Liver receptor homolog 1 (LRH-1) modulators and uses

Abstract

Described herein are modulators of liver receptor homolog 1 (LRH-1), and methods for managing diseases and conditions associated therewith. In certain examples, the modulators described herein are derivatives of hexahydropentalene. In certain examples, the present disclosure relates to a method for treating or preventing diabetes, cancer, or cardiovascular disease by administering an effective amount of the hexahydropentalene derivatives disclosed herein to a subject in need thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 420,005, filed October 27, 2022, which is incorporated herein by reference in its entirety for all purposes.

[0002] STATEMENT OF FEDERALLY FUNDED RESEARCH This invention was made with government support under Grant No. DK115213 awarded by the National Institutes of Health. The United States Government has certain rights in this invention. [Background technology]

[0003] Liver receptor homolog 1 (LRH-1) is a nuclear hormone receptor (NR) that acts as a transcription factor to regulate gene expression. LRH-1 was previously identified as being involved in cholesterol homeostasis and early fetal development. The use of LRH-1 agonists for the treatment of diabetes was reported in Lee et al. Nature, 2011, 474, 506-510. The medium-chain dietary phospholipid dilauroyl-phosphatidylcholine (DLPC) was identified as an LRH-1 agonist. Diabetic mice fed DLPC showed improved glucose tolerance, reduced hepatic fat accumulation, and reduced levels of circulating insulin, triglycerides, and free fatty acids. The antidiabetic effects were associated with altered expression of a select subset of LRH-1 target genes involved in lipid metabolism. Importantly, DLPC-induced health and gene expression differences were absent in LRH-1 liver-specific conditional knockout mice, demonstrating that LRH-1 is directly involved in these effects. In addition to DLPC, LRH-1 binds to phosphatidylinositol 3,4,5-trisphosphate (PIP3), a key signaling lipid in diabetes. LRH-1 is also aberrantly overexpressed in certain cancers. It is thought to promote tumor growth via estrogen receptor and β-catenin signaling. See Nadolny et al. Liver receptor homolog-1 (LRH-1): a potential therapeutic target for cancer. Cancer Biol Ther, 2015, 16(7):997-1004. Whitby et al. report a small molecule agonist of LRH-1. J Med Chem 2006, 49(23):6652-5. See also Whitby et al., J Med Chem, 2011, 54, 2266-2281; Busby et al. Probe Reports from the NIH Molecular Libraries Program, 2010, 1:1-55; Benod et al. Antagonists of nuclear receptor LRH-1. J Biol Chem, 2013, 288:19830-44, U.S. Published Patent Application No. 2013 / 0210143, U.S. Published Patent Application No. 2008 / 0227864, and U.S. Published Patent Application No. 2004 / 0038862. Mays et al. report the crystal structure of LRH-1 bound to a synthetic agonist. J Biol Chem, 2016, 291(49):25281-25291. References cited herein are not admissions of prior art. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Published Patent Application No. 2013 / 0210143 [Patent Document 2] U.S. Published Patent Application No. 2008 / 0227864 [Patent Document 3] U.S. Published Patent Application No. 2004 / 0038862 [Non-patent literature]

[0005] [Non-Patent Document 1] Lee et al.Nature,2011,474,506-510 [Non-patent document 2] Nadolny et al.Liver receptor homolog-1(LRH-1): a potential therapeutic target for cancer.Cancer Biol Ther,2015,16(7):997-1004 [Non-patent document 3] Whitby et al. J Med Chem 2006,49(23):6652-5 [Non-patent document 4] Whitby et al.,J Med Chem,2011,54,2266-2281 [Non-Patent Document 5] Busby et al.Probe Reports from the NIH Molecular Libraries Program,2010,1:1-55 [Non-patent document 6] Benod et al.Antagonists of nuclear receptor LRH-1.J Biol Chem,2013,288:19830-44 [Non-Patent Document 7] Mays et al. J Biol Chem,2016,291(49):25281-25291 Summary of the Invention [Means for solving the problem]

[0006] Described herein are modulators of liver receptor homolog 1 (LRH-1), and methods for managing diseases and conditions associated therewith. In certain examples, the modulators described herein are derivatives of hexahydropentalene. In certain examples, the present disclosure relates to a method for treating or preventing diabetes, cancer, or cardiovascular disease by administering an effective amount of the hexahydropentalene derivatives disclosed herein to a subject in need thereof. A compound having the formula: [ka] or a prodrug, salt, or stereoisomer thereof, wherein n is 1 to 6; p is 1 to 6; R 1 is alkyl, halogen, nitro, cyano, hydroxy, amino, sulfamoylamino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 1 is one or more of the same or different R 10 Optionally replaced by R 2 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 2 is one or more of the same or different R 10 Optionally replaced by R 3is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 3 is one or more of the same or different R 10 Optionally replaced by R 4 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 4 is one or more of the same or different R 10 Optionally replaced by R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 5 is one or more of the same or different R 10 Optionally replaced by R 6 is hydrogen, carboxy, or alkyl, and R 6 is optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 Optionally further substituted by R 7is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 7 is one or more of the same or different R 10 optionally replaced by R 1 and R 7 together are oxo or oxime, and an oxime is one or more of the same or different R 10 Optionally replaced by R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 10 is one or more of the same or different R 11 Optionally replaced by R 11is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl yl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl are described herein.

[0007] A compound having the formula: [ka] or a prodrug, salt, or stereoisomer thereof, wherein n is 1 to 6; p is 1 to 6; q is 1 to 6; R 1 is alkyl, halogen, nitro, cyano, hydroxy, amino, sulfamoylamino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 1 is one or more of the same or different R 10 Optionally replaced by R 2is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 2 is one or more of the same or different R 10 Optionally replaced by R 3 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 3 is one or more of the same or different R 10 Optionally replaced by R 4 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 4 is one or more of the same or different R 10 Optionally replaced by R 5is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 5 is one or more of the same or different R 10 Optionally replaced by R 6 is hydrogen, carboxy, or alkyl, and R 6 is optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 Optionally further substituted by R 7 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 7 is one or more of the same or different R 10 optionally replaced by R 1 and R 7 together are oxo or oxime, and an oxime is one or more of the same or different R 10 Optionally replaced by R 10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 10 is one or more of the same or different R 11 Optionally replaced by R 11 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl yl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

[0008] In some cases, the compound is 5-(4-(3-phenyl-3a-(1-phenylvinyl)-6-(sulfamoylamino)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)butoxy)pentanoic acid or a salt thereof. In some cases, the compound is 3-(3-(2-(3-phenyl-3a-(1-phenylvinyl)-6-(sulfamoylamino)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)ethoxy)propoxy)propanoic acid or a salt thereof.

[0009] A compound according to the following structure: [ka] or prodrugs or salts thereof are additionally described herein.

[0010] In certain instances, the present disclosure contemplates a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In certain instances, the pharmaceutical product may be in the form of a tablet, pill, capsule, gel, granules, or aqueous buffer solution.

[0011] Further described herein is a method for treating or preventing cancer, comprising administering an effective amount of the pharmaceutical composition described herein to a subject in need thereof. Optionally, the cancer is selected from the group consisting of bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, and thyroid cancer.

[0012] Also described herein are methods for treating or preventing diabetes, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition described herein. Optionally, the diabetes is insulin-dependent diabetes, non-insulin-dependent diabetes, or gestational diabetes.

[0013] Further described herein are methods for treating or preventing cardiovascular disease, inflammatory bowel disease (IBD), and / or colitis or ulcerative colitis, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition described herein.

[0014] The details of one or more examples are set forth in the drawings and description below. Other features, objects, and advantages will be apparent from the description and drawings, and from the claims. [Brief explanation of the drawings]

[0015] [Figure 1-1] 1 presents data on the pharmacokinetics, solubility, permeability, and metabolic stability of compounds disclosed herein. [Figure 1-2] 1 presents data on the pharmacokinetics, solubility, permeability, and metabolic stability of compounds disclosed herein. [Figure 2-1] Figure 1 shows target gene expression driven by 6N-10CA-ME. (A) Volcano plot showing RNA-seq of H-mLRH-1 mice treated with 3 mg / kg of 6N-10CA-ME via intraperitoneal administration. (B) Volcano plot showing RNA-seq of H-mLRH-1 mice treated with 30 mg / kg of 6N-10CA-ME via intraperitoneal administration. [Figure 2-2] Figure 1 shows target gene expression driven by 6N-10CA-ME.C is RT-qPCR showing target gene expression at doses of 3 and 30 mg / kg. [Figure 2-3] Figure 1 shows target gene expression driven by 6N-10CA-ME.C is RT-qPCR showing target gene expression at doses of 3 and 30 mg / kg. [Figure 3] We demonstrate that 6N-10CA-ME exhibits minimal cross-reactivity with other nuclear receptors (NRs). 6N-10CA-ME was introduced into reporter cells at 2 μM, and the activity of each NR was tested. Data were normalized to the activity induced by the appropriate reference agonist for each receptor. [Figure 4-1]Figure 1 shows that 6N-10CA-ME reduces glucose intolerance in the setting of diet-induced obesity. Male and female mice were treated with 6N-10CA-ME via intraperitoneal administration starting with 12 weeks of high-fat diet (HFD; 60% fat) feeding, and daily HFD feeding continued until 16 weeks. (Panel A) Summary of body weights of mice in each group at 0, 12, and 16 weeks of HFD feeding. (Panel B) Fasting blood glucose (mg / dL) levels of mice in each group at 12 and 16 weeks of HFD feeding. [Figure 4-2] Figure 1 shows that 6N-10CA-ME reduces glucose intolerance in the setting of diet-induced obesity. Male and female mice were treated with 6N-10CA-ME via intraperitoneal administration starting with 12 weeks of high-fat diet (HFD; 60% fat) feeding, and daily HFD feeding continued until 16 weeks. (Panel C) Fasting blood glucose (mg / dL) levels of mice in each group at 12 and 16 weeks of HFD feeding. (Panel D) Glucose tolerance test (GTT) following administration of glucose (2 g / kg) at 12 and 16 weeks of HFD feeding. (Panel E) Summary of the area under the curve (AUC) of GTT at 12 and 16 weeks of HFD feeding. Data are presented as mean ± standard error. Sample sizes ranged from 6 to 17 per group. **** indicates p<0.0001 versus chow. Data were analyzed by two-way ANOVA with Tukey's multiple comparison test. DETAILED DESCRIPTION OF THE INVENTION

[0016] Described herein are modulators of liver receptor homolog 1 (LRH-1) and methods for their use in managing diseases and conditions related thereto. In certain examples, the modulators described herein are derivatives of hexahydropentalene. The present disclosure also describes methods for treating and / or preventing diabetes, cancer, or cardiovascular disease by administering an effective amount of the hexahydropentalene derivatives disclosed herein to a subject in need thereof.

[0017] Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the claims.

[0018] I. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of this disclosure, the preferred methods and materials are now described.

[0019] All publications and patents cited herein are incorporated by reference as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

[0020] As will be apparent to one of ordinary skill in the art upon reading this disclosure, each individual embodiment described and illustrated herein has discrete components and features that may be readily separated from or combined with the features of any of the other embodiments without departing from the scope or spirit of the disclosure. Any recited method may be carried out in the order of events recited or in any other order that is logically possible.

[0021] Examples of the present disclosure employ, unless otherwise indicated, techniques of pharmaceutical, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of those in the art. Such techniques are explained fully in the literature.

[0022] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this specification and the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings unless a contrary intention is apparent.

[0023] Certain of the compounds described herein may contain one or more asymmetric centers and may give rise to enantiomers, diastereomers, and other stereoisomers that can be defined in terms of the absolute stereochemistry at each asymmetric atom as (R)- or (S)-. The chemical entities, pharmaceutical compositions, and methods of the invention are meant to encompass all such possible isomers, including racemic mixtures, tautomers, hydrated forms, optically substantially pure forms, and intermediate mixtures.

[0024] Unless otherwise stated, structures depicted herein are meant to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure may also include compounds having the present structure, such as compounds having the present structure, that differ only in the presence of one or more isotopically enriched atoms, such as ... 13 C or 14Except for the replacement or enrichment of carbon with C, it is within the scope of the present disclosure. In one example, isotopically labeled compounds are provided herein having one or more hydrogen atoms replaced or enriched with deuterium. In one example, isotopically labeled compounds are provided herein having one or more hydrogen atoms replaced or enriched with tritium. In one example, 13 Replaced by C or 13 Provided herein are isotopically labeled compounds having one or more carbon atoms enriched with C. In one example, 14 Replaced by C or 14 Provided herein are isotopically labeled compounds having one or more C-enriched carbon atoms.

[0025] The present disclosure also encompasses isotopically labeled compounds that are identical to those enumerated herein except 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 normally found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine (e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Certain isotopically labeled compounds (e.g., 3 H and / or 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C isotopes may allow for ease of preparation and detectability. Additionally, heavier isotopes (deuterium (i.e.2 Substitution with an isotopic group such as H) may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. In some instances, compounds are also provided herein that may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. All isotopic variations of the compounds disclosed herein, whether radioactive or non-radioactive, are intended to be encompassed within the scope of the present disclosure.

[0026] "Linking group" refers to any of a variety of molecular configurations that can be used to bridge molecular moieties together. An exemplary formula is -R m -, wherein R may be, individually and independently at each occurrence, -CR m R m -, -CHR m -, -CH-, -C-, -CH2-, -C(OH)R m , -C(OH)(OH)-, -C(OH)H, -C(Hal)R m -, -C(Hal)(Hal)-, -C(Hal)H-, -C(N3)R m -, -C(CN)R m -, -C(CN)(CN)-, -C(CN)H-, -C(N3)(N3)-, -C(N3)H-, -O-, -S-, -N-, -NH-, -NR m R is selected from -, -(C=O)-, -(C=NH)-, -(C=S)-, -(C=CH)-, which may individually and independently contain a single bond, a double bond, or a triple bond between the R groups. mIf branched by, R can terminate in a group such as -CH, -H, -CH=CH, -CCH, -OH, -SH, -NH, -N, -CN, or -Hal, or two branched Rs can form a cyclic structure. In certain instances, it is contemplated that the total R or "m" can be less than 100, 50, 25, 10, 5, 4, or 3. Examples of linking groups include bridging alkyl groups, alkoxyalkyl groups, and polyethylene glycol.

[0027] As used herein, a "lipid" group refers to a naturally occurring or non-naturally occurring hydrophobic group that is highly insoluble in water. As used herein, the attachment points on the lipid are replaced with hydrogens, and the resulting compound has a solubility of 3×10 in water. -3 Solubility (at 25°C) of less than w / w (e.g., 9.5 x 10 -4 A lipid group is considered highly insoluble in water if it has a percent solubility of hexane in water (at 25°C) by weight in % w / w. See page 193 of Solvent Recovery Handbook, 2nd Ed, Smallwood, 2002 by Blackwell Science. Examples of naturally occurring lipids include saturated or unsaturated hydrocarbon chains found in fatty acids, glycerolipids, cholesterol, steroids, polyketides, and derivatives. Non-naturally occurring lipids include derivatives of naturally occurring lipids, acrylic polymers, and alkylated compounds and their derivatives.

[0028] As used herein, "alkyl" means an acyclic, straight-chain or branched, unsaturated or saturated hydrocarbon (such as one containing 1 to 22 carbon atoms), while "lower alkyl" or "C 1-4The term "alkyl" has the same meaning as alkyl but contains 1 to 4 carbon atoms. The term "higher alkyl" has the same meaning as alkyl but contains 18 to 22 carbon atoms. Representative saturated straight-chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-septyl, n-octyl, n-nonyl, and the like, while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as "alkenyl" or "alkynyl," respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like, while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, and the like.

[0029] Non-aromatic monocyclic or polycyclic alkyls are referred to herein as "carbocycle" or "carbocyclyl" groups. Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, while unsaturated carbocycles include cyclopentenyl and cyclohexenyl, and the like.

[0030] A "heterocarbocycle" or "heterocarbocyclyl" group is a carbon ring containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be saturated or unsaturated (but not aromatic), monocyclic, or polycyclic, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Heterocarbocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0031] "Aryl" means an aromatic carbocyclic monocyclic or polycyclic ring (such as phenyl or naphthyl). Polycyclic ring systems can, but are not required to, contain one or more non-aromatic rings, so long as one of the rings is aromatic. "Arylalkyl" means an alkyl substituted with an aryl (e.g., benzyl, methyl substituted with phenyl).

[0032] As used herein, "heteroaryl" refers to an aromatic heterocarbocycle having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, containing at least one carbon atom, and including both monocyclic and polycyclic ring systems. Polycyclic ring systems may, but are not required to, contain one or more non-aromatic rings, so long as one of the rings is aromatic. Representative heteroaryls include furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. Use of the term "heteroaryl" is intended to include N-alkylated derivatives, such as a 1-methylimidazol-5-yl substituent.

[0033] As used herein, "heterocycle" or "heterocyclyl" refers to monocyclic and polycyclic ring systems containing at least one carbon atom and having one to four heteroatoms selected from nitrogen, oxygen, and sulfur. The monocyclic and polycyclic ring systems can be aromatic, non-aromatic, or mixtures of aromatic and non-aromatic rings. Heterocycles include heterocarbocycles, heteroaryls, and the like.

[0034] "Alkylthio" refers to an alkyl group as defined above attached through a sulfur bridge. An example of an alkylthio is methylthio (i.e., -S-CH3).

[0035] "Alkoxy" refers to an alkyl group as defined above attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, and t-butoxy.

[0036] "Alkylamino" refers to an alkyl group as defined above attached through an amino bridge. An example of an alkylamino is methylamino (i.e., -NH-CH3).

[0037] "Alkanoyl" refers to an alkyl as defined above attached through a carbonyl bridge (ie, --(C.dbd.O)alkyl).

[0038] "Alkylsulfonyl" refers to an alkyl as defined above attached through a sulfonyl bridge (i.e., -S(=O)2 alkyl), such as mesyl and the like, and "arylsulfonyl, sulfamoyl" refers to an aryl attached through a sulfonyl bridge (i.e., -S(=O)2 aryl).

[0039] "Aminosulfonyl" or "sulfamoyl" refers to an amino attached through a sulfonyl bridge (ie, -S(=O)2NH2).

[0040] "Sulfamoylamino" refers to a sulfamoyl attached through an amino bridge (i.e., -NH-S(=O)2NH2).

[0041] "Alkylsulfinyl" refers to an alkyl as defined above attached through a sulfinyl bridge (ie, --S(.dbd.O)alkyl).

[0042] "Aminoalkyl" refers to an amino group attached through an alkyl bridge. An example of an aminoalkyl is aminomethyl (i.e., NH2-CH2-).

[0043] "Hydroxyalkyl" refers to a hydroxy group attached through an alkyl bridge. An example of a hydroxyalkyl is hydroxyethyl (i.e., HO-CH2CH2-).

[0044] "Hal" refers to halogen such as F, Br, Cl, or I.

[0045] The term "substituted" refers to a molecule in which at least one hydrogen atom has been replaced by a substituent. When substituted, one or more of the groups is a "substituent." A molecule can be multiply substituted. In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced. Exemplary substituents in this context include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NR a R b , -NR a C(=O)R b , -NR a C(=O)NR a NR b , -NR a C(=O)OR b , -NR a SO2R b , -C(=O)R a , -C(=O)OR a , -C(=O)NR a R b , -OC(=O)NR a R b , -OR a , -SR a , -SOR a , -S(=O)2R a , -OS(=O)2R a , and -S(=O)2OR a In this context, R a and R bcan be the same or different and independently be hydrogen, halogen, hydroxy, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl.

[0046] The term "optionally substituted," as used herein, means that the substitution is optional; thus, the specified atom can be unsubstituted.

[0047] As used herein, "salt" refers to a derivative of the disclosed compounds in which the parent compound is modified to produce its acid salt or base salt. Examples of salts include, but are not limited to, mineral salts (such as sodium, potassium, or zinc carboxylates), or organic acid salts of basic residues (such as amines, alkylamines, or dialkylamines); alkali or organic salts of acidic residues (such as carboxylic acids); and the like. Typically, the salts are conventional non-toxic pharmaceutically acceptable salts, including quaternary ammonium salts of the parent compound formed with non-toxic inorganic or organic acids. Preferred salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane, disulfonic acid, oxalic acid, isethionic acid, and the like.

[0048] "Subject" refers to any animal, preferably a human patient, livestock, rodent, monkey, or household pet.

[0049] As used herein, the term "derivative" refers to a structurally similar compound that retains the full functional attributes of the identified analog. A derivative may be structurally similar because it lacks one or more atoms, is substituted with one or more substituents, is a salt, has a different hydration / oxidation state (e.g., replacing a single or double bond, replacing a hydroxyl group with a ketone), or has one or more atoms in the molecule switched (such as, but not limited to, replacing an oxygen atom with a sulfur or nitrogen atom, or replacing an amino group with a hydroxyl group, or vice versa). Replacing a carbon in an aromatic ring with nitrogen is a contemplated derivative. A derivative may be a prodrug. Derivatives can be prepared by any of a variety of synthetic methods or suitable modifications presented in the chemical literature, or as in synthetic or organic chemistry textbooks (such as those provided in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition (2007) Michael B. Smith or Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F. Tietze, which are incorporated herein by reference).

[0050] The term "prodrug" refers to a drug that is converted into a biologically active form in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. Prodrugs may be bioavailable, for example, by oral administration, while the parent compound is not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. Typical prodrugs are pharmaceutically acceptable esters or enol ethers. Prodrugs include compounds in which a hydroxy, amino, or sulfhydryl group of an active compound is cleaved to form a free hydroxy, amino, or sulfhydryl group, respectively, when the prodrug is administered to a subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohols in the active compound, or acetamide, formamide, and benzamide derivatives of amine functional groups, and the like.

[0051] For example, if a disclosed compound or a pharmaceutically acceptable form of the compound contains a carboxylic acid functional group, a prodrug can be prepared by replacing the hydrogen atom of the acidic group with a (C1-C4) alkyl, (C1-C8) alkyl, (C2-C 12) alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethoxy having 4 to 10 carbon atoms These may include pharmaceutically acceptable esters formed by replacing the alkyl group with groups such as methyl, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolactone-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl, and piperidino(C2-C3)alkyl, pyrrolidino(C2-C3)alkyl, or morpholino(C2-C3)alkyl.

[0052] If the disclosed compounds or pharmaceutically acceptable forms of the compounds contain an alcohol functional group, the prodrugs may be prepared by replacing the hydrogen atom of the alcohol group with a methyl group such as (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, -N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkano ... and α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids P(O)(OH), —P(O)(O(C-C)alkyl), and glycosyl (the radical resulting from removal of the hydroxy group of the hemiacetal form of a carbohydrate).

[0053] If the disclosed compounds or pharmaceutically acceptable forms of the compounds incorporate an amine functional group, prodrugs can be prepared by replacing a hydrogen atom in the amine group with an R-carbonyl, RO-carbonyl, NRR′-carbonyl, where R and R′ are each independently (C1-C- 10 )alkyl, (C-C)cycloalkyl, benzyl, natural α-aminoacyl], —C(OH)C(O)OY1 [where Y1 is H, (C-C)alkyl, or benzyl], —C(OY2)Y3 [where Y2 is (C-C4)alkyl and Y3 is (C-C6)alkyl, carboxy(C-C6)alkyl, amino(C-C4)alkyl, or mono-N or di-N,N-(C-C6)alkylaminoalkyl], —C(Y4)Y5 [where Y4 is H or methyl and Y5 is mono-N- or di-N,N-(C-C6)alkylamino], morpholino, piperidin-1-yl, or pyrrolidin-1-yl.

[0054] As used herein, "pharmaceutically acceptable esters" include, but are not limited to, alkyl esters, alkenyl esters, alkynyl esters, aryl esters, arylalkyl esters, and cycloalkyl esters of acidic groups (including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids, and boronic acids).

[0055] As used herein, "pharmaceutically acceptable enol ethers" include, but are not limited to, derivatives of the formula -C=C(OR), where R may be selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of the formula -C=C(OC(O)R), where R may be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl.

[0056] "Cancer" refers to any of a variety of cellular diseases caused by malignant neoplasms characterized by cell proliferation. It is not intended that diseased cells must actually invade surrounding tissues and metastasize to new body sites. Cancer can affect any tissue in the body and can have many different forms in each body region. Within the context of a particular example, whether "cancer is reduced" can be identified by various diagnostic modalities known to those skilled in the art, including, but not limited to, observing a decrease in the size or number of tumor masses or observing an increase in cancer cell apoptosis (e.g., observing a greater than 5% increase in cancer cell apoptosis for a sample compound compared to a control without the compound). This can also be identified by changes in relevant biomarkers or gene expression profiles (such as PSA for prostate cancer, HER2 for breast cancer, or others).

[0057] "Chemotherapeutic agent," "chemotherapy," "anti-cancer agent," or the like, refers to a molecule recognized to aid in the treatment of cancer.Contemplated examples include the following: temozolomide, carmustine, bevacizumab, procarbazine, lomustine, vincristine, gefitinib, erlotinib, cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, gemcitabine, tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin C, dactinomycin, mithramycin, vinblastine, bile acid, riboflavin ... Indesine, vinorelbine, paclitaxel, taxol, docetaxel, etoposide, teniposide, amsacrine, topotecan, camptothecin, bortezomib, anagrelide, tamoxifen, toremifene, raloxifene, droloxifene, idoxifene, fulvestrant, bicalutamide, flutamide, nilutamide, cyproterone, goserelin, leuprorelin, buserelin, megestrol, anastrozole, letrozole, vorozole, exemestane, finasteride, marimastat, trastuzumab, cetaxel Molecules or derivatives such as cimab, dasatinib, imatinib, combretastatin, thalidomide, azacitidine, azathioprine, capecitabine, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, doxifluridine, epothilone, irinotecan, mechlorethamine, mercaptopurine, mitoxantrone, thioguanine, valrubicin, and / or lenalidomide, or combinations thereof [cyclophosphamide, methotrexate, 5-fluorouracil (CMF); doxorubicin, cyclophosphamide (AC); These include: mustine, vincristine, procarbazine, prednisolone (MOPP); adriamycin, bleomycin, vinblastine, dacarbazine (ABVD); cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP); bleomycin, etoposide, cisplatin (BEP); epirubicin, cisplatin, 5-fluorouracil (ECF); epirubicin, cisplatin, capecitabine (ECX); methotrexate, vincristine, doxorubicin, cisplatin (MVAC), etc.

[0058] As used herein, the terms "prevent" and "prevention" include prevention of recurrence, spread, or onset. It is not intended that the present disclosure be limited to complete prevention. In some instances, onset is delayed or the severity of the disease is reduced.

[0059] As used herein, the terms "treat" and "treatment" are not limited to cases in which a subject (e.g., a patient) is cured and the disease is eradicated. Rather, examples of the present disclosure also contemplate treatment that merely reduces symptoms and / or slows disease progression.

[0060] As used herein, the term "in combination with," when used to describe administration with an additional therapy, means that the agent can be administered before, along with, or after the additional therapy, or a combination thereof.

[0061] Further explanations of the above-listed terms are provided below.

[0062] II. Hexahydropentalene Derivatives In certain instances, the present disclosure relates to compounds that are hexahydropentalene derivatives, which are any of the compounds disclosed herein optionally substituted with one or more substituents.

[0063] One class of compounds described herein has Formula I: [ka] and includes prodrugs, salts, and stereoisomers thereof.

[0064] In formula I, n is 1 to 6. For example, n can be 2 to 4.

[0065] Also in formula I, p is 1 to 6. For example, p can be 2 to 4.

[0066] Additionally, in Formula I, R 1 is alkyl, halogen, nitro, cyano, hydroxy, amino, sulfamoylamino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl. 1 is one or more of the same or different R 10 may be substituted by (as described below).

[0067] Further in Formula I, R 2 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl. 2 is one or more of the same or different R 10 may be replaced by

[0068] Also in formula I, R 3 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl. 3 is one or more of the same or different R 10may be replaced by

[0069] Additionally, in Formula I, R 4 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl. 4 is one or more of the same or different R 10 may be replaced by

[0070] Further in Formula I, R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl. 5 is one or more of the same or different R 10 may be replaced by

[0071] Also in formula I, R 6 is hydrogen, carboxy, or alkyl. In some examples, R 6 is optionally terminally substituted with hydroxy, carboxy, or phosphate. In some examples, R 6 is optionally substituted with hydroxy, carboxy, or phosphate. Optionally, the hydroxy, carboxy, or phosphate is substituted with R 10 is further substituted by

[0072] Additionally, in Formula I, R 7is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl. 7 is one or more of the same or different R 10 is replaced by

[0073] In some instances of Formula I, R 1 and R 7 together form an oxo or oxime. An oxime is a group consisting of one or more of the same or different R 10 may optionally be replaced by

[0074] In Formula I, R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl. 10 Optionally, R can be aminosulfonyl. 10 is one or more of the same or different R 11 may optionally be replaced by

[0075] Also in formula I, R 11is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

[0076] In some examples of Formula I, n is 2, 3, or 4; and p is 2, 3, or 4. In some examples, n is 2; and p is 2, 3, or 4. In some examples, n is 3; and p is 2, 3, or 4. In some examples, n is 4; and p is 2, 3, or 4. In some examples, n is 2; and p is 2. In some examples, n is 3; and p is 3. In some examples, n is 4; and p is 4. In some examples, n is 2; and p is 3. In some examples, n is 2; and p is 4. In some examples, n is 3; and p is 2. In some examples, n is 3; and p is 4. In some examples, n is 4; and p is 2. In some examples, n is 4; and p is 3.

[0077] In some examples of Formula I, R 1is hydroxy or sulfamoylamino. In some examples, R 7 is hydrogen. In some instances, R 7 is hydrogen and R 1 is hydroxy, sulfamoylamino, or sulfamic acid. In some examples, R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 7 is hydrogen. In some instances, R 6 is alkyl terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 In some examples, R 1 is hydroxy, alkyl, amino, sulfamoylamino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 Optionally replaced by R 7 is hydrogen.

[0078] Optionally, the compound of formula I has the structure IA, as shown below: [ka] and includes prodrugs, salts, and stereoisomers thereof.

[0079] In structure IA, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , and R 11 is as defined above for Formula I.

[0080] Also in structure IA, R 6is hydrogen, carboxy, or alkyl, and R 6 is optionally substituted with alkyl, hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 is optionally further replaced by

[0081] In addition, in structure IA, R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 10 is one or more of the same or different R 11 (as defined in formula I).

[0082] In some examples of Structure IA, n is 2, 3, or 4; p is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 2; R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 4; and R 1is hydroxy or sulfamoylamino. In some examples, n is 2; p is 2; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 4; and R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 2; 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 4; and R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 2; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 3; and R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 4; and R 1 is hydroxy or sulfamoylamino. In some examples, R 7 is hydrogen. In some instances, R 7 is hydrogen and R 1 is hydroxy, sulfamoylamino, or sulfamic acid. In some examples, R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 7 is hydrogen. In some instances, R1 is hydroxy, alkyl, amino, sulfamoylamino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 Optionally replaced by R 7 is hydrogen.

[0083] Optionally, the compound of formula I has structure IB, as shown below: [ka] and includes prodrugs, salts, and stereoisomers thereof.

[0084] In structure IB, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , and R 11 is as defined above for formula I. Also in structure IB:

[0085] R 6 is hydrogen or alkyl, and R 6 is optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 is optionally further replaced by

[0086] Additionally, in structure IB, R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 10is one or more of the same or different R 11 (as defined in formula I).

[0087] In some examples of structure IB, n is 2, 3, or 4; p is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 2; R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 4; and R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 4; and R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 2; 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 4; and R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 2; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 3; and R 1is hydroxy or sulfamoylamino. In some examples, n is 4; p is 4; and R 1 is hydroxy or sulfamoylamino. In some examples, R 7 is hydrogen. In some instances, R 7 is hydrogen and R 1 is hydroxy, sulfamoylamino, or sulfamic acid. In some examples, R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 7 is hydrogen. In some instances, R 6 is hydrogen. In some instances, R 6 is alkyl, methyl, or ethyl. In some examples, R 6 is alkyl optionally substituted with hydroxy, carboxy, or phosphate, and hydroxy, carboxy, or phosphate is R 10 In some examples, R 1 is hydroxy, alkyl, amino, sulfamoylamino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 Optionally replaced by R 7 is hydrogen.

[0088] In some examples of structure IB, n is 2, 3, or 4; p is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7is hydrogen. In some examples, n is 2; p is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 3; p is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 2; p is 2; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 3; p is 3; R 1is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 2; p is 3; and R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 2; p is 4; and R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 3; p is 2; and R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 3; p is 4; and R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 2; and R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 3; and R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen.

[0089] Optionally, the compound of formula I has the structure IC, as shown below: [ka] and includes prodrugs, salts, and stereoisomers thereof.

[0090] In the structure IC, n, p, R 2 , R 3 , R 4 , R 5 , and R 11 is as defined above for Formula I. Also in structure IC, X is a linking group -CH-, -C(OH)(OH)-, -C(OH)H, -C(Hal)(Hal)-, -C(Hal)H-, -O-, -S-, -(S=O)-, -SO-, -NH-, -(C=O)-, -(C=NH)-, or -(C=S)-.

[0091] In addition, in the structure IC, R 1 is hydrogen, hydroxy, alkyl, alkanoyl, amino, aminoalkyl, sulfamoylamino, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl.

[0092] Optionally, in the structure IC, X and R 1 is as follows: a) X is O and R 1 is alkanoyl; b) X is -NH- and R 1 is alkanoyl; c) X is O and R 1 is aminosulfonyl; d) X is —NH— and R 1 is aminosulfonyl; or e) X is —(C═O)— and R 1 is an amino.

[0093] Furthermore, in the structure IC, R6 is hydrogen or alkyl, and R 6 is optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 is optionally further replaced by

[0094] In addition, in the structure IC, R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 10 is one or more of the same or different R 11 (as defined in formula I).

[0095] In some examples of structure IC, n is 2, 3, or 4; p is 2, 3, or 4. In some examples, n is 2; p is 2, 3, or 4. In some examples, n is 3; p is 2, 3, or 4. In some examples, n is 4; p is 2, 3, or 4. In some examples, n is 2; p is 2. In some examples, n is 3; p is 3. In some examples, n is 4; p is 4. In some examples, n is 2; p is 3. In some examples, n is 2; p is 4. In some examples, n is 3; p is 2. In some examples, n is 3; p is 4. In some examples, n is 4; p is 2. In some examples, n is 4; p is 3.

[0096] In some examples of structural ICs, R 6is hydrogen. In some instances, R 6 is alkyl, methyl, or ethyl. In some examples, R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl. In some examples, R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen. In some instances, R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is alkyl, methyl, or ethyl. In some examples, R 6 is hydrogen or alkyl optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 In some examples, R 1 is hydroxy or sulfamoylamino, and R 1 is R 10 optionally replaced by R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen. In some instances, R 1 is hydroxy or sulfamoylamino, and R 1 is R 10 optionally replaced by R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R6 is alkyl, methyl, or ethyl. In some examples, R 1 is hydrogen, hydroxy, alkyl, amino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 In some examples, R 1 is hydrogen, hydroxy, alkyl, amino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 optionally replaced by R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen. In some instances, R 1 is hydrogen, hydroxy, alkyl, amino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 optionally replaced by R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is alkyl, methyl, or ethyl.

[0097] Optionally, the compound of Formula I has the structure ID: [ka] and includes prodrugs, salts, and stereoisomers thereof.

[0098] In the structure ID, n, p, R 2 , R3 , R 4 , R 5 , and R 11 is as defined above for Formula I.

[0099] Also in Structure ID, X is a linking group: -CH2-, -C(OH)(OH)-, -C(OH)H, -C(Hal)(Hal)-, -C(Hal)H-, -O-, -S-, -(S=O)-, -SO2-, -NH-, -(C=O)-, -(C=NH)-, or -(C=S)-.

[0100] Further in Structure ID, Y is -CH2-, -C(OH)(OH)-, -C(OH)H, -C(Hal)(Hal)-, -C(Hal)H-, -O-, -S-, -(S=O)-, -SO2-, -NH-, -(C=O)-, -(C=NH)-, or -(C=S)-.

[0101] In addition, in the structure ID, R 1 is hydrogen, hydroxy, alkyl, alkanoyl, amino, aminoalkyl, sulfamoylamino, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl.

[0102] Optionally, in the structure ID, X, Y, and R 1 is as follows: a) X is O and R 1 is alkanoyl; b) X is -NH- and R 1 is alkanoyl; c) X is O and R 1 is aminosulfonyl; d) X is —NH— and R 1 is aminosulfonyl; e) X is —(C═O)— and R 1 is amino; or f) X is O, Y is —(C═O)—, and R 1 is an amino.

[0103] Furthermore, in the structure ID, R 6 is hydrogen or alkyl, and R6 is optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 is optionally further replaced by

[0104] In addition, in the structure ID, R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 10 is one or more of the same or different R 11 (as defined in formula I).

[0105] In some examples of structure IDs, n is 2, 3, or 4; p is 2, 3, or 4. In some examples, n is 2; p is 2, 3, or 4. In some examples, n is 3; p is 2, 3, or 4. In some examples, n is 4; p is 2, 3, or 4. In some examples, n is 2; p is 2. In some examples, n is 3; p is 3. In some examples, n is 4; p is 4. In some examples, n is 2; p is 3. In some examples, n is 2; p is 4. In some examples, n is 3; p is 2. In some examples, n is 3; p is 4. In some examples, n is 4; p is 2. In some examples, n is 4; p is 3.

[0106] In some examples of structure IDs, R 6 is hydrogen. In some instances, R 6is alkyl, methyl, or ethyl. In some examples, R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl. In some examples, R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen. In some instances, R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is alkyl, methyl, or ethyl. In some examples, R 6 is hydrogen or alkyl optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 In some examples, R 1 is hydroxy or sulfamoylamino, and R 1 is R 10 optionally replaced by R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen. In some instances, R 1 is hydroxy or sulfamoylamino, and R 1 is R 10 optionally replaced by R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is alkyl, methyl, or ethyl. In some examples, R 1 is hydrogen, hydroxy, alkyl, amino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 In some examples, R 1 is hydrogen, hydroxy, alkyl, amino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 optionally replaced by R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen. In some instances, R 1 is hydrogen, hydroxy, alkyl, amino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 optionally replaced by R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is alkyl, methyl, or ethyl.

[0107] Optionally, the compound of formula I has the structure IE, as shown below: [ka] and includes prodrugs, salts, and stereoisomers thereof.

[0108] In the structure IE, n, p, R 2 , R 3 , R4 , R 5 , and R 11 is as defined above for Formula I.

[0109] Also, in the structure IE, R 1 is hydrogen, alkyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 1 is one or more of the same or different R 10 is optionally replaced by

[0110] In addition, in the structure IE, R 6 is a lipid or alkyl, and R 6 is optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 is optionally further replaced by

[0111] Furthermore, in the structure IE, R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 10 is one or more of the same or different R 11 is optionally replaced by

[0112] In some examples of Structure IE, n is 2, 3, or 4; and p is 2, 3, or 4. In some examples, n is 2; and p is 2, 3, or 4. In some examples, n is 3; and p is 2, 3, or 4. In some examples, n is 4; and p is 2, 3, or 4. In some examples, n is 2; and p is 2. In some examples, n is 3; and p is 3. In some examples, n is 4; and p is 4. In some examples, n is 2; and p is 3. In some examples, n is 2; and p is 4. In some examples, n is 3; and p is 2. In some examples, n is 3; and p is 4. In some examples, n is 4; and p is 2. In some examples, n is 4; and p is 3.

[0113] In some examples of Structure IE, n is 2, 3, or 4; p is 2, 3, or 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0114] Optionally, the compound of formula I has the structure IF, as shown below: [ka] and includes prodrugs, salts, and stereoisomers thereof.

[0115] In the structure IF, n, p, R 2 , R 3 , R 4 , R 5 , and R 11 is as defined above for Formula I.

[0116] Also, in the structure IF, R 1 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 1 is one or more of the same or different R 10 is optionally replaced by

[0117] In addition, in the structure IF, R 6 is a lipid or alkyl, and R 6 is optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 is optionally further replaced by

[0118] Furthermore, in the structure IF, R 10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 10 is one or more of the same or different R 11 is optionally replaced by

[0119] In some examples of the structure IF, n is 2, 3, or 4; and p is 2, 3, or 4. In some examples, n is 2; and p is 2, 3, or 4. In some examples, n is 3; and p is 2, 3, or 4. In some examples, n is 4; and p is 2, 3, or 4. In some examples, n is 2; and p is 2. In some examples, n is 3; and p is 3. In some examples, n is 4; and p is 4. In some examples, n is 2; and p is 3. In some examples, n is 2; and p is 4. In some examples, n is 3; and p is 2. In some examples, n is 3; and p is 4. In some examples, n is 4; and p is 2. In some examples, n is 4; and p is 3. In some examples, n is 2, 3, or 4; and p is 2, 3, or 4. In some examples, n is 2; and p is 2, 3, or 4. In some examples, n is 3; and p is 2, 3, or 4. In some examples, n is 4; and p is 2, 3, or 4. In some examples, n is 2; and p is 2. In some examples, n is 3; and p is 3. In some examples, n is 4; and p is 4. In some examples, n is 2; and p is 3. In some examples, n is 2; and p is 4. In some examples, n is 3; and p is 2. In some examples, n is 3; and p is 4. In some examples, n is 4; and p is 2. In some examples, n is 4; and p is 3.

[0120] In some examples of structure IF, n is 2, 3, or 4; p is 2, 3, or 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; and R 2 and R 3 is hydrogen and R 4is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0121] One class of compounds described herein has Formula II: [ka] and includes prodrugs, salts, and stereoisomers thereof.

[0122] In formula II, n is 1 to 6. For example, n can be 2 to 4.

[0123] In addition, in formula II, p is 1 to 6. For example, p can be 2 to 4.

[0124] Additionally, in formula II, q is 1 to 6. For example, q can be 2 to 4.

[0125] Also in formula II, R 1 is alkyl, halogen, nitro, cyano, hydroxy, amino, sulfamoylamino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl. 1 is one or more of the same or different R 10may be substituted by (as described below).

[0126] Further in formula II, R 2 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl. 2 is one or more of the same or different R 10 may be replaced by

[0127] Also in formula II, R 3 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl. 3 is one or more of the same or different R 10 may be replaced by

[0128] Additionally, in formula II, R 4 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl. 4is one or more of the same or different R 10 may be replaced by

[0129] Further in formula II, R 5 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl. 5 is one or more of the same or different R 10 may be replaced by

[0130] Also in formula II, R 6 is hydrogen, carboxy, or alkyl. In some examples, R 6 is optionally terminally substituted with hydroxy, carboxy, or phosphate. In some examples, R 6 is optionally substituted with hydroxy, carboxy, or phosphate. Optionally, the hydroxy, carboxy, or phosphate is substituted with R 10 is further substituted by

[0131] Additionally, in formula II, R 7 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl. 7 is one or more of the same or different R 10 is replaced by

[0132] In some instances of Formula II, R 1 and R 7 together form an oxo or oxime. An oxime is a group consisting of one or more of the same or different R 10 may optionally be replaced by

[0133] In Formula II, R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl. 10 Optionally, R can be aminosulfonyl. 10 is one or more of the same or different R 11 may optionally be replaced by

[0134] Also in formula II, R 11is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

[0135] In some examples of Formula II, n is 2, 3, or 4; and p is 2, 3, or 4. In some examples, n is 2; and p is 2, 3, or 4. In some examples, n is 3; and p is 2, 3, or 4. In some examples, n is 4; and p is 2, 3, or 4. In some examples, n is 2; and p is 2. In some examples, n is 3; and p is 3. In some examples, n is 4; and p is 4. In some examples, n is 2; and p is 3. In some examples, n is 2; and p is 4. In some examples, n is 3; and p is 2. In some examples, n is 3; and p is 4. In some examples, n is 4; and p is 2. In some examples, n is 4; and p is 3.

[0136] In some examples of Formula II, n is 2, 3, or 4; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 2; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 3; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 4; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 2; p is 2; and q is 2, 3, or 4. In some examples, n is 3; p is 3; and q is 2, 3, or 4. In some examples, n is 4; p is 4; and q is 2, 3, or 4. In some examples, n is 2; p is 2; and q is 2, 3, or 4. In some examples, n is 2; p is 3; q is 2. In some examples, n is 2; p is 3; q is 3. In some examples, n is 2; p is 3; q is 4. In some examples, n is 2; p is 4; q is 4. In some examples, n is 3; p is 2; q is 2. In some examples, n is 3; p is 3; q is 3. In some examples, n is 3; p is 4; q is 4. In some examples, n is 4; p is 2; q is 2. In some examples, n is 4; p is 3; q is 3. In some examples, n is 4; p is 4; q is 4.

[0137] In some examples of Formula II, R 1 is hydroxy or sulfamoylamino. In some examples, R 7 is hydrogen. In some instances, R 7 is hydrogen and R 1 is hydroxy, sulfamoylamino, or sulfamic acid. In some examples, R 2 and R 3 is hydrogen and R 4is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 7 is hydrogen. In some instances, R 6 is alkyl terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 In some examples, R 1 is hydroxy, alkyl, amino, sulfamoylamino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 Optionally replaced by R 7 is hydrogen.

[0138] Optionally, the compound of formula II has structure II-A, as shown below: [ka] and includes prodrugs, salts, and stereoisomers thereof.

[0139] In Structure II-A, n, p, q, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , and R 11 is as defined above for Formula II.

[0140] Also in structure II-A, R 6 is hydrogen, carboxy, or alkyl, and R 6 is optionally substituted with alkyl, hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 is optionally further replaced by

[0141] Additionally, in structure II-A, R 10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 10 is one or more of the same or different R 11 (as defined in formula II).

[0142] In some examples of structure II-A, n is 2, 3, or 4; p is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 2; R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 4; and R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 2; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 3; R 1is hydroxy or sulfamoylamino. In some examples, n is 2; p is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 4; and R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 2; 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 4; and R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 2; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 3; and R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 4; and R 1 is hydroxy or sulfamoylamino. In some examples, R 7 is hydrogen. In some instances, R 7 is hydrogen and R 1 is hydroxy, sulfamoylamino, or sulfamic acid. In some examples, R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 7 is hydrogen. In some instances, R 1 is hydroxy, alkyl, amino, sulfamoylamino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 Optionally replaced by R 7 is hydrogen.

[0143] In some examples of structure II-A, n is 2, 3, or 4; p is 2, 3, or 4; q is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 2, 3, or 4; q is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 2, 3, or 4; q is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 2, 3, or 4; q is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 2; q is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 3; q is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 4; q is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 2; q is 2; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 3; q is 2; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 3; q is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 3; q is 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 4; q is 4; R 1is hydroxy or sulfamoylamino. In some examples, n is 3; p is 2; q is 2; R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 3; q is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 4; q is 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 2; q is 2; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 3; q is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 4; q is 4; R 1 is hydroxy or sulfamoylamino. In some examples, R 7 is hydrogen. In some instances, R 7 is hydrogen and R 1 is hydroxy, sulfamoylamino, or sulfamic acid. In some examples, R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 7 is hydrogen. In some instances, R 1 is hydroxy, alkyl, amino, sulfamoylamino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 Optionally replaced by R 7 is hydrogen.

[0144] Optionally, the compound of formula II has structure II-B, as shown below: [ka] and includes prodrugs, salts, and stereoisomers thereof.

[0145] In structure II-B, n, p, q, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , and R 11 is as defined above for Formula II.

[0146] Also in structure II-B, R 6 is hydrogen or alkyl, and R 6 is optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 is optionally further replaced by

[0147] Additionally, in structure II-B, R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 10 is one or more of the same or different R 11 is optionally replaced by

[0148] In some examples of structure II-B, n is 2, 3, or 4; p is 2, 3, or 4; q is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 2, 3, or 4; q is 2, 3, or 4; R 1is hydroxy or sulfamoylamino. In some examples, n is 3; p is 2, 3, or 4; q is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 2, 3, or 4; q is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 2; q is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 3; q is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 4; q is 2, 3, or 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 2; q is 2; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 3; q is 2; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 3; q is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 3; q is 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 2; p is 4; q is 4; R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 2; q is 2; R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 3; q is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 3; p is 4; q is 4; R 1is hydroxy or sulfamoylamino. In some examples, n is 4; p is 2; q is 2; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 3; q is 3; R 1 is hydroxy or sulfamoylamino. In some examples, n is 4; p is 4; q is 4; R 1 is hydroxy or sulfamoylamino. In some examples, R 7 is hydrogen and R 1 is hydroxy, sulfamoylamino, or sulfamic acid.

[0149] In some examples of structure II-B, R 6 is hydrogen. In some instances, R 6 is alkyl, methyl, or ethyl. In some examples, R 7 is hydrogen. In some instances, R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 7 is hydrogen. In some instances, R 6 is hydrogen or alkyl optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 In some examples, R 1 is hydroxy, alkyl, amino, sulfamoylamino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 Optionally replaced by R 7 is hydrogen. In some examples, n is 2, 3, or 4; p is 2, 3, or 4; q is 2; R 1is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 2; p is 2, 3, or 4; q is 2; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 3; p is 2, 3, or 4; q is 2; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 2, 3, or 4; q is 2; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 2; p is 2; q is 2; R 1 is hydroxy or sulfamoylamino; R 2and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen.

[0150] In some examples of structure II-B, n is 3; p is 3; q is 2; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 4; q is 2; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 2; p is 3; q is 2; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 2; p is 4; q is 2; R 1 is hydroxy or sulfamoylamino; R 2 and R3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 3; p is 2; q is 2; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 3; p is 4; q is 2; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen.

[0151] In some examples of structure II-B, n is 4; p is 2; q is 2; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 3; q is 2; R 1 is hydroxy or sulfamoylamino; R 2 and R 3is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 4; q is 2; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 2, 3, or 4; p is 2, 3, or 4; q is 3; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 2; p is 2, 3, or 4; q is 3; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 3; p is 2, 3, or 4; q is 3; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 2, 3, or 4; q is 3; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 2; p is 2; q is 3; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen.

[0152] In some examples of structure II-B, n is 3; p is 3; q is 3; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 4; q is 3; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 2; p is 3; q is 3; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 2; p is 4; q is 3; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 3; p is 2; q is 3; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 3; p is 4; q is 3; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 2; q is 3; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 3; q is 3; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 4; q is 3; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen.

[0153] In some examples of structure II-B, n is 2, 3, or 4; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 2; p is 2, 3, or 4; q is 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 3; p is 2, 3, or 4; q is 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 2, 3, or 4; q is 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 2; p is 2; q is 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7is hydrogen. In some examples, n is 3; p is 3; q is 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 4; q is 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen.

[0154] In some examples of structure II-B, n is 2; p is 3; q is 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 2; p is 4; q is 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7is hydrogen. In some examples, n is 3; p is 2; q is 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 3; p is 4; q is 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 2; q is 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 3; q is 4; R 1 is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen. In some examples, n is 4; p is 4; q is 4; R 1is hydroxy or sulfamoylamino; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl; R 7 is hydrogen.

[0155] Optionally, the compound of formula II has structure II-C, as shown below: [ka] and includes prodrugs, salts, and stereoisomers thereof.

[0156] In structure II-C, n, p, q, R 2 , R 3 , R 4 , R 5 , and R 11 is as defined above for Formula II.

[0157] Also in Structure II-C, X is a linking group: -CH-, -C(OH)(OH)-, -C(OH)H, -C(Hal)(Hal)-, -C(Hal)H-, -O-, -S-, -(S=O)-, -SO-, -NH-, -(C=O)-, -(C=NH)-, or -(C=S)-.

[0158] Additionally, in structure II-C, R 1 is hydrogen, hydroxy, alkyl, alkanoyl, amino, aminoalkyl, sulfamoylamino, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl.

[0159] Optionally, in Structure II-C, X and R 1 is as follows: a) X is O and R 1 is alkanoyl; b) X is -NH- and R 1is alkanoyl; c) X is O and R 1 is aminosulfonyl; d) X is —NH— and R 1 is aminosulfonyl; or e) X is —(C═O)— and R 1 is an amino.

[0160] Furthermore, in structure II-C, R 6 is hydrogen or alkyl, and R 6 is optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 is optionally further replaced by

[0161] Additionally, in structure II-C, R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 10 is one or more of the same or different R 11 (as defined in formula II).

[0162] In some examples of Structure II-C, n is 2, 3, or 4; p is 2, 3, or 4. In some examples, n is 2; p is 2, 3, or 4. In some examples, n is 3; p is 2, 3, or 4. In some examples, n is 4; p is 2, 3, or 4. In some examples, n is 2; p is 2. In some examples, n is 3; p is 3. In some examples, n is 4; p is 4. In some examples, n is 2; p is 3. In some examples, n is 2; p is 4. In some examples, n is 3; p is 2. In some examples, n is 3; p is 4. In some examples, n is 4; p is 2. In some examples, n is 4; p is 3.

[0163] In some examples of Structure II-C, n is 2, 3, or 4; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 2; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 3; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 4; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 2; p is 2; and q is 2, 3, or 4. In some examples, n is 3; p is 3; and q is 2, 3, or 4. In some examples, n is 4; p is 4; and q is 2, 3, or 4. In some examples, n is 2; p is 2; and q is 2, 3, or 4. In some examples, n is 2; p is 3; q is 2. In some examples, n is 2; p is 3; q is 3. In some examples, n is 2; p is 3; q is 4. In some examples, n is 2; p is 4; q is 4. In some examples, n is 3; p is 2; q is 2. In some examples, n is 3; p is 3; q is 3. In some examples, n is 3; p is 4; q is 4. In some examples, n is 4; p is 2; q is 2. In some examples, n is 4; p is 3; q is 3. In some examples, n is 4; p is 4; q is 4. In some examples, R 6 is hydrogen. In some instances, R 6 is alkyl, methyl, or ethyl.

[0164] In some examples of structure II-C, R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl. In some examples, R 2 and R 3is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen. In some instances, R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is alkyl, methyl, or ethyl. In some examples, R 6 is hydrogen or alkyl optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 In some examples, R 1 is hydroxy or sulfamoylamino, and R 1 is R 10 optionally replaced by R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen. In some instances, R 1 is hydroxy or sulfamoylamino, and R 1 is R 10 optionally replaced by R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is alkyl, methyl, or ethyl. In some examples, R 1 is hydrogen, hydroxy, alkyl, amino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 In some examples, R 1is hydrogen, hydroxy, alkyl, amino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 optionally replaced by R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen. In some instances, R 1 is hydrogen, hydroxy, alkyl, amino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 optionally replaced by R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is alkyl, methyl, or ethyl.

[0165] In some examples of Structure II-C, n is 2, 3, or 4; p is 2, 3, or 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 2; R 2 and R 3 is hydrogen and R4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0166] In some examples of Structure II-C, n is 2, 3, or 4; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 3; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0167] In some examples of Structure II-C, n is 2; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 3; R 2and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2, 3, or 4; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 4; R 2 and R 3 is hydrogen and R4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0168] In some examples of structure II-C, n is 2; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 2; R 1 is hydroxy; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 2; R 1 is hydroxy; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 2; R 1 is hydroxy; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2, 3, or 4; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0169] In some examples of structure II-C, n is 2; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 3; R 2 and R 3is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0170] In some examples of Structure II-C, n is 4; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2, 3, or 4; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 4; R 2 and R3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0171] Optionally, the compound of formula II has structure II-D, as shown below: [ka] and includes prodrugs, salts, and stereoisomers thereof.

[0172] In Structure II-D, n, p, q, R 2 , R 3 , R 4 , R 5 , and R 11 is as defined above for Formula II.

[0173] Also in Structure II-D, X is a linking group: -CH-, -C(OH)(OH)-, -C(OH)H, -C(Hal)(Hal)-, -C(Hal)H-, -O-, -S-, -(S=O)-, -SO-, -NH-, -(C=O)-, -(C=NH)-, or -(C=S)-.

[0174] Additionally, in structure II-D, Y is —CH—, —C(OH)(OH)—, —C(OH)H, —C(Hal)(Hal)—, —C(Hal)H—, —O—, —S—, —(S═O)—, —SO—, —NH—, —(C═O)—, —(C═NH)—, or —(C═S)—.

[0175] Further in structure II-D, Z is —CH—, —C(OH)(OH)—, —C(OH)H, —C(Hal)(Hal)—, —C(Hal)H—, —O—, —S—, —(S═O)—, —SO—, —NH—, —(C═O)—, —(C═NH)—, or —(C═S)—.

[0176] Also in structure II-D, R 1 is hydrogen, hydroxy, alkyl, alkanoyl, amino, aminoalkyl, sulfamoylamino, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl.

[0177] Optionally in Structure II-D, X, Y, Z, and R 1 is as follows: a) X is O and R 1 is alkanoyl; b) X is -NH- and R 1 is alkanoyl; c) X is O and R 1 is aminosulfonyl; d) X is —NH— and R 1 is aminosulfonyl; e) X is —(C═O)— and R 1 is amino; f) X is O, Y is —(C═O)—, and R 1 is amino; g) X is O, Y is —(C═O)—, Z is —NH—, and R 1 is a sulfonate; and h) X is O, Y is —(C═O)—, Z is —NH—, and R 1 is aminosulfonyl.

[0178] Furthermore, in structure II-D, R 6 is hydrogen or alkyl, and R6 is optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 is optionally further replaced by

[0179] Additionally, in structure II-D, R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 10 is one or more of the same or different R 11 (as defined in formula II).

[0180] In some examples of structure II-D, n is 2, 3, or 4; p is 2, 3, or 4. In some examples, n is 2; p is 2, 3, or 4. In some examples, n is 3; p is 2, 3, or 4. In some examples, n is 4; p is 2, 3, or 4. In some examples, n is 2; p is 2. In some examples, n is 3; p is 3. In some examples, n is 4; p is 4. In some examples, n is 2; p is 3. In some examples, n is 2; p is 4. In some examples, n is 3; p is 2. In some examples, n is 3; p is 4. In some examples, n is 4; p is 2. In some examples, n is 4; p is 3.

[0181] In some examples of structure II-D, n is 2, 3, or 4; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 2; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 3; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 4; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 2; p is 2; and q is 2, 3, or 4. In some examples, n is 3; p is 3; and q is 2, 3, or 4. In some examples, n is 4; p is 4; and q is 2, 3, or 4. In some examples, n is 2; p is 2; and q is 2, 3, or 4. In some examples, n is 2; p is 3; q is 2. In some examples, n is 2; p is 3; q is 3. In some examples, n is 2; p is 3; q is 4. In some examples, n is 2; p is 4; q is 4. In some examples, n is 3; p is 2; q is 2. In some examples, n is 3; p is 3; q is 3. In some examples, n is 3; p is 4; q is 4. In some examples, n is 4; p is 2; q is 2. In some examples, n is 4; p is 3; q is 3. In some examples, n is 4; p is 4; q is 4. In some examples, R 6 is hydrogen. In some instances, R 6 is alkyl, methyl, or ethyl.

[0182] In some examples of structure II-D, R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl. In some examples, R 2 and R 3is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen. In some instances, R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is alkyl, methyl, or ethyl. In some examples, R 6 is hydrogen or alkyl optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 In some examples, R 1 is hydroxy or sulfamoylamino, and R 1 is R 10 optionally replaced by R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen. In some instances, R 1 is hydroxy or sulfamoylamino, and R 1 is R 10 optionally replaced by R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is alkyl, methyl, or ethyl. In some examples, R 1 is hydrogen, hydroxy, alkyl, amino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 In some examples, R 1is hydrogen, hydroxy, alkyl, amino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 optionally replaced by R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen. In some instances, R 1 is hydrogen, hydroxy, alkyl, amino, aminoalkyl, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R 1 is R 10 optionally replaced by R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is alkyl, methyl, or ethyl.

[0183] In some examples of structure II-D, n is 2, 3, or 4; p is 2, 3, or 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 2; R 2 and R 3 is hydrogen and R4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0184] In some examples of structure II-D, n is 2, 3, or 4; p is 2, 3, or 4; q is 3; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 3; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0185] In some examples of structure II-D, n is 2; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 3; R 2and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2, 3, or 4; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 4; R 2 and R 3 is hydrogen and R4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0186] In some examples of structure II-D, n is 2; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 2; R 1 is hydroxy; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 2; R 1 is hydroxy; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 2; R 1 is hydroxy; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2, 3, or 4; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0187] In some examples of structure II-D, n is 2; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 3; R 2 and R 3is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0188] In some examples of structure II-D, n is 4; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2, 3, or 4; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 4; R 2 and R3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0189] Optionally, the compound of formula II has structure II-E, as shown below: [ka] and includes prodrugs, salts, and stereoisomers thereof.

[0190] In structure II-E, n, p, q, R 2 , R 3 , R 4 , R 5 , and R 11 is as defined above for Formula II.

[0191] Also in structure II-E, R 1 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 1is one or more of the same or different R 10 is optionally replaced by

[0192] Additionally, in structure II-E, R 6 is a lipid or alkyl, and R 6 is optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 is optionally further replaced by

[0193] Furthermore, in structure II-E, R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 10 is one or more of the same or different R 11 is optionally replaced by

[0194] In some examples of Structure II-E, n is 2, 3, or 4; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 2; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 3; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 4; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 2; p is 2; and q is 2, 3, or 4. In some examples, n is 3; p is 3; and q is 2, 3, or 4. In some examples, n is 4; p is 4; and q is 2, 3, or 4. In some examples, n is 2; p is 2; and q is 2, 3, or 4. In some examples, n is 2; p is 3; q is 2. In some examples, n is 2; p is 3; q is 3. In some examples, n is 2; p is 3; q is 4. In some examples, n is 2; p is 4; q is 4. In some examples, n is 3; p is 2; q is 2. In some examples, n is 3; p is 3; q is 3. In some examples, n is 3; p is 4; q is 4. In some examples, n is 4; p is 2; q is 2. In some examples, n is 4; p is 3; q is 3. In some examples, n is 4; p is 4; q is 4.

[0195] In some examples of Structure II-E, n is 2, 3, or 4; p is 2, 3, or 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 2; R2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R6 is hydrogen, alkyl, methyl, or ethyl.

[0196] In some examples of Structure II-E, n is 2; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 2; R2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0197] In some examples of Structure II-E, n is 2, 3, or 4; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 3; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0198] In some examples of Structure II-E, n is 2, 3, or 4; p is 2, 3, or 4; q is 4; R2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 4; R 2 and R 3is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0199] In some examples of Structure II-E, n is 2; p is 2; q is 2; R 1 is hydroxy; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 2; R 1 is hydroxy; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 2; R 1 is hydroxy; R 2 and R 3is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2, 3, or 4; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0200] In some examples of Structure II-E, n is 2; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0201] In some examples of Structure II-E, n is 2, 3, or 4; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 4; R 2 and R 3is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0202] Optionally, the compound of formula II has structure II-F, as shown below: [ka] and includes prodrugs, salts, and stereoisomers thereof.

[0203] In structure II-F, n, p, q, R 2 , R 3 , R 4 , R 5 , and R 11 is as defined above for Formula II.

[0204] Also in structure II-F, R 1is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 1 is one or more of the same or different R 10 is optionally replaced by

[0205] Additionally, in structure II-F, R 6 is a lipid or alkyl, and R 6 is optionally terminally substituted with hydroxy, carboxy, or phosphate, and the hydroxy, carboxy, or phosphate is R 10 is optionally further replaced by

[0206] Furthermore, in structure II-F, R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl)2amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R 10 is one or more of the same or different R 11 is optionally replaced by

[0207] In some examples of Structure II-F, n is 2, 3, or 4; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 2; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 3; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 4; p is 2, 3, or 4; and q is 2, 3, or 4. In some examples, n is 2; p is 2; and q is 2, 3, or 4. In some examples, n is 3; p is 3; and q is 2, 3, or 4. In some examples, n is 4; p is 4; and q is 2, 3, or 4. In some examples, n is 2; p is 2; and q is 2, 3, or 4. In some examples, n is 2; p is 3; q is 2. In some examples, n is 2; p is 3; q is 3. In some examples, n is 2; p is 3; q is 4. In some examples, n is 2; p is 4; q is 4. In some examples, n is 3; p is 2; q is 2. In some examples, n is 3; p is 3; q is 3. In some examples, n is 3; p is 4; q is 4. In some examples, n is 4; p is 2; q is 2. In some examples, n is 4; p is 3; q is 3. In some examples, n is 4; p is 4; q is 4.

[0208] In some examples of Structure II-F, n is 2, 3, or 4; p is 2, 3, or 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 2; R2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0209] In some examples of Structure II-F, n is 2, 3, or 4; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 3; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 3; R 2 and R 3is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0210] In some examples of Structure II-F, n is 2, 3, or 4; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 4; R 2 and R3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0211] In some examples of Structure II-F, n is 2; p is 2; q is 2; R 1 is hydroxy; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 2; R 1 is hydroxy; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 2; R 1 is hydroxy; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 2; R 2 and R 3 is hydrogen and R 4is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 2; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0212] In some examples of Structure II-F, n is 2, 3, or 4; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 3; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 3; R 2 and R 3is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 3; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0213] In some examples of Structure II-F, n is 2, 3, or 4; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2, 3, or 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 2; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 4; R 2 and R3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 3; q is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 2; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 2; q is 4; and R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 3; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 2; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 3; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl. In some examples, n is 4; p is 4; q is 4; R 2 and R 3 is hydrogen and R 4 is 1-phenylvinyl or 1-phenylethyl, and R 5 is phenyl and R 6 is hydrogen, alkyl, methyl, or ethyl.

[0214] Compounds according to the present disclosure include enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, or hydrates thereof.

[0215] In some examples, a compound according to the present disclosure may be selected from the following compounds, an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof: [Table 4] Includes.

[0216] III. Methods of Making Compounds The compounds described herein can be prepared in a variety of ways. The compounds can be synthesized using a variety of synthetic methods. At least some of these methods are known in the art of synthetic organic chemistry. The compounds described herein can be prepared from readily available starting materials. Optimum reaction conditions may vary depending on the particular reaction or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0217] Variations of the compounds of Formula I and Formula II and other compounds described herein include the addition, subtraction, or movement of various constituents described for each compound. Similarly, when one or more chiral centers are present in a molecule, all chiral variants are included. Additionally, compound synthesis may involve the protection and deprotection of various chemical groups. The use of protection and deprotection and the selection of appropriate protecting groups can be determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts, Greene's Protective Groups in Organic Synthesis, 5th Ed., Wiley & Sons, 2014 (which is incorporated herein by reference in its entirety).

[0218] The reactions to produce the compounds described herein can be carried out in a solvent that can be selected by one skilled in the art of organic synthesis. The solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products under the conditions (i.e., temperature and pressure) at which the reaction is carried out. The reaction can be carried out in one solvent or a mixture of two or more solvents. The production of the product or intermediate can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means (e.g., nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry), or by chromatography (e.g., high performance liquid chromatography (HPLC) or thin layer chromatography).

[0219] IV. Pharmaceutical Compositions For use in therapy, a therapeutically effective amount of the compounds disclosed herein may be administered as raw chemicals, but are typically provided as active ingredients in pharmaceutical compositions or formulations. Accordingly, the present disclosure further provides pharmaceutical compositions comprising the compounds disclosed herein. The pharmaceutical compositions may further comprise one or more pharmaceutically acceptable carriers, diluents, and / or excipients. The carrier(s), diluents, and / or excipient(s) should be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient. According to another aspect of the present disclosure, there is also provided a process for preparing a pharmaceutical formulation, comprising mixing a compound disclosed herein with one or more pharmaceutically acceptable carriers, diluents, and / or excipients.

[0220] Pharmaceutical formulations may be presented in unit dosage forms containing a predetermined amount of active ingredient per unit dose. Such units may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, and more preferably 5 mg to 100 mg of a compound disclosed herein (as the free base, solvate (including hydrate), or salt in any form), depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient. Preferred unit dosage formulations are those containing a daily, weekly, or monthly dose of the active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the art of pharmacy.

[0221] Pharmaceutical formulations may be adapted for administration by any suitable route, for example, oral (including capsules, tablets, liquid-filled capsules, disintegrating tablets, immediate-release tablets, delayed-release tablets, and controlled-release tablets, oral strips, solutions, syrups, buccal, and sublingual), rectal, nasal, inhalation, topical (including transdermal), vaginal, parenteral (including subcutaneous, intramuscular, intravenous, intradermal). Such formulations may be prepared by any method known in the art of pharmacy, for example, by bringing the active ingredient into association with the carrier(s), excipient(s), or diluent. Generally, a carrier, excipient, or diluent used in a pharmaceutical formulation is "non-toxic," meaning that it / they are considered safe for consumption in the amounts delivered in the pharmaceutical composition, and is "inert," meaning that it / they do not react with the active ingredient or produce undesired effects on the therapeutic activity of the active ingredient.

[0222] Pharmaceutical formulations adapted for oral administration may be presented as discrete units, such as liquid-filled or solid capsules; immediate-, delayed-, or controlled-release tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous solutions; edible foams or whips; oil-in-water liquid emulsions, water-in-oil liquid emulsions, or oral strips (such as impregnated gel strips).

[0223] For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral pharmaceutically acceptable carrier (such as ethanol, glycerol, sterile water, and the like). Powders are prepared by pulverizing the compound to a suitable fine size and mixing with a similarly pulverized pharmaceutical carrier (such as an edible carbohydrate, for example, starch or mannitol). Flavoring agents, preservatives, dispersing agents, and coloring agents can also be present.

[0224] Solid capsules are made by preparing a powder mixture as described above and filling formed gelatin sheaths. Fluidizing and lubricating agents (such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol) can be added to the powder mixture before the filling operation. Disintegrating or solubilizing agents (such as agar-agar, calcium carbonate, or sodium carbonate) are added to improve the availability of the medicament when the capsule is ingested.

[0225] Furthermore, if desired or necessary, suitable binders, lubricants, disintegrants, and coloring agents may also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (such as glucose or β-lactose), corn syrup, natural and synthetic gums (such as acacia and tragacanth), or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating, smashing, and / or adding lubricants and disintegrants and pressing into tablets. Powder mixtures can be prepared by mixing suitably finely divided compounds with diluents or bases as described above, and optionally with binders (such as carboxymethylcellulose, alginates, gelatin, or polyvinylpyrrolidone), solution-retarding materials (such as paraffin), absorption enhancers (such as quaternary salts), and / or adsorbents (such as bentonite, kaolin, or dicalcium phosphate). The powder mixture can be granulated by wetting it with a binder (such as syrup, starch paste, or solutions of cellulosic or polymeric materials) and forcing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tablet machine; the result is imperfectly formed slugs broken into granules. The granules can be lubricated by the addition of stearic acid, stearate salts, talc, or mineral oil to prevent sticking to the tablet-forming dies. The lubricated mixture is then compressed into tablets. The compounds disclosed herein can also be combined with a free-flowing inert carrier and compressed into tablets directly without the steps of granulating or pounding. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided.Dyes can be added to these coatings to distinguish different unit dosages.

[0226] Oral fluids (such as solutions, syrups, and elixirs) can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Solutions and syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a pharmaceutically acceptable alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a pharmaceutically acceptable vehicle. Solubilizing and emulsifying agents (such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether), preservatives, flavor additives (such as peppermint oil), or natural sweeteners or saccharin or other artificial sweeteners, and the like, can be added.

[0227] Where appropriate, dosage unit formulations for oral administration can be microencapsulated. Formulations can be prepared to prolong or sustain release, for example by coating or embedding particulate material in polymers, waxes or the like.

[0228] The compounds of the present disclosure can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0229] Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles, and mouthwashes.

[0230] Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or enemas.

[0231] Pharmaceutical formulations adapted for nasal administration where the carrier is a solid include a coarse powder having a particle size in the range 20 to 500 microns, which is administered in the manner utilized by nasal insufflation, i.e., by rapid inhalation through the nasal passage from a container of the powder held close to the nose. Where the carrier is a liquid for administration as a nasal spray or nasal drops, suitable formulations include aqueous or oily solutions of the active ingredient.

[0232] Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered dose pressurized aerosols, metered dose inhalers, dry powder inhalers, nebulizers, or insufflators.

[0233] Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.

[0234] Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation pharmaceutically acceptable isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers (e.g., sealed ampoules and vials) and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier (e.g., water for injection) immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0235] It will be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question (e.g., those suitable for oral administration may include flavoring agents).

[0236] V. How to use In certain instances, the present disclosure relates to methods of treating or preventing a disease or condition associated with LRH-1 (such as diabetes, cancer, or cardiovascular disease) by administering to a subject in need thereof an effective amount of a hexahydropentalene derivative disclosed herein.

[0237] In certain instances, the present disclosure relates to a method of treating or preventing diabetes comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound disclosed herein, hi certain instances, the subject is at risk for, exhibits symptoms of, or has been diagnosed with diabetes, insulin-dependent diabetes, non-insulin-dependent diabetes, or gestational diabetes.

[0238] In certain instances, the present disclosure relates to compounds disclosed herein that are LRH-1 agonists for use in preventing the progressive loss of pancreatic beta cells. The present disclosure also relates to LRH-1 agonists for use in preserving or restoring pancreatic beta cells. Furthermore, the present disclosure relates to LRH-1 agonists for use in methods for preventing or treating type 1 diabetes or insulin-dependent diabetes, increasing pancreatic beta cell survival, increasing pancreatic beta cell performance, increasing beta cell graft survival, preserving pancreatic beta cells in vitro, maintaining insulin secretion, and / or transplanting pancreatic islet cells.

[0239] In some instances, the present disclosure relates to the treatment or prevention of pancreatitis. In certain instances, a method for treating or preventing pancreatitis comprises administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound disclosed herein.

[0240] Diabetes mellitus (DM), often simply referred to as diabetes, is a condition in which a person has high blood sugar (glucose) levels, either as a result of the body not producing enough insulin or because the body's cells do not respond properly to the insulin that is produced.

[0241] In healthy individuals, blood glucose levels are maintained within narrow limits primarily through the action of the hormone insulin. Insulin is released by pancreatic beta cells at an appropriate rate in response to circulating glucose concentrations, a response regulated by other factors, including other circulating nutrients, pancreatic islet innervation, and incretin hormones. Insulin maintains glucose concentrations by limiting the rate of hepatic glucose release to match the rate of glucose clearance.

[0242] Insulin therefore enables the body's cells to absorb glucose and convert it into energy. If the body's cells do not absorb glucose, it accumulates in the blood (hyperglycemia), leading to a variety of potential medical complications. Diabetes is therefore characterized by elevated blood glucose levels, which, if not properly controlled, can result in secondary complications (such as cardiovascular disease, renal failure, retinopathy, and neuropathy). Two major pathophysiologies are associated with increased blood glucose. The first is an autoimmune attack on insulin-producing beta cells in the pancreas (type 1 diabetes, or insulin-dependent diabetes), while the second is associated with insufficient beta cell function and increased peripheral insulin resistance (type 2 diabetes, or non-insulin-dependent diabetes). Similar to type 1, beta cell death is also observed in type 2 diabetes. Type 1 diabetes, and often type 2 diabetes, requires insulin injections.

[0243] Type 1 DM is typically characterized by the loss of insulin-producing beta cells in the islets of Langerhans in the pancreas, leading to insulin deficiency. This type of diabetes can be further classified as immune-mediated or idiopathic. Most type 1 diabetes is immune-mediated in nature, with beta cell loss resulting from a T-cell-mediated autoimmune attack. Insulin sensitivity and responsiveness are usually normal, especially in the early stages. Type 1 diabetes can affect children or adults, but because it represents the majority of diabetes cases in children, it has traditionally been referred to as "juvenile diabetes."

[0244] Type 2 DM is characterized by beta cell dysfunction combined with insulin resistance. The defective responsiveness of body tissues to insulin is thought to be related to insulin receptors. Similar to type 1 diabetes, insufficient beta cell mass is also a causative factor in many type 2 diabetes patients. In the early stages of type 2 diabetes, hyperglycemia can be ameliorated by various measures and medications that improve insulin secretion and reduce hepatic glucose production. As the disease progresses, dysfunction of insulin secretion occurs, and therapeutic insulin supplementation may sometimes be required in certain patients. In certain instances, treatment of diabetes by administering a compound disclosed herein is combined with administration of insulin.

[0245] Diabetes without proper treatment can lead to numerous complications. Acute complications include hyperglycemia, diabetic ketoacidosis, or nonketotic hyperosmolar coma. Serious long-term complications include cardiovascular disease, chronic renal failure, and retinal damage. In some instances, the present disclosure relates to methods for treating or preventing central nervous system (CNS) disorders (such as diabetic neuropathy). In some instances, the present disclosure relates to improving mitochondrial dysfunction and reducing the level of podocyte apoptosis.

[0246] In certain instances, the present disclosure relates to methods of treating or preventing cardiovascular disease comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound disclosed herein.

[0247] In certain instances, the cardiovascular disease is coronary artery disease (CAD), angina pectoris, myocardial infarction, stroke, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, cardiac arrhythmia, congenital heart disease, valvular heart disease, carditis, aortic aneurysm, peripheral arterial disease, and venous thrombosis.

[0248] In some instances, the present disclosure relates to methods of treating or preventing diabetic nephropathy (i.e., diabetic kidney disease), hi some instances, the present disclosure relates to improving mitochondrial dysfunction, reducing the level of podocyte apoptosis, and improving podocyte function / survival.

[0249] In certain examples, the present disclosure relates to methods for managing cancer. "Cancer" refers to any of a variety of cellular diseases resulting from malignant neoplasms characterized by cell proliferation. It is not intended that diseased cells must actually invade surrounding tissues and metastasize to new body sites. Cancer can affect any tissue in the body and can have many different forms in each body region. Within the context of certain examples, "cancer reduction" can be identified by various diagnostic modalities known to those skilled in the art, including, but not limited to, observing a reduction in the size or number of tumor masses or observing an increase in cancer cell apoptosis (e.g., observing a greater than 5% increase in cancer cell apoptosis for a sample compound compared to a control without the compound). This can also be identified by changes in relevant biomarkers or gene expression profiles (such as PSA for prostate cancer, HER2 for breast cancer, or others).

[0250] In certain instances, the present disclosure relates to a method of treating cancer, comprising administering an effective amount of an agent to a subject in need thereof. Optionally, the cancer is bladder cancer, brain cancer, breast cancer (e.g., triple-negative breast cancer), bronchial cancer, colorectal cancer (e.g., colon cancer, rectal cancer), cervical cancer, chondrosarcoma, endometrial cancer, gastrointestinal cancer, stomach cancer, genitourinary cancer, glioblastoma, head and neck cancer, liver cancer, hepatocellular carcinoma, leukemia, liver cancer, lung cancer, lymphoma, cutaneous melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, skin cancer, testicular cancer, thyroid cancer, or uterine cancer. Optionally, the cancer is located in one or more of the following locations: oral cavity and pharynx (e.g., tongue, mouth, pharynx, or other oral cavity); digestive system (e.g., esophagus, stomach, small intestine, colon, rectum, anus, anal canal, anorectum, liver and intrahepatic bile ducts, gallbladder and other bile ducts, pancreas, or other digestive organs); respiratory system (e.g., larynx, lungs and bronchi, or other respiratory organs); bones and joints; soft tissue (e.g., heart); skin (e.g., melanoma of the skin or other non-epithelial skin); breast; reproductive system (e.g., cervix, uterine corpus, ovaries, external septum, The cancer may be a cancer affecting the genitals, vagina, and other female genital areas, the prostate, testes, penis, and other male genital areas; the urinary system (e.g., the bladder, kidneys, renal pelvis, and ureters, and other urinary organs); the eyes and orbits; the brain and other nervous systems; the endocrine system (e.g., the thyroid and other endocrine systems); lymphoma (e.g., Hodgkin's lymphoma and non-Hodgkin's lymphoma); myeloma; or leukemia (e.g., acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, or other leukemias). Optionally, the cancer is a cancer having increased expression of LRH-1 compared to non-cancerous cells of the same cell type.

[0251] In certain instances, the cancer is pancreatic cancer, breast cancer, liver cancer, colon cancer, or gastrointestinal tumors.

[0252] Benod et al. reported that LRH-1 regulates pancreatic cancer cell growth and proliferation. Proc Natl Acad Sci USA, 2011, 108(41):16927-31. Pan et al. reported that LRH-1-dependent programming of mitochondrial glutamine processing drives liver cancer. Genes Dev, 2016, 30(11):1255-1260. Holly et al. reported that LRH-1 drives colon cancer cell proliferation by suppressing CDKN1A gene expression in a p53-dependent manner. Nucleic Acids Res, 2016, 44(2):582-594.

[0253] In certain instances, the cancer is selected from bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, and thyroid cancer.

[0254] The compounds disclosed herein can be used alone in the treatment of each of the aforementioned conditions or can be used to provide additive or potentially synergistic effects with certain existing chemotherapeutics, radiation, biologics or immunotherapeutics (including monoclonal antibodies), and vaccines. The compounds disclosed herein can be useful in restoring the effectiveness of, and / or increasing sensitivity to, certain existing chemotherapeutics and / or radiation.

[0255] Coste et al. report that LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease. PNAS, 2007, 104(32)13098-13103. See also Fernandez-Marcos et al., Emerging actions of the nuclear receptor LRH-1 in the gut, Biochim Biophys Acta. 2011 August;1812(8):947-955; and Mueller et al., The nuclear receptor LRH-1 critically regulates extra-adrenal glucocorticoid synthesis in the intestine, Journal of Experimental Medicine, Sep 2006, 203(9)2057-2062.

[0256] Thus, in certain instances, the present disclosure relates to a method of preventing or treating inflammation of the gastrointestinal tract, small intestine, and colon, comprising administering an effective amount of a compound disclosed herein to a subject in need thereof, hi certain instances, the subject is at risk for, exhibits symptoms of, or has been diagnosed with inflammation of the small intestine and colon.

[0257] In another aspect, the present disclosure relates to a method for preventing or treating inflammatory bowel disease (IBD), comprising administering an effective amount of a compound disclosed herein to a subject in need thereof. In certain instances, the subject is at risk for, exhibits symptoms of, or is diagnosed with inflammatory bowel disease (IBD). As reviewed in Mays et al., Cell Chemical Biology, 29:1174-1186 (2022), agonists of LRH-1 improve outcomes in a T cell-transfer mouse model of colitis, resulting in increased expression of genes involved in steroidogenesis and decreased expression of pro-inflammatory cytokine genes in the gastrointestinal tract.

[0258] Optionally, the present disclosure relates to methods of preventing or treating diseases characterized by intestinal inflammation, including celiac disease, immune checkpoint inhibitor colitis, IgA nephropathy, Crohn's disease, ulcerative colitis, regional enteritis, granulomatous enteritis, peripheral ileitis, regional ileitis, terminal ileitis, and others. In some cases, the present disclosure relates to methods of protecting tissue from inflammatory bowel disease, including ulcerative colitis and Crohn's disease.

[0259] In another aspect, the present disclosure relates to a method of preventing or treating Crohn's disease, comprising administering an effective amount of a compound disclosed herein to a subject in need thereof. In certain instances, the subject is at risk for, exhibits symptoms of, or is diagnosed with Crohn's disease.

[0260] In another aspect, the present disclosure relates to a method of preventing or treating colitis or ulcerative colitis, comprising administering an effective amount of a compound disclosed herein to a subject in need thereof, hi certain instances, the subject is at risk for, exhibits symptoms of, or has been diagnosed with colitis or ulcerative colitis.

[0261] Overweight and obesity are increasingly common conditions worldwide. Physicians screen for obesity by measuring body mass index (BMI). Obesity is a serious medical condition that can lead to complications such as metabolic syndrome, high blood pressure, atherosclerosis, heart disease, diabetes, high serum cholesterol, cancer, and sleep disorders. Therefore, there is a need to reduce obesity.

[0262] Fatty liver or hepatic steatosis is a term used to describe the accumulation of fat in the liver. Excessive alcohol use can lead to fat accumulation, damage to the liver, and the development of cirrhosis. Nonalcoholic fatty liver disease (NAFLD) is a fatty liver disease associated with obesity-related disorders, such as type 2 diabetes and metabolic syndrome, which occur in people who drink little or no alcohol. Nonalcoholic steatohepatitis (NASH) is a more advanced and severe subtype of NAFLD in which steatosis is accompanied by liver cell damage and inflammation, with or without fibrosis. NASH can be severe and lead to cirrhosis, in which the liver becomes permanently damaged and scarred and is no longer able to function properly. Insulin resistance, altered lipid storage and metabolism, cholesterol accumulation in the liver, oxidative stress leading to increased liver damage, and bacterial translocation secondary to disruption of the gut microbiota have all been implicated as important cofactors contributing to the progression of NASH. Due to the growing epidemic of obesity and diabetes, NASH is projected to become the most common cause of advanced liver disease and the most common indication for liver transplantation.

[0263] Lee et al. reported that dilauroylphosphatidylcholine (DLPC) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and reduces hepatic triglycerides and serum glucose. DLPC treatment also reduces hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Nature volume 474, pages 506-510 (2011). Sahini et al. reported the identification of differentially expressed genes (DEGs) mechanistically linked to lipid droplet (LD) formation in hepatocytes. LD-associated DEGs were identified that were frequently regulated in patient samples. Liver receptor homolog-1 (NR5A2) was commonly downregulated among the patients studied. Translational Research, 177:41-69 (2016).

[0264] In certain examples, the present disclosure relates to a method for preventing or treating hepatic steatosis or metabolic syndrome, comprising administering an effective amount of a compound disclosed herein to a subject in need thereof. In certain examples, the subject is at risk of, exhibits symptoms of, or is diagnosed with non-alcoholic fatty liver disease (NAFLD). In certain examples, the subject is at risk of, exhibits symptoms of, or is diagnosed with non-alcoholic steatohepatitis (NASH). In certain examples, the subject is at risk of, exhibits symptoms of, or is diagnosed with alcoholic liver disease (ALD). In certain examples, the subject is at risk of, exhibits symptoms of, or is diagnosed with alcoholic steatohepatitis (ASH).

[0265] In certain instances, a subject is at risk for NAFLD due to obesity, insulin resistance, liver enlargement, signs of cirrhosis, or abnormal levels of liver enzymes, triglycerides, and / or cholesterol. Signs of insulin resistance include dark patches of skin on the knuckles, elbows, and knees. Signs of cirrhosis include jaundice (a condition that causes the skin and whites of the eyes to turn yellow). Signs of NAFLD or NASH include blood tests showing increased levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Liver enlargement or abnormal amounts of fat in the liver can be identified by ultrasound, computed tomography (CT) scan, magnetic resonance imaging, or a combination thereof. Liver biopsy can be used to detect liver inflammation and damage, allowing NASH to be diagnosed.

[0266] Metabolic syndrome is typically diagnosed in the presence of three or more of the following medical problems: a large waist size (e.g., 40 inches or more), high triglycerides (e.g., triglyceride levels of 150 mg / dL or more), low levels of HDL cholesterol (less than 50 mg / dL), high blood pressure (e.g., 130 / 85 mmHg or more), and high blood glucose (or blood sugar) levels (fasting blood sugar levels of 100 mg / dL or more).

[0267] In another aspect, the present disclosure relates to a method for controlling or reducing serum cholesterol levels, comprising administering an effective amount of a compound disclosed herein to a subject in need thereof. In certain instances, the subject has borderline high serum cholesterol levels (200-239 mg / dL). In certain instances, the subject has high serum cholesterol levels (>240 mg / dL). In certain instances, the subject is at risk for, exhibits symptoms of, or has been diagnosed with hypercholesterolemia.

[0268] In another aspect, the present disclosure relates to a method for preventing or treating hepatic steatosis, comprising administering an effective amount of a compound disclosed herein to a subject in need thereof. In certain instances, the subject is at risk of, exhibits symptoms of, or has been diagnosed with alcoholic liver disease (ALD). In certain instances, the subject is at risk of, exhibits symptoms of, or has been diagnosed with alcoholic steatohepatitis (ASH). In certain instances, the subject is at risk of, exhibits symptoms of, or has been diagnosed with non-alcoholic fatty liver disease (NAFLD). In certain instances, the subject is at risk of, exhibits symptoms of, or has been diagnosed with non-alcoholic steatohepatitis (NASH). In certain instances, the subject is at risk of NAFLD due to obesity, insulin resistance, liver enlargement, signs of cirrhosis, or abnormal levels of liver enzymes, triglycerides, and / or cholesterol. Signs of insulin resistance include dark skin patches on the knuckles, elbows, and knees. Signs of cirrhosis include jaundice (a condition that causes the skin and whites of the eyes to turn yellow). Signs of NAFLD or NASH include blood tests that show increased levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Enlarged liver or an abnormal amount of fat in the liver can be identified by ultrasound, computed tomography (CT) scan, magnetic resonance imaging, or a combination thereof. A liver biopsy can be used to detect liver inflammation and damage, allowing NASH to be diagnosed.

[0269] The precise therapeutically effective amount of a compound of the present disclosure will depend on many factors. There are variables inherent to the compound, including, but not limited to, molecular weight, absorption, bioavailability, distribution throughout the body, tissue permeability, half-life, metabolism, protein binding, and excretion. These variables determine what dose of compound needs to be administered at a sufficient percentage and for a sufficient amount of time to have the desired effect on the condition (e.g., neoplasm) being treated. The duration of drug exposure will be limited only by the compound half-life and side effects from treatment that require discontinuation of dosing. The amount of compound administered will also depend on patient- and disease-related factors, including, but not limited to, the age, weight, concomitant medications, and medical condition of the subject being treated, the precise condition and its severity requiring treatment, the nature of the formulation, and the route of administration. Ultimately, the dosage will be at the discretion of the attending physician or veterinarian. Typically, the compounds disclosed herein will be administered for treatment of a recipient (mammal) in the range of 0.01 to 30 mg / kg body weight per day or per dose or per cycle of treatment, and more usually in the range of 0.1 to 10 mg / kg body weight per day or per dose or per cycle of treatment. Thus, for an adult human being treated for a condition, the actual amount per day or per dose or per cycle of treatment will usually be 1 to 2000 mg, and this amount may be administered in single or multiple doses per day or per dose or per cycle of treatment. Dosage regimens vary significantly and will be determined and modified based on clinical experience with the compound. A full range of dosing regimens, from continuous dosing (by daily dose) to intermittent dosing, may be used. The therapeutically effective amount of a pharmaceutically acceptable salt of a compound disclosed herein may be determined as a percentage of the therapeutically effective amount of the compound as the free base.

[0270] A method for treating or preventing a disease or condition associated with LRH-1 (e.g., diabetes, cancer, or cardiovascular disease) in a subject may further include administering one or more additional agents to the subject. The one or more additional agents and the compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, may be administered in any order, including concomitant, simultaneous, or sequential administration. Sequential administration may be in a temporally separated order, up to several days apart. The method may also include more than a single administration of one or more additional agents and / or compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof. The administration of the one or more additional agents and the compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, may be by the same or different routes and may be simultaneous or sequential.

[0271] Additional therapeutic agents include, but are not limited to, chemotherapeutic agents, antibodies, antivirals, steroidal and nonsteroidal anti-inflammatory agents, conventional immunotherapeutic agents, cytokines, chemokines, and / or growth factors. Additional therapeutic agents may be biomolecules.

[0272] A chemotherapeutic agent, chemotherapy agent, chemotherapy drug, anti-cancer agent, or the like, is a compound or composition that is effective in inhibiting or stopping the growth of abnormally proliferating cells. Such agents may be recognized to aid in the treatment of cancer. Thus, such agents may be used therapeutically to treat cancer and other diseases characterized by abnormal cell proliferation.Illustrative examples of chemotherapeutic compounds include bexarotene, gefitinib, erlotinib, gemcitabine, paclitaxel, docetaxel, topotecan, irinotecan, temozolomide, carmustine, vinorelbine, capecitabine, leucovorin, oxaliplatin, bevacizumab, cetuximab, panitumumab, bortezomib, oblimersen, hexamethylmelamine, ifosfamide, CPT-11, deflunomide, cycloheximide, dicarbazine, azine), asparaginase, mitotant, vinblastine sulfate, carboplatin, colchicine, etoposide, melphalan, 6-mercaptopurine, teniposide, vinblastine, antibiotic derivatives (e.g., anthracyclines (doxorubicin, liposomal doxorubicin, and diethylstilbestrol doxorubicin), bleomycin, daunorubicin, and dactinomycin); antiestrogens (e.g., tamoxifen); antimetabolites (e.g., fluorouracil, cyclosporine (FU), 5-FU, methotrexate, floxuridine, interferon alpha 2B, glutamic acid, plicamycin, mercaptopurine, and 6-thioguanine; cytotoxic agents (e.g., carmustine, BCNU, lomustine, CCNU, cytosine arabinoside, cyclophosphamide, estramustine, hydroxyurea, procarbazine, mitomycin, busulfan, cisplatin, vincristine, and vincristine sulfate); hormones (e.g., medroxyprogesterone, estramustine phosphate, These include, but are not limited to, ramustine sodium, ethinyl estradiol, estradiol, megestrol acetate, methyltestosterone, diethylstilbestrol diphosphate, chlorotrianisene, and testolactone; nitrogen mustard derivatives (e.g., mephalen, chlorambucil, mechlorethamine (nitrogen mustard), and thiotepa); and steroids (e.g., bethamethasone sodium phosphate).

[0273] In some cases, contemplated examples of chemotherapeutic agents include the following: temozolomide, carmustine, bevacizumab, procarbazine, lomustine, vincristine, gefitinib, erlotinib, cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, gemcitabine, tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin C, dactinomycin, mitramacycline, ribozyme, ribozyme inhibitors ... Isin, vinblastine, vindesine, vinorelbine, paclitaxel, taxol, docetaxel, etoposide, teniposide, amsacrine, topotecan, camptothecin, bortezomib, anagrelide, tamoxifen, toremifene, raloxifene, droloxifene, idoxifene, fulvestrant, bicalutamide, flutamide, nilutamide, cyproterone, goserelin, leuprorelin, buserelin, megestrol, anastrozole, letrozole, vorozole, exemestane, finasteride, marimastat, trametinib Molecules or derivatives such as stuzumab, cetuximab, dasatinib, imatinib, combretastatins, thalidomide, azacitidine, azathioprine, capecitabine, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, doxifluridine, epothilone, irinotecan, mechlorethamine, mercaptopurine, mitoxantrone, thioguanine, valrubicin, and / or lenalidomide, or combinations thereof [cyclophosphamide, methotrexate, 5-fluorouracil (CMF); doxorubicin, cyclophosphamide (AC); mustine, vincristine, procarbazine, prednisolone (MOPP); adriamycin, bleomycin, vinblastine, dacarbazine (ABVD); cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP); bleomycin, etoposide, cisplatin (BEP); epirubicin, cisplatin, 5-fluorouracil (ECF); epirubicin, cisplatin, capecitabine (ECX); methotrexate, vincristine, doxorubicin, cisplatin (MVAC), etc.

[0274] Any of the aforementioned therapeutic agents can be used in any combination with the compositions described herein. The combination can be administered concomitantly (e.g., as a mixture), separately but simultaneously (e.g., via separate intravenous lines into the same subject), or sequentially (e.g., one of the compounds or agents is administered first, followed by the second). Thus, the term "combination" refers to the concomitant, simultaneous, or sequential administration of two or more agents. When used to describe administration with an additional treatment, the term "combination with" means that the agent can be administered before, together with, or after the additional treatment, or a combination thereof.

[0275] Optionally, the compounds or therapeutic agents described herein can be administered in combination with radiation therapy, immunotherapy, gene therapy, or surgery.

[0276] The methods and compounds described herein are useful for prophylactic and therapeutic treatments. For prophylactic use, a therapeutically effective amount of the compounds and compositions described herein, or pharmaceutically acceptable salts thereof, is administered to a subject prior to onset (e.g., prior to overt signs of an LRH-1-related disorder), during early onset (e.g., at the first signs and symptoms of an LRH-1-related disorder), or after onset of an LRH-1-related disorder. Prophylactic administration can occur days to years before symptoms of an LRH-1-related disorder appear. Therapeutic treatment involves administering a therapeutically effective amount of the compounds and compositions described herein, or pharmaceutically acceptable salts thereof, to a subject after an LRH-1-related disorder has been diagnosed.

[0277] The compounds described herein are also useful for regulating LRH-1 in cells.The method for regulating LRH-1 activity in cells comprises contacting cells with an effective amount of one or more of the compounds described herein.Optionally, contacting is carried out in vivo.Optionally, contacting is carried out in vitro.

[0278] The methods herein for prophylactic and therapeutic treatment optionally include selecting subjects at risk or at risk for developing an LRH-1-associated disease. One skilled in the art can make such determinations using, for example, various predictive and diagnostic methods, including, for example, personal or family history of the disease or condition, clinical trials (e.g., imaging, biopsy, genetic testing), and the like. Optionally, the methods herein can be used to prevent cancer recurrence in subjects in remission (e.g., subjects who previously had cancer).

[0279] VI. Kit Also provided herein are kits for treating or preventing an LRH-1-related disease (e.g., diabetes, cancer, and / or cardiovascular disease) in a subject. The kits may include any of the compounds or compositions described herein. For example, the kits may include one or more compounds of Formula I and / or Formula II. The kits may further include one or more additional agents (such as one or more anti-inflammatory and / or chemotherapeutic agents). The kits may include an oral formulation of any of the compounds or compositions described herein. The kits may include an intravenous formulation of any of the compounds or compositions described herein. The kits may additionally include instructions for using the kit (e.g., instructions for treating a subject), a container, a means for administering the compound or composition (e.g., a syringe), and / or a carrier.

[0280] As used herein, the terms "treat," "treating," or "treating" refer to a method of reducing one or more symptoms of a disease or condition. Thus, in the disclosed methods, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of one or more symptoms of a disease or condition. For example, a method of treating a disease is considered therapeutic if there is a 10% reduction in one or more symptoms or signs of the disease (e.g., tumor size or rate of tumor growth) in a subject compared to a control. As used herein, a control refers to a non-treated condition (e.g., tumor cells not treated with the compounds and compositions described herein). Thus, a reduction can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percentage reduction between 10% and 100% compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete elimination of the disease, condition, or symptoms of the disease or condition.

[0281] As used herein, the terms "preventing," "preventing," and "prevention" refer to an action (such as administering a composition or a therapeutic agent) that occurs before or at approximately the same time as a subject begins to show one or more symptoms of a disease or disorder, and inhibits or delays the onset or severity of one or more symptoms of a disease or disorder.It is not intended that the present disclosure be limited to complete prevention.In some instances, the onset is delayed or the severity of the disease is reduced.

[0282] As used herein, reference to decrease, reduction, or inhibition includes a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to a control level. Such terms can, but do not necessarily, include complete elimination.

[0283] As used herein, subject refers to any animal, including mammals and non-mammals. Mammals include, for example, humans; non-human primates (such as apes and monkeys); cows; horses; sheep; rats; mice; pigs; and goats. Non-mammals include, for example, fish and birds. In some instances, subject refers to a human patient, livestock, rodents, monkeys, or household pets.

[0284] Throughout this application, various publications are referenced, the disclosures of which are incorporated by reference in their entireties into this application.

[0285] The following examples are intended to further illustrate certain aspects of the methods and compositions described herein, and are not intended to limit the scope of the claims. [Example]

[0286] Example 1: Synthesis of hexahydropentalene derivatives A general strategy for the preparation of hexahydropentalene derivatives is illustrated in the following scheme, using the procedures set out in Cato et al., Differential Modulation of Nuclear Receptor LRH-1 through Targeting Buried and Surface Regions of the Binding Pocket, Journal of Medicinal Chemistry, 65, 9, 6888-6902 (2022) and Whitby et al., Small molecule agonists of the orphan nuclear receptors steroidogenic factor-1 (SF-1, NR5A1) and liver receptor homologue-1 (LRH-1, NR5A2). Journal of Medicinal Chemistry, 54, 2266-2281 (2011), or procedures appropriately modified from the same literature.

[0287] Scheme 1: General synthetic scheme for bis-protected 5,5-bicyclic compounds of formula I [ka]

[0288] Scheme 2: General synthetic scheme for [3.3.0] bicyclic carboxylic acids of formula I [ka]

[0289] Scheme 3: General synthetic scheme for bis-protected 5,5-bicyclic compounds of formula II [ka]

[0290] Scheme 4: General synthetic scheme for [3.3.0] bicyclic carboxylic acids of formula II [ka] In Schemes 1-4, "PG" and "PG'" represent protecting groups such as methyoxylmethyl (MOM), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), and the like.

[0291] General Cyclization and Deprotection Procedure Bis(cyclopentadienyl)zirconium(IV) dichloride (zirconecene dichloride) (1.2 equiv.) was dried by azeotroping with benzene four times to remove potential water, then placed under nitrogen, dissolved in tetrahydrofuran (THF), and cooled to −78°C in a dry ice / acetone bath. The resulting zirconecene dichloride solution was treated with nBuLi (2.4 equiv.) to form a clear, pale yellow solution and allowed to stir. After approximately 30 min, azeotropic tert-butyldimethyl((7-phenylhept-1-en-6-yn-3-yl)oxy)silane (19) (1.0 equiv.) in anhydrous THF was added in small portions to give a pink-orange solution, and the reaction mixture was held at −78°C for 30 min, then allowed to warm and stirred at room temperature for 2.5 h. The reaction mixture was then recooled to -78°C, and the required azeotropic dibromoheptane (1.1 equiv.) was added in anhydrous THF. Freshly prepared lithium diisopropylamine (LDA, 1.0 M, 1.1 equiv.) was added at -78°C and stirred for 15 minutes. Lithium phenylacetylide (3.6 equiv.) was then prepared and added dropwise to the reaction mixture in anhydrous THF. The resulting dark reddish-brown solution was stirred at -78°C for 1.5 hours. The reaction was then quenched with methanol and saturated aqueous sodium bicarbonate and allowed to warm to room temperature, forming a pale yellow slurry. The resulting slurry was poured onto water and extracted four times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting yellow oil was crudely purified on a plug of silica, eluting with 20% EtOAc / hexanes to give a yellow oil, which was a mixture of phenylacetylene and the desired bis-protected [3.3.0] bicycle, and was carried on without further purification. This procedure yields a 1.6:1 ratio of exo and endo diastereomers, as determined by the characteristic 1-H NMR signals.

[0292] The crude mixture (1.0 equiv.) was dissolved in THF, tetrabutylammonium fluoride (1.5 equiv.) was added, and the resulting dark brown solution was stirred at ambient temperature for 18 h, concentrated, and directly subjected to silica gel chromatography in 5-10% EtOAc / hexanes to separate both the endo and exo diastereomers of the desired compound (endo eluting before exo) as a clear, colorless oil.

[0293] Synthesis of Representative Compounds According to Formula I and Formula II: [ka] Representative compounds according to Formulas I and II (including compounds 18a, 18b, 18c, and 18d shown above) were synthesized as outlined below. As outlined above in the general procedures, mixtures of diastereomers, for example, can be obtained.

[0294] Glycol derivative 6-iodohex-1-ene(1) [ka] To a round-bottom flask under nitrogen flow was added sodium iodide (93.68 g, 5 equiv., 625 mmol), acetone (300 mL), and 6-bromo-1-hexene (125 mmol, 1 equiv., 16.75 mL). The suspension was stirred and heated to reflux for 18 h. The reaction was then loaded onto a silica plug and eluted with hexane, 1:1 hexane and MTBE, and MTBE (75 mL each). The organics were concentrated to a colorless oil (21.9 g, 104 mmol, 83%). 1H NMR (600 MHz, chloroform-d) δ 5.76 (ddtd, J = 17.0, 10.2, 6.7, 1.5 Hz, 1H), 4.99 (dp, J = 17.1, 1.7 Hz, 1H), 4.94 (dp, J = 10.2, 1.6 Hz, 1H), 3.17 (td, J = 7.0, 1.5 Hz, 2H), 2.05 (qd, J = 7.3, 1.5 Hz, 2H), 1.85 - 1.76 (m, 2H), 1.48 (pd, J = 7.5, 1.5 Hz, 2H).

[0295] 5-(hex-5-en-1-yloxy)pentan-1-ol (2) [ka] Sodium hydride (60% in mineral oil, 3.46 g, 86 mmol, 1 equiv.) followed by 115 mL of DMF and 115 mL of THF was added to a flame-dried round-bottom flask under a positive nitrogen pressure. The mixture was cooled to 0°C, and then 1,5-pentanediol (27.2 mL, 3.0 equiv., 260 mmol) was added dropwise. The resulting solution was stirred for 20 minutes, and then 6-iodohex-1-ene (1) was added dropwise. The reaction was stirred overnight and allowed to warm to room temperature. The next morning, saturated ammonium chloride was added to quench the reaction, and then the mixture was extracted with ethyl acetate (3 x 100 mL). The organics were combined, dried, and concentrated to give a crude oil that was purified by silica chromatography (0-20% EtOAc:hexanes) to give the title compound (8.01 g, 43 mmol, 50% yield). 1H NMR (600 MHz, chloroform-d) δ 5.80 (ddtd, J = 16.9, 10.1, 6.7, 0.9 Hz, 1H), 5.00 (dtd, J = 17.1, 2.6, 1.5 Hz, 1H), 4.94 (ddq, J = 10.1, 2.2, 1.1 Hz, 1H), 3.64 (td, J = 6.5, 0.9 Hz, 2H), 3.40 (tdd, J = 6.6, 3.8, 0.9 Hz, 4H), 2.06 (tdd, J = 7.8, 6.4, 1.3 Hz, 2H), 1.63 - 1.55 (m, 6H), 1.47 - 1.40 (m, 4H).

[0296] tert-Butyl((5-(hex-5-en-1-yloxy)pentyl)oxy)diphenylsilane (3) [ka] 5-(Hex-5-en-1-yloxy)pentan-1-ol (2) (8.01 g, 43 mmol) was dissolved in 400 mL of anhydrous THF, followed by 4.39 g of imidazole (1.5 equiv., 64.5 mmol). The mixture was stirred for 5 minutes until homogeneous, and then TBDPS-Cl (1.2 equiv., 51.6 mmol, 13.42 mL) was added dropwise, followed by stirring at room temperature overnight. The reaction was concentrated to approximately 150 mL and passed through a Celite plug to remove the imidazolium salt. The filtrate was then concentrated to a clear oil, which was purified by silica chromatography (1–7% EtOAc / hexanes) (12.9 g, 30.37 mmol, 70% yield). 1H NMR (600 MHz, chloroform-d) δ 7.69 - 7.64 (m, 4H), 7.44 - 7.35 (m, 6H), 5.80 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.00 (dq, J = 17.1, 1.7 Hz, 1H), 4.94 (ddt, J = 10.2, 2.5, 1.2 Hz, 1H), 3.65 (t, J = 6.5 Hz, 2H), 3.38 (dt, J = 9.3, 6.6 Hz, 4H), 2.10 - 2.03 (m, 2H), 1.62 - 1.51 (m, 6H), 1.48 - 1.37 (m, 4H), 1.04 (s, 9H).

[0297] 5-((5-((tert-butyldiphenylsilyl)oxy)pentyl)oxy)pentanal (4) [ka] Starting material (3) (9.59 mmol; 4.06 g) was dissolved in 150 mL of anhydrous DCM and the reaction was cooled to -78 °C. Ozone was then bubbled through the reaction with stirring until a blue color persisted. Oxygen was then bubbled through the reaction to flush out residual ozone, and then 3 equivalents of triphenylphosphine (7.73 g) were added. The mixture was allowed to warm to room temperature and stirred for 3 hours. The solvent was removed under vacuum, and the resulting oil was purified by silica gel chromatography (0-20% EtOAc in hexanes). 3.083 g, 76%. 1 H NMR (600 MHz, chloroform-d) δ 9.76 (t, J = 1.8 Hz, 1H), 7.71 - 7.60 (m, 4H), 7.46 - 7.33 (m, 6H), 3.66 (t, J = 6.5 Hz, 2H), 3.39 (dt, J = 18.5, 6.5 Hz, 4H), 2.45 (td, J = 7.3, 1.8 Hz, 2H), 1.75 - 1.67 (m, 2H), 1.64 - 1.51 (m, 6H), 1.45 - 1.36 (m, 2H), 1.04 (s, 9H).

[0298] tert-Butyl((5-((5,5-dibromopentyl)oxy)pentyl)oxy)diphenylsilane(5) [ka] Under nitrogen, a solution of triphenyl phosphite (2.35 mL, 9 mmol, 1.1 equiv) in DCM (50 mL) was cooled to −78° C. Bromine (0.48 mL, 9 mmol, 1.1 equiv) and triethylamine (1.32 mL, 9 mmol, 1.1 equiv) were added dropwise successively at −78° C. The reaction was stirred for 5 minutes, and then 5-((5-((tert-butyldiphenylsilyl)oxy)pentyl)oxy)pentanal (4) (5.8 g, 14 mmol, 1.0 equiv) was added via syringe as a solution in DCM (10 mL) at −78° C. The reaction was stirred for 5 hours and allowed to warm to ambient temperature. The entire reaction was then poured onto a pad of silica. The filtrate was concentrated and purified on a short plug of silica with 5% MTBE in hexane to give the title compound as a clear, colorless oil (3.35 g, 72%). 1 H NMR (600 MHz, chloroform-d) δ 7.64 (dt, J = 8.0, 1.4 Hz, 4H), 7.44 - 7.31 (m, 6H), 5.67 (td, J = 6.2, 1.1 Hz, 1H), 3.63 (td, J = 6.5, 1.2 Hz, 2H), 3.42 - 3.29 (m, 4H), 2.38 (dddt, J = 7.6, 6.1, 4.2, 2.0 Hz, 2H), 1.66 - 1.46 (m, 9H).

[0299] Di(1,3-dioxan-2-yl)methane(6) [ka] Compound 6 (di(1,3-dioxan-2-yl)methane) was prepared as reported in Jahromi et al., J. Med. Chem., 2013, 56, 9471.

[0300] 3,3'-(propane-1,3-diylbis(oxy))bis(propan-1-ol (7) [ka] A dried three-necked round-bottom flask charged with a stir bar was removed from the drying oven, sealed with a septum stopper, and then connected to a vacuum line. The flask was left under vacuum to cool to room temperature. Once cooled, di(1,3-dioxan-2-yl)methane (21 g, 111.85 mmol, 1.0 equiv.) and freshly prepared Cu II (OTf)2 (810 mg, 2.24 mmol, 2% loading) was added to the flask under positive nitrogen pressure. The flask was resealed with a septum stopper. The atmosphere was exchanged by applying vacuum and refilling with N2 (this process was performed a total of three times). Degassed tetrahydrofuran (THF, 65 mL / mmol di(1,3-dioxan-2-yl)methane) was transferred to the flask, and the resulting solution was cooled to 0 °C. Once cooled, BH3·DMS (37.1 mL, 391.5 mmol, 3.5 equiv.) was added. The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with MeOH and applied to a short Celite plug. The resulting crude mixture was concentrated in vacuo and subjected to silica gel chromatography (5–15% MeOH / EtOAc) to give the title compound (13.3 g, 62%).

[0301] 2,2-Dimethyl-3,3-diphenyl-4,8,12-trioxa-3-silapentadecan-15-ol (8) [ka] To a solution of tripropylene glycol (13.3 g, 69.2 mmol, 1.3 equiv.) and imidazole (3.62 g, 53.2 mmol, 1 equiv.) in anhydrous THF (800 mL) in an oven-dried flask at room temperature under nitrogen was added tert-butyl(chloro)diphenylsilane (13.85 mL, 53.2 mmol, 1 equiv.) and stirred for 2.5 h. The resulting solution was concentrated in vacuo and subjected to silica gel chromatography (20-50% EtOAc / hexanes) to afford the title compound (12.3 g, 54%). 1 H NMR (600 MHz, chloroform-d) δ 7.67 - 7.65 (m, 4H), 7.43 - 7.35 (m, 6H), 3.77 - 3.73 (m, 4H), 3.61 - 3.58 (m, 2H), 3.54 (t, J = 6.4 Hz, 2H), 3.49 (t, J = 6.4 Hz, 2H), 3.46 (t, J = 6.3 Hz, 2H), 2.42 (s, 1H), 1.85 - 1.78 (m, 6H), 1.04 (d, J = 0.6 Hz, 9H). 13 C NMR (151 MHz, chloroform-d) δ 135.56, 133.99, 129.54, 127.60, 70.46, 68.46, 67.76, 67.63, 62.35, 60.84, 32.72, 31.96, 30.07, 26.86, 19.24.

[0302] 2,2-Dimethyl-3,3-diphenyl-4,8,12-trioxa-3-silapentadecan-15-al (9) [ka] To a solution of 2,2-dimethyl-3,3-diphenyl-4,8,12-trioxa-3-silapentadecan-15-ol (12.3 g, 28.6 mmol, 1 equiv.) in anhydrous THF (500 mL) in an oven-dried flask at 0 °C under nitrogen, Dess-Martin periodinane (14.5 g, 34.3 mmol, 1.2 equiv.) was added, allowed to warm to room temperature, and stirred for 1.5 h. The reaction mixture was then filtered through a pad of Celite. The resulting solution was concentrated in vacuo and subjected to silica gel chromatography (20–50% EtOAc / hexanes) to afford the title compound (10.5 g, 86%). 1 H NMR (600 MHz, chloroform-d) δ 9.77 (td, J = 2.0, 0.7 Hz, 1H), 7.69 - 7.64 (m, 4H), 7.44 - 7.34 (m, 6H), 3.74 (dt, J = 8.1, 6.1 Hz, 4H), 3.54 (t, J = 6.4 Hz, 2H), 3.49 (t, J = 6.4 Hz, 2H), 3.45 (t, J = 6.3 Hz, 2H), 2.66 - 2.61 (m, 2H), 1.81 (dp, J = 8.0, 6.4 Hz, 4H), 1.04 (s, 9H), 13 C NMR (151 MHz, chloroform-d) δ 201.30, 135.56, 133.99, 129.55, 127.61, 68.25, 67.58, 64.47, 60.83, 43.87, 32.75, 29.98, 26.85, 19.24.

[0303] 15,15-Dibromo-2,2-dimethyl-3,3-diphenyl-4,8,12-trioxa-3-silapentadecane (10) [ka] To a cold solution of triphenylphosphite (7.1 g, 27.0 mmol, 1.1 equiv.) in anhydrous dichloromethane (350 mL) maintained at −78°C under N2 flow, bromine (1.4 mL, 27.0 mmol, 1.1 equiv.) was added dropwise. Anhydrous triethylamine (4.1 mL, 29.5 mmol, 1.2 equiv.) and 2,2-dimethyl-3,3-diphenyl-4,8,12-trioxa-3-silapentadecan-15-al (10.5 g, 24.5 mmol, 1 equiv.) were added to the pale orange solution. The reaction mixture was stirred for 4 h and then allowed to warm to room temperature after 3 h. The resulting solution was concentrated in vacuo and subjected to silica gel chromatography (10–30% MTBE / hexanes) to give the title compound (10.9 g, 78%). 1 H NMR (600 MHz, chloroform-d) δ 7.68 - 7.65 (m, 4H), 7.44 - 7.40 (m, 2H), 7.40 - 7.36 (m, 4H), 5.82 (t, J = 6.7 Hz, 1H), 3.75 (t, J = 6.1 Hz, 2H), 3.55 (t, J = 6.4 Hz, 2H), 3.52 - 3.44 (m, 6H), 2.61 (q, J = 5.9 Hz, 2H), 1.86 - 1.77 (m, 4H), 1.05 (s, 9H). 13 C NMR (151 MHz, chloroform-d) δ 135.57, 133.98, 129.55, 128.35, 127.61, 77.23, 77.02, 76.81, 68.18, 68.05, 67.64, 67.58, 60.84, 45.59, 43.09, 32.76, 29.99, 27.25, 20.21.

[0304] Cyclization procedure for hexahydropentalene formation Prior to cyclization, all nonvolatile reagents were dried by azeotropic removal of water using benzene. A dry round-bottom flask containing bis(cyclopentadienyl)zirconium(IV) dichloride (1.2 equiv.) was dissolved in anhydrous, degassed tetrahydrofuran (THF, 8 mL / mmol enyne) under nitrogen and cooled to -78 °C. The resulting mixture was treated with n-BuLi (2.4 equiv.), and the pale yellow solution was stirred for 45 min. A solution of 11 ((5-(methoxymethoxy)hept-6-en-1-yn-1-yl)benzene) or 12 (tert-butyldimethyl((7-phenylhept-1-en-6-yn-3-yl)oxy)silane) (1.0 equiv.) in anhydrous, degassed THF (8 mL / mmol) was added. The resulting salmon-pink mixture was stirred at -78 °C for 45 min and then removed from the cooling bath. The reaction mixture continued to stir at room temperature for an additional 2.5 h. The reaction mixture was then cooled to −78° C., and the desired 1,1-dibromoether tail (5) or (10) (1.1 equiv.) was added, followed by freshly prepared lithium diisopropylamide (LDA, 1.0 M, 1.1 equiv.) as a solution in anhydrous THF (8 mL / mmol of enyne). After 15 min, a freshly prepared solution of lithium phenylacetylide (3.6 equiv.) in anhydrous THF (8 mL / mmol of enyne) was added dropwise, and the resulting rust-colored solution was stirred at −78° C. for 1.5 h. The reaction was quenched with methanol and saturated aqueous sodium bicarbonate and allowed to warm gradually to room temperature, resulting in a pale yellow slurry. The slurry was poured onto water and extracted four times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting yellow oil was passed through a short plug of silica (100% EtOAc eluent) and concentrated. The crude product was dissolved in THF and treated with either HCl or TBAF. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the diastereomers were purified and separated by flash chromatography.

[0305] 5-(4-(-6-(methoxymethoxy)-3-phenyl-3a-(1-phenylvinyl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)butoxy)pentan-1-ol (13a): [ka] Following the general procedure, 5 (2.50 g, 4.4 mmol) was reacted with 11 (1.20 g, 4 mmol) followed by treatment with 5 equivalents of tetrabutylammonium fluoride to afford the title compound as a yellow oil after purification by flash chromatography (0–50% EtOAc / Hex eluent) (1.2 g, 5:1 diastereomeric ratio, 60% yield over two steps). 1 H NMR (600 MHz, chloroform-d) δ 7.32 - 7.25 (m, 3H), 7.24 - 7.20 (m, 5H), 7.18 (dt, J = 8.1, 1.5 Hz, 2H), 5.02 (q, J = 2.5, 2.0 Hz, 1H), 4.98 (q, J = 2.4, 1.9 Hz, 1H), 4.60 - 4.54 (m, 2H), 3.79 - 3.73 (m, 1H), 3.66 - 3.57 (m, 4H), 3.34 (td, J = 6.6, 1.3 Hz, 2H), 3.28 (d, J = 1.3 Hz, 3H), 2.39 (dq, J LRMS (APCI) m / z C 33 H 44 O4: Calculated value 505.3, Found value 473.3 (13a - CH3O · )

[0306] 3-(3-(2-(-6-(methoxymethoxy)-3-phenyl-3a-(1-phenylvinyl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)ethoxy)propoxy)propan-1-ol (13b) [ka] Following the general cyclization procedure, 10 (2.50 g, 4.4 mmol) was reacted with 11 (1.20 g, 4 mmol) followed by treatment with 5 equivalents of tetrabutylammonium fluoride to afford the title compound as a yellow oil after purification by flash chromatography (0–50% EtOAc / Hex eluent) (1.24 g, 7:1 diastereomeric ratio, 61% yield over two steps). 1 H NMR: 1 H NMR (600 MHz, chloroform-d) δ 7.32 (ddq, J = 6.0, 2.3, 1.3 Hz, 2H), 7.28 - 7.25 (m, 2H), 7.26 - 7.19 (m, 6H), 5.03 (q, J = 1.3 Hz, 1H), 4.98 (dd, J = 2.0, 1.3 Hz, 1H), 4.58 - 4.53 (m, 2H), 3.76 - 3.75 (m, 1H), 3.58 - 3.54 (m, 2H), 3.48 - 3.44 (m, 2H), 3.42 - 3.35 (m, 4H), 3.27 (d, J = 2.0 Hz, 3H), 2.40 (ddt, J = 11.0, 7.1, 1.7 Hz, 2H), 2.36 - 2.25 (m, 3H), 2.07 (d, J = 16.9 Hz, 1H), 1.78 (ddt, J = 7.8, 5.9, 3.4, 1.8 Hz, 5H), 1.67 - 1.58 (m, 2H). LRMS (APCI) m / z[M+H] + C 32 H 42 O5: Calculated value 507.3, Found value 475.3 (13b - CH3O · )

[0307] 5-(4-((5-hydroxypentyl)oxy)butyl)-4-phenyl-3a-(1-phenylvinyl)-1,2,3,3a,6,6a-hexahydropentalen-1-ol (13c) [ka] Following the general procedure, 5 (2.50 g, 4.4 mmol) was reacted with 11 (1.20 g, 4 mmol) followed by treatment with 3 drops of HCl to afford the title compound as a yellow oil (1.21 g, 66% yield over two steps) after purification by flash chromatography (0–65% EtOAc / Hex eluent). 1 H NMR (600 MHz, chloroform-d) δ 7.35 - 7.30 (m, 5H), 7.25 (m, 2H), 7.20 (t, J = 6.8 Hz, 3H), 5.07 (d, J = 1.6 Hz, 1H), 4.99 (dp, J = 1.5 Hz, 1H), 3.95 (m, 1H), 3.65 (t, J = 6.6 Hz, 3H), 3.38 (t, J = 6.4 Hz, 4H), 3.33 (t, J = 6.3 Hz, 2H), 2.64 (d, J = 17.3 Hz, 1H), 2.47 (t, J = 8.7 Hz, 1H), 2.42 - 2.24 (m, LRMS (APCI) m / z[M+H] + C 31 H 41 O3: Calculated value 461.7, Measured value 461.3

[0308] 5-(2-(3-(3-hydroxypropoxy)propoxy)ethyl)-4-phenyl-3a-(1-phenylvinyl)-1,2,3,3a,6,6a-hexahydropentalen-1-ol (13d) [ka] Following the general procedure for cyclization, 8 (2.52 g, 4.4 mmol) was reacted with 12 (1.20 g, 4 mmol) and then treated with 3 drops of HCl to afford the title compound as a yellow oil (758.7 g, 41% yield over two steps) after purification by flash chromatography (10–100% EtOAc / Hex eluent). 1 H NMR (600 MHz, chloroform-d) δ 7.36 - 7.31 (m, 4H), 7.30 - 7.24 (m, 3H), 7.22 - 7.20 (m, 3H), 5.05 (d, J = 1.1 Hz, 1H), 4.97 (d, J = 1.0 Hz, 1H), 3.92 (m, 1H), 3.73 (t, J = 5.5 Hz, 4H), 3.57 (q, J = 5.9, 4.7 Hz, 4H), 3.48 (dt, J = 16.8, 6.0 Hz, 3H), 3.42 - 3.33 (m, 4H), 2.57 (td, J = 10.7, 9.6, 5.9 Hz, 2H), 2.42 (t, J = 8.3 Hz, 1H), 2.39 - 2.20 (m, 4H), 2.14 - 2.03 (m, 4H), 1.96 - 1.88 (m, 1H), 1.67 - 1.58 (m, 1H). LRMS (APCI) m / z[M+H] + C 30 H 39 O4: Calculated value 463.6, Measured value 463.3

[0309] Oxidation Method To a solution of 13a-d (1 equivalent) in acetonitrile (0.1 M), tetrapropylammonium perruthenate (TPAP) (0.1 equivalent), N-methylmorpholine N-oxide (NMO) (10 equivalents), and water (10 equivalents) were added and stirred at room temperature overnight. The reaction solution was then filtered through a silica pad with 100% EtOAc and concentrated. The resulting mixture was purified by flash chromatography to give the title compound.

[0310] 5-(4-(6-(methoxymethoxy)-3-phenyl-3a-(1-phenylvinyl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)butoxy)pentanoic acid (14a) [ka] A solution of the desired alcohol (504 mg, 1 equiv.) in 50 mL of acetonitrile was treated with tetrapropylammonium perruthenate (TPAP, 0.1 equiv., 17.55 mg), N-methylmorpholine-N-oxide (NMO, 10 equiv., 1.17 g), and water (10 equiv., 180 microliters). The reaction mixture was left stirring at room temperature overnight. The reaction mixture was passed through Celite, concentrated, and purified on silica (0-65% EtOAc (containing 0.1% AcOH) / hexanes eluent) to give the title compound. 70 mg, 13%. 1 H NMR (600 MHz, chloroform-d) δ 7.38 - 7.28 (m, 4H), 7.28 - 7.25 (m, 3H), 7.25 - 7.22 (m, 2H), 5.06 (d, J = 1.2 Hz, 1H), 5.04 (t, J = 1.2 Hz, 1H), 4.64 (s, 2H), 3.81 (dd, J = 4.5, 2.6 Hz, 1H), 3.42 (q, J = 5.8 Hz, 2H), 3.37 (dd, J = 6.1, 1.2 Hz, 5H), 2.39 (t, J = 7.6 Hz, 2H), 1.71 - 1.59 (m, 4H), 1.56 - 1.41 (m, 5H), 1.36 - 1.23 (m, 10H). LRMS (APCI) m / z C 33 H 42 O5: Calculated value 519.3, Measured value 487.3 (14a - CH3O · )

[0311] 3-(3-(2-(6-(methoxymethoxy)-3-phenyl-3a-(1-phenylvinyl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)ethoxy)propoxy)propanoic acid (14b) [ka] A solution of the desired alcohol (504 mg, 1 equiv.) in 50 mL of acetonitrile was treated with tetrapropylammonium perruthenate (TPAP, 0.1 equiv., 17.55 mg), N-methylmorpholine-N-oxide (NMO, 10 equiv., 1.17 g), and water (10 equiv., 180 microliters). The reaction mixture was left stirring at room temperature overnight. The reaction mixture was passed through Celite, concentrated, and purified on silica (20-80% EtOAc (containing 0.1% AcOH) / hexanes eluent) to give the title compound. 285 mg, 45% yield. 1 H NMR (600 MHz, chloroform-d) δ 7.35 - 7.30 (m, 2H), 7.29 - 7.25 (m, 2H), 7.24 - 7.20 (m, 6H), 5.03 (d, J = 1.4 Hz, 1H), 4.98 (d, J = 1.4 Hz, 1H), 4.61 - 4.55 (m, 2H), 3.80 - 3.74 (m, 1H), 3.67 - 3.63 (m, 2H), 3.52 - 3.46 (m, 2H), 3.42 - 3.34 (m, 5H), 3.29 (t, J = 1.0 Hz, 2H), 2.57 (td, J = 6.2, 1.4 Hz, 2H), 2.39 (dt, J = 9.3, 1.6 Hz, 1H), 2.35 - 2.29 (m, 2H), 2.26 (dt, J = 13.8, 6.5 Hz, 1H), 2.11 - 2.08 (m, 1H), 2.08 - 2.04 (m, LRMS (APCI) m / z C 32 H 40 O6: Calculated value 521.3, Measured value 489.3 (14a - CH3O · )

[0312] 5-(4-(6-oxo-3-phenyl-3a-(1-phenylvinyl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)butoxy)pentanoic acid (14c) [ka] Following the general oxidation procedure, 13c (1.21 g, 2.63 mmol) was reacted with TPAP (92.4 mg, 0.26 mmol), NMO (3.07 g, 26 mmol), water (473 μL, 473 mg, 26 mmol), and acetonitrile (40 mL) to afford the title compound as an oil (529 mg, 43% yield) after purification by flash chromatography (0–65% EtOAc / Hex). 1 H NMR (600 MHz, chloroform-d) δ 7.36 - 7.31 (m, 2H), 7.30 - 7.26 (m, 3H), 7.23 (m, 3H), 7.20 - 7.16 (m, 2H), 5.19 (d, J = 1.7 Hz, 1H), 5.08 (d, J = 1.6 Hz, 1H), 3.34 (t, J = 6.2 Hz, 2H), 3.27 (t, J = 6.5 Hz, 2H), 2.44 (d, J = 7.7 Hz, 1H), 2.35 (td, J = 7.4, 1.6 Hz, 2H), 2.28 (dd, J = 13.7, 9.0 Hz, 2H), 2.14 - 2.04 (m, 4H), 2.02 - 1.96 (m, 2H), 1.87 (dd, J = 16.5, 7.8 Hz, 1H), 1.67 (p, J = 7.4 Hz, 2H), 1.57 (dq, J = 12.4, 6.6 Hz, 2H), 1.40 (h, J = 6.5 Hz, 2H), 1.29 (p, J = 7.7 Hz, 2H). LRMS (APCI) m / z[M+H] + C 31 H 37 O4: Calculated value 473.6, Measured value 473.3

[0313] 3-(3-(2-(6-oxo-3-phenyl-3a-(1-phenylvinyl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)ethoxy)propoxy)propanoic acid (14d) [ka] Following the general oxidation procedure, 13d (1.51 g, 3.2 mmol) was reacted with TPAP (112.5 mg, 0.32 mmol), NMO (3.74 g, 32 mmol), water (576 μL, 576 mg, 32 mmol), and acetonitrile (53 mL) to afford the title compound as an oil (817 mg, 53% yield) after purification by flash chromatography (20–50% EtOAc / Hex). 1 H NMR (600 MHz, chloroform-d) δ 7.36 (d, J = 4.7 Hz, 4H), 7.28 (m, 4H), 7.24 - 7.20 (m, 2H), 5.25 (d, J = 1.5 Hz, 1H), 5.13 (d, J = 1.5 Hz, 1H), 3.69 (t, J = 6.1 Hz, 2H), 3.56 - 3.44 (m, 2H), 3.44 - 3.28 (m, 4H), 2.60 (t, J = 6.0 Hz, 2H), 2.47 (t, J = 7.8 Hz, 2H), 2.44 - 2.20 (m, 4H), 2.15- 2.07 (m, 2H), 1.97 - 1.88 (m, 1H), 1.77 (dq, J = 12.2, 6.2 Hz, 2H).

[0314] Methylation Method To a solution of 14c-d (1 equiv.) in methanol (0.1 M), 3 drops of concentrated HCl was added and stirred at room temperature overnight. The reaction solution was then concentrated in vacuo and filtered through a pad of silica to collect the title compound.

[0315] Methyl-5-(4-(6-oxo-3-phenyl-3a-(1-phenylvinyl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)butoxy)pentanoate (15a): [ka] Following the general procedure for methylation, 14c (529 mg, 1.1 mmol) was reacted with HCl in methanol to give the title compound as a yellow oil (545 mg, quantitative yield). 1 H NMR (600 MHz, chloroform-d) δ 7.39 - 7.33 (m, 2H), 7.33 - 7.28 (m, 3H), 7.26 (t, J = 3.9 Hz, 3H), 7.22 - 7.19 (m, 2H), 5.22 (d, J = 1.5 Hz, 1H), 5.11 (d, J = 1.4 Hz, 1H), 3.66 (s, 3H), 3.34 (t, J = 6.4 Hz, 2H), 3.28 (t, J = 6.5 Hz, 2H), 2.46 (d, J = 7.8 Hz, 1H), 2.38 - 2.24 (m, 4H), 2.14 - 1.99 (m, 5H), 1.91 (dd, J = 16.5, 7.8 Hz, 1H), 1.66 (ddd, J = 12.4, 8.8, 6.0 Hz, 2H), 1.56 (dq, J = 10.3, 6.6 Hz, 2H), 1.41 (dt, J = 9.8, 6.5 Hz, 2H), 1.31 (q, J = 7.8 Hz, 2H).

[0316] Methyl-3-(3-(2-(6-oxo-3-phenyl-3a-(1-phenylvinyl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)ethoxy)propoxy)propanoate (15b): [ka] Following the general procedure for methylation, 14dc (403.4 mg, 0.85 mmol) was reacted with HCl in methanol to afford the title compound as a yellow oil (299 mg, 70% yield) after purification by flash chromatography (30% EtOAc / Hex). 1H NMR (600 MHz, クロロホルム-d) δ 7.36 (d, J = 4.3 Hz, 4H), 7.32 (p, J = 4.2 Hz, 2H), 7.28 (d, J = 6.5 Hz, 2H), 7.23 (dd, J = 7.7, 2.0 Hz, 2H), 5.24 (d, J = 1.4 Hz, 1H), 5.12 (d, J = 1.5 Hz, 1H), 3.68 (s, 3H), 3.66 (d, J = 6.5 Hz, 2H), 3.46 (td, J = 6.4, 3.3 Hz, 2H), 3.41 - 3.28 (m, 4H), 2.56 (t, J = 6.4 Hz, 2H), 2.46 (d, J = 7.8 Hz, 1H), 2.39 (dd, J = 14.2, 7.1 Hz, 1H), 2.35 (d, J = 16.4 Hz, 1H), 2.32 - 2.24 (m, 2H), 2.16 - 2.00 (m, 3H), 1.96 (dd, J = 16.5, 7.9 Hz, 1H), 1.76 (p, J = 6.4 Hz, 2H), 1.26 (d, J = 2.6 Hz, 1H). LRMS (APCI) m / z[M+H] + C 31 H 37 O5:についての calculated value 489.6, measured value 489.3

[0317] Aminification of the original form To a flame-dried screw-cap test tube charged with a refilled (three times) stir bar, 15a-b (1.0 equiv.) and ethanol (0.1 M) were added. Ammonia (7 M in methanol, 5.0 equiv. or 20.0 equiv.) and titanium(IV) isopropoxide (0.33 mL, 1.08 mmol, 1.5 equiv.) were added via syringe and stirred at room temperature for 6 hours. The test tube cap was then removed, and sodium borohydride (3.0 equiv.) was added in small portions. The resulting solution was stirred at room temperature for 30 minutes and then diluted with EtOAc. The solution was adjusted to pH 1 with 1 M HCl. The layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were then dried over Na2SO4, filtered, concentrated in vacuo, and then purified by flash chromatography to provide the title compound.

[0318] Methyl-5-(4-(6-amino-3-phenyl-3a-(1-phenylvinyl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)butoxy)pentanoate (16a): [ka] Following the general procedure for reductive amination, 15a (545 mg, 1.13 mmol) was reacted with ammonia (816 μL, 5.65 mmol), Ti(OiPr)4 (517 μL, 1.7 mmol), and NaBH4 (128 mg, 3.4 mmol) in ethanol (11 mL) to afford the title compound as a clear oil (235 mg, 42% yield) after purification by flash chromatography (0–10% MeOH / DCM). 1H NMR (600 MHz, chloroform-d) δ 7.29 - 7.24 (m, 7H), 7.24 - 7.21 (m, 3H), 5.09 (d, J = 1.4 Hz, 1H), 4.97 (d, J = 1.5 Hz, 1H), 3.65 (s, 3H), 3.50 (td, J = 10.4, 9.2, 4.0 Hz, 1H), 3.30 (t, J = 6.4 Hz, 2H), 3.23 (q, J = 5.9 Hz, 2H), 2.67 (t, J = 9.1 Hz, 1H), 2.42 (d, J = 17.8 Hz, 1H), 2.31 (t, J = 7.5 Hz, 2H), 2.25 (dd, J = 17.8, 8.9 Hz, 1H), 2.17 (q, J = 7.4, 5.6 Hz, 2H), 2.07 - 2.00 (m, 1H), 1.75 (dt, J = 12.6, 5.6 Hz, 1H), 1.72 - 1.61 (m, 4H), 1.54 (dt, J = 9.4, 6.5 Hz, 2H), 1.38 (ddt, J = 23.5, 16.8, 8.7 Hz, 4H). LRMS (APCI) m / z[M+H] + C 32 H 42 NO3: Calculated value 488.7, Measured value 488.3

[0319] Methyl-3-(3-(2-(6-amino-3-phenyl-3a-(1-phenylvinyl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)ethoxy)propoxy)propanoate (16b): [ka] Following the general procedure for reductive amination, 15b (299.1 mg, 0.6 mmol) was reacted with ammonia (1.7 mL, 12.2 mmol), Ti(OiPr)4 (272 μL, 261.4 mmol), and NaBH4 (68.1 mg, 1.8 mmol) in ethanol (6 mL) to afford the title compound as an orange oil (210.8 mg, 67% yield) after purification by flash chromatography (0–10% methanol / DCM). 1 H NMR (600 MHz, chloroform-d) δ 7.53 - 7.36 (m, 2H), 7.31 (dd, J = 8.3, 6.5 Hz, 3H), 7.29 - 7.25 (m, 3H), 7.19 (dq, J = 5.3, 2.9, 2.5 Hz, 2H), 5.18 (d, J = 1.5 Hz, 1H), 5.07 (d, J = 1.6 Hz, 1H), 3.93 - 3.86 (m, 1H), 3.75 - 3.66 (m, 3H), 3.65 (s, 3H), 3.60 - 3.51 (m, 3H), 3.48 (ddd, J = 9.2, 5.6, 3.2 Hz, 1H), 2.89 - 2.75 (m, 1H), 2.70 (dd, J = 9.7, 6.7 Hz, 1H), 2.66 - 2.58 (m, 2H), 2.54 (ddd, J = 16.2, 6.8, 4.4 Hz, 2H), 2.24 - 2.16 (m, 1H), 2.00 - 1.94 (m, 3H), 1.93 - 1.79 (m, 2H), 1.73 (dq, J = 15.9, 6.0 Hz, 2H), 1.49 - 1.38 (m, 1H). LRMS (APCI) m / z[M+H] + C 31 H 40 NO4: Calculated value 490.6, Measured value 490.3

[0320] Sulfamidation Procedure To a solution of tert-butyl alcohol (5.5 equiv.) in anhydrous DCM (5 mL) in an oven-dried flask refilled with nitrogen three times at 0 °C, neat chlorosulfonyl isocyanate (5.0 equiv.) was added and stirred for 30 min. The reaction mixture was removed from the ice bath and allowed to stir at room temperature for an additional 90 min. 1 mL of the resulting solution was then added via syringe to a solution of 16a-b (1.0 equiv.) and triethylamine (2.5 equiv.) in anhydrous DCM (0.1 M) in an oven-dried flask under nitrogen at 0 °C. The reaction was then stirred and warmed to room temperature over 3 h, after which it was diluted with DCM and washed with 2 × 10 mL of 0.5 M aqueous HCl, 10 mL of water, and 10 mL of brine. The organic layer was then dried over Na SO , filtered, and concentrated in vacuo to give the crude material. This material was subjected to silica gel chromatography (1-40% EtOAc / hexanes) to collect the resulting material as crude for the next step.

[0321] Methyl-5-(4-(6-((N-(tert-butoxycarbonyl)sulfamoyl)amino)-3-phenyl-3a-(1-phenylvinyl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)butoxy)pentanoate (17a): [ka] Following the general sulfamidation procedure, 16a (135 mg, 0.26 mmol) was reacted with chlorosulfonyl isocyanate (113 μL, 183.9 mg, 1.3 mmol), t-BuOH (137 μL, 106.0 mg, 1.43 mmol), and TEA (90 μL, 0.65 mmol) in DCM (2.6 mL) to afford the title compound as a clear oil (139.4 mg, 80% yield) after flash chromatography (20–50% EtOAc / hexanes). 1H NMR (500 MHz, chloroform-d) δ 7.34 - 7.29 (m, 5H), 7.28 - 7.25 (m, 3H), 7.21 (d, J = 1.8 Hz, 1H), 7.20 (t, J = 1.6 Hz, 1H), 5.32 (d, J = 7.9 Hz, 1H), 5.11 (d, J = 1.3 Hz, 1H), 4.98 (d, J = 1.3 Hz, 1H), 3.76 (ddd, J = 11.0, 5.5, 2.5 Hz, 1H), 3.68 (s, 3H), 3.40 (t, J = 6.3 Hz, 2H), 3.35 (t, J = 6.1 Hz, 2H), 2.61 (td, J = 8.9, 2.0 Hz, 1H), 2.48 (dd, J = 17.7, 2.1 Hz, 1H), 2.36 (t, J = 7.5 Hz, 2H), 2.24 - 2.08 (m, 3H), 1.97 - 1.85 (m, LRMS (APCI) m / z[M+H] + C 37 H 51 Calculated value for N2O7S: 667.8, Found value: 610.1 (17a-t-Bu)

[0322] Methyl-3-(3-(2-(6-((N-(tert-butoxycarbonyl)sulfamoyl)amino)-3-phenyl-3a-(1-phenylvinyl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)ethoxy)propoxy)propanoate (17b): [ka] Following the general sulfamidation procedure, 16b (52.6 mg, 0.1 mmol) was reacted with chlorosulfonyl isocyanate (43.5 μL, 70.7 mg, 0.5 mmol), t-BuOH (52.6 μL, 40.8 mg, 0.55 mmol), and TEA (34.8 μL, 0.25 mmol) in DCM (1 mL) to afford the title compound as a clear oil (37.5 mg, 56% yield) after flash chromatography (50% EtOAc / hexanes). 1 H NMR (500 MHz, chloroform-d) δ 7.39 - 7.35 (m, 2H), 7.33 - 7.29 (m, 2H), 7.27 (dt, J = 5.9, 1.5 Hz, 3H), 7.26 - 7.23 (m, 3H), 5.64 (d, J = 8.9 Hz, 1H), 5.09 (d, J = 1.5 Hz, 1H), 5.08 (d, J = 1.5 Hz, 1H), 3.85 (dtd, J = 10.4, 9.2, 7.2 Hz, 1H), 3.71 (t, J = 6.4 Hz, 2H), 3.69 (s, 3H), 3.68 - 3.63 (m, 2H), 3.60 (dt, J = 9.4, 6.4 Hz, 1H), 3.55 (t, J = 6.3 Hz, 2H), 3.53 - 3.45 (m, 2H), 2.59 (t, J = 6.4 Hz, 2H), 2.57 - 2.47 (m, 3H), 2.08 (dt, J = 14.4, 5.0 Hz, 1H), 1.98 - 1.85 (m, 4H), 1.67 - 1.60 (m, 3H), 1.55 - 1.49 (m, 1H), 1.43 (s, 9H), 1.41 - 1.31 (m, 1H). LRMS (APCI) m / z[M+H] + C 36 H 49 Calculated for N2O8S: 669.8, Found: 686.3 (17b + H2O)

[0323] Deprotection procedure A reaction vial was charged with a stir bar, and 14a-b or 17a-b (160 mg, 0.24 mmol) was dissolved in dioxane, followed by the addition of a few drops of concentrated HCl. The reaction was gradually heated to 40 °C, then diluted with EtOAc and washed with 3 × 5 mL of 0.5 M aqueous HCl, 5 mL of water, and 5 mL of brine. The organic layer was then dried over Na SO , filtered, and concentrated in vacuo to give the title compound after flash chromatography.

[0324] 5-(4-(6-hydroxy-3-phenyl-3a-(1-phenylvinyl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)butoxy)pentanoic acid (18a; 10CA-monoether; 10CA-ME): [ka] Compound 14a (70 mg) was dissolved in 200 mL of DCM, and then 5 drops of TFA were added. The reaction was stirred at room temperature until complete by TLC and HPLC. The reaction was then concentrated and purified by silica chromatography (30-100% EtOAc / hexanes with 1% AcOH). 27 mg, 42% 1 H NMR: 1 H NMR (600 MHz, chloroform-d) δ 7.35 - 7.28 (m, 5H), 7.24 - 7.18 (m, 5H), 5.06 (d, J = 1.3 Hz, 1H), 5.00 (d, J = 1.4 Hz, 1H), 3.95 (s, 1H), 3.39 (t, J = 6.2 Hz, 2H), 3.34 (t, J = 6.3 Hz, 2H), 2.39 (t, J = 7.3 Hz, 2H), 2.34 - 2.28 (m, 1H), 2.12 - 1.98 (m, 4H), 1.77 - 1.57 (m, 11H), 1.52 - 1.45 (m, 1H), 1.42 (q, J = 7.6, 7.2 Hz, 1H). LRMS (APCI) m / z[M+H] + C 31 H 38O4: Calculated value 475.3, Measured value 475.3

[0325] 3-(3-(2-(6-hydroxy-3-phenyl-3a-(1-phenylvinyl)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)ethoxy)propoxy)propanoic acid (18b; 10CA-diether; 10CA-DE) [ka] Compound 14b (125 mg) was dissolved in 10 mL of acetonitrile and 5 drops of 12 M HCl. The reaction was stirred for 10 min, then concentrated and purified by preparative HPLC (15-75% ACN in water, 0.1% formic acid modifier, 30 min gradient). Yield: 97 mg, 85%. 1 H NMR (600 MHz, chloroform-d) δ 7.37 (dd, J = 6.6, 2.9 Hz, 2H), 7.32 (t, J = 7.3 Hz, 2H), 7.28 (d, J = 7.8 Hz, 6H), 5.09 (s, 1H), 5.03 (s, 1H), 4.01 - 3.93 (m, 1H), 3.70 (t, J = 6.2 Hz, 2H), 3.54 (t, J = 6.3 Hz, 2H), 3.44 (qd, J = 9.2, 4.6 Hz, 4H), 2.61 (t, J = 6.1 Hz, 2H), 2.42 - 2.33 (m, 2H), 2.31 (dd, J = 12.6, 6.9 Hz, 2H), 2.14 (d, J = 17.2 Hz, 1H), 1.83 (p, J = 6.3 Hz, 2H), 1.74 (tt, J = 10.9, 5.5 Hz, 1H), 1.49 (pd, J = 7.1, 3.4 Hz, 1H), 1.43 (q, J = 7.7, 6.6 Hz, 1H), 1.36 (p, J = 3.5 Hz, 1H). LRMS (APCI) m / z[M+H] + C 30 H 36 O5: Calculated value 477.3, Measured value 477.3

[0326] 5-(4-(3-phenyl-3a-(1-phenylvinyl)-6-(sulfamoylamino)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)butoxy)pentanoic acid (18c; 6N-10CA-monoether; 6N-10CA-ME) [ka] Following the general deprotection procedure, 17a (40 mg, 0.06 mmol) was reacted with two drops of HCl in dioxane (1.2 mL) to afford the title compound as a clear oil (15.2 mg, 46% yield) after flash chromatography (50–100% EtOAc / hexanes). 1 H NMR (600 MHz, chloroform-d) δ 7.34 - 7.27 (m, 4H), 7.26 - 7.24 (m, 5H), 7.19 - 7.15 (m, 2H), 5.55 (d, J = 8.2 Hz, 1H), 5.10 (d, J = 1.2 Hz, 1H), 4.91 (d, J = 1.2 Hz, 1H), 4.75 (s, 2H), 3.79 (dtd, J = 11.5, 8.5, 5.8 Hz, 1H), 3.51 - 3.36 (m, 5H), 2.63 (td, J = 9.0, 2.3 Hz, 1H), 2.47 (dd, J = 17.8, 2.4 Hz, 1H), 2.39 (t, J = 7.5 Hz, 2H), 2.21 - 2.10 (m, 3H), 1.98 (dq, J = 10.3, 6.3, 4.9 Hz, 2H), 1.80 (dt, J = 14.8, 7.4 Hz, 1H), 1.72 (tq, J = 18.0, 6.5, 5.4 Hz, 3H), 1.62 (p, J = 6.7 Hz, 3H), 1.58 - 1.46 (m, 6H). LRMS (APCI) m / z[M+H] + C 31 H 41 N2O5S: Calculated value 553.7, Measured value 553.3

[0327] 3-(3-(2-(3-phenyl-3a-(1-phenylvinyl)-6-(sulfamoylamino)-1,3a,4,5,6,6a-hexahydropentalen-2-yl)ethoxy)propoxy)propanoic acid (18d; 6N-10CA-diether; 6N-10CA-DE): [ka] Following the general deprotection procedure, 17b (37.5 mg, 0.05 mmol) was reacted with two drops of HCl in dioxane (3 mL) to afford the title compound as a clear oil (9.6 mg, 35% yield) after flash chromatography (30–50% EtOAc / hexanes). 1 H NMR (600 MHz, chloroform-d) δ 7.40 - 7.34 (m, 3H), 7.30 (m, 2H), 7.25 (m, 3H), 5.47 (d, J = 6.9 Hz, 2H), 5.30 (d, J = 1.2 Hz, 1H), 5.08 (s, 1H), 5.07 (s, 2H), 3.83 (m, 1H), 3.71 (d, J = 5.9 Hz, 2H), 3.69 - 3.58 (m, 2H), 3.53 (dd, J = 32.9, 9.4 Hz, 5H), 2.67 - 2.46 (m, 6H), 1.87 (dq, J = 13.4, 7.5, LRMS (APCI) m / z[M+H] + C 30 H 39 N2O6S: Calculated value 555.7, Measured value 555.3

[0328] Example 2: Biological evaluation of novel LRH-1 agonists and antagonists. Data on the pharmacokinetics, solubility, permeability, and metabolic stability of the compounds disclosed herein was performed using techniques in the art and is provided in Figure 1.

[0329] Protein Expression and Purification. The LRH-1 LBD (residues 299-541) in the pMSC7 vector was expressed in BL21(DE3)pLysS E. coli by induction with IPTG (1 mM) for 4 hours at 30°C. The protein was purified by nickel affinity chromatography. Proteins used for Thermofluor™ experiments were incubated with DLPC (5-fold molar excess) for 4 hours at room temperature and then repurified by size exclusion into an assay buffer of 20 mM Tris-HCl (pH 7.5), 150 mM NaCl, and 5% glycerol. Proteins used for crystallization were incubated with TEV protease to cleave the His tag. The cleaved protein was then separated from the His tag and TEV by a second round of nickel affinity chromatography. To generate protein-ligand complexes, proteins were incubated overnight with ligand (10-fold molar excess) and repurified by size exclusion using a final buffer of 100 mM ammonium acetate (pH 7.4), 150 mM sodium chloride, 1 mM DTT, 1 mM EDTA, and 2 mM CHAPS.

[0330] Thermofluor™ Assay: Purified LRH-1 LBD-His protein (0.2 mg / ml) was incubated with 50 μM of each compound overnight at 4°C. The final DMSO concentration in the reaction was 1%. SYPRO™ orange dye (Invitrogen; Waltham, MA) was then added at a 1:1000 dilution. The reaction was heated at a rate of 0.5°C per minute using a StepOne™ Plus Real-Time PCR System (ThermoFisher; Waltham, MA). Fluorescence was recorded at every degree using a ROX filter (602 nm). Data were analyzed by first subtracting baseline fluorescence (no protein, ligand + SYPRO™) and then fitting the curve using the Bolzman equation to determine the Tm. FP competition (binding) results are shown below in Table 1. [Table 1]

[0331] Luciferase reporter assay: HeLa cells were seeded at a density of 10,000 cells per well in white-walled, clear-bottom 96-well culture plates. The following day, cells were transfected with LRH-1 and reporters at a 5:2 Fugene™ (µl):DNA (µg) ratio using Fugene™ HD (Roche; Indianapolis, IN). The transfected plasmids included full-length LRH-1 in the pCI vector (5 ng / well) and the SHP-luc reporter (encoding the LRH-1 response element and surrounding sequences from the SHP promoter cloned upstream of firefly luciferase in a pGL3 base vector) (50 ng / well). Cells were also cotransfected with a constitutive Renilla luciferase reporter (utilizing a CMV promoter) used for normalization of the firefly signal (1 ng / well). Control cells received pCI empty vector at 5 ng / well instead of LRH-1-pCI. Following overnight transfection, cells were treated for 24 hours with agonists at the concentrations indicated in the figure legends. Agonists were dissolved in DMSO and then diluted into medium to a final concentration of 0.3% DMSO in all wells. Luciferase signals were quantified using a DualGlo™ kit (Promega; Madison, WI). Experiments were performed at least twice in triplicate. Compounds were synthesized and evaluated in biological assays. The results of the luciferase reporter (activation assay) are shown below in Table 2. [Table 2]

[0332] Thermostability assay: Thermal shifts were also assessed for each compound to determine protein thermal stability. The thermal stability of LRH-1 LBD complexed with ligand was determined using a Tycho NT.6 Nanotemper. LRH-1 LBD was incubated overnight at 4°C with a 5-fold molar excess of ligand (final DMSO concentration was 1.4%) in assay buffer (150 mM NaCl, 20 mM Tris-HCl, and 5% glycerol, pH 7.4). The complex was centrifuged at high speed for 5 minutes and then loaded into the capillary. Tryptophan / tyrosine fluorescence was monitored at wavelengths of 330 nm and 350 nm over a 30°C / min gradient (35°C to 95°C). The inflection point was determined using Tycho NT.6 software. Two separate experiments were performed in triplicate. The calculated inflection point values ​​were displayed as a bar graph constructed using Prism (version 9). The inflection points (melting points) for each of the compounds are shown below in Table 3. [Table 3]

[0333] Example 3: Compound Distribution and Targets The tissue distribution of the compounds described herein and the dosage required for in vivo activation of hepatic LRH-1 were evaluated. For these studies, H-mLRH-1 mice (male and female; 10 weeks old) were used. A single-dose time-course experiment was performed, in which different cohorts of H-mLRH-1 mice (n=6) were given a high dose (i.e., 30 mg / kg of compound) via oral and intraperitoneal (IP) delivery. Liver tissue was collected, and gene expression of Cyp7a1, Scarb1, ApoA4, and Shp was measured using standard qPCR methods at 1, 3, 6, 12, and 24 hours. The time of peak target gene expression was selected for the dose-finding study. Different cohorts of H-mLRH-1 mice were given six doses of the compound via oral or IP delivery using a semi-logarithmic scale (i.e., 0, 0.003, 0.03, 0.3, 3, and 30 mg / kg). The collected liver tissue was used to monitor the expression of the genes listed above. 6N-10CA monoether demonstrated desirable gene expression activity (elevated Cyp7a1 and Apoa4 and decreased Fasn), as well as novel gene targets, at 30 mg / kg IP injection. The results are shown in Figures 2A, 2B, and 2C.

[0334] Example 4: Assessment of off-target effects of compounds 6N-10CA-ME exhibits SF-1 activity as measured by LUC reporter gene activation in cultured cells. To assess whether 6N-10CA monoether activates SF-1 in vivo at the optimal dose determined to drive hepatic LRH-1, SF-1 activation was assessed. Specifically, adrenal and gonadal tissues were collected from all sacrificed mice.

[0335] SF-1 activity was assessed by morphological / histological examination of these organs using RT-qPCR for target genes (e.g., Star, Fdps, Hmgcr) and by monitoring circulating levels of cortisol, aldosterone, and androsterone using targeted LC / MS / MS. Preliminary data indicate minimal off-target NR activation (Figure 3).

[0336] Example 5: Efficacy of LRH-1 modulators as antidiabetic agents in obesity Activation of LRH-1 has been shown to attenuate hepatic steatosis and improve glucose homeostasis in experimental models of diet-induced obesity (DIO) and insulin resistance. In this study, a mouse model of DIO was used to evaluate the in vivo efficacy of the compounds described herein, including their ability to (1) attenuate hepatic steatosis and (2) improve glucose tolerance and insulin resistance.

[0337] H-mLRH-1 mice (male and female) were fed one of the following diets (OpenSource Diets) for up to 16 weeks, starting at 8 weeks of age: (1) a control diet (10% fat diet, D12450Ji) or (2) a high-fat diet (HFD, 60% fat; D12492i). Compounds and vehicle were given to cohorts of mice starting at 12 weeks of HFD feeding, targeting, rather than preventing, metabolic disturbances associated with HFD. Compounds tested to date do not activate (or suppress) mouse LRH-1. Data from male and female mice treated with 3 mg / kg of 6N-10CA monoether are shown in Figure 4.

[0338] The compounds and methods of the appended claims are not limited in scope by the specific compounds and methods described herein, which are intended as illustrations of a few aspects of the claims; any compounds and methods that are functionally equivalent are within the scope of this disclosure. Various modifications of the compounds and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Furthermore, while only certain representative compounds, methods, and aspects of these compounds and methods are specifically described, other compounds and methods are intended to fall within the scope of the appended claims. Thus, although a combination of steps, elements, components, or ingredients may be explicitly recited herein, all other combinations of steps, elements, components, and ingredients are included, even if not explicitly recited.

Claims

1. A compound having the formula: 【Chemistry 51】 or a prodrug, salt, or stereoisomer thereof, wherein: n is 1 to 6; p is 1 to 6; R １ is alkyl, halogen, nitro, cyano, hydroxy, amino, sulfamoylamino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １ represents one or more of the same or different R １０ optionally replaced by R ２ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ２ represents one or more of the same or different R １０ optionally replaced by R ３ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ３ represents one or more of the same or different R １０ optionally replaced by R ４ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ４ represents one or more of the same or different R １０ optionally replaced by R ５ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ５ represents one or more of the same or different R １０ optionally replaced by R ６ is hydrogen, carboxy, or alkyl; R ６ is optionally terminally substituted with hydroxy, carboxy, or phosphate, said hydroxy, carboxy, or phosphate being R １０ optionally further substituted by; R ７ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ７ is one or more of the same or different R １０ or R １ and R ７ together form an oxo or oxime, and the oxime may be one or more of the same or different R １０ optionally replaced by R １０ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １０ represents one or more of the same or different R １１ optionally replaced by R １１ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

2. R ４ The compound of claim 1, wherein is 1-phenylvinyl.

3. 3. The compound of claim 1 or 2, wherein n is 4 and p is 4.

4. R １ The compound according to any one of claims 1 to 3, wherein is hydroxy or sulfamoylamino.

5. R １ is sulfamoylamino, and R ６ is carboxy, and R ７ The compound according to any one of claims 1 to 4, wherein is hydrogen.

6. A compound having the formula: 【Chemistry 52】 or a prodrug, salt, or stereoisomer thereof, wherein: n is 1 to 6; p is 1 to 6; R １ is alkyl, halogen, nitro, cyano, hydroxy, amino, sulfamoylamino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １ represents one or more of the same or different R １０ optionally replaced by R ２ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ２ represents one or more of the same or different R １０ optionally replaced by R ３ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ３ represents one or more of the same or different R １０ optionally replaced by R ４ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ４ represents one or more of the same or different R １０ optionally replaced by R ５ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ５ represents one or more of the same or different R １０ optionally replaced by R ６ is hydrogen, carboxy, or alkyl; R ６ is optionally substituted with alkyl, hydroxy, carboxy, or phosphate, said hydroxy, carboxy, or phosphate being R １０ optionally further substituted by; R ７ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ７ is one or more of the same or different R １０ or R １ and R ７ together form an oxo or oxime, and the oxime may be one or more of the same or different R １０ optionally replaced by R １０ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １０ represents one or more of the same or different R １１ optionally replaced by R １１ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

7. R ４ The compound of claim 6, wherein is 1-phenylvinyl.

8. 8. The compound of claim 6 or 7, wherein n is 4 and p is 4.

9. R １ The compound according to any one of claims 6 to 8, wherein is hydroxy or sulfamoylamino.

10. R １ is sulfamoylamino, and R ６ is carboxy, and R ７ The compound according to any one of claims 6 to 9, wherein is hydrogen.

11. A compound having the formula: 【Chemistry 53】 or a prodrug, salt, or stereoisomer thereof, wherein: n is 1 to 6; p is 1 to 6; R １ is alkyl, halogen, nitro, cyano, hydroxy, amino, sulfamoylamino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １ represents one or more of the same or different R １０ optionally replaced by R ２ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ２ represents one or more of the same or different R １０ optionally replaced by R ３ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ３ represents one or more of the same or different R １０ optionally replaced by R ４ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ４ represents one or more of the same or different R １０ optionally replaced by R ５ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ５ represents one or more of the same or different R １０ optionally replaced by R ６ is hydrogen or alkyl, and R ６ is optionally terminally substituted with hydroxy, carboxy, or phosphate, said hydroxy, carboxy, or phosphate being R １０ optionally further substituted by; R ７ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ７ is one or more of the same or different R １０ or R １ and R ７ together form an oxo or oxime, and the oxime may be one or more of the same or different R １０ optionally replaced by R １０ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １０ represents one or more of the same or different R １１ optionally replaced by R １１ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

12. R ４ The compound of claim 11, wherein is 1-phenylvinyl.

13. 13. The compound of claim 11 or 12, wherein n is 4 and p is 4.

14. R １ The compound of any one of claims 11 to 13, wherein is hydroxy or sulfamoylamino.

15. R １ is sulfamoylamino, and R ６ is carboxy, and R ７ The compound according to any one of claims 11 to 14, wherein is hydrogen.

16. A compound having the formula: 【Chemistry 54】 or a prodrug, salt, or stereoisomer thereof, wherein: n is 1 to 6; p is 1 to 6; X is a linking group -CH ２ -, -C(OH)(OH)-, -C(OH)H, -C(Hal)(Hal)-, -C(Hal)H-, -O-, -S-, -(S=O)-, -SO ２ -, -NH-, -(C═O)-, -(C═NH)-, or -(C═S)-; R １ is hydrogen, hydroxy, alkyl, alkanoyl, amino, aminoalkyl, sulfamoylamino, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R ２ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ２ represents one or more of the same or different R １０ optionally replaced by R ３ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ３ represents one or more of the same or different R １０ optionally replaced by R ４ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ４ represents one or more of the same or different R １０ optionally replaced by R ５ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ５ represents one or more of the same or different R １０ optionally replaced by R ６ is hydrogen or alkyl, and R ６ is optionally terminally substituted with hydroxy, carboxy, or phosphate, said hydroxy, carboxy, or phosphate being R １０ optionally further substituted by; R １０ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １０ represents one or more of the same or different R １１ optionally replaced by R １１ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

17. X and R １ but, a) X is O and R １ is alkanoyl; b) X is —NH— and R １ is alkanoyl; c) X is O and R １ is aminosulfonyl; d) X is —NH— and R １ is aminosulfonyl; and e) X is —(C═O)—, and R １ is an amino 17. The compound of claim 16, which is selected from the group consisting of:

18. R ４ The compound according to claim 16 or 17, wherein is 1-phenylvinyl.

19. The compound according to any one of claims 16 to 18, wherein n is 4 and p is 4.

20. A compound having the formula: 【Transformation 55】 or a prodrug, salt, or stereoisomer thereof, wherein: n is 1 to 6; p is 1 to 6; X is a linking group -CH ２ -, -C(OH)(OH)-, -C(OH)H, -C(Hal)(Hal)-, -C(Hal)H-, -O-, -S-, -(S=O)-, -SO ２ -, -NH-, -(C=O)-, -(C=NH)-, or -(C=S)-; Y is -CH ２ -, -C(OH)(OH)-, -C(OH)H, -C(Hal)(Hal)-, -C(Hal)H-, -O-, -S-, -(S=O)-, -SO ２ -, -NH-, -(C=O)-, -(C=NH)-, or -(C=S)-; R １ is hydrogen, hydroxy, alkyl, alkanoyl, amino, aminoalkyl, sulfamoylamino, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R ２ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ２ represents one or more of the same or different R １０ optionally replaced by R ３ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ３ represents one or more of the same or different R １０ optionally replaced by R ４ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ４ represents one or more of the same or different R １０ optionally replaced by R ５ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ５ represents one or more of the same or different R １０ optionally replaced by R ６ is hydrogen or alkyl, and R ６ is optionally terminally substituted with hydroxy, carboxy, or phosphate, said hydroxy, carboxy, or phosphate being R １０ optionally further substituted by; R １０ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １０ represents one or more of the same or different R １１ optionally replaced by R １１ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

21. X and R １ but, a) X is O and R １ is alkanoyl; b) X is —NH— and R １ is alkanoyl; c) X is O and R １ is aminosulfonyl; d) X is —NH— and R １ is aminosulfonyl; e) X is —(C═O)—, and R １ is amino; and f) X is O, Y is —(C═O)—, and R １ is an amino 21. The compound of claim 20, which is selected from the group consisting of:

22. R ４ The compound according to claim 20 or 21, wherein is 1-phenylvinyl.

23. The compound according to any one of claims 20 to 22, wherein n is 4 and p is 4.

24. A compound having the formula: 【Transformation 56】 or a prodrug, salt, or stereoisomer thereof, wherein: n is 1 to 6; p is 1 to 6; R １ is hydrogen, alkyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １ represents one or more of the same or different R １０ optionally replaced by R ２ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ２ represents one or more of the same or different R １０ optionally replaced by R ３ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ３ represents one or more of the same or different R １０ optionally replaced by R ４ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ４ represents one or more of the same or different R １０ optionally replaced by R ５ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ５ represents one or more of the same or different R １０ optionally replaced by R ６ is a lipid or alkyl, and R ６ is optionally terminally substituted with hydroxy, carboxy, or phosphate, said hydroxy, carboxy, or phosphate being R １０ optionally further substituted by; R １０ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １０ represents one or more of the same or different R １１ optionally replaced by R １１ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

25. R ４ The compound of claim 24, wherein is 1-phenylvinyl.

26. 26. The compound of claim 24 or 25, wherein n is 4 and p is 4.

27. A compound having the formula: 【Chemistry 57】 or a prodrug, salt, or stereoisomer thereof, wherein: n is 1 to 6; p is 1 to 6; R １ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １ represents one or more of the same or different R １０ optionally replaced by R ２ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ２ represents one or more of the same or different R １０ optionally replaced by R ３ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ３ represents one or more of the same or different R １０ optionally replaced by R ４ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ４ represents one or more of the same or different R １０ optionally replaced by R ５ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ５ represents one or more of the same or different R １０ optionally replaced by R ６ is a lipid or alkyl, and R ６ is optionally terminally substituted with hydroxy, carboxy, or phosphate, said hydroxy, carboxy, or phosphate being R １０ optionally further substituted by; R １０ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １０ represents one or more of the same or different R １１ optionally replaced by R １１ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

28. R ４ The compound of claim 27, wherein is 1-phenylvinyl.

29. 29. The compound of claim 27 or 28, wherein n is 4 and p is 4.

30. A compound having the formula: 【Transformation 58】 or a prodrug, salt, or stereoisomer thereof, wherein: n is 1 to 6; p is 1 to 6; q is 1 to 6; R １ is alkyl, halogen, nitro, cyano, hydroxy, amino, sulfamoylamino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １ represents one or more of the same or different R １０ optionally replaced by R ２ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ２ represents one or more of the same or different R １０ optionally replaced by R ３ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ３ represents one or more of the same or different R １０ optionally replaced by R ４ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ４ represents one or more of the same or different R １０ optionally replaced by R ５ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ５ represents one or more of the same or different R １０ optionally replaced by R ６ is hydrogen, carboxy, or alkyl; R ６ is optionally terminally substituted with hydroxy, carboxy, or phosphate, said hydroxy, carboxy, or phosphate being R １０ optionally further substituted by; R ７ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ７ is one or more of the same or different R １０ or R １ and R ７ together form an oxo or oxime, and the oxime may be one or more of the same or different R １０ optionally replaced by R １０ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １０ represents one or more of the same or different R １１ optionally replaced by R １１ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

31. 31. The compound of claim 30, wherein n is 2, p is 3, and q is 2.

32. R ４ The compound of claim 30 or 31, wherein is 1-phenylvinyl.

33. R １ The compound of any one of claims 30 to 32, wherein is hydroxy or sulfamoylamino.

34. R １ is sulfamoylamino, and R ７ The compound of any one of claims 30 to 33, wherein is hydrogen.

35. R １ is sulfamoylamino, and R ６ is carboxy, and R ７ The compound of any one of claims 30 to 34, wherein is hydrogen.

36. A compound having the formula: 【Chemistry 59】 or a prodrug, salt, or stereoisomer thereof, wherein: n is 1 to 6; p is 1 to 6; q is 1 to 6; R １ is alkyl, halogen, nitro, cyano, hydroxy, amino, sulfamoylamino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １ represents one or more of the same or different R １０ optionally replaced by R ２ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ２ represents one or more of the same or different R １０ optionally replaced by R ３ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ３ represents one or more of the same or different R １０ optionally replaced by R ４ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ４ represents one or more of the same or different R １０ optionally replaced by R ５ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ５ represents one or more of the same or different R １０ optionally replaced by R ６ is hydrogen, carboxy, or alkyl; R ６ is optionally substituted with alkyl, hydroxy, carboxy, or phosphate, said hydroxy, carboxy, or phosphate being R １０ optionally further substituted by; R ７ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ７ is one or more of the same or different R １０ or R １ and R ７ together form an oxo or oxime, and the oxime may be one or more of the same or different R １０ optionally replaced by R １０ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １０ represents one or more of the same or different R １１ optionally replaced by R １１ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

37. 37. The compound of claim 36, wherein n is 2, p is 3, and q is 2.

38. R ４ The compound of claim 36 or 37, wherein is 1-phenylvinyl.

39. R １ The compound of any one of claims 36 to 38, wherein is hydroxy or sulfamoylamino.

40. R １ is sulfamoylamino, and R ７ The compound of any one of claims 36 to 39, wherein is hydrogen.

41. R １ is sulfamoylamino, and R ６ is carboxy, and R ７ The compound of any one of claims 36 to 40, wherein is hydrogen.

42. A compound having the formula: 【Transformation 60】 or a prodrug, salt, or stereoisomer thereof, wherein: n is 1 to 6; p is 1 to 6; q is 1 to 6; R １ is alkyl, halogen, nitro, cyano, hydroxy, amino, sulfamoylamino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １ represents one or more of the same or different R １０ optionally replaced by R ２ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ２ represents one or more of the same or different R １０ optionally replaced by R ３ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ３ represents one or more of the same or different R １０ optionally replaced by R ４ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ４ represents one or more of the same or different R １０ optionally replaced by R ５ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ５ represents one or more of the same or different R １０ optionally replaced by R ６ is hydrogen or alkyl, and R ６ is optionally terminally substituted with hydroxy, carboxy, or phosphate, said hydroxy, carboxy, or phosphate being R １０ optionally further substituted by; R ７ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ７ is one or more of the same or different R １０ or R １ and R ７ together form an oxo or oxime, and the oxime may be one or more of the same or different R １０ optionally replaced by R １０ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １０ represents one or more of the same or different R １１ optionally replaced by R １１ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

43. 43. The compound of claim 42, wherein n is 2, p is 3, and q is 2.

44. R ４ The compound of claim 42 or 43, wherein is 1-phenylvinyl.

45. R １ The compound of any one of claims 42 to 44, wherein is hydroxy or sulfamoylamino.

46. R １ is sulfamoylamino, and R ７ The compound of any one of claims 42 to 45, wherein is hydrogen.

47. R １ is sulfamoylamino, and R ６ is carboxy, and R ７ The compound of any one of claims 42 to 46, wherein is hydrogen.

48. A compound having the formula: 【Chemistry 61】 or a prodrug, salt, or stereoisomer thereof, wherein: n is 1 to 6; p is 1 to 6; q is 1 to 6; X is a linking group -CH ２ -, -C(OH)(OH)-, -C(OH)H, -C(Hal)(Hal)-, -C(Hal)H-, -O-, -S-, -(S=O)-, -SO ２ -, -NH-, -(C═O)-, -(C═NH)-, or -(C═S)-; R １ is hydrogen, hydroxy, alkyl, alkanoyl, amino, aminoalkyl, sulfamoylamino, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R ２ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ２ represents one or more of the same or different R １０ optionally replaced by R ３ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ３ represents one or more of the same or different R １０ optionally replaced by R ４ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ４ represents one or more of the same or different R １０ optionally replaced by R ５ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ５ represents one or more of the same or different R １０ optionally replaced by R ６ is hydrogen or alkyl, and R ６ is optionally terminally substituted with hydroxy, carboxy, or phosphate, said hydroxy, carboxy, or phosphate being R １０ optionally further substituted by; R １０ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １０ represents one or more of the same or different R １１ optionally replaced by R １１ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

49. X and R １ but, a) X is O and R １ is alkanoyl; b) X is —NH— and R １ is alkanoyl; c) X is O and R １ is aminosulfonyl; d) X is —NH— and R １ is aminosulfonyl; and e) X is —(C═O)—, and R １ is an amino 49. The compound of claim 48, which is selected from the group consisting of:

50. R ４ The compound of claim 48 or 49, wherein is 1-phenylvinyl.

51. 51. The compound of any one of claims 48 to 50, wherein n is 2, p is 3, and q is 2.

52. A compound having the formula: 【Transformation 62】 or a prodrug, salt, or stereoisomer thereof, wherein: n is 1 to 6; p is 1 to 6; q is 1 to 6; X is a linking group -CH ２ -, -C(OH)(OH)-, -C(OH)H, -C(Hal)(Hal)-, -C(Hal)H-, -O-, -S-, -(S=O)-, -SO ２ -, -NH-, -(C=O)-, -(C=NH)-, or -(C=S)-; Y is -CH ２ -, -C(OH)(OH)-, -C(OH)H, -C(Hal)(Hal)-, -C(Hal)H-, -O-, -S-, -(S=O)-, -SO ２ -, -NH-, -(C=O)-, -(C=NH)-, or -(C=S)-; Z is -CH ２ -, -C(OH)(OH)-, -C(OH)H, -C(Hal)(Hal)-, -C(Hal)H-, -O-, -S-, -(S=O)-, -SO ２ -, -NH-, -(C=O)-, -(C=NH)-, or -(C=S)-; R １ is hydrogen, hydroxy, alkyl, alkanoyl, amino, aminoalkyl, sulfamoylamino, carbamoyl, sulfate, sulfonate, aminosulfonyl, phosphate, phosphonate, or heterocyclyl; R ２ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ２ represents one or more of the same or different R １０ optionally replaced by R ３ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ３ represents one or more of the same or different R １０ optionally replaced by R ４ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ４ represents one or more of the same or different R １０ optionally replaced by R ５ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ５ represents one or more of the same or different R １０ optionally replaced by R ６ is hydrogen or alkyl, and R ６ is optionally terminally substituted with hydroxy, carboxy, or phosphate, said hydroxy, carboxy, or phosphate being R １０ optionally further substituted by; R １０ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １０ represents one or more of the same or different R １１ optionally replaced by R １１ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

53. a) X is O and R １ is alkanoyl; b) X is —NH— and R １ is alkanoyl; c) X is O and R １ is aminosulfonyl; d) X is —NH— and R １ is aminosulfonyl; e) X is —(C═O)—, and R １ is an amino; f) X is O, Y is —(C═O)—, and R １ is an amino; g) X is O, Y is —(C═O)—, Z is —NH—, and R １ is a sulfonate; or h) X is O, Y is —(C═O)—, Z is —NH—, and R １ is aminosulfonyl; 53. The compound of claim 52.

54. 54. The compound of claim 52 or 53, wherein n is 2, p is 3, and q is 2.

55. R ４ The compound of any one of claims 52 to 54, wherein is 1-phenylvinyl.

56. A compound having the formula: 【Transformation 63】 or a prodrug, salt, or stereoisomer thereof, wherein: n is 1 to 6; p is 1 to 6; q is 1 to 6; R １ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １ represents one or more of the same or different R １０ optionally replaced by R ２ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ２ represents one or more of the same or different R １０ optionally replaced by R ３ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ３ represents one or more of the same or different R １０ optionally replaced by R ４ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ４ represents one or more of the same or different R １０ optionally replaced by R ５ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ５ represents one or more of the same or different R １０ optionally replaced by R ６ is a lipid or alkyl, and R ６ is optionally terminally substituted with hydroxy, carboxy, or phosphate, said hydroxy, carboxy, or phosphate being R １０ optionally further substituted by; R １０ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １０ represents one or more of the same or different R １１ optionally replaced by R １１ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

57. R ４ is 1-phenylvinyl.

58. 58. The compound of claim 56 or 57, wherein n is 2, p is 3, and q is 2.

59. A compound having the formula: 【Chemistry 64】 or a prodrug, salt, or stereoisomer thereof, wherein: n is 1 to 6; p is 1 to 6; q is 1 to 6; R １ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １ represents one or more of the same or different R １０ optionally replaced by R ２ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ２ represents one or more of the same or different R １０ optionally replaced by R ３ is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ３ represents one or more of the same or different R １０ optionally replaced by R ４ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ４ represents one or more of the same or different R １０ optionally replaced by R ５ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R ５ represents one or more of the same or different R １０ optionally replaced by R ６ is a lipid or alkyl, and R ６ is optionally terminally substituted with hydroxy, carboxy, or phosphate, said hydroxy, carboxy, or phosphate being R １０ optionally further substituted by; R １０ is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) ２ amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aminosulfonyl, carbocyclyl, benzoyl, benzyl, aryl, or heterocyclyl; R １０ represents one or more of the same or different R １１ optionally replaced by R １１ is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydroxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzoyl, benzyl, carbocyclyl, aryl, or heterocyclyl.

60. R ４ is 1-phenylvinyl.

61. 61. The compound of claim 59 or 60, wherein n is 2, p is 3, and q is 2.

62. A compound of the following structure: 【Transformation 65】 or a prodrug or salt thereof.

63. A compound of the following structure: 【Chemical Formula 66】 or a prodrug or salt thereof.

64. A compound of the following structure: 【Transformation 67】 or a prodrug or salt thereof.

65. A compound of the following structure: 【Transformation 68】 or a prodrug or salt thereof.

66. 66. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of any one of claims 1 to 65, and a pharmaceutically acceptable excipient.

67. 67. A method for treating or preventing cancer, comprising administering an effective amount of the pharmaceutical composition of claim 66 to a subject in need thereof.

68. 68. The method of claim 67, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, and thyroid cancer.

69. 67. A method for treating or preventing diabetes, comprising administering an effective amount of the pharmaceutical composition of claim 66 to a subject in need thereof.

70. 70. The method of claim 69, wherein the diabetes is insulin-dependent diabetes, non-insulin-dependent diabetes, or gestational diabetes.

71. 67. A method for treating or preventing cardiovascular disease, comprising administering an effective amount of the pharmaceutical composition of claim 66 to a subject in need thereof.

72. 67. A method for treating or preventing inflammatory bowel disease (IBD), comprising administering an effective amount of the pharmaceutical composition of claim 66 to a subject in need thereof.

73. 67. A method for treating or preventing colitis or ulcerative colitis, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 66.

74. 67. A method for treating or preventing diabetic nephropathy, comprising administering an effective amount of the pharmaceutical composition of claim 66 to a subject in need thereof.

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