WO2022178544A1

WO2022178544A1 - Novel heterocyclic compounds and related methods of manufacture and use in hdac inhibition

Info

Publication number: WO2022178544A1
Application number: PCT/US2022/070742
Authority: WO
Inventors: Michael Joseph Bishop; James Plante
Original assignee: Klotho Therapeutics, Inc.
Priority date: 2021-02-20
Filing date: 2022-02-18
Publication date: 2022-08-25

Abstract

Novel compounds and compositions including the same and methods of manufacturing and using the same, particularly for inhibiting HDAC or HDAC activity, preferably HDAC8 or HDAC8 activity, and more particularly for enhancing renal recovery, preferably following acute kidney injury (AKI) and/or in connection with chronic kidney disease (CKD), more preferably through HDAC or HDAC8 inhibition.

Description

NOVEL HETEROCYCLIC COMPOUNDS AND RELATED METHODS OF MANUFACTURE AND USE IN HD AC INHIBITION

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63/151,686, filed February 20, 2021, the entirety of which is incorporated herein by specific reference.

BACKGROUND

1. Technical Field

[0002] The present disclosure relates to novel heterocyclic compounds (or heterocycles), and to compositions comprising the same, and to methods of manufacturing and using the same, particularly for use in inhibiting histone deacetylase (HDAC) activity, particularly HDAC8 activity, and/or for use in enhancing renal recovery following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), preferably through HDAC (or HDAC8) inhibition.

2. Related Technology

[0003] Severe acute kidney injury (AKI) is remarkably common and has an unacceptably high mortality that has been unchanged for the last twenty-plus years. AKI therapies that have been developed in experimental models when administered prior to the onset of injury have failed to show therapeutic benefit in humans. AKI is a multi-factorial disorder that occurs in approximately 7% of in-patients hospital admissions. It is an independent predictor of in-hospital mortality. Severe AKI requiring renal replacement therapy occurs in 4% of critically ill patients and has 50% in-patient mortality. Long term follow up studies in survivors of severe AKI indicate that approximately 12.5% become dialysis-dependent. Despite these sobering statistics, renal replacement is the only approved therapy for AKI, and there are no established therapies that have been proven to prevent renal injury or accelerate the rate of renal recovery following induction of AKI in man. Without being bound to any particular theory, chronic kidney disease (CKD) is similarly plagued with a lack of available therapies and may involve similar pathways of renal injury. Therefore there is an urgent need to develop effective therapies that will accelerate the rate of recovery following induction of renal injury.

[0004] Notwithstanding the foregoing, the kidney does have an innate capacity to undergo epithelial regeneration following injury, suggesting that drugs that enhance this regenerative capacity are more likely to be of benefit when given after the onset of injury. Guo et al. published the Epigenetic regulation in AKI and kidney repair: mechanisms and therapeutic implications (Nature Reviews Nephrology volume 15, pages 220-239(2019)), review the emerging role of epigenetic regulation in the process of AKI and kidney repair (e.g., involving remarkable changes in histone modifications, DNA methylation and the expression of various non-coding RNAs). In summary, increases in levels of histone acetylation seem to protect kidneys from AKI and promote kidney repair. AKI is also associated with changes in genome-wide and gene-specific DNA methylation; however, the role and regulation of DNA methylation in kidney injury and repair remains largely elusive. In 2010, de Groh et al. published Inhibition of histone deacetylase expands the renal progenitor cell population (J Am Soc Nephrol 21: 794-802, 2010), in which the group identified anew histone deacetylase inhibitor (HDACi), 4-(phenylthio)butanoic acid (PTBA), that seemed to expand the pool of renal progenitor cells in zebrafish embryos in a proliferation-dependent manner, thereby enhancing renal recovery, increasing renal tubular endothelial cell (RTEC) proliferation, reducing renal fibrosis. Without being bound to any theory, PTBA was shown to increase renal tubular cell proliferation, increase survival, and increase renal functional recovery in fish and various models of acute kidney injury. Immunohistological analyses suggested increased cell proliferation to be accompanied by increased epithelial-to-mesenchymal transition in the RTECs. Later, Cosentino et al. published Histone Deacetylase Inhibitor Enhances Recovery after AKI (Journal of the American Society of Nephrology, Vol. 24, Issue 6, June 2013), Skrypnyk et al. published 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), and Skvarca et al. published 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). In this publication, Skvarca et al. state “7¾e most likely target appears to be class I HDACs. One attractive candidate is HDAC8, which has been linked to the repression of the developmental important renal transcription factor gene Lhxl (Haber land et al, 2009; Saha et al, 2013). Furthermore, HDAC8 has been connected to RA signaling in cancer. Combined treatment of neuroblastoma cells with all-trans RA and an HDAC8 inhibitor resulted in enhanced tumor cell death (Rettig et al, 2015).” WO2012109527 and corresponding US20150246939 further disclose that a Class ofHDAC Inhibitors Expands the Renal Progenitor Cells Population and improves the Rate of Recovery from acute Kidney Injury. Each of the foregoing references is incorporated by herein by reference, in its entirety. [0005] However, there remains a need for improved and/or optimized compounds that serve as HDAC class 1 inhibitors, specifically and preferably HDAC8 inhibitors, and that are suitable for (U.S. Food and Drug Administration (FDA)-approved) administration, particularly for use in inhibiting HDAC activity and/or for enhancing renal recovery (e.g., following AKI or for treating chronic kidney disease CKD)), preferably through HDAC inhibition, and methods of manufacturing and using the same. [0006] As the so-called “baby boomers” generation continues to advance in age, the population of aging individuals (e.g., age 60-65) is rapidly increasing globally. This aging population increasingly suffers from AKI and CKD. The increased demand for health care for this aging population places significant financial burden on any healthcare system. Molecular compounds (or so-called “small molecules”) provide promising therapeutic agents to counter age-related health conditions. Developing strategies and health intervention methods based on the production and purification of compounds that inhibit HDAC (activity), and the administration of such compounds to subjects may help to ameliorate this situation and the problems associated therewith. Developing strategies and health intervention methods based on the administration of novel heterocycles (that inhibit HDAC activity and, thereby, improve renal recovery and/or function), especially humans and/or within an increasing aging population, may help to ameliorate this situation.

[0007] Currently, there is not a commercial, small molecule product (or treatment method for improving renal recovery and/or function (e.g., following AKI or in response to CKD), particularly through inhibition of HDAC activity, especially products and methods approved by the U.S. Food and Drug Administration (FDA). To date, all relevant data is connected to pre-clinical, research trials in animal models. Accordingly, there are a number of short comings in the art that can be addressed by the development, production, manufacture, and administration of new, heterocycles and compositions comprising the same, particularly for use in inhibiting HDAC activity, preferably including HDAC8 activity, and/or for enhancing renal recovery following AKI or treating chronic kidney disease, preferably through HDAC inhibition.

BRIEF SUMMARY

[0008] Embodiments of the present disclosure solve one or more of the foregoing or other problems in the art with compounds (a.k.a., “small molecules,” “therapeutic agents,” etc.) that serve or function as HDAC inhibitors, and compositions comprising the same, and methods of manufacturing and using the same, particularly for inhibiting histone deacetylase (HDAC) activity (e.g., HDAC8 activity) and/or for enhancing renal recovery, particularly following AKI or in connection with CKD (preferably through HDAC (e.g., HDAC8) inhibition). Embodiments include novel, non-toxic, and/or water soluble compounds that can accelerate recovery from AKI by enhancing the innate regenerative capacity of the kidney. Accordingly, the present disclosure provides a number of compounds with direct application in human AKI and, optionally, for CKD.

[0009] In a further embodiment, a method of treating kidney injury (AKI) or disease or improving kidney function in patients is provided. The method comprising administering to a patient an amount of a compound or composition as described herein, or a (pharmaceutically- acceptable) salt thereof. In various embodiments, the administered amount is effective to treat kidney injury (AKI) or disease or to improve kidney function in a patient. For example, the compound or (pharmaceutically-acceptable) salt thereof is administered in an amount and in a dosage regimen effective to improve kidney function in a patient, to inhibit a histone deacetylase (activity) in a cell (e.g., renal cell) or systemically, to expand renal progenitor cells, and/or to stimulate kidney repair in cells (in vitro, ex vivo or in vivo). The manufacture and/or use of any compound or composition described herein also is provided, preferably for treating kidney injury or disease or improving kidney function in a patient.

[0010] Illustratively, various embodiments of the present disclosure can be or comprise a substituted 2-amino-3-phenylpropanone (or 2-amino-3-phenylpropane-l-one):

[0011] In various embodiments of the present disclosure, the 2-amino-3-phenylpropanone (or 2-amino-3-phenylpropane-l-one) can be substituted, at the phenyl (or benzene), with 1, 2, 3, 4, or 5 substituents (at the 2, 3, 4, 5, and/or 6 position(s), respectively), independently selected from halo (Cl, Br, F, I), trifluoromethyl, etc. In a preferred embodiment, the 2- amino-3-phenylpropanone (or 2-amino-3-phenylpropane-l-one) can be substituted, at the phenyl (or benzene), with chloro, preferably 2-chloro and/or 4-chloro, more preferably dichloro, still more preferably 2,4-dichloro (forming 2,4-dichlorophenyl).

[0012] In various embodiments of the present disclosure, the 2-amino-3-phenylpropanone (or 2-amino-3-phenylpropane-l-one) can be substituted, at the 1 -position (or 1 -carbon), with a substituted (primary) heterocyclic (nitrogenous) ring structure, via a nitrogen of said (primary) heterocyclic (nitrogenous) ring structure. Non-limiting examples of heterocyclic (nitrogenous) ring structures are illustrated in Figure 1. In some embodiments, the (primary) heterocyclic (nitrogenous) ring structure can be or comprise a 3-member, 4-member, 5- member, 6-member, 7-member, or 8-member heterocyclic (nitrogenous) ring or an 8- member, 9-member, 10-member, 11 -member, 12-member, 13 -member, or 14-member fused, heterocyclic (nitrogenous) multi-ring structure.

[0013] Illustratively, the substituted (primary) heterocyclic (nitrogenous) ring structure (extending from the 1 -position or 1 -carbon of the 2-amino-3-phenylpropanone or 2-amino-3- phenylpropane-l-one) can be or comprise (i) a substituted isoindoline (or isoindolinyl) (e.g., a 2-isoindoline or isoindolin-2-yl, preferably a 5-substituted or 6-substituted, 2-isoindoline or isoindolin-2-yl), (ii) a substituted azetidine (or azetidinyl) (e.g., a 1-azetidine or azeti din-1 -yl, preferably a 3 -substituted, 1-azetidine or azetidin-l-yl), or (iii) a substituted azolidine (or azolidinyl, i.e., pyrrolidine or pyrrolidinyl) (e.g., a 1-azolidine or azolidin-l-yl, or 1- pyrrolidine or pyrrolidin-l-yl, preferably a 3-substituted, 1-azolidine or azolidin-l-yl, or 1- pyrrolidine or pyrrolidin-l-yl).

[0014] In some embodiments, the substituent of the (primary) heterocyclic (nitrogenous) ring structure, above, can be disposed (i) at the 1, 3, 3a, 4, 5, 6, 7, and/or 7a position(s), respectively, of the isoindoline (or isoindolinyl), preferably at the 5 position, (ii) at the 1, 2, and/or 3 position(s), respectively, of the azetidine (or azetidinyl), preferably at the 3 position, and/or (iii) at the 2, 3, 4, and/or 5 position(s), respectively, of the azolidine (or azolidinyl, i.e., pyrrolidine or pyrrolidinyl), preferably at the 3 position.

[0015] In some embodiments, the substituent of the (primary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted sulfonamide (including sulfonamidyl-N-methylene, as described herein), sulfonimidamide (including sulfonimidamidyl-N-methylene, as described herein), cycloalkyl, phenyl, or (secondary) heterocyclic (nitrogenous) ring structure, preferably selected from the group consisting of pyrazole, imidazole, benzene (phenyl), and pyridine.

[0016] In some embodiments, the optional substituent of the sulfonamide, sulfonimidamide, cycloalkyl, phenyl, or (secondary) heterocyclic (nitrogenous) ring structure, (immediately) above, preferably the sulfonamide or sulfonimidamide, can be or comprise methyl or an unsubstituted or substituted (tertiary) heterocyclic (nitrogenous) ring structure, preferably selected from the group consisting of triazole (e.g., a l,2,3-triazol-4-yl, forming 1,2,3- triazole-4-sulfonamide or l,2,3-triazole-4-sulfonimidamide), imidazole (e.g., imidazol-2-yl, forming imidazole-2-sulfonamide or imidazole-2-sulfonimidamide, or imidazol-4-yl, forming imidazole-4-sulfonamide or imidazole-4-sulfonimidamide), pyrazole (e.g., pyrazol-4-yl, forming pyrazole-4-sulfonamide or pyrazole-4-sulfonimidamide), pyrrolidine (e.g., pyrrolidin-l-yl, forming pyrrolidine-1 -sulfonamide or pyrrolidine-l -sulfonimidamide), piperidine (e.g., piperidin-4-yl, forming piperidine-4-sulfonamide or piperidine-4- sulfonimidamide), piperazine (e.g., piperazin-l-yl, forming piperazine- 1 -sulfonamide or piperazine- 1 -sulfonimidamide ), or azetidine (e.g., azetidin-3-yl, forming azetidine-3- sulfonamide or azetidine-3-sulfonimidamide).

[0017] In some embodiments, the optional substituent of the (tertiary) heterocyclic (nitrogenous) ring structure substituent, (immediately) above, can be or comprise methyl (e.g., methylpyrazole, preferably methylpyrazol-4-yl or 1 -methyl- lH-pyrazol-4-yl, forming, for example, 1 -methyl- lH-pyrazole-4-sulfonamide; or methylimidazole, preferably methylimidazol-4-yl or 1 -methyl- lH-imidazol-4-yl, forming, for example, 1 -methyl- 1H- imidazole-4-sulfonamide; or methylpiperazine, preferably methylpiperazin-l-yl or 4- methylpiperazin-l-yl, forming, for example, 4-methylpiperazine-l -sulfonamide), hydroxy or dihydroxy (e.g., dihydroxypyrrolidine, preferably dihydroxypyrrolidin-l-yl, more preferably 3,4-dihydroxypyrrolidine or 3,4-dihydroxypyrrolidin-l-yl, forming, for example, 3,4- dihydroxypyrrolidine- 1 -sulfonamide or 3,4-dihydroxypyrrolidine- 1 -sulfonimidamide).

[0018] Illustratively, various embodiments of the present disclosure can be or comprise a substituted (or N-substituted) 2-amino-3-phenylpropanamide (or 2-amino-3-phenylpropane- 1-amide) or 2-amino-3-phenylpropanamidyl (or 2-amino-3-phenylpropanamid-l-yl):

[0019] In various embodiments of the present disclosure, the nitrogen of the amide, at the 1- position (or 1 -carbon of the amide) of the 2-amino-3-phenylpropanamide (or 2-amino-3- phenylpropane-1 -amide) or 2-amino-3-phenylpropanamidyl (or 2-amino-3- phenylpropanamid-l-yl), can form a substituted (primary) heterocyclic (nitrogenous) ring structure, as described herein. In some embodiments, (i) the substituent of the (primary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted sulfonamide (including sulfonamidyl-N-methylene), sulfonimidamide (including sulfonimidamidyl-N-methylene), cycloalkyl, phenyl, or (secondary) heterocyclic (nitrogenous) ring structure, (ii) the optional substituent of the sulfonamide, sulfonimidamide, cycloalkyl, phenyl, or (secondary) heterocyclic (nitrogenous) ring structure, above, can be or comprise methyl or an unsubstituted or substituted (tertiary) heterocyclic (nitrogenous) ring structure, and (iii) the optional substituent of the (tertiary) heterocyclic (nitrogenous) ring structure, above, can be or comprise methyl, hydroxy or dihydroxy, as described herein. [0020] In various embodiments of the present disclosure, the substituted (or N-substituted) 2- amino-3-phenylpropanamide (or 2-amino-3-phenylpropane-l -amide) or 2-amino-3- phenylpropanamidyl (or 2-amino-3-phenylpropanamid-l-yl) can be substituted, at the phenyl (or benzene), with 1, 2, 3, 4, or 5 substituents (at the 2, 3, 4, 5, and/or 6 position(s), respectively), independently selected from halo (Cl, Br, F, I), trifluoromethyl, etc. In a preferred embodiment, the substituted (or N-substituted) 2-amino-3-phenylpropanamide (or 2-amino-3-phenylpropane-l -amide) or 2-amino-3-phenylpropanamidyl (or 2-amino-3- phenylpropanamid-l-yl) can be substituted, at the phenyl (or benzene), with chloro, preferably 2-chloro and/or 4-chloro, more preferably di chloro, still more preferably 2,4- dichloro (forming 2,4-dichlorophenyl).

[0021] Illustratively, various embodiments of the present disclosure can be or comprise a substituted (or N-substituted) 2-amino-3-(2,4-dichlorophenyl)propanamide (or 2-amino-3- (2,4-dichlorophenyl)propane-l -amide) or 2-amino-3-(2,4-dichlorophenyl)propanamidyl (or 2-amino-3-(2,4-dichlorophenyl)propanamid-l-yl):

[0022] In various embodiments of the present disclosure, the nitrogen of the amide, at the 1- position (or 1 -carbon of the amide) of the 2-amino-3-(2,4-dichlorophenyl)propanamide (or 2- amino-3-(2,4-dichlorophenyl)propane-l -amide) or 2-amino-3-(2,4-dichlorophenyl) propanamidyl (or 2-amino-3-(2,4-dichlorophenyl)propanamid-l-yl), can form a substituted (primary) heterocyclic (nitrogenous) ring structure, as described herein.

[0023] In some embodiments, (i) the substituent of the (primary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted sulfonamide (including sulfonamidyl-N-methylene), sulfonimidamide (including sulfonimidamidyl-N- methylene), (secondary) heterocyclic (nitrogenous) ring structure, cycloalkyl, or phenyl, (ii) the optional substituent of the sulfonamide, sulfonimidamide, (secondary) heterocyclic (nitrogenous) ring structure, cycloalkyl, or phenyl, above, can be or comprise methyl or an unsubstituted or substituted (tertiary) heterocyclic (nitrogenous) ring structure, and (iii) the optional substituent of the (tertiary) heterocyclic (nitrogenous) ring structure, above, can be or comprise methyl, hydroxy or dihydroxy, as described herein.

[0024] In alternative embodiments, the chlorides of the 2,4-dichloro can, independently, be at the 3-position, 5-position, and/or 6-position of the benzene (or phenyl) group. [0025] In various embodiments, the compound(s) of the present disclosure may be according to Formula I:

Formula I

[0026] In some embodiments of Formula I, R1 and R2 can, together with the nitrogen to which R1 and R2 are attached, form a substituted (primary) heterocyclic (nitrogenous) ring structure. In some embodiments, the heterocyclic (nitrogenous) ring structure can be or comprise a 3-member, 4-member, 5-member, 6-member, 7-member, or 8-member heterocyclic (nitrogenous) ring or an 8-member, 9-member, 10-member, 11 -member, 12- member, 13-member, or 14-member fused, heterocyclic (nitrogenous) multi-ring structure. Illustratively, R1 and R2 can form (i) a substituted isoindoline (or isoindolinyl) (e.g., a 2- isoindoline or isoindolin-2-yl, preferably a 5-substituted or 6-substituted, 2-isoindoline or isoindolin-2-yl), (ii) an unsubstituted or substituted azetidine (azetidinyl) (e.g., a 1-azetidine or azetidin-l-yl, preferably a 3 -substituted, 1-azetidine or azetidin-l-yl), or (iii) an unsubstituted or substituted azolidine (i.e., pyrrolidine, or azolidinyl, or pyrrolidinyl) (e.g., a 1-azolidine or azolidin-l-yl, or 1 -pyrrolidine or pyrrolidin-l-yl, preferably a 3 -substituted, 1- azolidine or azolidin-l-yl, or 1 -pyrrolidine or pyrrolidin-l-yl).

[0027] In some embodiments, the substituent of the (primary) heterocyclic (nitrogenous) ring structure, above, can be disposed (i) at the 1, 3, 3a, 4, 5, 6, 7, and/or 7a position(s), respectively, of the isoindoline (or isoindolinyl), preferably at the 5 position, (ii) at the 1, 2, and/or 3 position(s), respectively, of the azetidine (or azetidinyl), preferably at the 3 position, and/or (iii) at the 2, 3, 4, and/or 5 position(s), respectively, of the azolidine (or azolidinyl, i.e., pyrrolidine or pyrrolidinyl), preferably at the 3 position.

[0028] In some embodiments, the substituent of the (primary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or (optionally) substituted sulfonamide (including sulfonamidyl-N-methylene, as described herein), sulfonimidamide (including sulfonimidamidyl-N-methylene, as described herein), cycloalkyl, phenyl, or (secondary) heterocyclic (nitrogenous) ring structure, preferably selected from the group consisting of pyrazole, imidazole, benzene (phenyl), and pyridine.

[0029] In some embodiments, the optional substituent of the sulfonamide, sulfonimidamide, cycloalkyl, phenyl, or (secondary) heterocyclic (nitrogenous) ring structure, (immediately) above, preferably the sulfonamide or sulfonimidamide, can be or comprise methyl or an unsubstituted or substituted (tertiary) heterocyclic (nitrogenous) ring structure, preferably selected from the group consisting of triazole (e.g., a l,2,3-triazol-4-yl, forming 1,2,3- triazole-4-sulfonamide or l,2,3-triazole-4-sulfonimidamide), imidazole (e.g., imidazol-2-yl, forming imidazole-2-sulfonamide or imidazole-2-sulfonimidamide, or imidazol-4-yl, forming imidazole-4-sulfonamide or imidazole-4-sulfonimidamide), pyrazole (e.g., pyrazol-4-yl, forming pyrazole-4-sulfonamide or pyrazole-4-sulfonimidamide), pyrrolidine (e.g., pyrrolidin-l-yl, forming pyrrolidine-1 -sulfonamide or pyrrolidine-l -sulfonimidamide), piperidine (e.g., piperidin-4-yl, forming piperidine-4-sulfonamide or piperidine-4- sulfonimidamide), piperazine (e.g., piperazin-l-yl, forming piperazine- 1 -sulfonamide or piperazine- 1 -sulfonimidamide ), or azetidine (e.g., azetidin-3-yl, forming azetidine-3- sulfonamide or azetidine-3 -sulfonimidamide).

[0030] In some embodiments, the substituent of the (primary) heterocyclic (nitrogenous) ring structure (formed by R1 and R2, together with the nitrogen to which R1 and R2 are attached), above, can be or comprise an unsubstituted or substituted pyrazole (or pyrazolyl). Illustratively, the pyrazole can be or comprise a 4-pyrazole (or pyrazol-4-yl or pyrazole-4), a 3-pyrazole (or pyrazol-3-yl or pyrazole-3), or a 1-pyrazole (or pyrazol-l-yl or pyrazole-1). In some embodiments, the optional substituent (of the pyrazole (or pyrazolyl), above), can be or comprise methyl, preferably 1 -methyl.

[0031] In some embodiments, the substituent of the (primary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted pyridazine (or pyridazinyl). Illustratively, the pyridazine can be or comprise a 3-pyridazine (or pyridazin-3- yl) or 4-pyridazine (or pyridazin-4-yl). In some embodiments, the substituent of the (primary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted diazabenzene (or diazabenzenyl). Illustratively, the diazabenzene can be or comprise a 1 ,2-diazabenzene (or diazabenzen-l,2-yl) or a 1,6- diazabenzene (or diazabenzen- 1,6-yl).

[0032] In some embodiments, the substituent of the (primary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted cycloalkane (or cycloalkyl), preferably unsubstituted cycloalkyl. Illustratively, the cycloalkyl can be or comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, preferably cyclopropyl, more preferably unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, still more preferably unsubstituted cyclopropyl. [0033] In some embodiments, the substituent of the (primary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted imidazole (or imidazolyl). Illustratively, the imidazole can be or comprise 1 -imidazole (or imidazol-l-yl), 2-imidazole (imidazol-2-yl or imidazole-2), 4-imidazole (imidazol-4-yl or imidazole-4), or 5- imidazole (imidazol-5-yl or imidazole-5). In some embodiments, the optional substituent (of the imidazole (or imidazolyl), above), can be or comprise methyl, preferably 1 -methyl.

[0034] In some embodiments, the substituent of the (primary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted benzene (or phenyl), preferably an unsubstituted benzene.

[0035] In some embodiments, the substituent of the (primary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted pyridine (or pyridinyl), preferably unsubstituted pyridine. Illustratively, the pyridine can be or comprise 1 -pyridine (or pyridin-l-yl), 2-pyridine (or pyridin-2-yl), 3-pyridine (or pyridin-3-yl), or 4-pyridine (or pyridin-4-yl).

[0036] In some embodiments, the substituent of the (primary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted sulfonamide, illustratively comprising N-sulfonamide or N-methyl sulfonamide (or sulfonamidyl-N- methylene). In some embodiments, the substituent (of the sulfonamide, N-sulfonamide, or N- methyl sulfonamide (or sulfonamidyl-N-methylene), above), can be or comprise methyl, forming methanesulfonamide, N-methanesulfonamide, or N-methyl methanesulfonamide (or methanesulfonamidyl-N-methylene). In some embodiments, the substituent (of the sulfonamide, N-sulfonamide, or N-methyl sulfonamide (or sulfonamidyl-N-methylene), above), can be or comprise an unsubstituted or substituted (tertiary) heterocyclic (nitrogenous) ring structure. In some embodiments, the (tertiary) heterocyclic (nitrogenous) ring structure can be or comprise (i) a triazole (or triazolyl), illustratively (comprising) 1,2,3- triazole, preferably l,2,3-triazole-4, (ii) an imidazole (or imidazolyl), illustratively (comprising) 1 -imidazole (or imidazol-l-yl) or 2-imidazole (imidazol-2-yl or imidazole-2) or 4-imidazole (imidazol-4-yl or imidazole-4), with the optional substituent (of the imidazole (or imidazolyl), above), being or comprising methyl, preferably 1 -methyl, (iii) a pyrazole (or pyrazolyl), illustratively (comprising) a 4-pyrazole (or pyrazol-4-yl or pyrazole-4), a 3- pyrazole (or pyrazol-3-yl or pyrazole-3), or a 1-pyrazole (or pyrazol-l-yl or pyrazole-1), with the optional substituent (of the pyrazole (or pyrazolyl), above), being or comprising methyl, preferably 1 -methyl, (iv) a pyrrolidine (or pyrrolidinyl), illustratively (comprising) 1- pyrrolidine (or pyrrolidin-l-yl or pyrrolidine- 1), illustratively (comprising) hydroxy or dihydroxy, preferably 3-hydroxy and/or 4-hydroxy, more preferably 3,4-dihydroxy, (v) a piperidine (or piperidinyl), illustratively (comprising) 4-piperidine (or piperidin-4-yl or piperidine-4), 3 -piperidine (or piperidin-3-yl or piperidine-3), 2-piperidine (or piperidin-2-yl or piperidine-2), or 1 -piperidine (or piperidin-l-yl or piperidine- 1), (vi) a piperazine (or piperazinyl), illustratively (comprising) 1 -piperazine (or piperazin-l-yl or piperazine- 1), 2- piperazine (or piperazin-2-yl or piperazine-2), or 3-piperazine (or piperazin-3-yl or piperazine-3), with the optional substituent (of the piperazine (or piperazinyl), above) being or comprising methyl, preferably 4-methyl (or 3-methyl, 2-methyl, or 1 -methyl), or (vii) an azetidine (or azetidinyl), illustratively (comprising) 3-azetidine (or azetidine-3-yl or azetidine-3) (or 2-azetidine (or azetidine-2-yl or azetidine-2), or 1 -azetidine (or azetidine- 1-yl or azetidine-1)).

[0037] In some embodiments, the substituent of the (primary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted sulfonimidamide. Illustratively, the sulfonimidamide can be or comprise an N-sulfonimidamide or an N-methyl sulfonimidamide (or sulfonimidamidyl-N-methylene). In some embodiments, the optional substituent (of the sulfonimidamide, N-sulfonimidamide, or N-methyl sulfonimidamide (or sulfonimidamidyl-N-methylene), above), can be or comprise methyl, forming methanesulfonimidamide, N-methanesulfonimidamide, or N-methyl methanesulfonimidamide (or methanesulfonimidamidyl-N-methylene).

[0038] Thus, in some embodiments, the optional substituent of the sulfonamide or sulfonimidamide, above, can be or comprise methyl or an unsubstituted or substituted (tertiary) heterocyclic (nitrogenous) ring structure.

[0039] In some embodiments, the (tertiary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted triazole (or triazolyl). Illustratively, the triazole can be or comprise 1,2,3-triazole, preferably 1,2, 3 -triazole-4 (or l,2,3-triazole-3, l,2,3-triazole-2, or 1,2,3-triazole-l).

[0040] In some embodiments, the (tertiary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted imidazole (or imidazolyl). Illustratively, the imidazole can be or comprise 1-imidazole (or imidazol-l-yl) or 2-imidazole (imidazol-2- yl or imidazole-2) or 4-imidazole (imidazol-4-yl or imidazole-4). In some embodiments, the optional substituent (of the imidazole (or imidazolyl), above), can be or comprise methyl, preferably 1-methyl, (2-methyl, 4-methyl, or 5-methyl).

[0041] In some embodiments, the (tertiary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted pyrazole (or pyrazolyl). Illustratively, the pyrazole can be or comprise a 4-pyrazole (or pyrazol-4-yl or pyrazole-4), a 3-pyrazole (or pyrazol-3-yl or pyrazole-3), or a 1 -pyrazole (or pyrazol-l-yl or pyrazole- 1). In some embodiments, the optional substituent (of the pyrazole (or pyrazolyl), above), can be or comprise methyl, preferably 1 -methyl.

[0042] In some embodiments, the (tertiary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted pyrrolidine (or pyrrolidinyl). Illustratively, the pyrrolidine can be or comprise l-pyrrolidine (or pyrrolidin-l-yl or pyrrolidine- 1). In some embodiments, the optional substituent (of the pyrrolidine (or pyrrolidinyl), above), can be or comprise hydroxy or dihydroxy, preferably 3-hydroxy and/or 4-hydroxy, more preferably

3.4-dihydroxy.

[0043] In some embodiments, the (tertiary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted piperidine (or piperidinyl). Illustratively, the piperidine can be or comprise 4-piperidine (or piperidin-4-yl or piperidine-4).

[0044] In some embodiments, the (tertiary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted piperazine (or piperazinyl). Illustratively, the piperazine can be or comprise 1-piperazine (or piperazin-l-yl or piperazine-1). In some embodiments, the optional substituent (of the piperazine (or piperazinyl), above), can be or comprise methyl, preferably 4-methyl.

[0045] In some embodiments, the (tertiary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted azetidine (or azetidinyl). Illustratively, the azetidine can be or comprise 3-azetidine (or azetidine-3-yl or azetidine-3).

[0046] In some embodiments, the (optional) substituent of the (tertiary) heterocyclic (nitrogenous) ring structure, above, can be or comprise methyl, hydroxy, or dihydroxy.

[0047] In some embodiments, the optional substituent of the (tertiary) heterocyclic (nitrogenous) ring structure substituent, (immediately) above, can be or comprise (i) methyl (e.g., methylpyrazole, preferably methylpyrazol-4-yl or 1 -methyl- lH-pyrazol-4-yl, forming, for example, 1 -methyl- lH-pyrazole-4-sulfonamide; or methylimidazole, preferably methylimidazol-4-yl or 1 -methyl- lH-imidazol-4-yl, forming, for example, 1 -methyl- 1H- imidazole-4-sulfonamide; or methylpiperazine, preferably methylpiperazin-l-yl or 4- methylpiperazin-l-yl, forming, for example, 4-methylpiperazine-l -sulfonamide), (ii) hydroxy or dihydroxy (e.g., dihydroxypyrrolidine, preferably dihydroxypyrrolidin-l-yl, more preferably 3,4-dihydroxypyrrolidine or 3,4-dihydroxypyrrolidin-l-yl, forming, for example,

3.4-dihydroxypyrrolidine-l -sulfonamide or 3,4-dihydroxypyrrolidine-l -sulfonimidamide). [0048] In some embodiments of Formula I, R3 can be or comprise 1, 2, 3, 4, or 5 substituents (at the 2, 3, 4, 5, and/or 6 position(s), respectively), independently selected from halo (Cl, Br, F, I), trifluoromethyl, etc. In a preferred embodiment, one or more R3 is chloro, preferably 2- chloro and/or 4-chloro, more preferably di chloro, still more preferably 2, 4-di chloro (forming 2,4-dichlorophenyl).

[0049] In some embodiments, the compound(s) of the present disclosure may be according to Formula II:

Formula II

[0050] In some embodiments of Formula II, R3 and R4 can be independently selected from halo (Cl, Br, F, I), trifluoromethyl, etc. In a preferred embodiment, R3 and R4 are each chloro (forming 2,4-dichlorophenyl).

[0051] Illustratively, various embodiments of the present disclosure can be or comprise a substituted (or N-substituted) 2-amino-3-(2,4-dichlorophenyl)propanamide (or 2-amino-3- (2,4-dichlorophenyl)propane-l -amide) or 2-amino-3-(2,4-dichlorophenyl)propanamidyl (or 2-amino-3-(2,4-dichlorophenyl)propanamid-l-yl). In various embodiments of the present disclosure, the nitrogen of the amide, at the 1 -position (or 1 -carbon of the amide), can form an unsubstituted or substituted (primary) heterocyclic (nitrogenous) ring structure, as described herein. In some embodiments, the optional substituent of the (primary) heterocyclic (nitrogenous) ring structure, above, can be or comprise an unsubstituted or substituted sulfonamide (including sulfonamidyl-N-methylene), sulfonimidamide (including sulfonimidamidyl-N-methylene), cycloalkyl, phenyl, or (secondary) heterocyclic (nitrogenous) ring structure, as described herein. In some embodiments, the optional substituent of the sulfonamide, sulfonimidamide, cycloalkyl, phenyl, or (secondary) heterocyclic (nitrogenous) ring structure, above, can be or comprise methyl or an unsubstituted or substituted (tertiary) heterocyclic (nitrogenous) ring structure, as described herein. In some embodiments, the optional substituent of the (tertiary) heterocyclic (nitrogenous) ring structure, above, can be or comprise methyl, hydroxy or dihydroxy, as described herein.

[0052] In alternative embodiments, either of R3 and R4 can be at the 3-position, 5-position, and/or 6-position of the benzene (or phenyl or 3-phenyl) group. [0053] In some embodiments, compounds of the present disclosure may be according to Formula III:

Formula III

[0054] In some embodiments of Formula III, R5 can be or comprise a substitute or unsubstituted (i) pyrazole (or pyrazolyl) (forming a substitute or unsubstituted 3- pyrazolylazetidin-l-yl), illustratively (comprising) 4-pyrazole (or pyrazol-4-yl or pyrazole-4), a 3-pyrazole (or pyrazol-3-yl or pyrazole-3), or a 1 -pyrazole (or pyrazol-l-yl or pyrazole- 1), optionally substituted with methyl, preferably 1 -methyl, as described herein, (ii) imidazole (or imidazolyl) (forming a substitute or unsubstituted 3-imidazolylazetidin-l-yl), illustratively (comprising) 1 -imidazole (or imidazol-l-yl), 2-imidazole (imidazol-2-yl or imidazole-2), 4-imidazole (imidazol-4-yl or imidazole-4), or 5-imidazole (imidazol-5-yl or imidazole-5), optionally substituted with methyl, preferably 1 -methyl, as described herein, (iii) pyridine (or pyridinyl) (forming a substitute or unsubstituted 3-pyridinylazetidin-l-yl), illustratively (comprising) 1 -pyridine (or pyridin-l-yl), 2-pyridine (or pyri din-2 -yl), 3- pyridine (or pyridin-3-yl), or 4-pyridine (or pyridin-4-yl), as described herein, (iv) cycloalkane (or cycloalkyl), illustratively comprising cyclopropane (or cyclopropyl), cyclobutane (or cyclobutyl), cyclopentane (or cyclopentyl), cyclohexane (or cyclohexyl), cycloheptane (or cycloheptyl), or cyclooctane (or cyclooctyl), preferably cyclopropyl (forming a substitute or unsubstituted 3-cyclopropylazetidin-l-yl), as described herein, or (v) benzene (or phenyl) (forming a substitute or unsubstituted 3-phenylazeti din-1 -yl).

[0055] Alternatively, embodiments of Formula III, R5 can be or comprise a substitute or unsubstituted pyridazine (or pyridazinyl) (forming a substitute or unsubstituted pyridazinylazetidin-l-yl), illustratively (comprising) 3-pyridazine (or pyridazin-3-yl) or 4- pyridazine (or pyridazin-4-yl), or diazabenzene (or diazabenzenyl), illustratively, (comprising) 1,2- diazabenzene (or diazabenzen-l,2-yl) or a 1,6- diazabenzene (or diazabenzen-l,6-yl), as described herein. [0056] In alternative embodiments, (either of) the chloro moieties, independently, can be at the 3-position, 5-position, and/or 6-position of the benzene (or phenyl or 3-phenyl) group. [0057] In some embodiments, compounds of the present disclosure may be according to Formula IV:

[0058] In some embodiments of Formula IV, R6 can be or comprise a substitute or unsubstituted (i) pyrazole (or pyrazolyl) (forming a substitute or unsubstituted 3- pyrazolylazetidin-l-yl), illustratively (comprising) 4-pyrazole (or pyrazol-4-yl or pyrazole-4), a 3-pyrazole (or pyrazol-3-yl or pyrazole-3), or a 1 -pyrazole (or pyrazol-l-yl or pyrazole- 1), optionally substituted with methyl, preferably 1 -methyl, as described herein, (ii) pyridazine (or pyridazinyl), illustratively (comprising) 3-pyridazine (or pyridazin-3-yl) or 4-pyridazine (or pyridazin-4-yl), or diazabenzene (or diazabenzenyl), illustratively, (comprising) 1,2- diazabenzene (or diazabenzen-l,2-yl) or a 1,6- diazabenzene (or diazabenzen-l,6-yl), as described herein, (iii) sulfonamide, illustratively (comprising) N-sulfonamide or N-methyl sulfonamide (sulfonamidyl-N-methylene), optionally substituted with methyl, forming methanesulfonamide, N-methanesulfonamide, or N-methyl methanesulfonamide (or methanesulfonamidyl-N-methylene), or with an unsubstituted or substituted heterocyclic (nitrogenous) ring structure, as described herein, or (iv) sulfonimidamide, illustratively comprising an N-sulfonimidamide or an N-methyl sulfonimidamide (or sulfonimidamidyl-N- methylene), optionally substituted with methyl, forming methanesulfonimidamide, N- methanesulfonimidamide, or N-methyl methanesulfonimidamide (or methanesulfonimidamidyl-N-methylene), as described herein.

[0059] In alternative embodiments of Formula IV, R6 can be or comprise a substitute or unsubstituted (v) imidazole (or imidazolyl) (forming a substitute or unsubstituted 3- imidazolylazetidin-l-yl), illustratively (comprising) 1-imidazole (or imidazol-l-yl), 2- imidazole (imidazol-2-yl or imidazole-2), 4-imidazole (imidazol-4-yl or imidazole-4), or 5- imidazole (imidazol-5-yl or imidazole-5), optionally substituted with methyl, preferably 1- methyl, as described herein, (vi) pyridine (or pyridinyl) (forming a substitute or unsubstituted 3-pyridinylazetidin-l-yl), illustratively (comprising) 1 -pyridine (or pyridin-l-yl), 2-pyridine (or pyridin-2-yl), 3-pyridine (or pyridin-3-yl), or 4-pyridine (or pyridin-4-yl), as described herein, (v) cycloalkane (or cycloalkyl), illustratively comprising cyclopropane (or cyclopropyl), cyclobutane (or cyclobutyl), cyclopentane (or cyclopentyl), cyclohexane (or cyclohexyl), cycloheptane (or cycloheptyl), or cyclooctane (or cyclooctyl), preferably cyclopropyl (forming a substitute or unsubstituted 3-cyclopropylazetidin-l-yl), as described herein, or (vi) benzene (or phenyl) (forming a substitute or unsubstituted 3-phenylazetidin-l- yl), as described herein.

[0060] In alternative embodiments, (either ol) the chloro moieties, independently, can be at the 3-position, 5-position, and/or 6-position of the benzene (or phenyl or 3-phenyl) group. [0061] In some embodiments, compounds of the present disclosure may be according to Formula V:

[0062] In some embodiments of Formula V, R7 can be or comprise a substitute or unsubstituted cycloalkane (or cycloalkyl), illustratively comprising cyclopropane (or cyclopropyl), cyclobutane (or cyclobutyl), cyclopentane (or cyclopentyl), cyclohexane (or cyclohexyl), cycloheptane (or cycloheptyl), or cyclooctane (or cyclooctyl), preferably cyclopropyl (forming a substitute or unsubstituted 3-cyclopropylpyrrolidin-l-yl), as described herein. In alternative embodiments, R7 can be at the adjacent 2-position of the pyrrolidine (or pyrrolidinyl or pyrrolidin-l-yl) group (forming a substitute or unsubstituted 2- cyclopropylpyrrolidin-l-yl or 2-cycloalkylpyrrolidin-l-yl).

[0063] Alternatively, embodiments of Formula V, R7 can be or comprise a substitute or unsubstituted (i) pyrazole (or pyrazolyl) (forming a substitute or unsubstituted 3- pyrazolylazetidin-l-yl), illustratively (comprising) 4-pyrazole (or pyrazol-4-yl or pyrazole-4), a 3-pyrazole (or pyrazol-3-yl or pyrazole-3), or a 1 -pyrazole (or pyrazol-l-yl or pyrazole- 1), optionally substituted with methyl, preferably 1 -methyl, as described herein, (ii) imidazole (or imidazolyl) (forming a substitute or unsubstituted 3-imidazolylazetidin-l-yl), illustratively (comprising) 1 -imidazole (or imidazol-l-yl), 2-imidazole (imidazol-2-yl or imidazole-2), 4-imidazole (imidazol-4-yl or imidazole-4), or 5-imidazole (imidazol-5-yl or imidazole-5), optionally substituted with methyl, preferably 1 -methyl, as described herein, (iii) pyridine (or pyridinyl) (forming a substitute or unsubstituted 3-pyridinylazetidin-l-yl), illustratively (comprising) 1 -pyridine (or pyridin-l-yl), 2-pyridine (or pyri din-2 -yl), 3- pyridine (or py ri din-3 -yl), or 4-pyridine (or pyridin-4-yl), as described herein, or (iv) phenyl (or benzene) (forming a substitute or unsubstituted 3-phenylazetidin-l-yl), as described herein. In alternative embodiments, R7 can be at the adjacent 2-position of the pyrrolidine (or pyrrolidinyl or pyrrolidin-l-yl) group.

[0064] In alternative embodiments, (either ol) the chloro moieties can, independently, be at the 3-position, 5-position, and/or 6-position of the benzene (or phenyl or 3-phenyl) group. [0065] Nonlimiting examples of illustrative compounds are presented in Table 1, below.

Table 1. Nonlimiting examples of illustrative compounds

[0066] In various embodiments of the present disclosure, “R-group(s)” and/or “substituent(s)” are disclosed and/or described. Such “R-group(s)” and/or “substituent(s)” can be selected from any suitable “R-group(s)” or “substituent(s)” as known in the art and/or disclosed herein. Those skilled in the art will appreciate that “R-group(s)” and/or “substituent(s)” disclosed on certain embodiments may be suitable as “R-group(s)” and/or “substituent(s)” for other embodiments.

[0067] Illustratively, an “R-group” or “substituent” according to the present disclosure may be selected from the group consisting of: nothing; hydrogen; OH; halo; alkyl (e.g., methyl; Cl-6 alkyl); CH(CH3)2; CH2C6H5; CH2CH(CH3)2; CH(CH3)CH2CH3; CHO; CH20H; CONH2; OCH2COOH; CH3CH(OH); (CH2)2S03H; N02; CN; optionally substituted alkyl, cycloalkyl, cycloalkene, cyclodiene, heterocyclic alkyl, heterocyclic alkene, heterocyclic diene, keto, alkoxy (e.g., methoxy, Cl-6 alkoxy), thiol, thioalkyl, sulfone, sulfoxide, sulfoxyalkyl, sulfonylalkyl, alkylene dioxy, acetyl, acetoxy, haloalkyl, haloalkoxy, acetoxy, N(alkyl)2, aromatic ring system (e.g., phenyl, phenoxy, aryl, heterocyclic aryl, pyridyl, pyrimidinyl, pyrazinyl, naphthyl, benzyl, benzyloxy, benzodiazol, benzothiazole, methoxyphenyl, methylthiophenyl, a,a-dimethylbenzyl, lH-l,3-benzodiazol-2-yl, 1,3- benzothiazol-2-yl, or l-methyl-lH-l,3benzodiazol-2-yl); CHZCOOH, wherein Z is selected from the group consisting of an “R-group” according to the present disclosure; and combinations thereof. Illustrative cyclic or aromatic ring system R-groups may have one more substituents (e.g., up to 5 substituents) optionally present on the ring or aromatic ring system and optionally independently selected from an “R-group” according to the present disclosure. In some embodiments, adjacent substituents present on the ring or aromatic ring system together form an additional, optionally substituted ring or aromatic ring or ring system. Illustrative, adjacent substituents present on the additional, optionally substituted ring or aromatic ring or ring system together may form an optionally substituted cycloalkyl, cycloalkene, cyclodiene, heterocyclic alkyl, heterocyclic alkene, heterocyclic diene, or optionally substituted aromatic ring system, as described herein (e.g., phenyl, phenoxy, aryl, heterocyclic aryl, pyridyl, pyrimidinyl, pyrazinyl, naphthyl, benzyl, benzyloxy, benzodiazol, benzothiazole, methoxyphenyl, methylthiophenyl, a,a-dimethylbenzyl, lH-l,3-benzodiazol- 2-yl, l,3-benzothiazol-2-yl, or l-methyl-lH-l,3benzodiazol-2-yl).

[0068] In some embodiments of the inventive compound, the terminal phenyl group (or 2,4- dichlorophenyl) may be alternatively substituted. Illustratively, the terminal phenyl group (or 2,4-dichlorophenyl) be alternatively substituted with one or more “R-group(s)” or “substituent(s)” as described above or elsewhere herein.

[0069] In some embodiments of the inventive compound, the terminal phenyl group (or 2,4- dichlorophenyl) may be or comprise an alternative substituted or unsubstituted ring system, such as an alternative aromatic ring system as described herein. Illustratively, the alternative ring system can be selected from the group consisting of an optionally substituted cycloalkyl, cycloalkene, cyclodiene, heterocyclic alkyl, heterocyclic alkene, heterocyclic diene, or optionally substituted aromatic ring system, as described herein (e.g., phenyl, phenoxy, aryl, heterocyclic aryl, pyridyl, pyrimidinyl, pyrazinyl, naphthyl, benzyl, benzyloxy, benzodiazol, benzothiazole, methoxyphenyl, methylthiophenyl, a,a-dimethylbenzyl, lH-l,3-benzodiazol- 2-yl, l,3-benzothiazol-2-yl, or l-methyl-lH-l,3benzodiazol-2-yl). In some embodiments, the terminal phenyl group or alternative (aromatic) ring system may be optionally substituted at one or more positions. Illustratively, up to 5 substituents can optionally be present on the terminal phenyl group or alternative (aromatic) ring system. Each substituent can be optionally independently selected from an “R-group” according to the present disclosure. In some embodiments, adjacent substituents present on the terminal phenyl group or alternative (aromatic) ring system together form an additional, optionally substituted ring or aromatic ring (or ring system). Illustrative, adjacent substituents present on the terminal phenyl group or alternative (aromatic) ring system together may form an optionally substituted cycloalkyl, cycloalkene, cyclodiene, heterocyclic alkyl, heterocyclic alkene, heterocyclic diene, or optionally substituted aromatic ring system, as described herein (e.g., phenyl, phenoxy, aryl, heterocyclic aryl, pyridyl, pyrimidinyl, pyrazinyl, naphthyl, benzyl, benzyloxy, benzodiazol, benzothiazole, methoxyphenyl, methylthiophenyl, a,a-dimethylbenzyl, lH-l,3-benzodiazol- 2-yl, l,3-benzothiazol-2-yl, or l-methyl-lH-l,3benzodiazol-2-yl). [0070] Some embodiments are directed to a (pharmaceutical) composition comprising a (pharmaceutically-acceptable) carrier or excipient and a compound according to the present disclosure.

[0071] Some embodiments are directed to a (pharmaceutical) medicament comprising a (pharmaceutically-acceptable) carrier or excipient and a compound according to the present disclosure.

[0072] Some embodiments are directed to a

[0073] Embodiments of the present disclosure are designed to be heterocycles for use in inhibiting histone deacetylase (HDAC) activity (e.g., HDAC8 activity). Inhibition of HD AC activity has been shown to have several downstream and/or therapeutic effects. Those skilled in the art will appreciate that any disease or condition that is caused, worsened, or exacerbated, in whole or in part, by (or associated with) high or excessive HDAC activity, may be addressed and/or treated (post-diagnosis or prophylactically) by administration of the novel compound(s), or composition(s) comprising the same, disclosed herein. [0074] Some embodiments are directed to a composition or medicament including a compound of Formula I for use in (i) inhibiting histone deacetylase (HDAC) activity, (ii) enhancing renal recovery following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), preferably through HDAC inhibition, (iii) mitigating renal damage following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), (iv) treatment of AKI, and/or treating other related conditions or affecting other related molecular mechanisms, in a mammal or mammalian subject (in need thereof). In some embodiments, the mammal or mammalian subject is human.

[0075] Some embodiments are directed to use of the compound of Formula I, a pharmaceutical compositions comprising the same, or a medicament comprising the same, for (i) inhibiting histone deacetylase (HDAC) activity, (ii) enhancing renal recovery following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), preferably through HDAC inhibition, (iii) mitigating renal damage following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), (iv) treatment of AKI and/or CKD, and/or treating other related conditions or affecting other related molecular mechanisms, in a subject, mammal or mammalian subject (in need thereof). In some embodiments, the mammal or mammalian subject is human.

[0076] Some embodiments are directed to a method of (i) inhibiting histone deacetylase (HDAC) activity, (ii) enhancing renal recovery following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), preferably through HDAC inhibition, (iii) mitigating renal damage following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), (iv) treatment of AKI and/or CKD, and/or treating other related conditions or affecting other related molecular mechanisms, in a mammal or mammalian subject (in need thereof), the method comprising administering a compound according to Formula I, a pharmaceutical compositions comprising the same, or a medicament comprising the same, to the mammal or mammalian subject (in need thereof). In some embodiments, the mammal or mammalian subject is human. The various embodiments of the present disclosure may include any of the features, options, and/or possibilities set out elsewhere in the present disclosure, including in other aspects or embodiments of the present disclosure. It is also noted that each of the foregoing, following, and/or other features described herein represent a distinct embodiment of the present disclosure. Moreover, combinations of any two or more of such features represent distinct embodiments of the present disclosure. Such features or embodiments can also be combined in any suitable combination and/or order without departing from the scope of this disclosure. Thus, each of the features described herein can be combinable with any one or more other features described herein in any suitable combination and/or order. Accordingly, the present disclosure is not limited to the specific combinations of exemplary embodiments described in detail herein.

[0077] Additional features and advantages of exemplary embodiments of the present disclosure will be set forth in the description that follows, and in part will be obvious from the 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 become more fully apparent from the following description and appended claims, or may be learned by the practice of such exemplary embodiments as set forth hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS [0078] In order to describe the manner in which the above-recited and other advantages and features of the present disclosure can be obtained, a more particular description of the embodiments briefly described above will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings. For better understanding, the like elements have been designated by like reference numbers throughout the figure(s). Understanding that these drawings depict only typical embodiments of the disclosure and are not therefore to be considered to be limiting of its scope, the disclosure will be described and explained with additional specificity and detail through the use of the accompanying drawing(s) in which Figure 1 depicts non-limiting examples of heterocyclic (nitrogenous) rings and heterocyclic (nitrogenous) multi-ring structures.

DETAILED DESCRIPTION

[0079] Before describing various embodiments of the present disclosure in detail, it is to be understood that this disclosure is not limited only to the specific parameters, verbiage, and description of the particularly exemplified systems, methods, and/or products that may vary from one embodiment to the next. Thus, while certain embodiments of the present disclosure will be described in detail, with reference to specific features (e.g., configurations, parameters, properties, steps, components, ingredients, members, elements, parts, and/or portions, etc.), the descriptions are illustrative and are not to be construed as limiting the scope of the present disclosure and/or the claimed invention. In addition, the terminology used herein is for the purpose of describing the embodiments, and is not necessarily intended to limit the scope of the present disclosure and/or the claimed invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure pertains.

[0080] Various aspects of the present disclosure, including systems, methods, and/or products may be illustrated with reference to one or more embodiments, which are exemplary in nature. As used herein, the terms “embodiment” mean “serving as an example, instance, or illustration,” and should not necessarily be construed as preferred or advantageous over other aspects disclosed herein. In addition, reference to an “ embodiment” of the present disclosure or invention is intended to provide an illustrative example without limiting the scope of the invention, which is indicated by the appended claims.

[0081] 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 referents, unless the context clearly dictates otherwise. For example, reference to a “protein” contemplates and specifically discloses one, as well as a plurality of (e.g., two or more, three or more, etc.) proteins. Similarly, use of a plural referent does not necessarily require a plurality of such referents, but contemplates, includes, specifically discloses, and/or provides support for a single, as well as a plurality of such referents, unless the context clearly dictates otherwise.

[0082] As used throughout this disclosure, the words “can” and “may” are used in a permissive sense (i.e., meaning having the potential to), rather than the mandatory sense (i.e., meaning must). Additionally, the terms “including,” “having,” “involving,” “containing,” “characterized by,” variants thereof (e.g., “includes,” “has,” and “involves,” “contains,” etc.), and similar terms as used herein, including the claims, shall be inclusive and/or open-ended, shall have the same meaning as the word “comprising” and variants thereof (e.g., “comprise” and “comprises”), and do not exclude additional, un-recited elements or method steps, illustratively.

[0083] The term “condition” refers to any disorder, disease, injury, or illness, as understood by those skilled in the art, that is manifested or anticipated in a patient. Manifestation of “condition” can be an early, middle, or late stage manifestation, as known in the art, including pre-condition symptoms, signs, or markers. Anticipation of such a condition can be or include the predicted, expected, envisioned, presumed, supposed, and/or speculated occurrence of the same, whether founded in scientific or medical evidence, risk assessment, or mere apprehension or trepidation.

[0084] The term “patient,” as used herein, is synonymous with the term “subject” and generally refers to any animal under the care of a medical professional, as that term is defined herein, with particular reference to (i) humans (under the care of a doctor, nurse, or medical assistant or volunteer) and (ii) non-human animals, such as non-human mammals (under the care of a veterinarian or other veterinary professional, assistant, or volunteer).

[0085] For the sake of brevity, the present disclosure may recite a list or range of numerical values. It will be appreciated, however, that where such a list or range of numerical values (e.g., greater than, less than, up to, at least, and/or about a certain value, and/or between two recited values) is disclosed or recited, any specific value or range of values falling within the disclosed values or list or range of values is likewise specifically disclosed and contemplated herein.

[0086] To facilitate understanding, like references (i.e., like naming of components and/or elements) have been used, where possible, to designate like elements common to different embodiments of the present disclosure. Similarly, like components, or components with like functions, will be provided with similar reference designations, where possible. Specific language will be used herein to describe the exemplary embodiments. Nevertheless it will be understood that no limitation of the scope of the disclosure is thereby intended. Rather, it is to be understood that the language used to describe the exemplary embodiments is illustrative only and is not to be construed as limiting the scope of the disclosure (unless such language is expressly described herein as essential).

[0087] Unless context clearly indicates otherwise, the terms “primary,” “secondary,” “tertiary,” “quaternary,” “quinary,” “senary,” “septenary,” “octonary,” “nonary,” and “denary” are used herein for convenience in distinguishing between molecular substituents referenced by or with the same name, particularly, “heterocyclic (nitrogenous) ring structure,” and similar terms, and does not reflect a number of main-chain, carbon, or other molecules in said ring structure. Thus, where appropriate, the terms “primary,” “secondary,” “tertiary,” etc. are equivalent to and/or interchangeable with the terms “first,” “second,” “third,” etc.

[0088] Unless otherwise defined, the term “heterocyclic (nitrogenous) ring structure refers to a heterocyclic (nitrogenous) ring or fused, multi-ring structure, having one or more nitrogen atom(s) in the main chain of the ring or (fused) multi-ring structure. Non-limiting examples of heterocyclic (nitrogenous) ring structures, including heterocyclic (nitrogenous) rings and heterocyclic (nitrogenous) multi-ring structures are illustrated in Figure 1.

[0089] While the detailed description is separated into sections, the section headers and contents within each section are for organizational purposes only and are not intended to be self-contained descriptions and embodiments or to limit the scope of the description or the claims. Rather, the contents of each section within the detailed description are intended to be read and understood as a collective whole, where elements of one section may pertain to and/or inform other sections. Accordingly, embodiments specifically disclosed within one section may also relate to and/or serve as additional and/or alternative embodiments in another section having the same and/or similar products, methods, and/or terminology.

[0090] Provided herein are compounds useful for improving kidney function, inhibiting a histone deacetylase in a cell, expanding renal progenitor cells and/or stimulating kidney repair in cells in vitro, ex vivo or in vivo (in a patient). Compositions also are provided for delivery of the compounds to a patient. Also provided are methods for improving kidney function, inhibiting a histone deacetylase in a cell, expanding renal progenitor cells and/or stimulating kidney repair in cells in vitro, ex vivo or in vivo (in a patient) comprising contacting the cells with, or administering to a patient an amount of one or more of the compounds effective to improve kidney function in a patient, inhibit a histone deacetylase in a cell, expand renal progenitor cells and/or stimulate kidney repair in cells. Therefore provided are in vitro (including ex vivo) or in vivo (in a patient) methods. Efficacy of the compounds is demonstrated below.

[0091] Illustratively, various embodiments of the present disclosure can be or comprise a (primary) substituted 2-amino-3-(2,4-dichlorophenyl)propanone (or propane- 1 -one). The primary substituent can be or comprise a (secondary) substituted (e.g., a 4-substituted or 5- substituted) dihydroindole or dihydroisoindole (or dihydroisoindolyl), such as a (secondary) substituted 2,3-dihydro-lH-isoindolyl (or 2,3-dihydro-lH-isoindol-2-yl). The secondary substituent can be or comprise a sulfonoimidamide or sulfimidamide, such as methanesulfonimidamide. Alternatively, or specifically, the substituent can be or comprise methylsulfonimidamidyl methyl (N-methyl methanesulfonimidamide or methanesulfonimidamidyl-N-methylene), including the S- and/or R-enantiomer thereof. Alternatively, the secondary substituent can be or comprise a pyrazole (or pyrazolyl), preferably at the 5-position, such as 5-(lH-pyrazol-4-yl), 5-(lH-pyrazol-5-yl), 5-(l-methyl- lH-pyrazol-4-yl), 5-(l-methyl-lH-pyrazol-3-yl), etc., or a pyridazine (or pyridazinyl, pyridazin-3-yl, or pyridazin-4-yl), preferably at the 5-position, such as 5-(pyridazin-3-yl), 5- (pyridazin-4-yl), etc. Alternatively, the secondary substituent can be or comprise a sulfonamide or a sulfamide. Most commonly, a methyl sulfonamidyl or methyl sulfamidyl (or sulfamidyl-N-methylene (i.e., with a methylene (-CH2-) positioned or disposed between the aromatic ring and the sulfonamide or sulfamide, such as in Example 23 or 24)), with additional substitution. Alternatively, the primary substituent can be or comprise a

(secondary) substituted (or 3 -substituted) azetidine (or azetidinyl or azetidin-l-yl), such as such as 3-cyclopropylazetidin-l-yl, 3-(lH-pyrazol-l-yl)azetidin-l-yl, 3-(lH-imidazol-l- yl)azetidin-l-yl, 3-phenylazetidin-l-yl, 3-(pyridin-2-yl)azetidin-l-yl, etc. Alternatively, the primary substituent can be or comprise a (secondary) substituted (or 3 -substituted) pyrrolidine (or pyrrolidinyl or pyrrolidin-l-yl), such as 3-cyclopropylpyrrolidin-l-yl.

[0092] In some embodiments, compounds of the present disclosure may be according to Formula I:

Formula I

[0093] In some embodiments of Formula I, R1 and R2 can form a substituted or unsubstituted heterocyclic (nitrogenous) ring structure. In some embodiments, the heterocyclic (nitrogenous) ring structure can be or comprise a 3-member, 4-member, 5- member, 6-member, 7-member, or 8-member heterocyclic (nitrogenous) ring or an 8- member, 9-member, 10-member, 11 -member, 12-member, 13 -member, or 14-member fused, heterocyclic (nitrogenous) multi-ring structure. Illustratively, heterocyclic (nitrogenous) ring structure can be or comprise a substituted (e.g., a 4-substituted or 5 -substituted) dihydroindole or dihydroisoindole (or dihydroisoindolyl), such as a substituted 2,3-dihydro- lH-isoindolyl (or 2,3-dihydro-lH-isoindol-2-yl). The substituent can be or comprise a sulfonoimidamide, such as methanesulfonimidamide. Alternatively, or specifically, the substituent can be or comprise methylsulfonimidamidylmethyl (or methanesulfonimidamide- N-methylene), including the S- and/or R-enantiomer thereof. Alternatively, the substituent can be or comprise a pyrazole (or pyrazolyl), preferably at the 5-position, such as 5-(lH- pyrazol-4-yl), 5-(lH-pyrazol-5-yl), 5-(l-methyl-lH-pyrazol-4-yl), 5-(l-methyl-lH-pyrazol-3- yl), etc., or a pyridazine (or pyridazinyl, pyridazin-3-yl, or pyridazin-4-yl), preferably at the 5-position, such as 5-(pyridazin-3-yl), 5-(pyridazin-4-yl), etc. Alternatively, the substituent can be or comprise a sulfonamide or a sulfamide. Most commonly, a methyl sulfonamidyl or methyl sulfamidyl (or sulfonamidyl-N-methylene (i.e., with a methylene (-CH2-) positioned or disposed between the aromatic ring and the sulfonamide or sulfamide, such as in Example 23 or 24)), with additional substitution. The ring structure can alternatively be or comprise a substituted (or 3 -substituted) azetidine (or azetidinyl or azetidin-l-yl), such as such as 3- cyclopropylazetidin-l-yl, 3-(lH-pyrazol-l-yl)azetidin-l-yl, 3-(lH-imidazol-l-yl)azetidin-l- yl, 3-phenylazetidin-l-yl, 3-(pyridin-2-yl)azetidin-l-yl, etc. The ring structure can alternatively be or comprise a substituted (or 3-substituted) pyrrolidine (or pyrrolidinyl or pyrrolidin-l-yl), such as 3-cyclopropylpyrrolidin-l-yl.

[0094] In some embodiments of Formula I, R3 can be or comprise 1, 2, 3, 4, or 5 substituents independently selected from halo (Cl, Br, F, I), trifluoromethyl, etc. In a preferred embodiment, R3 comprises two Cl (chloro) substituents, more preferably 2,4-dichloro (forming 2,4-dichlorophenyl).

[0095] In some embodiments, compounds of the present disclosure may be according to Formula II:

Formula II

[0096] In some embodiments of Formula II, R1 and R2 can form a substituted or unsubstituted heterocyclic (nitrogenous) ring structure. In some embodiments, the heterocyclic (nitrogenous) ring structure can be or comprise a 3-member, 4-member, 5- member, 6-member, 7-member, or 8-member heterocyclic (nitrogenous) ring or an 8- member, 9-member, 10-member, 11 -member, 12-member, 13 -member, or 14-member fused, heterocyclic (nitrogenous) multi-ring structure. Illustratively, the heterocyclic (nitrogenous) ring structure can be or comprise a substituted (e.g., a 4-substituted or 5 -substituted) dihydroindole or dihydroisoindole (or dihydroisoindolyl), such as a substituted 2,3-dihydro- lH-isoindolyl (or 2,3-dihydro-lH-isoindol-2-yl). The substituent can be or comprise a sulfonoimidamide, such as methanesulfonimidamide. Alternatively, or specifically, the substituent can be or comprise methyl sulfonimidamidyl methyl (or N-methyl- methansulfonimidamide or methansulfonimidamidyl-N-methylene (i.e., with a methylene (- CH2-) positioned or disposed between the heterocyclic (nitrogenous) ring structure and the sulfonimidamide, as in Example 8)), including the S- and/or R-enantiomer thereof. Alternatively, the substituent can be or comprise a pyrazole (or pyrazolyl), preferably at the 5-position, such as 5-(lH-pyrazol-4-yl), 5-(lH-pyrazol-5-yl), 5-(l-methyl-lH-pyrazol-4-yl), 5-(l-methyl-lH-pyrazol-3-yl), etc., or a pyridazine (or pyridazinyl, pyridazin-3-yl, or pyridazin-4-yl), preferably at the 5-position, such as 5-(pyridazin-3-yl), 5-(pyridazin-4-yl), etc. The ring structure can alternatively be or comprise a substituted (or 3 -substituted) azetidine (or azetidinyl or azetidin-l-yl), such as such as 3-cyclopropylazetidin-l-yl, 3-(lH- pyrazol-l-yl)azetidin-l-yl, 3-(lH-imidazol-l-yl)azetidin-l-yl, 3-phenylazeti din-1 -yl, 3- (pyridin-2-yl)azetidin-l-yl, etc. The ring structure can alternatively be or comprise a substituted (or 3 -substituted) pyrrolidine (or pyrrolidinyl or pyrrolidin-l-yl), such as 3- cyclopropylpyrrolidin-1 -yl.

[0097] In some embodiments of Formula I, R3 and R4 can each be or comprise, independently, halo (Cl, Br, F, I), trifluoromethyl, etc. In a preferred embodiment, R3 and R4 are each chloro (Cl).

[0098] In some embodiments, compounds of the present disclosure may be according to Formula III:

Formula III

[0099] In some embodiments of Formula III, R5 can be or comprise a substitute or unsubstituted: cyclopropyl (forming a substitute or unsubstituted 3-cyclopropylazetidin-l-yl); lH-pyrazol-l-yl (forming a substitute or unsubstituted 3-(lH-pyrazol-l-yl)azetidin-l-yl); 1H- imidazol-l-yl (forming a substitute or unsubstituted 3-(lH-imidazol-l-yl)azetidin-l-yl); phenyl (forming a substitute or unsubstituted 3-phenylazeti din- 1 -yl); pyridin-2-yl (forming a substitute or unsubstituted 3-(pyridin-2-yl)azetidin-l-yl); or similar substituent. [00100] In some embodiments, compounds of the present disclosure may be according to Formula IV:

Formula IV

[00101] In some embodiments of Formula IV, R6 can be or comprise a substitute or unsubstituted: pyrazole or pyrazolyl, such as lH-pyrazol-4-yl or lH-pyrazol-5-yl (forming a substitute or unsubstituted 5-(lH-pyrazol-4-yl)-2,3-dihydro-lH-isoindol-2-yl or a substitute or unsubstituted 5-(lH-pyrazol-5-yl)-2,3-dihydro-lH-isoindol-2-yl, respectively); methylpyrazole or methylpyrazolyl, such as 1 -methyl- lH-pyrazol-3-yl or 1-methyl-lH- pyrazol-4-yl (forming a substitute or unsubstituted 5-(l-methyl-lH-pyrazol-4-yl)-2,3- dihydro- lH-isoindol-2-yl or a substitute or unsubstituted l-methyl-lH-pyrazol-3-yl)-2,3- dihydro-lH-isoindol-2-yl, respectively); pyridazine or pyridazinyl, such as pyridazin-3-yl or pyridazin-4-yl (forming a substitute or unsubstituted 5-(pyridazin-3-yl)-2,3-dihydro-lH- isoindol-2-yl or a substitute or unsubstituted 5-(pyridazin-4-yl)-2,3-dihydro-lH-isoindol-2-yl, respectively); or similar substituent. Alternatively, or specifically, the secondary substituent can be or comprise a sulfonamide or a sulfamide. Most commonly, a methyl sulfonamidyl or methyl sulfamidyl (or sulfonamidyl-N-methylene (i.e., with a methylene (-CH2-) positioned or disposed between the aromatic ring and the sulfonamide or sulfamide, such as in Example 23 or 24)), with additional substitution.

[00102] In an alternative embodiment, R1 can be at the adjacent 4-position or 6- position of the dihydroisoindol (or dihydroisoindolyl) group. In some embodiments, R1 can be at the 3-position or 7-position of the dihydroisoindol (or dihydroisoindolyl) group.

[00103] In some embodiments, compounds of the present disclosure may be according to Formula V:

[00104] In some embodiments of Formula IV, R7 can be or comprise a substitute or unsubstituted cyclopropyl (forming 3-cyclopropylpyrrolidin-l-yl) or similar substituent. [00105] In an alternative embodiment, R1 can be at the adjacent 2-position or 4- position of the pyrrolidine (or pyrrolidinyl or pyrrolidin-l-yl) group.

[00106] In various embodiments of the present disclosure, “R-group(s)” and/or

“substituent(s)” are disclosed and/or described. Such “R-group(s)” and/or “substituent(s)” can be selected from any suitable “R-group(s)” or “substituent(s)” as known in the art and/or disclosed herein. Those skilled in the art will appreciate that “R-group(s)” and/or “substituent(s)” disclosed on certain embodiments may be suitable as “R-group(s)” and/or “substituent(s)” for other embodiments.

[00107] Illustratively, an “R-group” or “substituent” according to the present disclosure may be selected from the group consisting of: nothing; hydrogen; OH; halo; alkyl (e g., methyl; Cl-6 alkyl); CH(CH3)2; CH2C6H5; CH2CH(CH3)2; CH(CH3)CH2CH3;

CHO; CH20H; CONH2; OCH2COOH; CH3CH(OH); (CH2)2S03H; N02; CN; optionally substituted alkyl, cycloalkyl, cycloalkene, cyclodiene, heterocyclic alkyl, heterocyclic alkene, heterocyclic diene, keto, alkoxy (e.g., methoxy, Cl-6 alkoxy), thiol, thioalkyl, sulfone, sulfoxide, sulfoxyalkyl, sulfonylalkyl, alkylene dioxy, acetyl, acetoxy, haloalkyl, haloalkoxy, acetoxy, N(alkyl)2, aromatic ring system (e.g., phenyl, phenoxy, aryl, heterocyclic aryl, pyridyl, pyrimidinyl, pyrazinyl, naphthyl, benzyl, benzyloxy, benzodiazol, benzothiazole, methoxyphenyl, methylthiophenyl, a,a-dimethylbenzyl, lH-l,3-benzodiazol-2-yl, 1,3- benzothiazol-2-yl, or l-methyl-lH-l,3benzodiazol-2-yl); CHZCOOH, wherein Z is selected from the group consisting of an “R-group” according to the present disclosure; and combinations thereof. Illustrative cyclic or aromatic ring system R-groups may have one more substituents (e.g., up to 5 substituents) optionally present on the ring or aromatic ring system and optionally independently selected from an “R-group” according to the present disclosure. In some embodiments, adjacent substituents present on the ring or aromatic ring system together form an additional, optionally substituted ring or aromatic ring or ring system. Illustrative, adjacent substituents present on the additional, optionally substituted ring or aromatic ring or ring system together may form an optionally substituted cycloalkyl, cycloalkene, cyclodiene, heterocyclic alkyl, heterocyclic alkene, heterocyclic diene, or optionally substituted aromatic ring system, as described herein (e.g., phenyl, phenoxy, aryl, heterocyclic aryl, pyridyl, pyrimidinyl, pyrazinyl, naphthyl, benzyl, benzyloxy, benzodiazol, benzothiazole, methoxyphenyl, methylthiophenyl, a,a-dimethylbenzyl, lH-l,3-benzodiazol- 2-yl, l,3-benzothiazol-2-yl, or l-methyl-lH-l,3benzodiazol-2-yl).

[00108] In some embodiments of the inventive compound, the terminal phenyl group (or 2,4-dichlorophenyl) may be alternatively substituted. Illustratively, the terminal phenyl group (or 2,4-dichlorophenyl) be alternatively substituted with one or more “R-group(s)” or “substituent(s)” as described above or elsewhere herein.

[00109] In some embodiments of the inventive compound, the terminal phenyl group (or 2,4-dichlorophenyl) may be or comprise an alternative substituted or unsubstituted ring system, such as an alternative aromatic ring system as described herein. Illustratively, the alternative ring system can be selected from the group consisting of an optionally substituted cycloalkyl, cycloalkene, cyclodiene, heterocyclic alkyl, heterocyclic alkene, heterocyclic diene, or optionally substituted aromatic ring system, as described herein (e.g., phenyl, phenoxy, aryl, heterocyclic aryl, pyridyl, pyrimidinyl, pyrazinyl, naphthyl, benzyl, benzyloxy, benzodiazol, benzothiazole, methoxyphenyl, methylthiophenyl, a,a- dimethylbenzyl, lH-l,3-benzodiazol-2-yl, l,3-benzothiazol-2-yl, or 1 -methyl- 1H- l,3benzodiazol-2-yl). In some embodiments, the terminal phenyl group or alternative (aromatic) ring system may be optionally substituted at one or more positions. Illustratively, up to 5 substituents can optionally be present on the terminal phenyl group or alternative (aromatic) ring system. Each substituent can be optionally independently selected from an “R-group” according to the present disclosure. In some embodiments, adjacent substituents present on the terminal phenyl group or alternative (aromatic) ring system together form an additional, optionally substituted ring or aromatic ring (or ring system). Illustrative, adjacent substituents present on the terminal phenyl group or alternative (aromatic) ring system together may form an optionally substituted cycloalkyl, cycloalkene, cyclodiene, heterocyclic alkyl, heterocyclic alkene, heterocyclic diene, or optionally substituted aromatic ring system, as described herein (e.g., phenyl, phenoxy, aryl, heterocyclic aryl, pyridyl, pyrimidinyl, pyrazinyl, naphthyl, benzyl, benzyloxy, benzodiazol, benzothiazole, methoxyphenyl, methylthiophenyl, a,a-dimethylbenzyl, lH-l,3-benzodiazol-2-yl, l,3-benzothiazol-2-yl, or 1- methyl-lH-l,3benzodiazol-2-yl). [00110] The various embodiments of the present disclosure may include any of the features, options, and/or possibilities set out elsewhere in the present disclosure, including in other aspects or embodiments of the present disclosure. It is also noted that each of the foregoing, following, and/or other features described herein represent a distinct embodiment of the present disclosure. Moreover, combinations of any two or more of such features represent distinct embodiments of the present disclosure. Such features or embodiments can also be combined in any suitable combination and/or order without departing from the scope of this disclosure. Thus, each of the features described herein can be combinable with any one or more other features described herein in any suitable combination and/or order. Accordingly, the present disclosure is not limited to the specific combinations of exemplary embodiments described in detail herein.

[00111] Embodiments of the present disclosure are designed to be effective heterocycles for use in inhibiting histone deacetylase (HDAC) activity (e.g., HDAC8 activity). Inhibition of HD AC activity has been shown to have several downstream and/or therapeutic effects. Those skilled in the art will appreciate that any disease or condition that is caused, worsened, or exacerbated, in whole or in part, by (or associated with) high or excessive HDAC activity, may be addressed and/or treated (post-diagnosis or prophylactically) by administration of the novel compound(s), or composition(s) comprising the same, disclosed herein.

Chemical Synthesis

[00112] All chemicals, reagents and solvents were obtained from commercial vendors, such as Enamine, Sigma-Aldrich, and Fisher Scientific. Indicated reaction temperatures refer to those of the reaction bath, while room temperature (rt) is noted as 25°C. Analytical thin layer chromatography (TLC) was performed with glass backed silica plates (20x 20 cm, pH = 5, MF254). Visualization was accomplished using a 254 nm UV lamp. 'H spectra were recorded on a 400 MHz spectrometer using solutions of samples in DMSO-d6 or other commercially- available deuterated solvents, as noted. Chemical shifts are reported in ppm with tetramethylsilane as standard. Data are reported as follows: chemical shift, number of protons, multiplicity (s = singlet, d = doublet, dd = doublet of doublet, t = triplet, q = quartet, b = broad, m = multiplet). All novel compounds were characterized by 'H-NMR and mass spectroscopy (MS).

[00113] Example 1. (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[5-(lH-pyrazol-4-yl)-2,3- dihy dro- lH-isoindol-2-yl] propan- 1 -one [00114] tert-butyl N-[(2R)-l-(5-bromo-2,3-dihydro-lH-isoindol-2-yl)-3-(2,4- dichlorophenyl)-l-oxopropan-2-yl] carbamate [00115] To a solution of (R)-2-((tert-Butoxycarbonyl)amino)-3-(2,4- dichlorophenyl)propanoic acid (3.3 g, 9.7 mmol) in DMF (30 mL), cooled to 0 °C, were added HATU (4.4 g, 11.7 mmol) and N-methylmorpholine (3.4 g, 34 mmol) and the mixture was stirred for 10 min maintaining the temperature below 0 °C. After that, 5— Bromoisoindoline hydrochloride (2.28 g, 9.7 mmol) was added at the same temperature. The reaction mixture was stirred for 3 h at r.t. and poured onto ice (100 mL); the precipitated solid was collected, washed with water (3 ^c 70 mL), and dried to afford 4.6 g of compound tert- butyl N-[(2R)-l-(5-bromo-2,3-dihydro-lH-isoindol-2-yl)-3-(2,4-dichlorophenyl)-l- oxopropan-2-yl] carbamate (92% yield).

[00116] tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)- 1 - {5-[ 1 -(oxan-2-yl)- lH-pyrazol-4-yl] - 2,3-dihydro-lH-isoindol-2-yl}-l-oxopropan-2-yl]carbamate

[00117] To a mixture of tert-butyl N-[(2R)-l-(5-bromo-2,3-dihydro-lH-isoindol-2-yl)-3- (2,4-dichlorophenyl)-l-oxopropan-2-yl]carbamate (0.439 g, 0.85 mmol), l-(tetrahydro-2H- pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.238 g, 0.85 mmol) and K2C03 (0.236 g, 1.7 mmol) in a mixture of dioxane/water (10/2 mL) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium(0) (0.050 g, 0.0043 mmol). The reaction mixture was stirred for 12 h at 90 °C, cooled to RT and diluted with ethyl acetate (50 mL). The organic layer was washed with water twice and brine, dried over anhydrous Na2S04 and evaporated under reduced pressure to obtain 0.420 g of tert-butyl N- [(2R)-3-(2,4-dichlorophenyl)-l-{5-[l-(oxan-2-yl)-lH-pyrazol-4-yl]-2,3-dihydro-lH-isoindol- 2-yl}-l-oxopropan-2-yl]carbamate (84% yield), which was used in the next step without further purification.

[00118] (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[5-(lH-pyrazol-4-yl)-2,3-dihydro-lH- isoindol-2-y 1] propan- 1 -one [00119] To a solution of tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-{5-[l-(oxan-2-yl)-lH- pyrazol-4-yl]-2,3-dihydro-lH-isoindol-2-yl}-l-oxopropan-2-yl]carbamate (0.420 g, 0.72 mmol) in dichloromethane (5 mL) was added HC1 in dioxane (1 mL) and the reaction mixture was stirred for 4 h at r.t. The precipitated solid was collected, washed with MTBE twice, dried and purified via HPLC to afford 0.033 g of (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[5- (lH-pyrazol-4-yl)-2,3-dihydro-lH-isoindol-2-yl]propan-l-one (24% yield).

[00120] HPLC-MS (Positive mode) m/z [M+H]+ 401.2. 1H NMR (500 MHz, DMSO-d6) d 1.40 - 2.32 (s, 2H), 2.75 - 2.86 (m, 1H), 2.90 - 2.99 (m, 1H), 3.73 - 3.87 (m, 1H), 4.47 - 4.78 (m, 3H), 4.91 - 5.06 (t, 1H), 7.21 - 7.30 (d, 1H), 7.31 - 7.35 (d, 1H), 7.37 - 7.44 (d, 1H), 7.45 - 7.62 (m, 3H), 7.83 - 7.98 (s, 1H), 8.07 - 8.26 (s, 1H), 12.68 - 13.12 (s, 1H). [00121] Example 2. (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[5-(lH-pyrazol-5-yl)-2,3- dihy dro- lH-isoindol-2-yl] propan- 1 -one

[00122] tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)- 1 - {5-[ 1 -(oxan-2-yl)- lH-pyrazol-5-yl] - 2,3-dihydro-lH-isoindol-2-yl}-l-oxopropan-2-yl]carbamate

[00123] To a mixture of tert-butyl N-[(2R)-l-(5-bromo-2,3-dihydro-lH-isoindol-2-yl)-3- (2,4-dichlorophenyl)-l-oxopropan-2-yl]carbamate (0.439 g, 0.85 mmol), l-(oxan-2-yl)-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.238 g, 0.85 mmol) and K2C03 (0.236 g, 1.7 mmol) in a mixture of dioxane/water (10/2 mL) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium(0) (0.050 g, 0.0043 mmol). The reaction mixture was stirred for 12 h at 90 °C under an argon atmosphere, cooled to RT and diluted with ethyl acetate (50 mL). The organic layer was washed with water twice and brine, dried over anhydrous Na2S04 and evaporated under reduced pressure to obtain 0.400 g of tert- butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-{5-[l-(oxan-2-yl)-lH-pyrazol-5-yl]-2,3-dihydro-lH- isoindol-2-yl}-l-oxopropan-2-yl] carbamate (80% yield), which was used in the next step without further purification.

[00124] (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[5-(lH-pyrazol-5-yl)-2,3-dihydro-lH- isoindol-2-y 1] propan- 1 -one

[00125] To a solution of tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-{5-[l-(oxan-2-yl)-lH- pyrazol-5-yl]-2,3-dihydro-lH-isoindol-2-yl}-l-oxopropan-2-yl]carbamate (0.400 g, 0.68 mmol) in dichloromethane (5 mL) was added HC1 in dioxane (1 mL) and the reaction mixture was stirred for 4 h at rt. The precipitated solid was collected, washed with MTBE twice, dried and purified via HPLC to afford 0.100 g of (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[5-(lH- pyrazol-5-yl)-2,3-dihydro-lH-isoindol-2-yl]propan-l-one (37% yield).

[00126] HPLC-MS (Positive mode) m/z [M+H]+ 401.2. 1H NMR (400 MHz, DMSO-d6) d 1.21 - 2.35 (s, 2H), 2.77 - 2.88 (m, 1H), 2.86 - 3.06 (m, 1H), 3.70 - 3.99 (m, 1H), 4.36 - 5.08 (m, 4H), 6.67 - 6.75 (s, 1H), 7.29 - 7.39 (m, 2H), 7.40 - 7.44 (d, 1H), 7.55 - 7.60 (m, 1H), 7.64 - 7.89 (m, 3H), 12.46 - 13.70 (m, 1H).

[00127] Example 3. (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[5-(pyridazin-3-yl)-2,3- dihy dro- lH-isoindol-2-yl] propan- 1 -one

[00128] tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-oxo-l-[5-(pyridazin-3-yl)-2,3-dihydro- lH-isoindol-2-yl]propan-2-yl]carbamate

[00129] To a mixture of tert-butyl N-[(2R)-l-(5-bromo-2,3-dihydro-lH-isoindol-2-yl)-3-(2,4 dichlorophenyl)-l-oxopropan-2-yl] carbamate (0.700 g, 1.36 mmol) and 3- (tributylstannyl)pyridazine (1 g, 2.7 mmol) in dioxane (15 mL) under an argon atmosphere were added tri tert-butylphosphine (0.030 g, 0.136 mmol) and Pd(OAc)2 (0.015 g, 0.068 mmol). The reaction mixture was stirred for 12 h at 100 °C under an argon atmosphere, cooled to RT and diluted with ethyl acetate (70 mL). The organic layer was washed with water twice and brine, dried over anhydrous Na2SC>4 and evaporated under reduced pressure to obtain 0.650 g of tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-oxo-l-[5-(pyridazin-3-yl)- 2,3-dihydro-lH-isoindol-2-yl]propan-2-yl]carbamate (92% yield), which was used in the next step without further purification. [00130] (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[5-(pyridazin-3-yl)-2,3-dihydro-lH- isoindol-2-y 1] propan- 1 -one

[00131] To a solution of tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-oxo-l-[5-(pyridazin-3- yl)-2,3-dihydro-lH-isoindol-2-yl]propan-2-yl] carbamate (0.650 g, 1.27 mmol) in dichloromethane (10 mL) was added HC1 in dioxane (2 mL) and the reaction mixture was stirred for 4 h at rt. The precipitated solid was collected, washed with MTBE twice, dried and purified viaHPLC to afford 0.079 g of (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[5-(pyridazin- 3-yl)-2,3-dihydro-lH-isoindol-2-yl]propan-l-one (15% yield).

[00132] HPLC-MS (Positive mode) m/z [M+H]+ 413. 1H NMR (400 MHz, DMSO-d6) d 1.61 - 2.03 (s, 2H), 2.77 - 2.90 (m, 1H), 2.89 - 3.04 (m, 1H), 3.77 - 3.87 (t, 1H), 4.57 - 4.85 (m, 3H), 5.04 - 5.15 (d, 1H), 7.30 - 7.38 (m, 1H), 7.39 - 7.46 (dd, 1H), 7.49 - 7.60 (m, 2H), 7.84 - 7.92 (d, 1H), 7.90 - 7.97 (d, 1H), 7.97 - 8.05 (dd, 1H), 9.23 - 9.33 (d, 1H), 9.60 - 9.69 (s, 1H).

[00133] Example 4. (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[5-(l-methyl-lH-pyrazol-4-yl)- 2,3-dihy dro- lH-isoindol-2-yl]propan- 1 -one

[00134] tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-[5-(l-methyl-lH-pyrazol-4-yl)-2,3- dihy dro- lH-isoindol-2-yl] - 1 -oxopropan-2-yl] carbamate

[00135] To a mixture of tert-butyl N-[(2R)-l-(5-bromo-2,3-dihydro-lH-isoindol-2-yl)-3- (2,4-dichlorophenyl)-l-oxopropan-2-yl]carbamate (0.500 g, 0.97 mmol), l-methyl-4-(3,3,4,4- tetramethylborolan-l-yl)-lH-pyrazole (0.202 g, 0.97 mmol) and K2CO3 (0.268 g, 1.94 mmol) in a mixture of dioxane/water (10/2 mL) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium(0) (0.056 g, 0.0049 mmol). The reaction mixture was stirred for 12 h at 90 °C, cooled to RT and diluted with ethyl acetate (50 mL). The organic layer was washed with water twice and brine, dried over anhydrous Na2S04 and evaporated under reduced pressure to obtain 0.400 g of tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-[5- (l-methyl-lH-pyrazol-4-yl)-2,3-dihydro-lH-isoindol-2-yl]-l-oxopropan-2-yl]carbamate (80% yield), which was used in the next step without further purification. [00136] (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[5-(l-methyl-lH-pyrazol-4-yl)-2,3-dihydro- 1 H-isoindol-2-y l]propan- 1 -one

[00137] To a solution of tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-[5-(l-methyl-lH- pyrazol-4-yl)-2,3-dihydro-lH-isoindol-2-yl]-l-oxopropan-2-yl]carbamate (0.400 g, 0.78 mmol) in dichloromethane (5 mL) was added HC1 in dioxane (1 mL) and the reaction mixture was stirred for 4 h at r.t. The precipitated solid was collected, washed with MTBE twice, dried and purified via HPLC to afford 0.040 g of compound (2R)-2-amino-3-(2,4- dichlorophenyl)-l-[5-(l-methyl-lH-pyrazol-4-yl)-2,3-dihydro-lH-isoindol-2-yl]propan-l- one (12% yield).

[00138] HPLC-MS (Positive mode) m/z [M+H]+ 415.2. 1H NMR (500 MHz, DMSO-d6) d 1.22 - 2.33 (s, 2H), 2.76 - 2.82 (m, 1H), 2.92 - 2.97 (m, 1H), 3.76 - 3.81 (m, 1H), 3.82 - 3.89 (s, 3H), 4.51 - 4.68 (m, 3H), 4.93 - 5.03 (t, 1H), 7.25 - 7.30 (m, 1H), 7.31 - 7.36 (d, 1H), 7.37 - 7.41 (d, 1H), 7.46 - 7.54 (dd, 2H), 7.53 - 7.57 (m, 1H), 7.79 - 7.89 (s, 1H), 8.07 - 8.15 (s, 1H).

[00139] Example 5. (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[5-(l-methyl-lH-pyrazol-3-yl)-

2,3-dihydro- lH-isoindol-2-yl]propan- 1 -one

[00140] tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-[5-(l-methyl-lH-pyrazol-3-yl)-2,3- dihy dro- lH-isoindol-2-yl] - 1 -oxopropan-2-yl] carbamate

[00141] To a mixture of tert-butyl N-[(2R)-l-(5-bromo-2,3-dihydro-lH-isoindol-2-yl)-3- (2,4-dichlorophenyl)-l-oxopropan-2-yl]carbamate (0.500 g, 0.97 mmol), l-methyl-3-(3,3,4,4- tetramethylborolan-l-yl)-lH-pyrazole (0.202 g, 0.97 mmol) and K2CO3 (0.268 g, 1.94 mmol) in a mixture of dioxane/water (10/2 mL) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium(0) (0.056 g, 0.0049 mmol). The reaction mixture was stirred for 12 h at 90 °C, cooled to RT and diluted with ethyl acetate (50 mL). The organic layer was washed with water twice and brine, dried over anhydrous Na2S04 and evaporated under reduced pressure to obtain 0.410 g of tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-[5- (l-methyl-lH-pyrazol-3-yl)-2,3-dihydro-lH-isoindol-2-yl]-l-oxopropan-2-yl]carbamate (82% yield), which was used in the next step without further purification. [00142] (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[5-(l-methyl-lH-pyrazol-3-yl)-2,3-dihydro- 1 H-isoindol-2-y l]propan- 1 -one

[00143] To a solution of tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-[5-(l-methyl-lH- pyrazol-3-yl)-2,3-dihydro-lH-isoindol-2-yl]-l-oxopropan-2-yl]carbamate (0.410 g, 0.79 mmol) in dichloromethane (5 mL) was added HC1 in dioxane (1 mL) and the reaction mixture was stirred for 4 h at r.t. The precipitated solid was collected, washed with MTBE twice, dried and purified via HPLC to afford 0.159 g of compound (2R)-2-amino-3-(2,4- dichlorophenyl)-l-[5-(l-methyl-lH-pyrazol-3-yl)-2,3-dihydro-lH-isoindol-2-yl]propan-l- one (39% yield). [00144] HPLC-MS (Positive mode) m/z [M+H]+ 415.2. 1H NMR (400 MHz, DMSO-d6) d

2.81 - 2.92 (m, 1H), 2.99 - 3.07 (m, 1H), 3.30 - 3.37 (s, 2H), 3.82 - 3.97 (m, 4H), 4.55 - 4.79 (m, 3H), 4.96 - 5.10 (m, 1H), 6.63 - 6.72 (s, 1H), 7.30 - 7.38 (m, 2H), 7.39 - 7.45 (d, 1H), 7.56 - 7.62 (m, 1H), 7.67 - 7.79 (m, 3H).

[00145] Example 6. (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[5-(pyridazin-4-yl)-2,3- dihydro- lH-isoindol-2-yl]propan- 1 -one

[00146] tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-oxo-l-[5-(pyridazin-4-yl)-2,3-dihydro- lH-isoindol-2-yl]propan-2-yl]carbamate [00147] To a mixture of tert-butyl N-[(2R)-l-(5-bromo-2,3-dihydro-lH-isoindol-2-yl)-3-

(2,4-dichlorophenyl)-l-oxopropan-2-yl]carbamate (0.800 g, 1.56 mmol), 4-(3,3,4,4- tetramethylborolan-l-yl)pyridazine (0.963 g, 4.67 mmol) and CS2CO3 (1.5 g, 4.67 mmol) in a mixture of dioxane/water (20/2 mL) under an argon atmosphere was added Pd(dppf)Cl2 (0.064 g, 0.078 mmol). The reaction mixture was stirred for 18 h at 80 °C under an argon atmosphere, cooled to RT and diluted with ethyl acetate (100 mL). The organic layer was washed with water twice and brine, dried over anhydrous Na2SC>4 and evaporated under reduced pressure to obtain 0.690 g of tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-oxo-l-[5- (pyridazin-4-yl)-2,3-dihydro-lH-isoindol-2-yl]propan-2-yl]carbamate (86% yield), which was used in the next step without further purification. [00148] (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[5-(pyridazin-4-yl)-2,3-dihydro-lH- isoindol-2-y 1] propan- 1 -one

[00149] To a solution of compound 15 (0.690 g, 1.34 mmol) in dichloromethane (10 mL) was added hydrochloric dioxane (2 mL) and the reaction mixture was stirred for 4 h at r.t. The precipitated solid was collected, washed with MTBE twice, dried and purified via HPLC to afford 0.181 g of (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[5-(pyridazin-4-yl)-2,3-dihydro- lH-isoindol-2-yl]propan-l-one (35% yield).

[00150] HPLC-MS (Positive mode) m/z [M+H]+ 413. 1H NMR (400 MHz, DMSO-d6) d 1.69 - 1.95 (s, 2H), 2.78 - 2.87 (m, 1H), 2.95 - 3.04 (m, 1H), 3.78 - 3.87 (t, 1H), 4.57 - 4.82 (m, 3H), 5.05 - 5.15 (m, 1H), 7.29 - 7.36 (m, 1H), 7.38 - 7.45 (dd, 1H), 7.46 - 7.61 (m, 2H),

7.83 - 7.89 (d, 1H), 7.91 - 7.95 (d, 1H), 7.99 - 8.04 (dd, 1H), 9.22 - 9.32 (d, 1H), 9.57 - 9.70 (s, 1H).

[00151] Example 7. N-({2-[(2R)-2-amino-3-(2,4-dichlorophenyl)propanoyl]-2,3-dihydro- lH-isoindol-5-yl}methyl)methanesulfonamide

[00152] tert-Butyl 5-(methanesulfonamidomethyl)-2,3-dihydro-lH-isoindole-2-carboxylate [00153] MeSChCl (0.926 g, 8.1 mmol) was added dropwise to a mixture of tert-butyl 5- (aminomethyl)-2,3-dihydro-lH-isoindole-2-carboxylate (1.8 g, 7.4 mmol) and TEA (0.967 g, 9.6 mmol) in dichloromethane (30 mL), and the reaction mass was left to stir overnight at rt.

After 1H NMR of an aliquot revealed completion of the reaction, the mixture was washed with water, dried over Na2SC>4, and concentrated in vacuo to give tert-butyl 5- (methanesulfonamidomethyl)-2,3-dihydro-lH-isoindole-2-carboxylate (1.9 g, 79.2% yield). [00154] N-[(2,3-dihydro-lH-isoindol-5-yl)methyl]methanesulfonamide\ [00155] A solution of tert-butyl 5-(methanesulfonamidomethyl)-2,3-dihydro-lH-isoindole- 2-carboxylate (1.9 g, 5.9 mmol) in 4 M dioxane/HCl (15 mL) was stirred overnight at r.t. After 1H NMR of an aliquot revealed completion of the reaction, the mixture was evaporated to dryness to obtain N-[(2,3-dihydro-lH-isoindol-5-yl)methyl]methanesulfonamide-HCl (1.5 g, 100% yield).

[00156] tert-Butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-[5-(methanesulfonamidomethyl)-2,3- dihydro- lH-isoindol-2-yl] - 1 -oxopropan-2-yl] carbamate

[00157] A solution of N-[(2,3-dihydro-lH-isoindol-5-yl)methyl]methanesulfonamide-HCl (1 eq.), (R)-2-((tert-Butoxycarbonyl)amino)-3-(2,4-dichlorophenyl)propanoic acid (1 eq.), HATU (1.3 eq.), and DIPEA (3 eq.) in DMF (5 mL) was stirred overnight at room temperature. Then the mixture was diluted with ethyl acetate, washed twice with water and once with brine, dried over Na2SC>4, filtered, and concentrated in vacuo to afford tert-butyl N- [(2R)-3-(2,4-dichlorophenyl)-l-[5-(methanesulfonamidomethyl)-2,3-dihydro-lH-isoindol-2- yl]-l-oxopropan-2-yl] carbamate (0.5 g, 63.1% yield). [00158] N-({2-[(2R)-2-amino-3-(2,4-dichlorophenyl)propanoyl]-2,3-dihydro-lH-isoindol-5- yl } methy l)methanesulfonamide

[00159] A solution of tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-[5- (methanesulfonamidomethyl)-2,3-dihydro-lH-isoindol-2-yl]-l-oxopropan-2-yl]carbamate (1 eq.) in 4 M dioxane/HCl (10 mL) was stirred overnight at r.t. After 1H NMR of an aliquot revealed completion of the reaction, the mixture was evaporated to dryness and purified by HPLC to obtain N-({2-[(2R)-2-amino-3-(2,4-dichlorophenyl)propanoyl]-2,3-dihydro-lH- isoindol-5-yl}methyl)methanesulfonamide (0.139 g, 27.8%).

[00160] HPLC-MS (Positive mode) m/z [M+H]+ 442. 1H NMR (400 MHz, DMSO-d6) d 2.83 - 2.91 (s, 3H), 3.21 - 3.35 (m, 2H), 4.07 - 4.22 (m, 2H), 4.25 - 4.36 (dd, 1H), 4.36 - 4.46 (m, 1H), 4.50 - 4.62 (dd, 1H), 4.69 - 4.86 (dd, 1H), 4.98 - 5.12 (m, 1H), 7.22 - 7.30 (m,

2H), 7.30 - 7.37 (m, 1H), 7.38 - 7.43 (d, 1H), 7.44 - 7.48 (dd, 1H), 7.56 - 7.67 (m, 2H), 8.43 - 8.68 (m, 3H).

[00161] Example 8. N-({2-[(2R)-2-amino-3-(2,4-dichlorophenyl)propanoyl]-2,3-dihydro- lH-isoindol-5-yl}methyl)methanesulfonoimidamide [00162] tert-butyl 5-(methanesulfonoimidamidomethyl)-2,3-dihydro-lH-isoindole-2- carboxylate [00163] 1 -(N-(tert-butyldimethylsilyl)-S-methylsulfonimidoyl)-3-methyl-lH-imidazol-3- ium trifluoromethane-sulfonate (4.3 g, 10.1 mmol) was added to a solution of tert-butyl 5- (aminomethyl)-2,3-dihydro-lH-isoindole-2-carboxylate (2.3 g, 9.2 mmol) in CH3CN (20 mL). The reaction mixture was stirred at r.t. for 8 h, and then CLLCN was distilled off. The aqueous solution was extracted with dichloromethane (3 ^c 50 mL). The organic extract was dried over sodium sulfate and concentrated to obtain tert-butyl 5- (methanesulfonoimidamidomethyl)-2,3-dihydro-lH-isoindole-2-carboxylate (2.3 g, 76.7% yield).

[00164] N-[(2,3-dihydro-lH-isoindol-5-yl)methyl]methanesulfonoimidamide-HCl [00165] A solution of tert-butyl 5-(methanesulfonoimidamidomethyl)-2,3-dihydro-lH- isoindole-2-carboxylate (2.3 g, 7 mmol) in 4 M dioxane/HCl (15 mL) was stirred overnight at r.t. After 1H NMR of an aliquot revealed completion of the reaction, the mixture was evaporated to dryness to obtain N-[(2,3-dihydro-lH-isoindol-5- yl)methyl]methanesulfonoimidamide-HCl (1.85 g, 100% yield).

[00166] tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-[5-(methanesulfonoimidamidomethyl)- 2,3-dihydro-lH-isoindol-2-yl]-l-oxopropan-2-yl]carbamate

[00167] A solution of N-[(2,3-dihydro-lH-isoindol-5-yl)methyl]methanesulfonoimidamide- HC1 (1 eq.), (R)-2-((tert-Butoxycarbonyl)amino)-3-(2,4-dichlorophenyl)propanoic acid (1 eq.), HATU (1.3 eq.), and DIPEA (3 eq.) in DMF (5 mL) was stirred overnight at room temperature. Then the mixture was diluted with ethyl acetate, washed twice with water and once with brine, dried over Na2S04, filtered, concentrated in vacuo and purified by HPLC to afford tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-[5-(methanesulfonoimidamidomethyl)- 2,3-dihydro-lH-isoindol-2-yl]-l-oxopropan-2-yl]carbamate (0.098 g, 12.5% yield).

[00168] N-( {2- [(2R)-2-amino-3 -(2,4-dichlorophenyl)propanoy 1] -2,3 -dihydro- 1 H-isoindol-5- yl } methy l)methanesulfonoimidamide

[00169] A solution of tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-[5- (methanesulfonoimidamidomethyl)-2,3-dihydro-lH-isoindol-2-yl]-l-oxopropan-2- yl]carbamate (1 eq.) in 4 M dioxane/HCl (10 mL) was stirred overnight at r.t. After 1H NMR of an aliquot revealed completion of the reaction, the mixture was evaporated to dryness and purified by HPLC to obtain N-({2-[(2R)-2-amino-3-(2,4-dichlorophenyl)propanoyl]-2,3- dihydro-lH-isoindol-5-yl}methyl)methanesulfonoimidamide (0.071 g, 82.6% yield).

[00170] HPLC-MS (Positive mode) m/z [M+H]+ 441. 1H NMR (400 MHz, DMSO-d6) d 3.21 - 3.28 (m, 2H), 3.47 - 3.51 (s, 3H), 4.22 - 4.36 (m, 3H), 4.36 - 4.48 (m, 1H), 4.50 -

4.60 (dd, 1H), 4.69 - 4.84 (d, 1H), 4.97 - 5.13 (t, 1H), 7.27 - 7.38 (m, 3H), 7.38 - 7.43 (m, 2H), 7.43 - 7.48 (d, 1H), 7.61 - 7.68 (m, 1H), 8.41 - 8.77 (m, 3H), 9.17 - 9.47 (s, 1H). [00171] Example 9. N-{2-[(2R)-2-amino-3-(2,4-dichlorophenyl)propanoyl]-2,3-dihydro- lH-isoindol-5 -y 1 } methanesulfonoimidamide

[00172] tert-butyl 5-methanesulfonoimidamido-2,3-dihydro-lH-isoindole-2-carboxylate [00173] l-(N-(tert-butyldimethylsilyl)-S-methylsulfonimidoyl)-3-methyl-lH-imidazol-3- ium trifluoro-methanesulfonate (4.5 g, 10.6 mmol) was added to a solution of tert-butyl 5- amino-2,3-dihydro-lH-isoindole-2-carboxylate (2.26 g, 9.6 mmol) in CfbCN (20 mL). The reaction mixture was stirred at r.t. for 8 h, and then CTbCN was distilled off. The aqueous solution was extracted with dichloromethane (3 ^c 50 mL). The organic extract was dried over sodium sulfate and concentrated to obtain tert-butyl 5-methanesulfonoimidamido-2,3- dihydro-lH-isoindole-2-carboxylate (2.5 g, 83.3%).

[00174] N-(2,3-dihydro-lH-isoindol-5-yl)methanesulfonoimidamide-HCl [00175] A solution of tert-butyl 5-methanesulfonoimidamido-2,3-dihydro-lH-isoindole-2- carboxylate (2.5 g, 8 mmol) in 4 M dioxane/HCl (15 mL) was stirred overnight at r.t. After 1H NMR of an aliquot revealed completion of the reaction, the mixture was evaporated to dryness to obtain N-(2,3-dihydro-lH-isoindol-5-yl)methanesulfonoimidamide-HCl (1.99 g, 100% yield).

[00176] tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-(5-methanesulfonoimidami do-2,3- dihydro- lH-isoindol-2-yl)- 1 -oxopropan-2-yl] carbamate

[00177] A solution of N-(2,3-dihydro-lH-isoindol-5-yl)methanesulfonoimidamide-HCl (1 eq.), (R)-2-((tert-Butoxycarbonyl)amino)-3-(2,4-dichlorophenyl)propanoic acid (1 eq.), HATU (1.3 eq.), and DIPEA (3 eq.) in DMF (5 mL) was stirred overnight at room temperature. Then the mixture was diluted with ethyl acetate, washed twice with water and once with brine, dried over Na2S04, filtered, concentrated in vacuo and purified by HPLC to afford tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-(5-methanesulfonoimidamido-2,3- dihydro-lH-isoindol-2-yl)-l-oxopropan-2-yl]carbamate (0.358 g, 51.14%).

[00178] N-{2-[(2R)-2-amino-3-(2,4-dichlorophenyl)propanoyl]-2,3-dihydro-lH-isoindol-5- yl}methanesulfonoimidamide [00179] A solution of tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-(5- methanesulfonoimidamido-2,3-dihydro-lH-isoindol-2-yl)-l-oxopropan-2-yl]carbamate (1 eq.) in 4 M dioxane/HCl (10 mL) was stirred overnight at r.t. After 1H NMR of an aliquot revealed completion of the reaction, the mixture was evaporated to dryness and purified by HPLC to obtain N-{2-[(2R)-2-amino-3-(2,4-dichlorophenyl)propanoyl]-2,3-dihydro-lH- isoindol-5-yl}methanesulfonoimidamide (0.0235 g, 7.56% yield).

[00180] HPLC-MS (Positive mode) m/z [M+H]+ 427. 1H NMR (400 MHz, DMSO-d6) d 1.57 - 2.48 (s, 2H), 2.55 - 2.69 (m, 1H), 2.74 - 2.87 (m, 1H), 2.91 - 2.97 (m, 1H), 3.07 - 3.15 (s, 3H), 3.74 - 3.84 (m, 1H), 4.42 - 4.63 (m, 3H), 4.86 - 4.97 (m, 1H), 6.65 - 6.74 (m, 1H), 6.84 - 6.98 (m, 2H), 7.05 - 7.14 (m, 1H), 7.31 - 7.37 (m, 1H), 7.36 - 7.43 (dd, 1H),

7.52 - 7.58 (m, 1H).

[00181] It will be appreciated that the compound of Example 9 (compound 9) is chiral (at the sulfur thereol). In other words, the sulfur of the sulfonimidamide is chiral. It is intended that the present disclosure include the individual stereoisomers of Example 9. Thus, the R- enantiomer, at the chiral sulfur, and the S-enantiomer, at the chiral sulfur, are hereby disclosed.

[00182] A l.lg batch of N-(2,3-dihydro-lH-isoindol-5-yl)methanesulfonoimidamide, synthesized as described, was purified by chiral chromatography to afford the individual stereoisomers, 0.598 g (isomer 1) and 0.572 g (isomer 2). These two individual isomers were used to make single stereoisomers of compound 9, using the methods described.

[00183] First eluting final product (compound 9, single isomer 1): HPLC-MS (Positive mode) m/z [M+H]+ 441.1. 1H NMR 5H (400 MHz, DMSO-d6): 3.20 - 3.27 (3H, m), 3.49 -

3.53 (3H, s), 4.17 - 4.35 (3H, m), 4.36 - 4.46 (1H, m), 4.47 - 4.66 (1H, dd), 4.70 - 4.90 (1H, d), 4.91 - 5.20 (1H, t), 7.25 - 7.42 (4H, m), 7.42 - 7.52 (1H, d), 7.59 - 7.71 (1H, s), 8.38 -

8.73 (3H, s), 8.95 - 10.05 (1H, s).

[00184] Second eluting final product (compound 9, single isomer 2): HPLC-MS (Positive mode) m/z [M+H]+ 441.0 purity. 1H NMR(DMSO-d6, 400 MHz): d (ppm) 3.27 (d, 2H),

3.54 (s, 4H), 4.25 (d, 1H), 4.37 (m, 3H), 4.55 (dd, 1H), 4.75 (d, 1H), 5.07 (t, 1H), 7.37 (m, 4H), 7.47 (d, 1H), 7.64 (m, 1H), 8.67 (t, 1H), 9.62 (s, 2H).

[00185] Example 10. (2R)-2-amino-l-(3-cyclopropylpyrrolidin-l-yl)-3-(2,4- dichlorophenyl)propan-l -one

[00186] tert-butyl N-[(2R)-l-(3-cyclopropylpyrrolidin-l-yl)-3-(2,4-dichlorophenyl)-l- oxopropan-2-yl] carbamate

[00187] A solution of 3-cyclopropylpyrrolidine hydrochloride (1 eq.), (R)-2-((tert- Butoxycarbonyl)amino)-3-(2,4-dichlorophenyl)propanoic acid (1 eq.), HATU (1.3 eq.), and DIPEA (3 eq.) in DMF (5 mL) was stirred overnight at room temperature. Then the mixture was diluted with ethyl acetate, washed twice with water and once with brine, dried over Na2S04, filtered, and concentrated in vacuo to afford tert-butyl N-[(2R)-l-(3- cyclopropylpyrrolidin-l-yl)-3-(2,4-dichlorophenyl)-l-oxopropan-2-yl]carbamate (0.5 g, 71.14%).

[00188] (2R)-2-amino-l-(3-cyclopropylpyrrolidin-l-yl)-3-(2,4-dichlorophenyl)propan-l-one [00189] A solution of tert-butyl N-[(2R)-l-(3-cyclopropylpyrrolidin-l-yl)-3-(2,4- dichlorophenyl)-l-oxopropan-2-yl] carbamate (1 eq.) in 4 M dioxane/HCl (10 mL) was stirred overnight at rt. After 1H NMR of an aliquot revealed completion of the reaction, the mixture was evaporated to dryness and purified by HPLC to obtain (2R)-2-amino-l-(3- cyclopropylpyrrolidin-l-yl)-3-(2,4-dichlorophenyl)propan-l-one (0.253 g, 66.3% yield). [00190] HPLC-MS (Positive mode) m/z [M+H]+ 327. 1H NMR (400 MHz, DMSO-d6) d - 0.12 - 0.18 (m, 2H), 0.30 - 0.42 (m, 2H), 0.48 - 1.09 (m, 1H), 1.29 - 1.62 (m, 2H), 1.75 - 2.21 (m, 1H), 2.61 - 2.98 (m, 1H), 2.98 - 3.35 (m, 4H), 3.46 - 3.66 (m, 1H), 4.14 - 4.28 (m, 1H), 7.34 - 7.40 (m, 1H), 7.40 - 7.45 (m, 1H), 7.59 - 7.75 (m, 1H), 8.36 - 8.71 (s, 3H). [00191] Example 11. (2R)-2-amino-l-(3-cyclopropylazetidin-l-yl)-3-(2,4- dichlorophenyl)propan-l -one

[00192] tert-butyl N-[(2R)-l-(3-cyclopropylazetidin-l-yl)-3-(2,4-dichlorophenyl)-l- oxopropan-2-yl] carbamate

[00193] A solution of 3-cyclopropylazetidine hydrochloride (1 eq.), (R)-2-((tert-

Butoxycarbonyl)amino)-3-(2,4-dichlorophenyl)propanoic acid (1 eq.) (1 eq.), HATU (1.3 eq.), and DIPEA (3 eq.) in DMF (5 mL) was stirred overnight at room temperature. Then the mixture was diluted with ethyl acetate, washed twice with water and once with brine, dried over Na2S04, filtered, concentrated in vacuo and purified by HPLC to afford tert-butyl N- [(2R)-l-(3-cyclopropylazetidin-l-yl)-3-(2,4-dichlorophenyl)-l-oxopropan-2-yl]carbamate (0.45 g, 64.3% yield).

[00194] (2R)-2-amino-l-(3-cyclopropylazetidin-l-yl)-3-(2,4-dichlorophenyl)propan-l-one [00195] A solution of tert-butyl N-[(2R)-l-(3-cyclopropylazetidin-l-yl)-3-(2,4- dichlorophenyl)-l-oxopropan-2-yl] carbamate (1 eq.) in 4 M CH2CI2/CF3COOH (10 mL) was stirred overnight at r.t. After 1H NMR of an aliquot revealed completion of the reaction, the mixture was evaporated to dryness and purified by HPLC to obtain (2R)-2-amino-l-(3- cyclopropylazetidin-l-yl)-3-(2,4-dichlorophenyl)propan-l-one (0.130 g, 28% yield).

[00196] HPLC-MS (Positive mode) m/z [M+H]+ 313.2. 1H NMR (400 MHz, DMSO-d6) d -0.14 - 0.19 (m, 2H), 0.28 - 0.51 (m, 2H), 0.60 - 1.04 (m, 1H), 2.07 - 2.27 (m, 1H), 2.65 - 2.81 (m, 1H), 2.98 - 3.18 (m, 2H), 3.30 - 3.54 (m, 1H), 3.82 - 4.12 (m, 3H), 7.31 - 7.38 (m, 1H), 7.43 - 7.54 (m, 1H), 7.66 - 7.75 (dd, 1H), 8.05 - 8.85 (s, 3H).

[00197] Example 12. (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[3-(lH-pyrazol-l-yl)azetidin- 1-yl] propan- 1 -one

[00198] tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-oxo-l-[3-(lH-pyrazol-l-yl)azetidin-l- yl]propan-2-yl] carbamate

[00199] A solution of l-(azetidin-3-yl)-lH-pyrazole hydrochloride (1 eq.), (R)-2-((tert- Butoxycarbonyl)amino)-3-(2,4-dichlorophenyl)propanoic acid (1 eq.), HATU (1.3 eq.), and DIPEA (3 eq.) in DMF (5 mL) was stirred overnight at room temperature. Then the mixture was diluted with ethyl acetate, washed twice with water and once with brine, dried over Na2SC>4, filtered, concentrated in vacuo and purified by HPLC to afford tert-butyl N-[(2R)-3- (2,4-dichlorophenyl)-l-oxo-l-[3-(lH-pyrazol-l-yl)azetidin-l-yl]propan-2-yl]carbamate (0.35 g, 50% yield).

[00200] (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[3-(lH-pyrazol-l-yl)azetidin-l-yl]propan-l- one [00201] A solution of tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-oxo-l-[3-(lH-pyrazol-l- yl)azetidin-l-yl]propan-2-yl]carbamate (1 eq.) in 4 M CH2CI2/CF3COOH (10 mL) was stirred overnight at rt. After 1H NMR of an aliquot revealed completion of the reaction, the mixture was evaporated to dryness and purified by HPLC to obtain (2R)-2-amino-3-(2,4- dichlorophenyl)-l-[3-(lH-pyrazol-l-yl)azetidin-l-yl]propan-l-one (0.163 g, 45% yield). [00202] HPLC-MS (Positive mode) /z [M+H]+ 339.1. 1H NMR (400 MHz, DMSO-d6) d

3.03 - 3.14 (m, 1H), 3.14 - 3.28 (m, 1H), 3.66 - 4.51 (m, 4H), 4.50 - 4.87 (m, 1H), 5.21 - 5.46 (m, 1H), 7.37 - 7.51 (m, 2H), 7.60 - 7.73 (m, 1H), 7.73 - 8.04 (m, 2H), 8.19 - 8.88 (m, 3H), 9.20 - 9.31 (s, 1H). [00203] Example 13. (2R)-2-amino-3 -(2, 4-di chi orophenyl)-l- [3 -(1 H-imidazol- 1- yl)azetidin-l -yl] propan- 1 -one

[00204] tert-butyl N- [(2R)-3-(2,4-dichlorophenyl)- 1 - [3 -( 1 H-imidazol- 1 -yl)azetidin- 1 -yl] - 1 - oxopropan-2-yl] carbamate

[00205] A solution of l-(azetidin-3-yl)-lH-imidazole hydrochloride (1 eq.), (R)-2-((tert- Butoxycarbonyl)amino)-3-(2,4-dichlorophenyl)propanoic acid (1 eq.), HATU (1.3 eq.), and DIPEA (3 eq.) in DMF (5 mL) was stirred overnight at room temperature. Then the mixture was diluted with ethyl acetate, washed twice with water and once with brine, dried over Na2S04, filtered, concentrated in vacuo and purified by HPLC to afford tert-butyl N-[(2R)-3-

(2,4-dichloropheny 1)- 1 - [3-(l H-imidazol- 1 -y l)azetidin- 1 -y 1] - 1 -oxopropan-2-yl] carbamate (0.35 g, 50% yield).

[00206] (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[3-(lH-imidazol-l-yl)azetidin-l-yl]propan- 1-one [00207] A solution of tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-[3-(lH-imidazol-l- yl)azeti din- l-yl]-l-oxopropan-2-yl] carbamate (1 eq.) in 4 M CH2CI2/CF3COOH (10 mL) was stirred overnight at r.t. After 1H NMR of an aliquot revealed completion of the reaction, the mixture was evaporated to dryness and purified by HPLC to obtain (2R)-2-amino-3-(2,4- dichlorophenyl)-l-[3-(lH-imidazol-l-yl)azetidin-l-yl]propan-l-one (0.163 g, 71.5% yield). [00208] HPLC-MS (Positive mode) m/z [M+H]+ 339.1. 1H NMR (400 MHz, DMSO-d6) d

3.01 - 3.26 (m, 2H), 3.47 - 4.41 (m, 4H), 4.47 - 4.66 (m, 1H), 5.13 - 5.31 (m, 1H), 5.97 - 6.47 (m, 1H), 7.33 - 7.51 (m, 2H), 7.53 - 7.60 (dd, 1H), 7.59 - 7.70 (dd, 1H), 7.69 - 7.87 (dd, 1H), 8.17 - 8.55 (m, 3H), 8.48 - 9.82 (s, 1H). [00209] Example 14. (2R)-2-amino-3-(2,4-dichlorophenyl)-l-(3-phenylazetidin-l- yl)propan-l-one

[00210] tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-oxo-l-(3-phenylazetidin-l-yl)propan-2- yl] carbamate

[00211] A solution of 3-phenylazetidine hydrochloride (1 eq.), (R)-2-((tert-

Butoxycarbonyl)amino)-3-(2,4-dichlorophenyl)propanoic acid (1 eq.), HATU (1.3 eq.), and DIPEA (3 eq.) in DMF (5 mL) was stirred overnight at room temperature. Then the mixture was diluted with ethyl acetate, washed twice with water and once with brine, dried over Na2SC>4, filtered, and concentrated in vacuo to afford tert-butyl N-[(2R)-3-(2,4- di chi orophenyl)-l -oxo-1 -(3 -phenylazeti din- l-yl)propan-2-yl] carbamate (0.55 g, 56.1% yield).

[00212] (2R)-2-amino-3-(2,4-dichlorophenyl)-l-(3-phenylazetidin-l-yl)propan-l-one [00213] A solution of tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-oxo-l-(3-phenylazetidin- l-yl)propan-2-yl] carbamate (1 eq.) in 4 M CH2CI2/CF3COOH (10 mL) was stirred overnight at rt. After 1H NMR of an aliquot revealed completion of the reaction, the mixture was evaporated to dryness and purified by HPLC to obtain (2R)-2-amino-3-(2,4-dichlorophenyl)- l-(3-phenylazetidin-l-yl)propan-l-one (0.145 g, 25% yield). [00214] HPLC-MS (Positive mode) m/z [M+H]+ 349.2. 1H NMR (400 MHz, DMSO-d6) d

3.06 - 3.20 (m, 2H), 3.65 - 3.83 (m, 2H), 3.83 - 4.04 (m, 1H), 4.04 - 4.20 (m, 1H), 4.21 - 4.58 (m, 2H), 7.01 - 7.05 (d, 1H), 7.24 - 7.31 (m, 1H), 7.32 - 7.43 (m, 4H), 7.46 - 7.53 (td, 1H), 7.69 - 7.74 (m, 1H), 8.01 - 8.74 (m, 3H).

[00215] Example 15. (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[3-(pyridin-2-yl)azetidin-l- yl] propan- 1 -one [00216] tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-oxo-l-[3-(pyridin-2-yl)azetidin-l- y 1] propan-2-y 1] carbamate [00217] A solution of 2-(azetidin-3-yl)pyridine hydrochloride (1 eq.), (R)-2-((tert-

Butoxycarbonyl)amino)-3-(2,4-dichlorophenyl)propanoic acid (1 eq.) (1 eq.), HATU (1.3 eq.), and DIPEA (3 eq.) in DMF (5 mL) was stirred overnight at room temperature. Then the mixture was diluted with ethyl acetate, washed twice with water and once with brine, dried over Na2SC>4, filtered, and concentrated in vacuo to afford tert-butyl N-[(2R)-3-(2,4- dichlorophenyl)-l-oxo-l-[3-(pyridin-2-yl)azetidin-l-yl]propan-2-yl]carbamate (0.46 g,

65.7% yield).

[00218] (2R)-2-amino-3-(2,4-dichlorophenyl)-l-[3-(pyridin-2-yl)azetidin-l-yl]propan-l-one [00219] A solution of tert-butyl N-[(2R)-3-(2,4-dichlorophenyl)-l-oxo-l-[3-(pyridin-2- yl)azetidin-l-yl]propan-2-yl] carbamate (1 eq.) in 4 M CH2CI2/CF3COOH (10 mL) was stirred overnight at rt. After 1H NMR of an aliquot revealed completion of the reaction, the mixture was evaporated to dryness and purified by HPLC to obtain (2R)-2-amino-3-(2,4- dichlorophenyl)-l-[3-(pyridin-2-yl)azetidin-l-yl]propan-l-one (0.278 g, 77.7% yield). HPLC-MS (Positive mode) m/z [M+H]+ 350.1. 1H NMR (400 MHz, DMSO-d6) d 3.04 - 3.24 (m, 2H), 3.34 - 4.17 (m, 4H), 4.17 - 4.33 (m, 1H), 4.35 - 4.58 (m, 1H), 7.25 - 7.43 (m, 3H), 7.43 - 7.52 (m, 1H), 7.56 - 7.75 (dd, 1H), 7.82 - 7.94 (t, 1H), 8.26 - 8.50 (m, 3H), 8.59

- 8.70 (m, 1H), 9.47 - 10.33 (s, 1H).

[00220] Examples 16-26 were prepared using a common late-stage intermediate, Intermediate 16-1, using the general scheme shown below. Final compounds of Examples 16- 26 were isolated as HC1 salts (some presumed di-HCl, as isolated). [00221] Synthesis of Intermediate 16-1. Intermediate 16-1 Intermediates 16-2_X Examples 16-26

[00222] tert-butyl (R)-(l-(5-(aminomethyl)isoindolin-2-yl)-3-(2,4-dichlorophenyl)-l- oxopropan-2-yl)carbamate

[00223] A mixture of (R)-2-((tert-butoxycarbonyl)amino)-3-(2,4-dichlorophenyl)propanoic acid (3.4 g; 10 mmol), 5-(azidomethyl)-2,3-dihydro-li/-isoindole hydrochloride (2.1 g; 10 mmol),), and DIPEA (2.9 g; 22 mmol) in DMA (40 mL) was stirred at -10 °C for 10 min before HATU (4.65 g; 12 mmol) was added. The resulting mixture was stirred at r.t. overnight, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SC>4, and concentrated under reduced pressure to obtain tert-butyl (R)-(l-(5-(azidomethyl)isoindolin-2-yl)-3-(2,4-dichlorophenyl)-l-oxopropan-2-yl)carbamate (4.5 g; 90%). HPLC-MS (Positive mode) m/z [M-tBu]⁺ 434. ¾ NMR (500 MHz, DMSO- de) d 7.56 - 7.17 (m, 6H), 4.76 - 4.63 (m, 2H), 4.63 - 4.50 (m, 2H), 4.43 (d, J= 4.0 Hz, 4H), 3.07 (d, J = 12.5 Hz, 1H), 2.91 (t, J= 11.8 Hz, 1H), 1.21 (d, .7= 54.1 Hz, 9H).

[00224] To a solution of tert-butyl (R)-(l-(5-(azidomethyl)isoindolin-2-yl)-3-(2,4- dichlorophenyl)-l-oxopropan-2-yl)carbamate (4.5 g; 9 mmol) in dry THF (50 mL), PPh3 (2.9 g; 11 mmol) was added in one portion, and the resulting mixture was stirred at r.t. for 2 h. Then H2O (1.7 g; 9 mmol) was added, and the reaction mass was stirred overnight at r.t. Upon completion, the volatiles were evaporated under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl (R)-(l-(5-(aminomethyl)isoindolin-2- yl)-3-(2,4-dichlorophenyl)-l-oxopropan-2-yl)carbamate (Intermediate 16-1) (2.5 g; 58%). LC-MS (Positive mode) m/z +464. ¾ NMR (500 MHz, DMSO-rie) d 7.57 (d, J = 16.0 Hz, 1H), 7.48 - 7.11 (m, 5H), 4.92 (dd, J = 14.5, 5.3 Hz, 1H), 4.75 - 4.43 (m, 4H), 3.78 - 3.61 (m, 2H), 3.14 - 2.99 (m, 2H), 2.99 - 2.84 (m, 1H), 1.21 (d, J= 52.9 Hz, 9H).

[00225] Examples 16-26 were all prepared using the following two-step process from Intermediate 16-1, using reagents RxSChCl as shown in Table 2.

[00226] A suspension of Intermediate 16-1 (0.170 g, 0.37 mmol, 1 eq.), RxSChCl (0.48 mmol, 1.3 eq.) and TEA (0.0486 g, 0.48 mmol, 1.3 eq.) in MeCN (5 mL) was stirred overnight at 50 °C. Upon completion, the volatiles were evaporated, and the residue (Intermediate 16-2_X, with each Example having a different Intermediate 16-2_X, corresponding to the RxSChCl used, and for reference Intermediates 16-2i6-16-226) was use as is in the next step.

[00227] A solution of Intermediate 16-2_X (-0.37 mmol, 1 eq) in 4 M dioxane/HCl (2 mL) was stirred overnight at r.t. Upon completion, the volatiles were evaporated under reduced pressure, and the residue was subjected to HPLC to obtain the final product. See Table 3 for data on Examples 16-26.

[00228] Example 16: As a representative example, below is the synthesis of ((R)-N-((2-(2- amino-3-(2,4-dichlorophenyl)propanoyl)isoindolin-5-yl)methyl)-2H-l, 2, 3-tri azole-4- sulfonamide

[00229] A suspension of Intermediate 16-1 (0.170 g, 0.37 mmol, 1 eq.), 2i/-l,2,3-triazole-4- sulfonyl chloride (0.808 g, 0.48 mmol, 1.3 eq.) and TEA (0.0486 g, 0.48 mmol, 1.3 eq.) in MeCN (5 mL) was stirred overnight at 50 °C. Upon completion, the volatiles were evaporated, and the residue (Intermediate 16-2 k,) was use as is in the next step.

[00230] A solution of Intermediate 16-2 ir, (-0.37 mmol, 1 eq) in 4 M dioxane/HCl (2 mL) was stirred overnight at r.t. Upon completion, the volatiles were evaporated under reduced pressure, and the residue was subjected to HPLC (Device (Mobile Phase, Column): SYSTEM 0-40% H2O/ACN 30 mL/min loading pump ACN 4 mL/min, column SunFire C18 target mass 496) to obtain 0.058g (30%) of (R)-N-((2-(2-amino-3-(2,4- dichlorophenyl)propanoyl)isoindolin-5-yl)methyl)-2H-l,2,3-triazole-4-sulfonamide as an HC1 salt. HPLC-MS (Positive mode) m/z +495. ¾ NMR (400 MHz, cd₃od) d 8.20 (s, 1H), 7.55 (s, 1H), 7.37 (d, 1H), 7.32 (d, 1H), 7.29 - 7.15 (m, 3H), 4.96 - 4.90 (m, 1H), 4.85 - 4.81 (m, 1H), 4.66 (d, 1H), 4.56 (q, 1H), 4.30 - 4.19 (m, 3H), 3.45 - 3.35 (m, 2H).

[00231] Nonlimiting examples of reagents used in the synthesis of Examples 16-26 are illustrated in Table 2, below.

Table 2. Reagents for Examples 16-26 Syntheses

[00232] as understood by those skilled in the art, the term “hoc” refers to tert- butyloxy carbonyl protecting group or tert-butoxy carbonyl protecting group.

[00233] Analytical data for the final compounds of Examples 16-26 are presented in Table 3, below.

Table 3: Final Compound Data for Examples 16-26

[00234] Embodiments of the present disclosure are designed to be effective for use as heterocycles for use in inhibiting histone deacetylase (HD AC) activity. Inhibition of HD AC activity has been shown to have several downstream and/or therapeutic effects. Those skilled in the art will appreciate that any disease or condition that is caused, worsened, or exacerbated, in whole or in part, by (or associated with) high or excessive HDAC activity, may be addressed and/or treated (post-diagnosis or prophylactically) by administration of the novel compound(s), or composition(s) comprising the same, disclosed herein.

[00235] Compounds of the invention have HDAC inhibition activity (see Table 3-1, above), notably inhibition of HDAC8.

[00236] Example 27. Inhibition of HDAC8

[00237] HDAC8 inhibition assays were run at Reaction Biology Corp (1 Great Valley Parkway, Suite 2, Malvern, PA USA 19355). Human HDAC8 activity was measured using a fiuorogemc peptide from p53 residues 379-382 (RHKA_CKA_C) (50 mM) as substrate. Aqueous DMSO solution was used as a control for full enzymatic activity. Starting with lOmM DMSO stock solutions of test compounds, the compounds were evaluated in 10-concentration IC50 mode with 3-fold serial dilution starting at 100 uM. HDAC reference compounds Trichostatin A (TSA) and TMP269 were tested in 10-concentration IC50 mode with 3 -fold serial dilution starting at or 1 uM or 10 uM. IC50 values were calculated using the GraphPad Prism 4 program based on a sigmoidal dose-response equation. The blank (DMSO) value concentration was entered as 1.00E-12 M for curve fitting. Curve fits were performed for compound data sets that displayed enzyme activity less than 65% at the highest concentration of compound tested. Human HDAC IC50 values for illustrative examples are found in Table 4.

Table 4 HD AC 8 Assay inhibition Data

[00238] Various routes of administration are possible for therapeutic utility of HD AC inhibitors. One possible route of administration is i.v., which is enabled by having the drug readily soluble in simple and well-tolerated formulations. Several compounds of the invention were tested for their solubility in saline as a surrogate for simple aqueous formulations.

[00239] Example 28: Measurement of Solubility in Saline solution

[00240] The solubility assay was performed according to Enamine’s in-house protocol. Saturated solutions of the test compound were prepared: samples (1 mg) of dry powder were mixed with 150 pi of saline in duplicates and allowed to equilibrate at 25°C on a thermostatic shaker for 2 hours. The filtrates of test compounds were diluted 10-fold with methanol before measuring. In parallel, compound dilutions in methanol were prepared to theoretical concentrations of 1 pg/ml, 50 pg/ml, 100 pg/ml, 200 pg/ml, 500 pg/ml, and 1000 pg/ml to generate calibration curves. 200 mΐ of each sample was transferred to 96-well plate and measured in 200-550 nm range with 5 nm step. The concentrations of compounds in saline filtrate are determined using a dedicated Microsoft Excel calculation script. Proper absorbance wavelengths for calculations are selected for each compound manually based on absorbance maximums (absolute absorbance unit values for the minimum and maximum concentration points within 0 - 3 OD range). Each of the final datasets is additionally visually evaluated by the operator and goodness of fit (R2) is calculated for each calibration curve. [00241] Many of the inventive compounds of the present disclosure exhibit excellent solubility, >2mg/mL, in saline, providing support of excellent drug-like properties, particularly for i.v administration, if desired. See Table 5.

Table 5. Solubility in Saline

[00242] Example 29: Solubility in Phosphate Buffered Saline (PBS) at pH=7.4 [00243] Kinetic solubility assay was performed according to the Enamine’s aqueous solubility standard protocol. Briefly, using a 20 mM stock solution of a test compound in 100% DMSO, dilutions were prepared to a theoretical concentration of 400 mM in duplicate in phosphate-buffered saline pH 7.4 (138 mM NaCl, 2.7 mM KC1, 10 mM K-phosphate) with 2% final DMSO concentration. The experimental compound dilutions in PBS were further allowed to equilibrate at 25°C on a thermostatic shaker for two hours and then filtered through HTS filter plates using a vacuum manifold. The filtrates of test compounds were diluted 2-fold with acetonitrile with 2% DMSO before measuring. In parallel, compound dilutions in 50% acetonitrile/PBS were prepared to theoretical concentrations of 0 pM (blank), 10 pM, 25 pM, 50 pM, 100 pM, and 200 pM with 2% final DMSO to generate calibration curves. Ondansetron was used as reference compound to control proper assay performance. 200 pi of each sample was transferred to 96-well plate and measured in 200- 550 nm range with 5 nm step. Samples were analyzed using an HPLC system coupled with tandem mass spectrometer. The effective range of this assay is approximately 2-400 pM and the compounds returning values close to the upper limit of the range may have higher actual solubility (e.g.5'-deoxy-5- fluorouridine).

[00244] Many of the inventive compounds of the present disclosure exhibit excellent solubility, >225 pM (and even >240pM, some >250pM or >260pM, or >270pM, >275 pM, >280pM, >285 pM, >290pM, >295pM, >300pM, >325pM, >340pM, >350pM, >360pM, >370pM, >380pM, >390pM, or >400pM) in phosphate buffered saline (PBS), while the compound of Example “X” — (i.e., (R)-2-Amino-3-(2,4-dichloro-phenyl)-l-(l,3- dihydroisoindol-2-yl)-propan-l-one (4), or (R)-l-isoindolin-2-yl-2-amino-3-(2,4- dichlorophenyl)propan-l-one) — exhibited a solubility of less than 225 mM. See Table 5.

Table 6: Solubility in Phosphate Buffered Saline (PBS) at pH=7.4 [00245] Example 30: Illustrative Compounds, Compositions, and Methods [00246] Non-limiting examples according to the present disclosure include one or more of the compounds of Examples 1-26 (see Table 1) or, where applicable, an R-enantiomer thereof, an S-enantiomer thereof, or a mixture of R- and S-enantiomers thereof (e.g., at a chiral center, such as a sulfur), or a (pharmaceutically-acceptable) salt thereof.

[00247] Some embodiments include a compound according to Formula I:

Formula I an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S- enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof, wherein: R1 and R2, together with the nitrogen to which R1 and R2 are attached, form a substituted primary heterocyclic nitrogenous ring structure selected from the group consisting of isoindoline, azetidine, and azolidine or pyrrolidine, wherein the primary heterocyclic nitrogenous ring structure is substituted with a substituted sulfonamide, substituted sulfonimidamide, or substituted or unsubstituted secondary heterocyclic nitrogenous ring structure selected from the group consisting of pyrazole, imidazole, pyridine, pyridazine or diazabenzene, cycloalkane, and benzene, wherein the sulfonamide or sulfonimidamide is substituted with methyl or a substituted or unsubstituted tertiary heterocyclic nitrogenous ring structure selected from the group consisting of a triazole, imidazole, pyrazole, pyrrolidine, piperidine, piperazine, and azetidine, wherein the tertiary heterocyclic nitrogenous ring structure is optionally substituted with methyl, hydroxy, or dihydroxy, and wherein the secondary heterocyclic nitrogenous ring structure is optionally substituted with methyl, and

R3 is 1, 2, 3, 4, or 5 substituents independently selected from halo or trifluoromethyl. [00248] In some embodiments R3 is chloro, preferably 2-chloro and/or 4-chloro, more preferably dichloro, still more preferably 2,4-dichloro, forming 2,4-dichlorophenyl or 2,4- dichlorobenzene.

[00249] In some embodiments the primary heterocyclic nitrogenous ring structure is selected from the group consisting of a 5-substituted isoindoline, a 3-substituted azetidine, and a 3- substituted azolidine or pyrrolidine.

[00250] In some embodiments the primary heterocyclic nitrogenous ring structure is selected from the group consisting of: a 5-substituted isoindoline, substituted at the 5-position with (i) a sulfonamide, preferably selected from the group consisting of N-methanesulfonamide, N-methyl- methanesulfonamide, N-methyl-triazolesulfonamide, N-methyl-imidazolesulfonamide, N- methyl-methylimidazolesulfonamide, N-methyl-pyrazolesulfonamide, N-methyl- methylpyrazolesulfonamide, N-methyl-piperidinesulfonamide, N-methyl- piperazinesulfonamide, N-methyl-methylpiperazinesulfonamide, N-methyl- azetidinesulfonamide, and N-methyl-dihydroxypyrrolidinesulfonamide, (ii) a sulfonimidamide selected from the group consisting of N-methanesulfonimidamide and N- methyl-methanesulfonimidamide, or (iii) a quaternary heterocyclic nitrogenous ring structure selected from the group consisting of pyrazole, methylpyrazole, and pyridazine; a 3-substituted azetidine, substituted at the 5-position with aryl, preferably benzene, cycloalkyl, preferably cyclopropyl, or a quinary heterocyclic nitrogenous ring structure selected from the group consisting of pyridine, imidazole, and pyrazol; and a 3-substituted azolidine or pyrrolidine, substituted at the 5-position with cycloalkyl, preferably cyclopropyl.

[00251] In some embodiments the compound is according to formula II:

Formula II an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S- enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof, wherein R3 and R4 are independently selected from halo, preferably chloro, and trifluoromethyl.

[00252] In some embodiments the compound is according to formula III:

Formula III an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S- enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof, wherein R5 is selected from the group consisting of pyridine, imidazole, pyrazol, aryl, and cycloalkyl.

[00253] In some embodiments the pyridine is 2-pyridine, the pyrazol is 1 -pyrazol, the imidazole is 1-imidazol, the aryl is benzene, and the cycloalkyl is cyclopropyl.

[00254] In some embodiments the compound is according to formula IV :

Formula IV an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S- enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof, wherein R6 is selected from the group consisting of: a sulfonamide, preferably selected from the group consisting of N-methanesulfonamide,

N-methyl-methanesulfonamide, N-methyl-triazolesulfonamide, N-methyl- imidazolesulfonamide, N-methyl-methylimidazolesulfonamide, N-methyl- pyrazolesulfonamide, N-methyl-methylpyrazolesulfonamide, N-methyl- piperidinesulfonamide, N-methyl-piperazinesulfonamide, N-methyl- methylpiperazinesulfonamide, N-methyl-azetidinesulfonamide, and N-methyl- dihydroxypyrrolidinesulfonamide; a sulfonimidamide, preferably selected from the group consisting of N- methanesulfonimidamide and N-methyl-methanesulfonimidamide; and a senary heterocyclic nitrogenous ring structure, preferably selected from the group consisting of pyrazole, methylpyrazole, pyridazine.

[00255] In some embodiments: the N-methyl-triazolesulfonamide is N-methyl-l,2,3-triazole-4-sulfonamide; the N-methyl-imidazolesulfonamide is selected from N-methyl-lH-imidazole-2- sulfonamide and N-methyl-lH-imidazole-4-sulfonamide; the N-methyl-methylimidazolesulfonamide is N-methyl-l-methyl-imidazole-4- sulfonamide; the N-methyl-pyrazolesulfonamide is N-methyl-lH-pyrazole-4-sulfonamide; the N-methyl-methylpyrazolesulfonamide is N-methyl-l-methyl-pyrazole-4-sulfonamide; the N-methyl-piperidinesulfonamide is N-methyl-piperidine-4-sulfonamide; the N-methyl-piperazinesulfonamide is N-methyl-piperazine-1 -sulfonamide; the N-methyl-methylpiperazinesulfonamide is N-methyl-4-methylpiperazine-l- sulfonamide; the N-methyl-azetidinesulfonamide is N-methyl-azetidine-3-sulfonamide; the N-methyl-dihydroxypyrrolidinesulfonamide is N-methyl-3,4-dihydroxypyrrolidine-l- sulfonamide; the pyrazole is selected from 4-pyrazole and 3-pyrazole; the methylpyrazole is selected from 1 -methyl-4-pyrazole and l-methyl-3-pyrazole; and/or the pyridazine is selected from 3 -pyridazine and 4-pyridazine. [00256] In some embodiments the compound is according to formula V :

Formula V an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S- enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof, wherein R7 is cycloalkyl.

[00257] Some embodiments include a method, comprising contacting a cell with the compound, an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S-enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof.

[00258] Some embodiments include a method, comprising administering to a subject the compound, an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S-enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof, wherein the subject is preferably a mammalian subject, more preferably a human subject.

[00259] Some embodiments include a (pharmaceutical) composition or medicament comprising a (pharmaceutically-acceptable) carrier or excipient and a compound according to the present disclosure, an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R- enantiomer and S-enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof.

[00260] Some embodiments include a composition or medicament comprising: a therapeutically effective amount of the compound of the present disclosure, an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S-enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof; and a carrier, wherein the composition is preferably a pharmaceutical composition and the carrier is a (pharmaceutically-acceptable) carrier.

[00261] Some embodiments include a composition or medicament for use in (i) inhibiting histone deacetylase (HDAC) activity, (ii) enhancing renal recovery following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), preferably through HDAC inhibition, (iii) mitigating renal damage following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), (iv) treatment of AKI and/or CKD, and/or treating other related conditions or affecting other related molecular mechanisms, in a mammal or mammalian subject (in need thereof). In some embodiments, the mammal or mammalian subject is human. In some embodiments, the composition or medicament can comprise a (pharmaceutically-acceptable) carrier or excipient and a compound according to the present disclosure, an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S-enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof, or a therapeutically effective amount of the compound of the present disclosure, an R-enantiomer thereof, an S- enantiomer thereof, a mixture of R-enantiomer and S-enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof; and a carrier, wherein the composition is preferably a pharmaceutical composition and the carrier is a (pharmaceutically-acceptable) carrier.

[00262] Some embodiments include use of the compound of the present disclosure, an R- enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S-enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof, or a (pharmaceutical) compositions or medicament comprising the same, for (i) inhibiting histone deacetylase (HD AC) activity, (ii) enhancing renal recovery following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), preferably through HDAC inhibition, (iii) mitigating renal damage following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), (iv) treatment of AKI and/or CKD, and/or treating other related conditions or affecting other related molecular mechanisms, in a subject, mammal or mammalian subject (in need thereof). In some embodiments, the subject, mammal or mammalian subject is human.

[00263] Some embodiments include a method, comprising administering to a subject the composition or medicament, wherein the subject is preferably a mammalian subject, more preferably a human subject.

[00264] In some embodiments administration of the composition: inhibits histone deacetylase (HDAC) activity, preferably HDAC8 activity, in the subject; and/or enhances renal recovery in the subject, preferably following acute kidney injury (AKI) or chronic kidney disease (CKD), wherein the subject optionally has AKI and/or CKD.

[00265] Some embodiments include a method of (i) inhibiting histone deacetylase (HDAC) activity, (ii) enhancing renal recovery following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), preferably through HDAC inhibition, (iii) mitigating renal damage following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), (iv) treatment of AKI and/or CKD, and/or treating other related conditions or affecting other related molecular mechanisms, in a subject, mammal or mammalian subject (in need thereof), the method comprising administering a compound according to the present disclosure, an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S-enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof, or a (pharmaceutical) compositions or medicament comprising the same, to the subject, mammal or mammalian subject (in need thereof). In some embodiments, the subject, mammal or mammalian subject is human.

[00266] Some embodiments include a compound according to Formula I:

Formula I

[00267] wherein: R3 is or comprise 1, 2, 3, 4, or 5 substituents independently selected from halo, Cl, Br, F, I), and trifluoromethyl; and R1 and R2 form a substituted or unsubstituted heterocyclic (nitrogenous) ring structure.

[00268] In some embodiments the heterocyclic (nitrogenous) ring structure (or “ring structure”) can be or comprise a 3-member, 4-member, 5-member, 6-member, 7-member, or 8-member heterocyclic (nitrogenous) ring or an 8-member, 9-member, 10-member, 11- member, 12-member, 13 -member, or 14-member fused, heterocyclic (nitrogenous) multi-ring structure.

[00269] In some embodiments the ring structure is or comprises a substituted or unsubstituted dihydroindole, dihydroisoindole, or dihydroisoindolyl, preferably a substituted or unsubstituted 2,3-dihydro-lH-isoindolyl or 2,3-dihydro-lH-isoindol-2-yl or a 4-position substituted or 5-position substituted dihydroindole, dihydroisoindole, or dihydroisoindolyl, more preferably a 4-position substituted or 5-position substituted 2,3-dihydro- lH-isoindolyl or 2,3-dihydro-lH-isoindol-2-yl. In some embodiments the substituent is or comprise a sulfonoimidamide, preferably methanesulfonimidamide. In some embodiments the substituent is or comprise a pyrazole or pyrazolyl group, preferably a lH-pyrazol-4-yl, 1H- pyrazol-5-yl, 1 -methyl- lH-pyrazol-4-yl, or l-methyl-lH-pyrazol-3-yl, more preferably 5- (lH-pyrazol-4-yl), 5-(lH-pyrazol-5-yl), 5-(l-methyl-lH-pyrazol-4-yl), or 5 -(1 -methyl- 1H- pyrazol-3-yl). In some embodiments the substituent is or comprise a pyridazine or pyridazinyl group, preferably a pyridazin-3-yl, or pyridazin-4-yl, more preferably 5- (pyridazin-3-yl) or 5-(pyridazin-4-yl).

[00270] In some embodiments the ring structure is or comprises a substituted or unsubstituted azetidine, azetidinyl, or azetidin-l-yl group, preferably a 3-position substituted azetidine, azetidinyl, or azetidin-l-yl group, more preferably 3-cyclopropylazetidin-l-yl, 3- (lH-pyrazol-l-yl)azetidin-l-yl, 3-(lH-imidazol-l-yl)azetidin-l-yl, 3-phenylazetidin-l-yl, or 3-(pyridin-2-yl)azetidin-l-yl. In some embodiments.

[00271] In some embodiments the ring structure is or comprises a substituted or unsubstituted pyrrolidine, pyrrolidinyl, or pyrrolidin-l-yl, preferably a 3-position substituted pyrrolidine, pyrrolidinyl, or pyrrolidin-l-yl, more preferably 3-cyclopropylpyrrolidin-l-yl. [00272] In some embodiments R3 is or comprises two Cl (chloro) substituents, preferably 2,4-dichloro, thereby forming 2,4-dichlorophenyl.

[00273] Some embodiments include a compound according to Formula II:

Formula II

[00274] wherein: R3 and R4 are independently selected from halo, Cl, Br, F, I, and trifluoromethyl; and R1 and R2 form a substituted or unsubstituted heterocyclic (nitrogenous) ring structure.

[00275] In some embodiments the ring structure is or comprises a substituted or unsubstituted dihydroindole, dihydroisoindole, or dihydroisoindolyl, preferably a substituted or unsubstituted 2,3-dihydro-lH-isoindolyl or 2,3-dihydro-lH-isoindol-2-yl or a 4-position substituted or 5-position substituted dihydroindole, dihydroisoindole, or dihydroisoindolyl, more preferably a 4-position substituted or 5-position substituted 2,3-dihydro- lH-isoindolyl or 2,3-dihydro-lH-isoindol-2-yl. In some embodiments the substituent is or comprise a sulfonoimidamide, preferably methanesulfonimidamide. In some embodiments the substituent is or comprise a pyrazole or pyrazolyl group, preferably a lH-pyrazol-4-yl, 1H- pyrazol-5-yl, 1 -methyl- lH-pyrazol-4-yl, or l-methyl-lH-pyrazol-3-yl, more preferably 5- (lH-pyrazol-4-yl), 5-(lH-pyrazol-5-yl), 5-(l-methyl-lH-pyrazol-4-yl), or 5 -(1 -methyl- 1H- pyrazol-3-yl). In some embodiments the substituent is or comprise a pyridazine or pyridazinyl group, preferably a pyridazin-3-yl, or pyridazin-4-yl, more preferably 5- (pyridazin-3-yl) or 5-(pyridazin-4-yl). In some embodiments the ring structure is or comprises a substituted or unsubstituted azetidine, azetidinyl, or azetidin-l-yl group, preferably a 3-position substituted azetidine, azetidinyl, or azetidin-l-yl group, more preferably 3-cyclopropylazetidin-l-yl, 3-(lH-pyrazol-l-yl)azetidin-l-yl, 3-(lH-imidazol-l- yl)azetidin-l-yl, 3-phenylazetidin-l-yl, or 3-(pyridin-2-yl)azetidin-l-yl. In some embodiments the ring structure is or comprises a substituted or unsubstituted pyrrolidine, pyrrolidinyl, or pyrrolidin-l-yl, preferably a 3-position substituted pyrrolidine, pyrrolidinyl, or pyrrolidin-l-yl, more preferably 3-cyclopropylpyrrolidin-l-yl.

[00276] In some embodiments R3 and R4 are each chloro (Cl), thereby forming 2,4- dichlorophenyl.

[00277] Some embodiments include a compound according to Formula III:

Formula III

[00278] wherein R5 is or comprises a substitute or unsubstituted: cyclopropyl, thereby forming a substitute or unsubstituted 3-cyclopropylazetidin-l-yl); lH-pyrazol-l-yl, thereby forming a substitute or unsubstituted 3-(lH-pyrazol-l-yl)azetidin-l-yl); lH-imidazol-l-yl, thereby forming a substitute or unsubstituted 3-(lH-imidazol-l-yl)azetidin-l-yl); phenyl, thereby forming a substitute or unsubstituted 3-phenylazetidin-l-yl; or pyridin-2-yl, thereby forming a substitute or unsubstituted 3-(pyri din-2-yl)azeti din-1 -yl).

[00279] Some embodiments include a compound according to Formula IV :

Formula IV

[00280] wherein R6 is or comprises a substitute or unsubstituted: pyrazole or pyrazolyl, preferably lH-pyrazol-4-yl or lH-pyrazol-5-yl, thereby forming a substitute or unsubstituted 5-(lH-pyrazol-4-yl)-2,3-dihydro-lH-isoindol-2-yl or a substitute or unsubstituted 5-(lH- pyrazol-5-yl)-2,3-dihydro-lH-isoindol-2-yl, respectively; methylpyrazole or methylpyrazolyl, preferably l-methyl-lH-pyrazol-3-yl or 1 -methyl- lH-pyrazol-4-yl, thereby forming a substitute or unsubstituted 5-(l-methyl-lH-pyrazol-4-yl)-2,3-dihydro-lH-isoindol-2-yl or a substitute or unsubstituted l-methyl-lH-pyrazol-3-yl)-2,3-dihydro-lH-isoindol-2-yl, respectively; or pyridazine or pyridazinyl, preferably pyridazin-3-yl or pyridazin-4-yl, thereby forming a substitute or unsubstituted 5-(pyridazin-3-yl)-2,3-dihydro-lH-isoindol-2-yl or a substitute or unsubstituted 5-(pyridazin-4-yl)-2,3-dihydro-lH-isoindol-2-yl, respectively). [00281] Some embodiments include a compound according to Formula V :

Formula V

[00282] wherein R7 is or comprises a substitute or unsubstituted cyclopropyl, thereby forming 3-cyclopropylpyrrolidin-l-yl.

[00283] Some embodiments include a method, comprising contacting a cell with a compound according to one of Formulas I-V, or according to one of Compounds 1-26, or an R-enantiomer thereof, an S-enantiomer thereof, or a mixture of the R-enantiomer and the S- enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof.

[00284] Some embodiments include a method, comprising administering to a subject a compound according to one of Formulas I-V, or according to one of Compounds 1-26, or an R-enantiomer thereof, an S-enantiomer thereof, or a mixture of the R-enantiomer and the S- enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof, wherein the subject is preferably a mammalian subject, more preferably a human subject.

[00285] Some embodiments include a (pharmaceutical) composition, comprising: a compound according to one of Formulas I-V, or according to one of Compounds 1-26, or an R-enantiomer thereof, an S-enantiomer thereof, or a mixture of the R-enantiomer and the S- enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof; and a (pharmaceutically- acceptable) carrier.

[00286] Some embodiments include a method, comprising contacting a cell with a (pharmaceutical) composition, comprising: a compound according to one of Formulas I-V, or according to one of Compounds 1-26, or an R-enantiomer thereof, an S-enantiomer thereof, or a mixture of the R-enantiomer and the S-enantiomer thereof, or a (pharmaceutically- acceptable) salt thereof; and a (pharmaceutically-acceptable) carrier. In some embodiments the method is or comprises: a method of inhibiting HDAC or HDAC activity, preferably HDAC8 or HDAC8 activity; a method of enhancing renal recovery following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), preferably through HDAC inhibition, more preferably through HDAC 8 inhibition.

[00287] Some embodiments include a method, comprising administering to a subject a (pharmaceutical) composition, comprising: a compound according to one of Formulas I-V, or according to one of Compounds 1-26, or an R-enantiomer thereof, an S-enantiomer thereof, or a mixture of the R-enantiomer and the S-enantiomer thereof, or a (pharmaceutically- acceptable) salt thereof; and a (pharmaceutically-acceptable) carrier, wherein the subject is preferably a mammalian subject, more preferably a human subject. In some embodiments the method is or comprises: a method of inhibiting HD AC or HD AC activity, preferably HDAC8 or HDAC8 activity; a method of enhancing renal recovery following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), preferably through HDAC inhibition, more preferably through HDAC 8 inhibition.

[00288] Some embodiments include a method, comprising contacting a cell with a compound according to one of Formulas I-V, or according to one of Compounds 1-26, or an R-enantiomer thereof, an S-enantiomer thereof, or a mixture of the R-enantiomer and the S- enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof.

[00289] Some embodiments include a method, comprising administering to a subject a compound according to one of Formulas I-V, or according to one of Compounds 1-26, or an R-enantiomer thereof, an S-enantiomer thereof, or a mixture of the R-enantiomer and the S- enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof, wherein the subject is preferably a mammalian subject, more preferably a human subject.

[00290] Some embodiments include a method

[00291] method, comprising administering to a subject a (pharmaceutical) composition, comprising: a compound according to one of Formulas I-V, or according to one of Compounds 1-26, or an R-enantiomer thereof, an S-enantiomer thereof, or a mixture of the R-enantiomer and the S-enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof; and a (pharmaceutically-acceptable) carrier, wherein the subject is preferably a mammalian subject, more preferably a human subject. In some embodiments the method is or comprises: a method of inhibiting HDAC or HDAC activity, preferably HDAC8 or HDAC8 activity; a method of enhancing renal recovery following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), preferably through HDAC inhibition, more preferably through HDAC 8 inhibition.

[00292] Some embodiments include a (pharmaceutical) composition or medicament comprising a (pharmaceutically-acceptable) carrier or excipient and a compound according to the present disclosure, an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R- enantiomer and S-enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof.

[00293] Some embodiments include a composition or medicament comprising: a therapeutically effective amount of the compound of the present disclosure, an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S-enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof; and a carrier, wherein the composition is preferably a pharmaceutical composition and the carrier is a (pharmaceutically-acceptable) carrier.

[00294] Some embodiments include a composition or medicament for use in (i) inhibiting histone deacetylase (HDAC) activity, (ii) enhancing renal recovery following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), preferably through HDAC inhibition, (iii) mitigating renal damage following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), (iv) treatment of AKI and/or CKD, and/or treating other related conditions or affecting other related molecular mechanisms, in a mammal or mammalian subject (in need thereof). In some embodiments, the mammal or mammalian subject is human. In some embodiments, the composition or medicament can comprise a (pharmaceutically-acceptable) carrier or excipient and a compound according to the present disclosure, an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S-enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof, or a therapeutically effective amount of the compound of the present disclosure, an R-enantiomer thereof, an S- enantiomer thereof, a mixture of R-enantiomer and S-enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof; and a carrier, wherein the composition is preferably a pharmaceutical composition and the carrier is a (pharmaceutically-acceptable) carrier.

[00295] Some embodiments include use of the compound of the present disclosure, an R- enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S-enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof, or a (pharmaceutical) compositions or medicament comprising the same, for (i) inhibiting histone deacetylase (HDAC) activity, (ii) enhancing renal recovery following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), preferably through HDAC inhibition, (iii) mitigating renal damage following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), (iv) treatment of AKI and/or CKD, and/or treating other related conditions or affecting other related molecular mechanisms, in a subject, mammal or mammalian subject (in need thereof). In some embodiments, the subject, mammal or mammalian subject is human.

[00296] Some embodiments include a method, comprising administering to a subject the composition or medicament, wherein the subject is preferably a mammalian subject, more preferably a human subject. [00297] In some embodiments administration of the composition: inhibits histone deacetylase (HDAC) activity, preferably HDAC8 activity, in the subject; and/or enhances renal recovery in the subject, preferably following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), wherein the subject optionally has AKI and/or CKD. [00298] Some embodiments include a method of (i) inhibiting histone deacetylase (HDAC) activity, (ii) enhancing renal recovery following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), preferably through HDAC inhibition, (iii) mitigating renal damage following acute kidney injury (AKI) or in connection with chronic kidney disease (CKD), (iv) treatment of AKI and/or CKD, and/or treating other related conditions or affecting other related molecular mechanisms, in a subject, mammal or mammalian subject (in need thereof), the method comprising administering a compound according to the present disclosure, an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S-enantiomer thereof, or a (pharmaceutically-acceptable) salt thereof, or a (pharmaceutical) compositions or medicament comprising the same, to the subject, mammal or mammalian subject (in need thereof). In some embodiments, the subject, mammal or mammalian subject is human.

[00299] In various embodiments of the present disclosure, the compound is not according to Example 1 - (R)-l-(5-(lH-pyrazol-4-yl)isoindolin-2-yl)-2-amino-3-(2,4- dichlorophenyl)propan-l -one.

[00300] In various embodiments of the present disclosure, the compound is not according to Example 2 - (R)-l-(5-(lH-pyrazol-3-yl)isoindolin-2-yl)-2-amino-3-(2,4- dichlorophenyl)propan-l -one

[00301] In various embodiments of the present disclosure, the compound is not according to Example 3 - (R)-2-amino-3-(2,4-dichlorophenyl)-l-(5-(pyridazin-3-yl)isoindolin-2- yl)propan-l-one.

[00302] In various embodiments of the present disclosure, the compound is not according to Example 4 - (R)-2-amino-3-(2,4-dichlorophenyl)-l-(5-(l-methyl-lH-pyrazol-4-yl)isoindolin- 2-yl)propan- 1 -one.

[00303] In various embodiments of the present disclosure, the compound is not according to Example 5 - (R)-2-amino-3-(2,4-dichlorophenyl)-l-(5-(l-methyl-lH-pyrazol-3-yl)isoindolin- 2-yl)propan- 1 -one.

[00304] In various embodiments of the present disclosure, the compound is not according to Example 6 - (R)-2-amino-3-(2,4-dichlorophenyl)-l-(5-(pyridazin-4-yl)isoindolin-2- yl)propan-l-one. [00305] In various embodiments of the present disclosure, the compound is not according to Example 7 - (R)-N-((2-(2-amino-3-(2,4-dichlorophenyl)propanoyl)isoindolin-5- yl)methyl)methanesulfonamide.

[00306] In various embodiments of the present disclosure, the compound is not according to Example 8 - N-((2-((R)-2-amino-3-(2,4-dichlorophenyl)propanoyl)isoindolin-5- yl)methyl)methanesulfonimidamide.

[00307] In various embodiments of the present disclosure, the compound is not according to Example 9 - N-(2-((R)-2-amino-3-(2,4-dichlorophenyl)propanoyl)isoindolin-5- yl)methanesulfonimidamide.

[00308] In various embodiments of the present disclosure, the compound is not according to Example 10 - (2R)-2-amino-l-(3-cyclopropylpyrrolidin-l-yl)-3-(2,4-dichlorophenyl)propan- 1-one.

[00309] In various embodiments of the present disclosure, the compound is not according to Example 11 - (R)-2-amino-l-(3-cyclopropylazetidin-l-yl)-3-(2,4-dichlorophenyl)propan-l- one.

[00310] In various embodiments of the present disclosure, the compound is not according to Example 12 - (R)-l-(3-(lH-pyrazol-l-yl)azetidin-l-yl)-2-amino-3-(2,4- dichlorophenyl)propan-l -one.

[00311] In various embodiments of the present disclosure, the compound is not according to Example 13 - (R)-l-(3-(lH-imidazol-l-yl)azetidin-l-yl)-2-amino-3-(2,4- dichlorophenyl)propan-l -one.

[00312] In various embodiments of the present disclosure, the compound is not according to Example 14 - (R)-2-amino-3-(2,4-dichlorophenyl)-l-(3-phenylazetidin-l-yl)propan-l-one. [00313] In various embodiments of the present disclosure, the compound is not according to Example 15 - (R)-2-amino-3-(2,4-dichlorophenyl)-l-(3-(pyridin-2-yl)azetidin-l-yl)propan-l- one.

[00314] In various embodiments of the present disclosure, the compound is not according to Example 16 - (R)-N-((2-(2-amino-3-(2,4-dichlorophenyl)propanoyl)isoindolin-5-yl)methyl)- 2H-l,2,3-triazole-4-sulfonamide.

[00315] In various embodiments of the present disclosure, the compound is not according to Example 17 - (R)-N-((2-(2-amino-3-(2,4-dichlorophenyl)propanoyl)isoindolin-5-yl)methyl)- lH-imidazole-2-sulfonamide. [00316] In various embodiments of the present disclosure, the compound is not according to Example 18 - (R)-N-((2-(2-amino-3-(2,4-dichlorophenyl)propanoyl)isoindolin-5-yl)methyl)- lH-imidazole-4-sulfonamide.

[00317] In various embodiments of the present disclosure, the compound is not according to Example 19 - (R)-N-((2-(2-amino-3-(2,4-dichlorophenyl)propanoyl)isoindolin-5-yl)methyl)- lH-pyrazole-4-sulfonamide.

[00318] In various embodiments of the present disclosure, the compound is not according to Example 20 - (R)-N-((2-(2-amino-3-(2,4-dichlorophenyl)propanoyl)isoindolin-5-yl)methyl)- 1 -methyl- lH-imidazole-4-sulfonamide.

[00319] In various embodiments of the present disclosure, the compound is not according to Example 21 - (R)-N-((2-(2-amino-3-(2,4-dichlorophenyl)propanoyl)isoindolin-5-yl)methyl)- 1 -methyl- lH-pyrazole-4-sulfonamide.

[00320] In various embodiments of the present disclosure, the compound is not according to Example 22 - N-((2-((R)-2-amino-3-(2,4-dichlorophenyl)propanoyl)isoindolin-5-yl)methyl)- 3,4-dihydroxypyrrolidine-l -sulfonamide.

[00321] In various embodiments of the present disclosure, the compound is not according to Example 23 - (R)-N-((2-(2-amino-3-(2,4-dichlorophenyl)propanoyl)isoindolin-5- yl)methyl)piperidine-4-sulfonamide.

[00322] In various embodiments of the present disclosure, the compound is not according to Example 24 - (R)-N-((2-(2-amino-3-(2,4-dichlorophenyl)propanoyl)isoindolin-5- yl)methyl)piperazine- 1 -sulfonamide.

[00323] In various embodiments of the present disclosure, the compound is not according to Example 25 - (R)-N-((2-(2-amino-3-(2,4-dichlorophenyl)propanoyl)isoindolin-5- yl)methyl)azetidine-3-sulfonamide.

[00324] In various embodiments of the present disclosure, the compound is not according to Example 26 - (R)-N-((2-(2-amino-3-(2,4-dichlorophenyl)propanoyl)isoindolin-5-yl)methyl)- 4-methy lpiperazine- 1 -sulfonamide.

[00325] Thus, any one or more of the illustrative compounds of the present disclosure can be specifically (or explicitly) restricted away from the inventive group (by proviso). Conclusion

[00326] While the foregoing detailed description makes reference to specific exemplary embodiments, the present disclosure may be embodied in other specific forms without departing from its spirit or essential characteristics. Accordingly, the described embodiments are to be considered in all respects only as illustrative and not restrictive. For instance, various substitutions, alterations, and/or modifications of the inventive features described and/or illustrated herein, and additional applications of the principles described and/or illustrated herein, which would occur to one skilled in the relevant art and having possession of this disclosure, can be made to the described and/or illustrated embodiments without departing from the spirit and scope of the disclosure as defined by the appended claims. Such substitutions, alterations, and/or modifications are to be considered within the scope of this disclosure.

[00327] The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. The limitations recited in the claims are to be interpreted broadly based on the language employed in the claims and not limited to specific examples described in the foregoing detailed description, which examples are to be construed as non exclusive and non-exhaustive. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

[00328] It will also be appreciated that various features of certain embodiments can be compatible with, combined with, included in, and/or incorporated into other embodiments of the present disclosure. For instance, systems, methods, and/or products according to certain embodiments of the present disclosure may include, incorporate, or otherwise comprise features described in other embodiments disclosed and/or described herein. Thus, disclosure of certain features relative to a specific embodiment of the present disclosure should not be construed as limiting application or inclusion of said features to the specific embodiment. [00329] In addition, unless a feature is described as being requiring in a particular embodiment, features described in the various embodiments can be optional and may not be included in other embodiments of the present disclosure. Moreover, unless a feature is described as requiring another feature in combination therewith, any feature herein may be combined with any other feature of a same or different embodiment disclosed herein. It will be appreciated that while features may be optional in certain embodiments, when features are included in such embodiments, they can be required to have a specific configuration as described in the present disclosure. [00330] Likewise, any steps recited in any method or process described herein and/or recited in the claims can be executed in any suitable order and are not necessarily limited to the order described and/or recited, unless otherwise stated (explicitly or implicitly). Such steps can, however, also be required to be performed in a specific order or any suitable order in certain embodiments of the present disclosure.

[00331] Furthermore, various well-known aspects of illustrative systems, methods, products, and the like are not described herein in particular detail in order to avoid obscuring aspects of the example embodiments. Such aspects are, however, also contemplated herein.

Claims

CLAIMS We claim:

1. A compound according to formula I:

Formula I an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S- enantiomer thereof, or a salt thereof, wherein:

R1 and R2, together with the nitrogen to which R1 and R2 are attached, form a substituted primary heterocyclic nitrogenous ring structure selected from the group consisting of isoindoline, azetidine, and azolidine or pyrrolidine, wherein the primary heterocyclic nitrogenous ring structure is substituted with a substituted sulfonamide, substituted sulfonimidamide, or substituted or unsubstituted secondary heterocyclic nitrogenous ring structure selected from the group consisting of pyrazole, imidazole, pyridine, pyridazine or diazabenzene, cycloalkane, and benzene, wherein the sulfonamide or sulfonimidamide is substituted with methyl or a substituted or unsubstituted tertiary heterocyclic nitrogenous ring structure selected from the group consisting of a triazole, imidazole, pyrazole, pyrrolidine, piperidine, piperazine, and azetidine, wherein the tertiary heterocyclic nitrogenous ring structure is optionally substituted with methyl, hydroxy, or dihydroxy, and wherein the secondary heterocyclic nitrogenous ring structure is optionally substituted with methyl, and

R3 is 1, 2, 3, 4, or 5 substituents independently selected from halo or trifluoromethyl.

2. The compound of claim 1, wherein R3 is chloro, preferably 2-chloro and/or 4-chloro, more preferably dichloro, still more preferably 2,4-dichloro, forming 2,4-dichlorophenyl or 2,4-dichlorobenzene.

3. The compound of claim 1 or claim 2, wherein the primary heterocyclic nitrogenous ring structure is selected from the group consisting of a 5-substituted isoindoline, a 3-substituted azetidine, and a 3-substituted azolidine or pyrrolidine.

4. The compound of claim 1 or claim 2, wherein the primary heterocyclic nitrogenous ring structure is selected from the group consisting of: a 5-substituted isoindoline, substituted at the 5-position with (i) a sulfonamide, preferably selected from the group consisting of N-methanesulfonamide, N-methyl- methanesulfonamide, N-methyl-triazolesulfonamide, N-methyl-imidazolesulfonamide, N- methyl-methylimidazolesulfonamide, N-methyl-pyrazolesulfonamide, N-methyl- methylpyrazolesulfonamide, N-methyl-piperidinesulfonamide, N-methyl- piperazinesulfonamide, N-methyl-methylpiperazinesulfonamide, N-methyl- azetidinesulfonamide, and N-methyl-dihydroxypyrrolidinesulfonamide, (ii) a sulfonimidamide selected from the group consisting of N-methanesulfonimidamide and N- methyl-methanesulfonimidamide, or (iii) a quaternary heterocyclic nitrogenous ring structure selected from the group consisting of pyrazole, methylpyrazole, and pyridazine; a 3-substituted azetidine, substituted at the 5-position with aryl, preferably benzene, cycloalkyl, preferably cyclopropyl, or a quinary heterocyclic nitrogenous ring structure selected from the group consisting of pyridine, imidazole, and pyrazol; and a 3-substituted azolidine or pyrrolidine, substituted at the 5-position with cycloalkyl, preferably cyclopropyl.

5. The compound of claim 1, wherein the compound is according to formula II:

Formula II an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S- enantiomer thereof, or a salt thereof, wherein R3 and R4 are independently selected from halo, preferably chloro, and trifluoromethyl.

6. The compound of claim 1, wherein the compound is according to formula III:

Formula III an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S- enantiomer thereof, or a salt thereof, wherein R5 is selected from the group consisting of pyridine, imidazole, pyrazol, aryl, and cycloalkyl.

7. The compound of claim 6, wherein the pyridine is 2-pyridine, the pyrazol is 1-pyrazol, the imidazole is 1-imidazol, the aryl is benzene, and the cycloalkyl is cyclopropyl.

8. The compound of claim 1, wherein the compound is according to formula IV :

Formula IV an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S- enantiomer thereof, or a salt thereof, wherein R6 is selected from the group consisting of: a sulfonamide, preferably selected from the group consisting of N-methanesulfonamide,

9. The compound of claim 8, wherein: the N-methyl-triazolesulfonamide is N-methyl-l,2,3-triazole-4-sulfonamide; the N-methyl-imidazolesulfonamide is selected from N-methyl-lH-imidazole-2- sulfonamide and N-methyl-lH-imidazole-4-sulfonamide; the N-methyl-methylimidazolesulfonamide is N-methyl-l-methyl-imidazole-4- sulfonamide; the N-methyl-pyrazolesulfonamide is N-methyl-lH-pyrazole-4-sulfonamide; the N-methyl-methylpyrazolesulfonamide is N-methyl-l-methyl-pyrazole-4-sulfonamide; the N-methyl-piperidinesulfonamide is N-methyl-piperidine-4-sulfonamide; the N-methyl-piperazinesulfonamide is N-methyl-piperazine-1 -sulfonamide; the N-methyl-methylpiperazinesulfonamide is N-methyl-4-methylpiperazine-l- sulfonamide; the N-methyl-azetidinesulfonamide is N-methyl-azetidine-3-sulfonamide; the N-methyl-dihydroxypyrrolidinesulfonamide is N-methyl-3,4-dihydroxypyrrolidine-l- sulfonamide; the pyrazole is selected from 4-pyrazole and 3-pyrazole; the methylpyrazole is selected from l-methyl-4-pyrazole and l-methyl-3-pyrazole; and the pyridazine is selected from 3-pyridazine and 4-pyridazine.

10. The compound of claim 1, wherein the compound is according to formula V:

Formula V an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S- enantiomer thereof, or a salt thereof, wherein R7 is cycloalkyl.

11. A compound selected from the group consisting of Compounds 1-26:

an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S- enantiomer thereof, or a salt thereof.

12. The compound of claim 11, an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S-enantiomer thereof, or a salt thereof, selected from the group consisting of Compounds 16-26.

13. The compound of claim 11, an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S-enantiomer thereof, or a salt thereof, selected from the group consisting of Compounds 16-21.

14. The compound of claim 11, an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S-enantiomer thereof, or a salt thereof, selected from the group consisting of Compounds 22-26.

15. A method, comprising contacting a cell with the compound of any one of claims 1-14, an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S- enantiomer thereof, or a salt thereof.

16. A method, comprising administering to a subject the compound of any one of claims 1- 14, an R-enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S- enantiomer thereof, or a salt thereof, wherein the subject is preferably a mammalian subject, more preferably a human subject.

17. A composition comprising: a therapeutically effective amount of the compound of any one of claims 1-14, an R- enantiomer thereof, an S-enantiomer thereof, a mixture of R-enantiomer and S-enantiomer thereof, or a salt thereof; and a carrier, wherein the composition is preferably a pharmaceutical composition, the salt is a pharmaceutically-acceptable salt, and the carrier is a pharmaceutically-acceptable carrier.

18. A method, comprising administering the composition of claim 17 to a subject, wherein the subject is preferably a mammalian subject, more preferably a human subject.

19. The method of claim 18, wherein administration of the composition: inhibits histone deacetylase (HD AC) activity, preferably HDAC8 activity, in the subject; and/or enhances renal recovery in the subject, preferably following acute kidney injury (AKI) or related to chronic kidney disease (CKD), wherein the subject optionally has AKI and/or CKD.

20. Use of the composition of claim 17 for inhibiting histone deacetylase (HD AC) activity, preferably HDAC8 activity, and/or for enhancing renal recovery, preferably following acute kidney injury (AKI) or in response to chronic kidney disease (CKD), in a subject, wherein the subject optionally has AKI and/or CKD.