Ci0)aryl, wherein said aryl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, R2 is unsubstituted (C6-Ci0)aryl. In another embodiment, R2 is (C6-Ci0)aryl substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (CrC6)alkyl or (Cr C6)alkoxy.
In some aspects, R2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (CrC6)alkyl or (Cr C6)alkoxy. In another embodiment, R2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (Cr
C6)alkyl or (Ci-C6)alkoxy. In another embodiment, R2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (d-C6)alkyl or (Cr Ce)alkoxy. In another embodiment, R2 is unsubstituted phenyl. In another embodiment, R2 is phenyl substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (d-C6)alkyl or (Cr C6)alkoxy.
In some embodiments, at least one of R1 is H and R2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, - C≡N, -N02, -SH, (Ci-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, at least one of R1 is H and R2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, at least one of R1 is H and R2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (Cr C6)alkoxy. In another embodiment, at least one of R1 is H and R2 is unsubstituted phenyl. In another embodiment, at least one of R1 is H and R2 is phenyl substituted with 1 substituent selected from halo, - OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy.
In some embodiments, each R1 is H and R2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, -ON, -N02, - SH, (Ci-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, each R1 is H and R2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -ON, -NO2, -SH, (C C6)alkyl or (C C6)alkoxy. In another embodiment, each R1 is H and R2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (C C6)alkyl or (C C6)alkoxy. In another embodiment, each R1 is H and R2 is unsubstituted phenyl. In another embodiment, each R1 is H and R2 is phenyl substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy.
In some embodiments, at least one of R1 is (Ci)alkyl and R2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, - C≡N, -NO2, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, at least one of R1 is (d)alkyl and R2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -ON, -N02, -SH, (Q- Ce)alkyl or (Ci-C6)alkoxy. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is unsubstituted phenyl. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is phenyl substituted with 1 substituent selected from halo, -OH, -NH2, -ON, -N02, -SH, (d-C6)alkyl or (Cr Ce)alkoxy.
In some embodiments, each R1 is (Ci)alkyl and R2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, - ON, -NO2, -SH, (Ci-C6)alkyl or (d-C6)alkoxy. In another embodiment, each R1 is (Ci)alkyl and R2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -ON, -N02, -SH, (C C6)alkyl or (C C6)alkoxy. In another embodiment, each R1 is (Ci)alkyl and R2 is phenyl, wherein said phenyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, each R1 is (Ci)alkyl and R2 is unsubstituted phenyl. In another embodiment, each R1 is (Ci)alkyl and R2 is phenyl substituted with 1 substituent selected from halo, -OH, -NH2, -ON, - N02, -SH, (CrC6)alkyl or (CrC6)alkoxy.
In some embodiments, at least one of R1 is H and X is S. In another embodiment, at least one of R1 is H and X is NH. In another embodiment, at least one of R1 is H and X is O. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3. In some embodiments, each R1 is H and X is S. In another embodiment, each R1 is H and X is NH. In another embodiment, each R1 is H and X is O. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3.
In some embodiments, at least one of R1 is (Ci)alkyl and X is S. In another embodiment, at least one of R1 is (Ci)alkyl and X is NH. In another embodiment, at least one of R1 is (Ci)alkyl and X is O. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In some embodiments, each R1 is (Ci)alkyl and X is S. In another embodiment, each R1 is (Ci)alkyl and X is NH. In another embodiment, each R1 is (Ci)alkyl and X is O. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is
NCH
In another embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (4b):
Figure imgf000096_0001
(4b), or a pharmaceutically acceptable salt thereof, wherein: each R is independently H or (Ci)alkyl;
X is O, NR7 or S;
R is (C3-C6)cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4; each R is independently selected from the group consisting of halo, -OH, -NH2, -C=N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr Ce)alkoxy, (C2-C6)alkenyloxy, (C2-Ce)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and
R7 is H or (CrC6)alkyl.
In some aspects of this embodiment, at least one of R1 is H. In other aspects, each R1 is H.
In some aspects of this embodiment, at least one of R1 is (Ci)alkyl. In other aspects, each R1 is (C alkyl. In some aspects of this embodiment, 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 NCH3.
In some aspects of this embodiment, R2 is (C3-C6)cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R4. In some embodiments, R2 is (C3-C6)cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (Ci-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, R2 is (C3-C6)cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, - C≡N, -N02, -SH, (C C6)alkyl or (CrC6)alkoxy. In another embodiment, R2 is (C3-C6)cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1 substituent selected from halo, - OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, R2 is unsubstituted (C3-C6)cycloalkyl. In another embodiment, R2 is (C3-C6)cycloalkyl substituted with 1 substituent selected from halo, -OH, -NH2, -ON, -N02, -SH, (C C6)alkyl or (CrC6)alkoxy.
In some aspects, R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from R4. In some aspects, R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R4. In some embodiments, R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, -ON, -N02, - SH, (Ci-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -NO2, -SH, (Ci-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, R2 is unsubstituted cyclohexyl. In another embodiment, R2 is cyclohexyl substituted with 1 substituent selected from halo, -OH, -NH2, - C≡N, -NO2, -SH, (Ci-C6)alkyl or (CrC6)alkoxy. In some embodiments, at least one of R1 is H and R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R4. In some embodiments, at least one of R1 is H and R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, - SH, (Ci-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, at least one of R1 is H and R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, at least one of R1 is H and R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (Q- C6)alkyl or (Ci-C6)alkoxy. In another embodiment, at least one of R1 is H and R2 is unsubstituted cyclohexyl. In another embodiment, at least one of R1 is H and R2 is cyclohexyl substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (C C6)alkyl or (CrC6)alkoxy.
In some embodiments, each R1 is H and R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R4. In some embodiments, each R1 is H and R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, -
SH, (Ci-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, each R1 is H and R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (C C6)alkyl or (C C6)alkoxy. In another embodiment, each R1 is H and R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, each R1 is H and R2 is unsubstituted cyclohexyl. In another embodiment, each R1 is H and R2 is cyclohexyl substituted with 1 substituent selected from halo, -OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy.
In some embodiments, at least one of R1 is (Ci)alkyl and R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from R4. In some embodiments, at least one of R1 is (Ci)alkyl and R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, - C=N, -NO2, -SH, (Ci-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -ON, -N02, -SH, (C C6)alkyl or (C C6)alkoxy. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -NO2, -SH, (d- C6)alkyl or (Ci-C6)alkoxy. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is unsubstituted cyclohexyl. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is cyclohexyl substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (CrC6)alkyl or (Cr C6)alkoxy. In some embodiments, each R1 is (Ci)alkyl and R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R4. In some embodiments, each R1 is (Ci)alkyl and R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, - SH, (Ci-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, each R1 is (Ci)alkyl and R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -ON, -N02, -SH, (C C6)alkyl or (C C6)alkoxy. In another embodiment, each R1 is (Ci)alkyl and R2 is cyclohexyl, wherein said cyclohexyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -ON, -N02, -SH, (d-C6)alkyl or (Cr Ce)alkoxy. In another embodiment, each R1 is (Ci)alkyl and R2 is unsubstituted cyclohexyl. In another embodiment, each R1 is (Ci)alkyl and R2 is cyclohexyl substituted with 1 substituent selected from halo, -OH, -NH2, -ON, -N02, -SH, (C C6)alkyl or (C C6)alkoxy.
In some embodiments, at least one of R1 is H and X is S. In another embodiment, at least one of R1 is H and X is NH. In another embodiment, at least one of R1 is H and X is O. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In some embodiments, each R1 is H and X is S. In another embodiment, each R1 is H and X is NH. In another embodiment, each R1 is H and X is O. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3.
In some embodiments, at least one of R1 is (Ci)alkyl and X is S. In another embodiment, at least one of R1 is (Ci)alkyl and X is NH. In another embodiment, at least one of R1 is (Ci)alkyl and X is O. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In some embodiments, each R1 is (Ci)alkyl and X is S. In another embodiment, each R1 is (Ci)alkyl and X is NH. In another embodiment, each R1 is (Ci)alkyl and X is O. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is
NCH
In another embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (4c):
Figure imgf000100_0001
(4c), or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
X is O, NR7 or S;
R is (C5-C7)heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr Ce)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and R7 is H or (Ci-C6)alkyl.
In some aspects of this embodiment, at least one of R1 is H. In other aspects, each R1 is H.
In some aspects of this embodiment, at least one of R1 is (Ci)alkyl. In other aspects, each R1 is (Ci)alkyl. In some aspects of this embodiment, 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 NCH3.
In some aspects of this embodiment, R2 is (C5-C7)heterocycloalkyl, wherein said
heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R4. In some embodiments, R2 is (C5-C7)heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, - C≡N, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, R2 is (C5- C7)heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (CrC6)alkyl or (Cr C6)alkoxy. In another embodiment, R2 is (C5-C7)heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (d- C6)alkyl or (Ci-C6)alkoxy. In another embodiment, R2 is unsubstituted (C5-C7)heterocycloalkyl. In another embodiment, R2 is (C5-C7)heterocycloalkyl substituted with 1 substituent selected from halo, - OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy.
In some aspects, R2 is (C6)heterocycloalkyl, wherein heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R4. In some embodiments, R2 is (C6)heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (d-C6)alkyl or (Cr Ce)alkoxy. In another embodiment, R2 is (C6)heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, - C≡N, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, R2 is (C6)heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1 substituent selected from halo, - OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, R2 is unsubstituted (C6)heterocycloalkyl. In another embodiment, R2 is (C6)heterocycloalkyl substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In some embodiments, at least one of R1 is H and R2 is (C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R4. In some embodiments, at least one of R1 is H and R2 is (C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (d-C6)alkyl or (d-C6)alkoxy. In another embodiment, at least one of R1 is H and R2 is (C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, - SH, (Ci-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, at least one of R1 is H and R2 is
(C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, at least one of R1 is H and R2 is unsubstituted (C6)heterocycloalkyl. In another embodiment, at least one of R1 is H and R2 is (C6)heterocycloalkyl substituted with 1 substituent selected from halo, -OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy.
In some embodiments, each R1 is H and R2 is (C6)heterocycloalkyl, wherein
(C6)heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R4. In some embodiments, each R1 is H and R2 is (C6)heterocycloalkyl, wherein said
(C6)heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, -ON, -N02, -SH, (d-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, each R1 is H and R2 is (C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -ON, -N02, -SH, (Ci-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, each R1 is H and R2 is (C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -ON, -N02, -SH, (C C6)alkyl or (C C6)alkoxy. In another embodiment, each R1 is H and R2 is unsubstituted (C6)heterocycloalkyl. In another embodiment, each R1 is H and R2 is
(C6)heterocycloalkyl substituted with 1 substituent selected from halo, -OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy.
In some embodiments, at least one of R1 is (Ci)alkyl and R2 is (C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R4. In some embodiments, at least one of R1 is (Ci)alkyl and R2 is (C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is (C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (d-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is (C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (d- Ce)alkyl or (Ci-C6)alkoxy. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is unsubstituted (C6)heterocycloalkyl. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is (C6)heterocycloalkyl substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy.
In some embodiments, each R1 is (Ci)alkyl and R2 is (C6)heterocycloalkyl, wherein
(C6)heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R4. In some embodiments, each R1 is (Ci)alkyl and R2 is (C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, each R1 is (Ci)alkyl and R2 is (C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (Ci-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, each R1 is (Ci)alkyl and R2 is
(C6)heterocycloalkyl, wherein said (C6)heterocycloalkyl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (C C6)alkyl or (CrC6)alkoxy. In another embodiment, each R1 is (Ci)alkyl and R2 is unsubstituted (C6)heterocycloalkyl. In another embodiment, each R1 is (Ci)alkyl and R2 is (C6)heterocycloalkyl substituted with 1 substituent selected from halo, -OH, -NH2, -ON, -N02, -SH, (C C6)alkyl or (CrC6)alkoxy.
In some embodiments, at least one of R1 is H and X is S. In another embodiment, at least one of R1 is H and X is NH. In another embodiment, at least one of R1 is H and X is O. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In some embodiments, each R1 is H and X is S. In another embodiment, each R1 is H and X is NH. In another embodiment, each R1 is H and X is O. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3.
In some embodiments, at least one of R1 is (Ci)alkyl and X is S. In another embodiment, at least one of R1 is (Ci)alkyl and X is NH. In another embodiment, at least one of R1 is (Ci)alkyl and X is O. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3. In some embodiments, each R1 is (Ci)alkyl and X is S. In another embodiment, each R1 is (Ci)alkyl and X is NH. In another embodiment, each R1 is (Ci)alkyl and X is O. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is
NCH
In another embodiment, a nitroxyl donating compound of the disclosure is a compound of the formula (4d):
Figure imgf000104_0001
(4d), or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl; X is O, NR7 or S;
R2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr Ce)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and
R7 is H or (C C6)alkyl.
In some aspects of this embodiment, at least one of R1 is H. In other aspects, each R1 is H. In some aspects of this embodiment, at least one of R1 is (Ci)alkyl. In other aspects, each R1 is (Ci)alkyl.
In some aspects of this embodiment, 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 NCH3. In some aspects of this embodiment, R2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R4. In some embodiments, R2 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, -NH2, -C≡N, -N02, - SH, (Ci-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, R2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, R2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, R2 is unsubstituted (5- or 6-membered)heteroaryl. In another embodiment, R2 is (5- or 6- membered)heteroaryl substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (Ci-C6)alkyl or (CrC6)alkoxy.
In some embodiments, at least one of R1 is H and R2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R4. In some embodiments, at least one of R1 is H and R2 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, -NH2, -C≡N, -N02, -SH, (d-C6)alkyl or (d-C6)alkoxy. In another embodiment, at least one of R1 is H and R2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (d- C6)alkyl or (Ci-C6)alkoxy. In another embodiment, at least one of R1 is H and R2 is (5- or 6- membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, at least one of R1 is H and R2 is unsubstituted (5- or 6-membered)heteroaryl. In another embodiment, at least one of R1 is H and R2 is (5- or 6-membered)heteroaryl substituted with 1 substituent selected from halo, -OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In some embodiments, each R1 is H and R2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R4. In some embodiments, each R1 is H and R2 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, -NH2, - C≡N, -N02, -SH, (Ci-C6)alkyl or (d-C6)alkoxy. In another embodiment, each R1 is H and R2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 or 2
substituent(s) independently selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (d-C6)alkyl or (Cr
C6)alkoxy. In another embodiment, each R1 is H and R2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, - N02, -SH, (Ci-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, each R1 is H and R2 is unsubstituted (5- or 6-membered)heteroaryl. In another embodiment, each R1 is H and R2 is (5- or 6- membered)heteroaryl substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy.
In some embodiments, at least one of R1 is (Ci)alkyl and R2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R4. In some embodiments, at least one of R1 is (Ci)alkyl and R2 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, -NH2, -C≡N, -N02, -SH, (d-C6)alkyl or (Cr Ce)alkoxy. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is (5- or 6- membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -ON, -N02, -SH, (C C6)alkyl or (C C6)alkoxy. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (Ci-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is unsubstituted (5- or 6-membered)heteroaryl. In another embodiment, at least one of R1 is (Ci)alkyl and R2 is (5- or 6-membered)heteroaryl substituted with 1 substituent selected from halo, - OH, -NH2, -C≡N, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy.
In some embodiments, each R1 is (Ci)alkyl and R2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from R4. In some embodiments, each R1 is (Ci)alkyl and R2 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, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy. In another embodiment, each R1 is (Ci)alkyl and R2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo, -OH, -NH2, -ON, -N02, -SH, (Ci-C6)alkyl or (Ci-C6)alkoxy. In another embodiment, each R1 is (Ci)alkyl and R2 is (5- or 6- membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 substituent selected from halo, -OH, -NH2, -C≡N, -N02, -SH, (Ci-C6)alkyl or (d-C6)alkoxy. In another embodiment, each R1 is (Ci)alkyl and R2 is unsubstituted (5- or 6-membered)heteroaryl. In another embodiment, each R1 is (Ci)alkyl and R2 is ((5- or 6-membered)heteroaryl substituted with 1 substituent selected from halo, - OH, -NH2, -ON, -N02, -SH, (CrC6)alkyl or (CrC6)alkoxy.
In some embodiments, at least one of R1 is H and X is S. In another embodiment, at least one of R1 is H and X is NH. In another embodiment, at least one of R1 is H and X is O. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In some embodiments, each R1 is H and X is S. In another embodiment, each R1 is H and X is NH. In another embodiment, each R1 is H and X is O. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3.
In some embodiments, at least one of R1 is (Ci)alkyl and X is S. In another embodiment, at least one of R1 is (Ci)alkyl and X is NH. In another embodiment, at least one of R1 is (Ci)alkyl and X is O. In another embodiment, at least one R1 is H and X is N(Ci-C6)alkyl. In another embodiment, at least one R1 is H and X is NCH3.
In some embodiments, each R1 is (Ci)alkyl and X is S. In another embodiment, each R1 is (Ci)alkyl and X is NH. In another embodiment, each R1 is (Ci)alkyl and X is O. In another embodiment, each R1 is H and X is N(Ci-C6)alkyl. In another embodiment, each R1 is H and X is NCH3.
In addition to the compounds of formulae (l)-(4), the present disclosure provides prodrugs thereof. In particular, the present disclosure provides compound of formula (5):
Figure imgf000107_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1, R2 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, -(C5- C7)heterocycloalkyl, benzyloxy, -0-(C C6)alkyl, -NH2, -NH-(C C4)alkyl, or -N((Ci-C4)alkyl)2, wherein said -(Ci-C6)alkyl, -(C2-C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(C5- C7)heterocycloalkyl, benzyloxy, -0-(CrC6)alkyl, -NH-(CrC4)alkyl, or -N((CrC4)alkyl)2 can be unsubstituted or substituted with 1, 2 or 3 substituents selected from halo, -(Ci-C6)alkyl, -(C2- C4)alkenyl, -(C2-C3)alkynyl, -(5- or 6-membered)heteroaryl, -0-(Ci-C6)alkyl, -S-(Ci-C6)alkyl, - C(halo)3, -CH(halo)2, -CH2(halo), -CN, -N02, -NH2, -NH-(CrC4)alkyl, -N(-(CrC4)alkyl)2, -C(0)(Cr C4)alkyl, -C(0)0(CrC4)alkyl, -OC(0)(CrC4)alkyl, -OC(0)NH2, -S(0)(CrC4)alkyl, or -S(0)2(Cr C4)alkyl.
In particular embodiments, 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.
Table 1.
Compound No. mpound Structure Compound Name
5-(N-hydroxylamino)-5-benzyl-N,N- dimethylbarbituric acid
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
1) -
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
4.3 Measuring Nitroxyl Donating Ability
Compounds are easily tested for nitroxyl donation by routine experiments. Although it is typically impractical to directly measure whether nitroxyl is donated, several analytical approaches are accepted as suitable for determining whether a compound donates nitroxyl. For example, 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. After sufficient time for disassociation has elapsed, such as from several minutes to several hours, the headspace gas is withdrawn and analyzed to determine its composition, such as by gas chromatography and/or mass spectrometry. If the gas N20 is formed (which occurs by HNO dimerization), the test is positive for nitroxyl donation and the compound is deemed to be a nitroxyl donor.
Alternatively, 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. The amount of nitroxyl released from the compound of interest can be detected by monitoring the formation of TXPTS aza-ylide by lH 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 for nitroxyl donation.
If desired, nitroxyl donation also can be detected by exposing the test compound to metmyoglobin ("Mb3+ "). See Bazylinski et al., J. Amer. Chem. Soc. 107(26):7982-7986 (1985). Nitroxyl reacts with Mb3+ to form a Mb2+-NO complex, which can be detected by changes in the ultraviolet/visible spectrum or by electron paramagnetic resonance ("EPR"). The Mb2+-NO complex has an EPR signal centered around a g-value of about 2. Nitric oxide, on the other hand, reacts with Mb3+ to form an Mb3+-NO complex that has a negligible, if any, EPR signal. Accordingly, if a compound reacts with Mb3+ to form a complex detectable by common methods, such as
ultraviolet/visible or EPR, then the test is positive for nitroxyl donation.
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. In particular embodiments, a compound donates from about 70% to about 90%) of its theoretical maximum amount of nitroxyl. In particular embodiments, a compound donates from about 85% to about 95% of its theoretical maximum amount of nitroxyl. In particular embodiments, 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. In particular embodiments, 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,
"physiological conditions"). In particular embodiments, 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
embodiments, 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.
It will be understood that 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. In certain embodiments, a compound of the disclosure can donate about 25 mole%> or less of nitric oxide under physiological conditions. In particular embodiments, a compound of the disclosure can donate about 20 mole%> or less of nitric oxide under physiological conditions. In particular embodiments, a compound of the disclosure can donate about 15 mole% or less of nitric oxide under physiological conditions. In particular embodiments, a compound of the disclosure can donate about 10 mole%> or less of nitric oxide under physiological conditions. In particular embodiments, 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.
4.4 Pharmaceutical Compositions
The disclosure encompasses pharmaceutical compositions comprising a nitroxyl donor at least one pharmaceutically acceptable excipient. Examples of 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. The selection and use of pharmaceutically acceptable excipients is taught, e.g., in Troy, Ed., Remington: The Science and Practice of Pharmacy, 21st Ed. (Lippincott Williams & Wilkins,
Baltimore, MD, 2005).
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.
The compounds and pharmaceutical 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. 4.4.1 Compositions for Parenteral Administration
The disclosure provides nitroxyl donating compositions for parenteral (e.g., intravenous) administration. In one embodiment, the pharmaceutical composition is formulated for intravenous administration by continuous infusion.
Various embodiments of pharmaceutical 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.
Pharmaceutical compositions administered parenterally can be administered in an acidic, neutral or basic solution. In one embodiment, 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.
Accordingly, in certain embodiments, 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. In another embodiment, 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 about 5.
To achieve the desired pH of the pharmaceutical composition, an N-hydroxylamino-barbituric acid type nitroxyl donor can be formulated in an aqueous buffer. For example, an N-hydroxylamino- barbituric acid type nitroxyl donor can be formulated in a phosphate or acetate buffer. In particular embodiments, an N-hydroxylamino-barbituric acid type nitroxyl donor is formulated in a potassium phosphate or sodium phosphate buffer. In other embodiments, an N-hydroxylamino-barbituric acid type nitroxyl donor is formulated in a potassium phosphate buffer or sodium phosphate buffer. In other embodiments, 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. For instance, 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).
4.4.2 Compositions for Oral Administration
Pharmaceutical 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. In particular embodiments where the nitroxyl donors are formulated as oral liquid dosage forms, polyethylene glycol (e.g., polyethylene glycol 300 (PEG300) or polyethylene glycol 400 (PEG400)) can usefully serve as an excipient.
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. Methods of formulating such slow or controlled release compositions of pharmaceutically active ingredients, such as the therapeutic agents herein and other compounds known in the art, are known in the art and disclosed in issued U.S. patents, some of which include, but are not limited to, U.S. Pat. Nos. 4,369,174, 4,842,866, and the references cited therein. Coatings can be used for delivery of compounds to the intestine (see, e.g., U.S. Pat. Nos. 6,638,534, 5,217,720, 6,569,457, and the references cited therein). An artisan will recognize that in addition to tablets, other dosage forms can be formulated to provide slow or controlled release of the active ingredient. Such dosage forms include, but are not limited to, capsules, granulations and gel-caps.
4.5 Methods of Using the Compounds and Pharmaceutical Compositions of the
Disclosure
In one aspect, 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. In various embodiments, the patient has, is suspected of having, or is at risk of having or developing a condition that is responsive to nitroxyl therapy. In particular embodiments, 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).
Particular conditions embraced by the methods disclosed herein include, without limitation, cardiovascular diseases, ischemia/reperfusion injury, pulmonary hypertension (PH), alcoholism, vascular dysfunction, and cancer. 4.5.1 Cardiovascular Diseases
In one embodiment, 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.
Examples of 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.
4.5.1.1 Heart Failure
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. In one embodiment, the compounds and compositions of the disclosure can be used to treat acute decompensated heart failure.
In embodiments in which the 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. In one such embodiment, the nitroxyl donor can be administered in conjunction with a positive inotrope such as a beta-agonist. Examples of beta-agonists include, without limitation, dopamine, dobutamine, isoproterenol, analogs of such compounds and derivatives of such compounds. In another embodiment, nitroxyl donor can be administered in conjunction with a ^eia-adrenergic receptor antagonist (also referred to herein as ^eia-antagonist or beta -blocker). Examples of beta- antagonists include, without limitation, propranolol, metoprolol, bisoprolol, bucindolol, and carvedilol.
4.5.1.2 Ischemia/Reperfusion Injury
In another embodiment, 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.
In a particular embodiment, the method is for preventing ischemia/reperfusion injury. In a particular embodiment, a pharmaceutical composition of the disclosure is administered prior to the onset of ischemia. In a particular embodiment, 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. In a particular embodiment, a
pharmaceutical composition of the disclosure is administered after ischemia but before reperfusion. In a particular embodiment, a pharmaceutical composition of the disclosure is administered after ischemia and reperfusion.
In another embodiment, a pharmaceutical composition of the disclosure can be administered to a patient who is at risk for an ischemic event. In a particular embodiment, 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. In a particular embodiment, the patient has had a prior ischemic event. Thus, 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).
In another embodiment, the subject of treatment is an organ that is to be transplanted. In a particular embodiment, a pharmaceutical composition of the disclosure can be administered prior to reperfusion of the organ in a transplant recipient. In a particular embodiment, 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. If 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. In a particular embodiment, the compounds or pharmaceutical compositions of the disclosure are administered by storing the organ in a solution comprising the compound or pharmaceutical composition. For example, a compound or pharmaceutical composition of the disclosure can be included in the organ preservation solution, such as the University of
Wisconsin "UW" solution, which is a solution comprising hydroxyethyl starch substantially free of ethylene glycol, ethylene chlorohydrin and acetone (see U.S. Pat. No. 4,798,824). In a particular embodiment, 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. In a particular embodiment, 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. In various embodiments, the ischemia/reperfusion injury is non-myocardial. In particular embodiments, 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. In another embodiment, 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. The following risk factors for stroke (or a subset of these risk factors) 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. Ingall, Postgrad. Med. 107(6):34-50 (2000). Further, complications of untreated infectious diarrhea in the elderly can include myocardial, renal, cerebrovascular and intestinal ischemia. Slotwiner-Nie et al, Gastroenterol. Clin. N. Amer. 30(3):625-635 (2001). Alternatively, 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. In another embodiment, 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.
4.5.2 Pulmonary Hypertension In another embodiment, a pharmaceutical composition of the disclosure can be used to prevent or delay the onset and/or development of pulmonary hypertension. In one such embodiment, a pharmaceutical composition of the disclosure can be used to prevent or delay the onset and/or development of pulmonary arterial hypertension (PAH).
In another embodiment, 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. In another embodiment, the MPAP is reduced by up to about 50%. In another embodiment, the MPAP is reduced by up to about 25%. In another embodiment, the MPAP is reduced by up to about 20%. In another embodiment, the MPAP is reduced by up to about 15%. In another embodiment, the MPAP is reduced by up to 10%. In another embodiment, the MPAP is reduced by up to about 5%. In another embodiment, the MPAP is reduced to be from about 12 mmHg to about 16 mmHg. In another embodiment, the MPAP is reduced to be about 15 mmHg.
4.6 Administration Modes, Regimens and Dose Levels
The compounds and pharmaceutical compositions of the disclosure can be administered via parenteral {e.g. , subcutaneous, intramuscular, intravenous or intradermal) administration. In certain embodiments, the N-hydroxylamino-barbituric acid type nitroxyl donor useful in a pharmaceutical composition of the disclosure is administered by intravenous infusion. In other embodiments, the compounds and pharmaceutical compositions of the disclosure can be administered by oral administration. When a pharmaceutical composition comprising a compound of the present disclosure is administered, 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.
For intravenous administration, 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.
In various embodiments, 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 μg/kg/min, at least about 0.2 μg/kg/min, at least about 0.3 μg/kg/min, at least about 0.4 μg/kg/min, at least about 0.5 μg/kg/min, at least about 1 μg/kg/min, at least about 2.5 μg/kg/min, at least about 5 μg/kg/min, at least about 7.5 μg/kg/min, at least about 10 μg/kg/min, at least about 11 μg/kg/min, at least about 12 μg/kg/min, at least about 13 μg/kg/min, at least about 14 μg/kg/min, at least about 15 μg/kg/min, at least about 16 μg/kg/min, at least about 17 μg/kg/min, at least about 18 μg/kg/min, at least about 19 μg/kg/min, at least about 20 μg/kg/min, at least about 21 μg/kg/min, at least about 22 μg/kg/min, at least about 23 μg/kg/min, at least about 24 μg/kg/min, at least about 25 μg/kg/min, at least about 26 μg/kg/min, at least about 27 μg/kg/min, at least about 28 μg/kg/min, at least about 29 μg/kg/min, at least about 30 μg/kg/min, at least about 31 μg/kg/min, at least about 32 μg/kg/min, at least about 33 μg/kg/min, at least about 34 μg/kg/min, at least about 35 μg/kg/min, at least about 36 μg/kg/min, at least about 37 μg/kg/min, at least about 38 μg/kg/min, at least about 39 μg/kg/min, or at least about 40 μg/kg/min. In various embodiments, 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 μg/kg/min, no more than about 90 μg/kg/min, no more than about 80 μg/kg/min, no more than about 70 μg/kg/min, no more than about 60 μg/kg/min, no more than about 50 μg/kg/min, no more than about 49 μg/kg/min, no more than about 48 μg/kg/min, no more than about 47 μg/kg/min, no more than about 46 μg/kg/min, no more than about 45 μg/kg/min, no more than about 44 μg/kg/min, no more than about 43 μg/kg/min, no more than about 42 μg/kg/min, no more than about 41 μg/kg/min, no more than about 40 μg/kg/min, no more than about 39 μg/kg/min, no more than about 38 μg/kg/min, no more than about 37 μg/kg/min, no more than about 36 μg/kg/min, no more than about 35 μg/kg/min, no more than about 34 μg/kg/min, no more than about 33 μg/kg/min, no more than about 32 μg/kg/min, no more than about 31 μg/kg/min, or no more than about 30 μg/kg/min In some embodiments, 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 0.1 μg/kg/min to about 100 μg/kg/min, about 1 μg/kg/min to about 100 μg/kg/min, about 2.5 μg/kg/min to about 100 μg/kg/min, about 5 μg/kg/min to about 100 μg/kg/min, about 10 μg/kg/min to about 100 μg/kg/min, about 1.0 μg/kg/min to about 80 μg/kg/min, from about 10.0 μg/kg/min to about 70 μg/kg/min, from about 20 μg/kg/min to about 60 μg/kg/min, from about 15 μg/kg/min to about 50 μg/kg/min, from about 0.01 μg/kg/min to about 1.0 μg/kg/min, from about 0.01 μg/kg/min to about 10 μg/kg/min, from about 0.1 μg/kg/min to about 1.0 μg/kg/min, from about 0.1 μg/kg/min to about 10 μg/kg/min, from about 1.0 μg/kg/min to about 5 μg/kg/min, from about 70 μg/kg/min to about 100 μg/kg/min, or from about 80 μg/kg/min to about 90 μg/kg/min.
In particular embodiments, 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 μg/kg/min to about 50 μg/kg/min, about 20 μg/kg/min to about 40 μg/kg/min, about 25 μg/kg/min to about 35 μg/kg/min, or about 30 μg/kg/min to about 40 μg/kg/min. In particular embodiments, 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 μg/kg/min to about 30 μg/kg/min.
In a variety of embodiments, including various oral administration embodiments, 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).
In certain embodiments, 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/d, at least about 60 mg/kg/d, at least about 70 mg/kg/d, at least about 80 mg/kg/d, at least about 90 mg/kg/d, or at least about 100 mg/kg/d. In certain embodiments, 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.
In a variety of embodiments, 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.
In certain embodiments, 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).
In particular embodiments, 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).
In certain embodiments, 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).
In various embodiments, 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. In various embodiments, 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. In certain embodiments, 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. In certain embodiments, 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. In certain embodiments, 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. In various embodiments, 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.
An 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. In such case, 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. Examples of 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.
It will be appreciated by those in the art that the "effective amount" or "dose" ("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. For example, the appropriate 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.
4.7 Kits Comprising the Compounds or Pharmaceutical Compositions
The disclosure provides kits comprising a compound or a pharmaceutical composition disclosed herein. In a particular embodiment, 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.
Pharmaceutically acceptable liquid diluents are known in the art and include but are not limited to sterile water, saline solutions, aqueous dextrose, glycerol, glycerol solutions, and the like. Other examples of 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).
In one embodiment, 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. In another embodiment, the instructions can be written instructions. In another embodiment, the instructions are contained in an electronic storage medium {e.g. , magnetic diskette or optical disk). In another embodiment, the instructions include information as to the compound or pharmaceutical composition and the manner of administering the compound or pharmaceutical composition to a patient. In another embodiment, 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). In another embodiment, 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. 4.8 Methods of Synthesizing the Compounds
The compounds of this disclosure may be prepared in light of the specification using steps know to those in the art. Scheme 2 depicts a general method for making compounds of formula (1).
Scheme 2.
Figure imgf000129_0001
BA-(l) (1)
Barbituric acid (BA) compound BA-(l) undergoes the nitroso-aldol reaction under standard conditions known to those skilled in the art to give compounds of formula (1). This general method can be followed to prepare compounds of formulae (2)-(4).
Should there be doubt over the agreement of a depicted chemical structure and a chemical name, the chemical name governs.
5. EXAMPLES
The following examples are presented for illustrative purposes and should not serve to limit the scope of the disclosed subject matter.
5.1 Synthesis of Compounds
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. For example, 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).
Example 1: Preparation of S-^-hydroxylaminoJ-S-benzyl-A^-dimethylbarbituric acid (1)
Figure imgf000130_0001
To 5-benzyl-N,N-dimethylbarbituric acid (BA1) (1.231 g, 5 mmol), Angeli's salt (1.22 g, 10 mmol), and powdered DTPA (0.983 g, 2.5 mmol) under nitrogen at room temperature was cannulated a degassed mixture of 50% aqueous ethanol (25 mL). The reaction was allowed to vigorously stir for 10 minutes in order to dissolve all solids followed by normal stirring under a gentle stream of nitrogen for an additional 1.5 hours. At which time, precipitation of a white solid was observed. The reaction was then diluted with ethanol (200 mL) and concentrated to dryness in vacuo with minimum heat (<30 °C). The resultant material was then taken up in dichloromethane (3 x 20 mL), filtered through cotton, and concentrated in vacuo to give 1 as a white solid (1.385 g, 99%). Mp: 155-157 °C. lH NMR (400 MHz, CDC13) δ: 7.26 (m, 3H), 6.96 (m, 2H), 6.28 (d, 1H, J= 3.2 Hz), 4.98 (d, 1H, J= 3.4 Hz, 1H), 3.13 (s, 6H), 3.08 (s, 2H). 13C NMR (100 MHz, CDC13) δ: 170.01, 150.02, 131.75, 129.19, 128.95, 128.71, 73.64, 42.89, 28.78. HR-MS (FAB): found m/z = 278.11411 (MH+); calc. for C13H16N304: 278.11408.
Example 2: Preparation of 5-(Ar-hydroxylamino)-5-(4-methoxybenzyl)-Ar,Ar- dimethylbarbituric acid (2)
/
Figure imgf000131_0001
To 5-(4-methoxybenzyl)-N,N-dimethylbarbituric acid (BA2) (55 mg, 0.2 mmol), Angeli's salt (49 mg, 0.4 mmol), and powdered DTPA (39 mg, 0.1 mmol) under argon at room temperature was added a degassed mixture of 50% aqueous ethanol (1 mL). The reaction was allowed to stir for 1.5 hours, diluted with ethanol (>5 mL), and concentrated to dryness in vacuo with minimum heat (<30 °C). The material was then taken up in dichloromethane, filtered through cotton, and concentrated in vacuo to give 2 as a white solid (61 mg, 99%). Mp: 108-110 °C. lH NMR (400 MHz, CDC13) δ: 6.88 (d, 2H, J= 8.6 Hz), 6.76 (d, 2H, J= 8.7 Hz), 6.25 (br. s, 1H), 5.09 (br. s, 1H), 3.76 (s, 3H), 3.15 (s, 6H), 3.03 (s, 2H). 13C NMR (100 MHz, CDC13) δ: 159.73, 150.11, 130.32, 123.47, 114.27, 73.70, 55.43, 42.08, 28.82. HR-MS (FAB): found m/z = 308.12476 (MH+); calc. for Ci4H18N305: 308.12465.
Example 3: Preparation of 5-(Ar-hydroxylamino)-5-(4-chlorobenzyl)-Ar,Ar- dimethylbarbituric acid (3)
Figure imgf000131_0002
To 5-(4-chlorobenzyl)-N,N-dimethylbarbituric acid (BA3) (56 mg, 0.2 mmol), Angeli's salt (49 mg, 0.4 mmol), and powdered DTPA (39 mg, 0.1 mmol) under argon at room temperature was added a degassed mixture of 50%> aqueous ethanol (1 mL). The reaction was allowed to stir for 1.5 hours, diluted with ethanol (>5 mL), and concentrated to dryness in vacuo with minimum heat (<30 °C). The material was then taken up in dichloromethane, filtered through cotton, and concentrated in vacuo to give 3 as a white solid (61 mg, 99%). Mp: 155-157 °C. lH NMR (400 MHz, CDC13) δ: 7.24 (d, 2H, J= 8.5 Hz), 6.91(d, 2H, J= 8.5 Hz), 6.23 (d, 1H, J= 3.3 Hz), 4.98 (d, 1H, J= 3.3 Hz), 3.17 (s, 6H), 3.06 (s, 2H). 13C NMR (100 MHz, CDC13) δ: 169.96, 149.93, 134.71, 130.60, 130.31, 129.19, 73.14, 41.74, 28.88. HR-MS (FAB): found m/z = 312.07483 (MH+, 35C1), 314.07293 (MH+, 37C1); calc. for Ci3H15ClN304: 312.07511 (MH+, 35C1), 314.07246 (MH+, 37C1).
Example 4: Preparation of S-^-hydroxylaminoJ-S-ethyl-barbituric acid (4)
Figure imgf000132_0001
To 5 -ethyl-barbituric acid (BA4) (0.781 g, 5 mmol), Angeli's salt (1.22 g, 10 mmol), and powdered DTPA (0.983 g, 2.5 mmol) under nitrogen at room temperature was cannulated a degassed mixture of 50% aqueous ethanol (25 mL). The reaction was allowed to vigorously stir for 10 minutes in order to dissolve all solids followed by normal stirring under a gentle stream of nitrogen for an additional 1.5 hours. The reaction was then diluted with ethanol (200 mL), filtered through cotton, and the clear filtrate was concentrated to dryness in vacuo with minimum heat (<30 °C). The resultant material was then triturated with diethylether and filtered to give 4 as a light yellow solid (0.707 g, 76%). Mp: >300 °C. 1H NMR (400 MHz, DMSO-i¾ δ: 11.50 (br. s, 2H), 7.95 (s, 1H), 6.23 (s, 1H), 1.66 (q, 2H, J= 7.5 Hz), 0.73 (t, 3H, J= 7.5 Hz). 13C NMR (100 MHz, DMSO-i¾ δ: 172.07, 149.96, 70.88, 26.92, 7.79. HR-MS (FAB): found m/z = 188.06752 (MH+); calc. for C6H10N3O4: 188.06713 (MH+).
Example 5: Preparation of S-^-hydroxylaminoJ-S-benzyl-barbituric acid (5)
Figure imgf000132_0002
In a solution of 50%> v/v aqueous ethanol (10 mL), 5 -benzyl -barbituric acid (BA5) (0.044 g, 0.2 mmol), N-tert-butoxycarbonyl-hydroxylamine (0.032 g, 0.24 mmol), and potassium carbonate (0.050 g) were dissolved under sonication for 30 minutes at 25 °C. To the solution, sodium periodate (0.051 g, 0.24 mmol) was added and the reaction was allowed to vigorously stir for an additional 2 hours. The reaction mixture was diluted with ethanol (10 mL), filtered and concentrated to dryness in vacuo. The resultant material dissolved in minimum ethanol, filtered thru a short pad of silica, and concentrated to dryness in vacuo to give 5-(N-teri-butoxycarbonyl-hydroxylamino)-5-benzyl-barbituric acid as a white solid (70 mg, 100%). 5-(N-teri-butoxycarbonyl-hydroxylamino)-5-benzyl-barbituric acid (0.040 g, 0.1 1 mmol) was dissolved in a solution of ethanol (2.5 mL) to which concentrated hydrochloric acid was added (1 mL). The solution was left to stand overnight at 4 °C, then diluted with ethanol (20 mL) and concentrated to dryness in vacuo (40 °C). The resultant material was triturated with ether and petroleum ether and filtered to give the HC1 salt of 5 as a white solid (0.009 g, 29%). ¾ NMR (400 MHz, MeOD-i/4) δ: 7.26 (m, 3H), 7.1 1 (m, 2H), 3.08 (2H). 13C NMR (100 MHz, MeOD-i/4) δ: 173.1 1 , 150.78, 133.82, 130.97, 129.89, 129.09, 73.88, 41.65.
Example 6: Preparation of 5-(Ar-hydroxylamino)-5-(4-methoxybenzyl)-barbituric acid
(6)
CH
/
Figure imgf000133_0001
In a solution of 50%> v/v aqueous ethanol (10 mL), 5-(4-methoxybenzyl)-barbituric acid (BA6) (0.050 g, 0.2 mmol), N-teri-butoxycarbonyl-hydroxylamine (0.032 g, 0.24 mmol), and potassium carbonate (0.050 g) were dissolved under sonication for 30 minutes at 25 °C. To the solution, sodium periodate (0.051 g, 0.24 mmol) was added and the reaction was allowed to vigorously stir for an additional 2 hours. The reaction mixture was diluted with ethanol (10 mL), filtered and concentrated to dryness in vacuo. The resultant material dissolved in minimum ethanol, filtered thru a short pad of silica, and concentrated to dryness in vacuo to give 5-(N-teri-butoxycarbonyl-hydroxylamino)-5-(4- methoxybenzyl)-barbituric acid as a white solid (77 mg, 101%). 5-(N-teri-butoxycarbonyl- hydroxylamino)-5-(4-methoxybenzyl)-barbituric acid (0.035 g, 0.09 mmol) was dissolved in a solution of ethanol (2.5 mL) to which concentrated hydrochloric acid was added (1 mL). The solution was left to stand overnight at 4 °C, then diluted with ethanol (20 mL) and concentrated to dryness in vacuo (40 °C). The resultant material was triturated with ether and petroleum ether and filtered to give the HC1 salt of 6 as a white solid (0.012 g, 42%). ¾ NMR (400 MHz, DMSO-i/6) δ: 1 1.35 (s, 2H), 6.92 (d, 2H, J= 8.7 Hz), 6.82 (d, 2H, J= 8.7 Hz), 3.70 (s, 3H), 2.92 (s, 2H). 13C NMR (100 MHz, DMSO-i/6) δ: 171.41, 158.50, 149.36, 130.62, 124.53, 113.90, 71.69, 55.00, 38.45.
Example 7: Preparation of 5-(Ar-hydroxylamino)-5-(4-chlorobenzyl)-barbituric acid (7)
Figure imgf000134_0001
In a solution of 50% v/v aqueous ethanol (10 mL), 5-(4-chlorobenzyl)-barbituric acid (BA7)
(0.050 g, 0.2 mmol), N-tert-butoxycarbonyl-hydroxylamine (0.032 g, 0.24 mmol), and potassium carbonate (0.050 g) were dissolved under sonication for 30 minutes at 25 °C. To the solution, sodium periodate (0.051 g, 0.24 mmol) was added and the reaction was allowed to vigorously stir for an additional 2 hours. The reaction mixture was diluted with ethanol (10 mL), filtered and concentrated to dryness in vacuo. The resultant material dissolved in minimum ethanol, filtered thru a short pad of silica, and concentrated to dryness in vacuo to give 5-(N-tert-butoxycarbonyl-hydroxylamino)-5-(4- chlorobenzyl) -barbituric acid as a white solid (83 mg, 108%). 5-(N-tert-butoxycarbonyl- hydroxylamino)-5-(4-chlorobenzyl)-barbituric acid (0.037 g, 0.10 mmol) was dissolved in a solution of ethanol (2.5 mL) to which concentrated hydrochloric acid was added (1 mL). The solution was left to stand overnight at 4 °C, then diluted with ethanol (20 mL) and concentrated to dryness in vacuo (40 °C). The resultant material was triturated with ether and petroleum ether and filtered to give 7 as a white solid (0.012 g, 42%). ¾NMR (400 MHz, DMSO-i 6) δ: 11.40 (s, 2H), 8.1 (s, 1H), 7.36 (d, 2H, J= 8.4 Hz), 7.02 (d, 2H, J= 8.4 Hz), 6.49 (br. s, 1H), 2.98 (s, 2H). 13C NMR (100 MHz, DMSO-i/6) δ: 171.37, 149.35, 132.20, 132.18, 131.42, 128.47, 71.37, 38.36.
Example 8: Preparation of S-^-hydroxylaminoJ-S-phenyl-barbituric acid (8)
Figure imgf000134_0002
In a solution of 50% v/v aqueous ethanol (50 mL), sodium 5-phenyl-barbiturate (BA8) (2.262 g, 10 mmol), and N-teri-butoxycarbonyl-hydroxylamine (1.598 g, 12 mmol) were dissolved under sonication for 30 minutes at 25 °C. To the solution, sodium periodate (2.567 g, 12 mmol) was added and the reaction was allowed to vigorously stir for an additional 2.5 hours. The reaction mixture was diluted with ethanol (100 mL), filtered and concentrated to dryness in vacuo. 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 solution was left to stand overnight at -20 °C, then diluted with ethanol (100 mL) and concentrated to dryness in vacuo (40 °C). The resulting material was triturated with ether and petroleum ether and filtered to give the HC1 salt of 8 as a white solid (1.1 g, 40% over two steps). ¾ NMR (400 MHz, DMSO-i/6) δ: 1 1.76 (s, 2H), 8.60 (br. s, 2H), 7.38 (m, 5H),. 13C NMR (100 MHz, DMSO-i/6) δ: 170.17, 149.62, 134.1 1 , 129.34, 128.93, 126.53, 73.14.
Example 9: Preparation of S-^-hydroxylaminoJ-S-^-propen-l-ylJ-barbituric acid (9)
Figure imgf000135_0001
In a solution of 50%> v/v aqueous ethanol (50 mL), sodium 5-(2-propen-l -yl)-barbiturate (BA9) (1.901 g, 10 mmol), and N-teri-butoxycarbonyl-hydroxylamine (1.598 g, 12 mmol) were dissolved under sonication for 30 minutes at 25 °C. To the solution, sodium periodate (2.567 g, 12 mmol) was added and the reaction was allowed to vigorously stir for an additional 3 hours. The reaction mixture was diluted with ethanol (100 mL), filtered and concentrated to dryness in vacuo. 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 solution was left to stand overnight at -20 °C, then diluted with ethanol (100 mL) and concentrated to dryness in vacuo (40 °C). The resultant material was dissolved in water (20 mL) and extracted 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). The organic layers were combined, dried over magnesium sulfate, and concentrated to dryness in vacuo. The resulting material was triturated with ether and petroleum ether and filtered to give 9 as a white solid (0.288 g, 14% over two steps). lH NMR (400 MHz, DMSO-i 6) δ: 11.51 (s, 2H), 8.02 (d, 1H, J= 2.4 Hz), 6.31 (d, 1H, J= 2.4 Hz), 5.52 (m, 1H), 5.12 (dd, 1H, J = 2.0, 8.3 Hz), 5.07 (dd, 1H, J = 1.9, 16.8 Hz), 2.42 (d, 2H, J = 7.5 Hz). 13C NMR (100 MHz, DMSO-i/6) δ: 171.56, 149.87, 129.63, 120.86, 69.95, 37.87.
Example 10: Preparation of S-^-hydroxylaminoJ-S-^-methylpropy -barbituric acid
(10)
Figure imgf000136_0001
In a solution of 50% v/v aqueous ethanol (50 mL), sodium 5-(2-methylpropyl)-barbiturate (BA10) (2.152 g, 10 mmol), and N tert-butoxycarbonyl-hydroxylamine (1.598 g, 12 mmol) were dissolved at 25 °C. To the solution, sodium periodate (2.567 g, 12 mmol) was added and the reaction was allowed to vigorously stir for an additional 2 hours. The reaction mixture was diluted with ethanol (100 mL), filtered and concentrated to dryness in vacuo. 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-tert- butoxycarbonyl-hydroxylamino)-5-(2-methylpropyl)-barbituric acid as a white solid. The solid was dissolved in a solution of ethanol (25 mL) to which concentrated hydrochloric acid (6 mL) was added. The solution was left to stand for 1.5 days at -20 °C, diluted with ethanol (100 mL), then concentrated to dryness in vacuo (40 °C). 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). ¾ NMR (400 MHz, DMSO-i 6) δ: 11.54 (s, 2H), 7.99 (d, 1H, J= 2.6 Hz), 6.21 (d, lH, J= 2.6 Hz), 1.62 (d, 2H, J = 6.6 Hz), 1.49 (dq, 1H, J = 6.6, 13 Hz), 0.79 (d, 6H, J = 6.6 Hz). 13C NMR (100 MHz, DMSO-i/6) δ: 172.36, 149.99, 69.24, 41.52, 23.97, 23.28. Example 11: Preparation of S-^-hydroxylaminoJ-S-il-methylethylJ-barbituric acid (11)
Figure imgf000137_0001
In a solution of 50% v/v aqueous ethanol (50 mL), sodium 5-(l -methylethyl)-barbiturate (BA11) (1.922 g, 10 mmol), and N-teri-butoxycarbonyl-hydroxylamine (1.598 g, 12 mmol) were dissolved under sonication for 30 minutes at 25 °C. To the solution, sodium periodate (2.567 g, 12 mmol) was added and the reaction was allowed to vigorously stir for an additional 3 hours. The reaction mixture was diluted with ethanol (100 mL), filtered and concentrated to dryness in vacuo. 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 a white solid, which was triturated with ether and petroleum ether at 0 °C and filtered to give 5-(N-teri-butoxycarbonyl-hydroxylamino)-5-(l-methylethyl)- barbituric acid as a white solid (1.243 g, 41%). The 5-(N-teri-butoxycarbonyl-hydroxylamino)-5-(l- methyl ethyl) -barbituric acid was dissolved in a solution of ethanol (25 mL) to which concentrated hydrochloric acid (10 mL) was added. The solution was left to stand overnight at 4 °C, then diluted with ethanol (100 mL) and concentrated to dryness in vacuo (40 °C). The resultant material was triturated with ether and petroleum ether and filtered to give the HC1 salt of 11 as a white solid (0.448 g, 54%). ¾NMR (400 MHz, DMSO-i/6) δ: 11.91 (s, 2H), 8.10 (br. s, 2H), 2.28 (t, 1H, J= 6.9 Hz), 0.92 (d, 6H, J = 6.8 Hz). 13C NMR (100 MHz, DMSO-i/6) δ: 168.69, 149.60, 73.52, 33.95, 17.02.
Example 12: Preparation of S-^-hydroxylaminoJ-S-il-methylbutylJ-barbituric acid (12)
Figure imgf000137_0002
In a solution of 50%> v/v aqueous ethanol (10 mL), sodium 5 -(1 -methylbutyl) -barbiturate (BA12) (0.440 g, 2 mmol), and N-tert-butoxycarbonyl-hydroxylamine (0.320 g, 2.4 mmol) were dissolved under sonication for 30 minutes at 25 °C. To the solution, sodium periodate (0.513 g, 2.4 mmol) was added and the reaction was allowed to vigorously stir for an additional 4 hours. The reaction mixture was diluted with ethanol (25 mL), filtered and concentrated to dryness in vacuo. The resultant material dissolved in 10 mL of ammonium chloride, extracted with diethyl ether (200 mL), dried over magnesium sulfate, concentrated to dryness in vacuo to give a white solid, which was triturated with ether and petroleum ether, and the solution was left to stand for 2 days at -20 °C and filtered to give 5-(N-teri-butoxycarbonyl-hydroxylamino)-5-(l -methylbutyl)-barbituric acid as a white solid (0.164 g, 25%). 5-(N-teri-butoxycarbonyl-hydroxylamino)-5-(l -methylbutyl)-barbituric acid (0.100 g, 0.3 mmol) was dissolved in a solution of ethanol (2.5 mL) to which concentrated hydrochloric acid was added (1 mL). The solution was left to stand overnight at 4 °C, then diluted with ethanol (20 mL) and concentrated to dryness in vacuo (40 °C). The resultant material was dissolved in ether, triturated with petroleum ether and filtered to give the HC1 salt of 12 as a white solid (0.027 g, 40%). 1H NMR (400 MHz, DMSO-i/6) δ: 1 1.49 (d, 2H, J = 3.6 Hz), 1.96 (m, 1H,), 1.39 (m, 2H), 1.07 (m, 2H), 0.89 (d, 3H, J = 6.8 Hz), 0.81 (t, 3H, J = 7.1 Hz). 13C NMR (100 MHz, DMSO-i/6) δ: 171.80, 149.99, 73.34, 38.37, 32.53, 19.85, 13.84, 13.59.
Example 13: Preparation of S-^-hydroxylaminoJ-S-^-chlorobenzy -barbituric acid
Figure imgf000138_0001
In a solution of 50%> v/v aqueous ethanol (10 mL), 5-(2-chlorobenzyl)-barbituric acid (BA14) (0.050 g, 0.2 mmol), N-teri-butoxycarbonyl-hydroxylamine (0.032 g, 0.24 mmol), and potassium carbonate (0.050 g) were dissolved under sonication for 30 minutes at 25 °C. To the solution, sodium periodate (0.051 g, 0.24 mmol) was added and the reaction was allowed to vigorously stir for an additional 2 hours. The reaction mixture was diluted with ethanol (10 mL), filtered and concentrated to dryness in vacuo. The resultant material dissolved in minimum ethanol, filtered thru a short pad of silica, and concentrated to dryness in vacuo to give 5-(N-teri-butoxycarbonyl-hydroxylamino)-5-(2- chlorobenzyl) -barbituric acid as a white solid (83 mg, 108%). 5-(N-teri-butoxycarbonyl- hydroxylamino)-5-(2-chlorobenzyl)-barbituric acid (0.043 g, 0.1 1 mmol) was dissolved in a solution of ethanol (2.5 mL) to which concentrated hydrochloric acid was added (1 mL). The solution was left to stand overnight at 4 °C, then diluted with ethanol (20 mL) and concentrated to dryness in vacuo (40 °C). The resultant material was triturated with ether and petroleum ether and filtered to give 14 as a white solid (0.019 g, 61%). ¾ NMR (400 MHz, DMSO-i 6) δ: 1 1.44 (s, 2H), 8.1 (s, 1H), 7.27 (m, 4H), 6.46 (br. s, 1H), 3.18 (s, 2H). 13C NMR (100 MHz, DMSO-i/6) δ: 170.79, 149.49, 133.93, 131.94, 131.43, 129.42, 129.17, 127.00, 70.34, 36.18.
Example 14: Preparation of S-^-hydroxylaminoJ-S-^-thienylmethy -barbituric acid
(16)
Figure imgf000139_0001
In a solution of 50% v/v aqueous ethanol (10 mL), 5 -(2-thienylmethyl) -barbituric acid (BA16) (0.448 g, 2 mmol), and N-tert-butoxycarbonyl-hydroxylamine (0.320 g, 2.4 mmol) were dissolved under sonication for 30 minutes at 25 °C. To the solution, sodium periodate (0.513 g, 2.4 mmol) was added and the reaction was allowed to vigorously stir for an additional 2 hours. The reaction mixture was diluted with ethanol (25 mL), filtered and concentrated to dryness in vacuo. The resultant material dissolved in 10 mL of ammonium chloride, extracted with diethyl ether (200 mL), dried over magnesium sulfate, concentrated to dryness in vacuo to give a white solid, which was triturated with ether and petroleum ether and filtered to give 5-(N-tert-butoxycarbonyl-hydroxylamino)-5-(2- thienylmethyl) -barbituric acid as an off-white solid (0.138 g, 19%>). 5-(N-tert-butoxycarbonyl- hydroxylamino)-5-(2-thienylmethyl)-barbituric acid (0.052 g, 0.15 mmol) was dissolved in a solution of ethanol (2.5 mL) to which concentrated hydrochloric acid was added (1 mL). The solution was left to stand overnight at 4 °C, then diluted with ethanol (20 mL) and concentrated to dryness in vacuo (40 °C). The resultant material was dissolved in ether, triturated with petroleum ether and filtered to give 16 as a white solid (0.026 g, 70%). ¾ NMR (400 MHz, DMSO-i 6) δ: 1 1.45 (s, 2H), 8.13 (s, 1H), 7.39 (s, 1H), 6.94 (s, 1H), 6.73 (s, 1H), 6.53 (br. s, 1H), 3.21 (s, 2H). 13C NMR (100 MHz, DMSO-i/6) δ: 171.59, 149.56, 134.24, 127.73, 127.12, 126.02, 71.08, 32.95.
Example 15: Preparation of S-^-hydroxylaminoJ-S-methyl-barbituric acid (17)
Figure imgf000140_0001
In a solution of 50% v/v aqueous ethanol (10 mL), sodium 5 -methyl-barbiturate (BA17) (0.328 g, 2 mmol), and N-teri-butoxycarbonyl-hydroxylamine (0.320 g, 2.4 mmol) were dissolved under vigorous stirring for 30 minutes at 25 °C. To the solution, sodium periodate (0.513 g, 2.4 mmol) was added, and the reaction was allowed to vigorously stir for an additional 2 hours. The reaction mixture was diluted with ethanol (25 mL), filtered and concentrated to dryness in vacuo. The resultant material dissolved in 1 OmL of saturated ammonium chloride, extracted with diethylether (200 mL), dried over magnesium sulfate, and concentrated in vacuo to give a white solid, which was triturated with ether and petroleum ether and filtered to give 5-(N-teri-butoxycarbonyl-hydroxylamino)-5-methyl-barbituric acid as a white solid (0.243 g, 45%). 5-(N-teri-butoxycarbonyl-hydroxylamino)-5-methyl-barbituric acid (0.214 g, 0.8 mmol) was dissolved in a solution of ethanol (5 mL) to which concentrated hydrochloric acid was added (2 mL). The solution was left to stand overnight at 4 °C, then diluted with ethanol (20 mL) and concentrated to dryness in vacuo (40 °C). The resultant material was triturated with ether and petroleum ether and filtered to give the HC1 salt of 17 as a white solid (0.156 g, 45 %). lU NMR (400 MHz, DMSO-i/6) δ: 1 1.78 (s, 2H), 7.56 (br. s, 2H), 1.49 (s, 3H). 13C NMR (100 MHz, DMSO-i/6) δ: 169.32, 149.49, 65.72, 19.20.
Example 16: Preparation of S-^-hydroxylaminoJ-S-il-methylpropylJ-barbituric acid
(18)
Figure imgf000140_0002
In a solution of 50%> v/v aqueous ethanol (10 mL), sodium 5-(l -methylpropyl)-barbiturate (BA18) (0.412 g, 2 mmol), and N-teri-butoxycarbonyl-hydroxylamine (0.320 g, 2.4 mmol) were dissolved under sonication for 30 minutes at 25 °C. To the solution, sodium periodate (0.513 g, 2.4 mmol) was added and the reaction was allowed to vigorously stir for an additional 2 hours. The reaction mixture was diluted with ethanol (25 mL), filtered and concentrated to dryness in vacuo. The resultant material dissolved in 10 mL of saturated ammonium chloride, extracted with diethyl ether (200 mL), dried over magnesium sulfate, and concentrated to dryness in vacuo to give a white solid, which was triturated with ether and petroleum ether and filtered to give 5-(N-feri-butoxycarbonyl- hydroxylamino)-5-(l -methylpropyl)-barbituric acid as a white solid (130 mg, 21%). 5-(N-tert- butoxycarbonyl-hydroxylamino)-5-(l -methylpropyl)-barbituric acid (0.101 g, 0.3 mmol) was dissolved in a solution of ethanol (2.5 mL) to which concentrated hydrochloric acid was added (1 mL). The solution was left to stand overnight at 4 °C, then diluted with ethanol (20 mL) and concentrated to dryness in vacuo (40 °C). The resultant material was triturated with ether and petroleum ether and filtered to give the HC1 salt of 18 as a white solid (0.026 g, 34%). lU NMR (400 MHz, DMSO-i/6) δ: 11.51 (s, 2H), 1.86 (m, 1H), 1.49 (m, 1H), 0.97 (m, 1H), 0.88 (d, 3H, J= 6.9 Hz), 0.81 (t, 3H, J= 7.4 Hz), 0.80 (m, 1H). 13C NMR (100 MHz, DMSO-i/6) δ: 171.49, 149.97, 73.46, 40.47, 23.30, 13.06, 11.84.
5.2 Example 17: Nitroxyl Production, Rate and Half-life Determined via ^ NMR Protocol using TXPTS
The 'H NMR procedure used was based on an HPLC protocol developed by S. Bruce King and co-workers (Reisz ei a/., 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).). According to this procedure, the amount of HNO released from a compound of the disclosure was determined by reacting the compound with a triarylphosphine and monitoring the resulting aza-ylide formation. Scheme 3 shows the conversion of a compound of formula (1) to its corresponding barbituric acid compound "BA-(l)" anion and HNO (trapped as one molecule of aza-ylide and one molecule of phosphine oxide.
Scheme 3
Figure imgf000142_0001
A procedure for determining the amount of HNO released from the compounds of the present disclosure is as follows. In the procedure that follows, the barbituric acid corresponding to a compound is referred to as "BA" followed by the compound number. For example, the barbituric acid corresponding to Compound 1 is referred to as BA1.
Compounds BA1-12, 14 and 16-18 are all known compounds, and were prepared according to literature procedures (Jursic, B. S.; Stevens, E. D. Tet. Lett., 2003, 44, 2203-2210; Lofberg, C; Grigg, R.; Keep, A.; Derrick, A.; Sridharan, V.; Kilner, C. Chem. Commun., 2006, 5000-5002). Tris(4,6- dimethyl-3-sulfanatophenyl)phosphine trisodium salt (TXPTS) was of reagent grade and used without further purification. 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.
All lH NMR spectra were obtained in pH 7.4 solution containing 0.25 M phosphate buffer, 0.2 mM of the metal chelator diethylenetriaminepentaacetic acid (DTP A), and 10 % D20 on a Bruker Avance 400 MHz FT-NMR spectrometer using a 1 second presaturation pulse to suppress the water signal. The data were processed with the academic version of ACDLabs NMR processor software: 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 lH 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.
To an argon-purged NMR solution (1.00 mL) containing TXPTS (3.3 mg, 5 mM) was added 1- 4, 11, 12, and 18 (10 μΐ. of 100 mM in methanol-cLi) to give 1 mM as the initial concentration of 1-4, 11, 12, and 18. The solution was briefly mixed, ca. 0.5 mL was transferred to an argon-purged NMR tube, and the sample was then either (1) externally incubated at 37 °C and lH NMR spectra were collected at regular time intervals or (2) internally incubated at 43 °C and lH NMR spectra were collected using a canned Broker pulse sequence, zg2d, modified to include a 1 second presaturation pulse during the relaxation delay. Table 2 shows the incubation of 1-4, 11, 12, and 18 in pH 7.4 phosphate buffer at 37 °C or 43
°C under argon with added TXPTS. Importantly, no other organic products arising from compounds 1- 4, 11, 12, and 18 are observed.
Table 2.
Figure imgf000143_0001
Figure imgf000144_0001
"Incubation conditions: Compound of the disclosure (1 mM) and TXPTS (5 mM) in 10%
phosphate buffer (0.25 M) with DTPA (0.2 mM) at 37 °C under argon; compounds 1-4 were incubated at 43 °C. *The rates are calculated best fits to a single exponential function of the integrated lH NMR data for disappearance of the compound of the disclosure and appearance of its corresponding barbituric acid (BA) byproduct. HNO yields were determined from the final TXPTS aza-ylide yield. ¾NO yield determined at 43 °C.
The complete decomposition of 1 to give BA1 and HNO-derived TXPTS aza-ylide under physiologically relevant conditions following the lH NMR assay is shown in FIG. la. FIG. lb shows the decompositions of 1, 2, 3, and 4.
5.3 Example 18: Rate and Half-life Determined via UV-vis Protocol using Glutathione
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 μΜ) was added 1-5, 7, 9, and 11-16 (50 μΐ. of 1 mM in methanol) to give ca. 12 μΜ 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.
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 3.
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
"Incubation conditions: Compound of the disclosure (12 μΜ) and glutathione (120 μΜ) in pH 7.4 phosphate buffered saline (0.1 M) with DTPA (0.1 mM) at 37 °C under argon. *The rates are calculated best fits to a single exponential function of the appearance of the corresponding barbituric acid (BA) byproduct. The maximum absorbance of the corresponding BA byproduct under the incubation conditions
5.4 Example 19: Graphical Titration Method for pATa Determination of BA
Compounds
All pH measurements were made using a Fisher Scientific Accumet AB15 Basic pH meter and carried out under ambient conditions at 22 - 25°C. The AB15 glass electrode was calibrated before titration against Fisher Scientific pH 4.00, 7.00, and 10.00 buffer solutions. A stock solution of 200 mM sodium hydroxide was prepared in 50% v/v aqueous ethanol. To 10 mL of 50% v/v aqueous ethanol was added 0.20 mmol of BA byproduct and sonicated for 30 s. The solution was filtered through a cotton plug and titrated with 10 μΐ. increments of the sodium hydroxide stock solution under constant stirring. The pH was recorded after each addition of base. The actual concentration of byproduct in the aqueous ethanol solution does not matter as long as the sodium hydroxide solution is ten times as concentrated to be able to titrate beyond the endpoint without adding a significant volume of solvent.
Table 4 shows the pKa determination for the BA compounds following the graphical titration method. Table 4.
Figure imgf000148_0001
"Determined by titration in 50% v/v aqueous ethanol.
The acidity of the benzyl barbituric acid, BA1, is comparable to benzoic acid. Like 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.)
As such, the rate of decomposition of 1, 2 and 3 correlate with the pKa values of their respective BA byproducts. As the stability of the resultant carbanion increases, so too does the rate of HNO evolution. 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.
5.5 Example 20: UV-vis Method for pATa Determination of Compound 4
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 μΕ of the compound 4 solution. The solution is mixed quickly by rapidly drawing up and dispensing the solution with a pipette.
Absorbance spectra are collected immediately after the solution has mixed and settled.
As shown in FIG. 2b, the ring nitrogen proton of 4 is mildly acidic. With a measured pKa of ca. 7.4, the pKa of 4 as a whole is more acidic than compounds 1-3. The relatively slower
decomposition of 4 is presumably due to slow tautomerization of the HOHN-BA-4 proton to the ring nitrogen anion, since the difference in acidity of these two positions are expected to be ca. 3-4 pKa units, based on the pKa values of 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,
M.; Ambrozak, A.; Hecker, T.; Giitschow, M. J. Org. Chem. 2002, 68, 4684^1692). Also, the expected byproduct of HNO release, BA4 anion, is not observed in the initial spectra of 4 in any of the buffers, and therefore, does not contribute to the absorbance of 4 anion in this UV-vis spectral analysis.
It will be apparent to those in the art that specific embodiments of the disclosed subject matter may be directed to one or more of the above- and below-indicated embodiments
While the invention has been disclosed in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. Therefore, the description and examples should not be construed as limiting the scope of the invention. All references, publications, patents, and patent applications disclosed herein are hereby incorporated by reference in their entirety.

Claims

WHAT IS CLAIMED IS:
1. An 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.
2. The N-hydroxylaminobarbituric acid type compound of claim 1, wherein said compound has a half-life from about 10 minutes to about 4000 minutes when measured under the conditions described in Example 17.
3. The N-hydroxylaminobarbituric acid type compound of claim 1, wherein said compound has a half-life from about 15 minutes to about 3900 minutes when measured under the conditions described in Example 17.
4. The N-hydroxylaminobarbituric acid type compound of claim 1, wherein said compound has a half-life from about 10 minutes to about 200 minutes when measured under the conditions described in Example 18.
5. The N-hydroxylaminobarbituric acid type compound of claim 1, wherein said compound has a half-life from about 12 minutes to about 190 minutes when measured under the conditions described in Example 18.
6. An N-hydroxylaminobarbituric acid type compound, wherein said compound produces a percent yield of ΗΝΟ 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.
7. The N-hydroxylaminobarbituric acid type compound of claim 6, wherein said compound produces a percent yield of ΗΝΟ from about 75% to about 100%> when measured under the conditions described in Example 17.
8. The N-hydroxylaminobarbituric acid type compound of claim 6, wherein said compound produces a percent yield of ΗΝΟ from about 85%> to about 100%) when measured under the conditions described in Example 17.
9. An 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 HNO 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.
10. The N-hydroxylaminobarbituric acid type compound of claim 9, wherein said compound has a half-life from about 10 minutes to about 4000 minutes when measured under the conditions described in Example 17 and said compound produces a percent yield of ΗΝΟ from about 75%) to about 100%) when measured under the conditions described in Example 17.
11. The N-hydroxylaminobarbituric acid type compound of claim 9, wherein said compound has a half-life from about 15 minutes to about 3900 minutes when measured under the conditions described in Example 17 and wherein said compound produces a percent yield of ΗΝΟ from about 85%o to about 100%> when measured under the conditions described in Example 17.
12. The N-hydroxylaminobarbituric acid type compound of claim 9, wherein said compound has a half-life from about 10 minutes to about 200 minutes when measured under the conditions described in Example 17 or Example 18 and said compound produces a percent yield of ΗΝΟ from about 75%> to about 100%> when measured under the conditions described in Example 17.
13. The N-hydroxylaminobarbituric acid type compound of claim 9, wherein said compound has a half-life from about 12 minutes to about 190 minutes when measured under the conditions described in Example 17 or Example 18 and wherein said compound produces a percent yield of ΗΝΟ from about 85% to about 100%> when measured under the conditions described in Example 17.
14. A compound of formula (1):
Figure imgf000152_0001
(1), or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
R2 is (Ci-C6)alkyl substituted with a substituent selected from the group consisting of (C6-Ci4)aryl, (C3-C6)cycloalkyl, (C5-C7)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 R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl; and
R7 is H or (C C6)alkyl. 15. The compound of claim 14, wherein X is O or S;
16. The compound of claim 14 or 15, wherein at least one of R1 is H.
17. The compound of claim 13 or 15 wherein at least one of R1 is (Ci)alkyl.
18. The compound of any one of claims 14-17, wherein each R1 is (Ci)alkyl.
19. The compound of any one of claims 14 or 16-18, wherein X is O.
20. The compound of any one of claims 14 or 16-18, wherein X is S.
21. The compound of any one of claims 14 or 16-18, wherein X is NH.
22. The compound of any one of claims 14-21 , wherein said compound has formula (l a):
Figure imgf000153_0001
(l a), or a pharmaceutically acceptable salt thereof, wherein:
R2 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 R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6.
23. The compound of claim 22, wherein R2 is (Ci)alkyl substituted with (C6-Ci4)aryl, wherein said aryl is unsubstituted or substituted with with 1 , 2, 3, 4 or 5 substituents selected from R4.
24. The compound of claim 22 or 23, wherein said aryl is phenyl.
25. The compound of any one of claims 22-24, wherein R4 is (Ci-C6)alkyl, -OH, (d- C3)alkoxy, -S(0)0(CrC6)alkyl or halo.
26. The compound of claim 14 or 15, wherein said compound has formula (l a-1):
Figure imgf000154_0001
or a pharmaceutically acceptable salt thereof, wherein: each R1 is (Ci)alkyl; each R5 is independently selected from the group consisting of H, halo, -OH, -NH2, - C≡N, -NO2, -SH, =0, =S,
Figure imgf000154_0002
(CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr
C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of H, halo and (Cr C6)alkyl.
27. The compound of claim 26, wherein one or more of R5 is selected from the group consisting of H, -OH, (C C3)alkoxy, S(0)0(CrC6)alkyl and halo.
28. The compound of claim 26 or 27, wherein one or more of R5 is methoxy.
29. The compound of claim 26 or 27, wherein one or more of R5 is CI.
30. The compound of any one of claims 26-29, wherein at least one of R6 is H.
31. The compound of any one of claims 26-29, wherein at least one of R6 is halo. 32. The compound of any one of claims 26-29, wherein at least one of R6 is methyl.
33. The compound of any one of claims 26-32, wherein X is O.
34. The compound of any one of claims 26-32, wherein X is S.
35. The compound of any one of claims 26-32, wherein X is NH.
36. The compound of claim 14 or 15, wherein said compound has formula (la-2):
Figure imgf000155_0001
(la-2), or a pharmaceutically acceptable salt thereof, wherein:
R1 is (Ci)alkyl; each R5 is independently selected from the group consisting of H, halo, -OH, -NH2, - C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Q- C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of H, halo and (Cp
C6)alkyl.
37. The compound of claim 36, wherein one or more of R5 is selected from the group consisting of H, -OH, (C C3)alkoxy, S(0)0(CrC6)alkyl and halo.
38. The compound of claim 36 or 37, wherein one or more of R5 is methoxy.
39. The compound of claim 36 or 37, wherein one or more of R5 is CI.
40. The compound of any one of claim 36-39, wherein at least one of R6 is H.
41. The compound of any one of claim 36-39, wherein at least one of R6 is halo.
42. The compound of any one of claim 36-39, wherein at least one of R6 is methyl.
43. The compound of any one of claim 36-42, wherein X is O.
44. The compound of any one of claim 36-42, wherein X is S.
45. The compound of any one of claim 36-42, wherein X is NH.
46. The compound of any one of claim 14-21, wherein said compound has formula (lb):
Figure imgf000156_0001
(lb), or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
R is (Ci-C6)alkyl substituted with (C3-C6)cycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr Ce)alkoxy, (C2-C6)alkenyloxy, (C2-Ce)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl.
47. The compound of claim 46, wherein R2 is (Ci)alkyl substituted with (C3-C6)cycloalkyl.
48. The compound of claim 46 or 47. wherein said (C3-C6)cycloalkyl is cyclohexyl.
49. The compound of any one of claim 14-21, wherein said compound has formula (lc):
Figure imgf000157_0001
(lc), or a pharmaceutically acceptable salt thereof, wherein:
R2 is (Ci-C6)alkyl substituted with (C5-C7)heterocycloalkyl, wherein said
heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R6; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N,
-N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr
C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl.
50. The compound of claim 49, wherein R is (Ci)alkyl substituted with (C5- C7)heterocycloalkyl.
51. The compound of any one of claims 14-21, wherein said compound has formula (Id):
Figure imgf000158_0001
(Id), or a pharmaceutically acceptable salt thereof, wherein:
R2 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 R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl.
52. The compound of claim 51, wherein R2 is (Ci)alkyl substituted with (5- or 6- membered)heteroaryl.
53. The compound of claim 51 or 52, wherein said heteroaryl is selected from the group consisting of furyl, thienyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,3,5-triazinyl, thiophenyl, and benzo[d][l,3]dioxolyl.
54. The compound of claim 14 having the formula:
Figure imgf000159_0001
or a pharmaceutically acceptable salt thereof.
The compound of claim 14 having the formula:
Figure imgf000159_0002
or a pharmaceutically acceptable salt thereof.
The compound of claim 14 having the formula:
Figure imgf000159_0003
or a pharmaceutically acceptable salt thereof.
57. A compound of formula (2):
Figure imgf000160_0001
or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
R2 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 R4;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and
R7 is H or (C C6)alkyl.
58. The compound of claim 57, wherein X is O or S.
59. The compound of claim 57 or 58, wherein at least one of R1 is H.
60. The compound of claim 57 or 58, wherein at least one of R1 is (Ci)alkyl.
61. The compound of any one of claims 57-60, wherein each R1 is methyl.
62. The compound of any one of claims 57-61, wherein R is selected from the group consisting of z' o-propyl, methylpropyl, sec-butyl, z o-butyl, teri-butyl, methylbutyl, z o-pentyl, methylpentyl, ethylbutyl, dimethylbutyl, and z' o-propylpropyl.
63. The compound of any one of claims 57 or 59-62, wherein X is O.
64. The compound of any one of claims 57 or 59-62, wherein X is S.
65. The compound of any one of claims 57 or 59-62, wherein X is NH.
66. A compound of formula (3):
Figure imgf000161_0001
(3), or a pharmaceutically acceptable salt thereof, wherein: each R is H;
R is selected from the group consisting of (Ci-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl and (Ci-C6)alkoxy, wherein said alkyl, alkenyl, alkynyl and alkoxy are unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, - CH2OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (Ci-C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3- C6)cycloalkyl, (5- or 6-membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, - C(0)OH, -NH-C(0)-NH2, -NH-C(NH)-NH2,-NH-C(S)-NH2, -SON, -S02NH2, - COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6-membered)heteroaryl and (C5- C7)heterocycloalkyl; and
R7 is H or (Ci-C6)alkyl.
67. The compound of claim 66, wherein X is O or S.
68. The compound of claim 66 or 67, wherein R2 is (Ci-C6)alkyl, wherein said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4.
69. The compound of claim 66-68, wherein R2 is methyl, ethyl, propylene, z' o-propyl, methylbutyl, methylpropyl, z o-pentyl or trifluoroethyl.
70. The compound of claim 66 or 67, wherein R2 is selected from the group consisting of a branched (C3-C6)alkyl, branched (C3-C6)alkenyl, and branched (C3-C6)alkoxy, wherein said alkyl, alkenyl, and alkoxy are unsubstituted or substituted with 1, 2 or 3 substituents selected from R4.
71. The compound of any one of claim 66 or 68-70, wherein X is O.
72. The compound of any one of claim 66 or 68-70, wherein X is S.
73. The compound of any one of claim 66 or 68-70, wherein X is NH.
74. The compound of claim 66 or 67, wherein said compound has formula (3 a):
Figure imgf000162_0001
(3a), or a pharmaceutically acceptable salt thereof, wherein:
R is (Ci-C4)alkyl substituted with phenyl, wherein said phenyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6; each R is independently selected from the group consisting of halo, -OH, -NH2, -C=N, -NO2, -SH, =0, =S, =N-(Ci-C4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr Ce)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of halo, -S(0)0(Cr C6)alkyl and (CrC6)alkyl.
75. The compound of claim 74, wherein R2 is (Ci)alkyl substituted with phenyl.
76. The compound of claim 74 or 75, wherein R4 is (Ci-C3)alkoxy or halo.
77. The compound of any one of claim 74-76, wherein X is O.
78. The compound of any one of claim 74-76, wherein X is S.
79. The compound of any one of claim 74-76, wherein X is NH.
80. The compound of claim 66 or 67, wherein said compound has formula (3a- 1):
Figure imgf000163_0001
or a pharmaceutically acceptable salt thereof, wherein: each R5 is selected from the group consisting of H, halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (CrC6)alkoxy, (C2- C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of H, halo and (Cr
C6)alkyl.
81. The compound of claim 80, wherein one or more of R5 is selected from the group consisting of H, -OH, (CrC3)alkoxy, -S(0)0(CrC6)alkyl and halo.
82. The compound of claim 80 or 81, wherein one or more of R5 is methoxy.
83. The compound of claim 80 or 81, wherein one or more of R5 is CI.
84. The compound of any one of claims 80-83, wherein at least one of R6 is H.
85. The compound of any one of claims 80-83, wherein at least one of R6 is halo.
86. The compound of any one of claims 80-83, wherein at least one of R6 is methyl.
87. The compound of any one of claims 80-86, wherein X is O.
88. The compound of any one of claims 80-86, wherein X is S.
89. The compound of any one of claims 83-86, wherein X is NH.
90. The compound of claim 66 or 67, wherein said compound has formula (3b):
Figure imgf000164_0001
(3b), or a pharmaceutically acceptable salt thereof, wherein:
R2 is (Ci-C4)alkyl substituted with (C3-C6)cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl.
91. The compound of claim 90, wherein R2 is (Ci)alkyl substituted with (C3-C6)cycloalkyl.
92. The compound of claim 90 or 91, wherein said (C3-C6)cycloalkyl is cyclohexyl.
93. The compound of any one of claims 90-92, wherein X is O.
94. The compound of any one of claims 90-92, wherein X is S.
95. The compound of any one of claims 90-92, wherein X is NH.
96. The compound of claim 66 or 67, wherein said compound has formula (3c):
Figure imgf000165_0001
(3c), or a pharmaceutically acceptable salt thereof, wherein: R is (Ci-C4)alkyl substituted with (C5-C7)heterocycloalkyl, wherein said
heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4 and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from R6; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl.
97. The compound of claim 96, wherein R2 is (Ci)alkyl substituted with (C5- C7)heterocycloalkyl.
98. The compound of claim 96 or 97, wherein said hetercycloalkyl is a
(C6)heterocycloalkyl selected from the group consisting of piperidinyl, piperazinyl, tetrahydro- oxazinyl, tetrahydropyran, dioxane, morpholine and thiomorpholine.
99. The compound of any one of claims 96-98, wherein X is O.
100. The compound of any one of claims 96-98, wherein X is S.
101. The compound of any one of claims 96-98, wherein X is NH.
102. The compound of claim 66 or 67, wherein said compound has formula (3d):
Figure imgf000166_0001
(3d), or a pharmaceutically acceptable salt thereof, wherein:
R2 is (Ci-C4)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 R4 and said alkyl is unsubstituted or substituted with 1 , 2 or 3 substituents selected from R6; each R4 is independently selected from the group consisting of halo, -OH, - CH2OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (Ci-C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3- C6)cycloalkyl, (5- or 6-membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, - C(0)OH, -NH-C(0)-NH2, -NH-C(S)-NH2, -SC≡N, -S02NH2, -
COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6-membered)heteroaryl and (C5- C7)heterocycloalkyl; and each R6 is independently selected from the group consisting of halo and (Ci-C6)alkyl.
103. The compound of claim 102, wherein R2 is (Ci)alkyl substituted with (5- or 6- membered)heteroaryl.
104. The compound of claim 102 or 103, wherein said 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]dioxolyl.
105. The compound of any one of claims 102-104, wherein X is O.
106. The compound of any one of claims 102-104, wherein X is S.
107. The compound of any one of claims 102-104, wherein X is NH.
108. The compound of claim 66 having the formula:
Figure imgf000168_0001
or a pharmaceutically acceptable salt thereof.
The compound of claim 66 having the formula:
Figure imgf000168_0002
or a pharmaceutically acceptable salt thereof.
The compound of claim 66 having the formula:
Figure imgf000168_0003
or a pharmaceutically acceptable salt thereof.
The compound of claim 66 having the formula:
Figure imgf000169_0001
or a pharmaceutically acceptable salt thereof.
1 12. A compound of formula (4):
Figure imgf000169_0002
(4), or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently H or (Ci)alkyl;
R is (C6-Cio)aryl, (C3-C6)cycloalkyl, (C5-C7)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 R4;
X is O, NR7 or S; each R4 is independently selected from the group consisting of halo, -OH, -NH2, -C≡N, -N02, -SH, =0, =S, =N-(CrC4)alkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr Ce)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C6-Ci4)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl, (C5-C7)heterocycloalkyl, -C(0)H, -C(0)NH2, -C(0)OH, -NH-C(O)- NH2, -NH-C(S)-NH2, -SON, -S02NH2, -COR', -C(0)OR',C(0)NHR', -C(0)NR'R", -NHR', -NR'R", -SR', -S(0)R', -S(0)OR', and -OR', wherein R' and R" are independently selected from (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C14)aryl, (C3-C6)cycloalkyl, (5- or 6- membered)heteroaryl and (C5-C7)heterocycloalkyl; and R7 is H or (Ci-C6)alkyl.
1 13. The compound of claim 1 12, wherein at least one of R1 is H.
1 14. The compound of claim 1 12, wherein at least one of R1 is (Ci)alkyl.
1 15. The compound of claim 1 12, wherein each R1 is (Ci)alkyl.
1 16. The compound of any one of claims 1 12-1 15, wherein X is O.
1 17. The compound of any one of claims 1 12-1 15, wherein X is S.
1 18. The compound of any one of claims 1 12-1 15, wherein X is NH.
1 19. The compound of any one of claims 1 12-1 16, wherein said compound has formula
(4a):
Figure imgf000170_0001
(4a), or a pharmaceutically acceptable salt thereof, wherein:
R2 is (C6-Cio)aryl, wherein said aryl is unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituents selected from R4.
120. The compound of claim 1 19, wherein:
R2 is phenyl unsubstituted or substituted with 1 , 2, 3, 4 or 5 substituents selected from
R4.
121. The compound of claim 120, wherein:
R2 is unsubstituted phenyl. The compound of any one of claims 112-118, wherein said compound has formula
(4b):
Figure imgf000171_0001
(4b), or a pharmaceutically acceptable salt thereof, wherein:
R is (C3-C6)cycloalkyl, wherein said cycloalkyl is unsubstituted or substituted with 1,
2, 3, 4 or 5 substituents selected from R .
The compound of claim 122, wherein R is cyclohexyl.
The compound of any one of claims 112-118, wherein said compound has formula
(4c):
Figure imgf000171_0002
(4c), or a pharmaceutically acceptable salt thereof, wherein:
R is (C5-C7)heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4.
125. The compound of claim 124, wherein R is (C6)heterocycloalkyl. The compound of any one of claims 112-118, wherein said compound has formula
(4d):
Figure imgf000172_0001
(4d), or a pharmaceutically acceptable salt thereof, wherein:
R2 is (5- or 6-membered)heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R4.
127. A compound of formula (5):
Figure imgf000172_0002
(5), or a pharmaceutically acceptable salt thereof, wherein:
R1, R2 and X are as defined in claim 10-122 ; and
R is hydrogen, -(Ci-C6)alkyl, -(C2-C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(C5-C7)heterocycloalkyl, benzyloxy, -0-(CrC6)alkyl, -NH2, -NH-(CrC4)alkyl, or -N((Ci-C4)alkyl)2, wherein said -(Ci-C6)alkyl, -(C2-C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(C5-C7)heterocycloalkyl, benzyloxy, -0-(Ci-C6)alkyl, -NH-(Ci-C4)alkyl, or -N((Ci-C4)alkyl)2 can be unsubstituted or substituted with 1, 2 or 3 substituents selected from halo, -(Ci-C6)alkyl, -(C2-C4)alkenyl, -(C2-C3)alkynyl, -(5- or 6-membered)heteroaryl, -O- (Ci-C6)alkyl, -S-(CrC6)alkyl, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -N02, -NH2, -NH-(Cr C4)alkyl, -N(-(CrC4)alkyl)2, -C(0)(CrC4)alkyl, -C(0)0(CrC4)alkyl, -OC(0)(CrC4)alkyl, - OC(0)NH2, -S(0)(Ci-C4)alkyl, or -S(0)2(CrC4)alkyl.
128. A compound selected from: 5-(N-hydroxylamino)-5-benzyl-N,N-dimethylbarbituric acid;
5-(N-hydroxylamino)-5-(4-methoxybenzyl)-N,N-dimethylbarbituric acid;
5-(N-hydroxylamino)-5-(4-chlorobenzyl)-N,N-dimethylbarbituric acid;
5-(N-hydroxylamino)-5-ethyl-barbituric acid;
5-(N-hydroxylamino)-5-benzyl-barbituric acid; 5-(N-hydroxylamino)-5-(4-methoxybenzyl)-barbituric acid;
5-(N-hydroxylamino)-5-(4-chlorobenzyl)-barbituric acid;
5-(N-hydroxylamino)-5-phenyl-barbituric acid;
5-(N-hydroxylamino)-5-(2-propen-l -yl)-barbituric acid;
5-(N-hydroxylamino)-5-(2-methylpropyl)-barbituric acid; 5-(N-hydroxylamino)-5-(l -methylethyl)-barbituric acid;
5-(N-hydroxylamino)-5-(l -methylbutyl) -barbituric acid;
5-(N-hydroxylamino)-5-phenyl-thiobarbituric acid;
5-(N-hydroxylamino)-5-(2-chlorobenzyl)-barbituric acid;
5-(N-hydroxylamino)-5-(2-furylmethyl)-barbituric acid; 5-(N-hydroxylamino)-5-(2-thienylmethyl)-barbituric acid;
5-(N-hydroxylamino)-5-methyl-barbituric acid;
5-(N-hydroxylamino)-5-(l -methylpropyl)-barbituric acid; 5-(hydroxylamino)-5-(3-methylbutyl) barbituric acid; 5-(hydroxyamino)-2-imino-5-phenyldihydropyrimidine-4,6(lH,5H)-dione; 5-(hydroxylamino)-5-(2,2,2-trifluoroethyl)barbituric acid; 5-(hydroxylamino)-5-(4-(methylsulfonyl)benzyl)barbituric acid 5-(hydroxylamino)-5-(benzo[d] [1 ,3]dioxol-5-ylmethyl)barbituric acid; 5-(hydroxylamino)-5-(pyridin-4-ylmethyl)barbituric acid;
5-(hydroxylamino)-5-(3-ethyl-5-hydroxy-6-methylpyridin-4-ylmethyl)barbituric acid; 5-(hydroxylamino)-5-(3-hydroxy-5-(hydroxylmethyl)-2-methylpyridin-4-ylmethyl)barbituric
Lcid;
5-(hydroxylamino)5-(2-(methylthio)ethyl)barbituric acid; 5-(hydroxyamino)-5-(4-hydroxybenzyl)barbituric acid; 5-((lH-indol-2-yl)methyl)-5-(hydroxyamino)barbituric acid;
2- (5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)acetic acid;
3- (5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propanoic acid
2- (5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)acetamide;
3- (5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propanamide; 5-((lH-imidazol-5-yl)methyl)-5-(hydroxyamino)barbituric acid; 5-(4-aminobutyl)-5-(hydroxyamino)barbituric acid; l-(3-(5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propyl)guanidine; 5-(hydroxylamino)5-(2-(methylthio)ethyl)barbituric acid; 5-(hydroxyamino)-5-(4-hydroxybenzyl)barbituric acid; 5-((lH-indol-2-yl)methyl)-5-(hydroxyamino)barbituric acid;
2- (5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)acetic acid;
3- (5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propanoic acid 2-(5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)acetamide; 3-(5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propanamide; 5-((lH-imidazol-5-yl)methyl)-5-(hydroxyamino)barbituric acid; 5-(4-aminobutyl)-5-(hydroxyamino)barbituric acid; and l-(3-(5-(hydroxyamino)-2,4,6-trioxohexahydropyrimidin-5-yl)propyl)guanidine.
129. A pharmaceutical composition comprising the compound of any one of claims 1-128 and at least one pharmaceutically acceptable excipient.
130. The pharmaceutical composition of claim 129, wherein said pharmaceutical composition is suitable for intravenous administration.
131. A method of treating a cardiovascular disease, comprising administering an effective amount of the compound of any one of claims 1-128 or the pharmaceutical composition of claim 129 or 130 to a patient in need thereof.
132. The method of claim 131, wherein said cardiovascular disease is heart failure.
133. The method of claim 131, wherein said cardiovascular disease is acute decompensated heart failure.
134. The method of any one of claims 131-133, wherein said compound is administered intravenously.
135. Use of a pharmaceutical composition of claim 129 or 130 for the manufacture of a medicament useful for treating a cardiovascular disease.
136. Use of a pharmaceutical composition of claim 129 or 130 for the manufacture of a medicament useful for treating heart failure.
137. Use of a pharmaceutical composition of claim 129 or 130 for the manufacture of a medicament useful for treating acute decompensated heart failure.
138. The pharmaceutical composition of claim 129 or 130 for use in the treatment of heart failure. 139. The pharmaceutical composition of claim 129 or 130 for use in the treatment of acute decompensated heart failure.
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