Mary1 and derivatives thereof for the treatment of mitochondrial dysfunction, vascular injury, kidney diseases, and organ aging

Abstract

In one aspect, the disclosure relates to pyridinylpiperazine-based compound MARY1 and derivatives thereof, methods of making the same, pharmaceutical compositions comprising the same, and methods of treating acute kidney injury and reducing senescent changes in the kidney using the same. In one aspect, the disclosed compounds are selective 5-HT2B agonists. In another aspect, the disclosed compounds are useful for stimulating mitochondrial biogenesis.

Description

ATTORNEY DOCKET NO.220111-2270 MARY1 AND DERIVATIVES THEREOF FOR THE TREATMENT OF MITOCHONDRIAL DYSFUNCTION, VASCULAR INJURY, KIDNEY DISEASES, AND ORGAN AGING CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Ser. No. 63 / 646,162, filed May 13, 2024, which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under grant number BX000851 awarded by the Veterans Administration. The government has certain rights in the invention. BACKGROUND

[0003] Mitochondrial biogenesis (MB) is a transcriptional program that results in additional functional mitochondria. This process involves an intricate network of transcriptional pathways for both nuclear- and mitochondrial DNA-encoded genes. MB is governed by peroxisomal proliferator γ coactivator-1α (PGC-1α), the “master regulator of MB,” which controls the expression of this network. PGC-1α interacts with and co-activates several transcription factors, including nuclear respiratory factors 1 and 2 (Nrf1 and 2), resulting in the transcription of not only nuclear-encoded mitochondrial genes, but also mitochondrial transcription factor A (TFAM), which activates transcription of mitochondrial-encoded genes . Nuclear-encoded proteins are then transferred to the mitochondria, where nuclear- and mitochondrial-encoded subunits of the ETC are assembled. Physiological and pathophysiological stimuli, such as exercise, caloric restriction, hypoxia, sepsis, and ischemic / reperfusion (I / R) are known to affect PGC-1α expression and MB. MB may be particular useful for treatment of acute kidney injury (AKI), a rapid decline in kidney function that can increase mortality and morbidity. Currently, there is no FDA-approved drug for the treatment of AKI.

[0004] .Currently, seven types of 5-HT receptors are known to exist: 5-HT1-7, three of which have additional subtypes, yielding 14 distinct receptors. As such, they elicit unique signals throughout the body, including specialized distribution and effects. Almost all 5-HT receptors are G protein- coupled receptors (GPCRs), meaning they are localized on membranes and modulate mechanisms via induction of secondary messenger pathways. Given the role of serotonin in various physiological and pathological processes both in and out of the central nervous system, 5-HT receptors are frequently pharmacologically targeted. Targeting 5-HT receptors for treating - 1 -ATTORNEY DOCKET NO.220111-2270 mitochondrial dysfunction-associated diseases in multiple organ systems via MB induction remains largely unexplored.

[0005] Despite advances in mitochondrial biogenesis research, there is still a scarcity of compounds that are potent, efficacious, and selective at targeting 5-HT receptors and also effective in the treatment of acute kidney injury and / or effective at promoting mitochondrial biogenesis after kidney injury or in other circumstances. These needs and other needs are satisfied by the present disclosure. SUMMARY

[0006] In accordance with the purpose(s) of the present disclosure, as embodied and broadly described herein, the disclosure, in one aspect, relates to pyridinylpiperazine-based compound MARY1 and derivatives thereof, methods of making the same, pharmaceutical compositions comprising the same, and methods of treating acute kidney injury and reducing senescent changes in the kidney using the same. In one aspect, the disclosed compounds are selective 5- HT2B agonists. In another aspect, the disclosed compounds are useful for stimulating mitochondrial biogenesis.

[0007] Other systems, methods, features, and advantages of the present disclosure will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims. In addition, all optional and preferred features and modifications of the described embodiments are usable in all aspects of the disclosure taught herein. Furthermore, the individual features of the dependent claims, as well as all optional and preferred features and modifications of the described embodiments are combinable and interchangeable with one another. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the several views.

[0009] FIGs.1A-1F show chemical structure, binding and function assays of MARY1. (FIG.1A) - 2 -ATTORNEY DOCKET NO.220111-2270 Chemical structure of MARY1. (FIG. 1B) Radioligand primary binding assay of human 5- HT2A / 2B / 2C receptor. (FIG.1C) Radioligand secondary binding assay of SB 206553, MARY1 and Quipazine against human 5-HT2B receptor. (FIG.1D) Agonist and antagonist radioligand functional assays of serotonin, Altanserin HCl and MARY1 against human 5-HT2A receptor. (FIG. 1E) Agonist and antagonist radioligand functional assays of serotonin, LY 272015 and MARY1 against human 5-HT2B receptor. (FIG.1F) Agonist and antagonist radioligand functional assays of serotonin, SB 242084 and MARY1 against human 5-HT2C receptor.

[0010] FIG. 2 shows Functional groups modification on the parent compound MARY1. R1: functional group comprises of trifluoro moiety of parent compound, R2: functional group comprises of pyridine moiety of parent compound, R3: functional group comprises of piperazine moiety of parent compound.

[0011] FIGs.3A-3B show Seahorse Assay to measure mitochondrial oxygen consumption rate of vehicle control, NMN and MARY1 and its derivatives (MARY 2-20) in renal proximal tubule cells. FIG. 3A: Representative FCCP-OCR of vehicle, NMN, MARY1 and MARY2-15 treated RPTCs, with measurements of FCCP-OCR normalized to vehicle control. FIG. 3B: Representative FCCP-OCR of vehicle, NMN, and MARY16-20 treated RPTCs, with measurements of FCCP-OCR normalized to vehicle control. Data is represented as mean ± SEM, n=4-5 per treatment group.

[0012] FIGs.4A-4B show Phosphorylation Levels of p-AKT (S473) of MARY1 and its Derivatives in RPTCs. FIG.4A: Densitometry analysis and representative immunoblot of p-AKT (S473) and beta actin (loading control) of vehicle, MARY1, and its derivatives (MARY2-15) treated in renal proximal tubule cells. FIG.4B. Densitometry analysis and representative immunoblot of p-AKT (S473) and beta actin (loading control) of vehicle and MARY1 derivatives (MARY16-20) treated in renal proximal tubule cells. Data is represented as mean ± SEM, n=4-5 per treatment group.

[0013] FIG.5 shows Linear regression analysis of MARY1 and its derivatives. Shown is a linear regression plot between FCCP-OCR (x-axis) and p-AKT (S473) (y-axis) with a confidence interval of 95%.

[0014] FIG.6 shows treatment with MARY1 (1nM) for 24h induces mitochondrial biogenesis and increases FCCP-OCR in RPTCs. RPTCs were treated with MARY1 at varied concentration for 24h and FCCP-OCR uncoupled mitochondrial respiration was measured using Seahorse XF96 analyzer. RPTCs were treated with MARY1 for 24h and measured mitochondrial copy number - 3 -ATTORNEY DOCKET NO.220111-2270 (DLOOP) and mRNA levels of PGC1α and mtTFAM were measured using RT-PCR. Data are represented as means ± SEM; p<0.05; n=3-6.

[0015] FIG.7 shows treatment with MARY1 (1nM) for 20 min activates PI3K-AKT signaling axis. RPTCs were pretreated with wortmannin and gallein for 30 min followed by the administration of MARY1 for 20 min and assessed the phophorylation levels of p-AKT, AKT, p-FOXO1A, FOXO1, p-GSK3β, GSK3β and vinculin. Data are represented as means ± SEM; p<0.05; n=3-6.

[0016] FIG.8 shows treatment with MARY1 (1nM) for 20 min activates MEK-ERK signaling axis. RPTCs were pretreated with trametinib for 30 min followed by the administration of MARY1 for 20 min and assessed the phophorylation levels of p-ERK, ERK, RAS and vinculin. Data are represented as means ± SEM; p<0.05; n=3-6.

[0017] FIG.9 shows 5-HT2B expression validated across different species. Immunoblot analysis of 5-HT2B and beta actin as assessed in rabbit RPTCs, mouse kidney cortex and human RPTCs. Data are represented as means ± SEM; n=2-4.

[0018] FIG.10 shows MARY1 phosphorylates p-AKT and p-ERK dependent of 5-HT2B receptor. RPTCs were pretreated with LY266097 for 30 min followed by MARY1 for 20 min and assessed the protein level of p-AKT, AKT, p-ERK, ERK, vinculin. Data are represented as means ± SEM; n=4-6.

[0019] FIG.11 shows a schematic representation of mode of action of MARY1 in vitro.

[0020] FIG.12 shows a schematic representation of dosing regimen of MARY1 in naïve mice.

[0021] FIG.13 shows the effect of MARY1 on MB markers in naïve mice kidney cortex. RT-PCR of mitochondrial DNA copy number (DLOOP, ND1), PGC1α and mtTFAM in kidney cortex of naïve mice. Immunoblot analysis of nuclear levels of PGC1α, ERRα and NRF1 in kidney cortex. Data are represented as means ± SEM; n=4-7.

[0022] FIG.14 shows the effect of MARY1 on OXPHOS subunit complex proteins in mice kidney cortex Immunoblot analysis of OXPHOS subunit complex proteins along with beta actin in mice kidney cortex. Data are represented as means ± SEM; n=4-7.

[0023] FIG.15 shows the effect of MARY1 on mitochondrial dynamics proteins in mice kidney cortex Immunoblot analysis of mitochondrial dynamics proteins – MFN1, MFN2 and DRP1 along with beta actin in mice kidney cortex. Data are represented as means ± SEM; n=4-7. - 4 -ATTORNEY DOCKET NO.220111-2270

[0024] FIG.16 shows the effect of MARY1 on antioxidants and fatty acid oxidation proteins in mice kidney cortex. Immunoblot analysis of GPX4, HO1, CPT1A, SCD1 and ACSM2A along with beta actin in mice kidney cortex. Data are represented as means ± SEM; n=4-7.

[0025] FIG.17 shows a schematic representation of bilateral (I / R) injury induced AKI.

[0026] FIG.18 shows the effect of MARY1 in renal recovery and mitochondrial markers following I / R induced AKI. Mice were subjected to I / R injury and measured serum creatinine, mitochondrial DNA copy number, protein levels of PGC1α, total ATP content, Evans Blue Dye and renal fibrosis markers post administration of MARY1 in kidney cortex. Data are represented as means ± SEM; n=4-7.

[0027] FIG. 19 shows the effect of MARY1 on mitochondrial morphology post I / R injury as assessed by TEM. TEM images of kidney cortex and mitochondrial damage score as assessed in the study groups following I / R injury. Data are represented as means ± SEM; n=4-7.

[0028] FIG. 20 shows the effect of MARY1 on recovery of mitochondrial OXPHOS proteins Immunoblot analysis of OXPHOS subunit complex proteins along with beta actin in mice kidney cortex. Data are represented as means ± SEM; n=4-7.

[0029] FIG.21 shows the effect of MARY1 on recovery of Fatty acid Oxidation proteins post I / R injury in mice. Immunoblot analysis was used to assess the protein levels of AMPK, ACADM, ACSM2A, and beta actin in kidney cortex in the experimental group. Data are represented as means ± SEM; n=4-7.

[0030] FIG. 22 shows the effect of MARY1 on recovery of mitochondrial dynamic proteins. Immunoblot analysis of mitochondrial dynamics proteins – MFN1, MFN2 and DRP1 along with beta actin in mice kidney cortex post I / R injury. Data are represented as means ± SEM; n=4-7.

[0031] FIG. 23 shows MARY1 effects on mitophagy and cell senescence through HKDC1 following I / R injury and recovery. Immunoblot analysis of HKDC1, VDAC, PINK1, PARKIN, P21, ACTIN as assessed in the kidney cortex post I / R injury. Data are represented as means ± SEM; n=4-7.

[0032] FIG. 24 shows the effect of MARY1 on serum creatinine Evan’s Blue Leakage and Junctional Proteins. Evans blue dye and its serum creatinine profile and immunoblot analysis of junctional proteins like Claudin 1 and CD 9 in kidney cortex post I / R injury. Data are represented as means ± SEM; n=4-7. - 5 -ATTORNEY DOCKET NO.220111-2270

[0033] FIG.25 shows the effect of MARY1 on Successful repair genes post I / R injury induced AKI in mice. RT-PCR of ACSM2A, LRP2, SCL5A12, HNF4A were assessed in the experimental groups in kidney cortex in mice. Data are represented as means ± SEM; n=4-7.

[0034] FIG. 26 shows the effect of MARY1 on drug-induced AKI model in mice. Graphical representation of total protein and total albumin leakage as assessed in the study subjects using Coomassie Blue Stain. Data are represented as means ± SEM; n=4-7.

[0035] FIG.27 shows the effect of MARY1 in kidney cortex of Aging mice. RT-PCR analysis of TERT and COL1A1 was assessed in the kidney cortex of all three groups. Immunoblot analysis of COL1A1 was assessed in the kidney cortex of aging mice. Data are represented as means ± SEM; n=4-7.

[0036] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. DETAILED DESCRIPTION

[0037] Disclosed herein are several selective small molecules with a common piperazine fingerprint that induces MB. These include, but are not limited to, amitriptyline, amoxapine, clozapine, cabergoline, mirtazapine, SRT1720, MK212 BRL17752, and MARY1 and its synthetic analogues. In one aspect, MARY1 binds to the 5-HT2B receptor and acts as an agonist and has greater selectivity over 5-HT2A / 2C receptors. In a further aspect, MARY1 induces MB in cellular and animal models. In yet another aspect, MARY1 increased the master regulator of mitochondrial biogenesis, peroxisome-proliferator-activated-receptor-gamma-coactivator-1alpha (PGC-1alpha), cellular respiration, and ATP levels. In one aspect, MARY1 selectively binds to 5- HT2B receptor and restores renal function and recovery following bilateral ischemia reperfusion induced AKI. In another aspect, administration of MARY1 restored cellular and mitochondrial homeostasis, reduced renal fibrosis and vascular permeability and showed beneficial effect in glomerular injury in AKI model and aging in mice.

[0038] Acute kidney injury (AKI) is defined as a sudden and rapid loss of renal function, which is accompanied by elevated serum creatinine, increased blood urea nitrogen and decreased urine - 6 -ATTORNEY DOCKET NO.220111-2270 volume. Globally, AKI affects around 28% of hospitalized patients, results in high morbidity and mortality, and results in annual healthcare costs between $5-$24 billion. Common triggers of AKI include ischemia reperfusion (I / R) injury, sepsis, hypovolemia, drug induced nephrotoxicity, and mitochondrial dysfunction.

[0039] Mitochondria are complex organelles involved in diverse cellular and molecular functions, including β-oxidation and production of ATP. The kidney is the second most energy demanding organ in the human body and is rich in mitochondrial number per cell. Mitochondrial homeostasis is governed by several quality control mechanisms, including mitochondrial biogenesis (MB), mitophagy, and mitochondrial dynamics. Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) is thought to be the master regulator of MB and is enriched in tissues with high metabolic demand such as the heart, kidney, and liver. Physiological and pathophysiological stimuli, such as exercise, caloric restriction, hypoxia, sepsis, and I / R are known to affect PGC1α expression and other MB markers. Mitochondrial dysfunction is linked to impaired renal function, is a major hallmark and exacerbates the onset of AKI. Ischemia, ROS production, persistent inflammation, impaired mitochondrial quality control pathways are the main drivers for the onset of AKI. A reduction in ATP production and mitochondrial dysfunction has been reported in animal models that result in the loss of mitochondrial respiratory proteins in proximal tubules. As a result of mitochondrial dysfunction which triggers imbalance in antioxidants, ATP production, impaired fatty acids metabolism leads to onset and progression of AKI in various cellular and animal models.

[0040] Serotonin / 5-Hydroxytryptamine (5-HT) not only plays a role as a neurotransmitter and hormone in the central nervous system, but also in several biological pathways and tissues. Recent evidence suggests that targeting 5-HT receptors could be beneficial for treating mitochondrial dysfunction-associated diseases in multiple organ systems. 5-HT receptors have also been found to modulate mitochondrial biogenesis (MB) in the brain, spinal cord, and kidneys. Previous research has shown that activation of the 5-hydroxytryptamine 1F (5-HT1F) receptor, 5- hydroxytryptamine 2 receptor (5-HT2) promotes MB in in vitro and in vivo models. Analogues of MARY1

[0041] In one aspect, disclosed herein is a compound having Formula I or a pharmaceutically acceptable salt thereof: - 7 -ATTORNEY DOCKET NO.220111-2270 R R R3f 3b3eR1aO R3aNR43hdwherein each of R1a-R1eis independently selected from halogen, methyl, hydrogen, or methoxy; wherein R2is hydrogen or methyl; wherein each of R3a-R3his independently selected from hydrogen, deuterium, or methyl, or wherein R3his absent and R3sis carboxy; and wherein R4is selected from CD3, methyl, ethyl, oxetane, hydrogen, methanesulfonyl, isopropyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; .

[0042] her aspect, R2is H. In still another aspect, each of R3a-R3his H. In an aspect, each of R3a-R3his D. In one aspect, R4is selected from or can be lower alkyl (i.e., C1-C4 lineR4is not lower alkyl.

[0043] In any of these aspects, the compound can be selected from: ,ATTORNEY DOCKET NO.220111-2270 , , , , , ,ATTORNEY DOCKET NO.220111-2270 Cl O N N N N , , , , ,- 10 -ATTORNEY DOCKET NO.220111-2270 ornd can be selective for 5-HT2B over 5-HT2A, 5-HT2C, or both 5-HT2A and 5-HT2C.

[0045] Also disclosed herein is a pharmaceutical composition including the disclosed compound or pharmaceutically acceptable salt. Methods of Using the Compounds

[0046] In one aspect, disclosed herein is a method for treating or preventing at least one symptom of acute kidney injury in a subject, the method comprising administering a therapeutically effective amount of a compound selected from amitriptyline, amoxapine, clozapine, cabergoline, mirtazapine, SRT1720, MK212, BRL17752, or a compound of Formula I or pharmaceutically acceptable salt thereof to the subject. In a further aspect, the compound of Formula I can be MARY1. In a further aspect, the at least one symptom of acute kidney injury can be renal fibrosis, reduced vascular permeability, impairment of cellular respiration, reduced ATP levels, impairment of cellular homeostasis, impairment of mitochondrial homeostasis, reduced mitochondrial biogenesis, glomerular injury, or any combination thereof. In one aspect, the method decreases collagen production, wherein decreased collagen production results in a decrease in renal fibrosis.

[0047] Also disclosed herein is a method for inducing mitochondrial biogenesis in a subject, the method comprising administering a therapeutically effective amount of a compound selected from amitriptyline, amoxapine, clozapine, cabergoline, mirtazapine, SRT1720, MK212, BRL17752, or a compound of Formula I or pharmaceutically acceptable salt thereof to the subject In one aspect, the compound of Formula I can be MARY1.

[0048] In yet another aspect, disclosed herein is a method for reducing senescent changes in a kidney of a subject, the method comprising administering a therapeutically effective amount of a - 11 -ATTORNEY DOCKET NO.220111-2270 compound selected from amitriptyline, amoxapine, clozapine, cabergoline, mirtazapine, SRT1720, MK212, BRL17752, or a compound of Formula I or pharmaceutically acceptable salt thereof to the subject. In one aspect, the compound of Formula I can be MARY1. In one aspect, the method increases expression of telomerase reverse transcriptase (TERT). In another aspect, the method increases expression of at least one gene involved in kidney repair after an injury. Further in this aspect, the at least one gene can be ACSM2, LRP2, SCL5912, or HNF4A.

[0049] In any of these aspects, subject can be a mammal such as, for example, a human, rat, mouse, hamster, guinea pig, rabbit, cat, dog, sheep, cattle, horse, goat, or non-human primate.

[0050] Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0051] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0052] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0053] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. - 12 -ATTORNEY DOCKET NO.220111-2270

[0054] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0055] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.

[0056] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. 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 disclosed compositions and methods belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0057] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure. Definitions

[0058] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of. - 13 -ATTORNEY DOCKET NO.220111-2270

[0059] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a MARY1 analogue,” “a symptom of acute kidney injury,” or “a subject,” includes, but not limited to, mixtures, combinations, or populations of two or more such MARY1 analogues, symptoms of acute kidney injury, or subjects, and the like.

[0060] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0061] When a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0062] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub- ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to - 14 -ATTORNEY DOCKET NO.220111-2270 about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

[0063] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0064] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0065] Unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (i.e. one atmosphere).

[0066] A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH2CH2O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more - CO(CH2)8CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

[0067] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and - 15 -ATTORNEY DOCKET NO.220111-2270 nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0068] In defining various terms, “A1,” “A2,” “A3,” and “A4” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0069] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0070] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t- butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 - 16 -ATTORNEY DOCKET NO.220111-2270 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.

[0071] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.

[0072] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0073] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The - 17 -ATTORNEY DOCKET NO.220111-2270 cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0074] The term “alkanediyl” as used herein, refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups, —CH2— (methylene), —CH2CH2—, —CH2C(CH3)2CH2—, and —CH2CH2CH2— are non-limiting examples of alkanediyl groups.

[0075] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA1where A1is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA1—OA2or —OA1—(OA2)a—OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3are alkyl and / or cycloalkyl groups.

[0076] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A1A2)C=C(A3A4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0077] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, - 18 -ATTORNEY DOCKET NO.220111-2270 aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0078] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0079] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0080] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized π electrons above and below the plane of the molecule, where the π clouds contain (4n+2) π electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “ Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0081] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, ─NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or - 19 -ATTORNEY DOCKET NO.220111-2270 attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0082] The term “aldehyde” as used herein is represented by the formula —C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C=O.

[0083] The terms “amine” or “amino” as used herein are represented by the formula —NA1A2, where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is ─NH2.

[0084] The term “alkylamino” as used herein is represented by the formula —NH(-alkyl) and — N(-alkyl)2, where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

[0085] The term “carboxylic acid” as used herein is represented by the formula —C(O)OH.

[0086] The term “ester” as used herein is represented by the formula —OC(O)A1or —C(O)OA1, where A1can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula — (A1O(O)C-A2-C(O)O)a— or —(A1O(O)C-A2-OC(O))a—, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

[0087] The term “ether” as used herein is represented by the formula A1OA2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula —(A1O-A2O)a—, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, - 20 -ATTORNEY DOCKET NO.220111-2270 cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0088] The terms “halo,” “halogen” or “halide,” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0089] The terms “pseudohalide,” “pseudohalogen” or “pseudohalo,” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0090] The term “heteroalkyl” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0091] The term “heteroaryl” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2- b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0092] The terms “heterocycle” or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, - 21 -ATTORNEY DOCKET NO.220111-2270 “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.

[0093] The term “bicyclic heterocycle” or “bicyclic heterocyclyl” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro- 1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2- b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.

[0094] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. - 22 -ATTORNEY DOCKET NO.220111-2270 Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0095] The term “hydroxyl” or “hydroxy” as used herein is represented by the formula —OH.

[0096] The term “ketone” as used herein is represented by the formula A1C(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0097] The term “azide” or “azido” as used herein is represented by the formula —N3.

[0098] The term “nitro” as used herein is represented by the formula —NO2.

[0099] The term “nitrile” or “cyano” as used herein is represented by the formula —CN.

[0100] The term “silyl” as used herein is represented by the formula —SiA1A2A3, where A1, A2, and A3can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0101] The term “sulfo-oxo” as used herein is represented by the formulas —S(O)A1, —S(O)2A1, —OS(O)2A1, or —OS(O)2OA1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula —S(O)2A1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A1S(O)2A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A1S(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0102] The term “thiol” as used herein is represented by the formula —SH.

[0103] “R1,” “R2,” “R3,”... “Rn,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within the second group or, alternatively, the first group can be - 23 -ATTORNEY DOCKET NO.220111-2270 pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0104] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0105] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0106] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R^; –(CH2)0–4OR^; -O(CH2)0-4Ro, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR^)2; –(CH2)0–4SR^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; – N3; -(CH2)0–4N(R^)2; –(CH2)0–4N(R^)C(O)R^; –N(R^)C(S)R^; –(CH2)0–4N(R^)C(O)NR^2; -N(R^)C(S)NR^2; –(CH2)0–4N(R^)C(O)OR^; – N(R^)N(R^)C(O)R^; -N(R^)N(R^)C(O)NR^2; -N(R^)N(R^)C(O)OR^; –(CH2)0–4C(O)R^; –C(S)R^; – (CH2)0–4C(O)OR^; –(CH2)0–4C(O)SR^; -(CH2)0–4C(O)OSiR^3; –(CH2)0–4OC(O)R^; –OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R^; –(CH2)0–4C(O)NR^2; –C(S)NR^2; –C(S)SR°; -(CH2)0–4OC(O)NR^2; -C(O)N(OR^)R^; –C(O)C(O)R^; –C(O)CH2C(O)R^; –C(NOR^)R^; -(CH2)0–4SSR^; – (CH2)0–4S(O)2R^; –(CH2)0–4S(O)2OR^; –(CH2)0–4OS(O)2R^; –S(O)2NR^2; -(CH2)0–4S(O)R^; -N(R^)S(O)2NR^2; –N(R^)S(O)2R^; –N(OR^)R^; –C(NH)NR^2; – - 24 -ATTORNEY DOCKET NO.220111-2270 P(O)2R^; -P(O)R^2; -OP(O)R^2; –OP(O)(OR^)2; SiR^3; –(C1–4straight or branched alkylene)O– N(R^)2; or –(C1–4straight or branched alkylene)C(O)O–N(R^)2, wherein each R^ may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0107] Suitable monovalent substituents on R^ (or the ring formed by taking two independent occurrences of R^ together with their intervening atoms), are independently halogen, –(CH2)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2; -O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, – 1–4straight or branched re preceded by “halo” issubstituted only with one or more halogens, and is independently selected from C1–4aliphatic, – CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R^ include =O and =S.

[0108] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0109] Suitable substituents on the aliphatic group of R*include halogen, –R^, -(haloR^), -OH, – OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^- 25 -ATTORNEY DOCKET NO.220111-2270 is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0110] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, – S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0111] Suitable substituents on the aliphatic group of R†are independently halogen, – R^, -(haloR^), –OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or – NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0112] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.

[0113] The terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).

[0114] The term “organic residue” defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, - 26 -ATTORNEY DOCKET NO.220111-2270 phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0115] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4- thiazolidinedione radical in a particular compound has the structure: regardless of whether thiazolidinedione iepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

[0116] “Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono- substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include - 27 -ATTORNEY DOCKET NO.220111-2270 heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.

[0117] “Inorganic radicals,” as the term is defined and used herein, contain no carbon atoms and therefore comprise only atoms other than carbon. Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations. Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals. The inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical. Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.

[0118] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

[0119] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

[0120] Many organic compounds exist in optically active forms having the ability to rotate the - 28 -ATTORNEY DOCKET NO.220111-2270 plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0121] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F, and36Cl, respectively. Compounds further comprise prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased - 29 -ATTORNEY DOCKET NO.220111-2270 in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[0122] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[0123] The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0124] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an α-hydrogen can exist in an equilibrium of the keto form and the enol form.Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, the invention includes all such possible tautomers.

[0125] It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according - 30 -ATTORNEY DOCKET NO.220111-2270 to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[0126] In some aspects, a structure of a compound can be represented by a formula: , which is understood to be equivalent to a, wherein n is typically an integer. Tnderstood to represent five independent substituents, Rn(a), Rn(b), Rn(c), Rn(d), and Rn(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance Rn(a)is halogen, then Rn(b)is not necessarily halogen in that instance.

[0127] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0128] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, - 31 -ATTORNEY DOCKET NO.220111-2270 it is no way intended that an order be inferred, in any respect. This holds for any possible non- express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0129] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0130] As used herein, “administering” can refer to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavernous, intrathecal, intravireal, intracerebral, and intracerebroventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheters, stents or via an implanted reservoir or other device that administers, either actively or passively (e.g. by diffusion) a composition the perivascular space and adventitia. For example a medical device such as a stent can contain a composition or formulation disposed on its surface, which can then dissolve or be otherwise distributed to the surrounding tissue and cells. The term “parenteral” can include subcutaneous, intravenous, intramuscular, intra-articular, - 32 -ATTORNEY DOCKET NO.220111-2270 intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0131] As used herein, “therapeutic agent” can refer to any substance, compound, molecule, and the like, which can be biologically active or otherwise can induce a pharmacologic, immunogenic, biologic and / or physiologic effect on a subject to which it is administered to by local and / or systemic action. A therapeutic agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. A therapeutic agent can be a secondary therapeutic agent, or in other words, the component(s) of a composition to which an additional part and / or other effect of the composition is attributed. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; - 33 -ATTORNEY DOCKET NO.220111-2270 immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0132] As used interchangeably herein, “subject,” “individual,” or “patient” can refer to a vertebrate organism, such as a mammal (e.g. human). "Subject" can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to human and constituents thereof.

[0133] As used herein, the terms "treating" and "treatment" can refer generally to obtaining a desired pharmacological and / or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as acute kidney injury and / or kidney senescence. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition. The term "treatment" as used herein can include any treatment of acute kidney injury and / or kidney senescence in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and / or its symptoms or conditions. The term "treatment” used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and / or those in which the disorder is to be prevented. As used herein, the term "treating", can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression - 34 -ATTORNEY DOCKET NO.220111-2270 of the disease, disorder and / or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

[0134] As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and / or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.

[0135] As used herein, “therapeutic” can refer to treating, healing, and / or ameliorating a disease, disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect.

[0136] As used herein, “effective amount” can refer to the amount of a disclosed compound or pharmaceutical composition provided herein that is sufficient to effect beneficial or desired biological, emotional, medical, or clinical response of a cell, tissue, system, animal, or human. An effective amount can be administered in one or more administrations, applications, or dosages. The term can also include within its scope amounts effective to enhance or restore to substantially normal physiological function.

[0137] As used herein, the term “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to halt the progression of the disease permanently. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition also can be delaying the onset or even - 35 -ATTORNEY DOCKET NO.220111-2270 preventing the onset of the disease or condition.

[0138] For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the invention (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

[0139] A response to a therapeutically effective dose of a disclosed compound and / or pharmaceutical composition, for example, can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied for example by increasing or decreasing the amount of a disclosed compound and / or pharmaceutical composition, by changing the disclosed compound and / or pharmaceutical composition administered, by changing the route of administration, by changing the dosage timing and so on. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

[0140] As used herein, the term “prophylactically effective amount” refers to an amount effective for preventing onset or initiation of a disease or condition.

[0141] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0142] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner. - 36 -ATTORNEY DOCKET NO.220111-2270

[0143] The term “pharmaceutically acceptable salts”, as used herein, means salts of the active principal agents which are prepared with acids or bases that are tolerated by a biological system or tolerated by a subject or tolerated by a biological system and tolerated by a subject when administered in a therapeutically effective amount. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to; sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to; those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.

[0144] The term “pharmaceutically acceptable ester” refers to esters of compounds of the present disclosure which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Examples of pharmaceutically acceptable, non- toxic esters of the present disclosure include C 1 -to-C 6 alkyl esters and C 5 -to-C 7 cycloalkyl esters, although C 1 -to-C 4 alkyl esters are preferred. Esters of disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable esters can be appended onto hydroxy groups by reaction of the compound that contains the hydroxy group with acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable esters are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine and an alkyl halide, for example with methyl iodide, benzyl iodide, cyclopentyl iodide or alkyl triflate. They also can be prepared by reaction of the compound with an acid such as hydrochloric acid and an alcohol such as ethanol or methanol. - 37 -ATTORNEY DOCKET NO.220111-2270

[0145] The term “pharmaceutically acceptable amide” refers to non-toxic amides of the present disclosure derived from ammonia, primary C 1 -to-C 6 alkyl amines and secondary C 1 -to-C 6 dialkyl amines. In the case of secondary amines, the amine can also be in the form of a 5- or 6- membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C 1 -to-C 3 alkyl primary amides and C 1 -to-C 2 dialkyl secondary amides are preferred. Amides of disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reaction of the compound that contains the amino group with an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable amides are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine, a dehydrating agent such as dicyclohexyl carbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine, for example with methylamine, diethylamine, and piperidine. They also can be prepared by reaction of the compound with an acid such as sulfuric acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid under dehydrating conditions such as with molecular sieves added. The composition can contain a compound of the present disclosure in the form of a pharmaceutically acceptable prodrug.

[0146] The term “pharmaceutically acceptable prodrug” or “prodrug” represents those prodrugs of the compounds of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use. Prodrugs of the present disclosure can be rapidly transformed in vivo to a parent compound having a structure of a disclosed compound, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V.14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).

[0147] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and - 38 -ATTORNEY DOCKET NO.220111-2270 N-oxides of a parent compound.

[0148] In various aspects, the disclosed compounds can be in the form of a co-crystal. The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889- 1896, 2004. Preferred co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0149] The term “pharmaceutically acceptable co-crystal” means one that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0150] In a further aspect, the disclosed compounds can be isolated as solvates and, in particular, as hydrates of a disclosed compound, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvate or water molecules can combine with the compounds according to the invention to form solvates and hydrates.

[0151] The disclosed compounds can be used in the form of salts derived from inorganic or organic acids. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the disclosed compounds. Suitable pharmaceutically acceptable salts include base addition salts, including alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts, which may be similarly prepared by reacting the drug compound with a suitable pharmaceutically acceptable base. The salts can be prepared in situ during the final isolation and purification of the compounds of the present disclosure; or following final isolation by reacting a free base function, such as a secondary or tertiary amine, of a disclosed compound with a suitable inorganic or organic acid; or reacting a free acid function, such as a carboxylic acid, of a disclosed compound with a suitable inorganic or organic base.

[0152] Acidic addition salts can be prepared in situ during the final isolation and purification of a disclosed compound, or separately by reacting moieties comprising one or more nitrogen groups with a suitable acid. In various aspects, acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. - 39 -ATTORNEY DOCKET NO.220111-2270 In a further aspect, salts further include, but are not limited, to the following: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, 2-hydroxyethanesulfonate (isethionate), nicotinate, 2- naphthalenesulfonate, oxalate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, undecanoate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Also, basic nitrogen- containing groups can be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others.

[0153] Basic addition salts can be prepared in situ during the final isolation and purification of a disclosed compound, or separately by reacting carboxylic acid moieties with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutical acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine. Pharmaceutical acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. In further aspects, bases which may be used in the preparation of pharmaceutically acceptable salts include the following: ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H- imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

[0154] Now having described the aspects of the present disclosure, in general, the following Examples describe some additional aspects of the present disclosure. While aspects of the - 40 -ATTORNEY DOCKET NO.220111-2270 present disclosure are described in connection with the following examples and the corresponding text and figures, there is no intent to limit aspects of the present disclosure to this description. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of the present disclosure. ASPECTS

[0155] The present disclosure can be described in accordance with the following numbered aspects, which should not be confused with the claims.

[0156] Aspect 1. A compound having Formula I or a pharmaceutically acceptable salt thereof: R3fR R3b3eRO R NR43hdwherein each of R1a-R1eis independently selected from halogen, methyl, hydrogen, or methoxy; wherein R2is hydrogen or methyl; wherein each of R3a-R3his independently selected from hydrogen, deuterium, or methyl, or wherein R3his absent and R3sis carboxy; and wherein R4is selected from CD3, methyl, ethyl, oxetane, hydrogen, methanesulfonyl, isopropyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; .

[0157] spec . e co pou o p a aceu ca y accepa e sa o aspect 1, wherein R1a, R1c, and R1eare F and R1band R1dare H. - 41 -ATTORNEY DOCKET NO.220111-2270

[0158] Aspect 3. The compound or pharmaceutically acceptable salt of aspect 1 or 2, wherein R2is H.

[0159] Aspect 4. The compound or pharmaceutically acceptable salt of any one of aspects 1-3, wherein each of R3a-R3his H.

[0160] Aspect 5. The compound or pharmaceutically acceptable salt of any one of aspects 1-4, wherein each of R3a-R3his D.

[0161] Aspect 6. The compound or pharmaceutically acceptable salt of any one of aspects 1-5, wherein R4is selected from .

[0162] Aspect 7. The compf aspects 1-6, F O NH N wherein the compound is selected,, , ,ATTORNEY DOCKET NO.220111-2270 , , , , , ,ATTORNEY DOCKET NO.220111-2270 , , ,-7, wherein the compound is a 5-HT2B agonist.

[0164] Aspect 9. The compound or pharmaceutically acceptable salt of aspect 8, wherein the compound is selective for 5-HT2B over 5-HT2A, 5-HT2C, or both 5-HT2A and 5-HT2C.

[0165] Aspect 10. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one of aspects 1-9.

[0166] Aspect 11. A method for treating or preventing at least one symptom of acute kidney injury in a subject, the method comprising administering a therapeutically effective amount of a compound selected from amitriptyline, amoxapine, clozapine, cabergoline, mirtazapine, SRT1720, MK212, BRL17752, or a compound of Formula I or pharmaceutically acceptable salt thereof to the subject - 44 -ATTORNEY DOCKET NO.220111-2270 R3R Rf 3b3eRO R NR41a 3a3hdwherein each of R1a-R1eis independently selected from halogen, methyl, hydrogen, or methoxy; wherein R2is hydrogen or methyl; wherein each of R3a-R3his independently selected from hydrogen, deuterium, or methyl, or wherein R3his absent and R3sis carboxy; and wherein R4is selected from CD3, methyl, ethyl, oxetane, hydrogen, methanesulfonyl, isopropyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.

[0167] Aspect 12. The method of aspect 11, wherein R1a, R1c, and R1eare F and R1band R1dare H.

[0168] Aspect 13. The method of aspect 11 or 12, wherein R2is H.

[0169] Aspect 14. The method of any one of aspects 11-13, wherein each of R3a-R3his H.

[0170] Aspect 15. The method of any one of aspects 11-14, wherein each of R3a-R3his D.

[0171] Aspect 16. The method of any one of aspects 11-15, wherein R4is selected from .p . y p 11-16, wherein the compound is selected F O NH ,ATTORNEY DOCKET NO.220111-2270 , , , , , ,ATTORNEY DOCKET NO.220111-2270 , C , , , ,- 47 -ATTORNEY DOCKET NO.220111-2270 ,ney injury comprises renal fibrosis, reduced vascular permeability, impairment of cellular respiration, reduced ATP levels, impairment of cellular homeostasis, impairment of mitochondrial homeostasis, reduced mitochondrial biogenesis, glomerular injury, or any combination thereof.

[0174] Aspect 19. The method of any one of aspects 11-18, wherein the method decreases collagen production, wherein decreased collagen production results in a decrease in renal fibrosis.

[0175] Aspect 20. A method for inducing mitochondrial biogenesis in a subject, the method comprising administering a therapeutically effective amount of a compound selected from amitriptyline, amoxapine, clozapine, cabergoline, mirtazapine, SRT1720, MK212, BRL17752, or a compound of Formula I or pharmaceutically acceptable salt thereof to the subject R R R3f 3b3eR43hdormua wherein each of R1a-R1eis independently selected from halogen, methyl, hydrogen, or methoxy; wherein R2is hydrogen or methyl; - 48 -ATTORNEY DOCKET NO.220111-2270 wherein each of R3a-R3his independently selected from hydrogen, deuterium, or methyl, or wherein R3his absent and R3sis carboxy; and wherein R4is selected from CD3, methyl, ethyl, oxetane, hydrogen, methanesulfonyl, isopropyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.

[0176] Aspect 21. The method of aspect 20, wherein the compound is selected from: F O NH N , , , , ,ATTORNEY DOCKET NO.220111-2270 , , , , , ,ATTORNEY DOCKET NO.220111-2270 , ,hod comprising administering a therapeutically effective amount of a compound selected from amitriptyline, amoxapine, clozapine, cabergoline, mirtazapine, SRT1720, MK212, BRL17752, or a compound of Formula I or pharmaceutically acceptable salt thereof to the subject R R3fR3b3eR43hdo ua wherein each of R1a-R1eis independently selected from halogen, methyl, hydrogen, or methoxy; wherein R2is hydrogen or methyl; wherein each of R3a-R3his independently selected from hydrogen, deuterium, or methyl, or wherein R3his absent and R3sis carboxy; and - 51 -ATTORNEY DOCKET NO.220111-2270 wherein R4is selected from CD3, methyl, ethyl, oxetane, hydrogen, methanesulfonyl, isopropyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.

[0178] Aspect 23. The method of aspect 22, wherein the compound is selected from: F O NH N N N , , , , , ,ATTORNEY DOCKET NO.220111-2270 , , , , , ,ATTORNEY DOCKET NO.220111-2270 ,of telomerase reverse transcriptase (TERT).

[0180] Aspect 25. The method of any one of aspects 11-24, wherein the method increases expression of at least one gene involved in kidney repair after an injury.

[0181] Aspect 26. The method of aspect 25, wherein the at least one gene comprises ACSM2, LRP2, SCL5912, or HNF4A.

[0182] Aspect 27. The method of any one of aspects 11-26, wherein the subject is a mammal.

[0183] Aspect 28. The method of aspect 27, wherein the mammal is a human, rat, mouse, hamster, guinea pig, rabbit, cat, dog, sheep, cattle, horse, goat, or non-human primate. EXAMPLES

[0184] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. Example 1: Synthesis of MARY1 and Derivatives

[0185] Disclosed herein is a novel pyridinylpiperazine class of drug called MARY1 (FIG. 1A). MARY1 is a 1,4- nitrogen substituted piperazine class of small molecule and obeys Lipinski’s rule - 54 -ATTORNEY DOCKET NO.220111-2270 of five. The synthesis route of the target compound MARY1 is illustrated in Scheme 1. Intermediate 3 is obtained by coupling activated 6-bromopyridine-2-carboxylic acid with N-methyl piperazine. Then, MARY1 is synthesized via the Buchwald-Hartwig C-N coupling reaction of 2,4,6-trifluoro benzamide with intermediate 3. After successful synthesis of target compound MARY1, the National Institute of Mental Health's Psychoactive Drug Screening Program at the University of North Carolina was used to evaluate in vitro binding affinities of MARY1 along with quipazine, a serotonergic drug containing piperazine moiety. MARY1 selectively binds to 5-HT2B receptor and not 5-HT2A / 2C receptors (FIG.1B) with a moderate affinity (Ki- 764 nM) and SB 206553, a mixed antagonist for the 5-HT2B and 5-HT2C receptor was used as a positive control (FIG.1C). Dose-response GPCR binding both agonist and antagonist radioligand LeadHunter assay (Eurofins Discovery) revealed that MARY1 selectively antagonizes 5-HT2B receptor (IC50- 380 nM) with a max response of 90 % (FIG.1E) and not 5-HT2A, 5-HT2C receptors (FIGs.1D, 1F). Collectively, the above data suggests that MARY1 is a novel pyridinylpiperazine class of molecule and a highly selective antagonist to human 5-HT2B receptor.

[0186] Following the drug discovery and development of MARY1, next generation novel class of piperazine molecules were designed and synthesized based on the structure of parent compound MARY1. As shown in Table 1, 27 different piperazine derivatives were generated based on parent compound MARY1, namely MARY2-MARY28. The series of compounds generated by performing modification on the R1, R2 and R3 functional groups of parent compound, MARY1 (FIG.2). Table 1: MARY1 Derivatives- 55 -ATTORNEY DOCKET NO.220111-2270 1 MARY2 F O NH N N N- 56 -ATTORNEY DOCKET NO.220111-2270 8 MARY9- 57 -ATTORNEY DOCKET NO.220111-2270 15 MARY16- 58 -ATTORNEY DOCKET NO.220111-2270 22 MARY23Example 2: Pharmacological Evaluations of MARY1 Derivatives

[0187] Seahorse Assay: A measure of mitochondrial respiration capacity: First, the mitochondrial biogenic potential of MARY1 derivatives was determined by measuring the mitochondrial maximum respiration capacity using Seahorse XF Pro (Agilent Technologies, CA). Primary renal proximal tubule cells isolated from rabbits were used as the in vitro model. Cells were treated with either vehicle control or 30 nM of MARY1 and their derivatives for 24 hours. Following treatment, - 59 -ATTORNEY DOCKET NO.220111-2270 the cells were subjected to Seahorse XF Pro with a final concentration of 2 µM of FCCP (Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone) in PORT A and assessed both basal and FCCP- OCR, a measure of mitochondrial maximum respiration. As shown in FIGs.3A-3B, MARY 1, 2, 4, 6, 8, 9, 15, 17, 18, 19 were shown to increase FCCP-OCR following treatment in renal proximal tubule cells. A cutoff of 115% FCCP-OCR was set as the threshold. Nicotinamide mononucleotide, a known and potent MB inducer was used as a positive control.

[0188] Next, the induction of phosphorylation state of protein kinase B (AKT) was assessed at serine 473 position. Renal proximal tubule cells post confluence were treated with 30 nM of MARY1 and its derivatives for 1 hour. Following treatment, proteins were harvested and subjected to immunoblot analysis and assessed the phosphorylation state of AKT (S473). As shown in FIGs. 4A-4B, MARY 1, 2, 3, 4, 6, 8, 11, 14, 15, 17, 18 and 19 increased protein levels of pAKT (S473) compared to vehicle control. Beta actin was used as a loading control.

[0189] Following assessment of both mitochondrial oxygen consumption rate and protein levels of pAKT, linear regression was next performed between oxygen consumption rate and protein levels to determine the association of all the MARY1 derivatives FIG.5. It was observed that there was a positive correlation in MARY 2, 3, 4, 6, 17, 18 and 19 in both FCCP-OCR and pAKT (S473) levels with a confidence interval of 95%. Example 3: Target Validation and Cell Signaling Cascade of MARY1 in Vitro

[0190] A number of novel chemicals were syntheized and screened, and it was found that the piperazine molecule MARY1 potently (1nM) induces MB in vitro. The transcriptional levels of PGC1α, mitochondrial transcription factor A (mtTFAM), mitochondrial copy number and mitochondrial respiration levels (FCCP-OCR) increased in renal proximal tubule cells (RPTCs) following 24h administration of MARY1 (FIG.6). MARY1 activates the PI3K-AKT signaling and MEK-ERK signaling axis

[0191] Administration of MARY1 in RPTCs activates the PI3K-AKT signaling and MEK-ERK signaling axis which are major players in cell growth, proliferation, metabolism, and survival. RPTCs were pretreated with inhibitors such as Wortmannin (PI3K inhibitor) and Gallein (Gβγ inhibitor) and trametinib (MEK inhibitor) and then treated with MARY1 for 20 min. MARY1 phosphorylated AKT through PI3K and its downstream targets such as FOXO1 and GSK3β with pretreatment with Gallein but not with Wortmannin (FIG.7). Also, MARY1 phosphorylated ERK - 60 -ATTORNEY DOCKET NO.220111-2270 through MEK (FIG.8). This affirms that MARY1 activates PI3K-AKT signaling and ERK signaling axis independent of Gβγ and dependent on PI3K and MEK. MARY1 is a selective 5-HT2B agonist

[0192] MARY1 and 18 other compounds were synthesized based on the structure of lasmiditan, an FDA-approved selective 5-HT1F agonist and MB inducer, to create the next generation of MB pharmacological agents. After synthesis, the physical and chemical properties of MARY1 were validated using available biophysical techniques. To determine the target of MARY1, its binding was evaluated against a wide range of human cloned GPCRs using the NIMH Psychoactive Drug Screening Program and found that MARY1 selectively binds to 5-HT2B and not 5-HT2A / 2C or any of the other 45 GPCRs tested (Table 1). The presence of 5-HT2B receptors in rabbit, mouse and human kidneys was then validated (FIG.9).

[0193] Table 2 shows results of a primary / secondary binding screening assay of MARY1 in human cloned GPCRs by the NIMH Psychoactive Drug Screening Program. Tabulated the mean % inhibition of MARY1 against pan 5-HT2 receptor family and dose dependent secondary binding assay of MARY1 and SB206553 (positive control) against 5-HT2B receptor. Table 2: Screening Assay of MARY1 on Human Cloned GPCRs

[0194] The relationship between MARY1 to 5-HT2B was next assessed, and it was found that MARY1 is a 5-HT2B agonist. RPTCs were pretreated with LY266097, a potent and selective 5- HT2B antagonist for 30 min followed by the administration of MARY1 for 20 min. MARY1 phosphorylates p-AKT and p-ERK dependent of 5-HT2B receptor (FIG.10).

[0195] From the in vitro data it was shown that MARY1 binds and an agonist to 5-HT2B receptor and activates the PI3K-AKT signaling and MEK-ERK signaling axis responsible for the MB action in vitro as shown in the schematic (FIG.11). Additional studies are needed to elucidate the cellular mechanism responsible for induction of MB. Example 4: MARY1 Induces Mitochondrial Biogenesis in Vivo - 61 -ATTORNEY DOCKET NO.220111-2270

[0196] To assess the MB effect of MARY1 in in vivo, mice were administered with 0.3 mg / kg of MARY1 at 0 h and 24 h and harvested the kidneys at 48 h to assess key markers responsible for MB as shown in FIG.12. Effect of MARY1 on MB markers in naïve mice kidney cortex

[0197] Immunoblot analysis and RT-PCR were used to assess the changes in key mitochondrial markers by the administration of MARY1. As shown in FIG. 13, there was an increase in mitochondrial DNA copy number by measuring both DLOOP and ND1. Also, there was an increase in the mRNA levels of PGC1α and no difference was observed in mtTFAM. Since, the transcription factor responsible for MB- PGC1α translocate to nucleus to activate battery of genes, the nuclear fraction of PGC1α, ERRα and NRF1 was assessed. There was an increase in the nuclear levels of PGC1α signifies induction of MB in naïve mice by the administration of MARY1 (0.3 mg / kg). Effect of MARY1 on OXPHOS subunit complex proteins in mice kidney cortex

[0198] Oxidative phosphorylation (OXPHOS) is a metabolic process that occurs in the mitochondria of eukaryotes, where cells use enzymes to oxidize nutrients and produce adenosine triphosphate (ATP). To assess the effect of MARY1 in OXPHOS subunit complex, an increase in OXPHOS subunit complex I (NDUFB8) and complex II (SDHB) was observed in naïve mice by the administration of MARY1 (0.3 mg / kg) as shown in FIG.14. Effect of MARY1 on mitochondrial dynamics proteins in mice kidney cortex

[0199] Mitochondrial dynamics are the fusion and fission of mitochondrial membranes, which are tightly regulated by a group of proteins called dynamin related GTPases. Mitofusin 1 (MFN1), Mitofusin 2 (MFN2) and Dynamin-related protein 1 (DRP1) are the key players regulating mitochondrial dynamics. An increase in DRP1 was observed, and no changes were observed in MFN1 and MFN2 in naïve mice by the administration of MARY1 (0.3 mg / kg) as shown in FIG.15. Effect of MARY1 on antioxidants and fatty acid oxidation proteins in mice kidney cortex

[0200] Antioxidants and fatty acid oxidation proteins are crucial for cell survival, metabolism and maintain cellular homeostasis. The protein levels of Glutathione peroxidase 4 (GPX4) were measured; this is an enzyme that protects cells from membrane lipid peroxidation and Heme oxygenase 1 (HO1). An increase in the protein levels of GPX4 was observed, while no changes were observed in HO1. Since mitochondria are involved in fatty acid oxidations, the protein levels of Carnitine Palmitoyl transferase 1A (CPT1A), Stearoyl-CoA desaturase 1 (SCD1) and Acyl-CoA - 62 -ATTORNEY DOCKET NO.220111-2270 synthetase medium chain family member 2A (ACSM2A) were measured. An increase in SCD1 and ACSM2A was observed when compared to vehicle in naïve kidney cortex in mice administered with 0.3 mg / kg of MARY1 (FIG.16). Example 5: MARY1 Restores Renal Function and Recovery Through Mitochondrial Biogenesis Following Acute Kidney Injury

[0201] Mitochondrial dysfunction is linked to impaired renal function, is a major hallmark and exacerbates the onset of AKI. Ischemia, ROS production, persistent inflammation, impaired mitochondrial quality control pathways are the main drivers for the onset of AKI.

[0202] To assess the therapeutic effects of MARY1 in renal function and recovery, C57BL / 6NCrL mice were subjected to bilateral ischemia-reperfusion (I / R) injury and administered with 0.3 mg / kg of MARY1 for 6 days as shown in FIG.17. Following ischemia, kidneys were reperfused at 37°C. At 24 h, injured mice were divided into three groups based upon serum creatinine levels (1.3-1.8 mg / dl): a) I / R mice at 24 h (I / R24h), b) I / R mice administered vehicle for 6 days (144h+Veh), c) I / R mice administered 0.3 mg / kg MARY1 for 6 days (144h+MARY1). Sham mice underwent surgery without clamping of renal pedicles. After administration of MARY1, kidney cortex was isolated and subjected to various molecular, vascular and histopathological assessments. Effect of MARY1 in renal recovery and mitochondrial markers following I / R induced AKI

[0203] To assess the effect of MARY1 post I / R induced AKI by daily administration for 6 days, serum creatinine was measured and observed a decrease compared for the groups subjected to daily administration of 0.3 mg / kg of MARY1 when compared to vehicle control. Also, to assess the vascular integrity a decrease in Evans Blue (EB) leakage was observed. Interestingly, observed a restoration of the protein levels of PGC1α, total ATP content and mitochondrial DNA copy number. To assess the effect of MARY1 in renal fibrosis, MARY1 was administered for 12 days and the renal corticaltubular injury and renal interstitial fibrosis were assessed (FIG.18). This affirms that administration of MARY1 has a beneficial effect on renal function and recovery following I / R induced AKI in mice. Effect of MARY1 on mitochondrial morphology post I / R injury as assessed by TEM

[0204] Transmission electron microscopy is a technique used to visualize mitochondria at higher resolution and able to distinguish normal and injured mitochondria at higher resolution in the kidney cortex. W observed an increase in the mitochondrial damage score in vehicle control and decreased in MARY1 administered group (FIG.19) - 63 -ATTORNEY DOCKET NO.220111-2270 Effect of MARY1 on recovery of mitochondrial OXPHOS proteins

[0205] To assess the effect of MARY1 in OXPHOS subunit complex post I / R injury, a decrease in OXPHOS complex proteins in vehicle was observed, and a restoration of subunit complex proteins such as Complex II and IV was observed, while an increase in mean values in Complex I, III, V was not a significant difference (FIG.20). Effect of MARY1 on recovery of Fatty acid Oxidation proteins post I / R injury in mice

[0206] To assess the effect of MARY1 in FAO proteins, the protein levels of AMP-activated protein kinase (AMPK), Acyl-CoA synthetase medium chain family member 2A (ACSM2A) and Acyl-CoA Dehydrogenase Medium Chain (ACADM) were measured. A decrease in ACSM2A and ACADM in vehicle and an increase in MARY1 administered group were observed. Interestingly, an increase in AMPK in MARY1 group was observed compared to vehicle group (FIG.21). Effect of MARY1 on recovery of mitochondrial dynamic proteins

[0207] To assess the effect of MARY1 in mitochondrial dynamic proteins, the protein levels of MFN1, MFN2 and DRP1 were measured in the experimental groups. A decrease in the level of MFN1 and MFN2 was observed upon injury and vehicle and restoration in MARY1 administered group. Interestingly, no change was observed in the protein levels of DRP1 post I / R injury in mice with either vehicle or administration of MARY1 (FIG.22). MARY1 effects on mitophagy and cell senescence through HKDC1 following I / R injury and recovery

[0208] Mitophagy is a cellular process that removes damaged mitochondria through autophagy and recent reports put forth that mitophagy regulated by hexokinase domain containing 1 (HKDC1) / PINK1 / PARKIN pathway and leads to amelioration of cellular senescence. The protein levels of key markers were assessed and it was found that there was an increase in the levels of HKDC1 in MARY1 administered group. Also, there was a decrease in VDAC1 and restoration of the same with the drug. Interestingly there was an increase in PINK1 and decrease in MARY1 administration, so does the cellular senescence marker-p21. This affirms that MARY1 has a role in crosstalk between mitophagy and cell senescence through HKDC1. Effect of MARY1 on serum creatinine Evan’s Blue Leakage and Junctional Proteins

[0209] Increased vascular permeability and impaired junctional proteins play a major role in impaired renal repair after AKI episode. In order to assess the effect of MARY1 in vascular - 64 -ATTORNEY DOCKET NO.220111-2270 permeability and junctional proteins, Evans Blue dye leakage was measured and it was found that there was a decrease in MARY1 group compared to vehicle group. Similarly, there was a restoration of junctional proteins such as Claudin 1 and CD 9 responsible for maintaining the renal junctional stability (FIG.24). Effect of MARY1 on Successful repair genes post I / R injury induced AKI in mice.

[0210] Recently, the key factors that regulate successful and failed repair states in the proximal tubule have been identified at a single cell resolution following bilateral ischemia reperfusion (I / R) in a mouse model of AKI. The transcriptional levels of the proximal tubule specific genes that drive adaptive repair following AKI such as Acyl-CoA synthetase medium chain family member 2A (ACSM2A), low-density lipoprotein receptor-related protein 2, solute carrier family 5 member 12 and hepatocyte nuclear factor 4 alpha were found to be restored to the sham groups by the administration of 0.3mg / kg of MARY1 post I / R injury in kidney cortex in mice (FIG.25). Example 6: Effect of MARY1` on Drug-Induced Acute Kidney Injury Model in Mice

[0211] After assessing the effect of MARY in I / R induced AKI in mice, it was sought to assess the effect of MARY1 in doxorubicin induced AKI in mice. Preliminary evidence suggests that daily administration of MARY1 for 10 days significantly reduced the total protein leakage and total albumin leakage when compared to vehicle group (FIG.26). This affirms the therapeutic potential of MARY1 in both I / R induced AKI and drug-induced nephrotoxicity AKI model in mice. Effect of MARY1 in Kidney Cortex of Aging Mice

[0212] Aging mice experience a progressive decline in organ function and the presence of senescent changes. Aging in mice experiences a progressive decline in organ function and the presence of senescent changes especially in kidney leads to impaired renal function and recovery. Here a well-recognized aging model was used with 22-24-month-old mice and administered either vehicle or 0.3 mg / kg of MARY1. Preliminary evidence suggests that an increase in the levels of enzyme TERT by the administration of MARY1 in aged mice. Telomerase reverse transcriptase, a catalytic subunit of the enzyme telomerase. The TERT gene provides instructions for making a component of telomerase, which maintains telomeres, DNA structures at the ends of chromosomes. Telomere shortening is a well-established hallmark of cellular aging. Telomerase reverse transcriptase (TERT) plays a crucial role in maintaining the length of telomeres, which are specialized protective caps at the end of chromosomes. Also, a decrease - 65 -ATTORNEY DOCKET NO.220111-2270 in the mean value of Collagen 1 (COL1A1) was observed; this is a marker of renal fibrosis in aged mice compared to vehicle group but not statistically significant (FIG.27). Conclusion

[0213] The data revealed that treatment with a novel chemical entity MARY1 for 24h in naïve RPTCs induced mitochondrial biogenesis though agonism of 5-HT2B. Also, treatment with MARY1 restored mitochondrial homeostasis and accelerated renal recovery following I / R induced AKI in mice. In addition, MARY1 showed beneficial effect on mice aging and doxorubicin induced AKI in mice.

[0214] It should be emphasized that the above-described embodiments of the present disclosure are merely possible examples of implementations set forth for a clear understanding of the principles of the disclosure. Many variations and modifications may be made to the above- described embodiment(s) without departing substantially from the spirit and principles of the disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure and protected by the following claims. REFERENCES 1. Bhargava, P. and R.G. Schnellmann, Mitochondrial energetics in the kidney. Nat Rev Nephrol, 2017.13(10): p.629-646. 2. Bonhaus, D.W., et al., The pharmacology and distribution of human 5-hydroxytryptamine2B (5-HT2B) receptor gene products: comparison with 5-HT2A and 5-HT2C receptors. Br J Pharmacol, 1995.115(4): p.622-8. 3. Cappelli, A., et al., Structure-affinity relationship studies on arylpiperazine derivatives related to quipazine as serotonin transporter ligands. Molecular basis of the selectivity SERT / 5HT3 receptor. Bioorg Med Chem, 2005.13(10): p.3455-60. 4. Corum, D.G., et al., PDE5 inhibition rescues mitochondrial dysfunction and angiogenic responses induced by Akt3 inhibition by promotion of PRC expression. J Biol Chem, 2020. 295(52): p.18091-18104. 5. Faizan, M., et al., The medicinal chemistry of piperazines: A review. Chem Biol Drug Des, 2024.103(6): p. e14537. - 66 -ATTORNEY DOCKET NO.220111-2270 6. Funk, J.A., S. Odejinmi, and R.G. Schnellmann, SRT1720 induces mitochondrial biogenesis and rescues mitochondrial function after oxidant injury in renal proximal tubule cells. J Pharmacol Exp Ther, 2010.333(2): p.593-601. 7. Harmon, J.L., et al., 5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists. J Pharmacol Exp Ther, 2016.357(1): p.1-9. 8. Hurtado, K., et al., Serotonin regulation of mitochondria in kidney diseases. Pharmacol Res, 2024.203: p.107154. 9. Hurtado, K.A., J. Janda, and R.G. Schnellmann, Lasmiditan promotes recovery from acute kidney injury through induction of mitochondrial biogenesis. Am J Physiol Renal Physiol, 2023. 324(1): p. F56-F63. 10. Janssen, W., et al., 5-HT2B receptor antagonists inhibit fibrosis and protect from RV heart failure. Biomed Res Int, 2015.2015: p.438403. 11. Lofdahl, A., et al., Pathological Insight into 5-HT(2B) Receptor Activation in Fibrosing Interstitial Lung Diseases. Int J Mol Sci, 2020.22(1). 12. Lynch, M.R., M.T. Tran, and S.M. Parikh, PGC1alpha in the kidney. Am J Physiol Renal Physiol, 2018.314(1): p. F1-F8. 13. Marshall, C.M., et al., An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013-2023). J Med Chem, 2024.67(14): p.11622- 11655. 14. Tan, Y., et al., Structural insights into the ligand binding and G(i) coupling of serotonin receptor 5-HT(5A). Cell Discov, 2022.8(1): p.50. - 67 -

Claims

ATTORNEY DOCKET NO.2220111-2270 CLAIMS What is claimed is:

1. A compound having Formula I or a pharmaceutically acceptable salt thereof: R3fR R3b3eRRO R3N413hdwherein each of R1a-R1eis independently selected from halogen, methyl, hydrogen, and methoxy; wherein R2is hydrogen or methyl; wherein each of R3a-R3his independently selected from hydrogen, deuterium, and methyl, or wherein R3his absent and R3sis carboxy; and wherein R4is selected from CD3, methyl, ethyl, oxetane, hydrogen, methanesulfonyl, isopropyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted aryl; .

2. The,a, R1c, and R1eare F and R1band R1dare H.

3. The compound or pharmaceutically acceptable salt of claim 1, wherein R2is H.

4. The compound or pharmaceutically acceptable salt of claim 1, wherein each of R3a-R3his H.

5. The compound or pharmaceutically acceptable salt of claim 1, wherein each of R3a-R3his D. 68ATTORNEY DOCKET NO.2220111-2270 6. The compound or pharmaceutically acceptable salt of claim 1, wherein R4is selected from . of claim 1, wherein the compound is, , , , ,69ATTORNEY DOCKET NO.2220111-2270 , , , , , ,70ATTORNEY DOCKET NO.2220111-2270 , and. , a 5- HT2B agonist.

9. The compound or pharmaceutically acceptable salt of claim 8, wherein the compound is selective for 5-HT2B over 5-HT2A, 5-HT2C, or both 5-HT2A and 5-HT2C.

10. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one of claims 1-9.

11. A method for treating or preventing at least one symptom of acute kidney injury in a subject, the method comprising administering a therapeutically effective amount of a compound selected from amitriptyline, amoxapine, clozapine, cabergoline, mirtazapine, SRT1720, MK212, BRL17752, or a compound of Formula I or pharmaceutically acceptable salt thereof to the subject R R3fR3b3eR43hdFormula I 71ATTORNEY DOCKET NO.2220111-2270 wherein each of R1a-R1eis independently selected from halogen, methyl, hydrogen, and methoxy; wherein R2is hydrogen or methyl; wherein each of R3a-R3his independently selected from hydrogen, deuterium, and methyl, or wherein R3his absent and R3sis carboxy; and wherein R4is selected from CD3, methyl, ethyl, oxetane, hydrogen, methanesulfonyl, isopropyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted aryl.

12. The method of claim 11, wherein R1a, R1c, and R1eare F and R1band R1dare H.

13. The method of claim 11, wherein R2is H.

14. The method of claim 11, wherein each of R3a-R3his H.

15. The method of claim 11, wherein each of R3a-R3his D. ,om: F O NH , , ,72ATTORNEY DOCKET NO.2220111-2270 , , , , ,, ,73ATTORNEY DOCKET NO.2220111-2270 , , , ,. , ses renal fibrosis, reduced vascular permeability, impairment of cellular respiration, reduced ATP levels, impairment of cellular homeostasis, impairment of mitochondrial homeostasis, reduced mitochondrial biogenesis, glomerular injury, or any combination thereof.

19. The method of claim 11, wherein the method decreases collagen production, wherein decreased collagen production results in a decrease in renal fibrosis.

20. A method for inducing mitochondrial biogenesis in a subject, the method comprising administering a therapeutically effective amount of a compound selected from amitriptyline, 74ATTORNEY DOCKET NO.2220111-2270 amoxapine, clozapine, cabergoline, mirtazapine, SRT1720, MK212, BRL17752, or a compound of Formula I or pharmaceutically acceptable salt thereof to the subject R3fR R3b3eRR NR41 O3a3hdwherein each of R1a-R1eis independently selected from halogen, methyl, hydrogen, and methoxy; wherein R2is hydrogen or methyl; wherein each of R3a-R3his independently selected from hydrogen, deuterium, and methyl, or wherein R3his absent and R3sis carboxy; and wherein R4is selected from CD3, methyl, ethyl, oxetane, hydrogen, methanesulfonyl, isopropyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted aryl.

21. The method of claim 20, wherein the compound is selected from: F O NH , , ,75ATTORNEY DOCKET NO.2220111-2270 , , , , ,, ,76ATTORNEY DOCKET NO.2220111-2270 , , , ,. , ing administering a therapeutically effective amount of a compound selected from amitriptyline, amoxapine, clozapine, cabergoline, mirtazapine, SRT1720, MK212, BRL17752, or a compound of Formula I or pharmaceutically acceptable salt thereof to the subject 77ATTORNEY DOCKET NO.2220111-2270 R R R3f 3b3eRO R3aNR41a3hdwherein each of R1a-R1eis independently selected from halogen, methyl, hydrogen, and methoxy; wherein R2is hydrogen or methyl; wherein each of R3a-R3his independently selected from hydrogen, deuterium, and methyl, or wherein R3his absent and R3sis carboxy; and wherein R4is selected from CD3, methyl, ethyl, oxetane, hydrogen, methanesulfonyl, isopropyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted aryl.

23. The method of claim 22, wherein the compound is selected from: F O NH , , ,78ATTORNEY DOCKET NO.2220111-2270 , , , , ,, ,79ATTORNEY DOCKET NO.2220111-2270 , , , ,. , rse transcriptase (TERT).

25. The method of claim 11, wherein the method increases expression of at least one gene involved in kidney repair after an injury.

26. The method of claim 25, wherein the at least one gene comprises ACSM2, LRP2, SCL5912, or HNF4A.

27. The method of any one of claims 11-26, wherein the subject is a mammal. 80ATTORNEY DOCKET NO.2220111-2270 28. The method of claim 27, wherein the mammal is a human, rat, mouse, hamster, guinea pig, rabbit, cat, dog, sheep, cattle, horse, goat, or non-human primate. 81

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