Nicorandil derivatives

Abstract

Disclosed herein are pyridyl compounds. Also described are certain conjugated nicorandil compounds. Pharmaceutical compositions containing the compounds are also disclosed. Methods of using the pyridyl compounds are disclosed for treating diseases or conditions related to the kidney or kidney function.

Description

[Technical field]

[0001] Technical Field

[0001] Described herein are compounds, pharmaceutical compositions and medicaments containing such compounds for treating diseases or conditions related to the kidney or renal function, as well as methods of using such compounds and compositions. [Background technology]

[0002] 2. Background of the Invention

[0002] Kidney diseases, such as chronic kidney disease, acute renal failure, and acute kidney disease, are major health concerns in the United States. Approximately 20 million people in the United States currently suffer from chronic kidney disease (CKD), and of these, 500,000 will be diagnosed with the most severe form, also known as end-stage renal disease (ESRD). One of the leading causes of chronic and ESRD in the United States is diabetes, which causes approximately 50% of all cases. In addition to diabetes, hypertension and cardiovascular disease remain the leading causes of death for patients with CKD. Similar to CKD, acute kidney injury (AKI), acute renal failure (AKF), and diabetic nephropathy, which ultimately progress to CKD, are also debilitating kidney diseases that affect millions of people in the United States and abroad. AKI is a relatively common condition in intensive care units, occurring in 20%-30% of critically ill patients, with approximately 6% eventually requiring renal replacement therapy (1). The development of AKI leads to increased mortality, prolonged hospital stays, and ultimately increased medical costs (2). In the majority of cases, the epidemiological causes of AKI are multifactorial (e.g., sepsis, ischemia / hyperperfusion), but recent studies have shown that nephrotoxic drugs are a contributing factor in 19%–25% of cases of severe acute renal failure in patients with severe underlying diseases (3, 4). The use of nephrotoxic drugs and the resulting acute kidney injury, also called drug-induced AKI, is a major problem for patients taking drugs such as antibiotics, anticancer agents, and anti-infective agents.

[0003]

[0003] Treatment options for CKD, AKI or AKF range from renal replacement therapy (RRT), transplantation and definitive surgery. Angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) or protein-restricted diets are used in certain conditions to mitigate the effects of these kidney diseases. However, in the majority of cases, the damage is irreversible and the patient must undergo a transplant or spend the rest of their life on dialysis. Below is an overview of drugs currently used or being developed for CKD: Renin inhibitors - Aliskerin, ACE inhibitors - Captopril, Ramipril and Lisinopril, Angiotensin receptor inhibitors - Telmisartan, Losartan, Mineralocorticoid antagonists - Spironolactone, Finerenone, CS-3150 and MT-3995. Drugs targeting glomerular abnormalities such as sulodexide, atrasentan, abatacept, Bis-T-23, rapamycin, lithium and gamma-secretase inhibitors. A large number of drugs are currently in clinical development for the diversity of pathways and targets that cause CKD. These drugs are canagliflozin, pyridolin, ASP8232, baricitinib, CCX140, CTP140, GKT137831, VPI-2690B, GS-4997, PF-04634817, and allopurinol.

[0004]

[0004] Nicorandil is a vasodilator used to treat angina and acute heart failure. It is a nitrate and a K+ ATP channel agonist. In addition to treating angina, nicorandil may be useful in treating renal disease (Lee et al., J. Hypertension 2009, 27, 618-625; Iranirad et al., Cardiology Journal (online) 2017, DOI 10.5603 / cj.a2017.0028; Ko et al., Yonsei Med J. 2013, 54(4), 957-964; Tamura et al., Am. J. Physiol Renal Physiol 2012, 303, 339-349; Nawa et al., Int. J. Cardiology 2015, 195, 228-234; Tanabe et al., Am. J. Physiol Renal Physiol 2012, 302, 151-160; and U.S. Patent Application Publication No. 20110257202). Summary of the Invention [Means for solving the problem]

[0005] Summary of the Invention

[0005] Described herein are pyridyl compounds and pharmaceutical compositions thereof. Also described herein are methods for using the compounds and pharmaceutical compositions to treat kidney-related diseases and conditions.

[0006] Also described herein is the use of pyridyl compounds and pharmaceutical compositions in the treatment of kidney disease or pathology.Further described is a pharmaceutical composition comprising pyridyl compounds.In particular, described herein is a conjugated nicorandil compound that can form nicorandil in vivo and its method of use for treating kidney-related disease and pathology.

[0007]

[0007] Accordingly, in some embodiments, the present invention provides a method for preventing, treating, or ameliorating a disease or condition associated with the kidney or renal function in a mammal, comprising administering to the mammal an effective amount of a compound of the structure: [ka] A compound according to formula (I) having the formula or a pharmaceutical composition thereof (In the formula, X - is a counter ion; Y is -C(H)2-, -O-, or -N(R 3 )- and; R 1 is a substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C3-C7-cycloalkyl, or a substituted or unsubstituted 4- to 7-membered heterocycloalkyl; R 2 is H or C1-C4 alkyl; R 3 is H or a substituted or unsubstituted C1-C4 alkyl; or R 1 and R 3 taken together form a 4- to 7-membered substituted or unsubstituted heterocycloalkyl. The method includes administering

[0008] In some embodiments, the present invention relates to a method for treating a kidney-related disease or condition comprising administering to a subject a therapeutically effective amount of a compound of the structure: [ka] A compound according to formula (I) having the formula (In the formula, X - is a counter ion; Y is -C(H)2-, -O-, or -N(R 3 )- and; R 1 is a substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C3-C7-cycloalkyl, or a substituted or unsubstituted 4- to 7-membered heterocycloalkyl; R 2is H or C1-C4 alkyl; R 3 is H or a substituted or unsubstituted C1-C4 alkyl; or R 1 and R 3 taken together form a 4- to 7-membered substituted or unsubstituted heterocycloalkyl. Provide for the use of.

[0009] In some embodiments, Y is -C(H)2-. In some embodiments, Y is -O-. In some embodiments, Y is -N(R 3 )-. In certain embodiments, Y is -N(H)-.

[0010] In some embodiments, R 2 is H, Me, Et, or i-Pr. In certain embodiments, R 2 is H.

[0011] In some embodiments, R 1 is ethyl substituted with cyclohexyl.

[0012] In some embodiments, R 1 is 2-cyclohexyl-ethyl.

[0013]

[0013] In some embodiments, the disease or condition is chronic kidney disease, diabetic nephropathy, IgA nephropathy, acute renal failure, acute tubular necrosis, transplant-related ischemia, acute kidney disease and types of AKI such as cisplatin-induced AKI, aminoglycoside-induced AKI, tenofovir-induced AKI, contrast nephropathy, AKI after surgery for partial nephrectomy, AKI after kidney transplant, AKI in patients with dialysis, AKI after cardiac surgery, AKI in patients in the ICU, AKI caused by cirrhosis or sepsis and AKI caused by hepatorenal syndrome.

[0014]

[0014] In certain embodiments, the disease or condition is contrast nephropathy.

[0015]

[0015] In certain embodiments, the disease or condition is tenofovir-induced AKI.

[0016] In certain embodiments, the disease or condition is aminoglycoside-induced AKI.

[0017] In certain embodiments, the disease or condition is post-operative AKI.

[0018] In certain embodiments, the disease or condition is AKI in a patient on dialysis.

[0019]

[0019] In certain embodiments, the disease or condition is diabetic nephropathy.

[0020] In a more particular embodiment, the disease or condition is chronic kidney disease or CKD.

[0021] In some embodiments, the compound is [ka] (In the formula, X - , and R 2 is as described herein for formula (I).

[0022] In some embodiments, the compound is [ka] (In the formula, X - , and R 2 is as described herein for formula (I).

[0023] In some embodiments, with respect to formula (IIIa) or (IIIb), R 2 is H or Me. In some embodiments, R 3is H, Me, Et, or i-Pr. In certain embodiments, each R 2 and R 3 , H.

[0024]

[0024] In some embodiments, with respect to formula (IIIa) or (IIIb), the compound is an R-isomer. In some embodiments, with respect to formula (IIIa) or (IIIb), the compound is an S-isomer.

[0025] In some embodiments, the compound is [ka] (In the formula, X - is as described herein for formula (I).

[0026] In some embodiments, the compound is [ka] (In the formula, X - is as described herein for formula (I).

[0027] In some embodiments, the compound is [ka] (In the formula, X - is as described herein for formula (I).

[0028] In some embodiments, the compound is [ka] (In the formula, X - is as described herein for formula (I).

[0029] In some embodiments, X - is Cl - In another embodiment, X - Br - In another embodiment, X - I - In another embodiment, X - is F - In another embodiment, X - is MeSO2O - It is.

[0030]

[0030] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharma ceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprising a compound of formula (I) is formulated for a route of administration selected from oral, parenteral, buccal, nasal, topical, or rectal administration. In some embodiments, the present invention provides a method for treating a disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I). In some embodiments, the disease is selected from chronic kidney disease (CKD), diabetic nephropathy, IgA nephropathy, acute renal failure, acute tubular necrosis, transplant-related ischemia, acute kidney disease, and types of AKI, such as cisplatin-induced AKI, aminoglycoside-induced AKI, tenofovir-induced AKI, contrast nephropathy, AKI after surgery for partial nephrectomy, AKI after kidney transplant, AKI in patients with dialysis, AKI after cardiac surgery, AKI in patients in ICU, AKI caused by cirrhosis or sepsis, and AKI caused by hepatorenal syndrome. In some embodiments, the present invention provides a method for treating CKD disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I). In some embodiments, the disease is diabetic nephropathy. In some embodiments, the disease or condition is acute renal failure (AKI).

[0031]

[0031] In some embodiments, the disease or condition is acute renal failure and types of AKI such as cisplatin-induced AKI, aminoglycoside-induced AKI, tenofovir-induced AKI, contrast nephropathy, AKI after surgery for partial nephrectomy, AKI after kidney transplant, AKI in patients on dialysis, AKI after cardiac surgery, AKI in patients in the ICU, AKI caused by cirrhosis or sepsis, and AKI caused by hepatorenal syndrome.

[0032]

[0032] In some embodiments, the present invention provides a method for treating types of AKI such as chronic kidney disease, diabetic nephropathy, IgA nephropathy, acute renal failure, acute tubular necrosis, transplant-related ischemia, acute kidney disease and AKI such as cisplatin-induced AKI, aminoglycoside-induced AKI, tenofovir-induced AKI, contrast nephropathy, AKI after surgery for partial nephrectomy, AKI after kidney transplant, AKI in patients with dialysis, AKI after cardiac surgery, AKI in patients in the ICU, AKI caused by cirrhosis or sepsis and AKI caused by hepatorenal syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0033]

[0033] It will be understood that one skilled in the art will provide compounds that are chemically stable and can be synthesized by techniques known in the art, not just those described herein.

[0034] In some embodiments, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound herein, or at least one of a pharma- ceutically acceptable salt, a pharma- ceutically active metabolite, a pharma- ceutically acceptable prodrug, or a pharma- ceutically acceptable solvate. In certain embodiments, the compositions provided herein further comprise a pharma- ceutically acceptable diluent, excipient, and / or binder.

[0035] Provided are pharmaceutical compositions containing an effective concentration of one or more of the compounds provided herein, or pharma- ceutically effective derivatives thereof, formulated for administration by a suitable route and means to deliver an amount effective for the treatment, prevention, or amelioration of one or more symptoms of a kidney-related disease, disorder, or condition, the effective amount and concentration being effective for ameliorating any of the symptoms of any of the diseases, disorders, or conditions disclosed herein.

[0036]

[0036] In certain embodiments, provided herein are pharmaceutical compositions containing: i) a physiologically acceptable carrier, diluent, and / or excipient; and ii) one or more compounds provided herein.

[0037]

[0037] In some embodiments, provided herein is a method for treating a kidney-related disease, disorder, or condition in a patient, comprising administering to the patient a therapeutically effective amount of at least one of a compound herein, or a pharma- ceutically acceptable salt, a pharma-ceutically active metabolite, a pharma-ceutically acceptable prodrug, or a pharma-ceutically acceptable solvate.

[0038] In some embodiments, the compounds provided herein are administered to a human.

[0039] In some embodiments, the compounds provided herein are administered orally.

[0040] In some embodiments, the compounds provided herein are used to formulate a medicament for treating a kidney-related disease, disorder, or condition. In some embodiments, the compounds provided herein are used to formulate a medicament for a kidney disease or condition.

[0041]

[0041] An article of manufacture is provided that includes packaging material, a compound or composition provided herein or a pharma- ceutically acceptable derivative thereof effective for treating a renal disease or condition within the packaging material, and a label indicating that the compound or composition, or a pharma- ceutically acceptable salt, pharma- ceutically active metabolite, pharma- ceutically acceptable prodrug, or pharma- ceutically acceptable solvate thereof, is used to treat a renal disease or condition.

[0042] In some embodiments, the present invention provides a method for treating a renal disease or condition in a subject in need thereof by administering to the subject a therapeutically effective amount of a composition comprising at least one compound having the structure of formula (I). In some embodiments, the subject in need thereof suffers from chronic kidney disease, diabetic nephropathy, IgA nephropathy, acute renal failure, acute tubular necrosis, transplant-related ischemia, acute kidney disease, and types of AKI, such as cisplatin-induced AKI, aminoglycoside-induced AKI, tenofovir-induced AKI, contrast nephropathy, AKI after surgery for partial nephrectomy, AKI after kidney transplantation, AKI in patients with dialysis, AKI after cardiac surgery, AKI in patients in ICU, AKI caused by cirrhosis or sepsis, and AKI caused by hepatorenal syndrome.

[0043]

[0043] In some embodiments, the subject in need is suffering from a renal condition or disease, such as chronic kidney disease, diabetic nephropathy, IgA nephropathy, acute renal failure, acute tubular necrosis, transplant-related ischemia, acute kidney disease and types of AKI such as cisplatin-induced AKI, aminoglycoside-induced AKI, tenofovir-induced AKI, contrast nephropathy, AKI after surgery for partial nephrectomy, AKI after kidney transplant, AKI in patients with dialysis, AKI after cardiac surgery, AKI in patients in the ICU, AKI caused by cirrhosis or sepsis and AKI caused by hepatorenal syndrome.

[0044]

[0044] In some embodiments, provided herein is a method for treating a renal disease or condition by administering to a subject in need thereof a therapeutically effective amount of a composition comprising at least one compound having the structure of Formula (I)-(Vb). In some embodiments, the renal disease or condition is chronic kidney disease, diabetic nephropathy, IgA nephropathy, acute renal failure, acute tubular necrosis, transplant-related ischemia, acute kidney disease, and types of AKI, such as cisplatin-induced AKI, aminoglycoside-induced AKI, tenofovir-induced AKI, contrast nephropathy, AKI after surgery for partial nephrectomy, AKI after kidney transplant, AKI in patients with dialysis, AKI after cardiac surgery, AKI in patients in the ICU, AKI caused by cirrhosis or sepsis, and AKI caused by hepatorenal syndrome.

[0045]

[0045] In any of the foregoing embodiments, there are some embodiments in which administration is enteral, parenteral, or both, and in which (a) an effective amount of a provided compound is administered systemically to the mammal; (b) an effective amount of a provided compound is administered orally to the mammal; (c) an effective amount of a provided compound is administered intravenously to the mammal; (d) an effective amount of a provided compound is administered by inhalation; (e) an effective amount of a provided compound is administered by intranasal administration; or (f) an effective amount of a provided compound is administered by injection to the mammal; (g) an effective amount of a provided compound is administered topically (transdermally) to the mammal; (h) an effective amount of a provided compound is administered by ocular administration; or (i) an effective amount of a provided compound is administered rectally to the mammal.

[0046]

[0046] In any of the foregoing embodiments, there are several embodiments that include a single administration of an effective amount of a provided compound, including several embodiments in which (i) a provided compound is administered once; (ii) a provided compound is administered to a mammal multiple times during the day; (iii) continuously; or (iv) continuously.

[0047] In any of the foregoing embodiments, there are some embodiments that include multiple administrations of an effective amount of a provided compound, including some embodiments in which (i) the provided compound is administered in a single dose; (ii) the time between the multiple administrations is every 6 hours; (iii) the provided compound is administered to the mammal every 8 hours. In some embodiments, the method includes a drug holiday, where administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, administration of the compound is resumed. The length of the drug holiday may vary from two days to one year.

[0048]

[0048] Other objects, features and advantages of the methods and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while showing specific embodiments, are given for illustrative purposes only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description. The headings used herein are merely for organizational purposes and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, papers, books, guides, and specialized books, are expressly incorporated herein by reference in their entirety for any purpose. [Brief description of the drawings]

[0049] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]

[0049] 1H NMR of compound A in DMSO-d6 is shown. [Diagram 2]

[0050] The conversion of the compound to nicorandil in rat plasma at various time points is shown. Complete conversion to nicorandil was observed without any traces of compound A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0050] Detailed Description of the Invention Specific Terminology

[0051] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In the event that there is more than one definition of a term in this specification, those in this section shall prevail. When a URL or other identifier or address is mentioned, it is understood that such identifiers may change and specific information on the Internet may come and go, but equivalent information may be found by searching the Internet. Reference thereto evidences the availability and public dissemination of such information.

[0051]

[0052] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to limit any of the subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. The use of the term "including" as well as other forms such as "include," "includes," and "included" are not limiting. Standard definitions of chemistry terms can be found in Carey and Sundberg "Advanced Organic Chemistry 4 thEd.” Vols. A (2000) and B (2001), Plenum Press, New The methods and techniques described herein may be found in references including, for example, Fischer, John Wiley & Sons, Inc., New York. Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology in the art are utilized. Unless specific definitions are provided, the nomenclature used in connection with analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein, and the laboratory procedures and techniques thereof, are those known in the art. Standard techniques may be used for chemical synthesis, chemical analysis, pharmaceutical preparations, formulations, and delivery, and treatment of patients. Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques may be performed, for example, using kits according to manufacturer's specifications, or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures are generally performed according to conventional methods well known in the art and may be as described in the various general and more specific references cited and discussed throughout this specification.

[0052]

[0053] It is understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein, and as such may vary. It is further understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods and compositions described herein, which will be limited only by the scope of the appended claims.

[0053]

[0054] All publications and patents described herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the constructs and methodologies described in the publications that may be used in connection with the methods, compositions and compounds described herein. The publications discussed herein are provided solely for their disclosure prior to the filing date of this application. Nothing herein should be construed as an admission that the inventors described herein are not entitled to antedate such disclosure by virtue of prior invention or for any other reason.

[0054]

[0055] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 15 carbon atoms (e.g., C1-C 15 In certain embodiments, alkyl is an alkyl group having 1 to 13 carbon atoms (e.g., C1 to C 13 In certain embodiments, an alkyl group contains 1 to 8 carbon atoms (e.g., C1 to C8 alkyl). In some embodiments, an alkyl group contains 5 to 15 carbon atoms (e.g., C5 to C6 alkyl). 15 In certain embodiments, an alkyl group includes 5-8 carbon atoms (e.g., C5-C8 alkyl). An alkyl group is attached to the remainder of the molecule by a single bond and is, for example, methyl (Me), ethyl (Et), n-propyl (n-pr), 1-methylethyl (iso-propyl or i-Pr), n-butyl (n-Bu), n-pentyl, 1,1-dimethylethyl (t-butyl, or t-Bu), 3-methylhexyl, 2-methylhexyl, and the like. Unless otherwise specifically stated herein, an alkyl group is defined below and herein, and is optionally substituted as described.

[0055]

[0056] The alkyl group can also be a "lower alkyl" having one to six carbon atoms.

[0056]

[0057] As used herein, C1-C x is C1~C2, C1~C3...C1~Cx Includes.

[0057]

[0058] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from 2 to 12 carbon atoms. In certain embodiments, an alkenyl contains from 2 to 8 carbon atoms. In some embodiments, an alkenyl contains from 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond, and is, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless otherwise specifically stated herein, an alkenyl group is defined below and herein, and is optionally substituted as described.

[0058]

[0059] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, and having from 2 to 12 carbon atoms. In certain embodiments, an alkynyl contains from 2 to 8 carbon atoms. In some embodiments, an alkynyl has from 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule by a single bond, and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless otherwise specifically stated herein, alkynyl groups are defined below and herein, and are optionally substituted as described.

[0059]

[0060] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing no unsaturation, having 1 to 12 carbon atoms, linking the remainder of the molecule to a radical group, such as methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon in the alkylene chain or through any two carbons within the chain. Unless otherwise specifically stated herein, alkylene chains are defined below and herein and are optionally substituted as described.

[0060]

[0061] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing at least one saturated double bond, having 2 to 12 carbon atoms, linking the remainder of the molecule to a radical group, such as ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a double bond or a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless otherwise specifically stated herein, the alkenylene chain is optionally substituted as defined and described below and herein. "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon of 6 to 18 carbon atoms, and at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic delocalized (4n+2) π-electron system according to the Hückel theory. Aryl groups include, but are not limited to, groups such as phenyl (Ph), fluorenyl, and naphthyl. Unless otherwise specifically stated herein, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is intended to include aryl radicals, optionally substituted as defined and described below and herein.

[0061]

[0062] "Aralkyl" is a group of the formula R c R refers to the aryl radical. c is an alkylene chain as defined above, e.g., benzyl, diphenylmethyl, etc. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0062]

[0063] "Aralkenyl" is a group of the formula -R d R refers to the aryl radical.d is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as defined above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0063]

[0064] "Aralkynyl" refers to a group of the formula -R e R refers to the aryl radical. e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as defined above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0064]

[0065] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, having 3 to 15 carbon atoms. In certain embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In some embodiments, a carbocyclyl contains 5 to 7 carbon atoms. A carbocyclyl is attached to the remainder of the molecule by a single bond. A carbocyclyl is optionally saturated (i.e., contains only a single C-C bond) or unsaturated (i.e., contains one or more double or triple bonds). A fully saturated carbocyclyl radical is also referred to as a "cycloalkyl". Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as a "cycloalkenyl". Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise specifically stated herein, the term "carbocyclyl" is intended to include carbocyclyl radicals as defined below and herein, and optionally substituted as described. "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0065]

[0066] The terms "haloalkyl", "haloalkenyl", "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures in which at least one hydrogen has been replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms have been replaced with halogen atoms, the halogen atoms are all the same as one another. In some embodiments in which two or more hydrogen atoms have been replaced with halogen atoms, the halogen atoms are not all the same as one another.

[0066]

[0067] "Fluoroalkyl" refers to an alkyl radical, as defined above, which is substituted by one or more fluoro radicals, as defined above, such as trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0067]

[0068] As used herein, the term "non-aromatic heterocycle", "heterocycloalkyl" or "heteroalicyclic" refers to a non-aromatic ring in which one or more of the atoms forming the ring are heteroatoms. A "non-aromatic heterocycle" or "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The radical may be fused with an aryl or heteroaryl. A heterocycloalkyl ring may be formed by 3 to 14 ring atoms, such as 3, 4, 5, 6, 7, 8, 9, or more than 9 atoms. A heterocycloalkyl ring may be optionally substituted. In certain embodiments, a non-aromatic heterocycle contains one or more carbonyl or thiocarbonyl groups, such as, for example, oxo- and thio-containing groups. Examples of heterocycloalkyls include lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1,3-dioxines, 1,3-dioxanes, 1,4-dioxanes, 1,4-dioxanes, piperazines, 1,3-oxathianes, 1,4-oxathiines, 1,4-oxathianes, tetrahydro-1,4-thiazines, 2H-1,2-oxazines, maleimides, succinimides, barbituric acids, thiobarbituric acids, dioxopiperazines, hydantoins, Examples of heterocycloalkyl groups include, but are not limited to, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane. Illustrative examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles, include: [ka] The term heteroalicyclic also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Depending on the structure, a heterocycloalkyl group can be a monoradical or a diradical (i.e., a heterocycloalkylene group).

[0068]

[0069] "Heteroaryl" refers to a radical derived from a 3-18 membered aromatic ring radical containing 2-17 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic delocalized (4n+2) π-electron system according to the Hückel theory. Heteroaryl includes fused or bridged ring systems. In some embodiments, a heteroaryl ring has 5, 6, 7, 8, 9, or more than 9 ring atoms. The heteroatoms in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryl include azepinyl, acridinyl, benzimidazolyl, benzoindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl,Isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, napthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl Examples of aryl groups include, but are not limited to, thienyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated herein, the term "heteroaryl" is intended to include heteroaryl radicals as defined below and herein, optionally substituted as described.

[0069]

[0070] "N-heteroaryl" refers to a heteroaryl radical as defined above that contains at least one nitrogen and the point of attachment of the heteroaryl radical to the remainder of the molecule is through a nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0070]

[0071] "C-heteroaryl" refers to a heteroaryl radical as defined above, where the point of attachment of the heteroaryl radical to the remainder of the molecule is through a carbon atom in the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0071]

[0072] "Heteroarylalkyl" refers to a group of the formula -R c R refers to the heteroaryl radical. c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0072]

[0073] "Sulfanyl" refers to the -S- radical.

[0073]

[0074] "Sulfinyl" refers to the -S(=O)- radical.

[0074]

[0075] "Sulfonyl" refers to the -S(=O)2- radical.

[0075]

[0076] "Amino" refers to the -NH2 radical.

[0076]

[0077] "Cyano" refers to the -CN radical.

[0077]

[0078] "Nitro" refers to the -NO2 radical.

[0078]

[0079] "Oxa" refers to the --O- radical.

[0079]

[0080] "Oxo" refers to the =O radical.

[0080]

[0081] "Imino" refers to the -NH radical.

[0081]

[0082] "Thioxo" refers to the =S radical.

[0082]

[0083] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is defined above.

[0083]

[0084] An "aryloxy" group refers to an (aryl)O- group, where aryl is defined above.

[0084]

[0085] "Carbocyclylalkyl" means an alkyl radical as defined above substituted with a carbocyclyl group. "Cycloalkylalkyl" means an alkyl radical as defined above substituted with a cycloalkyl group. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

[0085]

[0086] As used herein, the terms "heteroalkyl," "heteroalkenyl," and "heteroalkynyl" include optionally substituted alkyl, alkenyl, and alkynyl radicals in which one or more of the skeletal atoms is a heteroatom, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof. The heteroatom can be placed at any interior position of the heteroalkyl group or at the position at which the heteroalkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2,-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0086]

[0087] The term "heteroatom" refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from, but not limited to, oxygen, sulfur, nitrogen, silicon, and phosphorus. In embodiments where more than one heteroatom is present, the two or more heteroatoms may all be the same as each other, or some or all of the two or more heteroatoms may each be different from the others.

[0087]

[0088] The term "bond," "direct bond" or "single bond" refers to a chemical bond between two atoms, or two moieties, when the atoms connected by the bond are considered to be part of a larger substructure.

[0088]

[0089] An "isocyanato" group refers to a --NCO group.

[0089]

[0090] An "isothiocyanato" group refers to a -NCS group.

[0090]

[0091] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity that is incorporated within or appended to a molecule.

[0091]

[0092] A "thioalkoxy" or "alkylthio" group refers to an --S-alkyl group.

[0092]

[0093] An "alkylthioalkyl" group refers to an alkyl group substituted with an --S-alkyl group.

[0093]

[0094] As used herein, the term "acyloxy" refers to a group of formula RC(=O)O-.

[0094]

[0095] "Carboxy" means the radical -C(O)OH.

[0095]

[0096] As used herein, the term "acetyl" refers to a group of formula -C(=O)CH3.

[0096]

[0097] "Acyl" refers to the group -C(O)R.

[0097]

[0098] As used herein, the term "trihalomethanesulfonyl" refers to a group of formula X3CS(=O)2-- where Y is a halogen.

[0098]

[0099] "Cyanoalkyl" means an alkyl radical, as defined herein, substituted with at least one cyano group.

[0099]

[0100] As used herein, the term "N-sulfonamido" or "sulfonylamino" refers to a group of formula RS(=O)2NH-.

[0100]

[0101] As used herein, the term "O-carbamyl" refers to a group of formula -OC(=O)NR2.

[0101]

[0102] As used herein, the term "N-carbamyl" refers to a group of formula ROC(=O)NH-.

[0102]

[0103] As used herein, the term "O-thiocarbamyl" refers to a group of formula -OC(=S)NR2.

[0103]

[0104] As used herein, "N-thiocarbamyl" refers to a group of formula ROC(=S)NH-.

[0104]

[0105] As used herein, the term "C-amide" refers to a group of formula -C(=O)NR2.

[0105]

[0106] "Aminocarbonyl" refers to the -CONH2 radical.

[0106]

[0107] As used herein, the term "N-amido" refers to a group of formula RC(=O)NH-.

[0107]

[0108] "Hydroxyalkyl" refers to an alkyl radical, as defined herein, substituted with at least one hydroxy group. Non-limiting examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl.

[0108]

[0109] "Alkoxyalkyl" refers to an alkyl radical, as defined herein, substituted with an alkoxy group, as defined herein.

[0109]

[0110] An "alkenyloxy" group refers to an (alkenyl)O- group, where alkenyl is defined above.

[0110]

[0111] The term "alkylamine" refers to an -N(alkyl) x H y refers to the group, where x and y are selected from among x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, together with the N atom to which they are attached, can optionally form a cyclic ring system.

[0111]

[0112] "Alkylaminoalkyl" refers to an alkyl radical, as defined herein, substituted with an alkylamine, as defined herein.

[0112]

[0113] An amide is a chemical moiety having the formula -C(O)NHR or -NHC(O)R, where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). The amide moiety may form a bond between an amino acid or peptide molecule and a compound described herein, thereby forming a prodrug. Any amine or carboxyl side chain on a compound described herein may be amidated. Procedures and specific groups for making such amides are known to those of skill in the art and are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, incorporated herein by reference in its entirety. rd Ed., John Wiley & Sons, New York, NY, 1999.

[0113]

[0114] The term "ester" refers to a chemical moiety having the formula -COOR, where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon). Any hydroxy or carboxyl side chain on the compounds described herein can be esterified. Procedures and specific groups for making such esters are known to those of skill in the art and are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, incorporated herein by reference in its entirety. rd Ed., John Wiley & Sons, New York, NY, 1999.

[0114]

[0115] As used herein, the term "ring" refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryl and cycloalkyl), heterocycles (e.g., heteroaryl and non-aromatic heterocycles), aromatic (e.g., aryl and heteroaryl), and non-aromatic (e.g., cycloalkyl and non-aromatic heterocycles). Rings can be optionally substituted. Rings can be monocyclic or polycyclic.

[0115]

[0116] As used herein, the term "ring system" refers to one or more rings.

[0116]

[0117] The term "membered ring" can include any ring structure. The term "membered" is intended to mean the number of skeletal atoms that constitute the ring. Thus, for example, cyclohexyl, pyridine, pyran, and thiopyran are six-membered rings, and cyclopentyl, pyrrole, furan, and thiophene are five-membered rings.

[0117]

[0118] The term "fused" refers to a structure in which two or more rings share one or more bonds.

[0118]

[0119] As described herein, the compounds of the present invention may be "optionally substituted". In general, the term "substituted", whether preceded by the term "optionally", means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. The combination of substituents envisioned by the present invention is preferably one that results in the formation of a stable or chemically feasible compound. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0119]

[0120] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently: halogen; -(CH) 0~4 R ○ ;-(CH2) 0~4 OR ○ ;-O(CH2) 0~4 R ○ , -O-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 CH(OR ○ )2;-(CH2) 0~4 S.R. ○ ;R ○ may be substituted with -(CH2) 0~4 Ph;R ○ may be substituted with -(CH2) 0~4 O(CH2) 0~1 Ph;R ○ may be substituted with -CH=CHPh; R ○ may be substituted with -(CH2) 0~4 O(CH2) 0~1 -Pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0~4 N(R ○ )2;-(CH2)0~4 N(R ○ )C(O)R ○ ;-N(R ○ )C(S)R ○ ;-(CH2) 0~4 N(R ○ )C(O)NR ○ 2;-N(R ○ )C(S)NR ○ 2;-(CH2) 0~4 N(R ○ )C(O)OR ○ ;-N(R ○ )N(R ○ )C(O)R ○ ;-N(R ○ )N(R ○ )C(O)NR ○ 2;-N(R ○ )N(R ○ )C(O)OR ○ ;-(CH2) 0~4 C(O)R ○ ;-C(S)R ○ ;-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 C(O)SR ○ ;-(CH2) 0~4 C(O)OSiR ○ 3;-(CH2) 0~4 OC(O)R ○ ;-OC(O)(CH2) 0~4 SR-,□SC(S)SR ○ ;-(CH2) 0~4 SC(O)R ○ ;-(CH2) 0~4 C(O)NR ○ 2;-C(S)NR ○ 2;-C(S)SR ○ ;-(CH2) 0~4 OC(O)NR ○ 2;-C(O)N(OR ○ )R ○ ;-C(O)C(O)R ○ ;-C(O)CH2C(O)R ○ ;-C(NOR ○ )R ○ ;-(CH2) 0~4 SSR ○ ;-(CH2)0~4 S(O)2R ○ ;-(CH2) 0~4 S(O)2OR ○ ;-(CH2) 0~4 OS(O)2R ○ ;-S(O)2NR ○ 2;-(CH2) 0~4 S(O)R ○ ;-N(R ○ )S(O)NR ○ 2;-N(R ○ )S(O)2R ○ ;-N(OR ○ )R ○ ;-C(NH)NR ○ 2;-P(O)2R ○ ;-P(O)R ○ 2;-OP(O)R ○ 2;-OP(O)(OR ○ )2;SiR ○ 3;-(C 1~4 Linear or branched alkylene)ON(R ○ )2; or -(C 1~4 Linear or branched alkylene)C(O)ON(R ○ )2, and each R ○ are optionally substituted as defined below and independently represent hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definition, R ○ two independent occurrences of are taken together with their intervening atoms to form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0120]

[0121] R ○ (or R ○ Suitable monovalent substituents on the ring formed by combining two independent occurrences of -(CH) with their intervening atoms are independently halogen, -(CH) 0~2R ● , -(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 S.R. ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1~4 Linear or branched alkylene)C(O)OR ● , or -SSR ● And each R ● is unsaturated or substituted only with one or more halogens, which are preceded by "halo", and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 R is selected from Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ○ Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0121]

[0122] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR *, -O(C(R * 2)) 2~3 O- or -S(C(R * 2)) 2~3 S- is mentioned, R * Each independent occurrence of is hydrogen, C which may be substituted as defined below. 1~6 Aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to adjacent substitutable carbons of the "optionally substituted" group include -O(CR * 2) 2~3 O- and R * Each independent occurrence of is hydrogen, C which may be substituted as defined below. 1~6 It is selected from aliphatic, or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0122]

[0123] R * Suitable substituents on the aliphatic group include halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is unsaturated or substituted only with one or more halogens, which are preceded by "halo", and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0123]

[0124] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R †, -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † Each R † are independently hydrogen, C which may be substituted as defined below 1~6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definitions, R † two independent occurrences of are taken together with their intervening atoms to form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0124]

[0125] R † Suitable substituents on the aliphatic groups are independently halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is unsaturated or substituted only with one or more halogens, which are preceded by "halo", and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0125]

[0126] The term "nucleophile" or "nucleophilic" refers to a compound or portion thereof that is electron-rich.

[0126]

[0127] The term "electrophile" or "electrophilic" refers to an electron-poor or electron-deficient molecule or portion thereof. Examples of electrophiles include, but are in no way limited to, Michael acceptor moieties.

[0127]

[0128] The terms "acceptable" or "pharmaceutical acceptable" as used herein with respect to a formulation, composition, or ingredient means that it does not have any lasting deleterious effects on the general health of the subject being treated or inhibit the biological activity or properties of the compound, and is relatively non-toxic.

[0128]

[0129] As used herein, "amelioration" of symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to a reduction in severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, persistent or transient, that may result from or be associated with the administration of the compound or composition.

[0129]

[0130] "Bioavailability" refers to the percentage of the weight of an administered compound disclosed herein, such as any compound of Formula (I)-(Vb), that is delivered to the systemic circulation of the animal or human being being studied. (0~∞) ) is typically defined as 100% bioavailability (F%). "Oral bioavailability" refers to the extent to which a compound disclosed herein, such as any compound of Formulae (I)-(Vb), is absorbed into the systemic circulation when the pharmaceutical composition is taken orally, as compared to intravenous injection.

[0130]

[0131] "Plasma concentration" refers to the concentration of a compound disclosed herein, such as a compound of any of Formulae (I)-(Vb), in the plasma component of a subject's blood. It is understood that the plasma concentration of a compound of any of Formulae (I)-(Vb) may vary significantly between subjects due to variability in metabolism and / or possible interactions with other therapeutic agents. According to some embodiments disclosed herein, the plasma concentration of a compound of any of Formulae (I)-(Vb) may vary between subjects. Similarly, the maximum plasma concentration (C max ) or maximum plasma concentration (T max ) or the total area under the plasma concentration-time curve (AUC (0~∞) ) may vary from subject to subject. Due to this variability, the amount necessary to constitute a "therapeutically effective amount" of a compound of any of Formulas (I)-(Vb) may vary from subject to subject.

[0131]

[0132] As used herein, the term "co-administration" and the like is meant to encompass the administration of selected therapeutic agents to a single patient, and is intended to include therapeutic regimens in which agents are administered by the same or different routes of administration, or at the same time or at different times.

[0132]

[0133] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an agent or compound being administered that will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" used in therapy is the amount of a composition containing a compound disclosed herein that is necessary to provide a clinically significant reduction in disease symptoms without undue adverse side effects. An appropriate "effective amount" in any individual case can be determined using techniques such as dose escalation studies. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a compound disclosed herein is an amount effective to achieve a desired pharmacological effect or therapeutic improvement without undue adverse side effects. It is understood that an "effective amount" or a "therapeutically effective amount" may vary from subject to subject, depending on variations in metabolism of any of the compounds of Formulae (I)-(Vb), the age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, a therapeutically effective amount may be determined by routine experimentation, including, but not limited to, a dose escalation clinical trial.

[0133]

[0134] The term "enhance" or "enhancing" means to increase or prolong a desired effect, either in potency or duration. As an example, "enhancing" the effect of a therapeutic agent refers to the ability to increase or prolong, either in potency or duration, the effect of the therapeutic agent during the treatment of a disease, disorder or condition. As used herein, an "enhancing effective amount" refers to an amount sufficient to enhance the effect of a therapeutic agent in the treatment of a disease, disorder or condition. When used in a patient, the amount effective for this use will depend on the severity and duration of the disease, disorder or condition, previous therapy, the patient's health status and response to the drug, and the judgment of the treating physician.

[0134]

[0135] The term "identical" as used herein refers to two or more sequences or subsequences that are the same. In addition, the term "substantially identical" as used herein refers to two or more sequences that have a percentage of sequence units that are the same when compared and aligned for maximum correspondence over a comparison window, or named region, as measured using a comparison algorithm or by manual alignment and visual inspection. For illustrative purposes only, two or more sequences can be "substantially identical" if the sequence units are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical to a specified region. Such percentages are used to describe the "percent identity" of two or more sequences. The identity of the sequences can exist over a region of at least about 75-100 sequence units in length, over a region of about 50 sequence units in length, or over the entire sequence if not specified. This definition also refers to the complementary strand of a test sequence. For purposes of illustration only, two or more polypeptide sequences are identical when the amino acid residues are the same, while two or more polypeptide sequences are "substantially identical" if the amino acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical to a specified region. Identity can exist over a region that is at least about 75-100 amino acids in length, over a region that is about 50 amino acids in length, or, if not specified, over the entire sequence of the polypeptide sequence. In addition, for purposes of illustration only, two or more polynucleotide sequences are identical when the nucleic acid residues are the same, while two or more polynucleotide sequences are "substantially identical" if the nucleic acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical to a specified region. The identity can exist over a region that is at least about 75-100 nucleic acids in length, over a region that is about 50 nucleic acids in length, or, if not specified, over the entire sequence of the polynucleotide sequence.

[0135]

[0136] The term "isolated" as used herein refers to the separation and removal of a component of interest from components that are not of interest. An isolated material may be in either a dry or semi-dry state, or in a solution, including but not limited to an aqueous solution. An isolated component may be in a homogenous state, or the isolated component may be part of a pharmaceutical composition that includes additional pharma-ceutically acceptable carriers and / or excipients. By way of example only, a nucleic acid or protein is "isolated" when such nucleic acid or protein is free of at least some of the cellular components with which it is naturally associated, or when the nucleic acid or protein is concentrated to a level that exceeds the concentration of its in vivo or in vitro production. Also, by way of example, a gene is isolated when it is separated from open reading frames adjacent to the gene and that encode proteins other than the gene of interest.

[0136]

[0137] A "metabolite" of a compound disclosed herein is a derivative of the compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized" as used herein refers to the totality of processes by which a particular substance is changed by an organism, including but not limited to enzyme-catalyzed reactions such as hydrolysis and oxidation reactions. Thus, an enzyme may cause a particular structural change to a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolites may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified either by administering the compounds to a host and analyzing tissue samples from the host, or by incubating the compounds with hepatocytes in vitro and analyzing the resulting compounds. Both methods are well known in the art. In some embodiments, metabolites of the compounds are formed by oxidation processes and correspond to the corresponding hydroxy-containing compounds. In some embodiments, the compounds are metabolized to pharmacologically active metabolites.

[0137]

[0138] The term "modify," as used herein, means to interact with a target directly or indirectly to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0138]

[0139] As used herein, the term "modifier" refers to a compound that changes the activity of a molecule. For example, a modifier can result in an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modifier. In certain embodiments, a modifier is an inhibitor that reduces the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modifier is an activator that increases the magnitude of at least one activity of a molecule. In certain embodiments, the presence of a modifier results in an activity that does not occur in the absence of the modifier.

[0139]

[0140] The term "prophylactically effective amount," as used herein, refers to the amount of a composition applied to a patient that will relieve to some extent one or more of the symptoms of the disease, condition, or disorder being treated. In such prophylactic applications, such amounts may depend on the patient's health status, weight, and the like. It is considered well within the skill of one of ordinary skill in the art to determine such prophylactically effective amounts by routine experimentation, including, but not limited to, dose escalation clinical trials.

[0140]

[0141] As used herein, the term "selective binding compound" refers to a compound that selectively binds to any portion of one or more target proteins.

[0141]

[0142] As used herein, the term "selectively binds" refers to the ability of a selectively binding compound to bind to a target protein with higher affinity than it binds to a non-target protein. In certain embodiments, specific binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, 1000 times greater than the affinity for the non-target.

[0142]

[0143] As used herein, the term "selective modulator" refers to a compound that selectively modulates a target activity relative to a non-target activity. In certain embodiments, a specific modulator refers to modifying a target activity at least 10, 50, 100, 250, 500, 1000 times or more over a non-target activity.

[0143]

[0144] The term "substantially purified" as used herein refers to a component of interest that may be substantially or essentially free of other components that normally accompany or interact with the component of interest prior to purification. By way of example only, a component of interest may be "substantially purified" when a preparation of the component of interest contains less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% (by dry weight) of contaminating components. Thus, a "substantially purified" component of interest may have a purification level of about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or more.

[0144]

[0145] The term "subject" or "patient," as used herein, refers to an animal that is the object of treatment, observation, or experiment. By way of example only, the subject can be, but is not limited to, a mammal, including, but not limited to, a human.

[0145]

[0146] As used herein, the term "target activity" refers to a biological activity that can be regulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzyme activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or condition.

[0146]

[0147] As used herein, the term "target protein" refers to a molecule or portion of a protein capable of being bound by a selective binding compound.

[0147]

[0148] The terms "treat", "treating" or "treatment" as used herein include reducing, lowering or ameliorating the symptoms of a disease or condition, preventing further symptoms, ameliorating or preventing the underlying metabolic cause of the symptoms, inhibiting a disease or condition, e.g., arresting the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating conditions caused by a disease or condition, or halting the symptoms of a disease or condition. The terms "treat", "treating" or "treatment" include, but are not limited to, prophylactic and / or therapeutic treatment.

[0148]

[0149] As used herein, IC 50 refers to the amount, concentration or dose of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.

[0149]

[0150] As used herein, EC 50 refers to the dose, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of the maximal expression of a particular response induced, elicited or enhanced by the particular test compound.

[0150]

[0151] The methods described herein include administering to a subject in need thereof a therapeutically effective amount of a composition containing one or more compounds described herein.

[0151]

[0152] Several animal models are useful for establishing the therapeutically effective dose range of the Pyridyl Compounds for treating any of the aforementioned diseases.

[0152]

[0153] For example, dosing of Pyridyl Compounds for treating renal disease can be evaluated in a rat model as described herein.

[0153]

[0154] The therapeutic efficacy of a provided compound for one of the aforementioned diseases can be optimized during the treatment period.

[0154] compound

[0155] In the following description of pyridyl compounds suitable for use in the methods described herein, definitions of standard chemical terms referenced may be found in references including Carey and Sundberg "Advanced Organic Chemistry 4th Ed." Vols. A (2000) and B (2001), Plenum Press, New York (unless otherwise defined herein). Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology within the ordinary skill of the art are utilized unless specific definitions are provided, and the nomenclature used in connection with analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein, as well as the laboratory procedures and techniques thereof, are those known in the art. Standard techniques may be used for chemical synthesis, chemical analysis, pharmaceutical preparations, formulations, and delivery, and for the treatment of patients.

[0155]

[0156] The pyridyl compounds may be used for the manufacture of a medicament for treating any of the aforementioned pathologies, including chronic kidney disease, diabetic nephropathy, IgA nephropathy, acute renal failure, acute tubular necrosis, transplant-related ischemia, acute kidney disease, and types of AKI, such as cisplatin-induced AKI, aminoglycoside-induced AKI, tenofovir-induced AKI, contrast nephropathy, AKI after surgery for partial nephrectomy, AKI after kidney transplantation, AKI in patients with dialysis, AKI after cardiac surgery, AKI in patients in the ICU, AKI caused by cirrhosis or sepsis, and AKI caused by hepatorenal syndrome.

[0156]

[0157] Described herein are compounds of any of formulas (I)-(Vb). Also described herein are pharma-ceutically acceptable salts, pharma-ceutically acceptable solvates, pharma-ceutically acceptable metabolites, and pharma-ceutically acceptable prodrugs of such compounds. Provided are pharmaceutical compositions comprising at least one such compound or a pharma-ceutically acceptable salt, pharma-ceutically acceptable solvate, pharma-ceutically acceptable metabolite, or pharma-ceutically acceptable prodrug of such compounds. In some embodiments, when a compound disclosed herein contains a nitrogen atom that can be oxidized, the nitrogen atom can be converted to an N-oxide by methods well known in the art. In certain embodiments, isomers and chemically protected forms of compounds having a structure represented by any of formulas (I)-(Vb) are also provided.

[0157]

[0158] In some embodiments, provided herein are pyridyl compounds according to formula (I).

[0158]

[0159] In some embodiments, the present invention provides a method for the preparation of a compound having the structure: [ka] A compound according to formula (I) having the formula or a pharmaceutical composition thereof (In the formula, X - is a counter ion; Y is -C(H)2-, -O-, or -N(R 3 )- and; R 1 is a substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C3-C7-cycloalkyl, or a substituted or unsubstituted 4- to 7-membered heterocycloalkyl; R 2 is H or C1-C4 alkyl; R 3 is H or a substituted or unsubstituted C1-C4 alkyl; or R 1 and R 3 taken together form a 4- to 7-membered substituted or unsubstituted heterocycloalkyl. to provide.

[0159]

[0160] In some embodiments, provided herein is the use of a compound according to formula (I) in the treatment of a kidney-related disease or condition: [ka] (In the formula, X - is a counter ion; Y is -C(H)2-, -O-, or -N(R 3 )- and; R 1 is a substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C3-C7-cycloalkyl, or a substituted or unsubstituted 4- to 7-membered heterocycloalkyl; R 2 is H or C1-C4 alkyl; R 3 is H or a substituted or unsubstituted C1-C4 alkyl; or R 1 and R 3 taken together form a 4- to 7-membered substituted or unsubstituted heterocycloalkyl. The use of

[0160]

[0161] In some embodiments, R 2 is H, Me, Et, or i-Pr.

[0161]

[0162] In some embodiments, R 2 is H.

[0162]

[0163] In some embodiments, Y is -C(H)2-.

[0163]

[0164] In some embodiments, Y is --O--.

[0164]

[0165] In some embodiments, Y is -N(R 3 )-.

[0165]

[0166] In some embodiments, the compound is a compound according to formula (IIa), (IIb), or (IIc): [ka] (In the formula, X - is the counter ion; R 1 is a substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C3-C7-cycloalkyl, or a substituted or unsubstituted 4- to 7-membered heterocycloalkyl; R 2 is H or C1-C4 alkyl; R 3 is H or a substituted or unsubstituted C1-C4 alkyl; or R 1 and R 3 taken together form a 4- to 7-membered substituted or unsubstituted heterocycloalkyl. It is.

[0166]

[0167] In some embodiments, R 1 is a substituted or unsubstituted C1 to C4 alkyl.

[0167]

[0168] In some embodiments, R 1 is C1-C4 alkyl, unsubstituted or substituted with C3-C7 cycloalkyl.

[0168]

[0169] In some embodiments, R 1 is Me, Et, i-Pr, n-Pr, n-Bu, i-Bu, sec-Bu, or t-Bu.

[0169]

[0170] In some embodiments, R 1 is Me or Et substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0170]

[0171] In some embodiments, R 1is a C3-C7-cycloalkyl which is unsubstituted or substituted with Me or Et.

[0171]

[0172] In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0172]

[0173] In some embodiments, R 3 is H or a substituted or unsubstituted C1-C4 alkyl.

[0173]

[0174] In some embodiments, R 3 is H.

[0174]

[0175] In some embodiments, R 3 is Me, Et, i-Pr, n-Pr, n-Bu, i-Bu, sec-Bu, or t-Bu.

[0175]

[0176] In some embodiments, R 1 and R 3 taken together form a 4- to 7-membered substituted or unsubstituted heterocycloalkyl.

[0176]

[0177] In some embodiments, R 1 and R 3 taken together form pyrrolidinyl, piperidinyl, or morpholinyl.

[0177]

[0178] In some embodiments, the compound has formula (IIIa) or (IIIb): [ka] (In the formula, X - is the counter ion; R 2 is H or C1-C4 alkyl; R 3 is H or a substituted or unsubstituted C1-C4 alkyl. This is due to.

[0178]

[0179] In some embodiments, R 3 is H, Me, Et, or i-Pr.

[0179]

[0180] In some embodiments, R 3 is H.

[0180]

[0181] In some embodiments, R 2 is H or Me.

[0181]

[0182] In some particular embodiments, the compound is according to formula (IIIb); R 2 and R 3 is H.

[0182]

[0183] In some embodiments, the compound has formula (IVa) or (IVb): [ka] (In the formula, X - is the counter ion) This is due to.

[0183]

[0184] In some embodiments, the compound has formula (Va) or (Vb): [ka] (In the formula, X - is the counter ion) This is due to.

[0184]

[0185] In some embodiments, the counterion is any pharma- ceutically acceptable anion. In some embodiments, the counterion is a halide or a sulfonate. In certain embodiments, the counterion is F - , Cl - , Br - , I -In another particular embodiment, the counterion is benzenesulfonate or methyl sulfonate.

[0185]

[0186] In some embodiments, X - is F - , Cl - , Br - , I - , or MeSO2O - It is.

[0186]

[0187] In certain embodiments, X - is Cl - , or I - In a more particular embodiment, X - I - It is.

[0187]

[0188] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound according to formula (I).

[0188]

[0189] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharma- ceutically acceptable excipient.

[0189]

[0190] In some embodiments, the pharmaceutical composition is formulated for a route of administration selected from oral, parenteral, buccal, nasal, topical, or rectal administration.

[0190]

[0191] In some embodiments, the present invention provides a method for treating a renal disease or condition, comprising administering to a patient in need thereof a pharmaceutical composition of the present invention.

[0191]

[0192] In some embodiments, the renal disease is selected from chronic kidney disease, diabetic nephropathy, IgA nephropathy, acute renal failure, acute tubular necrosis, transplant-related ischemia, acute kidney disease and types of AKI such as cisplatin-induced AKI, aminoglycoside-induced AKI, tenofovir-induced AKI, contrast nephropathy, AKI after surgery for partial nephrectomy, AKI after kidney transplant, AKI in patients with dialysis, AKI after cardiac surgery, AKI in patients in the ICU, AKI caused by cirrhosis or sepsis, and AKI caused by hepatorenal syndrome.

[0192]

[0193] In certain embodiments, the disease or condition is contrast nephropathy.

[0193]

[0194] In certain embodiments, the disease or condition is tenofovir-induced AKI.

[0194]

[0195] In certain embodiments, the disease or condition is aminoglycoside-induced AKI.

[0195]

[0196] In certain embodiments, the disease or condition is post-operative AKI.

[0196]

[0197] In certain embodiments, the disease or condition is AKI in patients on dialysis.

[0197]

[0198] In certain embodiments, the disease or condition is diabetic nephropathy.

[0198]

[0199] In a more particular embodiment, the disease or condition is chronic kidney disease or CKD.

[0199]

[0200] In some embodiments, the disease or condition is:

[0200] [Table 1]

[0201]

[0201] In some embodiments, the disease or condition is:

[0202] [Table 2]

[0203]

[0202] In some embodiments, the compound is according to Formula (Va).

[0204]

[0203] In some embodiments, the compound is according to Formula (Vb).

[0205]

[0204] In some embodiments, the present invention provides a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a pharma- ceutically effective amount of a compound according to any one of the formulae described herein. In some embodiments, the compound is according to any one of formulae (I)-(Vb).

[0206]

[0205] In some embodiments, the pharmaceutical composition is formulated for a route of administration selected from oral, parenteral, buccal, nasal, topical, or rectal administration.

[0207]

[0206] In some embodiments, the carrier is a parenteral carrier.

[0208]

[0207] In some embodiments, the carrier is an oral carrier.

[0209]

[0208] In some embodiments, the carrier is a topical carrier.

[0210] Any combination of the groups described above for the various variables is contemplated herein. It is understood that the substituents and substitution patterns on the compounds provided herein can be selected by one skilled in the art to provide compounds that are chemically stable and can be synthesized by methods known in the art, not just those described herein.

[0211]

[0210] Throughout the specification, groups and substituents thereof can be chosen by one skilled in the art to provide stable moieties and compounds.

[0212]

[0211] In some embodiments, the compounds of formulae (I)-(Vb) are used to treat patients suffering from a renal condition or disease including, but not limited to, chronic kidney disease, diabetic nephropathy, IgA nephropathy, acute renal failure, acute tubular necrosis, transplant-related ischemia, acute kidney disease and types of AKI such as cisplatin-induced AKI, aminoglycoside-induced AKI, tenofovir-induced AKI, contrast nephropathy, AKI after surgery for partial nephrectomy, AKI after kidney transplant, AKI in patients with dialysis, AKI after cardiac surgery, AKI in patients in the ICU, AKI caused by cirrhosis or sepsis, and AKI caused by hepatorenal syndrome, and other diseases.

[0213] Preparation of compounds

[0212] The compounds of any of formulae (I)-(Vb) may be synthesized using synthetic reactions known to one of ordinary skill in the art or using methods known in the art. The reactions may be utilized in a linear sequence to provide the compounds, or they may be used to synthesize fragments that are subsequently coupled by methods known in the art.

[0214]

[0213] The starting materials used for the synthesis of the compounds described herein can be synthesized or obtained from commercial sources such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, California), or Sigma Chemical Co. (St. Louis, Mo.). The compounds described herein, and other related compounds having different substituents, can be found in, for example, March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001); Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999); Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., These can be synthesized using techniques and materials known to those skilled in the art, such as those described in "Chemical Synthesis, 1989," all of which are incorporated by reference in their entireties.Additional methods for the synthesis of the compounds described herein can be found in WO 01 / 01982901, Arnold et al. Bioorganic & Medicinal Chemistry Letters 10 (2000) 2167-2170; Burchat et al. Bioorganic & Medicinal Chemistry Letters 12 (2002) 1687-1690. The general methods for the preparation of the compounds as disclosed herein may be derived from reactions known in the art, and the reactions may be modified by the use of appropriate reagents and conditions, as recognized by those skilled in the art, for the introduction of the various moieties found in the formulae as provided herein.

[0215]

[0214] The products of the reactions may be isolated and purified, if necessary, using conventional techniques, including but not limited to filtration, dialysis, crystallization, chromatography, etc. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0216]

[0215] The compounds described herein may be prepared as a single isomer or a mixture of isomers.

[0217]

[0216] In some embodiments, representative compounds of formula (I) are prepared according to the synthetic schemes and methods described in US Patent No. 9,359,376 to Dugar et al.

[0218] Further forms of the compound

[0217] The compounds disclosed herein have the structure of formulas (I)-(Vb). When reference is made to a compound described herein, unless otherwise indicated, it is intended to include any compound of formula (I), (IIa)-(IIc), (IIIa)-(IIIb), (IVa)-(IVb), or (Va)-(Vb), and all of the specific compounds falling within the scope of these general formulas.

[0219]

[0218] The compounds described herein may have one or more stereocenters, and each center may exist in the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, and the appropriate mixtures thereof. Stereoisomers may be obtained, if necessary, by methods known in the art, for example, separation of stereoisomers by chiral chromatographic columns.

[0220]

[0219] Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by known methods, such as, for example, chromatography and / or fractional crystallization. In some embodiments, enantiomers can be separated by chiral chromatography columns. In some embodiments, enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., alcohol), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers (e.g., hydrolysis). All such isomers, including diastereomers, enantiomers, and mixtures thereof, are considered as part of the compositions described herein.

[0221]

[0220] The methods and formulations described herein include the use of N-oxides, crystalline forms, or pharma- ceutically acceptable salts of the compounds described herein, as well as the active metabolites of these compounds that have the same type of activity. In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In addition, the compounds described herein may exist in unsolvated and solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0222] The compounds described herein include isotopically labeled compounds, which are identical to those listed in the various formulas and structures presented herein, except for the fact that one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Certain isotopically labeled compounds described herein, such as 3 H and 14 Those incorporating radioactive isotopes such as C are useful for drug and / or substrate tissue distribution assays. Additionally, deuterium, i.e. 2 Substitution with isotopes such as H can confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0223]

[0222] The salts are recovered by at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization.

[0224]

[0223] Throughout the specification, groups and substituents thereof can be chosen by one skilled in the art to provide stable moieties and compounds.

[0225] Pharmaceutical Compositions / Formulations

[0224] The pharmaceutical composition can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliary agents that facilitate the processing of active compound into medicament that can be used.The appropriate formulation depends on the route of administration selected.Any of the well-known techniques, carriers, and excipients can be used as suitable and as understood in the art. Summary summaries of pharmaceutical compositions described herein may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference in their entireties.

[0226] As used herein, a pharmaceutical composition refers to a mixture of a compound described herein, such as, for example, any of the compounds of formulae (I)-(Vb), with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. A pharmaceutical composition facilitates administration of a compound to an organism. In carrying out the methods of treatment or use provided herein, a therapeutically effective amount of a compound described herein is administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. Preferably, the mammal is a human. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compound may be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0227]

[0226] In certain embodiments, the composition may also include one or more pH adjusters or buffers, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0228]

[0227] In some embodiments, the compositions may also include one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0229]

[0228] The term "pharmaceutical combination" as used herein means a product obtained by mixing or combining two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both active ingredients, e.g., the compounds described herein and the supplementary agent, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., the compounds described herein and the supplementary agent, are administered to a patient simultaneously, in parallel, or sequentially without a specific intervening time limit as separate entities, such that such administration results in an effective level of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0230] The pharmaceutical compositions described herein may be administered to a subject by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. The pharmaceutical compositions described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolving formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0231]

[0230] Pharmaceutical compositions containing the compounds described in this specification may be manufactured in a conventional manner, such as by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compressing processes, for example only.

[0232]

[0231] The pharmaceutical composition will include at least one compound described herein, such as any of compounds (I)-(Vb), as an active ingredient in free acid or free base form, or in pharma- ceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms, and active metabolites of these compounds with the same type of activity. In some situations, the compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In addition, the compounds described herein may exist in unsolvated and solvated forms with pharma- ceutically acceptable solvents, such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0233]

[0232] "Antifoaming agents" reduce foaming during processing that can lead to coagulation of the aqueous dispersion, bubbles in the finished film, or generally interfere with processing. Exemplary antifoaming agents include silicone emulsions or sorbitan sesquioleate.

[0234]

[0233] "Antioxidants" include, for example, butylhydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium disulfite, and tocopherol. In certain embodiments, antioxidants enhance chemical stability when needed.

[0235]

[0234] In certain embodiments, the compositions provided herein may also include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0236]

[0235] The formulations described herein may benefit from the addition of antioxidants, metal chelating agents, sulfur-containing compounds and other general stabilizers. Examples of such stabilizers include, but are not limited to, (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0237] "Binders" impart adhesive properties and include, for example, alginic acid and its salts; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonite; gelatin; polyvinylpyrrolidone / vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; sugars such as tragacanth, dextrin, sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and lactose; natural or synthetic gums such as gum arabic, tragacanth, gum ghatti, isapol husk (isapol husk), and the like. husk), polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like.

[0238]

[0237] "Carriers" or "carrier materials" include excipients commonly used in pharmaceutics and should be selected based on their compatibility with the compounds disclosed herein, such as any of the compounds of Formula (I)-(Vb), and the release profile characteristics of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegration agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. "Pharmaceutically compatible carrier materials" may include, but are not limited to, gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters, sodium caseinate, soybean lectin, taurocholic acid, phosphotidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sodium sugar stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0239] "Dispersing agents" and / or "viscosity modifiers" include materials that control the diffusion and uniformity of the drug through the liquid medium or the granulation or mixing process. In some embodiments, these agents also enhance the effect of coating or eroding the matrix. Exemplary diffusion enhancers / dispersing agents include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and, for example, hydroxypropylcellulose (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC Carbohydrate-based dispersants such as K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinylpyrrolidone / vinyl acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ).)), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone / vinyl acetate copolymer (S-630), polyethylene glycol (e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to 4000, or about 7000 to about 5400), sodium carboxymethylcellulose, methylcellulose, polysorbate-80, sodium alginate, gums such as tragacanth and gum arabic, guar gum, xanthan (including xanthan gum), sugars, celluloses such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomer, polyvinyl alcohol (PVA), alginates, chitosan, and combinations thereof. Plasticizers such as cellulose or triethylcellulose may also be used as dispersing agents. Particularly useful dispersing agents in liposomal and self-emulsifying dispersions are dimyristoyl phosphatidylcholine, natural phosphatidylcholine from eggs, natural phosphatidylglycerol from eggs, cholesterol and isopropyl myristate.

[0240]

[0239] A combination of one or more diffusion enhancers and one or more erosion enhancers may also be used in the present compositions.

[0241]

[0240] The term "diluent" refers to a chemical used to dilute the compound of interest before delivery. Diluents can also be used to stabilize the compound, as they can provide a more stable environment. Salts dissolved in buffer solutions (which can also provide pH control or maintenance) are utilized as diluents in the art, including but not limited to phosphate buffered saline solutions. In certain embodiments, diluents increase the volume of the composition to facilitate compression or provide sufficient volume for a homogeneous mixture for capsule filling. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®; calcium hydrogen phosphate, dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugars such as Di-Pac® (Amstar); mannitol, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluents, confectioner's sugar; calcium dihydrogen sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and the like.

[0242]

[0241] The term "disintegrate" includes both dissolution and dispersion of the dosage form when in contact with gastrointestinal fluids. A "disintegrant or disintegrant" promotes the breakup or disintegration of a substance. Examples of disintegrants include starches, e.g., natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, celluloses such as wood products, methyl crystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming crosslinked celluloses such as Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose; crosslinked starches such as sodium starch glycolate; crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone; alginates such as alginic acid or salts of alginic acid such as sodium alginate; clays such as Veegum® HV (magnesium aluminum silicate); gums such as agar, guar, carob, karaya, pectin, or tragacanth; sodium starch glycolate, bentonite, natural sponge, surfactants, resins such as cation exchange resins, citrus juice pomace, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.

[0243]

[0242] "Drug absorption" or "absorption" generally refers to the process by which a drug moves from the site of administration across a barrier to the blood vessels or site of action, for example, movement of a drug from the digestive tract into the portal vein or lymphatic system.

[0244]

[0243] An "enteric coating" is a material that remains substantially unchanged in the stomach but dissolves and releases a drug in the small intestine or colon. In general, enteric coatings comprise polymeric materials that prevent release in the low pH environment of the stomach, but ionize at a higher pH, usually pH 6-7, and thus dissolve sufficiently in the small intestine or colon to release the active agent therein.

[0245]

[0244] "Erosion enhancers" include materials that control the erosion of a particular material in gastrointestinal fluids. Erosion enhancers are generally known to those skilled in the art. Exemplary erosion enhancers include, for example, hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

[0246]

[0245] Examples of "fillers" include compounds such as lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, and polyethylene glycol.

[0247]

[0246] "Flavoring agents" and / or "sweetening agents" useful in the formulations described herein include, for example, gum arabic syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarois, berry, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, licorice (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhetinate, ... glyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, aces. These include potassium rufam, mannitol, talc, sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or combinations of these flavoring ingredients, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.

[0248]

[0247] "Lubricants" and "gliding agents" are compounds that prevent, reduce or inhibit the adhesion and friction of materials. Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, hydrocarbons such as mineral oils or hydrogenated vegetable oils such as hydrogenated soybean oil (Sterotex®), higher fatty acids and their alkali metal and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, glycerol, talc, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (e.g., PEG-4000) or methoxypolyethylene glycol such as Carbowax™, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as Syloid™, Cab-O-Sil®, starch such as corn starch, silicone oil, surfactants, and the like.

[0249]

[0248] "Measurable serum concentration" or "measurable plasma concentration" refers to the serum or plasma concentration, typically measured in mg, μg, or ng of therapeutic agent per ml, dl, or 1 of serum absorbed into the bloodstream following administration. As used herein, measurable plasma concentration is usually measured in ng / ml or μg / ml.

[0250]

[0249] "Pharmacokinetics" refers to the factors that determine the observed biologic response relative to the concentration of drug at a site of action.

[0251]

[0250] "Pharmacokinetics" refers to the factors that determine the achievement and maintenance of an adequate concentration of a drug at a site of action.

[0252]

[0251] "Plasticizer" is a compound used to soften microencapsulation materials or film coatings to make them less friable. Suitable plasticizers include, for example, polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, polyethylene glycol, oleic acid, triethylcellulose, and triacetin. In some embodiments, plasticizers can also function as dispersants or wetting agents.

[0253]

[0252] Examples of "solubilizing agents" include compounds such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.

[0254]

[0253] "Stabilizers" include compounds such as any antioxidant, buffer, acid, preservative, etc.

[0255]

[0254] "Steady state," as used herein, is when the amount of drug administered equals the amount of drug excreted within one dosing interval resulting in a plateau or constant plasma drug exposure.

[0256]

[0255] Examples of "suspending agents" include polyvinylpyrrolidone, for example, polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone / vinyl acetate copolymer (S630), polyethylene glycol (for example, the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate, Included are polysorbate-80, hydroxyethylcellulose, sodium alginate, gums such as gum tragacanth and gum arabic, guar gum, xanthan (including xanthan gum), sugars, celluloses such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, compounds such as polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0257]

[0256] "Surfactants" include compounds such as sodium lauryl sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF). Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkyl phenyl ethers, e.g., Octoxynol 10, Octoxynol 40. In some embodiments, surfactants may be included to enhance physical stability or for other purposes.

[0258]

[0257] Examples of "viscosity enhancing agents" include methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol, alginate, gum arabic, chitosan, and combinations thereof.

[0259]

[0258] "Wetting agents" include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, Tween 80, Vitamin E TPGS, ammonium salts, and the like.

[0260] Dosage form The compositions described herein can be formulated for administration to a subject via any conventional means, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal routes of administration. As used herein, the term "subject" is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject can be used interchangeably.

[0261]

[0260] Furthermore, the pharmaceutical compositions described herein comprising any of the compounds of Formulae (I)-(Vb) may be formulated into any suitable dosage form for oral ingestion by a patient, including, but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, and the like, including solid oral dosage forms, aerosols, controlled release formulations, fast dissolve formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixtures of fast release and controlled release formulations.

[0262]

[0261] Medicaments for oral use may be obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the mixture obtained after adding suitable auxiliary agents if necessary, and processing the mixture of granules to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants, such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, may be added.

[0263]

[0262] Dragee cores are provided with suitable coatings.For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solvent, and suitable organic solvents or solvent mixtures.Dyes or pigments can be added to tablets or dragee coatings to identify or characterize different combinations of active compound doses.

[0264]

[0263] The pharmaceuticals that can be used orally include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules can contain active ingredients in a mixture with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compounds can be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.

[0265] In some embodiments, the solid dosage forms disclosed herein may be in the form of a tablet (including a tablet for suspension, a fast dissolving tablet, a chewable disintegrating tablet, a rapid disintegrating tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e.g., capsules made of animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), a solid dispersion, a solid solution, a biodisintegrating dosage form, a controlled release formulation, a pulsed release dosage form, a multiparticulate dosage form, an implant, a granule, or an aerosol. In some embodiments, the pharmaceutical composition is in the form of a powder. In some embodiments, the pharmaceutical composition is in the form of a tablet, including, but not limited to, a fast dissolving tablet. Furthermore, the pharmaceutical compositions described herein may be administered as a single capsule or in a multiple capsule dosage form. In some embodiments, the pharmaceutical composition is administered in two, or three, or four capsules or tablets.

[0266]

[0265] In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by mixing particles of any compound of formula (I)-(Vb) with one or more pharmaceutical excipients to form a bulk blend composition. When these bulk blend compositions are referred to as homogeneous, it is meant that the particles of any compound of formula (I)-(Vb) are uniformly dispersed throughout the composition, such that the composition can be easily subdivided into similarly effective unit dosage forms, such as tablets, pills, capsules, etc. Individual dosage forms may also include a film coating that disintegrates upon oral ingestion or contact with a diluent. These formulations may be manufactured by conventional pharmacological techniques.

[0267]

[0266] Conventional pharmacological techniques include, for example, one or a combination of the following methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating), tangential coating, top spray, tabletting, extrusion, etc.

[0268]

[0267] The pharmaceutical solid dosage forms described herein may comprise a compound described herein and one or more pharma- ceutically acceptable excipients, such as a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetener, disintegrant, dispersant, surfactant, lubricant, colorant, diluent, solubilizer, humectant, plasticizer, stabilizer, permeation enhancer, humectant, antifoaming agent, antioxidant, preservative, or one or more combinations thereof. In some embodiments, a film coating is provided around the formulation of a compound of any of formulas (I)-(Vb) using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In some embodiments, some or all of the particles of a compound of any of formulas (I)-(Vb) are coated. In some embodiments, some or all of the particles of a compound of any of formulas (I)-(Vb) are microencapsulated. In some further embodiments, the particles of a compound of any of formulas (I)-(Vb) are not microencapsulated and are not coated.

[0269]

[0268] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lectin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0270]

[0269] Suitable fillers for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0271]

[0270] In order to release the compound of any of formulae (I)-(Vb) from the solid dosage form matrix as efficiently as possible, especially when the dosage form is compressed with a binder, a disintegrant is often used in the formulation. The disintegrant helps to rupture the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Disintegrants suitable for use in the solid dosage forms described herein include natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, celluloses such as wood products, methyl crystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Examples of suitable surfactants include, but are not limited to, Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked celluloses such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), gums such as agar, guar, carob, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactants, resins such as cation exchange resins, citrus juice pomace, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.

[0272] Binders provide cohesiveness to solid oral dosage form formulations: for powder filled capsule formulations, they aid in the formation of plugs that can be filled into soft or hard shell capsules, and for tablet formulations, they ensure that the tablet remains intact after compression and help ensure uniformity of the mix prior to the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., Hypromellose USP Pharmacoat-603, Hydroxypropyl methylcellulose acetate stearate (Aqoate Examples of suitable cellulose derivatives include cellulose acetate, cellulose phosphate, cellulose phosphate-soluble cellulose ... husk), starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethylene glycol, wax, sodium alginate, and the like.

[0273]

[0272] Generally, binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder usage levels in tablet formulations vary depending on direct compression, wet granulation, roller compaction, or the use of other excipients such as fillers that can act as moderate binders themselves. A formulator skilled in the art can determine the binder level for a formulation, but binder usage levels of up to 70% are common in tablet formulations.

[0274] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali metal and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, waxes, Stearone®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol such as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium lauryl sulfate or sodium lauryl sulfate.

[0275]

[0274] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and glucose), polysaccharides (including dextrates and maltodextrins), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like.

[0276]

[0275] The term "water-insoluble diluent" refers to compounds typically used in the formulation of pharmaceutical products, such as calcium phosphate, calcium sulfate, starch, modified starch, and microcrystalline cellulose, and microcellulose (e.g., about 0.45 g / cm 3 These include powdered cellulose (eg, Avicel), as well as talc.

[0277]

[0276] Suitable humectants for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10 (registered trademark)), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, and the like.

[0278]

[0277] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF), and the like.

[0279]

[0278] Suitable suspending agents for use in the solid dosage forms described herein include polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol (e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400), vinylpyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, polyisopropyl ... Examples of suitable cellulose derivatives include, but are not limited to, sorbate-80, hydroxyethylcellulose, sodium alginate, gums such as tragacanth and gum arabic, guar gum, xanthan (including xanthan gum), sugars, celluloses such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0280]

[0279] Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylhydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0281]

[0280] It should be understood that there is a great deal of overlap between the additives used in the solid dosage forms described herein.Therefore, the additives listed above should be understood as merely non-limiting examples of the types of additives that can be included in the solid dosage forms described herein.The amount of such additives can be easily determined by those skilled in the art according to the specific properties desired.

[0282] In some embodiments, one or more layers of the pharmaceutical composition are plasticized. Illustratively, plasticizers are generally high boiling solids or liquids. Suitable plasticizers can be added at about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearates, and castor oil.

[0283]

[0282] Compressed tablets are solid dosage forms prepared by compressing bulk blends of the formulations described above. In various embodiments, compressed tablets designed to dissolve in the mouth will include one or more flavorings. In some embodiments, compressed tablets will include a film around the final compressed tablet. In some embodiments, the film coating can provide delayed release of any of the compounds of Formulae (I)-(Vb) from the formulation. In some embodiments, the film coating aids in patient compliance (e.g., Opadry® coating or sugar coating). Film coatings, including Opadry®, typically range from about 1% to about 3% of the tablet weight. In some embodiments, the compressed tablets include one or more excipients.

[0284]

[0283] Capsules may be prepared, for example, by placing a bulk blend of a formulation of any of the compounds of formula (I)-(Vb) above into a capsule. In some embodiments, the formulation (non-aqueous suspension and solution) is placed into a soft gelatin capsule. In some embodiments, the formulation is placed into a non-gelatin capsule, such as a standard gelatin capsule or a capsule containing HPMC. In some embodiments, the formulation is placed into a sprinkle capsule, which may be swallowed whole or the capsule may be opened and the contents sprinkled onto food before eating. In some embodiments, the therapeutic dose is divided into multiple (e.g., two, three, or four) capsules. In some embodiments, the entire dose of the formulation is delivered in capsule form.

[0285]

[0284] In various embodiments, particles of a compound of any of Formulae (I)-(Vb) and one or more excipients are dry blended and compressed into a mass, such as a tablet, having sufficient hardness to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration, thereby releasing the formulation to the gastrointestinal fluids.

[0286] In some embodiments, the dosage form may comprise a microencapsulated formulation. In some embodiments, one or more other compatible materials are present in the microencapsulation material. Exemplary materials include, but are not limited to, pH adjusters, erosion promoters, antifoaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0287]

[0286] Materials useful for microencapsulation as described herein include materials compatible with any of the compounds of formulae (I)-(Vb) that sufficiently isolate the compound of formulae (I)-(Vb) from other incompatible excipients. Materials compatible with any of the compounds of formulae (I)-(Vb) are those that delay the release of any of the compounds of formulae (I)-(Vb) in vivo.

[0288] Exemplary microencapsulation materials useful for delaying the release of formulations comprising the compounds described herein include hydroxypropyl cellulose ethers (HPC), such as Klucel® or Nisso HPC, low substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methylcellulose ethers (HPMC), such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers, such as Methocel®-A, hydroxypropyl methylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS), and Metolose®, ethylcellulose (EC) and mixtures thereof, such as E461, Ethocel®, Aqualon®-EC, Surelease®, polyvinyl alcohol (PVA), such as Opadry®, AMB, hydroxyethylcellulose, e.g. Natrosol®, carboxymethylcellulose and salts of carboxymethylcellulose (CMC), e.g. Aqualon®-CMC, copolymers of polyvinyl alcohol and polyethylene glycol, e.g. Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycol, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers, e.g. Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D, Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, cellulose acetate phthalate, sepifilm, such as a mixture of HPMC and stearic acid, cyclodextrin, and mixtures of these materials.

[0289] In some embodiments, plasticizers such as polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In some embodiments, microencapsulation materials useful for delaying the release of pharmaceutical compositions are derived from the USP or National Formulary (NF). In some embodiments, the microencapsulation material is Klucel. In some embodiments, the microencapsulation material is Methocel.

[0290]

[0289] Microencapsulated compounds of any of formulae (I)-(Vb) can be formulated by methods known to those skilled in the art. Such known methods include, for example, spray drying process, spinning disk solvent process, hot melt process, spray cooling method, fluidized bed, electrostatic deposition, centrifugal extrusion, rotary suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spray solvent extrusion tank. In addition to these, some chemical methods can also be used, such as complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid medium, in situ polymerization, drying in liquid, and desolvation in liquid medium. Furthermore, other methods can be used, such as roller compaction, extrusion / spheronization, coacervation, or nanoparticle coating.

[0291] In some embodiments, particles of a compound of any of Formulae (I)-(Vb) are microencapsulated into one of the above forms prior to formulation. In some further embodiments, some or most of the particles are coated prior to further formulation by using standard coating procedures such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).

[0292]

[0291] In some embodiments, the solid dosage formulation of any of the compounds of formula (I)-(Vb) is plasticized (coated) with one or more layers. Illustratively, the plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added at about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearates, and castor oil.

[0293]

[0292] In some embodiments, a powder containing a formulation according to any of the compounds of Formulae (I)-(Vb) described herein may be formulated to include one or more pharmaceutical excipients and flavorings. Such powders may be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include a suspending agent and / or a wetting agent. This bulk blend is then evenly divided into unit dose packages or multi-dose package units.

[0294]

[0293] In addition, in some embodiments, effervescent powders are also prepared according to the present disclosure. Effervescent salts are used to disperse medicaments in water for oral administration. Effervescent salts are granules or coarse powders that contain medicaments in a dry mix and are usually composed of sodium bicarbonate, citric acid, and / or tartaric acid. When the salts of the compositions described herein are added to water, the acid and base react to release carbon dioxide gas, thereby producing "effervescence." Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate, or a mixture of sodium bicarbonate with sodium carbonate, citric acid, and / or tartaric acid. Any acid-base combination that results in the release of carbon dioxide may be used in place of the combination of sodium bicarbonate with citric acid and tartaric acid, as long as the ingredients are suitable for pharmaceutical use and result in a pH of about 6.0 or higher.

[0295] In some embodiments, the formulations described herein that include a compound of formula (I) are solid dispersions. Methods for producing such solid dispersions are known in the art, including, but not limited to, U.S. Patent Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269, and U.S. Patent Application Publication No. 2004 / 0013734, each of which is specifically incorporated by reference. In some embodiments, the formulations described herein are solid solutions. Solid solutions incorporate substances together with active agents and other excipients, such that heating the mixture results in dissolution of the drug, followed by cooling the resulting composition to produce a solid blend that can be further formulated or added directly to capsules or compressed into tablets. Methods for producing such solid solutions are known in the art and include, for example, but are not limited to, U.S. Pat. Nos. 4,151,273, 5,281,420, and 6,083,518, each of which is specifically incorporated by reference.

[0296]

[0295] Pharmaceutical solid oral dosage forms, including the formulations described herein that include any of the compounds (I)-(Vb), can be further formulated to provide controlled release of the compound of formula (I). Controlled release refers to the release of any of the compounds of formula (I)-(Vb) from the dosage form in which it is incorporated according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, extended release, pulsatile release, and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow delivery of a drug to a subject over an extended period of time according to a predefined profile. Such release can provide therapeutically effective levels of the drug for an extended period of time, thereby providing a longer-term pharmacological response while minimizing side effects compared to conventional rapid release dosage forms. Such longer-term response provides many unique benefits that are not achieved with the corresponding short-acting immediate release preparations.

[0297] In some embodiments, the solid dosage forms described herein may be formulated as enteric delayed release oral dosage forms, i.e., oral dosage forms of pharmaceutical compositions as described herein that utilize an enteric coating to affect release in the small intestine of the gastrointestinal tract. The enteric dosage form may be a compressed or molded or extruded tablet / form (coated or uncoated) containing granules, powders, pellets, beads or particles (themselves coated or uncoated) of the active ingredient and / or other composition components. The enteric oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules (themselves coated or uncoated) of the solid carrier or composition.

[0298]

[0297] The term "delayed release" as used herein refers to delivery such that release can be achieved at some generally predictable location in the intestinal tract that is distal to the location that would be achieved if no delayed release modification was made. In some embodiments, the method for delayed release is a coating. Any coating should be applied to a sufficient thickness such that the entire coating does not dissolve in gastrointestinal fluids at a pH below about 5, but dissolves at a pH of about 5 or higher. It is anticipated that any anionic polymer that exhibits a pH-dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract. In some embodiments, the polymers described herein are anionic carboxylic acid polymers. In some embodiments, the polymers and their compatible mixtures, as well as some of their properties, include, but are not limited to, the following:

[0299]

[0298] Shellac, also called refined lac, is a refined product obtained from the resinous secretions of insects. This coating dissolves in media with a pH>7.

[0300] Acrylic polymers. The performance of acrylic polymers (mainly their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. Eudragit series E, L, S, RL, RS, and NE (Rohm Pharma) are available as solubilized in organic solvents, aqueous dispersions, or dry powders. Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but permeable, and are primarily used for colon targeting. Eudragit series E dissolves in the stomach. Eudragit series L, L-30D, and S are insoluble in the stomach and dissolve in the intestine.

[0301]

[0300] Cellulose derivatives. Examples of suitable cellulose derivatives are ethyl cellulose; reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. Performance can vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH>6. Aquateric (FMC) is a water-based system and is a spray-dried CAP pseudolatex with particles of <1 μm. Other ingredients in Aquateric include Pluronic, Tween, and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). Performance can vary based on the degree and type of substitution. For example, HPMCP such as HP-50, HP-55, HP-55S, HP-55F grades are suitable. Performance may vary based on the degree and type of substitution. For example, suitable grades of hydroxypropyl methylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH. These polymers are provided as granules or as fine powders for aqueous dispersion.

[0302] Polyvinyl acetate phthalate (PVAP) PVAP is soluble at pH>5 and is nearly impermeable to water vapor and gastric fluids.

[0303] In some embodiments, the coating may, and typically does, contain plasticizers and possibly other coating excipients well known in the art, such as colorants, talc, and / or magnesium stearate. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxyl acrylic polymers will usually contain 10-25% by weight of plasticizers, particularly dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques, such as spray or pan coating, are utilized to apply the coating. The coating thickness must be sufficient to ensure that the oral dosage form remains intact in the intestinal tract until the desired site of topical delivery is reached.

[0304]

[0303] Colorants, release agents, surfactants, defoamers, lubricants (e.g., carnauba wax or PEG), in addition to plasticizers, may be added to the coating to solubilize or disperse the coating materials and improve coating performance and the coated product.

[0305] In some embodiments, the formulations described herein that contain a compound of formula (I) are delivered using a pulsatile dosage form. A pulsatile dosage form can provide one or more immediate release pulses at a predetermined time or at a specific site after a controlled delay time. A pulsatile dosage form that includes the formulations described herein that contain any compound of formula (I)-(Vb) can be administered using various pulsatile formulations known in the art. For example, such formulations include, but are not limited to, those described in U.S. Patent Nos. 5,011,692, 5,017,381, 5,229,135, and 5,840,329, each of which is specifically incorporated by reference. Other pulsatile release dosage forms suitable for use with the present formulations include, but are not limited to, U.S. Patent Nos. 4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441, and 5,837,284, all of which are specifically incorporated by reference. In some embodiments, the controlled release dosage form is a pulsatile release solid oral dosage form comprising at least two groups of particles (i.e., multiparticulates), each of which contains a formulation described herein. The first group of particles provides substantially immediate administration of any of the compounds (I)-(Vb) upon ingestion by a mammal. The first group of particles may be uncoated or may include a coating and / or sealant. The second group of particles includes coated particles comprising about 2% to about 75%, about 2.5% to about 70%, or about 40% to about 70% by weight of the total dose of any of the compounds of Formulae (I)-(Vb) in the formulation, mixed with one or more binders. The coating includes a pharma- ceutically acceptable component in an amount sufficient to provide a delay of about 2 hours to about 7 hours after ingestion, prior to release of the second dose.Suitable coatings include, by way of example only, pH-sensitive coatings (enteric coatings) alone or mixed with cellulose derivatives, e.g., ethylcellulose, one or more differentially degradable coatings such as, for example, acrylic resins (e.g., Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D, Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, and Eudragit® NE30D, Eudragit® NE 40D®), or non-enteric coatings having variable thicknesses that result in differential release of the formulation comprising any of the compounds of formula (I).

[0306] Many other types of controlled release systems are known to those skilled in the art and are suitable for use with the formulations described herein. Examples of such delivery systems include, for example, polymer-based systems, such as polylactic and polyglycolic acids, polyanhydrides and polycaprolactones; non-polymer-based systems of porous matrices that are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, biodegradable dosage forms, compressed tablets using conventional binders, and the like. For example, see Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2 Ed., pp. 209-214 (1990); each of which is specifically incorporated by reference. ndEd., pp. 751-753 (2002); see U.S. Patent Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, ​​5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014, and 6,932,983.

[0307]

[0306] In some embodiments, pharmaceutical compositions are provided that include particles of a compound of any of Formulae (I)-(Vb) described herein and at least one dispersing or suspending agent for oral administration to a subject. The formulation may be a powder and / or granules for suspension, which upon mixing with water results in a substantially uniform suspension.

[0308]

[0307] The liquid pharmaceutical dosage form for oral administration may be an aqueous suspension selected from the group including, but not limited to, pharma- ceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, for example, Singh et al., Encyclopedia of Pharmaceutical Technology, 2 nd Ed., pp. 754-757 (2002). In addition to particles of the compound of formula (A), the liquid dosage form may include additives such as: (a) a disintegrant; (b) a dispersant; (c) a wetting agent; (d) at least one preservative, (e) a viscosity enhancer, (f) at least one sweetener, and (g) at least one flavoring agent. In some embodiments, the aqueous dispersion may further include a crystallization inhibitor.

[0309]

[0308] The aqueous suspensions and dispersions described herein can remain homogeneous for at least 4 hours as defined in The USP Pharmacists' Pharmacopeia (2005 edition, chapter 905). Homogeneity should be determined by a consistent sampling method for determining the homogeneity of the entire composition. In some embodiments, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 1 minute. In some embodiments, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 45 seconds. In some embodiments, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 30 seconds. In some embodiments, agitation is not necessary to maintain a homogeneous aqueous dispersion.

[0310]

[0309] Examples of disintegrants for use in aqueous suspensions and dispersions include starches, e.g. natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, celluloses such as wood products, methylcrystalline cellulose, e.g. Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Examples of suitable surfactants include, but are not limited to, Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked celluloses such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), gums such as agar, guar, carob, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactants, resins such as cation exchange resins, citrus juice pomace, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.

[0311]

[0310] In some embodiments, disintegrants suitable for the aqueous suspensions and dispersions described herein are known in the art and include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and for example, hydroxypropylcellulose and hydroxypropylcellulose ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose and hydroxypropylmethylcellulose ethers (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose acetate stearate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone / vinyl acetate copolymers (Plasdone®, e.g., S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymers with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ)) and other carbohydrate-based dispersants.In some embodiments, the dispersing agent is selected from the group consisting of hydrophilic polymers; electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropylcellulose and hydroxypropylcellulose ethers (e.g., HPC, HPC-SL, and HPC-L); hydroxypropylmethylcellulose and hydroxypropylmethylcellulose ethers (e.g., HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu)); sodium carboxymethylcellulose; methylcellulose; hydroxyethylcellulose; hydroxypropylmethyl-cellulose phthalate; hydroxypropylmethyl-cellulose acetate stearate; amorphous cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymers with ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics, which are block copolymers of ethylene oxide and propylene oxide). F68®, F88®, and F108®); or poloxamine (e.g., Tetronic 908®, also known as Poloxamine 908®).

[0312]

[0311] Wetting agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include cetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (e.g., commercially available Tweens, such as Tween 20 and Tween 80 (ICI Specialty Chemicals)), and polyethylene glycols (e.g., Carbowaxs 3350 and 1450, and Carbopol 934 (Union Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin E. These include, but are not limited to, TPGS, sodium taurocholate, simethicone, phosphotidylcholine, and the like.

[0313] Suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben), benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. Preservatives, as used herein, are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth.

[0314] Suitable viscosity enhancing agents for the aqueous suspensions or dispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Plasdon® S-630, carbomer, polyvinyl alcohol, alginate, gum arabic, chitosan, and combinations thereof. The concentration of the viscosity enhancing agent will depend on the agent selected and the desired viscosity.

[0315]

[0314] Examples of sweeteners suitable for the aqueous suspensions or dispersions described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarois, berries, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, licorice syrup, grapes, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhetinate, ... glyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspar The sweeteners and flavorings may include tame, acesulfame potassium, mannitol, talc, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or combinations of these flavorings, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. In some embodiments, the aqueous liquid dispersion may include a sweetener or flavoring agent in a concentration ranging from about 0.001% to about 1.0% by volume of the aqueous dispersion.In some embodiments, the aqueous liquid dispersion may include a sweetener or flavoring agent at a concentration ranging from about 0.005% to about 0.5% by volume of the aqueous dispersion, and in some embodiments, the aqueous liquid dispersion may include a sweetener or flavoring agent at a concentration ranging from about 0.01% to about 1.0% by volume of the aqueous dispersion.

[0316] In addition to the additives listed above, the liquid formulation may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers.Exemplary emulsifiers include ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, sodium lauryl sulfate, sodium docusate, cholesterol, cholesterol esters, taurocholic acid, phosphotidylcholine, oils such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, or mixtures of these substances.

[0317] In some embodiments, the pharmaceutical compositions described herein may be self-emulsifying drug delivery systems (SEDDS). An emulsion is a dispersion of one immiscible phase in another, usually in the form of droplets. Generally, emulsions are generated by active mechanical dispersion. In contrast to emulsions or microemulsions, SEDDSs spontaneously form emulsions when added to excess water without external mechanical dispersion or agitation. The advantage of SEDDSs is that only gentle mixing is required to disperse the droplets throughout the solution. Furthermore, water or aqueous phase may be added immediately prior to administration, ensuring stability of unstable or hydrophobic active ingredients. Thus, SEDDSs provide an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. SEDDSs may provide improvements in the bioavailability of hydrophobic active ingredients. Methods for producing self-emulsifying dosage forms are known in the art and include, for example, but not limited to, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563, each of which is specifically incorporated by reference.

[0318]

[0317] It should be understood that there is overlap between the additives listed above that are used in the aqueous dispersions or suspensions described herein, since a given additive is often classified differently by different practitioners in the field or is commonly used for any of several different functions. Therefore, the additives listed above should be understood as merely non-limiting examples of the types of additives that can be included in the formulations described herein. The amount of such additives can be easily determined by those skilled in the art according to the specific properties desired.

[0319] Intranasal preparations Intranasal formulations are known in the art and are described, for example, in U.S. Patent Nos. 4,476,116, 5,116,817, and 6,391,452, each of which is specifically incorporated by reference. Formulations containing any of the compounds of formula (I)-(Vb) prepared according to these and other techniques well known in the art are prepared as solutions in saline, utilizing benzyl alcohol or other suitable preservatives, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. See, for example, Ansel, HC et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably, these compositions and formulations are prepared with suitable non-toxic pharma- ceutically acceptable ingredients. These ingredients are known to those skilled in the art in the preparation of nasal dosage forms, and some of these can be found in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005, a standard reference in the field. The selection of suitable carriers depends largely on the exact nature of the desired nasal dosage form, such as, for example, a solution, a suspension, an ointment, or a gel. Nasal dosage forms generally contain a large amount of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersants, preservatives, surfactants, gelling agents, or buffers and other stabilizers and solubilizers may also be present. Nasal dosage forms should be isotonic with nasal secretions.

[0320]

[0319] For administration by inhalation, any compound of formula (I)-(Vb) described herein may be in the form of an aerosol, mist or powder. The pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray provided from a pressurized pack or nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin, for example only, for use in an inhaler or insufflator can be formulated to contain a powder mix of the compound described herein and a suitable powder base, such as lactose or starch.

[0321] Buccal preparations

[0320] Buccal formulations containing any of the compounds of formula (I)-(Vb) can be administered using various formulations known in the art. For example, such formulations include, but are not limited to, those described in U.S. Patent Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136, each of which is specifically incorporated by reference. In addition, the buccal dosage forms described herein may further include a biodegradable (hydrolyzable) polymer carrier that also serves to adhere the dosage form to the buccal mucosa. The buccal dosage form is manufactured to gradually erode over a predetermined period of time, providing delivery of any of the compounds of formula (I)-(Vb) essentially throughout. Buccal drug delivery avoids the disadvantages that arise in the case of oral drug administration (e.g., slow absorption, degradation of the active agent by fluids present in the digestive tract, and / or first-pass inactivation in the liver), as understood by those skilled in the art. With respect to bioerodible (hydrolyzable) polymeric carriers, it will be understood that virtually any such carrier may be used as long as the desired drug release profile is not compromised and the carrier is compatible with any of the compounds of formulae (I)-(Vb) and any other ingredients that may be present in the buccal dosage unit. In general, polymeric carriers include hydrophilic (water-soluble and water-swellable) polymers that adhere to the moist surface of the buccal mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and, for example, those known as "carbomers" (Carbopol®, which may be obtained from BF Goodrich, is one such polymer). Other ingredients may be incorporated into the buccal dosage forms described herein, including, but not limited to, disintegrants, diluents, binders, lubricants, flavorings, colorings, preservatives, and the like. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner.

[0322] Transdermal formulations The transdermal formulations described herein can be administered using various devices described in the art.For example, such devices include those described in U.S. Patent Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, each of which is specifically incorporated by reference in its entirety. Examples of suitable amines include, but are not limited to, Nos. 4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144.

[0323]

[0322] The transdermal dosage forms described herein may incorporate certain pharma- ceutically acceptable excipients conventional in the art. In some embodiments, the transdermal formulations described herein include at least three components: (1) a formulation of any compound of formula (I); (2) a penetration enhancer; and (3) an aqueous adjuvant. In addition, the transdermal formulations may include additional components, such as, but not limited to, gelling agents, cream and ointment bases. In some embodiments, the transdermal formulations may further include a woven or nonwoven backing that enhances absorption and prevents removal of the transdermal formulation from the skin. In some embodiments, the transdermal formulations described herein may maintain a saturated or supersaturated state to promote diffusion into the skin.

[0324]

[0323] Formulations suitable for transdermal administration of the compounds described herein may utilize transdermal delivery devices and transdermal delivery patches, which may be lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in polymers or adhesives. Such patches may be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents. Additionally, transdermal delivery of the compounds described herein may be achieved by iontophoretic patches and the like. Additionally, transdermal patches may provide controlled delivery of any of the compounds of formula (I)-(Vb). The rate of absorption may be slowed by using a rate-controlling membrane or by retaining the compound within a polymer matrix or gel. Conversely, absorption enhancers may be used to increase absorption. The absorption enhancer or carrier may comprise an absorbable pharma- ceutically acceptable solvent that aids passage through the skin. For example, a transdermal device is in the form of a bandage, which includes a backing member, a reservoir containing the compound, optionally with a carrier, optionally a rate-controlling barrier for delivering the compound to the host's skin at a controlled, predetermined rate over an extended period of time, and a means for securing the device to the skin.

[0325] Injectable preparations

[0324] Formulations containing any of the compounds of formula (I)-(Vb) suitable for intramuscular, subcutaneous, or intravenous injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, cremophor, etc.), suitable mixtures thereof, vegetable oils (olive oil, etc.), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Formulations suitable for subcutaneous injection may also contain additives such as preservatives, wetting agents, emulsifying agents, and dispensing agents. Prevention of microbial growth can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical formulations can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.

[0326] For intravenous injection, the compounds described herein can be formulated in an aqueous solution, preferably in a physiologically compatible buffer such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, a penetrant suitable for permeating the barrier is used in the formulation. Such penetrants are generally known in the art. For other parenteral injection, suitable formulations can include aqueous or non-aqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art.

[0327] Parenteral injections may include bolus injections or continuous infusions. Injectable preparations may be provided in unit dosage form, for example, in ampoules or multi-dose containers, with the addition of a preservative. The pharmaceutical compositions described herein may be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in an oily or aqueous medium, and may contain forming agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of the active compound in water-soluble form. Additionally, suspensions of the active compound may be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds, allowing for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0328] formulation In certain embodiments, delivery systems for pharmaceutical compounds may be utilized, such as, for example, liposomes and emulsions. In certain embodiments, the compositions provided herein may also include a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylic acid), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0329] In some embodiments, the compounds described herein may be administered topically and may be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated adhesives, balsams, creams, or ointments. Such pharmaceutical compounds may contain solubilizers, stabilizers, osmolality enhancers, buffers, and preservatives.

[0330]

[0329] The compounds described herein may also be formulated into rectal compositions such as enema solutions, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enema solutions containing conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, PEG, etc. In a suppository form of the composition, a low melting wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally combined with cocoa butter, is melted first.

[0331] Examples of Methods of Administration and Treatment Regimens

[0330] The compounds described herein can be used in the preparation of medicaments for the treatment of kidney-related diseases or conditions.In addition, the method for treating any of the diseases or conditions described herein in a subject in need of such treatment comprises administering to said subject a pharmaceutical composition comprising at least one compound of any of formulas (I)-(Vb) described herein, or its pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate in a therapeutically effective amount.

[0332]

[0331] The compositions containing the compounds described herein can be administered for preventive and / or therapeutic treatment. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially suppress the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and duration of the disease or condition, previous therapy, the patient's health status, weight, and response to the drug, and the judgment of the treating physician. It is well within the skill of one of ordinary skill in the art to determine such therapeutically effective amounts by routine experimentation, including but not limited to dose escalation clinical trials.

[0333] In prophylactic applications, compositions containing the compounds described herein are administered to patients susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the exact amount will also depend on the patient's health status, weight, and the like. It is well within the skill of one of ordinary skill in the art to determine such prophylactically effective amounts by routine experimentation (e.g., dose escalation clinical trials). When used in patients, the effective amount for this use will depend on the severity and duration of the disease, disorder, or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0334]

[0333] If the patient's condition does not improve, then, at the physician's discretion, administration of the compound may be administered chronically, i.e., for an extended period of time, including throughout the patient's life, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0335]

[0334] If the patient's condition improves, at the discretion of the physician, administration of the compound may be continued; alternatively, the dose of the drug being administered may be temporarily reduced or temporarily discontinued for a period of time (i.e., a "drug holiday"). The length of the drug holiday may vary between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during drug holidays may be between 10% and 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0336]

[0335] After improvement of the patient's condition occurs, a maintenance dose is administered as needed. Thereafter, depending on symptoms, the dosage or frequency of administration, or both, may be reduced to a level at which the improved disease, disorder, or condition is maintained. However, patients may require long-term intermittent treatment based on recurrence of symptoms.

[0337] The amount of a given agent that would correspond to such an amount will vary depending on factors such as the particular compound, the disease or condition and its severity, the identity (e.g., body weight) of the subject or host requiring treatment, but may nevertheless be routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated. The desired dose may conveniently be provided in a single dose, or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example, two, three, four or more sub-doses per day.

[0338]

[0337] The pharmaceutical compositions described herein may be in unit dosage forms suitable for single administration of precise dosage amounts. In unit dosage forms, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dosages may be in the form of packages containing discrete amounts of the formulation. Non-limiting examples are tablets or capsules and powders packaged in vials or ampoules. Aqueous suspension compositions may be packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers may be used, in which case it is typical to include a preservative in the composition. For illustrative purposes only, formulations for parenteral injection may be provided in unit dosage forms, including but not limited to ampoules, or multi-dose containers, to which a preservative has been added.

[0339]

[0338] The foregoing ranges are merely suggestive, since there are many variables for each individual treatment regimen, and significant deviations from these recommendations are not uncommon. Such dosages may vary depending on several variables, including but not limited to the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0340]

[0339] The toxicity and therapeutic efficacy of such a treatment regimen are evaluated by the LD 50 (the dose at which 50% of the population is lethal) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the LD 50 and ED 50 Compounds that exhibit high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds can be expressed as a ratio between the ED 50 It is preferred that the dosage form be within a circulating concentration range that includes the dosage form and the route of administration utilized.

[0341] Kit / manufactured product

[0340] Kits and articles of manufacture are also described herein for use in the therapeutic applications described herein. Such kits may include carriers, packages, or containers that are compartmentalized to accommodate one or more containers, such as vials, tubes, each of which contains one of the separate elements to be used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. Containers may be formed from a variety of materials, such as glass or plastic.

[0342] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those skilled in the art. For example, see U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. Various formulations of the compounds and compositions provided herein are contemplated, as well as various treatments for any disease, disorder, or condition that would benefit from using the compounds of the present invention.

[0343] For example, a container may contain one or more compounds as described herein, optionally in a composition or in combination with another agent as disclosed herein. The container may optionally have a sterile access port (e.g., the container may be an intravenous fluid bag or a vial having a stopper pierceable by a hypodermic injection needle). Such a kit may optionally contain a compound with an identifying description or label or instructions for use in the methods described herein.

[0344]

[0343] The kit may typically include one or more additional containers, each with one or more of the various materials (such as reagents, optionally in concentrated form, and / or devices) that are desirable from a commercial and user standpoint for the use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; carriers, packages, containers, vials and / or tube labels listing the contents and / or instructions for use, and inserts with instructions for use. A set of instructions will also typically be included.

[0345]

[0344] The label may be on the container or associated with the container. The label may be on the container when the words, numbers or other characters forming the label are attached, molded or etched on the container itself; the label may be associated with the container when it is in a receptacle or carrier that also holds the container, for example, as a package insert. The label can be used to indicate that the contents are to be used for a particular therapeutic application. The label can also indicate instructions for the use of the contents, such as in the methods described herein.

[0346] In certain embodiments, the pharmaceutical compositions may be provided in a pack or dispenser device that may contain one or more unit dosage forms containing the compounds provided herein. The pack may contain, for example, metal or plastic foils, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the approval by the agency of the form of the drug for human or veterinary administration. Such notice may be, for example, the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. Compositions containing the compounds provided herein formulated in a compatible pharmaceutical carrier may also be prepared and placed in an appropriate container and labeled for treatment of a designated condition. EXAMPLES

[0347] Working Example

[0346] The following specific non-limiting examples should be construed as merely illustrative and do not limit the present disclosure in any way. Without further explanation, it is believed that a person skilled in the art can make the most of the present disclosure based on the description herein. All publications cited herein are incorporated by reference in their entirety. When a URL or other identifier or address is mentioned, it is understood that such identifiers may change and certain information on the Internet may come and go, but equivalent information may be found by searching the Internet. Reference hereto demonstrates that such information is available and generally disseminated.

[0348]

[0347] In the examples below and throughout the specification, the following abbreviations have the following meanings: If not defined, the terms have their generally accepted meanings. aq = aqueous Boc = tert-butoxycarbonyl t-BuOH = tertiary butanol DCE = 1,2-dichloroethane DCM = dichloromethane DIAD = diisopropyl azodicarboxylate DIEA or DIPEA = N,N-Diisopropylethylamine DMAP = dimethylaminopyridine DMF = dimethylformamide DMSO = dimethyl sulfoxide ESI = electrospray ionization EA = Ethyl Acetate g = grams HCl = Hydrogen Chloride HPLC = High Performance Liquid Chromatography hr = time 1 H NMR = proton nuclear magnetic resonance IPA = Isopropyl alcohol KOAc = Potassium Acetate LC-MS = liquid chromatography mass spectrometry M = molar concentration MeCN = acetonitrile MeOH = methanol mg = milligrams min = minutes ml = milliliters mM = millimolar mmol = millimoles mp = melting point MS = mass spectrometry m / z = mass to charge ratio N = regulation NIS = N-iodosuccinimide nM = nanomolar nm = nanometers Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PE = Petroleum Ether PyBOP = Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate quant.= quantitative RP = Reverse phase RT, rt or rt = room temperature Sat.= saturation TEA = triethylamine TFA = trifluoroacetic acid μL = microliter μM = micromolar

[0349] General synthesis scheme [ka] X, Y, R 1 , and R 2 is as described herein.

[0350] Working Example Example 1 Preparation of 1-(((3,3-dimethylbutanoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide (compound 1) [ka] To a solution of nicorandil, (2-(nicotinamide)-ethyl nitrate) (0.23 mmol) in acetonitrile (3 mL) was added iodomethyl isopropyl carbamate (0.28 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. Excess acetonitrile was removed under vacuum and the resulting residue was dissolved in MeOH and washed with excess diethyl ether. This process was repeated twice and the solvent was evaporated under vacuum to give the title compound 1 as a yellow sticky solid. m / z 340.1(M + ).

[0351] Example 2 Preparation of 3-((2-(nitrooxy)ethyl)carbamoyl)-1-(((piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium iodide (compound 2) (Dugar et al. U.S. Pat. No. 9,359,376) [ka] To a solution of nicorandil, (2-(nicotinamide)-ethyl nitrate) (0.56 mmol) in acetonitrile (5 mL) was added iodomethyl 1-piperidinyl carbamate (0.68 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. Excess acetonitrile was removed under vacuum and the resulting residue was dissolved in MeOH and washed with excess diethyl ether. This process was repeated twice and the solvent was evaporated under vacuum to give the title compound 2 as a yellow solid (0.230 g, 84%). (mp 117-120° C.) m / z 353.2(M + )

[0352] Example 3 Preparation of 1-(((diisopropylcarbamoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide (compound 3) [ka] To a solution of nicorandil, (2-(nicotinamide)-ethyl nitrate) (0.71 mmol) in acetonitrile (5 mL) was added iodomethyl diisopropylcarbamate (0.71 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. Excess acetonitrile was removed under vacuum and the resulting residue was dissolved in MeOH and washed with excess diethyl ether. This process was repeated twice and the solvent was evaporated under vacuum to give the title compound 3 as a yellow solid (0.220 g, 85%). (mp 122-125° C.). m / z 369.2(M + )

[0353] Example 4 Preparation of 1-(((tert-butoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide (compound 4) [ka] To a solution of nicorandil, (2-(nicotinamide)-ethyl nitrate) (0.47 mmol) in acetonitrile (mL) was added tert-butyl(iodomethyl)carbamate (0.52 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. Excess acetonitrile was removed under vacuum and the resulting residue was dissolved in MeOH and washed with excess diethyl ether. This process was repeated twice and the solvent was evaporated under vacuum to give the title compound 4 as a yellow sticky solid (0.120 g, 54%). m / z 342.1(M + )

[0354] Example 5 Preparation of 1-(((isopropoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide (compound 5) [ka] To a solution of nicorandil, (2-(nicotinamide)-ethyl nitrate) (0.47 mmol) in acetonitrile (5 mL) was added iodomethyl isopropyl carbonate (0.56 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. Excess acetonitrile was removed under vacuum and the resulting residue was dissolved in MeOH and washed with excess diethyl ether. This process was repeated twice and the solvent was evaporated under vacuum to give the title compound 5 as a brown sticky material (0.130 g, 60%). m / z 328.1(M + )

[0355] Example 6 Preparation of (R)-1-(((sec-butoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide (compound 6) (Dugar et al. U.S. Pat. No. 9,359,376) [ka] To a solution of nicorandil, (2-(nicotinamide)-ethyl nitrate) (0.28 mmol) in acetonitrile (3 mL) was added (R)-sec-butyl(iodomethyl)carbonate (0.28 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. Excess acetonitrile was removed under vacuum and the resulting residue was dissolved in MeOH and washed with excess diethyl ether. This process was repeated twice and the solvent was evaporated under vacuum to give the title compound 6 as a yellow semi-solid. m / z 342.5(M + ).

[0356] Example 7 Preparation of (S)-1-(((sec-butoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide (compound 7) (Dugar et al. U.S. Pat. No. 9,359,376) [ka] To a solution of nicorandil, (2-(nicotinamide)-ethyl nitrate) (0.28 mmol) in acetonitrile (3 mL) was added iodomethyl (S)-sec-butyl(iodomethyl)carbonate (0.28 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. Excess acetonitrile was removed under vacuum and the resulting residue was dissolved in MeOH and washed with excess diethyl ether. This process was repeated twice and the solvent was evaporated under vacuum to give the title compound 7 as a yellow semi-solid. m / z 342.5(M + ).

[0357] Example 8 Preparation of (S)-1-(((1-cyclohexylethylcarbamoyl)oxy)methyl)-3-((2-(nitroxy)ethyl)carbamoyl)pyridin-1-ium iodide (compound 8) (compound A) (Dugar et al. U.S. Pat. No. 9,359,376) [ka] To a solution of nicorandil, (2-(nicotinamide)-ethyl nitrate) (0.28 mmol) in acetonitrile (3 mL) was added iodomethyl (S)-(1-cyclohexylethyl)carbamate (0.28 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. Excess acetonitrile was removed under vacuum and the resulting residue was dissolved in MeOH and washed with excess diethyl ether. This process was repeated twice and the solvent was evaporated under vacuum to give the title compound 8 as a yellow solid. (mp 94-98° C.) m / z 395.5(M + ). 1 H NMR(300MHz,DMSO-d6):δ 9.53(s,1H),9.45(s,1H),9.28(d,J= 6.3Hz,1H),9.03(d,J= 8.1Hz,1H),8.36(dd,J=8.1,6.3Hz,1H),7.81(d,J=9 6.3Hz,1H),6.43(dd,J=15.5,6.6Hz,2H),4.69(t,J=5.1Hz,2H),3.71(dd,J=10.5,5.1Hz,2H),3.41(m,1H),1.61(m,5H),0.79-1.25(m,9H).

[0358] Example 9 Preparation of (R)-1-(((1-cyclohexylethylcarbamoyl)oxy)methyl)-3-((2-(nitroxy)ethyl)carbamoyl)pyridin-1-ium iodide (compound 9) (Dugar et al. U.S. Pat. No. 9,359,376) [ka] To a solution of nicorandil, (2-(nicotinamide)-ethyl nitrate) (0.28 mmol) in acetonitrile (3 mL) was added iodomethyl (R)-(1-cyclohexylethyl) carbamate (0.28 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. Excess acetonitrile was removed under vacuum and the resulting residue was dissolved in MeOH and washed with excess diethyl ether. This process was repeated twice and the solvent was evaporated under vacuum to give the title compound 9 as a yellow solid. (mp 98-102° C.) m / z 395.5(M + ).

[0359] Example 10 1 Preparation of 1-((isobutyryloxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide (compound 10) [ka] To a solution of nicorandil, (2-(nicotinamide)-ethyl nitrate) (0.47 mmol) in acetonitrile (5 mL) was added iodomethyl isobutyrate (0.71 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. Excess acetonitrile was removed under vacuum and the resulting residue was dissolved in MeOH and washed with excess diethyl ether. This process was repeated twice and the solvent was evaporated under vacuum to give the title compound 10 as a brown sticky material. m / z 312.1(M + )

[0360] Example 11 Preparation of 1-(1-((diisopropylcarbamoyl)oxy)ethyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide (compound 11) [ka] To a solution of nicorandil, (2-(nicotinamide)-ethyl nitrate) (0.23 mmol) in acetonitrile (3 mL) was added 1-iodoethyl diisopropylcarbamate (0.23 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. Excess acetonitrile was removed under vacuum and the resulting residue was dissolved in MeOH and washed with excess diethyl ether. This process was repeated twice and the solvent was evaporated under vacuum to give the title compound 11 as a yellow sticky material (0.042 g, 35%). m / z 383.4(M + ).

[0361] Example 12 Preparation of 1-(((ethoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide (compound 12) [ka] To a solution of nicorandil, (2-(nicotinamide)-ethyl nitrate) (0.47 mmol) in acetonitrile (5 mL) was added ethyl (iodomethyl) carbonate (0.71 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. Excess acetonitrile was removed under vacuum and the resulting residue was dissolved in MeOH and washed with excess diethyl ether. This process was repeated twice and the solvent was evaporated under vacuum to give the title compound 12 as a brown sticky material (0.150 g, 77%). m / z 314.1(M + )

[0362] Example 13 Preparation of 1-(((isopropylcarbamoyl)oxy)methyl)-3-((2-(nitroxy)ethyl)carbamoyl)pyridin-1-ium iodide (compound 13) (Dugar et al. U.S. Pat. No. 9,359,376) [ka] To a solution of nicorandil, (2-(nicotinamide)-ethyl nitrate) (0.28 mmol) in acetonitrile (3 mL) was added iodomethyl isopropyl carbamate (0.28 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. Excess acetonitrile was removed under vacuum and the resulting residue was dissolved in MeOH and washed with excess diethyl ether. This process was repeated twice and the solvent was evaporated under vacuum to give the title compound 13 as a yellow sticky solid (0.085 g, 88%). m / z 327(M + ). 1 H NMR(DMSO-d6,300MHz):δ ppm 9.54(s,1H),9.43-9.46(m,1H),9.27-9.29(d,1H),9.01-9.04(d,1H),8.33-8.38(m,1H),7.86-7.8 8(m,1H),6.41(s,2H),4.67-4.70(t,2H),3.69-3.74(m,2H),3.52-3.63(m,1H),1.04-1.11(m,6H).

[0363] [Table 3]

[0364] [Table 4]

[0365] [Table 5]

[0366] [Table 6]

[0367] [Table 7]

[0368] Additional Exemplary Compounds of the Invention

[0361] Other compounds of the present invention have been prepared or can be prepared according to the synthetic methods described herein, or some variations thereof. The compounds can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it should be understood that other process conditions can also be used unless otherwise stated. Although optimal reaction conditions may vary with the specific reactants or solvents used, such conditions can be determined by those skilled in the art through routine optimization procedures.

[0369]

[0362] The following additional compounds are or can be prepared from readily available starting materials using the following general methods and procedures. [ka]

[0370] Pharmacokinetic studies Example 101 (PK) Pharmacokinetic (PK) Protocol: Rat A pharmacokinetic study was performed to evaluate the plasma exposure of Compound A in rats. The dosing vehicle used in this study was PEG400. Oral doses of 1, 3, and 10 mg / kg were administered in overnight fasted SD rats and parent drug produced was monitored. The presence of modified drug was also confirmed. After oral (PO) dosing, blood was collected by serial bleeding at eight different time points into heparinized tubes. Blood samples were centrifuged at 10,000 rpm for 5 minutes at 4°C to obtain plasma, which was aspirated into separate labeled tubes and stored at -80°C. Extraction solvent was added to the plasma, vortexed, shaken on a shaker for 10 minutes, and centrifuged at 10,000 rpm for 10 minutes at 4°C. The supernatant was retained for analysis. A calibration curve of acetonitrile and plasma was generated to determine the percentage of drug recovery from plasma. Quantitative analysis was performed by liquid chromatography tandem mass spectrometry (API3000 LC-MS / MS). Cmax, Tmax, AUC and t1 / 2 were calculated using Graph Pad PRISM version 5.04, and the results are shown in Table 2.

[0371] [Table 8]

[0372] Example 102 (PK) Pharmacokinetic (PK) Protocol: Dogs A pharmacokinetic study was performed to evaluate the plasma exposure of Compound A in dogs. Overnight fasted male beagle dogs were administered 3 mg / kg Compound A by oral route. 0.5 ml of blood was collected at each time point from the femoral vein via direct adhesion in tubes containing anticoagulant at the designated time points. Blood samples were centrifuged at 10,000 rpm for 5 minutes at 4°C to obtain plasma, which was drawn into separate labeled tubes and stored at -80°C. Extraction solvent was added to the plasma, vortexed, shaken on a shaker for 10 minutes, and centrifuged at 10,000 rpm for 10 minutes at 4°C. The supernatant was retained for analysis. A calibration curve of acetonitrile and plasma was made to determine the percentage of drug recovery from plasma. Quantitative analysis was done by liquid chromatography tandem mass spectrometry (API3000 LC-MS / MS). Cmax, Tmax, AUC and t1 / 2 were calculated using Graph Pad PRISM version 5.04 and the results are shown in Table 3.

[0373] [Table 9]

[0374] Compound A showed excellent plasma exposure in rats and dogs. In both cases, only the parent drug was detected in plasma, and the modified drug was not detected. Plasma exposure in rats showed dose linearity. In dogs, plasma exposure was significantly higher as indicated by the relatively high AUC and Cmax pharmacokinetic parameters for Compound A (3 mg / kg oral dose in beagle dogs) (Table 4).

[0375] [Table 10]

[0376] Example 201 (Pharmacology Assay) Efficacy study of Compound A in diabetic nephropathy Animal studies using eNOSKO mice All animal experiments will be performed in accordance with Institutional Animal Care and Use Committee (IACUC) protocols. Male C57BL / 6J-Nos3tm1nc mice (eNOSKO mice) will be purchased from Jackson Laboratory (Bar Harbor, ME) at 8 weeks of age. Mice will be fed ad libitum with standard laboratory chow. Diabetic nephropathy will be induced by intraperitoneal injection of streptozotocin (50 mg / kg / day for 5 consecutive days) dissolved in 10 mM citrate buffer, pH 4.5. Diabetes will be defined as a nonfasting blood glucose of 250 mg / dl using a blood glucose meter (One Touch Ultra; Life Scan, Milpitas, CA). Only mice that developed hyperglycemia at week 4 will be included in the study. Mice will be divided into four subgroups: 1) non-diabetic group, 2) non-diabetic group treated with compound A, 3) diabetic group, and 4) diabetic group treated with compound A (n 8 / group) (Tanabe et al., Am. J. Physiol Renal Physiol 2012, 302, 151-160). At week 4, when the onset of diabetes is confirmed in all animals, 30 mg / kg compound A (Chugai Pharmaceutical Co., Tokyo, Japan) will be started. To always administer the same amount of compound A (30 mg / kg / day), the compound A concentration in the drinking water will be adjusted according to the water intake volume every 4 days. Water bottles will be monitored daily throughout the study to ensure there is no leakage. Systolic blood pressure will be measured every other week using a tail cuff sphygmomanometer (Visitech BP-2000; Visitech Systems, Apex, NC). Urine will be collected overnight using metabolic cages (Techniplast, Exton, PA). All mice will be euthanized 8 weeks after initiating Compound A treatment to collect blood samples and kidney tissue.

[0377] Laboratory Testing Urinary albumin, urinary 8-hydroxy-2-deoxyguanosine (8-OHdG), and urinary creatinine will be measured by Albuwell M (Exocell, Philadelphia, PA), OxiSelect Oxidative DNA Damage ELISA Kit (Cell Biolabs, San Diego, CA), and Creatinine LiquiColor test (Enzymatic Methodology; Stanbio, Boerne, TX), respectively. Serum creatinine concentrations will be analyzed by HPLC-tandem mass spectrometry (MS / MS; Applied Biosystems 3200 Qtrap). Creatinine and [2H3]creatinine (CDN isotope) will be detected in multiple reaction monitoring mode monitoring the transitions from m / z 114 to 44.2 and m / z 117 to 47.2, respectively. Serum levels of P-selectin and ICAM-1 will be measured with Mouse P-selectin / CD62 Quantikine ELISA kits and Mouse ICAM-1 / CD54 Quantikine ELISA kits, respectively (R&D Systems, Minneapolis, MN).

[0378] Histological analysis Formalin-fixed paraffin-embedded sections (2.5-m) will be stained with Periodic Acid-Schiff's reagent (PAS) for light microscopy. For coronal sections of the kidney, all glomeruli (50-100 glomeruli) will be examined for assessment of mesangial lysis and glomerulosclerosis. Glomerular sclerosis will be defined as the obstruction of the capillary lumen caused by mesangial expansion and capillary collapse, while the degree of mesangial lysis will be calculated as the number of glomeruli with mesangial lysis (melting of the mesangial matrix) divided by that of the total glomeruli. Kidney sections will be observed blinded by two investigators.

[0379] immunohistochemistry Either formalin or methyl Carnoy's solution-fixed paraffin-embedded sections will be used for immunohistochemistry. The following antibodies will be used as primary antibodies: 1) rabbit anti-type IV collagen antibody (Chemicon International, Temecula, CA); 2) rat anti-mouse F4 / 80 antibody (Serotec, Raleigh, NC); 3) rabbit anti-WT-1 antibody (Santa Cruz Biotechnology, Santa Cruz, CA); 4) goat anti-8-OHdG antibody (Abcam, Cambridge, MA); 5) rabbit anti-nitrotyrosine antibody (Chemicon); and 6) rabbit anti-NPHS2 (podocin) antibody (Abcam). Briefly, after deparaffinization, sections will be treated with 3% H2O2 for 10 minutes to inactivate endogenous peroxidase activity. For F4 / 80, 8-OHdG, and nitrotyrosine, sections will be treated with 10 mM citrate buffer (pH 6.0) for 30 min in a steamer for antigen retrieval. After incubation with Background Sniper (Biocare Medical, Concord, CA) for 15 min, sections will be incubated with primary antibodies overnight at 4°C. Sections will also be incubated with rabbit anti-IgG secondary antibody for 30 min, after which immunoperoxidase staining will be performed using Mach2 rabbit HRP polymer (Biocare Medical). Slides will be counterstained with methyl green. The number of positive cells for F4 / 80 will be counted in all glomeruli at 400x in each section. After immunohistochemistry for WT-1 is performed, the number of podocytes per glomerulus will be calculated using the Beibel-Gomez method. Ten representative glomeruli will be analyzed for each section for this calculation. To assess collagen IV and podocin positive areas, 400x digital images will be analyzed using Image scope software (Aperio Technologies, Vista, Calif.).The percent positive area will be determined as the 3,3-diaminobenzidine positive pixel value per area of ​​interest examined from all glomeruli in each section. Immunofluorescence in mouse kidney double immunofluorescence staining will be performed. Briefly, frozen sections (4-m) will be fixed in acetone for 10 min. Sections will be blocked with 5% animal serum conjugate, followed by incubation overnight at 4°C with primary antibodies (rabbit anti-ABCC9 (sulfonylurea receptor 2; SUR-2) antibody (Abcam), rabbit anti-cGMP antibody (Chemicon), or mouse monoclonal anti-synaptopodin antibody (Novus Biologicals, Littleton, CO)). After incubation with either Alexa Fluor 488-labeled goat anti-rabbit IgG (Invitrogen, Carlsbad, CA) or Alexa Fluor 546-labeled goat anti-mouse IgG (Invitrogen) for 2 h at room temperature, sections will be mounted with vectashield anti-fade mounting medium (Vector Labs, Burlingame, CA). A confocal laser microscope LSM 510 META (Carl Zeiss Microimaging, Thornwood, NY) will be used to capture images.

[0380] Western blotting Kidney tissue will be homogenized in cell lysis buffer (Cell Signaling, Danvers, MA) at 4°C. Briefly, samples will be processed for SDS-PAGE and electrophoretically transferred onto nitrocellulose membrane. Rabbit anti-nitrotyrosine (Chemicon) antibody, rabbit anti-actin antibody (Sigma-Aldrich, St. Louis, MO), HRP-labeled anti-rabbit IgG antibody (Cell Signaling), and Immun Star HRP (Bio-Rad, Hercules, CA) will be used. The density of each band will be determined using National Institutes of Health image software and expressed as a value relative to the density of the corresponding band of actin.

[0381] cell culture Conditionally immortalized human podocytes will be cultured in RPMI 1640 medium (Mediatech, Manassas, VA) supplemented with 10% FBS, penicillin (100 U / l), streptomycin (100 g / l), and insulin-transferrin-selenium A supplement (Invitrogen). Cells will be cultured at 33°C to enhance large T antigen expression and enrich for podocytes, followed by 10 days of incubation at 37°C to induce differentiation into mature podocytes before the start of experiments. For experimental testing, podocytes will be cultured for 72 hours in DMEM containing 5.5 mM normal glucose (NG), NG 19.5 mM mannitol (NGMan), 25 mM high glucose (HG), and HG 105M compound A (HG Nico).

[0382] PCR Total RNA will be extracted from cultured podocytes using RNeasy Mini kit (Qiagen, Chatsworth, CA). First strand cDNA will be synthesized from 1 g of total RNA using iScript cDNA synthesis kit (Bio-Rad). For detection of SUR2A and SUR2B mRNA, the following oligonucleotide primers will be used: SUR2A, 5=-TGAGGGTATTTTAGTGGAGTGTG-3=(forward) and 5=-CAAAGTGGAAAAGAGGCCATTC-3=(reverse); SUR2B, 5=-TGGTGACAATAGCTCATCGAG-3=(forward) and 5=-TCCATTTTCCTGAGCCAAGAG-3=(reverse); and -actin, 5=-TGAGATGCGTTGTTACAGGAAG-3=(forward) and 5=-GTGGACTTGGGAGAGGACTG-3=(reverse). The PCR program will be optimized and performed using a MyiQ Single-Color Real-Time PCR Detection System (Bio-Rad) with denaturation at 95° C. for 3 min followed by 50 cycles of amplification (SUR2A and SUR2B, 95° C. for 30 s, 54° C. for 30 s, 72° C. for 1 min, respectively; -actin, 95° C. for 30 s, 56° C. for 30 s, 72° C. for 1 min). The amount of PCR product will be normalized to -actin mRNA to determine the relative expression ratio for SUR2A and SUR2B mRNA.

[0383] ROS detection assay in cultured podocytes The generation of ROS will be measured using Image-iT LIVE Green Reactive Oxygen Species Detection Kit (Invitrogen). Briefly, podocytes will be incubated in PBS containing 25M 5-(and 6)-carboxy-2=,7=-dichlorodihydrofluorescein diacetate (carboxy-H2DCFDA) for 30 minutes at 37°C in the dark. This probe is converted by intracellular esterases and ROS to carboxy-DCF, which emits bright green fluorescence. After incubation, cells will be washed three times with PBS and observed by a confocal laser microscope LSM 510 META (Carl Zeiss) to obtain images. The intensity in podocytes will be measured by Zen 2009 software (Carl Zeiss). A total of 10 fields (at 400) will be examined to determine the average value of cells for each image.

[0384] number of cells The number of cultured podocytes will be evaluated using a conventional MTT assay. Podocytes will be seeded in 96-well plates at 10,000 cells / well and differentiated for 10 days at 37°C. After 72 hours of stimulation with NG or HG medium with or without compound A, 20 μl of thiazolyl blue tetrazolium bromide (Sigma-Aldrich) dissolved in PBS at 5 mg / ml will be added to each well containing 100 μl of medium, and the plate will be incubated at 37°C for 3 hours. After MTT solvent (4 mM HCl and 0.1% P-40 in isopropanol) is used, absorbance will be read at 590 nm with a reference filter of 620 nm. Data will be expressed as values ​​relative to NG.

[0385] statistical analysis All values ​​are expressed as mean SD. Statistical analysis will be performed with ANOVA using Tukey's method (for in vivo experiments) or Bonferroni's method (in vitro experiments) to compare the four groups. A level of P<0.05 will be considered statistically significant.

[0386] Example 202 (Pharmacology Assay) Efficacy study of Compound A in chronic kidney disease Animal studies using the remnant kidney (RK) model to test CKD All animal experiments will be performed in accordance with and with the approval of the Institutional Animal Care and Use Committee. Male Sprague-Dawley rats (200-240 g) will undergo baseline blood pressure (BP) and renal function assessments and will be randomly assigned to RK or sham-operated control groups. For the RK group, right subcapsular nephrectomy will be performed followed by surgical resection of the upper and lower thirds of the left kidney (Tamura et al., Am. J. Physiol Renal Physiol 2012, 303, 339-349). Rats will be divided into four subgroups: 1) sham group, 2) RK group, 3) RK with low dose Compound A (3 mg / kg / day), and 4) RK with high dose Compound A (30 mg / kg / day) (n 7 for each group). All rats will be fed ad libitum. Two weeks after surgery, rats will be randomized based on blood urea nitrogen (BUN) levels before compound A treatment (Chugai Pharmaceutical Co., Tokyo, Japan) is started. To always administer the same amount of compound A (30 mg / kg / day), the concentration of compound A in the drinking water will be adjusted according to the water intake volume every 4 days. Water bottles will be monitored daily throughout the study to ensure there is no leakage. Systolic BP will be measured at 0, 4, and 12 weeks using a tail cuff sphygmomanometer (Visitech BP-2000; Visitech Systems, Apex, NC). Urine will be collected overnight using metabolic cages (Techniplast, Exton, PA) before death. All of the rats will be killed at 12 weeks to obtain blood samples and kidney tissue.

[0387] Laboratory Testing Urinary albumin, urinary 8-hydroxy-2=-deoxyguanosine (8-OHdG), xanthine oxidase activity, and urinary creatinine will be measured by Nephrat (Exocell, Philadelphia, PA), OxiSelect oxidative DNA damage ELISA kit (Cell Biolaborators, San Diego, CA), xanthine oxidase assay kit (Cayman, Ann Arbor, MI), and creatinine LiquiColor test (enzymatic methodology; Stanbio, Boerne, TX), respectively. Uric acid levels in renal cortex will be determined by Quantichrom uric acid assay kit (Bioassay System, Hayward, CA). In contrast, serum levels of uric acid, BUN, and creatinine will be determined by VetACE clinical chemistry system (Alfa Will besermann, NJ). Serum cystatin-C concentrations will be determined by mouse / rat cystatin-C ELISA kits (R&D Systems, Minneapolis, MN). To examine renal NO, urinary nitrate (NO3) and nitrite (NO2) will be determined by a NO analyzer 280i (SIEVERS, Boulder, CO).

[0388] Histological analysis Formalin-fixed paraffin-embedded sections (2.5 m) will be stained with periodic acid-Schiff's reagent for light microscopy. For coronal sections of the kidney, all glomeruli (50-100 glomeruli) will be examined for assessment of glomerulosclerosis. Glomerulosclerosis will be defined as obstruction of the capillary lumen caused by mesangial expansion or capillary collapse. Kidney sections will be observed blinded by two investigators. Primary antibodies for immunohistochemistry and Western blotting. Goat anti-human type IV collagen antibody (Southern Biotech, Birmingham, AL) and mouse anti-rat CD68 antibody (AbD Serotec, Oxford, UK) will be used for glomerular injury. Rabbit anti-human WT-1 antibody (Santa Cruz, Santa Cruz, CA) and rabbit anti-human NPHS2 (podocin) antibody (Abcam, Cambridge, MA) will be used to detect podocytes. To examine tubulointerstitial injury, goat anti-human collagen type III antibody (Southern Biotech) will be used. Mouse anti-rat CD11b / c equivalent antibody (OX42) (Abcam) will identify the phenotype of immune cells in the interstitium. Goat anti-human sulfonylurea receptor (SUR)-2B (C-15) antibody (Santa Cruz) and rabbit anti-human ABCC9 antibody (Abcam) will detect SUR. Rabbit anti-rat manganese SOD (MnSOD) (Enzo Life Sciences, Farmingdale, NY), rabbit anti-human xanthine oxidase (H-110) antibody (Santa Cruz), mouse anti-nitrotyrosine antibody (Millipore, Billerica, MA), mouse anti-GAPDH antibody (Millipore), and rabbit anti-mouse heme oxygenase-1 antibody (Stressgen, Ann Arbor, MI) will also be used.

[0389] immunohistochemistry Either formalin or methyl Carnoy's solution-fixed paraffin-embedded sections will be used for immunohistochemistry. To identify cell types, serial section (1.5 m) techniques will be used with cell type specific markers. Briefly, after deparaffinization, sections will be treated with 3% H2O2 for 10 min to inactivate endogenous peroxidase activity. For WT-1, CD68, CD11b / c, and SUR2, sections will be treated with 10 mM citrate buffer (pH 6.0) for 30 min in a steamer for antigen retrieval. Sections will be incubated with primary antibodies overnight at 4°C, followed by secondary antibodies for 30 min. Color development will be achieved using diaminobenzidine with / without nickel chloride. All glomeruli at 400x or 15 fields (each field / 0.4mm2) in each section will be used to count the number of positive cells for CD68, CD11b / c, or WT-1. To evaluate collagen IV and podocin positive areas, 400x digital images will be analyzed using Image scope software (Aperio Technologies, Vista, CA). The percentage of positive area will be determined as diaminobenzidine positive pixels per total pixels in the area of ​​interest from all glomeruli in each section. Similarly, the positive area for collagen III in the interstitium will also be determined as the percentage of positive area by 15 fields (each field / 0.4mm2).

[0390] Western blotting Renal cortex will be homogenized in cell lysis buffer (Cell Signaling, Danvers, MA) at 4°C. Briefly, samples will be processed for SDS-PAGE and electrophoretically transferred onto nitrocellulose membranes. After overnight incubation with primary antibodies at 4°C, membranes will be incubated with secondary antibodies linked to horseradish peroxidase for 1 hour at room temperature. Signals will be detected by Immun Star HRP (Bio-Rad, Hercules, CA). The density of each band will be determined using National Institutes of Health image software and expressed as a value relative to the density of the corresponding band of -actin or GAPDH.

[0391] cell culture RAW264.7 cells (ATCC, Manassas, VA), a macrophage cell line, will be cultured in Dulbecco's modified Eagle's medium (Cellgro, Manassas, VA) supplemented with 10% FBS, penicillin (100 U / l), and streptomycin (100 g / l). Subconfluent cells will be stimulated with angiotensin II (Sigma-Aldrich) at 37°C after 30 min pretreatment with various concentrations of Compound A in serum-free medium. Xanthine oxidase expression will be tested after 8 h of exposure to glibenclamide (Sigma). Each experiment will be repeated at least four times.

[0392] statistical analysis

[0385] All values ​​are expressed as mean SE. Statistical analysis will be performed with ANOVA using Tukey's method. A level of P<0.05 will be considered statistically significant.

[0393] Example 203 (Pharmacology Assay) Efficacy study of Compound A in acute kidney injury Animal studies on drug-induced AKI models All animal experiments will be performed in accordance with and with the approval of the Institutional Animal Care and Use Committee. Adult male Wistar rats (150-200 g) will be used for this study. They will be housed in standard rat cages (421-290 mm). All animals will be exposed to a 12-hour light-dark cycle and will have access to drinking water and rat chow ad libitum.

[0394] Drug dose resulting in AKI A rat model of tenofovir disoproxil fumarate (TDF) nephrotoxicity recently standardized in the Isaac laboratory will be used. (8) TDF at a dose of 600 mg / kg body weight / day orally for 5 weeks (which is 12x the clinical dose) produces severe damage to renal proximal tubule mitochondria as seen in humans and will therefore be utilized for the purposes of this study.

[0395] Experimental design

[0388] Rats will be randomly assigned to two groups and will be treated as follows:

[0396] Group I (Control): This group of rats (n=6) received only sterile water by gavage.

[0397] Group II: This group of rats (n=6) received 600 mg / kg body weight TDF dissolved in sterile water by gavage for 5 weeks. Control animals will be treated with sterile water on the same schedule as the TDF treatment and will be sacrificed at the same time as the TDF-treated and control rats.

[0398] measurement Fluid and food intake, mortality, clinical findings, and body weight Animals will be checked daily for clinical signs of toxicity, morbidity, or mortality. Body weights will be measured weekly. All rats will be sacrificed 24 hours after the last dose of TDF / sterile water. 24 hours prior to sacrifice, rats will be placed individually in metabolic cages and urine will be collected for biochemical analysis. On day 36, blood samples will be collected from rats under halothane anesthesia by cardiac puncture into tubes and allowed to clot at room temperature. Serum will then be separated by centrifugation at 1200×g for 15 minutes at 4° C. for clinical chemistry. Both kidneys will be removed and weighed. One kidney will be cut into rings; one portion will be fixed in 10% buffered formalin for light microscopy, and the remaining portion will be fixed in 3% glutaraldehyde for electron microscopy. The other kidney will be stored at −70° C. until use.

[0399] Renal morphological experiments After fixation of kidney tissue in 10% buffered formalin for 24 hours at room temperature, sections will be embedded in paraffin and subsequently sectioned. Paraffin sections of 4 micrometer thickness will be stained with hematoxylin and eosin (H&E) for light microscopic examination using conventional protocols. A minimum of eight fields will be examined for each kidney section and assigned a severity of changes by an observer blinded to the treatment of the animals. Tubular damage will be graded on a semiquantitative scale. Tubular damage will be defined as necrosis of the tubular epithelium, cast formation, tubular swelling, and loss of the brush border. Tubular damage will be scored by grading the percentage of damaged tubules under 10 randomly selected non-overlapping fields (magnification, 200×) as follows: 0, 0%; 1, 10%; 2, 11-25%; 3, 26-45%; 4, 46-75%; and 5, 76-100%. To score damaged tubules, the number of total tubules per field will be taken as the standard under a magnification of 200×. The grading percentage will be calculated in each field as follows: Damage score (%) = number of damaged tubules / total number of tubules × 100.

[0400] Kidney Tissue Ultrastructure Electron Microscopy (EM) Study: Renal tissue will be fixed in 3% glutaraldehyde, held in buffer, postfixed with 1% osmium tetroxide, held in buffer, and dehydrated in increasing concentrations of alcohol. Tissue will be held with propylene oxide and embedded in epoxy resin embedding medium. Sections (0.5 μm) will be cut with a glass knife and stained with toluidine blue for orientation. Ultrathin (900A°) sections will be cut with a diamond knife, stained with uranyl acetate and lead citrate, examined, evaluated, and photographed by EM. Each EM photomicrograph will be independently reviewed by two investigators. Parameters included the presence of structurally abnormal mitochondria, increased number of mitochondrial profiles per field, intramitochondrial lamellar bodies, abnormal cristae density, cristae duplication, mitochondrial swelling, and intramitochondrial paracrystals. Next, the degree of mitochondrial ultrastructural damage in renal proximal tubule cells will be quantitatively assessed (on a scale of 0-5) based on a cell injury staining system. This staining system enumerates the characteristic deterioration of ultrastructural changes occurring in cells in various models of inflammatory injury. The association between the degree of mitochondrial injury and predefined stages of cell injury will be utilized to quantify and standardize the severity of ultrastructural damage to renal proximal tubule mitochondria.

[0401] serum clinical chemistry

[0394] Serum will be separated and used for estimation of phosphate, potassium, bicarbonate, uric acid, glucose, urea, and creatinine.

[0402] urinalysis

[0395] Urine samples will be centrifuged to remove suspended material and the supernatant will be used for estimation of bicarbonate, phosphate, potassium, and uric acid. Glucose and protein will be semi-quantified by urine dipstick. Low molecular weight proteins in urine will be detected by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE).

[0403] Detection of low molecular weight proteins in urine by SDS PAGE Urinary proteins will be measured by the Lowry method and fractionated by SDS-PAGE using an 8% resolving gel and a 5% stacking gel. Each sample containing 100 μg of urinary protein will be mixed with protein dissociation buffer in a 1:1 ratio and kept in a boiling water bath for 5 minutes. The samples will be centrifuged briefly; then they will be loaded into the wells. Running gel buffer (pH 8.6) will be added to the electrophoresis tank. The instrument will be connected to a power pack and run at 70 V until the samples reach the resolving gel. The applied voltage will be increased to 90 V at this point. Electrophoresis will be stopped when the marker dye reaches near the end of the gel. After electrophoretic separation, the gels will be stained with Coomassie Blue solution (0.01% Coomassie Brilliant Blue R 250, 50% (v / v) methanol, and 10% (v / v) glacial acetic acid) for 3 h at room temperature, followed by destaining in destaining solution (50% (v / v) methanol and 10% (v / v) acetic acid) for 2 h. Gel images will be captured and analyzed by a gel documentation system (Alpha Innotech) using Alpha Ease software.

[0404] Measurement of parameters of mitochondrial function Preparation of kidney homogenates The resulting kidney tissue will be kept in ice-cold saline, the capsule removed, divided into small pieces using sharp scissors, and immediately homogenized (10-15 strokes) in homogenization buffer containing 0.05 M HEPES and 125 mM KCL, pH 7.4 (10% w / v) at 5000 rpm for 3 min using a Potter-Elvehjem homogenizer. The homogenate will be centrifuged at 7500 rpm for 10 min. The supernatant will be used for biochemical assays.

[0405] Isolation of kidney mitochondria Kidney tissue will be homogenized (5%) using homogenization buffer consisting of 220 mM mannitol / 70 mM sucrose / 5 mM Tris / 1 mM EGTA; pH 7.4. The homogenate will be centrifuged at 4000 Å~g for 10 min and the nuclear pellet will be discarded. The crude mitochondrial fraction will be obtained by centrifugation at 12,000× for 20 min and the pellet will be washed with a washing buffer containing 220 mM mannitol / 70 mM sucrose / 20 mM HEPES; pH 7.4. The final pellet will be suspended in the same buffer. Mitochondrial purity will be confirmed by enrichment of the marker enzyme succinate dehydrogenase. The isolated mitochondria will also be used to assess their function and to measure mitochondrial activity.

[0406] Mitochondrial swelling Mitochondrial swelling will be determined by following the decrease in absorbance at 540 nm for 10 minutes. The mitochondrial suspension will be added to a cuvette containing buffer (250 mM sucrose / 5 mM HEPES, pH 7.4). The combination will be mixed quickly and the change in absorbance will be measured in a spectrophotometer at 540 nm for 10 minutes.

[0407] Example 301: Pharmaceutical Compositions

[0400] The following compositions are provided with compounds of Formulae (I)-(Vb) for illustrative purposes.

[0408] Example 301a: Parenteral Composition

[0401] To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a compound of Formulae (I)-(Vb) is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a unit dosage form suitable for administration by injection.

[0409] Example 301b: Oral Composition To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of Formulae (I)-(Vb) is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, suitable for oral administration.

[0410] Example 301c: Sublingual (hard lozenge) composition To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, 100 mg of a compound of Formulae (I)-(Vb) is mixed with 420 mg of powdered sugar mixed with 1.6 mL of light corn syrup, 2.4 mL of distilled water, and 0.42 mL of mint extract. The mixture is gently mixed and poured into a mold to form a lozenge suitable for buccal administration.

[0411] Example 301d: Inhalation Composition To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound of Formulae (I)-(Vb) is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, suitable for inhalation administration.

[0412] Example 301e: Rectal gel composition To prepare a pharmaceutical composition for rectal delivery, 100 mg of a compound of Formulae (I)-(Vb) is mixed with 2.5 g of methylcellulose (1500 mPa), 100 mg of methylparaben, 5 g of glycerin, and 100 mL of purified water. The resulting gel mixture is then incorporated into a rectal delivery unit, such as a syringe, suitable for rectal administration.

[0413] Example 301f: Topical gel composition To prepare a topical gel pharmaceutical composition, 100 mg of a compound of Formulae (I)-(Vb) is mixed with 1.75 g of hydroxypropylcellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate, and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into a container, such as a tube, suitable for topical administration.

[0414]

[0407] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various improvements or modifications in light of them will be suggested to those skilled in the art and are to be included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

[0415]

[0408] At least some of the chemical names of the compounds of the present invention provided and described in this application may be automatically generated by using commercially available chemical naming software programs and have not been independently verified. In the event that the chemical name shown and the structure depicted differ, the structure depicted shall prevail. In chemical structures in which a chiral center exists but no specific stereochemistry is shown at the chiral center, both enantiomers associated with the chiral structure are encompassed by the structure.

[0416] References: 1) Breyer MD, Susztak K. The next generation of therapeutics for chronic kidney disease. Nat Rev Drug Discov. 2016 Aug;15(8):568-88 2) Uchino S. The epidemiology of acute renal failure in the world. Curr Opin CritCare. 2006 Dec;12(6):538-43 3) Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol.2005 Nov;16(11):3365-70. 4) Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, Schetz M, TanI, Bouman C, Macedo E, Gibney N, Tolwani A, Ronco C; Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA.2005 Aug 17;294(7):813-8 5) Mehta RL, Pascual MT, Soroko S, Savage BR, Himmelfarb J, Ikizler TA, Paganini EP, Chertow GM; Program to Improve Care in Acute Renal Disease. Spectrum of acute renal failure in the intensive care unit: the PICARD experience. Kidney Int. 2004 Oct;66(4):1613-21 6) Pannu N, Nadim MK. An overview of drug-induced acute kidney injury. Crit Care Med. 2008 Apr; 36(4 Suppl:S216-23) 7) Awdishu L, Mehta RL. The 6R’s of drug induced nephrotoxicity. BMC Nephrol.2017 Apr 3;18(1):124 8) Ramamoorthy H, Abraham P, Isaac B. Mitochondrial dysfunction and electron transport chain complex defect in a rat model of tenofovir disoproxil fumarate nephrotoxicity. J Biochem Mol Toxicol. 2014 Jun; 28(6):246-55

Claims

1. 1. A pharmaceutical composition for treating a kidney-related disease or condition in a mammal, said pharmaceutical composition comprising a compound according to formula (Va) or formula (Vb): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof (In the formula, X - is I-) 13. A pharmaceutical composition comprising:

2. The compound has the formula (Va): 【Chemistry 2】 (In the formula, X - is I-) The pharmaceutical composition according to claim 1 ,

3. The compound has the formula (Vb): 【Chemistry 3】 (In the formula, X - is I-) The pharmaceutical composition according to claim 1 or 2,

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition comprises a pharma- ceutically acceptable excipient.

5. 5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is formulated for a route of administration selected from oral, parenteral, buccal, nasal, topical, or rectal administration.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the disease or condition is chronic kidney disease, diabetic nephropathy, IgA nephropathy, acute renal failure, acute tubular necrosis, transplant-related ischemia, acute kidney disease, as well as cisplatin-induced AKI, aminoglycoside-induced AKI, tenofovir-induced AKI, contrast nephropathy, AKI after surgery for partial nephrectomy, AKI after kidney transplantation, AKI in patients with dialysis, AKI after cardiac surgery, AKI in patients in the ICU, AKI caused by cirrhosis or sepsis, and AKI caused by hepatorenal syndrome.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the disease or condition is chronic kidney disease.

8. The pharmaceutical composition according to any one of claims 1 to 6, wherein the disease or condition is acute kidney injury.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the compound of formula (Va) or formula (Vb) is administered orally.

10. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is a non-aqueous formulation comprising one or more selected from the group consisting of one or more polyols and ethanol.

11. 11. The pharmaceutical composition of claim 10, wherein the one or more polyols are selected from propylene glycol, polyethylene glycol, cremophor, and glycerol.

12. 12. The pharmaceutical composition of claim 11, wherein the compound is chemically stable with a purity of at least 95%.

13. 13. The pharmaceutical composition of claim 12, wherein the purity is at least 99%.

14. The use of a compound according to formula (Va) or formula (Vb) in the manufacture of a pharmaceutical composition, medicament or kit for the treatment of a kidney-related disease or condition: 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof (Wherein, X- is I-) Use of.

15. The compound of claim 1, wherein the compound has formula (Va): 【Chemistry 5】 (Wherein, X- is I-) The use according to claim 14, 16. The compound of claim 1, wherein the compound has formula (Vb): 【Chemistry 6】 (Wherein, X- is I-) The use according to claim 14 or 15, 17. The use according to any one of claims 14 to 16, wherein the pharmaceutical composition comprises a pharma- ceutically acceptable excipient.

18. The use of claim 17, wherein the pharmaceutical composition is formulated for a route of administration selected from oral, parenteral, buccal, nasal, topical, or rectal administration.

19. The use according to any one of claims 14 to 18, wherein the disease or condition is chronic kidney disease, diabetic nephropathy, IgA nephropathy, acute renal failure, acute tubular necrosis, transplant-related ischemia, acute kidney disease, as well as cisplatin-induced AKI, aminoglycoside-induced AKI, tenofovir-induced AKI, contrast nephropathy, AKI after surgery for partial nephrectomy, AKI after kidney transplantation, AKI in patients on dialysis, AKI after cardiac surgery, AKI in patients in the ICU, AKI caused by cirrhosis or sepsis, and AKI caused by hepatorenal syndrome.

20. The use according to any one of claims 14 to 19, wherein the disease or condition is chronic renal disease.

21. The use described in any one of claims 14 to 19, wherein the disease or condition is acute kidney injury.

22. The use according to any one of claims 14 to 21, wherein the compound of formula (Va) or formula (Vb) is administered orally.

23. The use of claim 18, wherein the parenteral administration is selected from intravenous, subcutaneous, or intramuscular administration.

24. The use described in any one of claims 14 to 16, wherein the pharmaceutical composition is a non-aqueous formulation comprising one or more selected from the group consisting of one or more polyols and ethanol.

25. The use of claim 24, wherein the one or more polyols are selected from propylene glycol, polyethylene glycol, cremophor, and glycerol.

26. The use of claim 25, wherein the compound is chemically stable and has a purity of at least 95%.

27. The use of claim 26, wherein the purity is at least 99%.

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