Water-soluble prodrugs of PTBA for use in HDAC inhibition and promoting renal recovery after acute kidney injury

Abstract

In particular, novel compounds and compositions comprising same, methods for their manufacture and use are disclosed for inhibiting HDAC or HDAC activity, more particularly and preferably for promoting renal recovery after acute kidney injury (AKI) through HDAC inhibition.

Description

[Technical Field]

[0001] The present invention relates to novel prodrugs of 4-(phenylthio)butanoic acid (PTBA) and compositions containing same, and methods for their preparation and use, particularly for use in inhibiting histone deacetylase (HDAC) activity and / or preferably for use in promoting renal recovery after acute kidney injury (AKI) through HDAC inhibition. [Background technology]

[0002] Severe acute kidney injury (AKI) is highly prevalent, and this unacceptably high mortality rate has remained unchanged for over 20 years. AKI treatments developed in experimental models have failed to demonstrate therapeutic efficacy in humans when administered before the onset of injury. AKI is a multifactorial disease that occurs in approximately 7% of hospitalized patients. It is an independent predictor of in-hospital mortality. Severe AKI requiring renal replacement therapy occurs in 4% of critically ill patients, with a 50% mortality rate among hospitalized patients.

[0003] Long-term follow-up studies of survivors of severe AKI have shown that approximately 12.5% ​​become dialysis-dependent. Despite these alarming statistics, renal replacement is the only approved treatment for AKI, and no established treatment has yet been proven to prevent kidney damage in humans or accelerate the rate of kidney recovery after AKI induction. While not wishing to be bound by any particular theory, chronic kidney disease (CKD) similarly suffers from a lack of available treatments and may involve a similar pathway of kidney injury. Therefore, there is an urgent need to develop effective therapies to accelerate the rate of recovery after induction of kidney injury. WO2012109527 (the entire text of which is incorporated herein by reference) provides examples of useful specific therapies.

[0004] Despite the above, the kidney has an innate ability to undergo epithelial regeneration after injury, suggesting that drugs that enhance this regenerative capacity may be more beneficial if provided after the onset of injury. Guo et al. (2014) published a paper entitled "Epigenetic Regulation of Kidney Injury and Kidney Repair," in which they investigated the role of epigenetic regulation (e.g., involving notable changes in histone modification, DNA methylation, and expression of various non-coding RNAs) in the process of AKI and kidney repair. In summary, increased histone acetylation levels appear to protect the kidney from AKI and promote kidney repair. AKI is also associated with genome-wide and gene-specific DNA methylation changes, but the role and regulation of DNA methylation in kidney injury and repair remain largely unknown. In 2010, DeGroh et al. (2010) published a paper entitled "Protein-Based Imaging of Zebrafish Embryos and Renal Progenitor Cells," in which they identified 4-(phenylthio)butanoic acid (PTBA), a novel histone deacetylase inhibitor (HDACi), that appears to promote renal recovery by expanding a population of renal progenitor cells in a proliferation-dependent manner in zebrafish embryos, increasing renal tubular endothelial cell (RTEC) proliferation, and reducing renal fibrosis. Without being bound by any theory, PTBA has been shown to increase renal tubular cell proliferation, improve survival, and enhance recovery of renal function in fish and various models of acute kidney injury. Immunohistochemical analysis suggested increased cell proliferation accompanied by increased epithelial-mesenchymal transition in RTECs. Subsequently, Cosentino et al. (2010) published a paper entitled "Protein-Based Imaging of Zebrafish Embryos and Renal Progenitor Cells," ... Patent Document 1 and corresponding Patent Document 2 further disclose a document titled "A Class of HDAC Inhibitors Expands the Renal Progenitor Cells Population and Improves the Rate of Recovery from Acute Kidney Injury." Each of the aforementioned references is incorporated herein by reference in its entirety.

[0005] However, there remains a need for improved and / or optimized compounds that act as non-toxic, water-soluble prodrugs of PTBA suitable for (FDA-approved) administration, particularly for use in inhibiting HDAC activity and / or, preferably, for use in improving renal recovery (e.g., after AKI) through HDAC inhibition, or for use in treating chronic kidney disease (CKD), as well as methods for their preparation and use. The use of water-soluble prodrugs has been studied and reported (e.g., Non-Patent Document 6, the entire text of which is specifically incorporated herein by reference). However, the techniques of small molecule optimization, particularly the combination of aqueous solubility of prodrugs, are unpredictable and require time-consuming and highly precise experimentation, unlike simple routine optimization.

[0006] With the aging of the so-called "baby boom" generation, the elderly population (e.g., 60-65 years old) is rapidly increasing worldwide. This aging population is increasingly suffering from AKI and CKD. The increased demand for medical services from this aging population poses a significant financial burden on all healthcare systems. Molecular compounds (or so-called "small molecules") offer promising therapeutic agents to address age-related health conditions. Developing strategies and interventions based on the production and purification of compounds that inhibit HDAC activity and administering such compounds to subjects may help ameliorate this condition and its associated problems. Developing strategies and interventions based on the administration of small molecule prodrugs of PTBA (which inhibit HDAC activity and improve kidney recovery and / or function) may help improve this condition, particularly in humans and / or the growing aging population.

[0007] Currently, there are no commercially available small molecule products (e.g., (highly) water-soluble PTBA prodrugs or pharmaceutically acceptable salts thereof and / or compositions containing same) or treatment methods, particularly U.S. Food and Drug Administration (FDA)-approved products and methods, for improving renal recovery and / or function (e.g., following AKI or in response to CKD), particularly by inhibiting HDAC activity. To date, all relevant data relate to preclinical research studies in animal models. Thus, there are many deficiencies (or problems) in the art that could be overcome by the development, production, manufacturing, and administration of new water-soluble prodrugs of PTBA and compositions containing same, particularly for use in inhibiting HDAC activity and / or preferably for promoting renal recovery following AKI or treating chronic kidney disease through HDAC inhibition. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2012 / 109527 [Patent Document 2] US Patent Application Publication No. 20150246939 [Non-patent literature]

[0009] [Non-Patent Document 1] Epigenetic regulation in AKI and kidney repair:mechanisms and therapeutic implications,Nature Reviews Nephrology,2019,volume 15,pages 220-239 [Non-patent document 2] Inhibition of histone deacetylase expands the renal progenitor cell population,J Am Soc Nephrol,2010,21:794-802 [Non-patent document 3] Histone Deacetylase Inhibitor Enhances Recovery after AKI,Journal of the American Society of Nephrology,June 2013,Vol.24,Issue 6 [Non-patent document 4] Delayed treatment with PTBA analogs reduces postinjury renal fibrosis after kidney injury. Am J Physiol Renal Physiol. 2016 Apr 15;310(8):F705-F716; Published online 2015 Dec 9 [Non-patent document 5] Enhancing regeneration after acute kidney injury by promoting cellular dedifferentiation in zebrafish, Dis Model Mech. 2019 Apr 1;12(4):dmm037390; Published online 2019 Apr 5 [Non-patent document 6] Jornadaet al.,The Prodrug Approach:A Successful Tool for Improving Drug Solubility,Molecules 2016,21,42 Summary of the Invention

[0010] Embodiments of the present invention solve one or more of the above-mentioned or other problems in the art by providing novel compounds (e.g., so-called small molecules) that preferably inhibit HDAC activity and / or act as (water-soluble and / or non-toxic) prodrugs of PTBA, and compositions or medicaments containing same, and methods for making and using same, to promote renal recovery after AKI or to address (or treat) chronic kidney disease, preferably through HDAC inhibition.

[0011] For example, the novel compounds may be or function as therapeutic agents that promote recovery from AKI, e.g., by enhancing the kidney's innate regenerative capacity through HDAC inhibition. Accordingly, the present invention provides numerous compounds for direct use in treating human (and other mammalian) AKI and, optionally, CKD. Embodiments of the present invention include compounds, compositions comprising the compounds, medicaments comprising the compounds or compositions, methods for making the medicaments, compounds, and compositions, and uses of or methods for using the medicaments, compounds, and compositions.

[0012] Some embodiments include methods of treating a renal disorder or disease or improving renal function in a patient. The methods include administering to the patient an amount of a compound, composition, or medicament described herein. In various embodiments, the administered amount is effective to treat a renal disorder or disease or improve renal function in the patient. For example, the compound or a pharmaceutically acceptable salt thereof may be administered in an amount and dosage regimen effective to improve renal function in the patient, inhibit histone deacetylase activity in cells (e.g., kidney cells) or systemically, expand renal progenitor cells, and / or stimulate renal repair in cells (in vitro, ex vivo, or in vivo). Also provided is the manufacture and / or use of any of the compounds, compositions, and / or medicaments described herein, preferably for treating a renal disorder or disease or improving renal function in a patient.

[0013] Embodiments of the present invention are designed to be effective for use as prodrugs of 4-(phenylthio)butanoic acid (PTBA) and / or for use in inhibiting histone deacetylase (HDAC) activity. Inhibition of HDAC activity has been shown to have a variety of downstream and / or therapeutic effects. One of ordinary skill in the art will appreciate that any disease or disorder caused, exacerbated, or exacerbated, in whole or in part, by (or associated with) high or excessive HDAC activity may be resolved and / or treated (post-diagnostic or prophylactic) by administration of the novel compounds disclosed herein or compositions comprising the same.

[0014] Embodiments of the present invention include prodrugs of PTBA. An exemplary embodiment of the present invention is a compound according to Formula I:

[0015] [ka]

[0016] or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. In various embodiments, R1 is O or NH. In some embodiments, R1 is O. In some embodiments, R1 is NH.

[0017] In some embodiments, R2 is not H. In some embodiments, R2 is not CH3. In some embodiments, R2 is not one or more of alkyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R2 is not aryl, phenyl, or benzyl. In some embodiments, R2 is not carboxyl (COOH). In some embodiments, R2 is not one or more of methanol, ethanol, propanol, or isopropanol. In some embodiments, when R1 is O, R2 is not H. In some embodiments, when R1 is O, R2 is not CH3. In some embodiments, when R1 is O, R2 is not one or more of alkyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, when R1 is O, R2 is not aryl, phenyl, or benzyl. In some embodiments, when R1 is O, R2 is not carboxyl (COOH). In some embodiments, when R1 is NH, R2 is not H. In some embodiments, when R1 is NH, R2 is not CH3. In some embodiments, when R1 is NH, R2 is not one or more of alkyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, when R1 is NH, R2 is not aryl, phenyl, or benzyl. In some embodiments, when R1 is NH, R2 is not carboxyl (COOH).

[0018] In various embodiments, R2 is selected from the group consisting of: substituted or unsubstituted amines, preferably substituted or unsubstituted tertiary or quaternary amines (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)ethanamine, 1-(1-methyl-N,N-dimethyl)ethanamine, or 1-(N,N,N-trimethyl)ethanamine, Substituted or unsubstituted heterocyclic amine or azaspiroalkyl (or hetero-dual cycloalkyl), preferably 5-7 membered heterocyclic amine or azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl; or 4-7 membered substituted or unsubstituted heterocycloalkyl or hetero-dual cycloalkyl (also known as azaspiroalkyl) optionally substituted at 1-4 (ring) positions with each (ring) substituent selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C3 alkyl or cycloalkyl, more preferably substituted or unsubstituted pyrrolidine, piperidine or Piperazine, more preferably substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine or 4-N-piperazine, more preferably 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, more preferably 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, 4-N-methylpiperazine, or substituted or unsubstituted azaspiroheptyl, preferably 2-azaspiroheptyl or azaspiro[3.3]heptyl, more preferably 2-azaspiro[3.3]heptyl, more preferably 2-methyl-2-azaspiro[3.3]heptyl, alkanolamines, preferably ethanolamines, more preferably N-ethylethanolamine or 2-(ethylamino)ethanol; an alkoxy alcohol, preferably an alkoxy ethanol or an ethoxy alcohol, more preferably 2-ethoxyethanol; a polyol, preferably a diol, more preferably a propanediol, more preferably 2,3-propanediol; Carboxylic acids, preferably dicarboxylic acids, more preferably butane dioic acid, more preferably butane dioic acid, an amide, preferably a substituted amide, more preferably N-ethyl-N-amide, N-propyl-N-amide, or 2-amino-propanamide, more preferably 2,6-diamino-N-ethyl-N-hexanamide, 2-amino-3-methyl-N-propyl-N-butanamide, or N-(1,3-dicarboyl)-2-amino-propanamide, or said amide is: -R3-C(=O)NH-R4, where R3 is a substituted alkyl, preferably a substituted ethyl, more preferably aminoethyl, more preferably 2-aminoethyl, and R4 is a carboxylic acid, preferably a dicarboxylic acid, more preferably pentanediol, more preferably pentanediol or pentanediol; or an amide comprising -R5-NHC(=O)-R6, where R5 is substituted alkyl, ethyl or propyl, and R6 is substituted alkyl, preferably 1-amino-2-methylpropane or 1,5-diaminopentane; or branched or unbranched, substituted or unsubstituted C2-C10 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, trisubstituted ammonium, optionally substituted at positions 1-5 with each substituent selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C5 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, and trisubstituted ammonium; -X-R7 (wherein X is branched or unbranched C1-C3 alkyl and R7 is a 4-7 membered substituted or unsubstituted heterocycloalkyl or hetero-dual cycloalkyl (also known as azaspiroalkyl) optionally substituted at the 1-4 (ring) positions with each (ring) substituent selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C3 alkyl or cycloalkyl, preferably substituted or unsubstituted pyrrolidine, piperidine or is piperazine, more preferably substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine, or 4-N-piperazine, more preferably 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, more preferably 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, 4-N-methylpiperazine, most preferably 4-N-methylpiperazine, or when X is (CH2)2, or a tertiary amine or a quaternary amine (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)ethanamine, 1-(1-methyl-N,N-dimethyl)ethanamine, or 1-(N,N,N-trimethyl)ethanamine, the amine is a branched or unbranched, substituted or unsubstituted C2-C10 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, or trisubstituted ammonium optionally substituted at the 1-5 positions with each substituent selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C5 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, and trisubstituted ammonium; -(CR8R9) z -R 10 wherein Z is an integer from 1 to 3; each R is independently selected from the group consisting of H or CH; and each R is independently selected from H, hydroxyl (OH), carboxyl (COOH), amino (NH), or R 10together with a substituted or unsubstituted heterocyclic amine or azaspiroalkyl (or hetero-dual cycloalkyl), preferably a 5-7 membered heterocyclic amine or azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl, more preferably a 5-6 membered heterocyclic amine or a 7 membered azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl, substituted or unsubstituted pyrrolidine, piperidine or piperazine, more preferably substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine or 4-N-piperazine, more preferably forming an unsubstituted 3-N-pyrrolidine or a substituted 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, more preferably 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, or 4-N-methyl-1-piperazine, or a substituted or unsubstituted azaspiroheptyl, preferably a substituted or unsubstituted 2-azaspiroheptyl or azaspiro[3.3]heptyl, more preferably a substituted or unsubstituted 2-azaspiro[3.3]heptyl, more preferably 2-methyl-2-azaspiro[3.3]heptyl, wherein each R 10 is independent, an amine, preferably a tertiary or quaternary amine (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)amine, 1-(1-methyl-N,N-dimethyl)amine, or 1-(N,N,N-trimethyl)amine; optionally substituted heterocyclic amines, preferably 6-membered heterocyclic amines, more preferably 6-membered heterocyclic amines, more preferably piperazine, more preferably 4-N-piperazine, more preferably 4-N-methylpiperazine or 4-N-methyl-1-1-piperazine; alkanolamines, preferably ethanolamine, N-ethanolamine or 1-aminoethanol; alkoxy alcohols, preferably alkoxy ethanols or ethoxy alcohols; a polyol, preferably a diol, more preferably ethanediol; carboxyl (COOH); an amide, preferably a substituted amide, more preferably a substituted N-pentanamide, N-hexanamide, or 1-amide, more preferably 2,6-diamino-N-hexanamide, 2-amino-3-methyl-N-butanamide, or N-(1,3-dicarboyl)-2-amino-1-amide, or said amide is: -C(=O)NH-R 11 (where R 11 is a carboxylic acid, preferably a dicarboxylic acid, more preferably a pentanediol, more preferably a pentanediol or pentanediol, or -NHC(=O)-R 12 (where R 12 is a substituted alkyl, preferably 1-amino-2-methylpropane or 1,5-diaminopentane; or R9 together with a substituted or unsubstituted heterocyclic amine or azaspiroalkyl (or hetero-dual cycloalkyl), preferably a 5- to 7-membered heterocyclic amine or azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl, more preferably a 5- to 6-membered heterocyclic amine or a 7-membered azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl, substituted or unsubstituted pyrrolidine, piperidine or piperazine, more preferably substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine or 4-N-piperazine, more preferably unsubstituted 3-N-pyrrolidine or substituted 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, more preferably 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, or 4-N-methyl-1-piperazine, or substituted or unsubstituted azaspiroheptyl, preferably substituted or unsubstituted 2-azaspiroheptyl or azaspiro[3.3]heptyl, more preferably substituted or unsubstituted 2-azaspiro[3.3]heptyl, more preferably 2-methyl-2-azaspiro[3.3]heptyl; or -(CR 13 R 14 ) z -R 15 (where each R 13 is H, and each R 14 are independently selected from the group consisting of H, CH, carboxyl (COOH), ethanol (CHOH), preferably 2-ethanol, an amine or an alkylamine, preferably propylamine, a carboxylic acid, preferably ethanoic acid or propanoic acid, Z is an integer from 1 to 3, R 15 is carboxyl (—COOH), amino (—NH) or amido, preferably 1-amido, more preferably N-substituted-1-amido (or N-substituted carboxamide) (—CONH—R 16 , where R 16is a substituted alkyl, preferably 1,3-dicarboxypropane), 1-(1-carboxy)butyric acid or butanedioic acid, 1-carboxy-2-pentanoic acid or pentanedioic acid, preferably 2-pentanedioic acid, or 2-(3-aminopropyl)ethanoic acid.

[0019] In some embodiments, when R1 is O, R2 is selected from the group consisting of: substituted or unsubstituted amines, preferably substituted or unsubstituted tertiary or quaternary amines (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)ethanamine, 1-(1-methyl-N,N-dimethyl)ethanamine, or 1-(N,N,N-trimethyl)ethanamine, Substituted or unsubstituted heterocyclic amines or azaspiroalkyls (or hetero-dual cycloalkyls), preferably 5-7 membered heterocyclic amines or azaspiroalkyls optionally substituted at one or more ring positions with C1-C2 alkyl; or 4-7 membered substituted or unsubstituted heterocycloalkyls or hetero-dual cycloalkyls (also known as azaspiroalkyls) optionally substituted at 1-4 (ring) positions with each (ring) substituent selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C3 alkyl or cycloalkyl, more preferably substituted or unsubstituted pyrrolidine, piperidine or Piperazine, more preferably substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine or 4-N-piperazine, more preferably 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, more preferably 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, 4-N-methylpiperazine, or substituted or unsubstituted azaspiroheptyl, preferably 2-azaspiroheptyl or azaspiro[3.3]heptyl, more preferably 2-azaspiro[3.3]heptyl, more preferably 2-methyl-2-azaspiro[3.3]heptyl, alkanolamines, preferably ethanolamines, more preferably N-ethylethanolamine or 2-(ethylamino)ethanol; an alkoxy alcohol, preferably an alkoxy ethanol or an ethoxy alcohol, more preferably 2-ethoxyethanol; a polyol, preferably a diol, more preferably a propanediol, more preferably 2,3-propanediol; Carboxylic acids, preferably dicarboxylic acids, more preferably butane dioic acid, more preferably butane dioic acid or butane dioic acid; an amide, preferably a substituted amide, more preferably N-ethyl-N-amide, N-propyl-N-amide, or 2-amino-propanamide, more preferably 2,6-diamino-N-ethyl-N-hexanamide, 2-amino-3-methyl-N-propyl-N-butanamide, or N-(1,3-dicarboyl)-2-amino-propanamide, or said amide is: -R3-C(=O)NH-R4, where R3 is a substituted alkyl, preferably a substituted ethyl, more preferably aminoethyl, more preferably 2-aminoethyl, and R4 is a carboxylic acid, preferably a dicarboxylic acid, more preferably pentanediol, more preferably pentanediol or pentanediol; or an amide comprising -R5-NHC(=O)-R6, where R5 is substituted alkyl, ethyl or propyl, and R6 is substituted alkyl, preferably 1-amino-2-methylpropane or 1,5-diaminopentane; or branched or unbranched, substituted or unsubstituted C2-C10 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, trisubstituted ammonium, optionally substituted at positions 1-5 with each substituent selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C5 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, and trisubstituted ammonium; or -X-R7 (wherein X is branched or unbranched C1-C3 alkyl and R7 is a 4-7 membered substituted or unsubstituted heterocycloalkyl or hetero-dual cycloalkyl (also known as azaspiroalkyl) optionally substituted at the 1-4 (ring) positions with each (ring) substituent selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C3 alkyl or cycloalkyl, preferably substituted or unsubstituted pyrrolidine, piperidine or is piperazine, more preferably substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine, or 4-N-piperazine, more preferably 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, more preferably 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, 4-N-methylpiperazine, most preferably 4-N-methylpiperazine, or when X is (CH2)2, or a tertiary amine or quaternary amine (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)ethanamine, 1-(1-methyl-N,N-dimethyl)ethanamine, or 1-(N,N,N-trimethyl)ethanamine, the amine is a branched or unbranched, substituted or unsubstituted C2-C10 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, or trisubstituted ammonium optionally substituted at the 1-5 positions with each substituent selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C5 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, and trisubstituted ammonium.

[0020] In some embodiments, when R1 is O, R2 is selected from the group consisting of: substituted or unsubstituted amines, preferably substituted or unsubstituted tertiary or quaternary amines (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)ethanamine, 1-(1-methyl-N,N-dimethyl)ethanamine, or 1-(N,N,N-trimethyl)ethanamine, substituted or unsubstituted heterocyclic amines or azaspiroalkyls, preferably 5-7 membered heterocyclic amines or azaspiroalkyls optionally substituted at one or more ring positions with C1-C2 alkyl; alkanolamines, preferably ethanolamines, more preferably N-ethylethanolamine or 2-(ethylamino)ethanol; an alkoxy alcohol, preferably an alkoxy ethanol or an ethoxy alcohol, more preferably 2-ethoxyethanol; a polyol, preferably a diol, more preferably a propanediol, more preferably 2,3-propanediol; Carboxylic acids, preferably dicarboxylic acids, more preferably butane dioic acid, even more preferably butane dioic acid or butane dioic acid; an amide, preferably a substituted amide, more preferably N-ethyl-N-amide, N-propyl-N-amide, or 2-amino-propanamide, more preferably 2,6-diamino-N-ethyl-N-hexanamide, 2-amino-3-methyl-N-propyl-N-butanamide, or N-(1,3-dicarboyl)-2-amino-propanamide, or said amide is: -R3-C(=O)NH-R4, where R3 is a substituted alkyl, preferably a substituted ethyl, more preferably aminoethyl, more preferably 2-aminoethyl, and R4 is a carboxylic acid, preferably a dicarboxylic acid, more preferably pentanediol, more preferably pentanediol or pentanediol; or Amides comprising -R5-NHC(=O)-R6, where R5 is selected from the group consisting of substituted alkyl, ethyl, or propyl, and R6 is substituted alkyl, preferably 1-amino-2-methylpropane or 1,5-diaminopentane.

[0021] In some embodiments, when R is O, R is (CR R ). z -R 10 where: Z is an integer from 1 to 3, each R8 is independently H or CH3; Each R9 is independently selected from the group consisting of H, hydroxyl (OH), carboxyl (COOH), amino (NH2), or R 10 together with a substituted or unsubstituted heterocyclic amine or azaspiroalkyl (or hetero-dual cycloalkyl), preferably a 5- to 7-membered heterocyclic amine or azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl, more preferably a 5- to 6-membered heterocyclic amine or a 7-membered azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl, substituted or unsubstituted pyrrolidine, piperidine or piperazine, more preferably substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine or 4-N-piperazine, more preferably to form an unsubstituted 3-N-pyrrolidine or a substituted 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, more preferably 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, or 4-N-methyl-1-piperazine, or a substituted or unsubstituted azaspiroheptyl, preferably a substituted or unsubstituted 2-azaspiroheptyl or azaspiro[3.3]heptyl, more preferably a substituted or unsubstituted 2-azaspiro[3.3]heptyl, more preferably 2-methyl-2-azaspiro[3.3]heptyl, Each R 10 is independent, an amine, preferably a tertiary or quaternary amine (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)amine, 1-(1-methyl-N,N-dimethyl)amine, or 1-(N,N,N-trimethyl)amine; an optionally substituted heterocyclic amine, preferably a 6-membered heterocyclic amine, more preferably a 6-membered heterocyclic amine, more preferably piperazine, more preferably 4-N-piperazine, more preferably 4-N-methylpiperazine or 4-N-methyl-1-1-piperazine; alkanolamines, preferably ethanolamine, N-ethanolamine or 1-aminoethanol, alkoxy alcohols, preferably alkoxy ethanols or ethoxy alcohols; a polyol, preferably a diol, more preferably ethanediol; Carboxyl (COOH), an amide, preferably a substituted amide, more preferably a substituted N-pentanamide, N-hexanamide, or 1-amide, more preferably 2,6-diamino-N-hexanamide, 2-amino-3-methyl-N-butanamide, or N-(1,3-dicarboyl)-2-amino-1-amide, or said amide is: -C(=O)NH-R 11 (where R 11 is a carboxylic acid, preferably a dicarboxylic acid, more preferably a pentanediol, more preferably a pentanediol or pentanediol, or -NHC(=O)-R 12 (where R 12 is a substituted alkyl, preferably 1-amino-2-methylpropane or 1,5-diaminopentane, or R9 together with a substituted or unsubstituted heterocyclic amine or azaspiroalkyl (or hetero-dual cycloalkyl), preferably a 5- to 7-membered heterocyclic amine or azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl, more preferably a 5- to 6-membered heterocyclic amine or a 7-membered azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl, substituted or unsubstituted pyrrolidine, piperidine or piperazine, more preferably substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine or 4-N-piperazine, more preferably unsubstituted 3-N-pyrrolidine or substituted 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, more preferably 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, or 4-N-methyl-1-piperazine, or substituted or unsubstituted azaspiroheptyl, preferably substituted or unsubstituted 2-azaspiroheptyl or azaspiro[3.3]heptyl, more preferably substituted or unsubstituted 2-azaspiro[3.3]heptyl, more preferably 2-methyl-2-azaspiro[3.3]heptyl;

[0022] In some embodiments, when R1 is O, R2 is selected from the group consisting of formulas Ia-Ip:

[0023] [ka]

[0024] In some embodiments, when R1 is O, R2 is (CR 17 R 18 )2-R 19 where each R 17 is H, and each R 18 are independently H or CH; R 19 is N(CH3) Y where Y is an integer between 2 and 3.

[0025] In some embodiments, when R is O, R is (CH)—R 19 and R 19 teeth + N(CH3)3, or in other words,

[0026] [ka]

[0027] is. In such cases, the compound or composition may contain an appropriate (negatively charged) counterion (W - ) can be included. - is any suitable (negative or single negative) counterion, optionally or preferably C1 - C1 - Suitable (negatively or singly negatively charged) counterions such as will be readily apparent to those skilled in the art.

[0028] In some embodiments, when R1 is NH, R2 is selected from the group consisting of: Branched or unbranched, substituted or unsubstituted C2-C10 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, or trisubstituted ammonium, optionally substituted at positions 1-5 with substituents selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C5 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, and trisubstituted ammonium.

[0029] In some embodiments, when R1 is NH, R2 is selected from the group consisting of: Carboxylic acids or dicarboxylic acids, preferably pentanoic acid, butanedioic acid or pentanedioic acid, more preferably 2-(6-amino)-pentanoic acid, 2-butanedioic acid or 2-butanedioic acid, or 2-pentanedioic acid or 2-pentanedioic acid, and Amides, preferably substituted amides, more preferably substituted ethanamides, more preferably substituted 2-ethanamides, more preferably 2-(3-aminopropane)-N-2-butanedioic-2-ethanamide, 2-(3-aminopropane)-N-2-butanedioic-2-ethanamide, 2-(3-aminopropane)-N-2-pentanedioic-2-ethanamide, 2-(3-aminopropane)-N-2-pentanedioic-2-ethanamide, 2-(2-carboxyethyl)-N-(2-(3-aminopropane)-carboxymethyl)-2-ethanamide, 2-carboxymethyl-N-(2-(3-aminopropane)-carboxymethyl)-2-ethanamide, or 2-(hydroxymethyl)-N-2-pentanedioic-2-ethanamide.

[0030] In some embodiments, when R1 is NH, R2 is selected from the group consisting of: 2-butanedioic acid, 2-pentanedioic acid, or 2-(5-amino)-pentanoic acid, and 2-(3-aminopropane)-N-2-butanedioic-2-ethanamide, 2-(3-aminopropane)-N-2-butanedioic-2-ethanamide, 2-(3-aminopropane)-N-2-pentanedioic-2-ethanamide, 2-(3-aminopropane)-N-2-pentanedioic-2-ethanamide, 2-(2-carboxyethyl)-N-(2-(3-aminopropane)-carboxymethyl)-2-ethanamide, 2-carboxymethyl-N-(2-(3-aminopropane)-carboxymethyl)-2-ethanamide, or 2-(hydroxymethyl)-N-2-pentanedioic-2-ethanamide.

[0031] In some embodiments, when R1 is NH, R2 is (CR13 R 14 ) z -R 15 where Each R 13 is H; Each R 14 are independently selected from the group consisting of H, CH, carboxyl (COOH), ethanol (CHOH), preferably 2-ethanol, an amine or an alkylamine, preferably propylamine, a carboxylic acid, preferably ethanoic acid or propanoic acid; Z is an integer from 1 to 3, R 15 is selected from the group consisting of carboxyl (-COOH), amino (-NH2) or amide, preferably 1-amide, more preferably N-substituted-1-amide (or N-substituted carboxamide) (-CONH-R 16 , where R 16 is a substituted alkyl, preferably 1,3-dicarboxypropane), 1-(1-carboxy)butyric acid or butanedioic acid, 1-carboxy-2-pentanoic acid or pentanedioic acid, preferably 2-pentanedioic acid, or 2-(3-aminopropyl)ethanoic acid.

[0032] In some embodiments, when R1 is NH, R2 is selected from the group consisting of formulas Iq-Ix:

[0033] [ka]

[0034] In some embodiments, the compound according to Formula I can be one of compounds 1-24 in Table 1.

[0035] [Table 1-1]

[0036] [Table 1-2]

[0037] [Table 1-3]

[0038] [Table 1-4]

[0039] Additionally, all compounds of the present invention that exist in free base or acid form can be converted into their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of the compounds of the present invention can be converted into their free base or acid form by standard techniques.

[0040] Some embodiments relate to (pharmaceutical) compositions comprising a pharmaceutically acceptable carrier or excipient and a compound of Formula I. Some embodiments relate to a (pharmaceutical) medicament comprising a pharmaceutically acceptable carrier or excipient and a compound of Formula I or a composition comprising same.

[0041] Some embodiments relate to compositions or medicaments comprising a compound of Formula I for use in (i) inhibiting histone deacetylase (HDAC) activity, (ii) promoting renal recovery after acute kidney injury (AKI), preferably through HDAC inhibition, (iii) attenuating renal damage after AKI, and (iv) treating AKI and / or other related diseases or affecting other related molecular mechanisms in a mammal or mammalian subject in need of treatment of AKI. In some embodiments, the mammal or mammalian subject is a human.

[0042] Some embodiments relate to the use of a compound of Formula I, a pharmaceutical composition comprising the same, or a medicament comprising the same for (i) inhibiting histone deacetylase (HDAC) activity, (ii) promoting renal recovery after acute kidney injury (AKI), preferably through HDAC inhibition, (iii) attenuating renal damage after AKI, and / or (iv) treating AKI and / or other related diseases or affecting other related molecular mechanisms in a mammal or mammalian subject (in need of AKI treatment). In some embodiments, the mammal or mammalian subject is a human.

[0043] Some embodiments relate to methods of (i) inhibiting histone deacetylase (HDAC) activity, (ii) preferably by HDAC inhibition, promoting renal recovery after acute kidney injury (AKI), (iii) attenuating renal damage after AKI, and / or (iv) treating AKI and / or other related diseases or affecting other related molecular mechanisms in a mammal or mammalian subject (in need thereof), the method comprising administering to the mammal or mammalian subject (in need thereof) a compound according to Formula I, a pharmaceutical composition comprising the same, or a medicament comprising the same. In some embodiments, the mammal or mammalian subject is a human.

[0044] Some embodiments may include any feature, option, and / or possibility described elsewhere in the present invention, including other aspects or embodiments of the present invention. Additionally, each of the other features described above, below, and / or otherwise herein is a distinct embodiment of the present invention. Furthermore, any combination of two or more of such features is also a separate embodiment of the present invention. Such features or embodiments may also be combined in any suitable combination and / or sequence without departing from the scope of the present disclosure. Thus, each feature described herein may be combined with any one or more other features described herein in any suitable combination and / or sequence. Therefore, the present invention is not limited to the specific combination of representative embodiments detailed herein.

[0045] Additional features and advantages of exemplary embodiments of the present invention will be set forth in the detailed description that follows, and in part will be obvious from such description, or may be learned by the practice of such exemplary embodiments. The features and advantages of such embodiments may be realized and obtained by means of the instruments and combinations particularly pointed out in the appended claims. These and other features will be more fully understood from the following detailed description and the appended claims, or may be learned by the practice of exemplary embodiments as set forth hereinafter.

[0046] To illustrate the manner in which the foregoing and other advantages and features of the present invention are obtained, a more particular description of the embodiments briefly described above will be provided by reference to specific embodiments illustrated in the accompanying drawings. For ease of understanding, like elements have been designated by like reference numerals throughout the drawings. Such drawings illustrate only typical embodiments of the invention and are not to be considered as limiting the scope of the invention, which will be described and explained with additional specificity and detail using the accompanying drawings below. [Brief explanation of the drawings]

[0047] [Figure 1-1]Figure 1 shows 24 example compounds and their associated information. [Figure 1-2] Same as above. [Figure 1-3] Same as above. [Figure 1-4] Same as above. [Figure 1-5] Same as above. [Figure 2] 1 shows the stability of exemplary compound 22 in rat plasma. [Figure 3] 1 shows the stability of exemplary compound 22 in dog plasma. [Figure 4] 1 shows the stability of exemplary compound 22 in human plasma. [Figure 5] 1 shows the percentage of exemplary compound 22 remaining in monkey plasma over time. [Figure 6] 1 shows PTBA levels in monkey plasma over time after administration of Compound 22. [Figure 7A] 1 shows plasma concentrations of prodrug (compound 22) and PTBA over time in rats after iv administration of prodrug (compound 22). [Figure 7B] 1 shows the plasma concentrations of the prodrug (compound 17) and PTBA over time in rats. [Figure 7C] 1 shows plasma concentrations of prodrug (Compound 1) and PTBA over time in rats. [Figure 7D] 1 shows the plasma concentrations of the prodrug (compound 15) and PTBA over time in rats. [Figure 8] 1 shows urea levels in cisplatin-induced AKI mice treated with exemplary compound 22. [Figure 9A] 1 shows the body weight of cisplatin-induced AKI mice treated with exemplary compound 22 once or twice daily from day 2 to day 8. [Figure 9B] 1 shows the body weight of cisplatin-induced AKI mice treated with exemplary compound 22 once or twice daily from day 0 to day 6. [Figure 10] 1 shows serum creatinine levels in rats treated with exemplary compound 22. [Figure 11] 1 shows urea levels in cisplatin-induced AKI mice treated with exemplary compound 3. [Figure 12] 1 shows serum creatinine levels in rats treated with exemplary compound 3. [Figure 13] 1 shows the body weight of mice with cisplatin-induced AKI treated with exemplary compound 3. DETAILED DESCRIPTION OF THE INVENTION

[0048] [Definitions and Disclaimers] Before describing various embodiments of the present invention in detail, it should be understood that the present invention is not limited to descriptions of specific parameters, terminology, and specifically illustrated systems, methods, and / or products, which vary from embodiment to embodiment. Therefore, while certain embodiments of the present invention will be described in detail with reference to specific features (e.g., configurations, parameters, properties, steps, components, ingredients, members, elements, parts, and / or portions), this description is illustrative and should not be construed as limiting the scope of the present invention and / or the claimed invention. Furthermore, the terms used in this application are used to describe the embodiments, and do not limit the scope of the present invention and / or the claimed invention.

[0049] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Various "aspects" of the present invention, including systems, methods, and / or articles of manufacture, may be described with reference to one or more "embodiments" that are exemplary in nature. As used herein, the terms "aspect" and "embodiment" may be used interchangeably. The term "embodiment" may also mean "serving as an example, instance, or illustration," and should not necessarily be construed as preferred or advantageous over other aspects disclosed herein. Furthermore, references to "embodiments" of the present disclosure or invention are intended to provide illustrative examples without limiting the scope of the invention, which is indicated by the appended claims.

[0050] As used in this specification and the appended claims, the singular forms "a," "an," and "the" each contemplate, include, and specifically disclose both the singular and plural forms, unless the context clearly dictates otherwise. For example, a reference to a "protein" contemplates and specifically discloses not only one protein but a number (e.g., two or more, three or more, etc.) of proteins. Similarly, the use of a plural referent does not necessarily require a plurality of such referents, but contemplates, includes, specifically discloses, and / or supports a plurality of such referents, not just a single referent, unless the context clearly dictates otherwise.

[0051] As used throughout this specification, the words "can" and "may" are used in a permissive (i.e., possible) sense rather than a mandatory (i.e., must) sense. Furthermore, the terms "including," "having," "involving," "containing," "characterized by," and variations thereof (e.g., "includes," "has," "involves," "contains," etc.), and similar terms used herein, including the claims, are inclusive and / or open-ended, have the same meaning as "comprising" and variations thereof (e.g., "comprises"), and do not exclude additional elements or method steps not specifically recited.

[0052] The term "disease," as understood by one of skill in the art, refers to any disorder, illness, injury, or disease that is manifest or predicted in a patient. Indications of such disease may be early, intermediate, or late signs, as known in the art, including pre-disease symptoms, signs, or markers. Such predictions of disease may be or include predictions, forecasts, assumptions, estimates, hypothesized, and / or inferred development of the disease, whether based on scientific or medical evidence, risk assessment, or simple fear or apprehension.

[0053] As used herein, the term "patient" is synonymous with the term "subject" and generally refers to any animal under the care of a medical professional, and specifically refers to (i) humans (under the care of a doctor, nurse, or paramedic or volunteer) and (ii) non-human animals, e.g., non-human mammals (under the care of a veterinarian or other veterinary professional, paramedic, or volunteer), as defined herein.

[0054] The term "prodrug" is meant to refer to a compound that can be converted under physiological conditions or by solvolysis to a bioactive compound described herein (e.g., a compound according to Formula I). ​​Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a bioactive compound. In some embodiments, a prodrug can be inactive / low activity or inactive / low activity when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds may offer advantages of solubility, tissue compatibility, or sustained release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions of prodrugs are provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14 and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, the entire text of each of which is incorporated herein by specific reference.

[0055] Embodiments of the present invention are intended to cover all pharmaceutically acceptable compounds of Formula I that are isotopically labeled by replacing one or more atoms with an atom having a different atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18F, 36 Cl, 123 I, and 125 I, respectively. Such radiolabeled compounds may be useful for determining or measuring the efficacy of the compound, for example, by characterizing its site or mode of action, or its binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds according to Formula I, for example, compounds containing a radioisotope, are useful in drug and / or substrate tissue distribution studies. The radioisotope tritium 3 H and carbon-14, i.e., 14 C are particularly useful for such purposes because of their ease of incorporation and readily available means of detection.

[0056] Deuterium, i.e., 2 Substitution with heavier isotopes, such as H, may be preferred in some circumstances because they may offer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Positron-emitting isotopes, such as 11 C. 18 F, 15 O, and 13 Substitution with N is useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula I can generally be prepared by conventional methods known to those skilled in the art, or can be prepared by methods analogous to those described below in the preparations and examples, substituting appropriate isotopically labeled reagents for the unlabeled reagents already used.

[0057] Embodiments of the present invention also include in vivo metabolic products of the disclosed compounds. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily due to enzymatic processes. Accordingly, embodiments of the present invention include compounds produced by a method comprising administering a compound of the present invention to a mammal for a time sufficient to produce a metabolic product of the compound. Such products are typically identified by administering a detectable amount of a radiolabeled compound of the present invention to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the transformation products from urine, blood, or other biological sample.

[0058] The terms "carrier, diluent and / or excipient" and "pharmaceutically acceptable carrier, diluent and / or excipient" include, without limitation, any adjuvant, carrier, excipient, lubricant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent or emulsifier approved by the U.S. Food and Drug Administration as acceptable for human or veterinary use.

[0059] The term "salt" or "pharmaceutically acceptable salt" includes both acid and base addition salts. Reference to salts can include "acid addition salts" or "pharmaceutically acceptable acid addition salts," which refers to salts that retain the biological efficacy and properties of the free base, without being biologically or otherwise objectionable, including, but not limited to, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and salts with other acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, carboxylic ... Puric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid It is formed with organic acids such as naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0060] Salts can include "base addition salts" or "pharmaceutically acceptable base addition salts," which refer to salts that retain the biological effectiveness and properties of the free acid without being biologically or otherwise objectionable. Such salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, denol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benezamine, benzathine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, trometamol, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0061] Crystallization may produce solvates of the compounds of the invention. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of a compound of the invention together with one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, embodiments of the compounds of the invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as corresponding solvated forms. While embodiments of the compounds of the invention may be true solvates, in other cases the compounds of the invention may possess only associated water or may be a mixture of water and any associated solvents.

[0062] A "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a bioactive compound to a mammal, e.g., a human. Such a medium includes any pharmaceutically acceptable carrier, diluent, or excipient therefor.

[0063] "Mammal" includes both humans and domestic animals, such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wild animals.

[0064] "An effective amount" or "therapeutically effective amount" refers to the amount of a compound of the present invention that, when administered to a mammal, preferably a human, is sufficient to treat a disease associated with overexpression of cyclin-dependent kinase (CDK) in the mammal, preferably a human, as defined below. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease and its severity, the mode of administration, and the age of the mammal to be treated, but can be determined routinely by anyone skilled in the art taking into account their own knowledge and the content of the present invention.

[0065] The term "treat" or "treatment" as used herein encompasses treatment of a mammal, preferably a human, suffering from a disease or disorder of interest, for that disease or disorder of interest, and includes: (i) preventing the onset of a disease or disorder in a mammal, particularly where the mammal is predisposed to the disorder but does not yet have the disorder; (ii) inhibiting the disease or disorder, i.e., preventing its onset; (iii) alleviating the disease or disorder, i.e., inducing regression of the disease or disorder; or (iv) Relieving the symptoms of a disease or disorder, i.e., relieving pain without solving the underlying disease or disorder. As used herein, the terms "disease" and "disease" may be used interchangeably or may differ in that a particular disease or condition does not have a known causative agent (and therefore, its etiology has not yet been determined) and is not yet recognized as a disease, but rather only as an undesirable disorder or syndrome in which a specific set of symptoms has been identified by clinicians to varying degrees.

[0066] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and therefore provide enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-, or, in the case of amino acids, (D)- or (L)-. The present invention is meant to encompass all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral intermediates or chiral reagents or separated using conventional methods, such as chromatography and fractional crystallization. Conventional methods for the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or separation of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers, as well as all tautomeric forms.

[0067] "Stereoisomers" refer to compounds consisting of identical atoms joined by identical bonds, but having different, non-interchangeable three-dimensional structures. Embodiments of the present invention contemplate various stereoisomers and mixtures thereof, and include "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0068] "Tautomer" refers to the migration of a proton from one atom in a molecule to another atom in the same molecule. Embodiments of the invention include tautomers of any of the aforementioned compounds. For the avoidance of brevity, the present invention may refer to lists or ranges of numerical values. However, when such a list or range of numerical values ​​(e.g., greater than, less than, up to, at least, and / or about a particular value and / or between two recited values) is disclosed or referred to, any particular value or range of values ​​falling within the disclosed list or range of values ​​is also specifically disclosed and considered herein.

[0069] For ease of understanding, like reference numerals (i.e., like names of components and / or components) have been used where possible to designate like components common to different embodiments of the present invention. Similarly, like components or components having similar functions have been provided with like reference numerals where possible. Specific language is used herein to describe exemplary embodiments. However, it should be understood that no limitation of the scope of the present invention is intended thereby. Rather, the language used to describe exemplary embodiments is merely exemplary and should not be construed as limiting the scope of the present invention (unless such language is expressly stated herein as essential).

[0070] Although the Detailed Description has been separated into sections, the section titles and tables of contents within each section are for organizational purposes only and are not intended to represent independent Detailed Descriptions and embodiments or to limit the scope of the Detailed Description or claims. Rather, the contents of each section within the Detailed Description are intended to be read and understood as a collective whole, in which elements of one section may be relevant to and / or inform other sections. Thus, embodiments specifically disclosed in one section may relate to and / or serve as additional and / or alternative embodiments in other sections having the same and / or similar products, methods and / or terminology.

[0071] Provided herein are compounds useful for improving renal function, inhibiting histone deacetylase in cells, expanding renal progenitor cells, and / or promoting renal repair in cells in vitro, ex vivo, or in vivo (in-patient) cells. Also provided are compositions and medicaments for delivering the compounds to patients. Also provided are methods for improving renal function, inhibiting histone deacetylase in cells, expanding renal progenitor cells, and / or promoting renal repair in cells in vitro, ex vivo, or in vivo (in-patient) cells, comprising contacting the cells or administering to the patient an amount of one or more compounds effective to improve renal function, inhibit histone deacetylase in cells, expand renal progenitor cells, and / or promote renal repair in cells. Accordingly, in vitro (including ex vivo) or in-vivo (in-patient) methods are provided. The efficacy of the compounds is described below. [Compound] Embodiments of the present invention include prodrugs of PTBA. An exemplary embodiment of the present invention is a compound according to Formula I:

[0072] [ka]

[0073] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In various embodiments, R1 is O or NH. In some embodiments, R1 is O. In some embodiments, R1 is NH.

[0074] In some embodiments, R2 is not H. In some embodiments, R2 is not CH3. In some embodiments, R2 is not one or more of alkyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R2 is not aryl, phenyl, or benzyl. In some embodiments, R2 is not carboxyl (COOH). In some embodiments, R2 is not one or more of methanol, ethanol, propanol, or isopropanol.

[0075] In various embodiments, R2 is selected from the group consisting of: substituted or unsubstituted amines, preferably substituted or unsubstituted tertiary or quaternary amines (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)ethanamine, 1-(1-methyl-N,N-dimethyl)ethanamine, or 1-(N,N,N-trimethyl)ethanamine, Substituted or unsubstituted heterocyclic amines or azaspiroalkyls (or hetero-dual cycloalkyls), preferably 5-7 membered heterocyclic amines or azaspiroalkyls optionally substituted at one or more ring positions with C1-C2 alkyl; or 4-7 membered substituted or unsubstituted heterocycloalkyls or hetero-dual cycloalkyls (also known as azaspiroalkyls) optionally substituted at 1-4 (ring) positions with each (ring) substituent selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C3 alkyl or cycloalkyl, more preferably substituted or unsubstituted pyrrolidine, piperidine or Piperazine, more preferably substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine or 4-N-piperazine, more preferably 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, more preferably 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, 4-N-methylpiperazine, or substituted or unsubstituted azaspiroheptyl, preferably 2-azaspiroheptyl or azaspiro[3.3]heptyl, more preferably 2-azaspiro[3.3]heptyl, more preferably 2-methyl-2-azaspiro[3.3]heptyl, alkanolamines, preferably ethanolamines, more preferably N-ethylethanolamine or 2-(ethylamino)ethanol; an alkoxy alcohol, preferably an alkoxy ethanol or an ethoxy alcohol, more preferably 2-ethoxyethanol; a polyol, preferably a diol, more preferably a propanediol, more preferably 2,3-propanediol; Carboxylic acids, preferably dicarboxylic acids, more preferably butane dioic acid, more preferably butane dioic acid, an amide, preferably a substituted amide, more preferably N-ethyl-N-amide, N-propyl-N-amide, or 2-amino-propanamide, more preferably 2,6-diamino-N-ethyl-N-hexanamide, 2-amino-3-methyl-N-propyl-N-butanamide, or N-(1,3-dicarboyl)-2-amino-propanamide, or said amide is: -R3-C(=O)NH-R4, where R3 is a substituted alkyl, preferably a substituted ethyl, more preferably aminoethyl, more preferably 2-aminoethyl, and R4 is a carboxylic acid, preferably a dicarboxylic acid, more preferably pentanediol, more preferably pentanediol or pentanediol; or an amide comprising -R5-NHC(=O)-R6, where R5 is substituted alkyl, ethyl or propyl, and R6 is substituted alkyl, preferably 1-amino-2-methylpropane or 1,5-diaminopentane; or branched or unbranched, substituted or unsubstituted C2-C10 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, trisubstituted ammonium, optionally substituted at positions 1-5 with each substituent selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C5 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, and trisubstituted ammonium; -X-R7 (wherein X is branched or unbranched C1-C3 alkyl and R7 is a 4-7 membered substituted or unsubstituted heterocycloalkyl or hetero-dual cycloalkyl (also known as azaspiroalkyl) optionally substituted at the 1-4 (ring) positions with each (ring) substituent selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C3 alkyl or cycloalkyl, preferably substituted or unsubstituted pyrrolidine, piperidine or is piperazine, more preferably substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine, or 4-N-piperazine, more preferably 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, more preferably 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, 4-N-methylpiperazine, most preferably 4-N-methylpiperazine, or when X is (CH2)2, or a tertiary amine or a quaternary amine (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)ethanamine, 1-(1-methyl-N,N-dimethyl)ethanamine, or 1-(N,N,N-trimethyl)ethanamine, the amine is a branched or unbranched, substituted or unsubstituted C2-C10 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, or trisubstituted ammonium optionally substituted at the 1-5 positions with each substituent selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C5 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, and trisubstituted ammonium; -(CR8R9) z -R 10 wherein Z is an integer from 1 to 3; each R is independently selected from the group consisting of H or CH; and each R is independently selected from H, hydroxyl (OH), carboxyl (COOH), amino (NH); or R 10together with a substituted or unsubstituted heterocyclic amine or azaspiroalkyl (or hetero-dual cycloalkyl), preferably a 5-7 membered heterocyclic amine or azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl, more preferably a 5-6 membered heterocyclic amine or a 7 membered azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl, substituted or unsubstituted pyrrolidine, piperidine or piperazine, more preferably substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine or 4-N-piperazine, more preferably forming an unsubstituted 3-N-pyrrolidine or a substituted 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, more preferably 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, or 4-N-methyl-1-piperazine, or a substituted or unsubstituted azaspiroheptyl, preferably a substituted or unsubstituted 2-azaspiroheptyl or azaspiro[3.3]heptyl, more preferably a substituted or unsubstituted 2-azaspiro[3.3]heptyl, more preferably 2-methyl-2-azaspiro[3.3]heptyl, wherein each R 10 is independent an amine, preferably a tertiary or quaternary amine (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)amine, 1-(1-methyl-N,N-dimethyl)amine, or 1-(N,N,N-trimethyl)amine; an optionally substituted heterocyclic amine, preferably a 6-membered heterocyclic amine, more preferably a 6-membered heterocyclic amine, more preferably piperazine, more preferably 4-N-piperazine, more preferably 4-N-methylpiperazine or 4-N-methyl-1-1-piperazine; alkanolamines, preferably ethanolamine, N-ethanolamine or 1-aminoethanol, alkoxy alcohols, preferably alkoxyethanols or ethoxy alcohols, a polyol, preferably a diol, more preferably ethanediol; Carboxyl (COOH), an amide, preferably a substituted amide, more preferably a substituted N-pentanamide, N-hexanamide, or 1-amide, more preferably 2,6-diamino-N-hexanamide, 2-amino-3-methyl-N-butanamide, or N-(1,3-dicarboyl)-2-amino-1-amide, or said amide is: -C(=O)NH-R 11 (where R 11 is a carboxylic acid, preferably a dicarboxylic acid, more preferably a pentanediol, more preferably a pentanediol or pentanediol, or -NHC(=O)-R 12 (where R 12 is a substituted alkyl, preferably 1-amino-2-methylpropane or 1,5-diaminopentane, or R9 together with a substituted or unsubstituted heterocyclic amine or azaspiroalkyl (or hetero-dual cycloalkyl), preferably a 5- to 7-membered heterocyclic amine or azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl, more preferably a 5- to 6-membered heterocyclic amine or a 7-membered azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl, substituted or unsubstituted pyrrolidine, piperidine or piperazine, more preferably substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine or 4-N-piperazine, more preferably unsubstituted 3-N-pyrrolidine or substituted 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, more preferably 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, or 4-N-methyl-1-piperazine, or substituted or unsubstituted azaspiroheptyl, preferably substituted or unsubstituted 2-azaspiroheptyl or azaspiro[3.3]heptyl, more preferably substituted or unsubstituted 2-azaspiro[3.3]heptyl, more preferably 2-methyl-2-azaspiro[3.3]heptyl; or -(CR 13 R 14 ) z -R 15 (where each R 13 is H, and each R 14 are independently selected from the group consisting of H, CH, carboxyl (COOH), ethanol (CHOH), preferably 2-ethanol, an amine or an alkylamine, preferably propylamine, a carboxylic acid, preferably ethanoic acid or propanoic acid, Z is an integer from 1 to 3, R 15 is carboxyl (—COOH), amino (—NH) or amido, preferably 1-amido, more preferably N-substituted-1-amido (or N-substituted carboxamide) (—CONH—R 16 , where R 16 is a substituted alkyl, preferably 1,3-dicarboxypropane), 1-(1-carboxy)butyric acid or butanedioic acid, 1-carboxy-2-pentanoic acid or pentanedioic acid, preferably 2-pentanedioic acid, or 2-(3-aminopropyl)ethanoic acid).

[0076] In some embodiments, when R1 is O, R2 is selected from the group consisting of: substituted or unsubstituted amines, preferably substituted or unsubstituted tertiary or quaternary amines (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)ethanamine, 1-(1-methyl-N,N-dimethyl)ethanamine, or 1-(N,N,N-trimethyl)ethanamine, Substituted or unsubstituted heterocyclic amines or azaspiroalkyls (or hetero-dual cycloalkyls), preferably 5-7 membered heterocyclic amines or azaspiroalkyls optionally substituted at one or more ring positions with C1-C2 alkyl; or 4-7 membered substituted or unsubstituted heterocycloalkyls or hetero-dual cycloalkyls (also known as azaspiroalkyls) optionally substituted at 1-4 (ring) positions with each (ring) substituent selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C3 alkyl or cycloalkyl, more preferably substituted or unsubstituted pyrrolidine, piperidine or Piperazine, more preferably substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine or 4-N-piperazine, more preferably 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, more preferably 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, 4-N-methylpiperazine, or substituted or unsubstituted azaspiroheptyl, preferably 2-azaspiroheptyl or azaspiro[3.3]heptyl, more preferably 2-azaspiro[3.3]heptyl, more preferably 2-methyl-2-azaspiro[3.3]heptyl, alkanolamines, preferably ethanolamines, more preferably N-ethylethanolamine or 2-(ethylamino)ethanol; an alkoxy alcohol, preferably an alkoxy ethanol or an ethoxy alcohol, more preferably 2-ethoxyethanol; a polyol, preferably a diol, more preferably a propanediol, more preferably 2,3-propanediol; Carboxylic acids, preferably dicarboxylic acids, more preferably butane dioic acid, more preferably butane dioic acid or butane dioic acid; an amide, preferably a substituted amide, more preferably N-ethyl-N-amide, N-propyl-N-amide, or 2-amino-propanamide, more preferably 2,6-diamino-N-ethyl-N-hexanamide, 2-amino-3-methyl-N-propyl-N-butanamide, or N-(1,3-dicarboyl)-2-amino-propanamide, or said amide is: -R3-C(=O)NH-R4, where R3 is a substituted alkyl, preferably a substituted ethyl, more preferably aminoethyl, more preferably 2-aminoethyl, and R4 is a carboxylic acid, preferably a dicarboxylic acid, more preferably pentanediol, more preferably pentanediol or pentanediol; or an amide comprising -R5-NHC(=O)-R6, where R5 is substituted alkyl, ethyl or propyl, and R6 is substituted alkyl, preferably 1-amino-2-methylpropane or 1,5-diaminopentane; or branched or unbranched, substituted or unsubstituted C2-C10 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, trisubstituted ammonium, optionally substituted at positions 1-5 with each substituent selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C5 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, and trisubstituted ammonium; or -X-R7 (wherein X is branched or unbranched C1-C3 alkyl and R7 is a 4-7 membered substituted or unsubstituted heterocycloalkyl or hetero-dual cycloalkyl (also known as azaspiroalkyl) optionally substituted at the 1-4 (ring) positions with each (ring) substituent selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C3 alkyl or cycloalkyl, preferably substituted or unsubstituted pyrrolidine, piperidine or is piperazine, more preferably substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine, or 4-N-piperazine, more preferably 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, more preferably 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, 4-N-methylpiperazine, most preferably 4-N-methylpiperazine, or when X is (CH2)2, or a tertiary amine or quaternary amine (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)ethanamine, 1-(1-methyl-N,N-dimethyl)ethanamine, or 1-(N,N,N-trimethyl)ethanamine, the amine is a branched or unbranched, substituted or unsubstituted C2-C10 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, or trisubstituted ammonium optionally substituted at the 1-5 positions with each substituent selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C5 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, and trisubstituted ammonium.

[0077] In some embodiments, when R1 is O, R2 is selected from the group consisting of: substituted or unsubstituted amines, preferably substituted or unsubstituted tertiary or quaternary amines (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)ethanamine, 1-(1-methyl-N,N-dimethyl)ethanamine, or 1-(N,N,N-trimethyl)ethanamine, substituted or unsubstituted heterocyclic amines or azaspiroalkyls, preferably 5-7 membered heterocyclic amines or azaspiroalkyls optionally substituted at one or more ring positions with C1-C2 alkyl; alkanolamines, preferably ethanolamines, more preferably N-ethylethanolamine or 2-(ethylamino)ethanol; an alkoxy alcohol, preferably an alkoxy ethanol or an ethoxy alcohol, more preferably 2-ethoxyethanol; a polyol, preferably a diol, more preferably a propanediol, more preferably 2,3-propanediol; Carboxylic acids, preferably dicarboxylic acids, more preferably butane dioic acid, more preferably butane dioic acid or butane dioic acid; an amide, preferably a substituted amide, more preferably N-ethyl-N-amide, N-propyl-N-amide, or 2-amino-propanamide, more preferably 2,6-diamino-N-ethyl-N-hexanamide, 2-amino-3-methyl-N-propyl-N-butanamide, or N-(1,3-dicarboyl)-2-amino-propanamide, or said amide is: -R3-C(=O)NH-R4, where R3 is a substituted alkyl, preferably a substituted ethyl, more preferably aminoethyl, more preferably 2-aminoethyl, and R4 is a carboxylic acid, preferably a dicarboxylic acid, more preferably pentanediol, more preferably pentanediol or pentanediol; or Amides comprising -R5-NHC(=O)-R6, where R5 is selected from the group consisting of substituted alkyl, ethyl, or propyl, and R6 is substituted alkyl, preferably 1-amino-2-methylpropane or 1,5-diaminopentane.

[0078] In some embodiments, when R is O, R is (CR R ). z -R 10 where: Z is an integer from 1 to 3, each R8 is independently H or CH3; Each R9 is independently selected from the group consisting of H, hydroxyl (OH), carboxyl (COOH), amino (NH2), or R 10 together with a substituted or unsubstituted heterocyclic amine or azaspiroalkyl (or hetero-dual cycloalkyl), preferably a 5- to 7-membered heterocyclic amine or azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl, more preferably a 5- to 6-membered heterocyclic amine or a 7-membered azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl, substituted or unsubstituted pyrrolidine, piperidine or piperazine, more preferably substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine or 4-N-piperazine, more preferably to form an unsubstituted 3-N-pyrrolidine or a substituted 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, more preferably 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, or 4-N-methyl-1-piperazine, or a substituted or unsubstituted azaspiroheptyl, preferably a substituted or unsubstituted 2-azaspiroheptyl or azaspiro[3.3]heptyl, more preferably a substituted or unsubstituted 2-azaspiro[3.3]heptyl, more preferably 2-methyl-2-azaspiro[3.3]heptyl, Each R 10 is independent an amine, preferably a tertiary or quaternary amine (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)amine, 1-(1-methyl-N,N-dimethyl)amine, or 1-(N,N,N-trimethyl)amine; an optionally substituted heterocyclic amine, preferably a 6-membered heterocyclic amine, more preferably a 6-membered heterocyclic amine, more preferably piperazine, more preferably 4-N-piperazine, more preferably 4-N-methylpiperazine or 4-N-methyl-1-1-piperazine; alkanolamines, preferably ethanolamine, N-ethanolamine or 1-aminoethanol, alkoxy alcohols, preferably alkoxy ethanols or ethoxy alcohols; a polyol, preferably a diol, more preferably ethanediol; Carboxyl (COOH), an amide, preferably a substituted amide, more preferably a substituted N-pentanamide, N-hexanamide, or 1-amide, more preferably 2,6-diamino-N-hexanamide, 2-amino-3-methyl-N-butanamide, or N-(1,3-dicarboyl)-2-amino-1-amide, or said amide is: -C(=O)NH-R 11 (where R 11 is a carboxylic acid, preferably a dicarboxylic acid, more preferably a pentanediol, more preferably a pentanediol or pentanediol, or -NHC(=O)-R 12 (where R 12 is a substituted alkyl, preferably 1-amino-2-methylpropane or 1,5-diaminopentane, or R9 together with a substituted or unsubstituted heterocyclic amine or azaspiroalkyl (or hetero-dual cycloalkyl), preferably a 5- to 7-membered heterocyclic amine or azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl, more preferably a 5- to 6-membered heterocyclic amine or a 7-membered azaspiroalkyl optionally substituted at one or more ring positions with C1-C2 alkyl, substituted or unsubstituted pyrrolidine, piperidine or piperazine, more preferably substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine or 4-N-piperazine, more preferably unsubstituted 3-N-pyrrolidine or substituted 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, more preferably 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, or 4-N-methyl-1-piperazine, or substituted or unsubstituted azaspiroheptyl, preferably substituted or unsubstituted 2-azaspiroheptyl or azaspiro[3.3]heptyl, more preferably substituted or unsubstituted 2-azaspiro[3.3]heptyl, more preferably 2-methyl-2-azaspiro[3.3]heptyl;

[0079] In some embodiments, when R1 is O, R2 is selected from the group consisting of formulas Ia-Ip:

[0080] [ka]

[0081] In some embodiments, when R1 is O, R2 is (CR 17 R 18 )2-R 19 where each R 17 is H, and each R 18 are independently H or CH; R 19 is N(CH3) Y where Y is an integer between 2 and 3.

[0082] In some embodiments, when R is O, R is (CH)—R 19 and R 19 is N(CH3)3. In some embodiments, when R1 is NH, R2 is selected from the group consisting of: Branched or unbranched, substituted or unsubstituted C2-C10 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, or trisubstituted ammonium, optionally substituted at positions 1-5 with substituents selected from the group consisting of branched or unbranched, substituted or unsubstituted C1-C5 alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, and trisubstituted ammonium.

[0083] In some embodiments, when R1 is NH, R2 is selected from the group consisting of: Carboxylic acids or dicarboxylic acids, preferably pentanoic acid, butanedioic acid or pentanedioic acid, more preferably 2-(6-amino)-pentanoic acid, 2-butanedioic acid or 2-butanedioic acid, or 2-pentanedioic acid or 2-pentanedioic acid, and Amides, preferably substituted amides, more preferably substituted ethanamides, more preferably substituted 2-ethanamides, more preferably 2-(3-aminopropane)-N-2-butanedioic-2-ethanamide, 2-(3-aminopropane)-N-2-butanedioic-2-ethanamide, 2-(3-aminopropane)-N-2-pentanedioic-2-ethanamide, 2-(3-aminopropane)-N-2-pentanedioic-2-ethanamide, 2-(2-carboxyethyl)-N-(2-(3-aminopropane)-carboxymethyl)-2-ethanamide, 2-carboxymethyl-N-(2-(3-aminopropane)-carboxymethyl)-2-ethanamide, or 2-(hydroxymethyl)-N-2-pentanedioic-2-ethanamide.

[0084] In some embodiments, when R1 is NH, R2 is selected from the group consisting of: 2-butanedioic acid, 2-pentanedioic acid, or 2-(5-amino)-pentanoic acid, and 2-(3-aminopropane)-N-2-butanedioic-2-ethanamide, 2-(3-aminopropane)-N-2-butanedioic-2-ethanamide, 2-(3-aminopropane)-N-2-pentanedioic-2-ethanamide, 2-(3-aminopropane)-N-2-pentanedioic-2-ethanamide, 2-(2-carboxyethyl)-N-(2-(3-aminopropane)-carboxymethyl)-2-ethanamide, 2-carboxymethyl-N-(2-(3-aminopropane)-carboxymethyl)-2-ethanamide, or 2-(hydroxymethyl)-N-2-pentanedioic-2-ethanamide.

[0085] In some embodiments, when R1 is NH, R2 is (CR 13 R 14 ) z -R 15 where Each R 13 is H; Each R 14 are independently selected from the group consisting of H, CH, carboxyl (COOH), ethanol (CHOH), preferably 2-ethanol, an amine or an alkylamine, preferably propylamine, a carboxylic acid, preferably ethanoic acid or propanoic acid; Z is an integer from 1 to 3, R 15 is selected from the group consisting of carboxyl (—COOH), amino (—NH) or amide, preferably 1-amide, more preferably N-substituted-1-amide (or N-substituted carboxamide) (—CONH—R 16 , where R 16is a substituted alkyl, preferably 1,3-dicarboxypropane), 1-(1-carboxy)butyric acid or butanedioic acid, 1-carboxy-2-pentanoic acid or pentanedioic acid, preferably 2-pentanedioic acid, or 2-(3-aminopropyl)ethanoic acid.

[0086] In some embodiments, when R1 is NH, R2 is selected from the group consisting of formulas Iq-Ix:

[0087] [ka]

[0088] In some embodiments, the compound according to Formula I can be one of compounds 1-24 in Table 1. Additionally, all compounds of the present invention that exist in free base or acid form can be converted into their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of the compounds of the present invention can be converted into their free base or acid form by standard techniques. [Compositions and medicines] The compounds of the present invention or their pharmaceutically acceptable salts may be administered in pure form or in suitable pharmaceutical compositions or medicaments by any accepted administration route for formulations that provide similar benefits. Pharmaceutical compositions or medicaments according to embodiments of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable carriers, diluents, or excipients, and formulated into solid, semi-solid, liquid, or gaseous preparations, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administration of such pharmaceutical compositions or medicaments include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and nasal. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, and intrasternal injection or infusion. The pharmaceutical compositions or medicaments of the present invention are formulated so that the active ingredients contained therein are bioavailable when the composition or medicament is administered to a patient. The composition or medicament administered to a subject or patient may take the form of one or more dosage units, for example, a tablet may be a single dosage unit, and a container of the compound of the present invention in aerosol form may contain multiple dosage units. Actual methods for preparing such formulations are known or obvious to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition or medicament administered will, in any case, contain a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof for treating the disease or disorder of interest according to the teachings of the present invention.

[0089] The pharmaceutical composition or medicament of some embodiments of the present invention may be in solid or liquid form. In one aspect, the carrier is particulate, so that the composition or medicament is, for example, in tablet or powder form. The carrier may also be liquid, so that the composition may be, for example, an oral syrup, an injectable liquid, or an aerosol useful, for example, for inhalation or inhalation administration.

[0090] For oral administration, the pharmaceutical composition or medicament is preferably in solid or liquid form, with semi-solid, semi-liquid, suspension and gel forms being included within the forms considered herein to be solid or liquid.

[0091] A solid composition or medicament for oral administration may be formulated in the form of a powder, granules, compressed tablet, pill, capsule, chewing gum, wafer, or the like. Such solid compositions or medicaments typically contain one or more inert diluents or edible carriers. One or more of the following may also be present: binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch, lactose, or dextrin; disintegrants such as alginic acid, sodium alginate, Primogel, corn starch, and the like; lubricants such as magnesium stearate or Sterotex; lubricants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavorings such as peppermint, methyl salicylate, or orange flavor; and coloring agents.

[0092] When the pharmaceutical composition or medicament is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

[0093] The pharmaceutical composition or medicament may be in the form of a liquid, such as an elixir, syrup, solution, emulsion, or suspension. The liquid may be for oral administration or for injection, as two examples. For oral administration, a preferred composition or medicament contains, in addition to the compound of the present invention, one or more sweeteners, preservatives, dyes / coloring agents, and flavor enhancers. A composition or medicament for injection administration may contain one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer, and isotonic agent.

[0094] Liquid pharmaceutical compositions and medicaments of some embodiments of the present invention, whether in solution, suspension, or other similar form, may contain one or more of the following adjuvants: sterile diluents, such as water for injection, saline, preferably saline, Ringer's solution, isotonic sodium chloride, fixed oils, such as synthetic mono- or diglycerides, polyethylene glycol, glycerin, propylene glycol, or other solvents that can act as solvents or suspending media; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; and isotonicity adjusting agents such as sodium chloride or dextrose. Parenteral preparations may be packaged in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. Injectable pharmaceutical compositions or medicaments are preferably sterilized.

[0095] A liquid pharmaceutical composition or medicament according to certain embodiments of the invention intended for either parenteral or oral administration should contain an amount of a compound of the invention such that a suitable volume will be obtained. In some embodiments, the pharmaceutical composition or medicament of the present invention may be for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment, or gel base. The base may, for example, comprise one or more of the following: petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, diluents such as water and alcohol, emulsifiers, and stabilizers. Thickeners may be present in pharmaceutical compositions or medicaments for topical administration. For transdermal administration, the composition or medicament may comprise a transdermal patch or iontophoresis device.

[0096] In various embodiments of the present invention, the pharmaceutical composition or medicament may be for rectal administration, for example, in the form of a suppository that melts in the rectum and releases the drug. The rectal administration composition or medicament may contain an oily base as a suitable non-irritating excipient. Such bases include, but are not limited to, lanolin, cocoa butter, and polyethylene glycol.

[0097] Embodiments of the pharmaceutical composition or medicament of the present invention can include various materials that modify the physical form of a solid or liquid dosage unit. For example, the composition or medicament can include a material that forms a coating shell around the active ingredient. The material that forms the coating shell is generally inert and can be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredient can be placed in a gelatin capsule.

[0098] In some embodiments of the present invention, pharmaceutical compositions or medicaments in solid or liquid form may contain agents that bind to the compounds of the present invention and aid in the delivery of the compounds. Suitable agents that may act in this capacity include monoclonal or polyclonal antibodies, proteins, or liposomes.

[0099] In another embodiment of the present invention, the pharmaceutical composition or medicament may comprise a dosage unit that can be administered as an aerosol. The term aerosol is used to refer to a variety of systems, from systems with colloidal properties to systems consisting of pressurized packages. Delivery can be by liquefied or compressed gas or by a suitable pump system that dispenses the active ingredient. The aerosol of the compound of the present invention can be delivered in a single-phase, two-phase, or three-phase system to deliver the active ingredient. Aerosol delivery includes the necessary container, activator, valve, subcontainer, etc., which can all be combined to form a kit. Anyone skilled in the art can determine a preferred aerosol without undue experimentation.

[0100] In some embodiments, the pharmaceutical composition or medicament of the present invention can be prepared by methods well known in the pharmaceutical arts. For example, a pharmaceutical composition or medicament for injection can be prepared by combining a compound of the present invention with sterile distilled water to form a solution. A surfactant can also be added to promote the formation of a homogeneous solution or suspension. A surfactant is a compound that non-covalently interacts with a compound of the present invention to promote dissolution or homogeneous suspension of the compound in an aqueous delivery system.

[0101] The compounds of the present invention or pharmaceutically acceptable salts thereof are administered in a therapeutically effective amount, which will vary depending on a variety of factors, including the activity of the specific compound used; the metabolic stability and duration of action of the compound; the age, weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; drug combinations; the severity of the particular disorder or disease; and the subject being treated.

[0102] The compounds of the present invention or pharmaceutically acceptable derivatives thereof can also be administered simultaneously with, before, or after the administration of one or more other therapeutic agents. Such combination therapy includes not only administration of a single pharmaceutical dosage formulation containing the compounds of the present invention and one or more additional active agents, but also administration of the compounds of the present invention and each active agent in their own separate pharmaceutical dosage formulations. For example, the compounds of the present invention and the other active agents can be administered to a patient together in a single oral dosage composition such as a tablet or capsule, or each formulation can be administered in a separate oral dosage formulation. When separate dosage formulations are used, the compounds of the present invention and one or more additional active agents can be administered essentially at the same time, i.e., simultaneously, or separately with a time lag, i.e., sequentially; combination therapy is understood to include all such therapies.

[0103] In some embodiments, the concentration of the compound of Formula I provided in a pharmaceutical composition or medicament of the invention is 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, ... less than 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w / w, w / v or v / v.

[0104] In some embodiments, the concentration of the compound of Formula I provided in a pharmaceutical composition or medicament of the present invention is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16. 50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w / w, w / v or v / v.

[0105] In some embodiments, the concentration of the compound of Formula I provided in a pharmaceutical composition or medicament of the present invention is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, or from about 0.06% to about 25% of the pharmaceutical composition or medicament. , about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v or v / v range.

[0106] In some embodiments, the concentration of the compound of Formula I provided in a pharmaceutical composition or medicament of the invention is within the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, or about 0.1% to about 0.9% w / w, w / v, or v / v of the pharmaceutical composition or medicament.

[0107] In some embodiments, the amount of a compound of Formula I provided in a pharmaceutical composition or medicament of the present invention is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.0 g, 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.0 g, 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.5 g, 0.65 g, 0.65 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.0 g, 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.65 g, 0.65 g, 0.45 g, 0.45 g, 0.45 g, 0.0 g, 0. 35g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g or 0.0001g.

[0108] In some embodiments, the amount of a compound of Formula I provided in a pharmaceutical composition or medicament of the present invention is 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 ... , 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g , 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g , 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g or more than 10g.

[0109] In some embodiments, the amount of the compound of Formula I provided in a pharmaceutical composition or medicament of the present invention ranges from 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g of the pharmaceutical composition or medicament. [Chemical synthesis] All chemicals, reagents, and solvents were obtained from commercial suppliers such as Enamine, Sigma-Aldrich, and Fisher Scientific. The reaction temperatures indicated refer to the reaction vessel temperature, while room temperature (rt) is 25°C. Analytical thin-layer chromatography (TLC) was performed on glass-backed silica plates (20 × 20 cm, pH = 5, MF254). Color development was performed using a 254 nm UV lamp. 1H spectra were recorded on a 400 MHz spectrometer using sample solutions in DMSO-d6 or other commercially available deuterated solvents as noted. Chemical shifts are reported in ppm using tetramethylsilane as the standard. Data are reported as follows: chemical shift, proton number, and multiplicity (s = singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, b = broad, m = multiplet). All new compounds were 1 It was characterized by 1 H-NMR and mass spectroscopy (MS).

[0110] Example 1. 1-Ethylpiperidin-4-yl 4-(phenylsulfanyl)butanoate

[0111] [ka]

[0112] A solution of 1-ethyl-4-piperidinol (0.993 g, 7.68 mmol) and triethylamine (1.46 mL, 10.48 mmol) in dichloromethane (30 mL) was prepared in a round-bottom flask under inert atmosphere. The mixture was cooled to 0°C, and phenylthiobutanoyl chloride (1.500 g, 6.99 mmol) in dichloromethane (20 mL) was added dropwise. After stirring overnight at room temperature, the mixture was worked up by adding distilled water (20 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (3 × 20 mL). The combined organic layers were dried (NaSO) and concentrated under reduced pressure. The crude product was purified by HPLC to obtain compound 1 as a TFA salt (0.268 g, 9.1%). 1 H NMR (400MHz, d6-DMSO) δ1.20(t, 3H), 1.71(m, 1H), 1.83(m, 2H), 1.94(m, 2H), 2.10(m, 1H), 2.45( m, 2H), 2.99(q, 3H), 3.10(m, 3H), 3.44(dd, 2H), 4.88(m, 1H), 7.19(m, 1H), 7.33(m, 4H), 9.57(br s, 1H). m / z 308[M+H]+.

[0113] Example 2. 1,4-Dimethylpiperidin-4-yl 4-(phenylsulfanyl)butanoate

[0114] [ka]

[0115] A solution of 1,4-dimethyl-4-piperidinol (0.993 g, 7.68 mmol) and triethylamine (1.46 mL, 10.48 mmol) in dichloromethane (30 mL) was prepared in a round-bottom flask under inert atmosphere. The mixture was cooled to 0 °C, and phenylthiobutanoyl chloride (1.500 g, 6.99 mmol) in dichloromethane (20 mL) was added dropwise. After stirring overnight at room temperature, the mixture was worked up by adding distilled water (20 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (3 × 20 mL). The combined organic layers were dried (NaSO) and concentrated under reduced pressure. The crude product was purified by HPLC to obtain compound 2 as a TFA salt (0.612 g, 20.8%). 1 H NMR (400MHz, d6-DMSO) δ1.38(m, 3H), 1.69(m, 2H), 1.78(m, 2H), 2.31(m, 2H), 2 .39(m, 2H), 2.65(m, 3H), 2.87(m, 4H), 3.21(m, 2H), 7.15(m, 1H), 7.26(m, 4H). m / z 308[M+H]+.

[0116] Example 3: 2-(Dimethylamino)ethyl 4-(phenylsulfanyl)butanoate

[0117] [ka]

[0118] Phenylthiobutanoic acid (30 g, 152.8 mmol) and N,N-dimethylethanolamine (15 g, 168 mmol) were dissolved in CHCl (300 mL). The stirred solution was cooled in an ice bath, and 4-dimethylaminopyridine (1.86 g, 15.28 mmol) and N,N'-dicyclohexylcarbodiimide (31.52 g, 152.8 mmol) were added sequentially. The temperature was gradually raised to room temperature, and the reaction mixture was stirred overnight. After the starting material was consumed, water (300 mL) was added to the solution. The organic layer was separated, washed with water (2 × 200 mL), dried over NaSO, and evaporated under reduced pressure. The final product, compound 3, was purified by flash chromatography (hexane:ethyl acetate:triethylamine) (10.1 g, 24.7%). 1 H NMR (400MHz, d6-DMSO) δ7.34-7.28(m, 4H), 7.21-7.15(m, 1H), 4.08(t, 2H), 3.02-2.95(m, 2H), 2.47-2.42(m, 4H), 2.13(s, 6H), 1.80(m, 2H). m / z 268[M+H]+.

[0119] Example 4: N,N,N-trimethyl-2-{[4-(phenylsulfanyl)butanoyl]oxy}ethane-1-aminium chloride

[0120] [ka]

[0121] Phenylthiobutanoic acid (24 g, 122.28 mmol, 1 equiv.) and choline chloride (18.78 g, 134.5 mmol, 1.1 equiv.) were dissolved in CHCl (240 mL). The solution was cooled in an ice bath and stirred, followed by the sequential addition of 4-dimethylaminopyridine (1.494 g, 12.22 mmol, 0.1 equiv.) and N,N'-dicyclohexylcarbodiimide (25.23 g, 122.28 mmol, 1 equiv.). The temperature was gradually raised to room temperature, and the solution was stirred overnight. After the starting material was consumed, water (250 mL) was added to the solution. The aqueous layer was separated and washed with CHCl (200 mL), and the water was evaporated. The final product, compound 22, was purified by flash chromatography (acetonitrile:water) to yield 10.3 g (29.8%). Chloride content: 0.048 g of the final compound was dissolved in 30 ml of solution (2-propanol:water 1:2) and adjusted with 0.10058 n AgNO3. The equivalence point (1.55 ml) was fixed with Eosin indicator. 1 H NMR (400MHz, d6-DMSO) δ7.35-7.27(m, 4H), 7.21-7.15(m, 1H), 4.43(m, 2H), 3.69-3 .65(m, 2H), 3.11(s, 9H), 3.04-2.96(m, 2H), 2.53-2.48(m, 2H), 1.82-1.77(m, 2H). m / z 282[M+] Example 5: Additional exemplary compounds A list of exemplary compounds 1-24 is shown in Figure 1. Compounds 4-21 and 23-24 were prepared and formulated in a manner similar to that of compounds 1, 2, 3, and 22, and then coupled to PTBA or the corresponding acid chloride using the appropriate alcohol or amine, or protected form, followed by deprotection if necessary. 1 It was characterized by 1 H NMR, HPLC and MS.

[0122] Example 6: Measurement of kinetic solubility 20 mM stock concentrations of test compounds in 100% DMSO dilutions were prepared in duplicate at a theoretical concentration of 400 mM in phosphate-buffered saline pH 7.4 (138 mM NaCl, 2.7 mM KCl, 10 mM K-phosphate) using 2% final DMSO. Experimental compound dilutions in PBS were further equilibrated at 25°C for 2 hours in an incubator shaker before filtering through HTS filter plates using a vacuum manifold. Test compound filtrates were diluted 2-fold with acetonitrile containing 2% DMSO prior to measurement.

[0123] In parallel, compound dilutions in 50% acetonitrile / PBS were prepared with 2% final DMSO at theoretical concentrations of 0 pM (blank), 10 μM, 25 μM, 50 μM, 100 μM, and 200 μM to generate calibration curves. Ondansetron was used as a reference compound to calibrate the analytical performance. 200 μl of each sample was transferred to a 96-well plate and measured over the range of 200–550 nm in 5 nm steps.

[0124] Compound concentrations in the PBS filtrate were calculated using a dedicated Microsoft Excel calculation script. The absorbance wavelengths appropriate for calculation were manually selected for each compound based on the absorbance maximum (absolute absorbance unit values ​​for the minimum and maximum concentration points within the 0-3 OD range). Each final data set was further visually evaluated by an operator, and the goodness of fit (R2) was calculated for each calibration curve. The valid range of the analysis was approximately 2-400 μm, and compounds showing values ​​near the upper end of the range may actually have a higher solubility.

[0125] [Table 2]

[0126] The compounds of the present invention (prodrugs) are designed to release the activated carboxylic acid, PTBA, in vivo. The compounds of the present invention were tested for plasma stability in vitro and in vivo to demonstrate the disappearance of the prodrug and the appearance of PTBA over time.

[0127] Example 7: Plasma stability studies Plasma stability studies were performed in the plasma of various species. For example, the stability of compound 22 was evaluated in rat, dog, and human plasma at five time points over 120 minutes using HPLC-MS / MS.

[0128] All measurements were performed using a Shimadzu HPLC system, including a vacuum degasser, gradient pump, reversed-phase column, column oven, and automatic sample injector. The HPLC system was coupled to a tandem mass spectrometer, API 3000 (PE Sciex). A TurboIonSpray ion source was used in both positive and negative ion modes. Data collection and analysis were performed using Analyst 1.5.2 software (PE Sciex). Incubation was performed in duplicate with five 70 μL aliquots (one for each time point). Test compounds (1 mM, final DMSO concentration 1%) were incubated at 37°C with shaking at 100 rpm. Five time points were analyzed for 120 min. The reaction was terminated by adding 420 μL of a 90:10 acetonitrile-water mixture, followed by centrifugation at 5500 rpm for 5 min to precipitate plasma proteins. The supernatant was analyzed using the HPLC system coupled to the tandem mass spectrometer. The percentage of test compound remaining in plasma after incubation and the half-life (T 1 / 2 ) was calculated.

[0129] Figures 2-4 show the plasma stability of exemplary compound 22 over time in rats, dogs, and humans, respectively. Further experiments measured the disappearance of the prodrug from plasma samples, while assessing the appearance of the active agent, PTBA (see Figures 5-6). The prodrug was incubated in monkey plasma, and prodrug levels were measured using HPLC-MS / MS, along with semiquantitative measurement of one metabolite, PTBA. All measurements were performed using a Shimadzu Prominence HPLC system, including a vacuum degasser, gradient pump, reversed-phase column, column oven, and automatic sample injector. The HPLC system was coupled to a tandem mass spectrometer, API 3000 (PE Sciex). A TurboIonSpray ion source was used in both positive and negative ion modes. Data collection and analysis were performed using Analyst 1.5.2 software (PE Sciex). Incubations were performed in duplicate, with multiple aliquots (one for each time point), each 70 μL in volume. Test compounds (1 mM, final DMSO concentration 1%) were incubated at 37°C with shaking at 100 rpm. Three to five time points were analyzed over a 120-minute period. The reaction was terminated by adding 420 μL of an acetonitrile-water mixture (90:10, stop solution) and then centrifuged at 5500 rpm for 5 minutes to precipitate plasma proteins. The supernatant was analyzed using an HPLC system coupled to a tandem mass spectrometer. Due to the rapid degradation of some prodrugs in plasma, the corresponding compounds were added to a mixture of stop solution and plasma to establish a "true zero" time point (no direct contact of the compound with plasma prior to the stop solution). For example, compound 22 was incubated in monkey plasma, and the disappearance of compound 22 and the appearance of PTBA were assessed.

[0130] Figure 5 shows the percentage of exemplary compound 22 remaining in monkey plasma over time. Figure 6 shows PTBA levels in monkey plasma over time after administration of compound 22. Example 8: Rat Pharmacokinetic Studies Compounds of the invention were evaluated in a rat PK study to measure the release of PTBA in vivo after iv injection (see Figure 7).

[0131] Typically, the vehicle was Captisol for injection, saline, and water (20%:40%:40%, v / v / v). To prepare the formulation, the compound was dissolved in the required volume of 20% Captisol solution (Captisol was predissolved in a 1:1 v / v mixture of saline and water for injection), vortexed for 1 minute, and then sonicated at 40°C for 1 minute. The resulting solution was clear. The actual formulation batch was prepared 30 minutes prior to the in vivo study. Study design, animal selection, handling, and treatment all followed the CRO's pharmacokinetics study protocol and the guidelines of the Animal Experiment Ethics Committee. Animal handling and plasma sample preparation were performed by the CRO's animal laboratory staff. Male Wistar rats were used in the study. All animals were fasted for 16 hours prior to dosing. Generally, seven time points (pre-dose (0), 5, 15, 30, 60, 120, and 480 min) and intravenous (IV) administration route were established for this pharmacokinetic study. Three animals were included in each compound treatment group. Lidocaine solution (7 mg / kg) was administered subcutaneously 5 min before catheter placement in the left lateral tail vein. The catheter was flushed with 500-IU / ml heparin. Test compound formulations were injected into the right lateral tail vein. Blood was collected from the tail vein into tubes containing K3EDTA. Plasma samples were immediately prepared, flash-frozen, and stored at -70°C until further analysis. Analysis of the plasma samples was performed by the CRO's bioanalytical laboratory staff. The concentrations of the prodrug test compounds and PTBA were measured using high-performance liquid chromatography / tandem mass spectrometry (HPLC-MS / MS) on a Shimadzu HPLC system consisting of two isocratic pumps, an LC-10ADvp, an automatic sample injector SIL-20AC, a sub-controller FCV-14AH, and a degasser DGU-14A. Mass spectrometry analysis was performed using an AB Sciex (Canada) API 3000 (triple quadrupole) instrument equipped with an electrospray ionization (ESI) interface. Data acquisition and system control were performed using Analyst 1.5.2 software (AB Sciex, Canada).

[0132] Chromatographic conditions for prodrug test compounds: Column: Discovery HS C18 (50 x 2.1 mm, 5 μm) Mobile phase A: acetonitrile:water:formic acid = 50:950:1 Mobile phase B: acetonitrile: formic acid = 100:0.1 Linear gradient: 0 min 12% B, 1.00 min 90% B, 1.15 min 90% B, 1.16 min 12% B, 2.7 min stop Elution rate: 400 μL / min. A diversion valve directed the flow to the detector from 1.3 to 1.8 min.

[0133] Column temperature: 30℃ MS / MS detection: Scan type: positive MRM, ion source: Turbo spray, ionization mode: ESI Gas spray: 15L / min, curtain gas: 8L / min, collision gas: 4L / min Ion spray voltage: 5000V, temperature: 400℃ Chromatographic conditions for PTBA: Column: Hypersil BDS C8 (50 x 2.1 mm, 3 μm) Mobile phase A: acetonitrile:water:formic acid = 50:950:1 Mobile phase B: acetonitrile: formic acid = 100:0.1 Linear gradient: 0 min 17% B, 1.40 min 100% B, 1.41 min 17% B, stop at 2.6 min. Elution rate: 400 μL / min. A diversion valve directed the flow to the detector from 1.45 to 1.95 min.

[0134] Column temperature: 30℃ MS / MS detection: Scan type: Negative MRM, Ion source: Turbo spray, Ionization mode: ESI Gas spray: 15L / min, curtain gas: 8L / min, collision gas: 4L / min Ion spray voltage: -4200V, temperature: 400℃ Exemplary compound 22 was administered to three rats at 2 mg / kg iv. Figure 7A shows the concentration-time profiles of the prodrug (compound 22) and PTBA.

[0135] Exemplary compound 17 was administered to three rats at 2 mg / kg iv. Figure 7B shows the concentration-time profiles of the prodrug (compound 17) and PTBA. Exemplary Compound 1 was administered to three rats at 2 mg / kg iv. Figure 7C shows the concentration-time profiles of the prodrug (Compound 1) and PTBA.

[0136] Exemplary compound 15 was administered to five rats at 6 mg / kg iv. Figure 7D shows the concentration-time profiles of the prodrug (compound 15) and PTBA. Example 9: In vivo efficacy in a murine AKI model The purpose of this study was to investigate the efficacy of test compounds in a mouse model of acute kidney injury. Specifically, this study investigated the efficacy of test compounds in a mouse model of cisplatin-induced acute kidney injury (CI-AKI). For example, the effect of repeated daily intraperitoneal (IP) administration of compound 22 at a dose of 50 mg / kg for 7 consecutive days with four different treatment regimens on the development of pathology in mice in the CI-AKI model was evaluated. Serum analysis for blood urea (BUN) was performed on days 5 and 12 after cisplatin administration. The average weight loss per group, as a percentage loss of initial (day 0) body weight for each individual animal, was calculated daily during the study period.

[0137] Study design, animal selection, handling, and treatment all followed the CRO research protocol and guidelines of the Animal Experiments Ethics Committee. Animal treatment and serum sample preparation were performed by CRO animal laboratory staff. One hundred 11-14 week-old female C57BL / 6J mice were randomly assigned by weight to five groups of 20 mice each. Weight ranged from 16.9 to 22.5 g, with a mean weight of 19.54 g (SD = 1.04; CV = 5.3%) across all groups. Each mouse was treated with a single dose of 11 mg / kg cisplatin via IP administration on study day 0. Mice in groups 2 and 4 were repeatedly treated with 50 mg / kg compound 22 every 24 hours for 7 consecutive days, starting on study day 2 or day 0, respectively. Mice in groups 3 and 5 were repeatedly treated with Compound 22 at a dose of 50 mg / kg twice daily (injected at 9:00 AM and 6:00 PM daily) for 7 consecutive days starting on study day 2 or day 0, respectively. Mice in group 1 were maintained untreated after cisplatin injection until final sacrifice.

[0138] To induce acute kidney injury, cisplatin was administered undiluted with a factory-prepared 1 mg / ml infusion solution at an injection volume of 11 ml / kg for a dose of 11 mg / kg. The formulation vehicle for compound 22 was Captisol-saline-water for injection (20%:40%:40%, w / v / v). Only freshly prepared formulations were used for each administration; each actual formulation batch was prepared immediately before administration. The actual formulations were sterile filtered using a 0.2 μm cellulose acetate syringe filter before injection. The administration volume of the test compound was 5 ml per kg body weight. The actual formulations were administered as clear, transparent solutions. The intraperitoneal (IP) route of administration was used in the study. Urea (BUN) was measured in serum using a commercially available kit according to the manufacturer's instructions. The principle of the method is that urease reacts with urea to form H2O. + The product of this reaction is NH4 + and CO3 2- The rate of change in absorbance at λ=340 nm is proportional to the urea concentration. Reproducibility: CV=5.75%.

[0139] A significant, gradual loss of mean body weight was observed in mice in all groups within 1-4 days after cisplatin administration. A gradual recovery of mean body weight was observed in mice treated with compound 22 in G2-G3 starting on study day 5 and in G4-G5 starting on study day 7. Mice in G1 generally showed very poor weight recovery. Mean urea levels were significantly lower in the compound 22-treated groups (G2-G5) compared to G1 on day 5 after cisplatin injection.

[0140] Figure 8. Urea levels in serum of C57B1 / 6J female mice on study days 5 and 12 (mean ± SE, %) per group. Cisplatin was administered IP to all mice on day 0 at a dose of 11 mg / kg. Mice in groups G2, G3, G4, and G5 were repeatedly treated with compound 22 once or twice daily on study days 2-8 (D2-8) or 0-6 (D0-6). Significance levels (ANOVA) of differences compared to G1: *p<0.05, **p0.01.

[0141] Figures 9A-9B. Weight loss (mean ± SE, %) of surviving mice during the study period. Weight loss was measured on different days relative to the initial weight on day 0. Cisplatin was administered IP to all mice on day 0 at a dose of 11 mg / kg. Mice in groups G2, G3, G4, and G5 were repeatedly treated with Compound 22 once or twice daily on (Figure 9A) study days 2-8 (D2-8) or (Figure 9B) study days 0-6 (D0-6). Statistically significant differences relative to G1 were determined by two-way ANOVA and Tukey's post-hoc analysis and are indicated by * for G2 or G4, or ‡ for G3 or G5, respectively.

[0142] Example 10: In vivo efficacy in a rat AKI model The purpose of this study was to investigate the efficacy of test compounds in an ischemia-reperfusion-induced acute kidney injury (IRI-AKI) model in male Sprague-Dawley rats. The IRI-AKI model was developed by applying bilateral renal occlusion in experimental animals. The occlusion period was 60 minutes. The effect of repeated intravenous (IV) administration of 10 mg / kg of compound 22 for 7 days on the pathodynamics of rats subjected to IRI-AKI was evaluated. Animals were observed daily for 8 consecutive days for mortality and clinical signs of toxicity. Serum analysis for creatinine was performed 1 day before ischemia-reperfusion surgery, 24 hours after surgery, and on days 3, 5, and 7 after IRI-AKI intervention.

[0143] Study design, animal selection, handling, and treatment all followed the CRO research protocol and the guidelines of the Animal Experiment Ethics Committee. Animal handling and serum sample preparation were performed by CRO animal laboratory staff. Twenty-eight male Sprague-Dawley rats, aged 11 to 14 weeks, were randomly assigned based on body weight. All experimental animals were anesthetized with 40 mg Telazol per kg body weight and 7 mg / kg Xylazine per kg body weight prior to surgical intervention. The acute kidney injury model was established by bilateral renal occlusion. Renal vessels (in both kidneys) were clamped with a ligator for 60 minutes. After ligation, the kidneys were removed and reperfusion was observed. During the 60-minute occlusion, the kidneys were placed within the rat's body cavity to prevent dehydration and freezing of the parenchymal organs. During the surgery, the animals were placed on a heated platform to observe their breathing patterns. After surgery, the animals were intraperitoneally injected with 2 ml of saline to prevent dehydration.

[0144] The formulation for compound 22 was Captisol-saline-water for injection (20%:40%:40%, w / v / v). The formulation vehicle for the compounds was Captisol-saline-water for injection (20%:40%:40%, w / v / v). The actual formulations were sterile filtered using a 0.2 μm cellulose acetate syringe filter prior to injection. The intravenous (IV) route of administration was used in the study for all compounds. The formulation was slowly injected (5 min) into each animal. Each actual formulation batch was prepared immediately prior to administration. The actual formulation was administered as a clear, transparent solution for all doses of all compounds. The administration volume for the test compound and vehicle was 5 ml per kg of body weight.

[0145] Creatinine was measured using a modified Jaffe's method without removing proteins. Picrate reacts with creatinine in alkaline solution to form yellow-red 2,4,6-trinitrocyclohexadienate. The color intensity is proportional to the creatinine concentration. Reproducibility: CV = 6.1%.

[0146] Creatinine levels in experimental animals exposed to bilateral renal occlusion for 60 min and treated with compound 22 were significantly reduced on day 3 after IRI compared with the vehicle-treated group. Figure 10. Serum creatinine levels in male Sprague-Dawley rats after renal ischemia and repeated IV administration of Compound 22 for 7 days. Values ​​are shown as mean ± SEM for 8-14 rats per group. Noted differences were determined by two-way ANOVA, and individual comparisons were performed by Bonferroni analysis, indicated by **.

[0147] Example 11: In vivo efficacy in a murine AKI model The purpose of this study was to investigate the efficacy of test compounds in a cisplatin-induced acute kidney injury (CI-AKI) model in mice. For example, the effect of repeated daily intraperitoneal (IP) administration of Compound 3 at a dose of 50 mg / kg for 7 consecutive days on the development of pathology in mice in the CI-AKI model was evaluated. Serum analysis for blood urea (BUN) was performed on days 5 and 9 after cisplatin administration. The mean weight loss per group, as a percentage loss of initial (day 0) body weight for each individual animal, was calculated daily during the study period.

[0148] Study design, animal selection, handling, and treatment all followed the CRO research protocol and guidelines of the Animal Experiments Ethics Committee. Animal treatment and serum sample preparation were performed by CRO animal laboratory staff. Sixty female C57BL / 6J mice, 9-12 weeks old, were randomly assigned according to body weight and divided into two groups of 30 mice each. Body weight ranged from 13.9 to 22.0 g, with a mean weight of 17.75 g (SD = 1.30; CV = 7.3%) across all groups. Each mouse was treated with a single dose of 11 mg / kg cisplatin via IP administration on study day 0. Mice in group 2 were repeatedly treated with 50 mg / kg Compound 3 every 24 hours for 7 consecutive days, starting on study day 2. Mice in group 1 were maintained untreated after cisplatin injection until final sacrifice.

[0149] Cisplatin was administered undiluted from a factory-prepared 1 mg / ml infusion solution at an injection volume of 11 ml / kg for a dose of 11 mg / kg. The formulation vehicle for Compound 3 was Captisol-saline-water for injection (20%:40%:40%, w / v / v). Only freshly prepared formulations were used for each administration; each actual formulation batch was prepared immediately before administration. The actual formulations were sterile filtered using a 0.2 μm cellulose acetate syringe filter before injection. The administration volume of the test compound was 5 ml per kg body weight. The actual formulations were administered as clear, transparent solutions. The intraperitoneal (IP) route of administration was used in the study. Urea (BUN) was measured in serum using a commercially available kit according to the manufacturer's instructions. The principle of the method is that urease reacts with urea to form H2O.+ The product of this reaction is NH4 + and CO3 2- The rate of absorbance change at λ = 340 nm is proportional to the urea concentration. Reproducibility: CV = 5.75%. Creatinine was measured using a modified Jaffe method without removing protein. In alkaline solution, picrate reacts with creatinine to form yellow-red 2,4,6-trinitrocyclohexadienate. The color intensity is proportional to the creatinine concentration. Reproducibility: CV = 6.1%.

[0150] A significant gradual decrease in mean body weight was observed in mice in all groups within 1-5 days after cisplatin administration. A gradual recovery of mean body weight was observed in mice treated with Compound 3 in G2 starting on day 6 of the study. Mice in G1 generally showed very poor weight recovery. Mean urea and creatinine levels were significantly lower in the Compound 3-treated group compared to G1 on day 5 after cisplatin injection.

[0151] Figure 11. Urea levels in serum of C57B1 / 6J female mice during the study (mean ± SE, %) per group. Cisplatin was administered IP to all mice on day 0 at a dose of 11 mg / kg. Mice in G1 or G2 were repeatedly treated with vehicle or compound 3, respectively, every 24 hours on days 2-9. Statistical significance was determined by ANOVA (p<0.05) followed by Bonferroni's multiple comparison test. **p<0.01.

[0152] Figure 12. Creatinine levels in serum of C57B1 / 6J female mice during the study (mean ± SE, %) per group. Cisplatin was administered IP to all mice on day 0 at a dose of 11 mg / kg. Mice in G1 or G2 were repeatedly treated with vehicle or Compound 3, respectively, every 24 hours on days 2-9. Statistical significance was determined by ANOVA (p<0.05) followed by Bonferroni's multiple comparison test. **p<0.05.

[0153] Figure 13. Weight loss of mice in the study (mean ± SE, %) per group. Weight loss was measured on different days relative to the initial weight on day 0. Cisplatin was administered IP to all mice on day 0 at a dose of 11 mg / kg. Mice in G1 or G2 were repeatedly treated with vehicle or compound 3, respectively, every 24 hours on days 2-9. Statistical significance was determined by ANOVA (p<0.05) followed by Bonferroni's multiple comparison test. **p<0.05. [Conclusion] Although the foregoing detailed description refers to specific exemplary embodiments, the present invention may be embodied in other specific forms without departing from its concept or essential characteristics. Accordingly, the described embodiments are to be considered in all respects as illustrative and not restrictive. For example, various substitutions, modifications, and / or variations to the features of the present invention described and / or illustrated herein, and further applications of the principles described and / or illustrated herein, may occur to those skilled in the relevant art and to those possessing the present invention, and may be made to the described and / or exemplified embodiments without departing from the concept and scope of the present invention as defined by the appended claims. All such substitutions, modifications, and / or variations are considered to be within the scope of the present disclosure.

[0154] Accordingly, the scope of the present invention is defined by the appended claims rather than the foregoing detailed description. The limitations set forth in the claims should not be limited to the specific embodiments described in the foregoing detailed description, but should be interpreted broadly based on the language used in the claims, and such embodiments should be interpreted as neither exclusive nor complete. All changes that come within the meaning and range equivalent to the claims are embraced within their scope.

[0155] It is also understood that various features of particular embodiments may be compatible with, combinable with, included in, and / or integrated into other embodiments of the invention. For example, systems, methods, and / or products according to particular embodiments of the invention may include, integrate, or be configured differently from features described in other embodiments disclosed and / or described herein. Thus, the disclosure of specific features for particular embodiments of the invention should not be construed as limiting the application or inclusion of such features to that particular embodiment.

[0156] Additionally, unless any feature is described as required in a particular embodiment, features described in various embodiments may be optional and may not be included in other embodiments of the present invention. Furthermore, unless any feature is described as requiring other features in that combination, any feature herein may be combined with any other feature of the same or different embodiments disclosed herein. While a feature may be optional in a particular embodiment, it is understood that if such an embodiment includes a feature, it must have the specific configuration as described in the present invention.

[0157] Similarly, any steps recited in any method or process described and / or claimed herein may be performed in any suitable order and are not necessarily limited to the order described and / or recited unless otherwise stated (expressly or implicitly). However, such steps may be required to be performed in a particular order, or in any suitable order, in particular embodiments of the invention.

[0158] Moreover, various well-known aspects of example systems, methods, articles of manufacture, etc. have not been described in particular detail herein to avoid obscuring aspects of the example embodiments, although such aspects are contemplated herein.

Claims

1. A compound according to Formula I below or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof: 【Chemistry 1】 In the above formula, R １ is O; R ２ are represented by the following chemical formulas Ia to Ip 【Chemistry 2】 is selected from the group consisting of:

2. 10. A composition comprising a compound of claim 1; and a pharmaceutically acceptable carrier.

3. A composition for use in a mammal for (i) inhibiting histone deacetylase (HDAC) activity, (ii) promoting renal recovery after acute kidney injury (AKI), preferably by HDAC inhibition, (iii) attenuating renal damage after AKI and / or (iv) treating AKI, said composition comprising a compound of claim 1; and a pharmaceutically acceptable carrier.

4. A composition for use in treating acute kidney injury (AKI) in a mammalian subject by inhibiting HDAC activity, thereby alleviating renal damage and / or promoting renal recovery after AKI, the composition comprising a compound described in claim 1; and a pharmaceutically acceptable carrier.

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