Targeted delivery of 1,2,4,5-tetraoxane compounds and uses thereof

Abstract

Disclosed are 1,2,4,5-tetraoxane compounds and derivatives thereof having anticancer properties. Disclosed are pharmaceutical compositions and pharmaceutical formulations in unit dosage form suitable for delivering the compounds to a subject in need thereof. In addition to the compounds, the pharmaceutical compositions or formulations can include one or more active agents, such as one or more additional anticancer agents. Also disclosed are methods of treating, mitigating, or treating or ameliorating one or more symptoms associated with cancer in a subject. The methods include (i) administering to a subject in need thereof an effective amount of a compound. The compound can be administered by oral administration, parenteral administration, inhalation, mucosal administration, or a combination thereof. The compound can selectively kill cancer cells and / or cancer stem cells, but not non-cancer cells, by inducing ferroptosis in the cancer cells and / or cancer stem cells.

Description

Technical Field

[0001] This invention is generally situated in the field of 1,2,4,5-tetraoxane compounds and their use as anticancer agents and anticancer stem cell agents. Background Technology

[0002] Triple-negative breast cancer (TNBC) MDA-MB-231 cells are more aggressive and harder to kill than estrogen-, progesterone-, and HER2-positive breast cancer cells. Since there are no known targets for TNBC, chemotherapy and radiation therapy are the only options. However, patients often suffer severe side effects from these treatments. Furthermore, traditional therapies such as radiation therapy and photodynamic therapy require an external light source to generate therapeutic reactive oxygen species to kill the cancer. Both of these methods suffer from problems such as shallow laser penetration and tumor-induced hypoxia, leading to poor treatment outcomes.

[0003] Cancer cells and cancer stem cells (CSCs) can also develop resistance to certain existing drugs, such as paclitaxel (Taxol) and artesunate. Since chemotherapy and radiation therapy primarily kill cancer cells by inducing apoptosis, these methods can develop resistance to apoptotic cell death, thus failing to achieve their therapeutic goals. Furthermore, CSCs are known to be resistant to chemotherapy or radiation therapy. CSCs have the capacity for self-renewal. If a drug can treat cancer cells but not CSCs, the patient's chances of cancer recurrence are higher. If a drug can only treat CSCs, the patient will still suffer from the disease due to the presence of cancer cells.

[0004] Ferroptosis is an iron-dependent and reactive oxygen species (ROS)-dependent cell death pathway. Cancer cells are known to have elevated iron levels, which promotes ferroptosis, inducing harmful lipid peroxidation and irreversible cell death, thus bypassing anti-apoptotic pathways. However, most ferroptosis inducers lack selectivity for cancer cells compared to non-cancer cells. For example, erastin and RSL3 are more cytotoxic to non-cancer cells than to cancer cells, indicating their lack of selectivity for cancer cells.

[0005] There is still a need to develop anticancer compounds that are selective against cancer cells and cancer stem cells relative to non-cancer cells.

[0006] Therefore, the object of this invention is to provide an anticancer compound.

[0007] Another object of the present invention is to provide a method for using anticancer compounds. Summary of the Invention

[0008] 1,2,4,5-tetraoxane compounds and derivatives are described, as well as methods of using these compounds to treat cancer, alleviate cancer, or treat or improve one or more cancer-related symptoms in subjects.

[0009] Typically, compounds may have three moieties: a cyclic moiety, a 1,2,4,5-tetraoxane moiety, and a targeting moiety. In some forms, compounds may have the structure of Formula I.

[0010]

[0011] (a) Wherein A' can be a substituted or unsubstituted monocyclic or a substituted or unsubstituted polycyclic; (b) Wherein R1 and R2 can be independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclic, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, amide, amino, phosphonium, phosphanyl, phosphonyl, silyl, sulfinyl, mercapto, hydroxyl, or R1 and R2 together with the carbons to which they are attached form a substituted or unsubstituted monocyclic, or take (c) wherein the substituent may be a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclic, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, halogen, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, carboxyl, amino, amide, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphorium, phosphonyl, phosphoryl, phosphonyl, mercapto, amino acid, peptide, polypeptide, or sugar group (e.g., glucosyl or acetylated glucose), or a combination thereof.

[0012] In some forms, the compound may have the structure of Formula II.

[0013]

[0014] (a) wherein A' and B' may be independently substituted or unsubstituted monocyclic or substituted or unsubstituted polycyclic, such as those described above for A'; and (b) wherein the substituent may be any of the substituents described above.

[0015] In some forms, the compound may have the structure of formula III.

[0016]

[0017] (a) Where A' can be as described above; (b) Where a can be an integer from 1 to 20; (c) Where b can be an integer from 0 to 24; and (d) Where R3 can be a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, halogen, hydroxyl, substituted or unsubstituted alkoxy, aryloxy, cyano, isocyano, nitro, substituted or unsubstituted carbonyl, amino, amide, silyl, sulfinyl, substituted or unsubstituted sulfonyl, phosphoronium, phosphonyl, phosphoryl, phosphonyl, mercapto, or sugar group (e.g., glucosyl or acetylated glucose); wherein the substituent can be any of the above substituents.

[0018] In some forms, the compound may have the structure of Formula IV.

[0019]

[0020] (a) wherein A' and a can be as described above; (b) wherein Z' and R4 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amino, amide, silyl, sulfinyl, sulfonyl, phosphoronium, phosphonyl, phosphoryl, phosphonyl, mercapto, or sugar group (e.g., glucosyl or acetylated glucose); wherein the substituent can be any of the substituents described above.

[0021] In some forms, the compound may have the structure of formula V.

[0022]

[0023] (a) where A', a, and Z' can be as described above; (b) where X' can be O, NR6, or S, where c can be an integer from 0 to 30; (c) where W' can be C, PR7, S, or Si; (d) where Y' can be NR8 or O; (e) where R6 and R7 can independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, aryloxy, amide, amino, phosphorium, phosphonyl, phosphonyl, phosphoryl, phosphate, silyl, sulfinyl, mercapto, or hydroxyl; (f) where R5 and R8 can independently be hydrogen, substituted or unsubstituted alkyl, The substituents may be substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, aryloxy, amide, amino, phosphorium, phosphonyl, phosphonyl, phosphoryl, phosphate, silyl, sulfinyl, mercapto, or hydroxyl, or R5 and R8 together with the Y' to which they are attached to form substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, or substituted or unsubstituted polyheteroaryl; wherein the substituents may be any of the above substituents.

[0024] In some forms, the compound may have the structure of formula VI.

[0025]

[0026] (a) Wherein A' and a can be as described above; (b) Wherein Z' can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amino, amide, silyl, phosphonium, or sugar group (e.g., glucosyl or acetylated glucose); (c) Wherein X' can be Or O, c can be an integer from 0 to 10; (d) wherein R5 and R8 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amide, amino, phosphonium, phosphonyl or silyl, or R5 and R8 together with the nitrogen to which they are attached form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted heterocyclic alkenyl, substituted or unsubstituted heterocyclic alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, or substituted or unsubstituted polyheteroaryl.

[0027] In some forms, the compound may have the structure of formula VII.

[0028]

[0029] (a) wherein a, X', R5, and R8 may be as described above; (b) wherein Z' may be hydrogen or a substituted or unsubstituted alkyl group; (c) wherein R9 may be hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted alkoxy group, an amide group, an amino group, a phosphorium group, a phosphonyl group, or a silyl group, and d is an integer from 0 to 9; wherein the substituent may be any of the substituents described above.

[0030] In some forms, the compound may have the structure of formula VIII.

[0031]

[0032] (a) wherein a, X', R5, and R8 can be as described above; (b) wherein a' can be an integer from 1 to 20; (c) wherein Z' can be hydrogen or a substituted or unsubstituted alkyl group; (d) wherein R 10 It can be a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclic, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, amide, amino, phosphorium, phosphinyl, or silyl, and e is an integer from 0 to 24; wherein the substituent can be any of the above substituents.

[0033] In some forms, the compound may have the structure of formula IX.

[0034]

[0035] (a) where a, a', Z, X', R5, and R8 can be as described above; (b) where R 14 It can be hydrogen, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy or amide.

[0036] Compounds can have the structure of formula X.

[0037]

[0038] (a) Wherein A' and A” can be independently substituted or unsubstituted monocyclic or substituted or unsubstituted polycyclic; (b) Wherein L' can be a linking group, such as oxygen, sulfur, carbon, boron, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted heteroaryl, phosphoryl, sulfinyl, sulfonyl, ether, polyether, disulfide, and amino; (c) Wherein the substituent can be independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or Unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, halogen, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, carboxyl, amino, amide, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphoronium, phosphonyl, phosphoryl, phosphonyl, mercapto, amino acid, peptide, polypeptide or sugar group (e.g., glucosyl or acetylated glucose), or combinations thereof.

[0039] In some forms, the compound may have the structure of formula XI.

[0040]

[0041] (a) where A', A”, and L' can be as described above; (b) where a and a” can be independent integers from 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 3, or 1 or 2; (c) where Z', Z”, and R 21 and R' 21It may independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amino, amide, silyl, sulfinyl, sulfonyl, phosphoronium, phosphonyl, phosphoryl, phosphonyl, mercapto, or sugar group (e.g., glucosyl or acetylated glucose); wherein the substituent may be any of the above substituents.

[0042] In some forms, the compound may have the structure of formula XII.

[0043]

[0044] (a) where A', A”, L', a, a”, Z', and Z” can be as described above; (b) where X' and X” can be independently O, NR6, or S, and c can be an integer from 0 to 30, 0 to 25, 0 to 20, 0 to 15, 0 to 10, 0 to 5, 0 to 3, or 0, 1, or 2; (c) where W' and W” can be independently C, PR7, S, or Si; (d) where Y' and Y” can be independently a bond or NR8 or O; (e) where R 22 and R' 22 It can be independent j is an integer from 0 to 20, 0 to 15, 0 to 10, 0 to 5, 0 to 3 or 0, 1 or 2; (f) wherein R6, R7 and R8 may independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, aryloxy, amide, amino, phosphoronium, phosphonyl, phosphonyl, phosphoryl, phosphate ester, silyl, sulfinyl, mercapto or hydroxyl; wherein the substituent may be any of the above substituents.

[0045] Pharmaceutical compositions and pharmaceutical formulations in unit dose forms suitable for delivering compounds and their formulations are disclosed. Typically, the pharmaceutical composition or formulation contains a compound and pharmaceutically acceptable excipients. The compound in the pharmaceutical composition or formulation treats, alleviates, or treats or improves one or more cancer-related symptoms in a subject in an effective amount. In some forms, the pharmaceutical composition or formulation may further contain one or more active agents in addition to the compound, such as one or more additional anticancer agents.

[0046] Methods of using the compound include (i) administering an effective amount of the compound to a subject to treat, alleviate, or treat or improve one or more cancer-related symptoms in the subject. The subject is typically a mammal, such as a human. In some forms, the cancer being treated or alleviated may be colon cancer, breast cancer, ovarian cancer, cervical cancer, lung cancer, rectal cancer, kidney cancer, liver cancer, brain cancer, or leukemia, or a combination thereof. The compound may be administered orally, parenterally, by inhalation, through a mucosa, topically, or a combination thereof. In some forms, the method may further include administering one or more secondary active agents, such as additional anticancer agents, to the subject before, during, and / or after step (i).

[0047] A method for treating cancer cells and / or cancer stem cells in subjects in need is also disclosed. This method involves administering an effective amount of a compound to the subject, wherein the compound has an IC50 effect on cancer cells. 50 The value was lower than the IC50 of the same compound tested under the same conditions for non-cancer cells. 50 Value, and / or IC50 of the compounds therein against cancer cells or cancer stem cells. 50 The value was lower than that of known compounds tested under the same conditions, such as OZ277, OZ439, RKA182, FINO2, or cholic acid / deoxycholic acid / steroid derivatives of 1,2,4,5-tetraoxane, against the same cancer cells or cancer stem cells. 50 Value. In some forms, the treated cancer cells may be MDA-MB-231 cells, MCF7 cells, HeLa cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells, or combinations thereof; and / or non-cancer cells may be NIH3T3 cells, MDCK cells, or bEnd.3 cells, or combinations thereof. In some forms, the compound induces ferroptosis in cancer cells and / or cancer stem cells, optionally wherein the intracellular pH of the cancer cells and / or cancer stem cells is in the range of 6 to 7.5. Attached Figure Description

[0048] Figure 1 This is a schematic diagram showing the biological characteristics of an exemplary compound.

[0049] Figure 2 This is a schematic diagram of the in vivo experimental procedure.

[0050] Figures 3A-3B Compound 37b (which exhibits responses to HeyA8, HeyA8 CSC, and NIH3T3) Figure 3A ) and 48 ( Figure 3BA graph of the results of three independent experiments on dose-dependent activity curves after 48 hours of treatment (mean ± standard deviation, n = 3). Figure 3C This is a bar graph showing that compounds 37b and 48 attenuated the cell viability of ovarian cancer cells and cancer stem cells (CSCs). *P ≤ 0.05 compared with the drug-treated control. Data are plotted as mean ± SD, n = 3 biologically independent samples. All P values ​​were determined using a two-tailed Student's t-test.

[0051] Figure 4 This is a bar graph showing the protective effects of DFO and Fer-1 on HeyA8 cancer cells after 24 hours of treatment with compound 48. *P≤0.01, ***P≤0.001 compared to the untreated group. Data represent mean ± SD, n = 3 biologically independent samples. All p-values ​​were determined using a two-tailed Student's t-test.

[0052] Figures 5A-5B This indicates that after 24 hours of treatment with compounds 48 and 37b, respectively, Q-VD-OPh, deferasirox (DFX), and ferrostatin-1 (Fer-1) have an effect on HeyA8 cancer stem cells (…). Figure 5A ) and HeyA8 sphere ( Figure 5B Bar graph showing the protective effect of the pretreated group. *P≤0.05, **P≤0.01, compared with the untreated group. Data are plotted as mean ± SD, n = 3 biologically independent samples. NS, no statistically significant change. All p-values ​​were determined using a two-tailed Student's t-test.

[0053] Figure 6 This is a bar graph showing the effects of alastin, RSL3, and artesunate on the cell viability of ovarian cancer cells and cancer stem cells (CSCs). *P≤0.05 and **P≤0.01, relative to the DMSO control. Data are plotted as mean ± SD, n = 3 biologically independent samples. All p-values ​​were determined using a two-tailed Student's t-test.

[0054] Figure 7A This is a graph showing the relationship between tumor volume and time in xenograft tumors after subcutaneous injection of DMSO, PTX, compound 37b, or compound 48. Subcutaneous injection of HEYA8 CSC cells (10...) into nude mice... 6Animals were randomly assigned to one of six treatment groups (n=4): (i) DMSO, (ii) paclitaxel (PTX), 5 mg / kg, (iii) compound 37b, 5 mg / kg, (iv) compound 37b, 10 mg / kg, (v) compound 48, 5 mg / kg, or (vi) compound 48, 10 mg / kg. All animals were sacrificed and photographed when tumor ulceration began to appear in the control animals (DMSO) at day 25. Figure 7B These are tumor photos of animals euthanized from different treatment groups 25 days later. Figure 7C This graph shows the relationship between tumor weight and time in xenograft tumors after subcutaneous injection of DMSO, PTX, compound 37b, or compound 48. Data are presented as mean ± SEM. *P≤0.05 compared to the DMSO group.

[0055] Figure 8A This is a bar graph showing the effect of Fer-1 (50 μM) on MDA-MB-231 cells treated with specified concentrations of compounds 37b, 37a, and 30b for 24 hours. Compared with untreated cells, *P ≤ 0.5, **P ≤ 0.01, ***P ≤ 0.001, NS, no statistically significant change. Data represent mean ± SD, n = 3 biologically independent samples. All p-values ​​were determined using a two-tailed Student's t-test. Figure 8B This is a bar graph showing the effect of Fer-1 (50 μM) on MDA-MB-231 cells treated for 24 hours with specified concentrations of compounds 6b, 48, 30a, and 37f, respectively. *P ≤ 0.01, **P ≤ 0.002, ***P ≤ 0.001 compared to untreated cells. Data represent mean ± SD, n = 3 biologically independent samples. Figure 8C This is a bar graph showing the effects of Fer-1 and DFO on MDA-MB-231 cells treated with specified concentrations of compounds 56 and 53 for 24 hours. *P≤0.01, **P≤0.002, ***P≤0.001 compared to untreated cells. All P values ​​were determined using a two-tailed Student's t-test.

[0056] Figure 9 This is a bar graph showing the effect of liproxstatin (30 μM) on MDA-MB-231 cells treated with specified concentrations of compounds 48 and 37b for 24 hours. **P ≤ 0.01 compared to untreated cells. Data represent mean ± SD, n = 3 biologically independent samples. All P values ​​were determined using a two-tailed Student's t-test.

[0057] Figure 10This is a bar graph showing the relative mean fluorescence intensity of HKOH-1r cells measured from confocal images of MDA-MB-231 cells treated with compounds 48 and 37b, respectively. The scale bar represents 50 μm. Data for HKOH1 are mean ± sem, n = 20 cells. Statistical significance was determined by Student's t-test as ***P ≤ 0.01.

[0058] Figure 11 This is a bar graph showing the lipid ROS of compounds 48 (5 μM), 37b (1 μM), or RSL3 (0.5 μM) detected by BODIPY 581 / 591C11 after 6 hours of incubation in MDA-MB-231 cells. **P ≤ 0.01 compared to the DMSO group. Data are plotted as mean ± SD, n = 3 biologically independent samples. All P values ​​were determined using a two-tailed Student's t-test.

[0059] Figure 12A This is a graph showing the tumor volume of xenograft tumors relative to the time following subcutaneous injection of DMSO, PTX, compound 37b, or compound 48. MDA-MB-231 cells (10...) were subcutaneously injected into nude mice. 6 Animals were randomly assigned to one of six treatment groups (n=5): (i) DMSO, (ii) paclitaxel (PTX), 5 mg / kg, (iii) compound 37b, 5 mg / kg, (iv) compound 37b, 10 mg / kg, (v) compound 48, 5 mg / kg, or (vi) compound 48, 10 mg / kg. All animals were sacrificed and photographed when tumor ulceration began to appear in the control animals (DMSO) at day 25. Figure 12B These are tumor photos of animals euthanized from different treatment groups 25 days later. Figure 12C This is a graph showing the tumor weight of xenograft tumors relative to the time following SC injection of DMSO, PTX, compound 37b, or compound 48. Data are presented as mean ± SEM. *P≤0.05 compared to the DMSO group. Figure 12D These are morphological photographs (200x) of mouse tissues treated with DMSO, paclitaxel, compound 37b, or compound 48, after H&E staining in the heart, liver, kidney, lung, and spleen. Detailed Implementation

[0060] I. Definition

[0061] It should be understood that, unless otherwise stated, the disclosed compounds, compositions, and methods are not limited to specific synthetic methods, specific analytical techniques, or specific reagents, and therefore can vary. It should also be understood that the terminology used herein is for the purpose of describing particular forms and embodiments only and is not intended to be limiting.

[0062] As used herein, “substituted” means all permissible substituents of the compounds or functional groups described herein. In the broadest sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Representative substituents include substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclic groups, substituted or unsubstituted phenyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted polyaryl groups, substituted or unsubstituted polyhexaaryl groups, substituted or unsubstituted aralkyl groups, halogens, hydroxyl groups, alkoxy groups, phenoxy groups, aryloxy groups, silyl groups, mercapto groups, alkylthio groups, substituted alkylthio groups, phenylthio groups, arylthio groups, cyano groups, isocyano groups, nitro groups, substituted or unsubstituted carbonyl groups, carboxyl groups, amino groups, amide groups, oxo groups, sulfinyl groups, sulfonyl groups, sulfonic acid groups, phosphoronium groups, phosphono groups, phosphoryl groups, phosphonoyl groups, amino acids, poly(lactic-co-glycolic acid) copolymers, peptides, polypeptide groups, and sugar groups (e.g., glucosyl, acetylated glucose, fructose, acetylated fructose, etc.). Such substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted phenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, halogen, hydroxyl, alkoxy, phenoxy, aryloxy, silyl, mercapto, alkylthio, substituted alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, substituted or unsubstituted carbonyl, carboxyl, amino, amide, oxo, sulfinyl, sulfonyl, sulfonic acid, phosphorium, phosphono, phosphoryl, phosphonyl, amino acid, polylactic acid-glycolic acid copolymer, peptide, polypeptide group and sugar group can be further substituted.

[0063] As used herein, "alkyl" refers to a free radical of a saturated aliphatic group, including straight-chain alkyl, branched-chain alkyl, and cycloalkyl (alicyclic). In some forms, straight-chain or branched alkyl groups have 30 or fewer atoms in their main chain (e.g., straight-chain C1-C1). 30 The branch is C3-C. 30Alkyl groups have 20 or fewer, 15 or fewer, or 10 or fewer carbon atoms. Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, etc. Similarly, cycloalkyl groups are non-aromatic carbonyl rings consisting of at least three carbon atoms, such as non-aromatic monocyclic or non-aromatic polycyclic rings containing 3-30, 3-20, or 3-10 carbon atoms in their ring structure, and ring structures having 5, 6, or 7 carbons. Cycloalkyl groups containing polycyclic systems can have two or more non-aromatic rings, where two or more carbons are shared by two adjacent rings (i.e., "fused cycloalkyl rings"). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0064] Throughout the specification, examples, and claims, the term "alkyl" is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter referring to an alkyl moiety having one or more substituents substituted for hydrogen on one or more carbons of the hydrocarbon backbone. These substituents can be any of the substituents listed above, such as halogens (e.g., fluorine, chlorine, bromine, or iodine), hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetates, or thiocarbamates), aryl, alkoxy, aralkyl, phosphoronium, phosphonyl, phosphonyl, phosphoryl, phosphate, phosphonate, hypophosphonate, amino, amide, amidine, imine, cyano, nitro, azide, oxo, mercapto, mercapto, alkylthio, silyl, sulfinyl, sulfate, sulfonate, sulfamoyl, and sulfonamido. Sulfonyl, heterocyclic, aromatic or heteroaromatic moiety; -NRR', wherein R and R' are independently hydrogen, alkyl or aryl, and wherein the nitrogen atom is optionally quaternized; -SR, wherein R is phosphono, sulfinyl, silyl, hydrogen, alkyl or aryl; -CN; -NO2; -COOH; carboxylate; -COR, -COOR or -CON(R)2, wherein R is hydrogen, alkyl or aryl; imino, silyl, ether, haloalkyl (e.g. -CF3, -CH2-CF3, -CCl3); -CN; -NCOCOCH2CH2; -NCOCOCHCH; and -NCS; and combinations thereof. The term "alkyl" also includes "heteroalkyl".

[0065] Unless otherwise specified, “lower alkyl” as used herein refers to alkyl as defined above, but having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, in its main chain structure. Similarly, “lower alkenyl” and “lower alkynyl” have similar chain lengths.

[0066] As used herein, “heteroalkyl” refers to a straight-chain, branched, or cyclic carbon-containing alkyl radical, or a combination thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, wherein nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term “heterocycloalkyl” is a cycloalkyl group as defined above, wherein at least one carbon atom of the ring is substituted by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.

[0067] As used herein, the term "alkenyl" refers to a hydrocarbon group having 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon double bond. Alkenyl groups include straight-chain alkenyl, branched alkenyl, and cycloalkenyl. A cycloalkenyl is a non-aromatic carbonyl ring consisting of at least three carbon atoms and at least one carbon-carbon double bond, for example, a non-aromatic monocyclic or non-aromatic polycyclic ring containing 3-30 carbon atoms and at least one carbon-carbon double bond, 3-20 carbon atoms and at least one carbon-carbon double bond, 3-10 carbon atoms and at least one carbon-carbon double bond in its ring structure, and a ring structure having 5, 6, or 7 carbons and at least one carbon-carbon double bond. Cycloalkenyl groups containing polycyclic systems may have two or more non-aromatic rings, wherein two or more carbons are shared by two adjacent rings (i.e., "fused cycloalkenyl rings"), and contain at least one carbon-carbon double bond. Asymmetric structures such as (AB)C=C (C'D) are intended to include E and Z isomers. This can be assumed in the structural formulas herein to include the presence of an asymmetric olefin, or it can be explicitly indicated by the bond symbol C. The term "alkenyl" as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkenyl" and "substituted alkenyl," the latter referring to an alkenyl moiety having one or more substituents replacing hydrogen on one or more carbons of the hydrocarbon backbone. The term "alkenyl" also includes "heteroalkenyl."

[0068] The term "substituted alkenyl" refers to an alkenyl moiety having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can be any of the substituents described above.

[0069] As used herein, “heteroalkenyl” refers to a straight-chain, branched, or cyclic carbon-containing alkenyl radical, or a combination thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, wherein nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term “heterocyclic alkenyl” is a cycloalkenyl group in which at least one carbon atom of the ring is substituted by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.

[0070] As used herein, the term "alkynyl" refers to a hydrocarbon group having 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon triple bond. Alynyl groups include straight-chain alkynyls, branched-chain alkynyls, and cycloalkynyls. A cycloalkynyl is a non-aromatic carbonyl ring consisting of at least three carbon atoms and at least one carbon-carbon triple bond, for example, a non-aromatic monocyclic or non-aromatic polycyclic ring having 3-30 carbon atoms and at least one carbon-carbon triple bond, 3-20 carbon atoms and at least one carbon-carbon triple bond, or 3-10 carbon atoms and at least one carbon-carbon triple bond, as well as having 5, 6, or 7 carbon atoms and at least one carbon-carbon triple bond. Cycloalkynyls containing polycyclic systems may have two or more non-aromatic rings, wherein two or more carbons are shared by two adjacent rings (i.e., "fused cycloalkynyl rings"), and contain at least one carbon-carbon triple bond. The term "alkynyl" as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkynyl" and "substituted alkynyl," the latter referring to an alkynyl moiety having one or more substituents replacing hydrogen on one or more carbons of the hydrocarbon backbone. The term "alkynyl" also includes "heterynyl."

[0071] The term "substituted alkynyl" refers to an alkynyl moiety having one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone replaced by one or more substituents. Such substituents can be any of the substituents described above.

[0072] As used herein, “heteroyne” refers to a straight-chain, branched, or cyclic carbonaceous ynyl radical, or a combination thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, wherein nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term “heterocyclic ynyl” is a cycloynyl group in which at least one carbon atom of the ring is substituted by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.

[0073] As used in this article, the term "aryl" refers to any C5-C 26 Carbonyl aromatic groups, heteroaromatic groups, fused aromatic groups, or fused heteroaromatic groups. For example, the term "aryl" as used herein may include 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and 24-membered monocyclic aromatic groups, including but not limited to benzene, naphthalene, anthracene, phenanthrene, etc. (chrysene), pyrene, corannulene, coronene, etc. "Aryl" also includes polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings (i.e., "fused aromatic rings"), and at least one ring is an aromatic ring; for example, the other one or more rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclic. Aryl groups can be substituted with one or more groups, including but not limited to alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxyl, carboxylic acid, or alkoxy.

[0074] The term "substituted aryl" refers to an aryl group in which one or more hydrogen atoms on one or more aromatic rings are replaced by one or more substituents. Such substituents can be any of the substituents mentioned above.

[0075] "Heterocycle" and "heterocyclic group" are used interchangeably. They refer to cyclic free radicals consisting of non-aromatic monocyclic or polycyclic carbon or nitrogen atoms linked together, containing 3-30, 3-20, 3-10, or 5-6 ring atoms. Each ring contains carbon and 1-4 heteroatoms, each heteroatom selected from non-peroxide oxygen, sulfur, and N(Y), where Y is absent or is H, O, or Cl-C. 10 The group is alkyl, phenyl, or benzyl, and optionally contains 1-3 double bonds and is optionally substituted with one or more substituents. Heterocyclic groups are distinguished by definition from heteroaryl groups. Heterocyclic groups can be heterocyclic alkyl, heterocyclic alkenyl, heterocyclic alkynyl, etc., such as piperazinyl, piperidinyl, piperidoneyl, 4-piperidoneyl, dihydrofurano[2,3-b]tetrahydrofuran, morpholinyl, piperazinyl, piperidinyl, piperidoneyl, 4-piperidoneyl, piperinyl, pyranyl, 2H-pyrroleyl, 4H-quinolizinyl, quininecycloyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl. Heterocyclic groups may optionally be substituted with one or more substituents as defined above for alkyl and aryl groups.

[0076] The term "heteroaryl" refers to C5-C 30A heteroaryl group is a monocyclic aromatic ring, a fused aromatic ring, a bicyclic aromatic ring system, or a combination thereof, wherein one or more carbon atoms in one or more aromatic ring structures have been replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen. As used herein, “heteroaryl” in a broad sense includes 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and 24-membered monocyclic aromatic groups, which may include one to four heteroatoms, such as pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, tetraazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl groups may also be referred to as “aryl heterocycles” or “heteroaromatics.” “Heteroaryl” also includes polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings (i.e., “fused rings”), wherein at least one ring is heteroaromatic, for example, the other ring or rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic, or a combination thereof. Examples of heteroaromatic rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzosoxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazole, 4aH-carbazole, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-Dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazole, indolenyl, indolinyl, indolizinyl, indole, 3H-indole, isatinoyl, isobenzofuranyl, isochromanyl, isoindazole, isoindolinyl, isoindole, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxy Phenyl (methylenedioxyphenyl), naphthyridinyl, octahydroisoquinolinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, Phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridooxazole, pyridoimidazole, pyridine pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 1,2,3-Thiadiazolyl, 1,2,4-Thiadiazolyl, 1,2,5-Thiadiazolyl, 1,3,4-Thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, and xanthenyl. One or more rings may be substituted, as defined below for “substituted heteroaryl”.

[0077] The term "substituted heteroaryl" refers to a heteroaryl group in which one or more hydrogen atoms on one or more heteroaryl rings are replaced by one or more substituents. Such substituents can be any of the substituents mentioned above.

[0078] The term "polyaryl" refers to a chemical moiety comprising two or more aryl, heteroaryl, and combinations thereof. Aryl, heteroaryl, and combinations thereof are fused or linked by single bonds, ethers, esters, carbonyl groups, amides, sulfonyl groups, sulfonamides, alkyl groups, azo groups, and combinations thereof. For example, a "polyaryl" can be a polycyclic system having two or more rings, wherein two or more carbons are shared by two adjacent rings (i.e., "fused aromatic rings"), wherein two or more rings are aromatic. When two or more heteroaryl groups are involved, the chemical moiety may be referred to as a "polyheteroaryl".

[0079] The term "substituted polyaryl" refers to a polyaryl compound in which one or more aryl or heteroaryl groups are replaced by one or more substituents. Such substituents can be any of the substituents mentioned above. When two or more heteroaryl groups are involved, the chemical part may be referred to as "substituted polyheteroaryl".

[0080] The term "cycle" refers to a substituted or unsubstituted monocyclic or polycyclic (e.g., those formed from monocyclic or fused ring systems), such as substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted polyheteroaryl, having 3 to 30 carbon atoms where geometric constraints permit. The substituted cycloalkyl, cycloalkenyl, cycloynyl, and heterocyclic groups are substituted as defined above for alkyl, alkenyl, ynyl, heterocyclic, aryl, heteroaryl, polyaryl, and polyheteroaryl, respectively.

[0081] As used herein, the term "aralkyl" refers to an aryl or heteroaryl group having an alkyl, ynyl, or alkenyl group as defined above attached to an aromatic group (e.g., aryl, heteroaryl, polyaryl, or polyheteroaryl). An example of an aralkyl group is a benzyl group.

[0082] The terms "alkoxy" ("alkoxyl" or "alkoxy") and "aroxy" ("aroxy" or "aryloxy") are generally used to describe compounds derived from the formula -OR v The compound represented by R v This includes, but is not limited to, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, glycosyl, phosphonium, phosphonyl, sulfinyl, silyl, mercapto, amide, and amino. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc. A “lower alkoxy” is an alkoxy group containing one to six carbon atoms. An “ether” is two functional groups covalently linked by oxygen as defined below. Therefore, the substituent of the alkyl group that makes the alkyl group an ether is or similar to an alkoxy group, and may be represented by one of -O-alkyl, -O-alkenyl, -O-ynyl, -O-aryl, -O-heteroaryl, -O-polyaryl, -O-polyheteroaryl, -O-heterocyclic, etc.

[0083] The term "substituted alkoxy" refers to an alkoxy group having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the alkoxy backbone. Such substituents can be any of the substituents mentioned above.

[0084] The term "ether" as used in this article is derived from formula A. 2 OA 1 It means that A 2 and A 1 It can independently be a glycosyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, a phosphonium group, a phosphonyl group, a sulfinyl group, a silyl group, a mercapto group, a substituted or unsubstituted carbonyl group, an alkoxy group, an amide group, or an amino group as described above.

[0085] The term "polyether" as used in this article is represented by the following formula:

[0086]

[0087] Where A 3 It can be a sugar group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, a phosphorium group, a phosphonyl group, a substituted or unsubstituted carbonyl group, an alkoxy group, an amide group, or an amino group, as described above; g can be a positive integer from 1 to 30.

[0088] The term "phenoxy" is recognized in the art and refers to the formula -OR v The compound in which R v Yes (i.e., -O-C6H5). Those skilled in the art will recognize that phenoxy is a member of the aryloxy group.

[0089] The term "substituted phenoxy" refers to a phenoxy group as defined above that has one or more hydrogen atoms on one or more carbons of a benzene ring substituted by one or more substituents.

[0090] The terms “aroxy” and “aryloxy”, which may be used interchangeably herein, are denoted by -O-aryl or -O-heteroaryl, where aryl and heteroaryl are as defined herein.

[0091] The terms “substituted aroxy” and “substituted aryloxy”, used interchangeably herein, refer to a -O-aryl or -O-heteroaryl group having one or more substituents on one or more ring atoms of the aryl or heteroaryl group. Such substituents can be any of the substituents described above.

[0092] The term "amino" as used in this article includes the following groups:

[0093]

[0094] Wherein, E is absent, or E is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic group, wherein, independent of E, R x R xi and R xiiEach of these groups independently represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aralkyl group (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, a substituted or unsubstituted heterocyclic group, a hydroxyl group, an alkoxy group, a phosphorium group, a phosphono group, a phosphonyl group, a sulfinyl group, a silyl group, a mercapto group, an amide group, an amino group, or -(CH2). m -R”'; R”' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphorium group, a phosphonyl group, an amide group, or an amino group; and m is zero or an integer from 1 to 8. The term "quaternary amino" also includes groups in which nitrogen, R x R xi and R xii N connected to them + It constitutes a heterocyclic group or heteroaryl group with 3 to 14 atoms in the ring structure.

[0095] The terms "amide" or "acylamino" are used interchangeably to refer to "unsubstituted acylamino" and "substituted acylamino," and are represented by the following general formula:

[0096]

[0097] Wherein, E is as defined above for "amino", and independently of E, R and R' each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic, hydroxyl, alkoxy, phosphonium, phosphonyl, sulfinyl, silyl, mercapto, amide, amino, or -(CH2). m -R”', or R and R' together with the N atom they are attached to, form a heterocycle with 3 to 14 atoms in the ring structure; R”' and m are defined as in the definition of “amino” above. In some forms, when E is oxygen, urethane is formed.

[0098] As used herein, "carbonyl" is recognized in the art and includes portions that can be represented by the following general formula:

[0099]

[0100] Where X is a bond, or represents oxygen or sulfur, and R represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic, hydroxyl, alkoxy, phosphonium, phosphinyl, amide, amino, or -(CH2). m -R”, or a pharmaceutically acceptable salt; E” is absent, or E” is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic group; R' represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic group, hydroxyl, alkoxy, phosphonium, phosphinyl, amide, amino, or -(CH2). m -R”; R” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphorium group, a phosphono group, an amide group, or an amino group; m is zero or an integer from 1 to 8. When X is oxygen and R is as defined above, this part is also called a carboxyl group. When X is oxygen and R is hydrogen, this formula represents a “carboxylic acid.” When X is oxygen and R’ is hydrogen, this formula represents a “formate.” When X is oxygen and R or R’ is not hydrogen, this formula represents an “ester.” Generally, when the oxygen atom in the above formula is replaced by a sulfur atom, this formula represents a “thiocarbonyl.” When X is sulfur and R or R’ is not hydrogen, this formula represents a “thioester.” When X is sulfur and R is hydrogen, this formula represents a “thiocarboxylic acid.” When X is sulfur and R' is hydrogen, the formula represents "thiocarbamate". When X is a bond and R is not hydrogen, the formula represents "ketone". When X is a bond and R is hydrogen, the formula represents "aldehyde".

[0101] The term "substituted carbonyl" refers to a carbonyl group as defined above, wherein one or more hydrogen atoms in the group to which R, R', or the following part is attached are independently substituted. These substituents can be any of the substituents described above.

[0102]

[0103] The term "carboxyl group" is as defined above for the carbonyl group and more specifically by formula -R iv COOH is defined, where R iv It is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclic, a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, or a substituted or unsubstituted heteroaryl.

[0104] The term "substituted carboxyl group" refers to a carboxyl group as defined above, where R iv One or more hydrogen atoms are replaced. Such a substituent can be any of the substituents mentioned above.

[0105] The term "phosphine group" is represented by the following formula.

[0106]

[0107] Wherein, E is absent, or E is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic, wherein independent of E, R vi and R vii Each of these groups independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic, hydroxyl, alkoxy, phosphonium, phosphonyl, sulfinyl, silyl, mercapto, amide, amino, or -(CH2). m -R”', or R vi and R vii Together with the P atoms they are attached to, they form heterocycles with 3 to 14 atoms in the ring structure; R”' and m are defined as “amino” above.

[0108] The term "phosphonium" is represented by the following formula.

[0109]

[0110] Where E is as defined above for "phosphine group", and independent of E, R vi R vii and R viii Each of these groups independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic, hydroxyl, alkoxy, phosphonium, phosphonyl, sulfinyl, silyl, mercapto, amide, amino, or -(CH2). m -R”', or R vi R vii and R viii Together with the P they are connected to + Atoms together form a heterocycle with 3 to 14 atoms in the ring structure; R”' and m are defined as in the definition of “amino” above.

[0111] The term "phosphonoyl" is represented by the following formula.

[0112]

[0113] Where E is absent, or E is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic, wherein independent of E, R vi and R vii Independently, it is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic, hydroxyl, alkoxy, phosphonium, phosphonyl, sulfinyl, silyl, mercapto, amide, amino, or -(CH2). m -R”', or R vi and R viiTogether with the P atoms they are attached to, they form heterocycles with 3 to 14 atoms in the ring structure; R”' and m are defined as “amino” above.

[0114] The term "substituted phosphonoyl group" indicates that E and R are substituted. vi and R vii The phosphonoyl group is substituted independently. Such a substituent can be any of the substituents mentioned above.

[0115] The term "phosphonyl" is defined as follows, where E is absent, oxygen, alkoxy, aryloxy, substituted alkoxy, or substituted aryloxy, as defined above, and independent of E, R vi and R vii Independently, it is a hydroxyl, alkoxy, aryloxy, substituted alkoxy, or substituted aryloxy group, as defined above. When E is oxygen, the phosphoryl group cannot be attached to another chemical class, for example, to form an oxygen-oxygen bond or other unstable bond, as understood by one of ordinary skill in the art.

[0116] The term "sulfinyl" is represented by the following formula.

[0117]

[0118] Where E is as defined above for "phosphonoyl", and independent of E, R represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic, hydroxyl, alkoxy, phosphonium, phosphonoyl, silyl, mercapto, amide, amino, or -(CH2). m -R”', or E and R together with the S atoms they are attached to form a heterocycle with 3 to 14 atoms in the ring structure; R”' and m are defined as in the definition of “amino” above.

[0119] The term "sulfonyl" is represented by the following formula.

[0120]

[0121] Where E is as defined above for "phosphonoyl", and independent of E, R represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic, hydroxyl, alkoxy, phosphonium, phosphono, amide, amino, or -(CH2). m -R”', or E and R together with the S atoms they are attached to form a heterocycle with 3 to 14 atoms in the ring structure; R”' and m are defined as in the definition of “amino” above.

[0122] The term "substituted sulfonyl" means a sulfonyl group in which E, R, or both are independently substituted. Such a substituent can be any of the substituents mentioned above.

[0123] The term "sulfonic acid" refers to a sulfonyl group as defined above, wherein R is a hydroxyl group, E is absent, or E is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, or substituted or unsubstituted heteroaryl.

[0124] The term "sulfate ester" refers to a sulfonyl group as defined above, wherein E is an oxygen, alkoxy, aryloxy, substituted alkoxy, or substituted aryloxy group as defined above, and R is independently a hydroxyl, alkoxy, aryloxy, substituted alkoxy, or substituted aryloxy group as defined above. When E is oxygen, the sulfate ester cannot be bonded to another chemical class, for example, to form an oxygen-oxygen bond or other unstable bond, as understood by one of ordinary skill in the art.

[0125] The term "sulfonate" refers to a sulfonyl group as defined above, wherein E is oxygen, alkoxy, aryloxy, substituted alkoxy, or substituted aryloxy as defined above, and R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, -(CH2). m-R”', where R”' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, an aryl group, a cycloalkyl ring, a cycloalkenyl ring, a heterocyclic ring, an amide group, an amino group, or a polycyclic ring; and m is zero or an integer from 1 to 8. When E is oxygen, the sulfonate ester cannot be attached to another chemical class, such as forming an oxygen-oxygen bond or other unstable bonds, as understood by one of ordinary skill in the art.

[0126] The term "aminosulfonyl" refers to sulfonamides or sulfonamides represented by the following formula.

[0127]

[0128] Where E is absent, or E is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic, wherein independently of E, R and R' each independently represent hydrogen, substituted or unsubstituted alkane. Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclic, hydroxyl, alkoxy, phosphonium, phosphinyl, amide, amino, or -(CH2). m -R”', or R and R' together with the N atom they are attached to form a heterocycle with 3 to 14 atoms in the ring structure; R”' and m are defined as "amino" above.

[0129] As used herein, the term "silyl" is represented by the formula -SiRR'R", wherein R, R', and R" can independently be hydrogen, glycosyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted carbonyl, phosphonium, phosphonyl, phosphonyl, sulfinyl, mercapto, amide, amino, alkoxy, or oxo, as described above.

[0130] The term "thiol" is used interchangeably and is represented by -SR, where R can be hydrogen, glycosyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted carbonyl, phosphonium, phosphonyl, amide, amino, alkoxy, oxo, phosphonyl, sulfinyl, or silyl, as described above.

[0131] The term "alkathioyl" refers to an alkyl group having a sulfur group attached to it as defined above. The "alkathioyl" part is indicated by -S-alkyl. Representative alkathioyl groups include methylthioyl, ethylthioyl, etc. The term "alkathioyl" also includes cycloalkyl groups having a sulfur group attached to them.

[0132] The term "substituted alkathio" refers to an alkathio group having one or more substituents replacing one or more hydrogen atoms on one or more carbon atoms of the alkathio backbone.

[0133] The term "phenylthio" is generally accepted in the field to refer to -S-C6H5, i.e., a phenyl group bonded to a sulfur atom.

[0134] The term "substituted phenylthio" refers to a phenylthio group as defined above, having one or more substituents replacing hydrogen on one or more carbons of the benzene ring.

[0135] "Arylthio" refers to -S-aryl or -S-heteroaryl, where aryl and heteroaryl are as defined herein.

[0136] The term “substituted arylthio” means a -S-aryl or -S-heteroaryl group having one or more substituents replacing hydrogen atoms on one or more ring atoms of the aryl and heteroaryl rings as defined herein.

[0137] The terms "hydroxyl" and "hydroxyl" are used interchangeably and are represented by -OH.

[0138] The term "oxo" refers to the =O atom bonded to a carbon atom.

[0139] The terms “cyano” and “nitrile” are used interchangeably to refer to -CN.

[0140] The term "nitro" refers to -NO2.

[0141] The term "phosphate" refers to -O-PO3.

[0142] The terms “azide” or “azido” are used interchangeably to refer to -N3.

[0143] The disclosed compounds and substituents may independently have two or more of the groups listed above. For example, if the compound or substituent is a straight-chain alkyl group, one hydrogen atom of the alkyl group may be replaced by a hydroxyl, alkoxy, etc. Depending on the chosen groups, the first group may be incorporated into the second group, or the first group may be side-attached (i.e., connected) to the second group. For example, for the phrase "alkyl group containing an ester group," the ester group may be incorporated into the backbone of the alkyl group. Alternatively, the ester may be attached to the backbone of the alkyl group. The nature of the chosen groups will determine whether the first group is inserted into or attached to the second group.

[0144] Compounds and substituents can be independently substituted by substituents as described in the above definition of "substituted".

[0145] II. Composition

[0146] 1,2,4,5-tetraoxane compounds and their derivatives (collectively referred to herein as "compounds") with anticancer properties targeting cancer cells and / or cancer stem cells have been developed. They possess broad anticancer properties and should be suitable for treating a variety of cancer types and / or improving the symptoms of a variety of cancer types.

[0147] Typically, a compound consists of three parts:

[0148]

[0149] Unbound by theory, the cyclic portion of a compound can provide lipophilicity for cell permeability and maintain the compound's killing power against cancer cells and / or cancer stem cells; while the targeting portion provides water solubility, cytotoxicity, and selectivity against cancer cells and / or cancer stem cells compared to non-cancer cells. For example, the targeting portion can localize the compound to specific sites within cancer cells and / or cancer stem cells to enhance potency and minimize off-target effects, i.e., binding to non-cancer cells.

[0150] The overall structure of these compounds makes them suitable for inducing ferroptosis to kill cancer cells and / or cancer stem cells. The term "cancer cell" refers to cells that grow and divide abnormally and have invasive potential. Tumors contain cancer cells that exhibit dysregulation and promote angiogenesis. "Cancer stem cells" refer to tumor-initiating cells characterized by their ability to self-renew, differentiate, and develop resistance to chemotherapy. Unbound by theory, cancer cells differ from cancer stem cells in at least the following ways: For example, the Wnt / β-catenin, Notch, or Hedgehog signaling pathways are more responsible for regulating the growth and development of cancer stem cells than cancer cells. Cancer stem cells can be positive for stem cell surface markers such as CD133, CD117, Bmi-1, Nanog, Sox4, and CD44. Compared to cancer cells, cancer stem cells can overexpress ABC drug transporters to refute chemotherapeutic drugs such as paclitaxel and doxorubicin. Cancer stem cells can belong to a side population that excludes the Hoechst 33342 DNA-specific dye. Ferroptosis is an iron-dependent and reactive oxygen species (ROS)-dependent cell death pathway. It is well known that cancer cells have elevated iron levels, which favor ferroptosis, inducing harmful lipid peroxides and irreversible cell death. These compounds can also selectively induce ferroptosis in both cancer cells and cancer stem cells, compared to non-cancer cells. Furthermore, regardless of pH, these compounds can generate reactive oxygen species (e.g., hydroxyl radicals and lipid peroxides at neutral pH) within cancer cells and cancer stem cells, eliminating the need for complex formulations encapsulating multiple components (e.g., enzymes catalyzing hydrogen peroxide production, iron oxide, etc.) and the acidic intracellular environment required for chemokinetic therapy, i.e., ferroptosis.

[0151] Pharmaceutical compositions and formulations containing these compounds were also disclosed.

[0152] A. Compound

[0153] 1,1,2,4,5-Tetraoxane and its derivatives

[0154] The compound may have the structure of Formula I.

[0155]

[0156] (a) Wherein A' can be a substituted or unsubstituted monocyclic or a substituted or unsubstituted polycyclic; (b) Wherein R1 and R2 can independently be hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclic, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, amide, amino, phosphonium, phosphonyl, silyl, sulfinyl, mercapto, hydroxyl, or R1 and R2 together with the carbons to which they are attached form a substituted or unsubstituted monocyclic or a substituted or unsubstituted polycyclic. E.

[0157] Exemplary substituents may be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, halogen, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, carboxyl, amino, amide, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphorium, phosphonyl, phosphoryl, phosphonyl, mercapto, amino acid, peptide, polypeptide, or sugar group (e.g., glucosyl or acetylated glucose), or combinations thereof.

[0158] In some forms, A' can be a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted cycloalkynyl, a substituted or unsubstituted heterocyclic group (e.g., a substituted or unsubstituted heterocyclic alkyl, a substituted or unsubstituted heterocyclic alkenyl, a substituted or unsubstituted heterocyclic alynyl), a substituted or unsubstituted aryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted heteroaryl, and a substituted or unsubstituted polyheteroaryl, having 3 to 30 carbon atoms where geometric constraints permit.

[0159] The alkyl group can be a straight-chain alkyl group, a branched alkyl group, or a cyclic alkyl group (monocyclic or polycyclic). Exemplary alkyl groups include straight-chain C1-C1 alkyl groups. 30 Alkyl, branched C4-C 30 Alkyl, cyclic C3-C 30 Alkyl, straight-chain C1-C 20 Alkyl, branched C4-C 20 Alkyl, cyclic C3-C 20 Alkyl, straight-chain C1-C 10 Alkyl, branched C4-C 10 Alkyl, cyclic C3-C 10Alkyl, straight-chain C1-C6 alkyl, branched-chain C4-C6 alkyl, cyclic C3-C6 alkyl, straight-chain C1-C4 alkyl, cyclic C3-C4 alkyl, such as straight-chain C1-C6 alkyl 10 C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2 alkyl groups, branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkyl groups, or cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkyl groups.

[0160] The alkenyl group can be a straight-chain alkenyl, a branched alkenyl, or a cyclic alkenyl (monocyclic or polycyclic). Exemplary alkenyl groups include straight-chain C1-C... 30 Alkenyl, branched C4-C 30 Alkenyl, cyclic C3-C 30 Alkenyl, straight-chain C1-C 20 Alkenyl, branched C4-C 20 Alkenyl, cyclic C3-C 20 Alkenyl, straight-chain C1-C 10 Alkenyl, branched C4-C 10 Alkenyl, cyclic C3-C 10 Alkenyl, straight-chain C1-C6 alkenyl, branched-chain C4-C6 alkenyl, cyclic C3-C6 alkenyl, straight-chain C1-C4 alkenyl, cyclic C3-C4 alkenyl, such as straight-chain C1-C6 alkenyl. 10 C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2 alkenyl groups, branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkenyl groups, or cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkenyl groups.

[0161] The alkynyl group can be a straight-chain alkynyl group, a branched-chain alkynyl group, or a cyclic alkynyl group (monocyclic or polycyclic). Exemplary alkynyl groups include straight-chain C1-C... 30 Alkyne group, branched C4-C 30 Alkyne group, cyclic C3-C 30 Alkyne group, straight-chain C1-C 20 Alkyne group, branched C4-C 20 Alkyne group, cyclic C3-C 20 Alkyne group, straight-chain C1-C 10 Alkyne group, branched C4-C 10 Alkyne group, cyclic C3-C 10Alkynyl, straight-chain C1-C6 alkynyl, branched-chain C4-C6 alkynyl, cyclic C3-C6 alkynyl, straight-chain C1-C4 alkynyl, cyclic C3-C4 alkynyl, such as straight-chain C1-C 10 C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2 alkynyl groups; branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkynyl groups; or cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkynyl groups.

[0162] It should be understood that any exemplary alkyl, alkenyl, and ynyl groups can be heteroalkyl, heteroalkenyl, and heteroynyl, respectively. For example, the alkyl group can be a straight-chain C2-C group. 30 Heteroalkyl, branched C4-C 30 Heteroalkyl, cyclic C3-C 30 Heteroalkyl (i.e., heterocyclic alkyl), straight-chain C1-C 20 Heteroalkyl, branched C4-C 20 Heteroalkyl, cyclic C3-C 20 Heteroalkyl, straight-chain C1-C 10 Heteroalkyl, branched C4-C 10 Heteroalkyl, cyclic C3-C 10 Heteroalkyl, straight-chain C1-C6 heteroalkyl, branched-chain C4-C6 heteroalkyl, cyclic C3-C6 heteroalkyl, straight-chain C1-C4 heteroalkyl, cyclic C3-C4 heteroalkyl, for example, straight-chain C1-C6 heteroalkyl. 10 C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2 heteroalkyl groups, branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 heteroalkyl groups, or cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 heteroalkyl groups.

[0163] Alkenes can be straight-chain C2-C 30 Heteroalkenyl, branched C4-C 30 Heteroalkenyl, cyclic C3-C 30 Heteroalkenyl (i.e., heterocyclic alkenyl), straight-chain C1-C 20 Heteroalkenyl, branched C4-C 20 Heteroalkenyl, cyclic C3-C 20 Heteroalkenyl, straight-chain C1-C 10 Heteroalkenyl, branched C4-C 10 Heteroalkenyl, cyclic C3-C 10heteroalkenyl, straight-chain C1-C6 heteroalkenyl, branched-chain C4-C6 heteroalkenyl, cyclic C3-C6 heteroalkenyl, straight-chain C1-C4 heteroalkenyl, cyclic C3-C4 heteroalkenyl, for example, straight-chain C1-C6 heteroalkenyl. 10 C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2 heteroalkenyl groups, branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 heteroalkenyl groups, or cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 heteroalkenyl groups.

[0164] The alkynyl group can be a straight-chain C2-C 30 Heterynyl group, branched C4-C 30 Heterynyl, cyclic C3-C 30 heterocyclic ynyl group (i.e., heterocyclic ynyl group), straight-chain C1-C 20 Heterynyl group, branched C4-C 20 Heterynyl, cyclic C3-C 20 Heterynyl, straight-chain C1-C 10 Heterynyl group, branched C4-C 10 Heterynyl, cyclic C3-C 10 Xyrynyl, straight-chain C1-C6 xyrynyl, branched C4-C6 xyrynyl, cyclic C3-C6 xyrynyl, straight-chain C1-C4 xyrynyl, cyclic C3-C4 xyrynyl, such as straight-chain C1-C 10 C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2 heteroyne groups; branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 heteroyne groups; or cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 heteroyne groups.

[0165] Aryl groups can be C5-C 30 Aryl, C5-C 20 Aryl, C5-C 12 Aryl, C5-C 11 Aryl, C5-C9 aryl, C6-C 20 Aryl, C6-C 12 Aryl, C6-C 11 Aryl, or C6-C9 aryl. It should be understood that the aryl group can be a heteroaryl group, such as C5-C9. 30 heteroaryl, C5-C 20 heteroaryl, C5-C 12 heteroaryl, C5-C 11 heteroaryl, C5-C9 heteroaryl, C6-C30 heteroaryl, C6-C 20 heteroaryl, C6-C 12 heteroaryl, C6-C 11 Polyaryl groups can be C6-C9 heteroaryl groups. 10 -C 30 Polyaryl, C 10 -C 20 Polyaryl, C 10 -C 12 Polyaryl, C 10 -C 11 Polyaryl, or C 12 -C 20 Polyaryl. It should be understood that the aryl group can be a polyheteroaryl group, such as C. 10 -C 30 Polyarylene, C 10 -C 20 Polyarylene, C 10 -C 12 Polyarylene, C 10 -C 11 Polyarylene, or C 12 -C 20 Mixed aromatic compounds.

[0166] In some forms, the compound may have the structure of Formula II.

[0167]

[0168] (a) wherein A' and B' can be independently substituted or unsubstituted monocyclic or substituted or unsubstituted polycyclic, such as those described above for A'; (b) wherein the substituent can be any of the substituents described above.

[0169] In some forms, the compound may have the structure of formula III.

[0170]

[0171] (a) Where A' can be as described above; (b) Where a can be an integer from 1 to 20; (c) Where b can be an integer from 0 to 24; (d) Where R3 in each occurrence can be a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, halogen, hydroxyl, substituted or unsubstituted alkoxy, aryloxy, cyano, isocyano, nitro, substituted or unsubstituted carbonyl, amino, amide, silyl, sulfinyl, substituted or unsubstituted sulfonyl, phosphoronium, phosphonyl, phosphoryl, phosphonyl, mercapto, or sugar group (e.g., glucosyl or acetylated glucose); wherein the substituent can be any of the above substituents.

[0172] In some forms of Equation III, a can be an integer from 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 5, or 1 to 3, such as 1 or 2; b is an integer from 1 to 10, 1 to 8, 1 to 5, or 1 to 3, such as 1 or 2.

[0173] In some forms, the compound may have the structure of Formula IV.

[0174]

[0175] (a) wherein A' and a can be as described above; (b) wherein Z' and R4 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amino, amide, silyl, sulfinyl, sulfonyl, phosphoronium, phosphonyl, phosphoryl, phosphonyl, mercapto, or sugar group (e.g., glucosyl or acetylated glucose); wherein the substituent can be any of the substituents described above.

[0176] In some forms of Formula IV, a can be an integer from 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 5, or 1 to 3, such as 1 or 2. In some forms of Formula IV, Z' can be hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group. In some forms of Formula IV, R4 can be a substituted or unsubstituted alkyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted alkoxy group, an amide group, an amino group or a sulfinyl group, a sulfonyl group, a phosphoronium group, a phosphoryl group, a phosphonyl group, a thiol group, or a sugar group (e.g., glucosyl or acetylated glucose). In some forms of Formula IV, R4 can contain at least one oxygen atom and can be attached to a carbon atom via oxygen.

[0177] In some forms of Formula IV, a can be an integer from 1 to 5, or from 1 to 3, such as 1 or 2; Z' can be hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl; and R4 can be a substituted or unsubstituted alkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, amide, amino or sulfinyl, sulfonyl, phosphoronium, phosphonyl, phosphoryl, phosphonyl, mercapto, or a sugar group (e.g., glucosyl or acetylated glucose).

[0178] In some forms, the compound may have the structure of formula V.

[0179]

[0180] (a) where A', a, and Z' can be as described above; (b) where X' can be O, NR6, or S, where c can be an integer from 0 to 30; (c) where W' can be C, PR7, S, or Si; (d) where Y' can be NR8 or O; (e) where R6 and R7 can independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, aryloxy, amide, amino, phosphoronium, phosphonyl, phosphonyl, phosphoryl, phosphate ester, silyl, sulfinyl, mercapto, or hydroxyl; (f) where R5 and R8 can independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted... The substituent may be an alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted alkoxy group, an aryloxy group, an amide group, an amino group, a phosphorium group, a phosphonyl group, a phosphonyl group, a phosphoryl group, a phosphate group, a silyl group, a sulfinyl group, a mercapto group, or a hydroxyl group, or R5 and R8 together with Y' to which they are attached to form a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted cycloalkynyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, or a substituted or unsubstituted polyheteroaryl group; wherein the substituent may be any of the above substituents.

[0181] In some forms of Formula V, a can be an integer from 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 5, or 1 to 3, such as 1 or 2. In some forms of Formula V, Z' can be hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group. In some forms of Formula V, X' can be... Or O, and c can be zero or an integer from 1 to 10, 1 to 8, 1 to 5, or 1 to 3, such as 1 or 2. In some forms of formula V, X' can be O. In some forms of formula V, W' can be C, PR7, or S, where R7 can be hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, an amino, a mercapto, or a substituted or unsubstituted alkoxy.

[0182] In some forms of formula V, a can be an integer from 1 to 5, or from 1 to 3, for example, 1 or 2; Z' can be hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group; X' can be Or O, and c can be zero or an integer from 1 to 10, 1 to 8, 1 to 5, or 1 to 3; W' can be C, PR7, or S, wherein R7 can be hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, an amino, a mercapto, or a substituted or unsubstituted alkoxy; Y' can be NR8 or O; and R5 and R8 can independently be hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted). Substituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heteroarylalkyl, etc.), substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amide, amino or sulfinyl, sulfonyl, phosphoronium, phosphonyl, phosphoryl, phosphonyl, mercapto, silyl or sugar group (e.g. glucosyl or acetylated glucose), or R5 and R8 together with the Y' to which they are attached to form substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted heterocyclic alkenyl, or substituted or unsubstituted heterocyclic alkynyl.

[0183] In some forms, the compound may have the structure of formula VI.

[0184]

[0185] (a) Wherein A' and a can be as described above; (b) Wherein Z' can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amino, amide, silyl, phosphonium, or sugar group (e.g., glucosyl or acetylated glucose); (c) Wherein X' can be Or O, c can be an integer from 0 to 10; (d) wherein R5 and R8 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amide, amino, phosphonium, phosphonyl or silyl, or R5 and R8 together with the nitrogen to which they are attached form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted heterocyclic alkenyl, substituted or unsubstituted heterocyclic alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, or substituted or unsubstituted polyheteroaryl.

[0186] In some forms of Equation VI, X' can be O. In some forms of Equation VI, X' can be... And c can be zero or an integer from 1 to 10, 1 to 8, 1 to 5, or 1 to 3, such as 1 or 2. In some forms of Formula VI, a can be an integer from 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 5, or 1 to 3, such as 1 or 2. In some forms of Formula VI, Z' can be hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group.

[0187] In some forms of Formula VI, a can be an integer from 1 to 5, or from 1 to 3, for example, 1 or 2; Z' can be hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl; X' can be O; and R5 and R8 can independently be hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted aralkyl (e.g., a substituted or unsubstituted alkylaryl, a substituted or unsubstituted aryl). Alkyl, substituted or unsubstituted alkyl heteroaryl, substituted or unsubstituted heteroarylalkyl, etc.), substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amide, amino or sulfinyl, sulfonyl, phosphoronium, phosphonyl, phosphoryl, phosphonyl, mercapto, silyl or sugar group (e.g. glucosyl or acetylated glucose), or R5 and R8 together with the nitrogen to which they are attached to form a substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted heterocyclic alkenyl, or substituted or unsubstituted heterocyclic alkynyl.

[0188] In some forms of Formulas I-VI, A' can be a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted cycloynyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heterocycloalkenyl, a substituted or unsubstituted heterocycloynyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, or a substituted or unsubstituted polyheteroaryl. In some forms of Formulas I-VI, A' can be a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted cycloynyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heterocycloalkenyl, or a substituted or unsubstituted heterocycloynyl.

[0189] In some forms of formulas I-VI, A' can be a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl, such as a substituted or unsubstituted C3-C. 30 Cycloalkyl, substituted or unsubstituted C3-C 30 Heterocyclic alkyl, substituted or unsubstituted C3-C 25 Cycloalkyl, substituted or unsubstituted C3-C 25 Heterocyclic alkyl, substituted or unsubstituted C3-C 20 Cycloalkyl, substituted or unsubstituted C3-C 20 Heterocyclic alkyl, substituted or unsubstituted C3-C 15 Cycloalkyl, substituted or unsubstituted C3-C 15 Heterocyclic alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C5-C 30 Cycloalkyl, substituted or unsubstituted C5-C 30 Heterocyclic alkyl, substituted or unsubstituted C5-C 25 Cycloalkyl, substituted or unsubstituted C5-C 25 Heterocyclic alkyl, substituted or unsubstituted C5-C 20 Cycloalkyl, substituted or unsubstituted C5-C 20 Heterocyclic alkyl, substituted or unsubstituted C5-C 15 Cycloalkyl, substituted or unsubstituted C5-C 15 Heterocyclic alkyl, substituted or unsubstituted C5-C 10 Cycloalkyl, substituted or unsubstituted C5-C 10 Heterocyclic alkyl groups.

[0190] In some forms of formulas I-VI, A' can be substituted or unsubstituted C6-C. 30 Polycyclic, substituted or unsubstituted C6-C 30 Polyhexacyclic alkyl, substituted or unsubstituted C6-C 25 Polycyclic, substituted or unsubstituted C6-C 25Polyhexacyclic alkyl, substituted or unsubstituted C6-C 20 Polycyclic, substituted or unsubstituted C6-C 20 Polyhexacyclic alkyl, substituted or unsubstituted C6-C 15 Polycyclic, substituted or unsubstituted C6-C 15 Polyhexacyclic alkyl, substituted or unsubstituted C6-C 10 Polycyclic, substituted or unsubstituted C6-C 10 Polyhexacyclic alkyl, substituted or unsubstituted C 10 -C 30 Polycyclic, substituted or unsubstituted C 10 -C 30 Polyhexacyclic alkyl, substituted or unsubstituted C 10 -C 25 Polycyclic, substituted or unsubstituted C 10 -C 25 Polyhexacyclic alkyl, substituted or unsubstituted C 10 -C 20 Polycyclic, substituted or unsubstituted C 10 -C 20 Polyhexacyclic alkyl, substituted or unsubstituted C 10 -C 15 Polycyclic, substituted or unsubstituted C 10 -C 15 Polyhexacyclic alkyl groups, such as substituted or unsubstituted C46 ... 10 Polycyclic alkyl or substituted or unsubstituted C 10 Polyhexacyclic alkyl groups.

[0191] In some forms of equations I-VI, A' can be substituted or unsubstituted C3-C. 10 Monocycloalkyl, substituted or unsubstituted C3-C 10 Monocyclic alkyl, substituted or unsubstituted C3-C8 monocyclic alkyl, substituted or unsubstituted C3-C6 monocyclic alkyl, substituted or unsubstituted C3-C6 monocyclic alkyl, substituted or unsubstituted C3-C5 monocyclic alkyl, substituted or unsubstituted C3-C5 monocyclic alkyl, such as cyclohexyl.

[0192] In some forms of Formulas I-VI, A' can be a substituted adamantylidine, or a substituted or unsubstituted cyclohexyl group.

[0193] In some forms, the compound may have the structure of formula VII.

[0194]

[0195] (a) wherein a, X', R5, and R8 may be as described above; (b) wherein Z' may be hydrogen or a substituted or unsubstituted alkyl group; (c) wherein R9 may be a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted alkoxy group, an amide group, an amino group, a phosphorium group, a phosphono group, or a silyl group, and d may be an integer from 0 to 9; wherein the substituent may be any of the substituents described above.

[0196] In some forms of equation VII, a can be an integer from 1 to 5, or from 1 to 3, such as 1 or 2. Or O, and c can be zero or an integer from 1 to 10, 1 to 8, 1 to 5, or 1 to 3. In some forms of Formula VII, X' can be O. In some forms of Formula VII, d can be zero. In some forms of Formula VII, d can be an integer from 1 to 5, 1 to 3, or 1 or 2, and R9 can be hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, or an amide.

[0197] In some forms of Formula VII, a can be an integer from 1 to 5, from 1 to 3, or 1 or 2; X' can be O; R5 and R8 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amide, amino, phosphonium, phosphonyl, or silyl, or R5 and R8 together with the nitrogen to which they are attached form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, or substituted or unsubstituted heterocycloalkynyl; R9 is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, or substituted or unsubstituted alkoxy.

[0198] In some forms, the compound may have the structure of formula VIII.

[0199]

[0200] (a) wherein a, X', R5, and R8 can be as described above; (b) wherein a' can be an integer from 1 to 20; (c) wherein Z' can be hydrogen or a substituted or unsubstituted alkyl group; (d) wherein R 10It can be a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclic, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, amide, amino, phosphorium, phosphinyl, or silyl, where e can be an integer from 0 to 24; wherein the substituent can be any of the above substituents.

[0201] In some forms of Equation VIII, a and a' can each be integers from 1 to 5 and from 1 to 3, for example, 1 or 2. In some forms of Equation VIII, X' can be... Or 0, and c can be zero or an integer from 1 to 10, 1 to 8, 1 to 5, or 1 to 3. In some forms of equation VIII, X' can be 0.

[0202] In some forms of equation VIII, e can be zero. In some forms of equation VIII, e can be an integer from 1 to 5, from 1 to 4, or 1 or 2, and where R... 10 It can be a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, or a substituted or unsubstituted alkoxy. In some forms of formula VIII, e can be an integer from 1 to 5, from 1 to 4, or 1 or 2, and wherein R 10 The C1-C branch can be substituted or unsubstituted. 20 Alkyl, substituted or unsubstituted branched C1-C 15 Alkyl, substituted or unsubstituted branched C1-C 10 Alkyl, substituted or unsubstituted branched C1-C8 alkyl, substituted or unsubstituted branched C1-C6 alkyl, or substituted or unsubstituted branched C1-C4 alkyl. In some forms of formula VIII, e can be an integer from 1 to 5, from 1 to 4, or 1 or 2; and R wherein 10 It can be Where G' can be p can be an integer from 0 to 10, 0 to 8, 0 to 6, 0 to 4, 0 to 3, or 0 to 2, where R 11 It can be hydrogen or Where R 12 and R 13 It can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In some forms of formula VIII, e can be an integer from 1 to 5, from 1 to 4, or 1 or 2, and R 10 It can be a substituted or unsubstituted tert-butyl group, wherein the substituent can be any of the above-mentioned substituents, such as a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted alkoxy group, or an amide group.

[0203] In some forms, the compound may have the structure of formula IX.

[0204]

[0205] (a) where a, a', Z, X', R5, and R8 can be as described above; (b) where R 14 It can be hydrogen, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, or amide.

[0206] In some forms of equation IX, a and a' can each be integers from 1 to 5 and from 1 to 3, for example, 1 or 2. In some forms of equation IX, X' can be... Or O, and c can be 0 or an integer from 1 to 10, 1 to 8, 1 to 5, or 1 to 3. In some forms of equation IX, X' can be O. In some forms of IX, R 14 It can be hydrogen or Where R 12 and R 13 It can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, independently.

[0207] In some forms of formula V-Ⅸ, R5 and R8 may independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heteroarylalkyl, etc.), substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amide, amino or sulfinyl, sulfonyl, phosphonium, phosphoryl, phosphonyl, mercapto, silyl, or sugar group (e.g., glucosyl or acetylated glucose), or R5 and R8 together with the nitrogen linked to them may form a substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted heterocyclic alkenyl, or substituted or unsubstituted heterocyclic alkynyl. In some forms of formula V-Ⅸ, R5 and R8 may be phosphonium, amino, or silyl.

[0208] In some forms of equation IX, R5 and R8 can be independent.

[0209] Where h and i can be independent integers from 0 to 10, 0 to 8, 0 to 6, or 0 to 3, where R 15 -R 20It may be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted alkylaryl, or substituted or unsubstituted arylalkyl, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, or benzyl.

[0210] In some forms of formulas I-IX, the substituent of the substituted functional group may be a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclic, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, amino, amide, phosphorium, phosphonyl, phosphoryl, phosphonyl, or a sugar group (e.g., glucosyl or acetylated glucose), or a combination thereof.

[0211] In some forms of formulas I-IX, the substituent of the substituted functional group can be an unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted heterocyclic, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted aralkyl, unsubstituted carbonyl, unsubstituted alkoxy, amino, amide, phosphorium, or sugar group (e.g., glucosyl or acetylated glucose), or a combination thereof.

[0212] This compound may have the structure of formula X.

[0213]

[0214] (a) Wherein A' and A” can be independently substituted or unsubstituted monocyclic or substituted or unsubstituted polycyclic; (b) Wherein L' can be a linking group, such as oxygen, sulfur, carbon, boron, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted heteroaryl, phosphoryl, sulfinyl, sulfonyl, ether, polyether, disulfide, and amino; (c) Wherein the substituent can be independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or Unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, halogen, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, carboxyl, amino, amide, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphoronium, phosphonyl, phosphoryl, phosphonyl, mercapto, amino acid, peptide, polypeptide or sugar group (e.g., glucosyl or acetylated glucose), or combinations thereof.

[0215] In some forms, A' and A” can be the same. In some forms, A' and A” can be different. In some forms, B' and B” can be the same. In some forms, B' and B” can be different. In some forms, A' and A” can be the same, and B' and B” can be different. In some forms, A' and A” can be different, and B' and B” can be the same. In some forms, A' and A” can be different, and B' and B” can be different. In some forms, A' and A” can be the same, and B' and B” can be the same. When A' and A” are the same and B' and B” are the same, the compound of formula X is a dimer.

[0216] In some forms, the compound may have the structure of formula XI.

[0217]

[0218] (a) where A', A”, and L' can be as described above; (b) where a and a” can be independent integers from 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 3, or 1 or 2; (c) where Z', Z”, and R 21 and R' 21It may independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amino, amide, silyl, sulfinyl, sulfonyl, phosphoronium, phosphonyl, phosphoryl, phosphonyl, mercapto, or sugar group (e.g., glucosyl or acetylated glucose); wherein the substituent may be any of the above substituents.

[0219] In some forms, the compound of formula XI can be a dimer, wherein A' and A” are identical, Z and Z” are identical, and R 21 and R' 21 same.

[0220] In some forms, the compound may have the structure of formula XII.

[0221]

[0222] (a) where A', A”, L', a, a”, Z', and Z” can be as described above; (b) where X' and X” can be independently O, NR6, or S, and c can be an integer from 0 to 30, 0 to 25, 0 to 20, 0 to 15, 0 to 10, 0 to 5, 0 to 3, or 0, 1, or 2; (c) where W' and W” can be independently C, PR7, S, or Si; (d) where Y' and Y” can be independently a bond or NR8 or O; (e) where R 22 and R' 22 It can be independent j is an integer from 0 to 20, 0 to 15, 0 to 10, 0 to 5, 0 to 3 or 0, 1 or 2; (f) wherein R6, R7 and R8 may independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, aryloxy, amide, amino, phosphoronium, phosphonyl, phosphonyl, phosphoryl, phosphate ester, silyl, sulfinyl, mercapto or hydroxyl; wherein the substituent may be any of the above substituents.

[0223] In some forms of formulas XI and XII, Z' and Z” can independently be hydrogen or substituted or unsubstituted alkyl groups. In some forms of formula XII, X' and X” can independently be Or O, and c can be an integer from 0 to 10, 0 to 5, 0 to 3, or 0, 1, or 2. In some forms of formula XII, W' and W” can be independently C, PR7, or S, where R7 can be hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, an amino, a mercapto, or a substituted or unsubstituted alkoxy. In some forms, the compound of formula XII can be a dimer, where A' and A” are the same, Z and Z” are the same, X' and X” are the same, Y' and Y” are the same, and R 21 and R' 21 same.

[0224] In some forms of formulas X-XII, L' can be phosphoryl, sulfinyl, sulfonyl, disulfide, ether, or polyether.

[0225] In some forms of formulas X-XII, the substituent of the substituted functional group may be a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclic, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, amino, amide, phosphorium, phosphonyl, phosphoryl, phosphonyl, or a sugar group (e.g., glucosyl or acetylated glucose), or a combination thereof.

[0226] In some forms of formulas X-XII, the substituent of the substituted functional group may be an unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted heterocyclic, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted aralkyl, unsubstituted carbonyl, unsubstituted alkoxy, amino, amide, phosphorium, or sugar group (e.g., glucosyl or acetylated glucose), or a combination thereof.

[0227] These compounds may contain one or more chiral centers or may exist in the form of multiple stereoisomers. These can be pure (single) stereoisomers or mixtures of stereoisomers, such as enantiomers, diastereomers, and mixtures enriched with enantiomers or diastereomers. These compounds may be able to exist as geometric isomers. Therefore, it should be understood that the present invention includes pure geometric isomers or mixtures of geometric isomers.

[0228] 2. Exemplary 1,2,4,5-tetraoxane derivatives

[0229] Exemplary 1,2,4,5-tetraoxane derivatives are shown below.

[0230]

[0231]

[0232]

[0233] 3. Pharmaceutically acceptable salts

[0234] Compounds may be neutral or may be one or more pharmaceutically acceptable salts, crystalline forms, amorphous forms, hydrates or solvates, or combinations thereof. References to compounds may refer collectively and individually, in the context, to the neutral molecule and / or its additional forms. Pharmaceutically acceptable salts of compounds include their acid addition salts and base addition salts.

[0235] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camphorsulfonates, citrates, ethanedisulfonates, ethanesulfonates, formates, fumarates, gluceptates, gluconates, glucurons, hexafluorophosphates, hibenzates, hydrochlorides / chlorides, hydrobromates / bromines, hydroiodates / iodides, hydroxyethylsulfonates, lactates, malates, maleates, malonates, methanesulfonates, methyl sulfates, naphthylates, 2-napsylates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxynaphthylates, phosphates / hydrogen phosphates / dihydrogen phosphates, glycosides, stearates, succinates, tartrates, toluenesulfonates, and trifluoroacetates.

[0236] Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts.

[0237] It can also form half-salts of acids and bases, such as half-sulfates and half-calcium salts.

[0238] B. Pharmaceutical Composition

[0239] Pharmaceutical compositions and pharmaceutical formulations (also referred to herein as “pharmaceutical formulations”) in unit dose forms suitable for delivering their compounds and formulations are disclosed. Typically, a pharmaceutical composition or formulation contains a compound described herein and / or a pharmaceutically acceptable salt of a compound, and a pharmaceutically acceptable excipient. The term “pharmaceutically acceptable excipient” is used herein to describe any component in a formulation other than a compound described herein. A pharmaceutical composition or formulation may contain an effective amount of one or more compounds of any formula described herein and / or pharmaceutically acceptable salts thereof, including any one or any combination of compounds of any formula described herein and / or pharmaceutically acceptable salts thereof, for the purpose of treating, alleviating, or treating or improving one or more cancer-related symptoms in a subject of need. In some forms, a pharmaceutical composition or formulation may contain an enzyme that catalyzes the production of hydrogen peroxide and / or iron oxide. In some forms, a pharmaceutical composition or formulation does not contain an enzyme that catalyzes the production of hydrogen peroxide and / or iron oxide.

[0240] In some forms, a pharmaceutical composition or formulation may further comprise one or more active agents in addition to the compound, such as one or more other anticancer agents.

[0241] It should be understood that combinations and / or mixtures of compounds and / or their pharmaceutically acceptable salts may be included in a composition or formulation. In some forms, a pharmaceutical composition or formulation comprises an effective amount of a compound and / or its pharmaceutically acceptable salt for the purpose of treating, alleviating, or treating or improving one or more cancer-related symptoms in a subject in need.

[0242] Any one or more compounds provided herein may be explicitly included within or explicitly excluded from the pharmaceutical compositions, dosage units and / or uses or treatments disclosed herein.

[0243] 1. Oral preparations

[0244] The compound and / or its pharmaceutically acceptable salts may be administered orally. Oral administration may involve swallowing, thereby allowing the compound to enter the gastrointestinal tract, or it may be administered orally or sublingually, allowing the compound to enter the bloodstream directly through the mouth.

[0245] Formulations suitable for oral administration include solid dosage forms such as tablets, capsules containing particles, liquids, powders, lozenges (including liquid-filled lozenges), chewable tablets, multiparticle and nanoparticle formulations, gels, solid solutions, liposomes, films, ovules, sprays, and liquid formulations.

[0246] Liquid formulations include suspensions, solutions, syrups, and elixirs. These formulations can be used as fillers in soft or hard capsules and typically contain a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, as well as one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared, for example, by reconstructing a solid from a small sachet.

[0247] Compounds and / or their pharmaceutically acceptable salts may also be used in rapidly dissolving, rapidly disintegrating dosage forms, such as those described in Expert Opinion in Therapeutic Patents, 11(6), 981-986, by Liang and Chen (2001).

[0248] For tablet or capsule dosage forms, depending on the dosage, the compound and / or its pharmaceutically acceptable salt may comprise 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight. In addition to the compounds described herein, tablets generally contain disintegrants. Examples of disintegrants include sodium glycolate starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant comprises 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0249] Binders are commonly used to impart cohesiveness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (e.g., monohydrate, spray-dried monohydrate, or anhydrous form), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and calcium hydrogen phosphate dihydrate.

[0250] The tablets or capsules may optionally contain surfactants, such as sodium lauryl sulfate and polysorbate 80, and gliding agents such as silica and talc. When present, the surfactants may comprise 0.2% to 5% by weight of the tablets, and the gliding agents may comprise 0.2% to 1% by weight of the tablets.

[0251] Tablets or capsules typically also contain lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant typically constitutes 0.25% to 10% by weight of the tablet, preferably 0.5% to 3% by weight.

[0252] Other possible ingredients include flow aids (e.g., about 0.1% to about 3% by weight of talc or colloidal anhydrous silica), antioxidants, colorants, flavorings, preservatives, and taste masking agents.

[0253] An exemplary tablet contains up to about 80% of one or more of the compounds described herein, about 10% to about 90% by weight of a binder, about 0% to about 85% by weight of a diluent, about 2% to about 10% by weight of a disintegrant, and about 0.25% to about 10% by weight of a lubricant.

[0254] Tablet or capsule mixtures can be formulated into tablets directly or by roller compression. Tablet or capsule blends, or portions thereof, may alternatively be prepared by wet, dry, or melt granulation, melt coagulation, or extrusion prior to tableting. The final formulation may contain one or more layers and may be coated or uncoated; it may even be sealed.

[0255] Solid dosage forms intended for oral administration can be formulated for immediate release and / or modified release. Modified release includes delayed, sustained, pulsatile, controlled, targeted, and programmed release formulations.

[0256] 2. Parenteral preparations

[0257] Compounds and / or their pharmaceutically acceptable salts can also be administered directly into the bloodstream, muscles, or visceral organs. Suitable routes of parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, epidural, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous delivery. Suitable methods of parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0258] Parenteral preparations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (preferably at pH 3 to 9). However, for some applications, they may be better formulated as sterile non-aqueous solutions or used as dry forms in combination with a suitable carrier (e.g., sterile, pyrogen-free water).

[0259] The preparation of parenteral preparations under aseptic conditions, such as by lyophilization, can be easily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0260] The solubility of compounds used in the preparation of parenteral formulations can be increased by using appropriate formulation techniques (e.g., incorporation of solubility enhancers).

[0261] Formulations intended for parenteral administration can be formulated for immediate release and / or modulated release. Modulated-release formulations include delayed, sustained, pulsatile, controlled, targeted, and programmed release formulations. Therefore, compounds can be formulated as solids, semi-solids, or thixotropic liquids for administration as implanted depots providing modulated release of the active compound. Examples of such formulations include drug-coated scaffolds and poly(dl-lactic-co-glycolic acid) (PGLA) microspheres.

[0262] 3. Lung and mucosal preparations

[0263] The compound and / or its pharmaceutically acceptable salts may be formulated for pulmonary or mucosal administration. Administration may include delivery of the composition to the mucosa of the lungs, nose, mouth (sublingual, oral), vagina, or rectum.

[0264] For example, compounds can also be administered via nasal or oral inhalation, typically as dry powder from a dry powder inhaler (either alone or as a mixture, such as a dry mix with lactose, or as mixed component particles, such as a mixture with phospholipids (e.g., phosphatidylcholine), or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably one that uses electrohydrodynamics to generate a fine mist), or nebulizer, with or without a suitable propellant, such as water, a mixture of ethanol and water, 1,1,1,2-tetrafluoroethane, or 1,1,1,2,3,3,3-heptafluoropropane. For nasal or oral inhalation, the powder may contain a bio-binder, such as chitosan or cyclodextrin. The term aerosol as used herein refers to any formulation of fine particulate matter, which may be a solution or suspension, whether or not it is generated using a propellant. Aerosols can be produced using standard techniques, such as ultrasonic or high-pressure processing.

[0265] Pressurized containers, pumps, sprayers, atomizers, or nebulizers contain solutions or suspensions of one or more compounds, including, for example, ethanol, aqueous ethanol solutions, or suitable alternatives for dispersing, solubilizing, or prolonging the release of active substances, propellants as solvents, and optional surfactants such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0266] Before being used in dry powder or suspension formulations, drug products are micronized to a size suitable for inhalation delivery (typically less than 5 micrometers). This can be achieved by any suitable pulverization method, such as helical jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high-pressure homogenization, or spray drying.

[0267] Capsules (e.g., made of gelatin or hydroxypropyl methylcellulose), blister packs, and cartridges for inhalers or blow-off devices can be formulated as powder mixtures containing the compounds described herein, suitable powder matrices such as lactose or starch, and performance modifiers such as 1-leucine, mannitol, or magnesium stearate. Lactose can be in anhydrous or monohydrate form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0268] Suitable solution formulations used in aerosol generators that generate fine mists using electrohydrodynamics may contain 1 μg to 20 mg of one or more compounds per start-up, and the start-up volume may vary from 1 μl to 100 μl. Typical formulations may contain one or more of the compounds described herein, propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol.

[0269] Suitable flavoring agents, such as menthol and levmentol, or sweeteners, such as saccharin or sodium saccharin, can be added to formulations intended for inhalation / nasal administration.

[0270] Formulations intended for inhalation / nasal administration can be formulated as immediate-release and / or sustained-release using, for example, PGLA. Modulated-release formulations include delayed, sustained-release, pulsatile, controlled-release, targeted-release, and programmed-release formulations.

[0271] In the case of dry powder inhalers and aerosol inhalers, the dosage unit is determined by a valve that delivers the measured amount. Units consistent with the compound are typically arranged to administer the measured dose, or "puff." The total daily dose will be administered as a single dose or, more commonly, in multiple doses throughout the day.

[0272] In some forms, compounds and / or their pharmaceutically acceptable salts can be formulated for pulmonary delivery, such as intranasal administration or oral inhalation. Carriers for pulmonary formulations can be categorized into those for dry powder formulations and those for administration as solutions. Aerosols for delivering therapeutic agents to the respiratory tract are known in the art. For administration via the upper respiratory tract, formulations can be formulated as buffered or unbuffered aqueous solutions (e.g., water or isotonic saline), or as aqueous suspensions, for intranasal administration as drops or sprays. Such aqueous solutions or suspensions can be isotonic relative to nasal secretions and have substantially the same pH, ranging, for example, from about pH 4.0 to about pH 7.4 or from pH 6.0 to pH 7.0. Buffers should be physiologically compatible and include, by way of example only, phosphate buffers. Those skilled in the art can readily determine the appropriate salt content and pH of a harmless aqueous solution for nasal and / or upper respiratory tract administration.

[0273] In some forms, the aqueous solution is water, a physiologically acceptable aqueous solution containing salts and / or buffers, such as phosphate-buffered saline (PBS), or any other aqueous solution acceptable for administration to animals or humans. Such solutions are well known to those skilled in the art and include, but are not limited to, distilled water, deionized water, pure or ultrapure water, saline, and phosphate-buffered saline (PBS). Other suitable aqueous carriers include, but are not limited to, Ringer's solution and isotonic sodium chloride. The aqueous suspension may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone, and astragalus gum, and wetting agents such as lecithin. Preservatives suitable for aqueous suspensions include ethylparaben and n-propylparaben.

[0274] In some formulations, solvents with low-toxicity organic (i.e., non-aqueous) Class III residual solvents, such as ethanol, acetone, ethyl acetate, tetrahydrofuran, diethyl ether, and propanol, can be used. Solvent selection is based on its ability to facilitate atomization of the formulation. The solvent should not react harmfully with the compound. A suitable solvent should be used to dissolve the compound or form a suspension of the compound. The solvent should have sufficient volatility to form an aerosol of the solution or suspension. Additional solvents or atomizing agents, such as Freon, may be added as needed to increase the volatility of the solution or suspension.

[0275] In some forms, the pharmaceutical composition may contain small amounts of polymers, surfactants, or other excipients well known to those skilled in the art. In this document, “small amounts” means the absence of excipients that could affect or mediate cellular uptake of the compound, and that the amount of excipients present does not adversely affect cellular uptake of the compound.

[0276] Due to its hydrophobic properties, the dry lipid powder can be directly dispersed in ethanol. For lipids stored in organic solvents (such as chloroform), the required amount of solution is placed in a vial, and then the chloroform is evaporated under a nitrogen stream, forming a dry film on the surface of the glass vial. When reconstituted with ethanol, the film readily expands. To completely disperse the lipid molecules in the organic solvent, the suspension is sonicated. Alternatively, a non-aqueous suspension of lipids can be prepared in anhydrous ethanol using the reusable PARI LC Jet+ nebulizer (PARI Respiratory Equipment, Monterey, CA).

[0277] 4. Topical preparations

[0278] The compound and / or its pharmaceutically acceptable salt may be administered directly to the outer surface of the skin or mucous membrane (including the surface membranes of the nose, lungs and mouth), allowing the compound and / or its pharmaceutically acceptable salt to penetrate the outer surface of the skin or mucous membrane and enter the underlying tissues.

[0279] Formulations intended for topical administration typically contain a skin-acceptable carrier suitable for application to the skin, possess good aesthetic properties, are compatible with the active agent and any other ingredients, and do not cause any adverse safety or toxicity issues.

[0280] The carrier can take many forms. For example, emulsion carriers, including but not limited to oil-in-water, oil-in-water, water-in-oil-in-water, and oil-in-water-in-silicone emulsions, can be used herein. These emulsions can cover a wide viscosity range, for example, from about 100 cps to about 200,000 cps. These emulsions can also be delivered in the form of sprays using mechanical pump containers or pressurized aerosol containers using conventional propellants. These carriers can also be delivered in the form of mousse or transdermal patches. Other suitable local carriers include anhydrous liquid solvents, such as oils, alcohols, and silicones (e.g., mineral oil, ethanol, isopropanol, polydimethylsiloxane, cyclomethicone, etc.); aqueous single-phase liquid solvents (e.g., aqueous alcohol solvent systems, such as mixtures of ethanol and / or isopropanol with water); and thickening forms of these anhydrous and aqueous single-phase solvents (e.g., by adding appropriate gums, resins, waxes, polymers, salts, etc., to increase the viscosity of the solvent to form a solid or semi-solid). Examples of local carrier systems that can be used in this formulation are described in the following four references, all of which are incorporated herein by reference in their entirety: “Sun Products Formulary,” Cosmetics & Toiletries, vol. 105, pp. 122-139 (December 1990); “Sun Products Formulary,” Cosmetics & Toiletries, vol. 102, pp. 117-136 (March 1987); U.S. Patent No. 5,605,894 to Blank et al. and U.S. Patent No. 5,681,852 to Bissett.

[0281] Formulations for topical administration can be formulated as immediate-release and / or modulated-release formulations. Modulated-release formulations include delayed, sustained-release, pulsatile, controlled, targeted, and programmed-release formulations. Therefore, compounds can be formulated as solids, semi-solids, or thixotropic liquids for delivery as implantable reservoirs providing modulated release of the active compound. Examples of such formulations include drug-coated scaffolds and poly(dl-lactic-co-glycolic acid) (PGLA) microspheres.

[0282] 5. Other surfactants

[0283] In some forms, a pharmaceutical composition or pharmaceutical formulation may include one or more additional active agents, such as one or more additional anticancer agents. Anticancer agents that may be included in a pharmaceutical composition or formulation are known, for example, see the National Cancer Institute database, “Ato Z List of Cancer Drugs,” website cancer.gov / about-cancer / treatment / drugs.

[0284] Exemplary anticancer drugs that may be included in pharmaceutical compositions or formulations include, but are not limited to, olaparib, abemaciclib, abiraterone acetate, methotrexate, paclitaxel, adriamycin, acalabrutinib, brentuximab vedotin, ado-trastuzumab-mtansine conjugate, aflibercept, afatinib, netupitant, palonosetron, imiquimod, aldesleukin, alectinib, alemtuzumab, and pemetrexed disodium. Disodium, copanlisib, melphalan, brigatinib, chlorambucil, aifostine, aminolevulinic acid, anastrozole, apalutamide, aprepitant, pamidronate disodium, exemestane, nelarabine, arsenic trioxide, ofatumumab, atezolizumab, bevacizumab, avelumab, axicabtagene ciloleucel, axitinib, azacitidine, carmustine, belinostat, bendamustine, inotuzumab ozogamicin, bevacizumab, bexarotene, bicalutamide, bleomycin, blinatumomab, bortezomib, bosutinib, brentuximabVedotin, Brigatinib, Busulfan, Irinotecan, Capecitabine, Fluorouracil, Carboplatin, Carfilzomib, Ceritinib, Daunorubicin, Cetuximab, Cisplatin, Cladribine, Cyclophosphamide, Clofarabine, Cobime tinib), cabozantinib-S-malate, dactinomycin, crizotinib, ifosfamide, ramucirumab, cytarabine, dabrafenib, dacarbazine, decitabine, daratumumab, dasatinib, defibrotide, degarelix, denileukin Diftitox, denosumab, dexamethasone, dexrazoxane, dinutuximab, docetaxel, doxorubicin, durvalumab, rasburicase, epirubicin, elotuzumab, oxaliplatin, eltrombopagolamine, enasidenib, enzalutamide, eribulin, vismodegib, erlotinib, etoposide, everolimus, raloxifene, toremifene, panobinostat, fulvestrant, letrozole, filgrastim, fludarabine, flutamide, pralatrexate, obinutuzumab, gefitinib, gemcitabine, gemtuzumab ozogamicin, glucarpidase, goserelin, propranolol, trastuzumab, topotecan, palbociclib, ibritumomab tiuxetan, ibrutinib, ponatinib, idarubicin, idelalisib, imatinib, talimogenelaherparepvec, ipilimumab, romidepsin, ixabepilone, ixazomib, ruxolitinib, cabazitaxel, palifermin, pembrolizumab, ribociclib, tisagenlecleucel, lanreotide, lapatinib, olaratumab, lenalidomide Enalidomide, lenvatinib, leucovorin, leuprolide, lomustine, trifluridine, olaparib, vincristine, procarbazine, mechlorethamine, megestrol, trametinib, temozolomide, methylnaltrexone bromide, midostaurin, mitomycinC) Mitoxantrone, Plerixafor, Vinorelbine, Nexitumumab, Neratinib, Sorafenib, Nilutamide, Nilotinib, Niraparib, Nivolumab, Tamoxifen, Romiplostim, Sonidegib, Omacetaxine, Pegaspargase, Ondansetron, Osimertinib, Panitumumab, Pazopanib, Interferon α-2b, Pertuzumab Pertuzumab, pomalidomide, mercaptopurine, regorafenib, rituximab, rolapitant, rucaparib, siltuximab, sunitinib, thioguanine, temsirolimus, thalidomide, thiotepa, trabectedin, valrubicin, vandetanib, vinblastine, vemurafenib, vorinostat, zoledronic acid (acid), or combinations thereof such as cyclophosphamide, methotrexate, 5-fluorouracil (CMF); doxorubicin, cyclophosphamide (AC); nitrogen mustard, vincristine, mebenzylhydrazine, prednisolone (MOPP); sdriamycin, bleomycin, vinblastine, dacarbazine (ABVD); cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP); rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone (RCHOP); bleomycin, etoposide, cisplatin (BEP); epirubicin, cisplatin, 5-fluorouracil (ECF); epirubicin, cisplatin, capecitabine (ECX); methotrexate, vincristine, doxorubicin, cisplatin (MVAC).

[0285] 6. Effective dosage

[0286] The effective amount of a compound included in a pharmaceutical composition or formulation depends on many factors, including the indication being treated, the route of administration, concomitant administration of other therapeutic compositions, and the patient's overall condition. Exemplary effective amounts (in unit dose) of a compound included in a pharmaceutical formulation may be 0.01 mg to 1500 mg, 0.1 mg to 1500 mg, 1 mg to 1500 mg, 10 mg to 1500 mg, 20 mg to 1500 mg, 0.01 mg to 1000 mg, 0.1 mg to 1000 mg, 1 mg to 1000 mg, 10 mg to 1000 mg, 20 mg to 1000 mg, 0.0 1 mg to 700 mg, 0.1 mg to 700 mg, 1 mg to 700 mg, 10 mg to 700 mg, 20 mg to 700 mg, 50 mg to 700 mg, 0.01 mg to 500 mg, 0.1 mg to 500 mg, 1 mg to 500 mg, 10 mg to 500 mg, 20 mg to 500 mg, 50 mg to 500 mg, 0.01 mg to 100 mg, or 0.1 mg to 100 mg.

[0287] III. Manufacturing Method

[0288] Compounds can be synthesized using methods known in the field of organic synthesis, such as methods for forming tetraoxanes using one or more starting materials in a suitable solvent medium; the resulting tetraoxane is then derivatized to carry a targeting group. Typically, starting materials that can be used to form tetraoxanes are ketones or acetyl groups. Exemplary ketones and acetals for forming tetraoxanes include, but are not limited to, 4-tert-butylcyclohexanone, cyclohexanone, 2-adamantanone, and starting materials 1, 3, and 26 as shown below. Typically, the targeting group comprises amines, such as N,N'-dimethylpropylamine, 3-bromopropylamine hydrobromide, and targeting group 68 as shown below.

[0289] For example, as shown in the following general reaction scheme, starting materials 1, 3, or 26, or combinations thereof, react with 4-tert-butylcyclohexanone, cyclohexanone, or 2-adamantanone, or combinations thereof, to form tetraoxane; the formed tetraoxane then reacts with N,N'-dimethylpropylamine, 3-bromopropylamine hydrobromide, or targeting group 68, or combinations thereof, to form the compounds disclosed herein.

[0290]

[0291] Additional exemplary starting materials and targeting groups, as well as more specific methods for synthesizing exemplary compounds, are described in the following embodiments.

[0292] IV. Usage Method

[0293] A. Treating cancer, alleviating cancer symptoms, or treating or improving cancer-related symptoms.

[0294] Methods for using compounds to treat cancer, alleviate cancer, or treat or improve one or more cancer-related symptoms in subjects in need are disclosed.

[0295] Typically, the method includes (i) administering an effective amount of the compound to a subject to treat, alleviate, or treat or improve one or more cancer-related symptoms in the subject. The subject may be a mammal. In some forms, the subject may be at risk of cancer, exhibiting symptoms of cancer, or diagnosed with cancer. The compound may be administered by a medical professional or by the subject receiving treatment (e.g., self-administration).

[0296] In some forms of this method, whether cancer has lessened can be identified by a variety of diagnostic methods 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, for example, observing an increase in cancer cell apoptosis of more than 5% compared to a control without the compound. It can also be identified by changes in relevant biomarkers or gene expression profiles, such as HER2 in breast cancer, PSA in prostate cancer, or others.

[0297] In some forms, compounds and / or their pharmaceutically acceptable salts can be administered as pharmaceutical compositions or formulations in combination with one or more pharmaceutically acceptable excipients, such as the pharmaceutical compositions or formulations described above. The choice of pharmaceutically acceptable excipients will depend heavily on factors such as the specific route of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0298] 1. Cancer

[0299] As used in this article, the term "cancer" refers to any of the various cellular diseases characterized by malignant tumors with cell proliferation. It does not mean that the diseased cells must actually invade surrounding tissues and metastasize to new parts of the body. Cancer can involve any tissue in the body and has many different forms in each region.

[0300] In some forms of this method, cancer can be a tumor, such as a tumor or hematopoietic and lymphoid tissue tumor or hematopoietic and lymphoid malignancy, a tumor affecting the blood, bone marrow, lymphatic and lymphatic system, and a tumor located in the colon, abdomen, bones, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal glands, parathyroid glands, pituitary gland, testes, ovaries, thymus, thyroid gland), eyes, head and neck, nervous system (central and peripheral), lymphatic system, pelvis, skin, soft tissue, spleen, thoracic cavity and genitourinary organs.

[0301] In some forms of this method, the cancer can be colon cancer, breast cancer, ovarian cancer, cervical cancer, lung cancer, rectal cancer, kidney cancer, liver cancer, brain cancer, or leukemia, or a combination thereof. In some forms of this method, the cancer can be breast cancer, such as triple-negative breast cancer (TNBC).

[0302] In some forms of this method, cancer can be AIDS-related malignancies, anal cancer, astrocytoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, renal pelvis and ureter cancer, primary central nervous system lymphoma, central nervous system lymphoma, cerebellar astrocytoma, brain astrocytoma, cervical cancer, pediatric (primary) hepatocellular carcinoma, pediatric (primary) liver cancer, pediatric acute lymphoblastic leukemia, pediatric acute myeloid leukemia, pediatric brainstem glioma, pediatric cerebellar astrocytoma, pediatric brain astrocytoma, pediatric extracranial germ cell tumor, pediatric Hodgkin's disease, pediatric Hodgkin's lymphoma, pediatric visual pathways and Hypothalamic glioma, childhood lymphocytic leukemia, childhood medulloblastoma, childhood non-Hodgkin lymphoma, childhood supratentorial primitive cell neuroectodermal and pineal gland tumors, childhood primary liver cancer, childhood rhabdomyosarcoma, childhood soft tissue sarcoma, childhood visual pathway and hypothalamic glioma, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, cutaneous T-cell lymphoma, endocrine pancreatic islet cell carcinoma, endometrial cancer, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's sarcoma and related tumors, pancreatic exocrine carcinoma, extracranial germ cell tumors, gonadal extragerminal tumors, extrahepatic bile duct cancer, eye cancer, female breast cancer, Gaucher's disease. Diseases, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal tumors, germ cell tumors, gestational trophoblastic tumors, tricholeukemia, head and neck cancer, hepatocellular carcinoma, Hodgkin's disease, Hodgkin's lymphoma, hypergammaglobulinemia, laryngopharyngeal cancer, colorectal cancer, intraocular melanoma, islet cell carcinoma, islet cell pancreatic cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, lip and oral cancer, liver cancer, lung cancer, lymphoproliferative disorders, macroglobulinemia, male breast cancer, malignant mesothelioma, malignant thymoma, medulloblastoma, melanoma, mesothelioma, occult primary and metastatic squamous neck cancer, primary and metastatic squamous neck cancer, metastatic squamous neck cancer, multiple myeloma, multiple myeloma / plasma cell tumor, myelodysplastic syndrome, myelogenous leukemia, myeloid leukemia.Leukemia, myeloproliferative disorders, sinus and nasal cavity carcinoma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma during pregnancy, non-melanoma skin cancer, non-small cell lung cancer, primary occult metastatic squamous neck cancer, buccal pharyngeal carcinoma, malignant fibrous histiocytoma, malignant fibrous osteosarcoma / bone histiocytoma, epithelial ovarian cancer, ovarian germ cell tumors, low-grade malignant potential ovarian tumors, pancreatic cancer, paraproteinemia, purpura, parathyroid carcinoma, penile cancer, pheochromocytoma, pituitary adenoma, plasmacytoma / multiple myeloma, primary central nervous system lymphoma, primary liver cancer, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureter cancer, retinal cancer. Blastoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoidosis, sarcoma, skin cancer, small cell lung cancer, small intestinal cancer, soft tissue sarcoma, squamous neck cancer, gastric cancer, pineal and supratentorial primitive neuroectodermal tumors, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, transitional renal pelvis and ureter cancer, trophoblastic tumor, renal pelvis and ureteral cell carcinoma, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, optic nerve pathway and hypothalamic glioma, vulvar cancer, Waldenström's macroglobulinemia, Wilms' tumor, and any other hyperproliferative disease located in the above organ systems, as well as tumor formation.

[0303] 2. Route of administration

[0304] The compound and / or its pharmaceutically acceptable salt, or a pharmaceutical composition or preparation containing the compound and / or its pharmaceutically acceptable salt, may be administered to the subject orally, parenterally, by inhalation, by mucosal administration, by topical administration, or by a combination thereof.

[0305] For example, a compound and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation containing a compound and / or a pharmaceutically acceptable salt thereof, may be administered orally to a subject by a healthcare professional or by a subject receiving treatment (e.g., self-administration). A compound or a pharmaceutical composition or formulation containing a compound and / or a pharmaceutically acceptable salt thereof may be administered as tablets, capsules containing granules, granules, powders, lozenges (including liquid-filled lozenges), chewable tablets, multi-particle and nanoparticle formulations, gels, or liquids (e.g., solutions or suspensions in aqueous or non-aqueous solvents).

[0306] Optionally, the compound and / or its pharmaceutically acceptable salt, or a pharmaceutical composition or formulation containing the compound and / or its pharmaceutically acceptable salt, may be administered to the subject by intravenous or intraperitoneal injection. Intravenous or intraperitoneal injection may be performed by a healthcare professional or by the treated subject (e.g., self-injection).

[0307] Alternatively, the compound and / or its pharmaceutically acceptable salt, or a pharmaceutical composition or formulation containing the compound and / or its pharmaceutically acceptable salt, may be administered to the subject by inhalation, such as oral inhalation and / or nasal inhalation.

[0308] Optionally, a compound and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation containing a compound and / or a pharmaceutically acceptable salt thereof, may be administered to a subject by topically applying the compound or pharmaceutical composition or formulation to one or more exposed surfaces of the subject.

[0309] 3. Effective dosage

[0310] The therapeutically effective amount of a compound depends on many factors, including the indication being treated, the route of administration, the combination with other therapeutic compositions, and the patient’s overall condition.

[0311] Generally, treatment regimens using the compound involve administering the compound daily in multiple or single doses at a rate of about 0.1 mg to about 300 mg per kilogram of recipient body weight. In some embodiments, suitable doses may range from 0.1 to 300 mg per kilogram of recipient body weight per day, optionally from 6 to 150 mg per kilogram of body weight per day, optionally from 15 to 100 mg per kilogram of body weight per day, optionally from 15 to 80 mg per kilogram of body weight per day, optionally from 15 to 50 mg per kilogram of body weight per day, and optionally from 15 to 30 mg per kilogram of body weight per day.

[0312] The required dose can be presented as two, three, four, five, six, or more sub-dose administered at appropriate intervals throughout the day. These sub-dose can be administered in unit dosage forms, for example, containing 0.01 mg to 1500 mg, 0.1 mg to 1500 mg, 1 mg to 1500 mg, 10 mg to 1500 mg, 20 mg to 1500 mg, 0.01 mg to 1000 mg, 0.1 mg to 1000 mg, 1 mg to 1000 mg, 10 mg to 1000 mg, 20 mg to 1000 mg, 0.01 mg to 700 mg, Compound / unit dosage forms of 0.1 mg to 700 mg, 1 mg to 700 mg, 10 mg to 700 mg, 20 mg to 700 mg, 50 mg to 700 mg, 0.01 mg to 500 mg, 0.1 mg to 500 mg, 1 mg to 500 mg, 10 mg to 500 mg, 20 mg to 500 mg, 50 mg to 500 mg, 0.01 mg to 100 mg, or 0.1 mg to 100 mg.

[0313] 4. Optional steps

[0314] a. Apply additional surfactant

[0315] One or more active agents other than the compound may be administered to the subject throughout the method or at different time intervals during the method. For example, one or more additional active agents may be administered to the subject before, during, and / or after step (i). In some forms, one or more additional active agents are included in a pharmaceutical composition or formulation containing the compound and are administered to the subject simultaneously with the compound in the pharmaceutical composition or formulation and one or more pharmaceutically acceptable excipients.

[0316] In some forms, one or more additional active agents are one or more of the aforementioned anticancer agents. The amount of one or more additional anticancer agents required will vary from person to person depending on the needs of the subject.

[0317] B. Treating cancer cells

[0318] In some forms, the compound can be used to treat cancer cells and / or cancer stem cells in subjects in need.

[0319] This method may follow the steps described above, such as administering an effective amount of the compound to the subject via oral administration, parenteral administration, inhalation, mucosal administration, topical administration, or a combination thereof. In some forms, the method may include the additional steps described above. For example, the user may administer one or more additional active agents to the subject before, during, and / or after administering the compound.

[0320] In some forms of this method, the compound can induce ferroptosis to kill cancer cells and / or cancer stem cells in a subject. Additionally or alternatively, these compounds can selectively induce ferroptosis in cancer cells and cancer stem cells compared to non-cancer cells in the subject. Additionally or alternatively, regardless of pH, the compound can generate reactive oxygen species (e.g., hydroxyl radicals and lipid peroxides at neutral pH) within cancer cells and cancer stem cells, eliminating the need for an acidic intracellular environment, i.e., ferroptosis, in complex formulations encapsulating multiple components (enzymes catalyzing hydrogen peroxide production, iron oxide, etc.) and in chemokinetic therapy. For example, the compound can induce ferroptosis in cancer cells and / or cancer stem cells where the intracellular pH is in the range of 6 to 7.5.

[0321] In some forms of this method, the compound targets the IC of cancer cells or cancer stem cells. 50 The value can be lower than the IC50 of the same compound tested under the same conditions against non-cancer cells. 50 Value. Additionally or alternatively, this compound targets the IC50 of cancer cells or cancer stem cells. 50The value may be lower than the IC50 values ​​of known compounds tested under the same conditions, such as OZ277, OZ439, RKA182, FINO2, or cholic acid / deoxycholic acid / steroid derivatives of 1,2,4,5-tetraoxane, against the same cancer cells or cancer stem cells. 50 value.

[0322] 1. Cancer cell line

[0323] The cancer cells and / or cancer stem cells used to treat the subject can be cancer cells of any of the aforementioned cancers. For example, cancer cells can be MDA-MB-231 cells, MCF7 cells, HeLa cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells, or combinations thereof. In some forms of this method, the cancer cells or cancer stem cells can be MDA-MB-231 cells, HCT116 cells, HEYA8 cells, or HL-60 cells, or combinations thereof. In some forms of this method, the cancer cells or cancer stem cells are MDA-MB-231 cells.

[0324] When compounds target the IC50 of cancer cells or cancer stem cells 50 The value is the same as the IC50 value of the same compound against non-cancer cells. 50 When comparing values, non-cancerous cells can be derived from any normal tissue of the subject, such as NIH3T3 cells, MDCK cells, or bEnd.3 cells, or a combination thereof.

[0325] 2. The compound exhibits higher selectivity for cancer cells than for non-cancer cells.

[0326] In some forms of this method, tested under the same conditions, the compound targets the IC50 of cancer cells or cancer stem cells. 50 The value can be lower than the IC50 of the same compound tested under the same conditions against non-cancer cells. 50 Value. The term "same conditions" means using the same assay, such as the MTT assay, using the same protocol, such as the same cell volume and enzymes, the same dyes and dye concentrations, and the same incubation time and temperature, etc.

[0327] For example, this compound targets MDA-MB-231 cells, MCF7 cells, HeLa cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells, or combinations thereof, with IC50. 50The value may be lower than the IC50 of the same compound tested under the same conditions against NIH3T3 cells, MDCK cells, or bEnd.3 cells, or combinations thereof, such as the IC50 value for NIH3T3 cells. 50 Values. For example, the IC50 values ​​of compounds against MDA-MB-231 cells, HCT116 cells, or HL-60 cells. 50 The value was lower than the IC50 of the same compound tested under the same conditions against NIH3T3 cells. 50 Value. For example, the compound targets the IC50 value of MDA-MB-231 cells. 50 The value was lower than the IC50 of the same compound tested under the same conditions against NIH3T3 cells. 50 value.

[0328] In some forms, this compound targets the IC50 of cancer cells or cancer stem cells. 50 The value was the same as the IC50 value of the same compound tested under the same conditions for non-cancer cells. 50 Compared to the value, it is at least 2 times lower, at least 3 times lower, at least 4.5 times lower, at least 5 times lower, at least 8 times lower, at least 10 times lower, at least 12 times lower, at least 15 times lower, at least 20 times lower, at least 22 times lower, at least 24 times lower, at least 25 times lower, at least 30 times lower, at least 35 times lower, at least 40 times lower, at least 45 times lower, at least 50 times lower, at least 55 times lower, at least 60 times lower, at least 6 times lower. 5 times, at least 70 times, at least 75 times, at least 80 times, at least 90 times, at least 100 times, 2 to 1000 times, 2 to 500 times, 2 to 250 times, 2 to 200 times, 2 to 150 times, 2 to 100 times, 5 to 1000 times, 5 to 500 times, 5 to 250 times, 5 to 200 times, 5 to 150 times, or 5 to 100 times.

[0329] For example, this compound targets MDA-MB-231 cells, MCF7 cells, HeLa cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells, or combinations thereof, with IC50. 50 The IC50 values ​​were the same as those of the same compounds tested under the same conditions against NIH3T3 cells, MDCK cells, or bEnd.3 cells, or combinations thereof. 50Compared to the value, it can be at least 2 times lower, at least 3 times lower, at least 4.5 times lower, at least 5 times lower, at least 8 times lower, at least 10 times lower, at least 12 times lower, at least 15 times lower, at least 20 times lower, at least 22 times lower, at least 24 times lower, at least 25 times lower, at least 30 times lower, at least 35 times lower, at least 40 times lower, at least 45 times lower, at least 50 times lower, at least 55 times lower, at least 60 times lower, at least... 65 times, at least 70 times, at least 75 times, at least 80 times, at least 90 times, at least 100 times, 2 to 1000 times, 2 to 500 times, 2 to 250 times, 2 to 200 times, 2 to 150 times, 2 to 100 times, 5 to 1000 times, 5 to 500 times, 5 to 250 times, 5 to 200 times, 5 to 150 times, or 5 to 100 times.

[0330] For example, this compound targets MDA-MB-231 cells, MCF7 cells, HeLa cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells, or combinations thereof, with IC50. 50 The value was the same as the IC50 of the same compound tested under the same conditions against NIH3T3 cells. 50 Compared to the value, it can be at least 2 times lower, at least 3 times lower, at least 4.5 times lower, at least 5 times lower, at least 8 times lower, at least 10 times lower, at least 12 times lower, at least 15 times lower, at least 20 times lower, at least 22 times lower, at least 24 times lower, at least 25 times lower, at least 30 times lower, at least 35 times lower, at least 40 times lower, at least 45 times lower, at least 50 times lower, at least 55 times lower, at least 60 times lower, at least... 65 times, at least 70 times, at least 75 times, at least 80 times, at least 90 times, at least 100 times, 2 to 1000 times, 2 to 500 times, 2 to 250 times, 2 to 200 times, 2 to 150 times, 2 to 100 times, 5 to 1000 times, 5 to 500 times, 5 to 250 times, 5 to 200 times, 5 to 150 times, or 5 to 100 times.

[0331] For example, this compound targets the IC50 of MDA-MB-231 cells, HCT116 cells, or HL-60 cells. 50 The value was the same as the IC50 of the same compound tested under the same conditions against NIH3T3 cells. 50Compared to the value, it can be at least 2 times lower, at least 3 times lower, at least 4.5 times lower, at least 5 times lower, at least 8 times lower, at least 10 times lower, at least 12 times lower, at least 15 times lower, at least 20 times lower, at least 22 times lower, at least 24 times lower, at least 25 times lower, at least 30 times lower, at least 35 times lower, at least 40 times lower, at least 45 times lower, at least 50 times lower, at least 55 times lower, at least 60 times lower, at least... 65 times, at least 70 times, at least 75 times, at least 80 times, at least 90 times, at least 100 times, 2 to 1000 times, 2 to 500 times, 2 to 250 times, 2 to 200 times, 2 to 150 times, 2 to 100 times, 5 to 1000 times, 5 to 500 times, 5 to 250 times, 5 to 200 times, 5 to 150 times, or 5 to 100 times.

[0332] For example, this compound targets the IC50 of MDA-MB-231 cells. 50 The value was the same as the IC50 of the same compound tested under the same conditions against NIH3T3 cells. 50 Compared to the value, it can be at least 2 times lower, at least 3 times lower, at least 4.5 times lower, at least 5 times lower, at least 8 times lower, at least 10 times lower, at least 12 times lower, at least 15 times lower, at least 20 times lower, at least 22 times lower, at least 24 times lower, at least 25 times lower, at least 30 times lower, at least 35 times lower, at least 40 times lower, at least 45 times lower, at least 50 times lower, at least 55 times lower, at least 60 times lower, at least... 65 times, at least 70 times, at least 75 times, at least 80 times, at least 90 times, at least 100 times, 2 to 1000 times, 2 to 500 times, 2 to 250 times, 2 to 200 times, 2 to 150 times, 2 to 100 times, 5 to 1000 times, 5 to 500 times, 5 to 250 times, 5 to 200 times, 5 to 150 times, or 5 to 100 times.

[0333] Exemplary compounds, as determined under specific conditions, target cancer cells and cancer stem cells (e.g., MDA-MB-231 cells, MCF7 cells, HeLa cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells), and non-cancer cells (e.g., NIH3T3 cells, MDCK cells, and bEnd.3 cells). 50 The values ​​are described in the following embodiments.

[0334] 3. Cytotoxicity of the compound against cancer cells compared to other compounds.

[0335] In some forms of this method, the compound targets the IC of cancer cells or cancer stem cells.50 The value can be lower than the IC50 values ​​of known compounds tested under the same conditions, such as OZ277, OZ439, RKA182, FINO2, or cholic acid / deoxycholic acid / steroid derivatives of 1,2,4,5-tetraoxane, against the same cancer cells or cancer stem cells. 50 value.

[0336] For example, this compound targets MDA-MB-231 cells, MCF7 cells, HeLa cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells, or combinations thereof, with IC50. 50 The value can be lower than the IC50 values ​​of known compounds tested under the same conditions, such as OZ277, OZ439, RKA182, FINO2, or cholic acid / deoxycholic acid / steroid derivatives of 1,2,4,5-tetraoxane, against the same cancer cells. 50 Values. For example, this compound targets the IC50 values ​​of MDA-MB-231 cells, HCT116 cells, or HL-60 cells. 50 The value can be lower than the IC50 values ​​of known compounds tested under the same conditions, such as OZ277, OZ439, RKA182, FINO2, or cholic acid / deoxycholic acid / steroid derivatives of 1,2,4,5-tetraoxane, against the same cancer cells. 50 Value. For example, the compound targets the IC50 value of MDA-MB-231 cells. 50 The value may be lower than the IC50 values ​​of known compounds tested under the same conditions, such as OZ277, OZ439, RKA182, FINO2, or cholic acid / deoxycholic acid / steroid derivatives of 12,4,5-tetraoxane, against the same cancer cells. 50Values. Descriptions of cholic acid / deoxycholic acid / steroid derivatives of OZ277, OZ439, RKA182, FINO2 or 1,2,4,5-tetraoxane are found in: O'Neill PM et al., Angew Chem Int Ed Engl, 2010, 49(33), 5693-5697; Opsenica D et al., Bioorg Med Chem., 2003, 3; 11(13): 2761-8; Coghi P et al., Chem Med Chem., 2018, 13(9): 902-908; Amewu R.K. et al., Bioorg Med Chem., 2013, 21(23), 7392-7397; Marti F et al., Med Chem Comm., 2011, 2(7); Terzic N et al., J Med Chem., 2007, 50(21), 5118-5127; Opsenica D. et al., J Med Chem., 2000, 43(17), 3274-3282; Solaja BA et al., J Med Chem., 202, 45(16), 3331-3336; Opsenica D. et al., Bioorg Med Chem., 2003, 11(13), 2761-2768; Opsenica D. et al., J. Serb. Chem. Soc., 2015, 80(11) 1339–1359; Dong YX et al., J. Org. Chem., 1998, 63, 23, 8582-8585; Abrams RP et al., ACS Chem Biol, 2016, 11(5), 1305-1312; Zhang Y. et al., Cell Chem Biol., 2019, 26(5):623-633; Friedmann Angeli JP et al., Nat Cell Biol., 2014, 16(12):1180-91; Llabani E. et al., J. Nat Chem., 2019, 11(6):521-532; Dolma S. et al., Cancer Cell, 2003, 3(3), 285-296; Mai TT et al., Nat Chem, 2017, 9(10), 1025-1033; WO 2008038030; WO 2010134678; IN 2008DE02103; US 6906098; DE 10205864; DE10205864; WO 9307119 and WO2010109172.

[0337] In some forms, this compound targets the IC50 of cancer cells or cancer stem cells. 50 The value is compared with the IC50 of known compounds tested under the same conditions against the same cancer cells. 50 Compared to the value, it is at least 5 times lower, at least 10 times lower, at least 15 times lower, at least 20 times lower, at least 25 times lower, at least 30 times lower, at least 35 times lower, 5 to 1000 times lower, 5 to 500 times lower, 5 to 250 times lower, 5 to 200 times lower, 5 to 150 times lower, 5 to 100 times lower, 10 to 1000 times lower, 10 to 500 times lower, 10 to 250 times lower, 10 to 200 times lower, 10 to 150 times lower, 15 to 1000 times lower, 15 to 500 times lower. 15 to 250 times lower, 15 to 200 times lower, 15 to 150 times lower, 20 to 1000 times lower, 20 to 500 times lower, 20 to 250 times lower, 20 to 200 times lower, 20 to 150 times lower, 25 to 1000 times lower, 25 to 500 times lower, 25 to 250 times lower, 25 to 200 times lower, 25 to 150 times lower, 30 to 1000 times lower, 30 to 500 times lower, 30 to 250 times lower, 30 to 200 times lower, or 30 to 150 times lower.

[0338] For example, this compound targets MDA-MB-231 cells, MCF7 cells, HeLa cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells, or combinations thereof, with IC50. 50 The values ​​were compared with the IC50 values ​​of cholic acid / deoxycholic acid / steroid derivatives of OZ277, OZ439, RKA182, FINO2, or 1,2,4,5-tetraoxane tested under the same conditions against the same cancer cells. 50 Compared to the value, it can be at least 5 times lower, at least 10 times lower, at least 15 times lower, at least 20 times lower, at least 25 times lower, at least 30 times lower, at least 35 times lower, 5 to 1000 times lower, 5 to 500 times lower, 5 to 250 times lower, 5 to 200 times lower, 5 to 150 times lower, 5 to 100 times lower, 10 to 1000 times lower, 10 to 500 times lower, 10 to 250 times lower, 10 to 200 times lower, 10 to 150 times lower, 15 to 1000 times lower, 15 to 500 times lower. 15 to 250 times lower, 15 to 200 times lower, 15 to 150 times lower, 20 to 1000 times lower, 20 to 500 times lower, 20 to 250 times lower, 20 to 200 times lower, 20 to 150 times lower, 25 to 1000 times lower, 25 to 500 times lower, 25 to 250 times lower, 25 to 200 times lower, 25 to 150 times lower, 30 to 1000 times lower, 30 to 500 times lower, 30 to 250 times lower, 30 to 200 times lower, or 30 to 150 times lower.

[0339] For example, this compound targets the IC50 of MDA-MB-231 cells, HCT116 cells, or HL-60 cells. 50 The values ​​were compared with those of known compounds tested under the same conditions, such as OZ277, OZ439, RKA182, FINO2, or cholic acid / deoxycholic acid / steroid derivatives of 1,2,4,5-tetraoxane, against the same cancer cells. 50 Compared to the value, it can be at least 5 times lower, at least 10 times lower, at least 15 times lower, at least 20 times lower, at least 25 times lower, at least 30 times lower, at least 35 times lower, 5 to 1000 times lower, 5 to 500 times lower, 5 to 250 times lower, 5 to 200 times lower, 5 to 150 times lower, 5 to 100 times lower, 10 to 1000 times lower, 10 to 500 times lower, 10 to 250 times lower, 10 to 200 times lower, 10 to 150 times lower, 15 to 1000 times lower, 15 to 500 times lower. 15 to 250 times lower, 15 to 200 times lower, 15 to 150 times lower, 20 to 1000 times lower, 20 to 500 times lower, 20 to 250 times lower, 20 to 200 times lower, 20 to 150 times lower, 25 to 1000 times lower, 25 to 500 times lower, 25 to 250 times lower, 25 to 200 times lower, 25 to 150 times lower, 30 to 1000 times lower, 30 to 500 times lower, 30 to 250 times lower, 30 to 200 times lower, or 30 to 150 times lower.

[0340] For example, this compound targets the IC50 of MDA-MB-231 cells. 50 The IC50 value was compared with that of known compounds tested under the same conditions, such as OZ277, OZ439, RKA182, FINO2, or cholic acid / deoxycholic acid / steroid derivatives of 1,2,4,5-tetraoxane, against the same cancer cells. 50 Compared to the value, it can be at least 5 times lower, at least 10 times lower, at least 15 times lower, at least 20 times lower, at least 25 times lower, at least 30 times lower, at least 35 times lower, 5 to 1000 times lower, 5 to 500 times lower, 5 to 250 times lower, 5 to 200 times lower, 5 to 150 times lower, 5 to 100 times lower, 10 to 1000 times lower, 10 to 500 times lower, 10 to 250 times lower, 10 to 200 times lower, 10 to 150 times lower, 15 to 1000 times lower, 15 to 500 times lower. 15 to 250 times lower, 15 to 200 times lower, 15 to 150 times lower, 20 to 1000 times lower, 20 to 500 times lower, 20 to 250 times lower, 20 to 200 times lower, 20 to 150 times lower, 25 to 1000 times lower, 25 to 500 times lower, 25 to 250 times lower, 25 to 200 times lower, 25 to 150 times lower, 30 to 1000 times lower, 30 to 500 times lower, 30 to 250 times lower, 30 to 200 times lower, or 30 to 150 times lower.

[0341] Exemplary compounds and exemplary known compounds, as determined under specific conditions, target cancer cells and cancer stem cells (e.g., MDA-MB-231 cells, MCF7 cells, HeLa cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells), and non-cancer cells (e.g., NIH3T3 cells, MDCK cells, and bEnd.3 cells). 50 The values ​​are described in the following embodiments.

[0342] The invention will be further understood by referring to the following non-limiting embodiments.

[0343] Example

[0344] Example 1. Synthesis of an exemplary compound

[0345] Compound Structure

[0346] Compounds containing adamantane alkyl groups

[0347]

[0348]

[0349] Compounds containing tert-butylcyclohexyl

[0350]

[0351] Alkyne-labeled tetraoxane

[0352]

[0353] Prodrugs and Dimers

[0354]

[0355] Materials and Methods

[0356] Chemical synthesis

[0357] All reagents and solvents used in the reaction were analytical or HPLC grade, and dried and distilled as necessary. Silica gel was used. Analytical thin-layer chromatography was performed on F254 plates, with spot observation achieved by staining in UV and / or phosphomolybdic acid (PMA) or KMnO4 solution followed by heating. Rapid chromatography was performed on silica gel (230-400 mesh) using the specified solvent system. Tetrahydrofuran (THF), dichloromethane (CH2Cl2), diethyl ether (Et2O), ethyl acetate (EtOAc), and N,N-dimethylformamide (DMF) were dried by filtration through alumina. All drying reactions were carried out in glassware dried directly under an argon or nitrogen atmosphere. Generally, hydrogen peroxide and organic peroxides should be handled with care. Exposure to strong heat, strong light, mechanical shock, oxidizable organic materials, and metals should be avoided. All reactions should be carried out behind a protective barrier. Excess hydrogen peroxide can be quenched by slowly adding sodium metabisulfite solution (Liu et al. Water Res. 2003, 37, 15, 3697-3703; Keen et al. J. Environ Eng. 2013, 139, 137-140).

[0358] Synthetic schemes for compounds 6a and 6b:

[0359]

[0360] Compound 2 was prepared according to literature reports (O'Neill et al. Angew Chem Int Ed. 2010, 49, 5693-5697; Yan et al. Synlett. 2011, 2827-2830). Trimethylphosphonoacetate (16.00 g, 48 mmol) was added to a solution of 1,4-cyclohexanedione monovinyl acetal (1) (5.00 g, 32 mmol) in toluene (76 mL). The mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude material was diluted with diethyl ether (70 mL) to precipitate triphenylphosphine oxide. The insoluble material was filtered through a diatomaceous earth septum, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / EtOAc = 4 / 1) to give 2 (5.60 g, 78% yield) as a colorless oil. 3 was prepared according to literature reports (O'Neill et al. Angew Chem Int Ed. 2010, 49, 5693-5697; Yan et al. Synlett. 2011, 2827-2830). 2 (6.440 g, 30.3 mmol) was premixed with palladium on carbon (10% by weight, 3.20 g, 30.3 mmol). The reaction solvent (EtOH, 50 mL) was evacuated and backfilled with hydrogen three times before being added to the reaction mixture. Et3N (0.1 mL, 2.3 mmol) was added. The reaction flask was then evacuated and backfilled with hydrogen three times, followed by stirring under a hydrogen atmosphere (balloon). The reaction was monitored by TLC (n-hexane / EtOAc = 4:1). 2 was consumed after 5 hours. The reaction mixture was filtered through a diatomaceous earth pad and then washed with EtOH. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / EtOAc = 4 / 1) to obtain colorless oil 3 (5.011 g, yield 77%).

[0361] Compound 6 was prepared according to a modified literature report and purified as a white solid by rapid column chromatography (16%, 3 steps) (O'Neill et al. Angew Chem Int Ed. 2010, 49, 5693-5697; Yan et al. Synlett. 2011, 2827-2830). At 0 °C, 1.1 mL (38.2 mmol) of 50% aqueous hydrogen peroxide solution was added to a stirred solution of 3 (1.30 g, 7.6 mmol) in formic acid / acetonitrile (1:1, 17 mL), and the mixture was stirred at room temperature. TLC analysis (n-hexane / EtOAc = 2:1) showed that 3 was consumed after 3 hours. The mixture was then poured into ice-cold water and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the corresponding gem-dihydroperoxide 4. The solvent CH2Cl2 was dried and distilled. Dehydrated PMA was prepared according to this procedure; commercially available PMA hydrate was dried to constant weight in a microwave oven. A mixture of 2-adamantanone (1.26 g, 8.4 mmol), PMA (0.14 g, 1 mol%), and anhydrous MgSO4 (1.38 g, 11.5 mmol) in CH2Cl2 (25 mL) was stirred at room temperature for 30 min. 4 (7.6 mmol) of CH2Cl2 (10 mL) solution was added dropwise to this solution over 15 min. The mixture was stirred at room temperature and monitored by TLC (n-hexane:EtOAc = 4:1). When 4 was completely consumed, deionized H2O (10 mL) was added. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / EtOAc = 8:1) to give a mixture of 5- and 2-adamantanone. It was impossible to separate analytically pure 5 by rapid chromatography on silica gel because it co-eluted with 2-adamantanone. Therefore, the product mixture was used for the next step. A deionized aqueous solution (2.7 mL) of sodium hydroxide (0.45 g, 11.1 mmol) was added to a solution of 5 and 2-adamantanone (total 1.308 g) in EtOH (17 mL). The mixture was heated at 50 °C for 2 hours. The solution was then cooled to room temperature and concentrated under reduced pressure. The crude product was dissolved in water (20 mL) and washed with diethyl ether (3 × 30 mL). The aqueous layer was acidified to pH 1 with 1 M HCl and then extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the pure compound. Carboxylic acid 6 was given as a white solid (0.4199 g, 16% yield over 3 steps) without further purification.TPP salt 68 was prepared according to literature reports and separated as a white solid upon recrystallization (Millard et al. J Med Chem. 2013, 56, 22, 9170-9179). DIPEA (0.1 mL) and HBTU (0.015 g, 0.046 mmol) were added to a CH2Cl2 (1 mL) solution of compound 6 (0.010 g, 0.036 mmol). After stirring for 5 minutes, 68 (0.014 g, 0.036 mmol) was added. The reaction was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (10% EtOH in DCM solution) to give a foamy compound 6b (0.016 g, 87% yield). DIPEA (19.1 μL, 0.11 mmol) was added to a DMF (1 mL) solution of compound 6 (0.017 g, 0.050 mmol) at 0 °C. Five minutes later, EDCI (0.017 g, 0.11 mmol), HOBt (0.023 g, 0.11 mmol), and 3-(dimethylamino)-1-propylamine (0.014 mL, 0.11 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. The reaction was quenched with NH4Cl (10 mL) and diluted with EtOAc. The aqueous layer was back-extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with saturated NaHCO3 and brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (7% EtOH in DCM, 1% NH4OH) to give a pink oily compound 6a (0.011 g, 52% yield).

[0362] Synthetic scheme of compound 10:

[0363]

[0364] Et3N (1.3 mL, 9.37 mmol) and methyl 3-bromopropionate (0.74 mL, 6.6 mmol) were added sequentially to a solution of tetradecylamine 7 (1.00 g, 4.7 mmol) in anhydrous CH2Cl2 (15 mL). The reaction mixture was stirred for 12 hours. The reaction mixture was filtered through a sintered glass filter to remove the Et3N salt. The solvent was removed under vacuum. The crude product was purified by silica gel column chromatography (n-hexane / EtOAc = 1:1) to give 8 (0.25 g, 31% yield) as a yellow solid. DIPEA (0.2 mL) and HBTU (0.053 g, 0.13 mmol) were added to a solution of compound 6 (0.016 g, 0.044 mmol) in anhydrous CH2Cl2 (1 mL). After 5 minutes, 8 (0.014 g, 0.044 mmol) was added. The turbid reaction mixture was stirred for 2 days. Water (5 mL) was added. The aqueous layer was extracted with CH₂Cl₂ (20 × 3 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / EtOAc = 6:1) to give compound 9 (0.027 g, 94% yield), a colorless oil. LiOH (0.052 g, 0.22 mmol) was added to a solution of compound 9 (0.027 g, 0.043 mmol) in THF:H₂O (4:1, 0.5 mL). The reaction mixture was stirred at room temperature for 2 hours. Water (5 mL) was added. The aqueous layer was acidified with 1 M HCl and then extracted with EtOAc (20 × 3 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / EtOAc = 1:1) to give compound 10 (0.020 g, 75% yield), a colorless oil.

[0365] Synthetic scheme of compound 18:

[0366]

[0367] Synthesis scheme for 71:

[0368]

[0369] Chloromethyl chloroformate (3.2 mL, 36.3 mmol) was added to an ice-cold solution of p-nitrophenol (5.00 g, 35.9 mmol) in CH₂Cl₂ (60 mL), followed by dropwise addition of pyridine (4.3 mL, 53.9 mmol) over 20 minutes. The mixture was stirred in an ice bath for 15 minutes and then incubated overnight at room temperature. The reaction mixture was washed successively with water (10 mL × 2), 1N HCl (10 mL × 2), saturated NaHCO₃ solution, and brine. After drying with anhydrous sodium sulfate, the organic solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / n-hexane = 1 / 3) to give a white solid 69 (4.5281 g, 54% yield). Sodium iodide (1.070 g, 7.1 mmol) was added to a solution of 69 (1.500 g, 6.5 mmol) in acetone (40 mL). The mixture was stirred overnight at 50 °C. The solvent was evaporated. The residue was transferred to diethyl ether and washed with saturated NaHCO3 solution. After drying with anhydrous sodium sulfate, the organic solution was concentrated to give crude product 70, which was immediately dissolved in toluene (9 mL). Silver acetate (1.30 g, 7.78 mmol) was added to this solution. The mixture was refluxed overnight. The mixture was filtered through a diatomaceous earth stencil, and the filtrate was evaporated. The mixture was dissolved in diethyl ether and washed with saturated Na2SO3 solution and brine. After drying with anhydrous sodium sulfate, the organic solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / n-hexane = 1 / 3) to give a white solid product 71 (0.931 g, 56% two-step yield). Under Ar, at 0 °C, BH3-SMe2 (3.63 mL, 37.7 mmol) was added dropwise to 11 (1.50 g, 4.74 mmol) of anhydrous THF (18 mL) over 5 minutes. The turbid solution was slowly heated to room temperature and stirred for 12 hours. Methanol (10 mL) was added dropwise to the reaction mixture until it turned red. The solvent was evaporated under reduced pressure, and the residue was redissolved in ethyl acetate and washed with saturated NaHCO3, water, and brine. After drying with anhydrous sodium sulfate, the organic solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% EtOH in CH2Cl2 solution) to give a white solid 12 (0.69 g, 53% yield). Triphenylphosphine (1.89 g, 7.19 mmol) and CBr4 (2.39 g, 7.19 mmol) were then added to a solution of 12 (0.44 g, 2.4 mmol) in anhydrous CH2Cl2 (15 mL) at 0 °C under Ar. The yellow solution was stirred at 0 °C for 1.5 h. Water (10 mL) and diethyl ether (100 mL) were added. Any white solid was filtered through a diatomaceous earth sieve. The aqueous layer was back-extracted three times with diethyl ether. The combined organic layers were washed with brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (EtOAc / n-hexane = 1:4) to give 13 as a white solid (0.61 g, 82% yield). A solution of potassium cyanide (0.740 g, 11.3 mmol) in water (6.3 mL) was added to a stirred solution of 13 (1.00 g, 3.24 mmol) in ethanol (30 mL) at room temperature. The reaction mixture was stirred for 12 hours and diluted with water and diethyl ether. The aqueous layer was extracted three times with diethyl ether. The organic phase was washed with saturated NaHCO3 solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / n-hexane = 3 / 1) to give 14 as a white solid (0.274 g, 42% yield). Under Ar atmosphere and at 0 °C, a solution of borane tetrahydrofuran complex (1.00 M in tetrahydrofuran; 5 mL, 4.97 mmol) was added to a stirred solution of 14 (0.100 g, 0.5 mmol) in anhydrous tetrahydrofuran (3 mL). The resulting mixture was heated to room temperature and stirred for 2 hours. At 0 °C, 3N HCl (3 mL) was added dropwise. EtOAc was added to dilute the mixture. 2N NaOH (15 mL) was added. The aqueous layer was back-extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide crude product 15, which was used in the next step. Product 15 (0.048 g, 0.23 mmol) was dissolved in anhydrous DMF (1.5 mL). Under an argon atmosphere, 71 (0.122 g, 0.48 mmol) and Et3N (0.2 mL) were added sequentially to this solution. The reaction mixture was stirred for 12 hours. Excess 71 was added until the starting material was completely consumed (EtOAc / n-hexane = 3:2) was monitored by TLC. EtOAc (60 mL) was added. The organic layer was washed with 1 M K₂CO₃ solution (3 × 10 mL) and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product, which was purified by rapid column chromatography (EtOAc / n-hexane = 3:2) to obtain a colorless oily product 16 (0.022 g, 13% yield in two steps). Product 16 (0.022 g, 0.050 mmol) was premixed with palladium on carbon (0.053 g, 10% wt% solid). The reaction solvent EtOH (1 mL) was placed under vacuum and backfilled with hydrogen three times, then added to the reaction mixture. Et₃N (7 μL) was added. The reaction flask was then evacuated and backfilled with hydrogen three times, and stirred under a hydrogen atmosphere (balloon). The reaction was monitored by TLC (n-hexane / EtOAc = 1:1). 16 was consumed after 2 hours. The reaction mixture was filtered through a diatomaceous earth pad and then washed with EtOH. After removing the solvent under reduced pressure, the crude product was purified by preparative TLC (80% EtOAc in n-hexane solution) to give 17 (0.015 g, 71% yield) as a yellow oil.DIPEA (19.1 μL, 0.11 mmol) was added to a solution of compound 6 (0.017 g, 0.050 mmol) in anhydrous CH2Cl2 (1 mL). After 5 minutes, a solution of EDCI (0.017 g, 0.11 mmol), HOBt (0.023 g, 0.11 mmol), and 17 (19.1 μL, 0.11 mmol) in anhydrous CH2Cl2 (1 mL) was added. The reaction mixture was stirred at room temperature for 36 hours. Excess EDCI and 6 were added until TLC (EtOAc / n-hexane = 1:1) showed complete consumption of the starting material. The reaction was quenched with NH4Cl (10 mL) and diluted with CH2Cl2. The aqueous layer was back-extracted with CH2Cl2 (3 × 30 mL). The combined organic phases were washed with brine (10 mL), dried with Na2SO4, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (EtOAc / n-hexane = 3:2) to give foamy compound 18 (0.019 g, 75% yield).

[0370] Synthetic schemes for compounds 24a and 24b:

[0371]

[0372] 21 was prepared from D-glucose (3.00 g, 16.7 mmol) according to literature reports and separated into a white powder (4.70 g, 72% yield) by recrystallization (Huo et al., Chem Res Toxicol. 2004, 17, 8, 1112-1120). 22 was prepared from 21 (4.669 g, 11.9 mmol) according to literature reports and separated into a pale yellow syrup (1.560 g, 37% yield) after purification by rapid column chromatography (Huo et al., Chem Res Toxicol. 2004, 17, 8, 1112-1120). 23 was prepared from 22 (0.305 g, 0.88 mmol) with modifications based on literature reports and was separated by silica gel column chromatography (EtOAc / n-hexane = 1 / 4) as a white powder (0.31 g, 69% yield, a mixture of α and β isomers) (Cai et al. J Org Chem. 2005, 70, 9, 3518-3524). The α and β isomers were separated by gradient elution with silica gel chromatography (diethyl ether / n-hexane = 1 / 4) to give the α isomer (0.074 g) and the β isomer (0.022 g). Et3N (50 μL, 0.18 mmol) and HBTU (0.037 g, 0.098 mmol) were added to a solution of compound 6 (0.030 g, 0.089 mmol) in anhydrous CH2Cl2 (1 mL). After 5 minutes, 1,3-diaminopropane (7.4 μL, 0.089 mmol) was added. The reaction mixture was stirred for 12 hours. Water (5 mL) was added. The aqueous layer was extracted with CH2Cl2 (20 × 3 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residue 19 was used directly for the next step. To a stirred solution of 23b (0.022 g, 0.043 mmol) in anhydrous DCM (2 mL), 9 (0.019 g, 0.047 mmol) and Et3N (20 μL) were added. The reaction mixture was stirred for 4 hours. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to provide a colorless oily compound 24b (0.029 g, 87% yield). To a stirred solution of 23a (0.052 g, 0.10 mmol) in anhydrous DCM (3 mL), 9 (0.044 g, 0.11 mmol) and Et3N (40 μL) were added. The reaction mixture was stirred for 48 hours. DMAP was then added. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to provide compound 24a (0.048 g, 61% yield) as a white foam.

[0373] Synthetic scheme of compound 77:

[0374]

[0375] 72 was prepared from carbon disulfide (1.58 mL, 26.3 mmol) according to literature reports and immediately used in the next step (Pervez et al. Nat Prod Res. 2007, 1, 13, 1178-1186). 73 was prepared from 72 (26.3 mmol) according to literature reports, and was isolated as a white solid (1.40 g, 44% yield in two steps) without purification (Pervez et al. Nat Prod Res. 2007, 1, 13, 1178-1186). 74 was prepared from 73 (0.30 g, 2.5 mmol) according to literature reports, and was isolated as a dark green solid (0.074 g, 13% yield) after purification by rapid column chromatography (4% EtOH in DCM) (Greenbaum et al. J Med Chem. 2004, 47, 12, 3212-3219). Add 11.1 μL of 1,3-diaminopropane to a solution of 74 (0.030 g, 0.13 mmol) in EtOH (2 mL). Set to reflux and stir the reaction mixture overnight. Remove EtOH under reduced pressure. Purify the crude product by silica gel column chromatography (EtOH / DCM, 1% NH4OH) to give a yellow oily 75 (0.020 g, 57% yield). Add 40 μL of Jone's reagent to a solution of 29 (0.030 g, 0.10 mmol) in acetone (0.5 mL). Stir the reaction mixture at room temperature for 30 min. Add EtOAc and H2O. Add saturated NaHCO3 until the pH of the aqueous layer becomes 7. Extract the crude product with EtOAc, wash with brine, and dry with MgSO4. Filter 76 from EtOAc through a silica gel saddle. Remove the solvent under reduced pressure. 76 is used immediately for the next step without purification. Dissolve crude product 76 in DCM (1 mL). The solution was added to 75 (0.016 g, 0.064 mmol) of DCM solution and stirred for 30 minutes. Sodium triacetoxyborohydride (0.020 g, 0.094 mmol) was added. The reaction was stirred for 2 hours. i-PrOH (0.2 mL) was added. Saturated NH4Cl was added. DCM was used for extraction from the aqueous layer. The combined organic layers were washed with brine and then dried over MgSO4. The concentrated filtrate was purified by silica gel column chromatography (4% EtOH in DCM solution) to give compound 77 (0.020 g, 87% yield).

[0376] Synthetic schemes for compounds 30a and 30b:

[0377]

[0378] 25. According to literature reports 21The solution was prepared and purified by rapid column chromatography as an oil (Uyanik et al., J Am Chem Soc. 2009, 131, 1, 251-262). 26 was prepared according to literature reports and purified by rapid column chromatography as an oil (Kovalenko et al., Chemistry 2015, 21, 7, 2785-2788). Tetraoxane 29 was prepared by modification according to literature reports (O'Neill et al., Angew Chem Int Ed. 2010, 49, 5693-5697; Yan et al., Synlett. 2011, 2827-2830). At 0 °C, formic acid (2.6 mL, 69 mmol) was added to a stirred solution of 26 (0.70 g, 3.5 mmol) in acetonitrile (3.8 mL), followed by the addition of 50% aqueous hydrogen peroxide solution (1.3 mL, 46 mmol). The mixture was stirred at room temperature. TLC analysis showed that acetate 26 (n-hexane / EtOAc = 2:1) was consumed after 4 hours. 1 mL of 50% H₂O₂ was added. After 1 hour, the mixture was poured into ice water and extracted with CH₂Cl₂. The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the corresponding gem-dihydroperoxide 27, which was immediately used in the next step. A mixture of 2-adamantanone (0.79 g, 5.2 mmol), PMA (0.0627 g, 1 mol%), and anhydrous MgSO₄ (0.63 g, 5.2 mmol) in CH₂Cl₂ (13 mL) was stirred at room temperature for 30 minutes. A solution of 27 (3.5 mmol) in CH₂Cl₂ (13 mL) was added dropwise to this solution over 15 minutes. The mixture was stirred at room temperature and monitored by TLC (n-hexane / EtOAc = 4:1). When 27 was completely consumed, deionized H₂O (10 mL) was added. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / EtOAc = 8:1) to give a mixture of 28 and 2-adamantane. Analytically pure 28 could not be separated by rapid silica gel chromatography because it co-eluted with 2-adamantane. Therefore, the product mixture was used for the next step. K2CO3 (2.64 g, 19.1 mmol) was added to a mixture of 28 and 2-adamantane (total 0.94 g) in MeOH (62 mL) at room temperature. Water (20 mL) was added. CH2Cl2 (3 × 30 mL) was used to extract the product from the aqueous layer. The combined organic phases were washed with brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / EtOAc = 2 / 1) to give 29 (0.252 g, 3-step yield 24%) as a white solid.Under an argon atmosphere, p-nitrobenzene chloroformate (0.098 g, 0.49 mmol) and Et3N (0.1 mL, 0.71 mmol) were added sequentially to a solution of 29 (0.014 g, 0.049 mmol) in anhydrous dichloromethane (3 mL). The reaction mixture was stirred for 12 hours. DCM (60 mL) was added, the organic layer was washed with 1 M K2CO3 solution (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was dissolved in anhydrous dichloromethane (1 mL). Under an argon atmosphere, 68 (0.021 g, 0.044 mmol) and Et3N (22 μL, 0.16 mmol) were added sequentially to this solution. The reaction mixture was stirred for 12 hours. Dichloromethane (10 mL) was added. The organic layer was washed with 1M K₂CO₃ solution (3 × 5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product, which was purified by rapid column chromatography to give a yellow oily compound 30b (0.068 g, 19% yield in two steps). Following the stoichiometric procedure and the synthetic protocol for compound 30b, a colorless oily compound 30a (0.0083 g, 53% yield in two steps) was obtained from 29 (0.011 g, 0.037 mmol) and 3-(dimethylamino)-1-propylamine (5 μL, 0.037 mmol) (7% EtOH in DCM, 1% NH₄OH).

[0379] Synthetic scheme of compound 35a:

[0380]

[0381] 32 was prepared according to literature reports and isolated as an oil without purification (An et al., Chemistry 2015, 21, 30, 10786-10798). Following the stoichiometric procedure of compound 6, 35 (0.52 g, 3-step yield 15%) was obtained as a white solid from 2-adamantanone (1.90 g, 12.7 mmol) and 32 (1.50 g, 11.5 mmol) (EtOAc / n-hexane = 1 / 3). Following the stoichiometric procedure of compound 6a, 35 (0.009 g, 0.031 mmol) and 3-(dimethylamino)-1-propylamine (3.4 μL, 0.031 mmol) were obtained as a yellow oily compound 35a (0.010 g, 88% yield) (7% EtOH in DCM, 1% NH4OH).

[0382] Synthetic schemes for compounds 37a and 37b:

[0383]

[0384] Following the stoichiometric procedure and that of compound 29, compound 37 (0.18 g, 16% yield in 3 steps) was obtained as a white solid from compound 4-tert-butylcyclohexanone (0.57 g, 3.7 mmol) and compound 26 (0.73 g, 3.6 mmol) (n-hexane / EtOAc = 2 / 1). Compound 37 appeared as a mixture (dr) of diastereomers. Following the stoichiometric procedure and that of compound 30b, compound 37c (0.534 g, 94% yield) was obtained as a white solid from compound 37 (0.0367 g, 1.2 mmol) and p-nitrobenzene chloroformate (0.738 g, 3.7 mmol) (EtOAc / n-hexane = 1 / 8). Compound 37c appeared as a mixture (dr) of diastereomers. Following the stoichiometric synthesis procedure of compound 30a, a yellow oily compound 37a (0.007 g, 40% two-step yield) (3% EtOH in DCM) was obtained from compound 37c (0.019 g, 0.04 mmol) and 3-(dimethylamino)-1-propylamine (28.5 μL, 0.044 mmol). Compound 37a was presented as a mixture (dr) of diastereomers. Following the stoichiometric synthesis procedure of compound 30b, a yellow foamy compound 37b (0.17 g, 82% yield) (3% EtOH in DCM) was obtained from compound 37c (0.133 g, 0.29 mmol) and 68 (0.137 g, 0.28 mmol). Compound 37b was presented as a mixture (dr) of diastereomers.

[0385]

[0386] Compound 72 was prepared according to literature reports and purified as a yellow oil by rapid column chromatography (5% EtOH in DCM, 1% NH4OH) (Hou et al. J Org Chem. 2004, 69, 18, 6094-6099). Following the stoichiometric synthesis procedure of compound 30a, a yellow oily compound 37d (0.019 g, 30% yield) (1% EtOH in DCM) was obtained from compounds 37c (0.049 g, 0.11 mmol) and 72 (0.053 g, 0.16 mmol). Compound 37d appeared as a mixture (dr) of diastereomers. Compound 73 was prepared according to literature reports and purified as a yellow oil by rapid column chromatography (5% EtOH in DCM, 1% NH4OH) (Ghedira et al. J Med Chem. 2018, 158, 51-67). Following the stoichiometric procedure and the synthetic sequence of compound 30a, a yellow oily compound 37e (0.013 g, 40% yield) was obtained from compounds 37c (0.031 g, 0.066 mmol) and 73 (0.012 g, 0.066 mmol) (1% EtOH in DCM). Compound 37e was presented as a mixture (dr) of diastereomers.

[0387] Synthesis scheme for compound 37g:

[0388]

[0389] Compound 37c (0.031 g, 0.066 mmol) was dissolved in anhydrous dichloromethane (1 mL). Piperazine (0.011 g, 0.133 mmol) and Et3N (60 μL, 0.4 mmol) were added sequentially to the solution under an argon atmosphere. The reaction mixture was stirred for 12 hours. Dichloromethane (60 mL) was added. The organic layer was washed with 1 M K2CO3 solution (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product, which was purified by rapid column chromatography to give a yellow oily product 37f (0.025 g, 90% yield). Compound 37f appeared as a mixture of diastereomers (dr). It was prepared and isolated as a grayish-white solid according to literature reports, requiring no further purification or characterization (Ji et al. J.ACS Med Chem Lett. 2015, 6, 6, 707-710). 42 was prepared and isolated as a grayish-white solid according to literature reports, requiring no further purification or characterization (Ji et al., J. ACS Med Chem Lett. 2015, 6, 6, 707-710). 43 was prepared according to literature reports and isolated as a yellow solid after rapid column chromatography purification (Ji et al., J. ACS Med Chem Lett. 2015, 6, 6, 707-710). Subsequently, Et3N (12 μL, 0.087 mmol) and HBTU (0.020 g, 0.052 mmol) were added to a solution of 43 (0.008 g, 0.035 mmol) in anhydrous CH2Cl2 (1 mL). After 5 minutes, compound 37f (0.014 g, 0.035 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. When TLC (EtOAc / n-hexane = 1:1) showed that 43 had been completely consumed, the solvent was removed under reduced pressure. The crude product was purified by preparative TLC (EtOAc / n-hexane = 1:4) to give 37 g (0.016 g, 70% yield) of a bright yellow oily compound. Compound 37 g was present as a mixture (dr) of diastereomers.

[0390] Synthetic scheme of compound 37i:

[0391]

[0392] 44. According to literature reports, it was prepared from 4-amino-1-butanol (0.5 mL, 5.4 mmol) and purified by rapid column chromatography (EtOAc / n-hexane = 1:4) to a bright yellow oil (0.255 g, 17%) (De et al. J Enzyme Inhib Med Chem. 2016, 31, 106-113). Subsequently, it was reacted with an anhydrous DCM solution of 1,2,3,4,6-penta-O-acetyl-D-pyranose (0.349 g, 0.89 mmol) (…). 44 (0.255 g, 0.95 mmol) and BF3·Et2O (0.55 mL, 4.5 mmol) were added to the MS solution. The reaction mixture was stirred at room temperature and sonicated until the starting material was completely consumed (as monitored by TLC) (Deng et al. J Org Chem. 2006, 71, 5179-5185). The reaction mixture was quenched by the addition of NaHCO3 and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give crude product 45, which was used for the next step without further purification. 20% wt Pd / C (0.099 g, 10 mol%) was added to a solution of crude product 45 (0.070 g, 0.93 mmol) in methanol (15 mL) with stirring at room temperature. The air in the flask was purged with hydrogen, and the mixture was stirred for 2 days under a hydrogen atmosphere. The reaction mixture was filtered through a diatomaceous earth pad, washed with EtOH, and concentrated to give a crude product, which was purified by rapid column chromatography to give a yellow oily compound 46 (0.026 g, 7% yield in two steps). Compound 37c (0.0436 g, 0.094 mmol) was dissolved in anhydrous dichloromethane (1 mL). 46 (0.023 mg, 0.055 mmol) and Et3N (30 μL, 0.22 mmol) were added sequentially to this solution under an argon atmosphere. The reaction mixture was stirred for 12 hours. Dichloromethane (60 mL) was added. The organic layer was washed with 1 M K2CO3 solution (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product, which was purified by rapid column chromatography to give a yellow oily compound 37h (0.0133 g, 33% yield). Compound 37h appeared as a mixture of diastereomers (dr). A solution of NaOMe in MeOH (0.03 M, 0.5 mL) was added to compound 37h (0.013 g, 0.018 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. Dichloromethane and water were added. The aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude product, which was purified by rapid column chromatography to give a white solid compound 37i (0.0015 g, 15% yield). Compound 37i appeared as a mixture of diastereomers (dr).

[0393] A solution of compound 37c (0.012 g, 0.025 mmol) in CH2Cl2 was added to a solution of 2,2'-(ethylenedioxy)bis(ethylamine) (1.8 μL, 0.0125 mmol), followed by the addition of 4-(dimethylamino)pyridine (DMAP) and Et3N (10 μL, 0.025 mmol). The reaction mixture was stirred at room temperature for 48 hours. The solvent was concentrated under reduced pressure to give a crude product, which was purified by rapid column chromatography to give an oily compound 37j (0.010 g, 50% yield). Compound 37j appeared as a mixture of diastereomers (dr). At 0 °C, sodium hexamethyldisilazide [NaHMDS, 1.0 M in THF] (0.33 mL, 0.32 mmol) was added to a solution of 37 (0.100 g, 0.32 mmol) in THF (7 mL). The resulting mixture was stirred at 0 °C for 10 min, and then a suitable amount of dichlorophosphate (0.024 mL, 0.16 mmol) was added. The reaction mixture was kept at 0 °C for 2 h, then heated to room temperature and stirred for 12 h. The mixture was then cooled back to 0 °C and quenched with water. The organic layer was extracted three times with diethyl ether, and the combined organic fractions were washed with saturated NaCl and dried over MgSO4. The organic extract was removed under reduced pressure, and the product was purified by rapid column chromatography to give an oily compound 37k (0.030 g, 26% yield). Compound 37k appeared as a mixture of diastereomers (dr).

[0394] Synthetic scheme of compound 37l:

[0395]

[0396] 47 was prepared from 2-mercaptoethanol (2 mL, 28.5 mmol) according to literature reports and purified as an oil (1.036 g, 30% yield) by rapid column chromatography (EtOAc / n-hexane = 1 / 1) (Chen et al. J. Mater. Sci. 2018, 53 16169–16181). Compound 37c (0.017 g, 0.036 mmol) was added to a solution in CH2Cl2 with 2,2'-dithiodimethylbis(ethane-1-ol) (0.0086 g, 0.018 mmol), Et3N (10 μL), and DMAP. The reaction was stirred at room temperature for 48 hours. The crude product was purified by preparative TLC using EtOAc / n-hexane (1:8) to give compound 37l (0.005 g, 7% yield). Compound 37l appeared as a mixture (dr) of diastereomers.

[0397] Synthetic schemes for compounds 49, 50, 51, 53, 54, 56, and 57:

[0398]

[0399]

[0400] Iodomethane:acetonitrile (1:1) was added to the tertiary amine. The reaction mixture was stirred at room temperature for 4 to 12 hours. UPLC was used to check the conversion. The solvent was removed under reduced pressure. The crude product was purified by rapid column chromatography (100% EtOAc, then 4% EtOH / DCM) to give a bright yellow oily quaternary ammonium (“QA”). Following the procedure used for the synthesis of compounds QA, oily compound 48 (0.016 g, 70% yield) was obtained from compound 37d (0.018 g, 0.031 mmol). Compound 48 appeared as a mixture (dr) of diastereomers. 55 was prepared from 3-bromopropylamine hydrobromide (3.00 g, 13.7 mmol) according to literature reports, isolated as an oil without any further purification and characterization (2.644 g, 46% yield) (Millard et al. J MedChem. 2013, 56, 22, 9170-9179). Following the stoichiometric procedure and the synthetic procedure of compound 37b, an oily compound 56 (0.020 g, 20% yield) (3% EtOH in DCM solution) was obtained from 55 (0.066 g, 0.156 mmol). Compound 37l appeared as a mixture (dr) of diastereomers. Following the stoichiometric procedure and the synthetic procedure of compounds 30a and QA, an oily compound 50 (0.006 g, 17% yield in 3 steps) (3% EtOH in DCM) was obtained from compound 37 (0.020 g, 0.067 mmol). Compound 50 appeared as a mixture (dr) of diastereomers. Following the stoichiometric procedure and the synthetic procedure of compounds 30a and QA, an oily compound 51 (0.027 g, 48% yield in 2 steps) (3% EtOH in DCM) was obtained from compound 37 (0.030 g, 0.10 mmol). Compound 51 was presented as a mixture (dr) of diastereomers. Compound 49 was obtained from compound 37a (0.042 g, 0.097 mmol) as an oil (0.0086 g, 16%) (3% EtOH in DCM) according to the stoichiometric and QA compound synthesis procedure. Compound 49 was presented as a mixture (dr) of diastereomers. Compound 52 was prepared from 3-bromopropylamine hydrobromide (2.00 g, 9.1 mmol) according to literature reports and isolated as an oil (1.33 g, 78% yield) after purification by rapid column chromatography (5% EtOH in DCM, 1% NH4OH) (Labadie et al. Bioorg Med Chem Lett. 2004, 14, 3, 615-619). Compound 53 was obtained from compound 37c (0.031 g, 0.16 mmol) as an oil (0.058 g, 55% yield in 2 steps) (3% EtOH in DCM) following the stoichiometric and synthetic procedures of compounds 30a and QA.Compound 53 was presented as a mixture (dr) of diastereomers. Compound 54 was obtained from compound 37e (0.0054 g, 0.011 mmol) as an oil (0.004 g, 58% yield) (3% EtOH in DCM) according to the stoichiometric and QA compound synthesis procedure. Compound 54 was presented as a mixture (dr) of diastereomers. Benzyl iodide was prepared and isolated as an oil according to literature reports, without any further purification or characterization (Hoang et al. J Org Chem. 2009, 74, 11, 4177-4187). Benzyl iodide (0.022 g, 0.10 mmol) was added to a solution of 37d (0.020 g, 0.034 mmol) in acetonitrile. The reaction mixture was stirred at room temperature for 72 hours. The solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (100% EtOAc, then 6% EtOH / DCM) to give compound 57 (0.0065 g, 24% yield) as a bright yellow oil. Compound 57 is shown as a mixture of diastereomers (dr).

[0401] Synthetic schemes for compounds 59a and 59b:

[0402]

[0403] Following the stoichiometric procedure and the synthetic procedure of compound 30a, 59 was obtained from 26 (2.00 g, 9.9 mmol) and cyclohexanone (0.49 mL, 4.7 mmol), as an oil (0.106 g, 9% yield in two steps) (EtOAc / n-hexane = 1 / 2). Following the stoichiometric procedure and the synthetic procedure of compounds 30a and QA, compound 59a (0.018 g, 38% yield in two steps) was obtained from 59 (0.028 g, 0.35 mmol) and 72 (0.034 g, 0.14 mmol), as a yellow oil (0.018 g, 38% yield in two steps). Following the synthetic procedure of compound 30b, compound 59b was obtained from 59 (0.010 g, 0.023 mmol) and 68 (0.012 g, 0.023 mmol), as a white solid (0.006 g, 39% yield in two steps) (2% EtOH in DCM).

[0404]

[0405] To a solution of alk-72 (0.113 g, 0.44 mmol) in DCM (1 mL), 22.2 μL (0.24 mmol) of 4-bromobut-1-yne was added, followed by Et3N (47.4 μL, 0.34 mmol). The reaction was stirred at room temperature for 24 h. The solvent was removed under reduced pressure. The crude product was purified by rapid chromatography (20% EtOH in DCM, 1% NH4OH) to give an oily compound alk-72 (0.0154 g, 21% yield). Following the stoichiometric ratio and the synthetic procedure for compounds 30a and QA described above, a yellow oily compound alk-R-48 (0.0071 g, 18% yield in two steps) (5% EtOH in DCM) was obtained from compounds 37c (0.0432 g, 0.093 mmol) and alk-72 (0.0154 g, 0.05 mmol). Compound alk-R-48 occurred as a mixture of diastereomers (dr). 4-Bromobut-1-yne (20.5 μL, 0.22 mmol) was added to a solution of alk-68 (0.105 g, 0.22 mmol) in DMF (1 mL), followed by Et3N (33.8 μL, 0.24 mmol). The reaction was stirred at room temperature for 24 h. The solvent was removed under reduced pressure. The crude product was purified by rapid chromatography (20% EtOH in DCM, 1% NH4OH) to provide an oily alk-68 (0.0224 g, 23%). Following the stoichiometric ratio and the synthetic procedure for compounds 30a and the quaternary ammonium compounds described above, compound alk-R-37b was obtained from compound 37 (0.020 g, 0.067 mmol) and alk-68 (0.022 g, 0.049 mmol) as a yellow oil (0.0067 g, 18% yield for both steps) (in DCM solution of 3% EtOH). Compound alk-R-37b was presented as a mixture (dr) of diastereomers.

[0406] Synthetic scheme of compound alk-L-37b:

[0407]

[0408] Synthesis of 67:

[0409]

[0410] Samples 62 and 63 were prepared with modifications according to literature reports and separated into a mixture of products after purification by rapid column chromatography (WO2010039789A1, Stamford et al.). Anhydrous N,N-diisopropylamine (DIPA) was prepared fresh by distillation. A THF (10 mL) solution of DIPA (1.3 mL, 9 mmol) was maintained at -78 °C under argon. A solution of n-butyllithium in hexane (1 M, 8.9 mL, 8 mmol) was added dropwise to the DIPA solution. The reaction mixture was stirred at -78 °C for 30 min. Half of the LDA solution was transferred to a round-bottom flask purified with argon and maintained at 0 °C. Methyl ester 3 (0.949 g, 4.4 mmol) was dissolved in THF (8 mL) and maintained at 0 °C under argon. This solution was added dropwise to the half LDA solution at -78 °C. The reaction mixture was stirred at -78 °C for 15 min. Then methyl iodine (0.58 mL, 8.8 mmol) was added. The reaction mixture was heated to 0°C and stirred for 15 minutes. The reaction mixture was cooled to -78°C, and half of the LDA solution was added, followed by stirring for 30 minutes. Methyl iodine (0.58 mL, 8.8 mmol) was then added. The reaction mixture was heated to 0°C for 5 minutes and then stirred at room temperature for 2 hours. The mixture was then diluted with diethyl ether and acidified with 1N HCl. The crude product was extracted with diethyl ether (3 × 30 mL). The combined organic layers were washed with saturated NaHCO3, then with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane / EtOAc = 4 / 1) to give inseparable mixtures 62 and 63 (total 0.465 g). 64 was prepared according to a modified literature report and separated as an oil after rapid column chromatography purification (Stamford et al., WO2010039789A1). A mixture of 62 and 63 (0.387 g) was added dropwise to a suspension of LiAlH4 (0.091 g, 2.4 mmol) in THF (20 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred for 4 hours. The reaction mixture was cooled to 0 °C, and then water, NaOH (1 N), and water were added sequentially. The mixture was stirred at room temperature for 15 minutes. MgSO4 was added. The solid was filtered off and washed with EtOAc. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (n-hexane / EtOAc = 4 / 1) to give 64 (0.25 g, 26% yield in two steps) as a colorless oil. 65 (CAS: 156042-33-0) is reported in the literature. 32Prepared from 64 (0.415 g, 1.9 mmol), and separated into an oil (0.257 g, 78% yield) after purification by rapid column chromatography (n-hexane / EtOAc = 4 / 1). To a solution of 65 (0.25 g, 1.5 mmol) in anhydrous CH2Cl2 (30 mL), p-nitrobenzene chloroformate (0.89 g, 4.4 mmol) and triethylamine (0.6 mL, 4.4 mmol) were added sequentially. After stirring at room temperature for 12 hours, the crude mixture was diluted with another portion of CH2Cl2 (50 mL) and then washed with brine and water. The CH2Cl2 layer was dried over anhydrous Na2SO4 and then concentrated. Crude product 66 was used in the next step without further purification. To a stirred solution of crude product 66 (1.5 mmol) in anhydrous CH2Cl2 (8 mL), 1-amino-3-butynediate hydrochloride (0.186 g, 1.7 mmol) and Et3N (0.63 mL, 4.4 mmol) were added. The reaction mixture was stirred for 12 hours. The crude mixture was diluted with CH2Cl2 (50 mL), washed with 1 M K2CO3, then washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography to give colorless oily compound 67 (0.179 g, 46% yield in two steps). Following the synthetic procedure for compound 29 described above, oily compound alk-L-37 (0.0576 g, 21% yield in three steps) (EtOAc / n-hexane = 1:3) was obtained from compounds 26 (0.800 g, 3.99 mmol) and 67 (0.179 g, 0.67 mmol). Compound alk-L-37 was obtained as a mixture (dr) of diastereomers. Following the synthetic procedure for compounds 30a and QA described above, compound alk-L-48 was obtained from alk-L-37 (0.0501 g, 0.12 mmol) and 72 (0.017 g, 0.067 mmol) as an oil (0.0389 g, 74% yield in 3 steps). Compound alk-L-48 was obtained as a mixture (dr) of diastereomers. Following the synthetic procedure for compound 30b described above, compound alk-L-37b (0.0197 g, 39% yield in 2 steps) (3% EtOH / DCM) was obtained from alk-L-37 (0.0501 g, 0.12 mmol) and 68 (0.026 g, 0.054 mmol). Compound alk-L-37b was obtained as a mixture (dr) of diastereomers.

[0411] Compound characterization

[0412] On a Bruker Avance DPX 300 Fourier Transform Spectrometer, a Bruker Avance DRX 400 Fourier Transform Spectrometer, or an AVIII-600 Spectrometer, conventional NMR spectra were recorded in CDCl3 at ambient temperature or at a temperature specified therein. 1 H NMR spectra were recorded at 400, 500, or 600 MHz. 13 C10 NMR spectra were recorded at 100, 125, or 150 MHz. Chemical shifts were reported in ppm on the δ scale, with reference to the internal standard tetramethylsilane (δ 0.00) or residual solvent ( 1 ¹H NMR: CDCl₃ δ 7.26, C₆D₆ 7.16, CD₂Cl₂ 5.32, (CD₃)₂CO 2.05 or CD₃OD 3.31; 13 CNMR: CDCl3 δ 77.16, C6D6 128.1, CD2Cl2 53.84, (CD3)2CO 29.84 and 206.26 or CD3OD 49). Two-dimensional NMR spectra were recorded on a Bruker Avance DRX500 Fourier transform spectrometer at room temperature or the temperatures described herein. The following abbreviations are used to report spectra: brs (broad singlet), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet). High-resolution mass spectra were obtained using ESI mode in a Bruker Maxis II high-resolution QTOF spectrometer. All LCMS analyses were performed on an AQUITY UPLC@BEH C... 18 The reaction was performed on a Waters SQ Detector V4.1SCN 805 column (17 μm) using water (containing 0.1% TFA) and acetonitrile at a flow rate of 0.3 mL / min.

[0413] 2-(1,4-dioxaspiro[4.5]dec-8-ylidene)methyl acetate (2): 1 H NMR (400MHz, CDCl3) δ5.58(s,1H),3.89(s,4H),3.59(s,3H),2.93–2.91(m,2H),2.31–2.28(m,2H),1.70–1.68(m,4H). 13 CNMR (100MHz, CDCl3) δ166.84,160.53,113.83,107.89,64.40,50.82,35.72,34.94,34.54,26.01.

[0414] 2-(1,4-dioxaspiro[4.5]dec-8-yl)methyl acetate (3):1 H NMR (500MHz, CDCl3) δ3.91 (s, 4H), 3.65 (s, 3H), 2.22 (d, J = 7.0Hz, 2H), 1.83–1.8 0 (m, 1H), 1.72 (d, J = 9.8Hz, 4H), 1.55 (td, J = 15, 5.5Hz, 3H), 1.31 (q, J = 10Hz, 2H). 13 C NMR (125MHz, CDCl3) δ173.39,108.74,64.37,51.44,40.87,34.44,33.62,30.16.

[0415] 2-((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1”-cyclohexane]-4”-yl)acetic acid(6): 1 H NMR (600MHz, CDCl3) δ3.15(br,1H,COOH),2.29(brs,2H),1.98–1.86(m,9H),1.75–1.61(m,12H),1.31–1.25(m,2H). 13 C NMR (150MHz, CDCl3) δ178.20,110.63,107.68,40.44,37.08,34.41,33.61,33.28,31.22,30.23,28.97,28.49,27.74,27.18.C 18 H 27 O6[M+H] + ESI-HRMS: Calculated value 338.1729, measured value 338.3400 or C 18 H 26 NaO6[M+Na] + The calculated value is 361.1627, and the measured value is 361.1601.

[0416] (3-(bromo-15-azalkyl)propyl)triphenylphosphine bromide (68): 1 H NMR (400MHz, CD3OD) δ8.15–7.55(m,15H), 3.71–3.64(m,2H), 3.23(t,J=8.7,2H), 2.07–2.04(m,2H). 13 C NMR(100MHz,CD3OD)δ: 134.93(d, 4 J C,P =2.3Hz), 133.36(d, 3 J C,P =10.5Hz), 130.18(d,2 J C,P =12.6Hz), 117.65(d, 1 J C,P =86.6Hz), 39.16(d, 2 J C,P =21.0Hz), 20.34, 19.12(d, 1 J C,P =53.9Hz). 31 PNMR (160MHz, CD3OD) δ 23.96. C 21 H 24 NP's ESI-HRMS([M–2Br) + ): Calculated value 320.1563, measured value 320.1559.

[0417] (3-(2-((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1”-cyclohexane]-4”-yl)acetamido)propyl)triphenylphosphine bromide(6b): 1 H(600MHz, CDCl3)δ7.83–7.81(m,3H),7.71–7.68(m,6H),7.65–7.61(m,6H),6.75–6.72(m,1H),3 .61–3.41(m,4H),3.2–3.05(m,4H),2.16(d,J=12Hz,2H),1.95–1.85(m,10H),1.69–1.60(m,11H). 13 C NMR (150MHz, CDCl3) δ173.60,135.52(d, 4 J C,P =3Hz), 133.40(d, 3 J C,P =9Hz,),130.82(d, 2 J C,P =12Hz), 117.97(d, 1 J C,P =86Hz),110.42,107.88,42.64,39.18(d, 2 J C,P =17Hz),37.11,34.41,33.27,31.36,30.21,29.84,29.09,27.81,27.20(d,J=3Hz),22.60(d,J=3Hz),20.26(d, 1 J C,P =54Hz). 31P NMR (160MHz, CDCl3) δ 23.98.

[0418] C 39 H 47 NO5P's ESI-HRMS[M] + Calculated value: 640.3186, measured value: 640.3149.

[0419] N-(3-(dimethylamino)propyl)-2-((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1”-cyclohexane]-4”-yl)acetamide (6a): 1 H(600MHz,CD3OD,320K)δ3.20(t,J=6Hz,2H),3.15–3.07(m,2H),2.4–2.38(m, 2H), 2.28 (s, 6H), 2.10 (d, J = 6Hz, 2H), 2.02–1.89 (m, 6H), 1.86–1.51 (m, 17H).

[0420] 13 C(150MHz,CD3OD,320K)δ174.98,111.24,108.7,58.09,45.31,43.58,38.44 ,37.98,35.6,34.12,34.09,32.06,31.46,29.88,29.39,28.76,28.56,28.1. C 23 H 39 ESI-HRMS[M+H] of N2O5 + Calculated value: 423.2781, measured value: 423.2830.

[0421] 3-(tetradecylamino)propionate methyl ester (8): 1 H NMR (400MHz, CDCl3) δ3.61(s,3H),2.81(t,J=6.5Hz,2H),2.53(t,J=7.2Hz,2H),2.45( t,J=6.5Hz,2H),1.68(s,1H),1.42–1.38(m,2H),1.19(s,23H),0.81(t,J=6.7Hz,3H). 13 C NMR (100MHz, CDCl3) δ173.25,77.48,77.36,77.16,76.84,51.52,49.86,45 .07,34.52,31.94,30.07,29.70,29.65,29.59,29.38,27.35,22.70,14.10. C 18 H38 ESI-HRMS[M+H] of NO2 + Calculated value: 300.2824, measured value: 300.2895.

[0422] 3-(2-((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1”-cyclohexane-4”-yl)-N-tetradecylacetamido)methyl propionate (9): 1 H(500MHz,C6D6)(343K)δ3.52(br,2H),3.38(s,3H),3.05(br,3H),2.51(br,6H),2.15–2.04(m,9H ),1.75–1.69(m,6H),1.61–1.51(m,11H),1.38–1.31(m,16H),1.16(br,2H),0.90(t,J=6.9Hz,3H). 13 C(125MHz,C6D6)(343K)δ170.98,110.44,108.19,51.07,43.3,39.53,37.48,34.28,33.67,33. 61,32.32,30.75,30.12,30.08,30.02,29.98,29.74,28.84,27.86,27.83,27.29,23.02,14.13. C 36 H 62 NO7's ESI-HRMS[M+H] + Calculated value: 620.4448, measured value: 620.4491.

[0423] 3-(2-((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1”-cyclohexane]-4”-yl)-N-(tetradecylacetamido)propionic acid (10): 1 H NMR(500MHz, CDCl3)δ3.58(t,J=6.7Hz,2H),3.30–3.09(m,4H),2.65–2.57(m,2 H), 2.22 (brs, 2H), 1.97–1.51 (m, 23H), 1.26 (brs, 22H), 0.88 (t, J = 6.9Hz, 3H). 13C NMR (125MHz, CDCl3) δ175.63,172.78,110.58,107.89,49.40,46.03,43.40,42.87,39.19,37.09,34.40,34.18,34.06,33.4 9,33.29-33.27,32.06,31.39,30.23,29.79,29.76,29.68,29.50,29.47,29.41,28.71,27.21,27.19,26.94,22.83,14.26. C 35 H 60 NO7's ESI-HRMS[M+H] + Calculated value: 606.4292, measured value: 606.4335.

[0424] Chloromethyl (4-nitrophenyl) carbonate (69): 1 H NMR (300MHz, CDCl3) δ8.30 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 9.2 Hz, 2H), 5.84 (s, 2H). 13 C NMR (100MHz, CDCl3) δ154.9,151.1,145.8,125.5,121.7,72.8. LRMS(EI,20eV)m / z(%)230.9(M + ;6),152.0(100)186.9(42). HRMS(EI):C8H6O5NCl(M + Calculated value: 230.9935, measured value: 230.9937.

[0425] (((4-nitrophenoxy)carbonyl)oxy)methyl acetate (71): 1 H NMR (300MHz, CDCl3) δ8.25 (d, J = 9.2 Hz, 2H), 7.36 (d, J = 9.3 Hz, 2H), 5.84 (s, 2H), 2.14 (s, 3H). 13 C NMR (100MHz, CDCl3) δ169.2,155.0,151.4,145.6,125.3,121.7,82.4,20.6. LRMS(EI,20eV)m / z(%)182.0([M–CH2OAc] + ,2),73.0(100). HRMS(EI):C 10 H9NO7([M–CH2OAc)) + The calculated value is 182.0089, and the measured value is 182.0124.

[0426] (5-nitro-1,3-phenylene)diethanol(12): 1 H NMR (400MHz, CD3OD) δ8.13(s,2H),7.71(s,1H),4.71(s,4H). 13 C NMR (100MHz, CDCl3) δ147.0, 143.2, 129.2, 118.3, 61.6. LRMS(EI,20eV)m / z(%)183.0(M + ;59),137.0(100),166.0(49). HRMS(EI):C8H9NO4(M + The calculated value is 183.0532, and the measured value is 183.0523.

[0427] 1,3-bis(bromomethyl)-5-nitrobenzene (13): 1 H NMR (400MHz, CD3OD) δ8.18(s,2H),7.75(s,1H),4.52(s,4H). 13 C NMR (100MHz, CDCl3) δ148.6, 140.4, 135.4, 123.8, 30.8. LRMS(EI,20eV)m / z(%)309.1(M + ;6),230.1(100). HRMS(EI):C8H7Br2NO2(M + Calculated value: 308.8844, measured value: 308.8813.

[0428] 2,2'-(5-nitro-1,3-phenylene)diacetonitrile (14): 1 H NMR (400MHz, acetone-d6) δ8.27(s,2H),7.92(s,1H),4.23(s,4H). 13 C NMR (100MHz, acetone-d6) δ205.7,134.6,134.1,122.5,117.4,23.3. LRMS(EI,20eV)m / z(%)201.2(M + ;50),175.2(47),155.2(97); HRMS(EI):calcd for C 10 H7N3O2(M + Calculated value: 201.1815, measured value: 201.0530.

[0429] (((((5-nitro-1,3-phenylene)bis(ethane-2,1-diyl))bis(azadiyl))bis(carbonyl))bis(oxy))bis(methylene)diacetate (16):1 H NMR (400MHz, CDCl3) δ7.91 (s, 2H), 7.41 (s, 1H), 5.19 (br, 2H), 3.51 (q, J = 6.6Hz, 4H), 2.92 (t, J = 6.7Hz, 4H), 2.08 (s, 6H). 13 C NMR (100MHz, CDCl3) δ170.19,154.79,148.56,140.92,135.73,122.29,79.95,77.48,77.16,76.84,41.81,35.71,20.88. C 18 H 24 N3O 10 [M+H] + ESI-HRMS: Calculated value 442.1383, measured value 442.1428 or C 18 H 23 N3NaO 10 [M+Na] + Calculated value: 464.1281, measured value: 464.1246.

[0430] (((((5-amino-1,3-phenylene)bis(ethane-2,1-diyl))bis(azadiyl))bis(carbonyl))bis(oxy))bis(methylene)diacetate (17): 1 H NMR (400MHz, CDCl3) δ3.43 (q, J=8Hz, 4H), 2.70 (t, J=6.8Hz, 4H), 2.10 (s, 6H). 13 C NMR (100MHz, CDCl3) δ170.28,154.67,147.12,140.16,119.46,113.89,79.97,42.10,35.84,20.99. C18H26N3O8[M+H] + ESI-HRMS: Calculated value 412.1642, measured value 412.1688.

[0431] (((((5-(2-((1r,3r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1”-cyclohexane]-4”-yl)acetamido)-1,3-phenylene)bis(ethane-2,1-diyl))bis(azadiyl))bis(carbonyl))bis(oxy))bis(methylene)diacetate (18): 1H NMR(600MHz,CD2Cl2)δ7.4(s,1H),7.25(s,2H),6.79(s,1H),5.64(s,4H),5.11–5.10(m,2H),3.42 (q,J=8Hz,4H),3.13(br,2H),2.76(t,J=4Hz,4H),2.25(brs,2H),2.07(s,6H),1.96–1.61(m,21H). 13 C NMR (150MHz, CD2Cl2) δ170.56,170.34,154.87,140.27,138.95,125.30,118.66,110.69,107.99,80.19,54.20,54.02,53.8 4,53.66,53.48,44.41,42.37,37.24,36.08,34.72,34.49,33.49,33.45,31.49,30.52,29.24,28.82,28.12,27.58,21.04. C 36 H 50 N3O 13 [M+H] + ESI-HRMS: Calculated value 732.3265, measured value 732.3300 or C 36 H 49 N3NaO 13 [M+Na] + Calculated value: 754.3163, measured value: 754.3119.

[0432] (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(((4-nitrophenoxy)carbonyl)oxy)tetrahydro-2H-pyran-3,4,5-triacetic acid triester (23): β-isomer: 1 ¹H NMR (400MHz, CDCl₃) δ 8.29 (d, J = 9.2Hz, 2H), 7.42 (d, J = 9.2Hz, 2H), 5.67 (d, J = 7.7Hz, 1H), 5.31–5.17 (m, 3H), 4.32 (dd, J = 12.6, 4.4Hz, 1H), 4.17 (dd, J = 12.6, 2.1Hz, 1H), 3.90 (ddd, J = 9.8, 4.2, 2.2Hz, 1H), 2.10 (s, 6H), 2.05 (s, 3H), 2.03 (s, 3H). β isomer: 1H NMR (400MHz, CDCl3) δ8.29(d,J=9.2Hz,2H),7.42(d,J=9.2Hz,2H),5.67(d,J=7.7Hz,1H),5.23(ddd,J=18.9,16.0,9.1Hz,3 H), 4.32 (dd, J = 12.6, 4.4Hz, 1H), 4.17 (dd, J = 12.6, 2.1Hz, 1H), 3.90 (ddd, J = 9.8, 4.2, 2.2Hz, 1H), 2.10 (s, 6H), 2.05 (m, 6H). 13 C NMR (100MHz, CDCl3) δ 170.76, 169.49, 169.31, 155.00, 150.97, 145.85, 125.55, 121.77, 96.00, 73.08, 72.62, 70.13, 67.53, 61.38, 20.77, 20.69. α-Isomer: 1 H NMR (400MHz, CDCl3) δ8.30(d,J=9.2Hz,2H),7.42(d,J=9.2Hz,2H),6.28(d,J=3.6Hz,1H),5.56(t,J=9.9Hz,1H),5.20(t,J=12H),5.1 6(dd,J=14,4Hz,2H),4.30(dd,J=12.4,3.9Hz,1H),4.32–4.28(m,1H),4.15(dd,J=12.4,2.1Hz,1H),2.10(s,3H),2.04–2.05(m,6H). 13 C NMR (100MHz, CDCl3) δ170.69,170.22,169.73,169.49,155.10,150.85,145.78,125 .57,121.65,94.22,70.58,69.49,69.23,67.59,61.29,20.80,20.73,20.65,20.59.

[0433] (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(((3-(2-((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1”-cyclohexane]-4”-yl)acetamido)propyl)carbamoyl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate (24b): 1H NMR(400MHz, CDCl3)δ6.31(br,1H),5.63(d,J=10Hz,1H),5.53–5.45(m,1H),5.29–5.23(m,1H),5.14–5.07(m,2H),4.31– 4.28(d,J=15Hz,1H),4.12–4.10(d,J=10Hz,1H),3.84–3.83(m,1H),3.28(m,6H),2.12–1.85(m,26H),1.69–1.60(m,11H). 13 C NMR (100MHz, CDCl3) δ172.96,170.81,170.24,169.56,154.58,110.57,107.77,92.99,72.94,72.53,70.36,67.89,61.55,43.36,37 .97,37.04,36.23,34.38,34.14,33.25,33.23,31.23,30.19,29.93,29.80,28.94,28.53,27.88,27.16,27.14,20.87,20.80,20.70. C 36 H 53 N2O 16 [M+H] + ESI-HRMS: Calculated value 769.3317, measured value 769.3360.

[0434] (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(((3-(2-((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1”-cyclohexane]-4”-yl)acetamido)propyl)carbamoyl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate (24a): 1 H NMR (400MHz, CDCl3) δ6.21 (s, 2H), 5.7 (br, 1H), 5.44 (t, J = 12Hz, 1H), 5.20–5.05 (m, 2H), 4.2 5–4.23(m,1H),4.11–4.06(m,3H),3.30–3.12(m,7H),2.11–1.84(m,26H),1.84–1.59(m,9H). 13C NMR (100MHz, CDCl3) δ173.03,170.79,170.30,169.80,169.54,154.51,110.54,107.73,89.99,70.04,69.44,69.39,68.03,61.62,60 .51,43.31,37.67,37.01,35.94,34.34,34.14,33.21,31.21,30.18,30.06,28.93,28.50,27.84,27.12,20.81,20.77,20.68,20.65. C 36 H 53 N2O 16 [M+H] + ESI-HRMS: Calculated value 769.3317, measured value 769.3358.

[0435] 1,4-Dioxaspiro[4.5]dec-8-ol (25): 1 H NMR (400MHz, CDCl3) δ3.80(s,4H),3.61(br,1H),3.04–3.01(m,1H),1.72–1.66(m,4H),1.54–1.40(m,4H). 13 C NMR (100MHz, CDCl3) δ108.24,76.84,67.65,64.04,31.72,31.47.

[0436] 1,4-Dioxaspiro[4.5]dec-8-ylacetate (26): 1 H NMR (400MHz, CDCl3) δ4.74(br,1H),3.84(s,4H),1.93(s,3H),1.64–1.53(m,6H),1.41–1.37(m,2H). 13 C NMR (100MHz, CDCl3) δ170.45,107.84,70.13,64.24,64.22,31.25,28.26,21.22.

[0437] (1r,3r,5r,7r)-Dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1”-cyclohexane]-4”-ol(29): 1 H NMR (400MHz, CDCl3, 298K) δ3.83(br,1H),3.13(br s,1H),2.63(br,1H),2.11–1.6(m,20H). 1H NMR (500MHz, CDCl3, 253K) δ3.88(s,1H),3.14(s,1H),2.66(s,1H),2.12(s,1H),1.94(t,J=11.3Hz, 2H),1.89–1.86(m,6H),1.82–1.81(m,2H),1.74–1.72(m,2H),1.69–1.64(m,3H),1.62–1.52(m,4H). 13 C NMR (100MHz, CDCl3, 298K) δ110.57,107.42,67.80,37.01,34.34,33.21,30.20,29.61,28.32,27.12,25.73. 13 CNMR (125MHz, CDCl3, 253K) δ110.65,107.39,67.76,36.66,34.03,32.98,32.96,32.95,30.20,29.83,29.36,28.18,26.75,25.58. C 16 H 24 NaO5[M+Na] + ESI-HRMS: Calculated value 319.1521, measured value 319.1498.

[0438] (3-(((((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1”-cyclohexane]-4”-yl)oxy)carbonyl)amino)propyl)triphenylphosphine bromide (30b): 1 H NMR (400MHz, CDCl3) δ7.8–7.76(m,9H),7.7–7.68(m,6H),6.75(t,J=5Hz,1H),4.69(br,1H),3.84–3.80 (m,2H),3.51–3.50(m,2H),3.14–3.12(br,1H),2.48(br,1H),2.32–2.28(br,1H),1.95–1.59(m,20H). 13 C NMR (125MHz, CDCl3), δ156.8,135.21(d, 4 J C,P =2.5Hz), 133.70(d, 3 J C,P =10.08Hz), 130.66(d, 2 J C,P =12.6Hz), 118.45(d, 1 J C,P=85.7Hz),110.54,107.31,70.38,40.46(d, 2 J C,P =17.6Hz),37.08,34.38,33.26,30.19,29.82,28.36,27.18,26.7,25.79,23.04,20.86(d, 1 J C,P =51.7Hz). 31 P NMR (160MHz, CDCl3) δ24.79. C 38 H 45 NO6P[M] + ESI-HRMS: Calculated value 642.2979, measured value 642.2954.

[0439] (1r,3r,5r,7r)-Dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1”-cyclohexane]-4”-yl(3-(dimethylamino)propyl)carbamate (30a): 1 H NMR (400MHz, CDCl3) δ5.5(brs,1H),4.8(brs,1H),3.25–3.15(m,3H),2.42–2.32(m,4H),2.21(s,6H),1.98–1.63(m,21H). 13 C NMR (100MHz, CDCl3) δ156.22,110.68,107.34,69.93,58.14,45.58,40.33,37.05,34.4,33.26,30.21,28.19,27.17,27.16,26.62,25.65. C 22 H 37 N₂O₆[M+H] + ESI-HRMS: Calculated value 425.2573, measured value 425.2618.

[0440] 3-((1r,3r,5r,7r)-6'-methylspiro[adamantane-2,3'-[1,2,4,5]tetraoxane]-6'-yl)propionic acid (35): 1 H NMR (500MHz, CDCl3) δ10.64(br,1H),3.11(br,1H),2.61–2.49(m,4H),1.95–1.61(m,14H),1.27(br,2H). 13C15H22NaO6[M+Na] NMR (125MHz, CDCl3) δ 179.43, 110.37, 108.43, 37.08, 34.34, 33.26, 33.23, 30.31, 29.26, 27.77, 27.19, 20.06. ESI-HRMS of C15H22NaO6[M+Na] + Calculated value: 321.1314, measured value: 321.1288.

[0441] N-(3-(dimethylamino)propyl)-3-((1r,3r,5r,7r)-6'-methylspiro[adamantane-2,3'-[1,2,4,5]tetraoxane]-6'-yl)acrylamide (35a): 1 H(500MHz,CD3OD)δ3.23(t,J=10Hz,2H),3.16-3.11(br,1H),2.64(t,J=10Hz ,2H),2.53–2.48(m,7H),2.33–2.3(m,2H),1.97–1.67(m,16H),1.25(br,2H). 13 C(150MHz, CD3OD)δ175.6,110.02,110.00,57.54,44.7,37.93,35.55,34.11,34.08,33.36,31.91,31.47,29.71,28.53,27.42,20.17. C 20 H 35 N₂O₅[M+H] + ESI-HRMS: Calculated value 383.2468, measured value 383.2516.

[0442] 12-(tert-butyl)-7,8,15,16-tetraoxabispiro[5.2.59.26]hexadecane-3-ol (37): 1 HNMR(400MHz, CDCl3,298K)δ3.85–3.83(m,1H),3.13(br,1H),2.62(br,1H),2.1 2(br,1H),1.88–1.4(m,12H),1.25–1.23(m,2H),1.06–1.03(m,1H),0.84(s,9H). 1 H NMR (400MHz, CDCl3, 320K) δ3.85–3.83(m,1H),3.10(br,1H),2.44–1.62(m,12H),1. 49–1.40(tt,J=13.5,3.9Hz,2H),1.32–1.22(m,2H),1.10–1.04(m,1H),0.86(s,9H).1 H NMR (500MHz, CDCl3, 258K) δ3.90(s,1H),3.86(s,1H),3.15(s,1H),3.13(s,1H),2.70(s,1H),2.60(s,1H),2.19(s,1H),2.07 (s,1H),1.84–1.73(m,10H),1.66–1.54(m,10H),1.48–1.43(m,4H),1.25–1.19(m,4H),1.06(t,J=12.0Hz,2H),0.83(s,18H). 13 C NMR (100MHz, CDCl3, 298K) δ108.33,107.49(dr),107.46(dr),67.76(dr),67.52(dr) ,47.39(dr),47.36(dr),32.3,31.97,30.2,29.56,28.2,27.57,25.55,23.13,22.66. 13 C NMR (100MHz, CDCl3, 320K) δ108.45, 107.64(dr), 107.61(dr), 67.91(dr), 67.74(dr), 47.70(dr), 47.68(dr), 32.44, 30.08, 27.71, 23.10. 13 C NMR (125MHz, CDCl3, 258K) δ108.51,107.60,107.53,68.00,67.49,47.15,47.11,32.43 ,31.84,30.26,30.05,29.45,29.24,28.37,27.97,27.64,25.67,25.27,23.09,22.53. C 16 H 29 O5[M+H] + ESI-HRMS: Calculated value 301.1937, measured value 301.1393 or C 16 H 28 NaO5[M+Na] + ESI-HRMS: Calculated value 323.1834, measured value 323.1810.

[0443] 12-(tert-butyl)-7,8,15,16-tetraoxabisspiro[5.2.59.26]hexadecane-3-yl(4-nitrophenyl) carbonate (37c): 1H NMR(500MHz, CDCl3)δ8.28(d,J=9.1Hz,2H),7.39(d,J=9.1Hz,2H),4.95–4.93(m,1H),3.16(br, 1H),2.51–2.45(m,2H),1.96–1.61(m,10H),1.51–1.45(m,3H),1.12–1.07(m,1H),0.87(s,9H). 13 C NMR (125MHz, CDCl3), δ155.7,152,145.59,125.43,121.88,108.75,106.99(dr),106.94(dr) ,75.9(dr),75.73(dr),47.6,32.47,32.11,31.71,29.83,27.72,26.27,25.34,23.11,22.78. C 23 H 31 NNaO9[M+Na] + ESI-HRMS: Calculated value 488.1897, measured value 488.1867.

[0444] 12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecane-3-yl(3-(dimethylamino)propyl)carbamate (37a): 1 H NMR (500MHz, CDCl3, 320K) δ5.38(br,1H),4.82(br,1H),3.25(q,J=5.7Hz,2H),2.40–2.25(m,10H),1. 83–1.67(m,9H),1.47(td,J=13.6,3.7Hz,2H),1.32–1.27(m,4H),1.09(t,J=11.6Hz,1H),0.86(s,9H). 13 C2 NMR (125MHz, CDCl3, 320K) δ 156.27, 108.58, 107.55 (dr), 107.52 (dr), 70.25 (dr), 70.11 (dr), 58.01, 47.79 (dr), 47.77 (dr), 45.4, 40.29, 32.51, 29.85, 27.76, 27.33, 26.98, 23.17. ESI-HRMS calculated values ​​of C2H4N2O6 [M+H] + Calculated value: 429.2886, measured value: 429.2934.

[0445] (3-((((12-(tert-butyl)-7,8,15,16-tetraoxabispiro[5.2.59.26]hexadecane-3-yl)oxy)carbonyl)amino)propyl)triphenylphosphonium bromide (37b): 1 H NMR (600MHz, CDCl3) δ7.8–7.74(m,9H),7.69–7.66(m,6H),6.8–6.72(dt,J=38.7,6.1Hz,1H),4.71–4.68(m,1H),3.79–3.75(m,2H),3.4 9(brs,2H),3.15–3.13(br,1H),2.5–2.24(m,2H),1.84–1.68(m,10H),1.55(br,2H),1.45–1.43(m,2H),1.07–1.06(m,1H),0.85(d,9H). 13 C NMR (150MHz, CDCl3) δ156.79,135.23(d, 4 J C,P =3Hz), 133.64(d, 3 J C,P =10.6Hz), 130.64(d, 2 J C,P =12.1Hz), 118.34(d, 1 J C,P =86.1Hz),108.41,107.53(dr),107.43(dr),70.4(dr),70.1(dr),47.53(dr),47.45(dr),40.45(d, 2 J C-p =18Hz),32.45,32.05,29.82,28.35,28.11,27.7,27.20,26.58,25.66,25.41,23.26,22.94,22.73,20.56(d, 1 J C-P =52.9Hz). 31 P NMR (160MHz, CDCl3) δ24.70. C38H49NO6P[M] + ESI-HRMS: Calculated value 646.3292, measured value 646.3261.

[0446] N1,N1-Dibenzylpropane-1,3-diamine (72): 1H NMR(400MHz, CDCl3)δ7.33–7.27(m,8H),7.24–7.19(m,2H),3.64(brs,2H),3 .53(s,4H),2.71(t,J=6.5Hz,2H),2.45(t,J=6.4Hz,2H),1.70–1.68(m,2H). 13 C NMR (100MHz, CDCl3) δ139.22,128.87,128.28,126.96,58.31,50.63,39.79,28.74.

[0447] 12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecane-3-yl(3(dibenzylamino)propyl)carbamate (37d): 1 H NMR(600MHz, CDCl3)δ7.33(br,10H),5.23–5.21(m,1H),4.79(m,1H),3.51(brs,5H),3.17–3.1 1(m,3H),2.48–2.41(m,4H),1.79–1.63(m,10H),1.48(m,2H),1.11–1.07(m,1H),0.87(s,9H). 13 C NMR (150MHz, CDCl3), δ139.40,129.14,128.53,127.53,108.57,107.60(dr),107.52(dr),69.69(dr),69.39(dr),58.7 9(CH2),51.26(CH2),47.58,39.6(CH2),32.49,32.15,29.85,27.74,27.11,26.56,26.28,25.51,25.34,23.33,22.84. C 34 H 49 N₂O₆[M+H] + ESI-HRMS: Calculated value 581.3512, measured value 581.3558.

[0448] N1-Benzyl-N1-Methylpropane-1,3-Diamine (73): 1 H NMR (400MHz, CDCl3) δ7.30 (d, J=4.4Hz, 4H), 7.23 (dq, J=8.7, 4.2Hz, 1H), 3.46 (s, 2H ), 2.73 (t, J = 6.8 Hz, 2H), 2.40 (t, J = 7.0 Hz, 2H), 2.18 (s, 3H), 1.64 (p, J = 6.9 Hz, 2H). 13C NMR (100MHz, CDCl3) δ139.18,128.89,128.14,126.84,62.48,54.99,42.20,40.50,31.05.

[0449] 12-(tert-butyl)-7,8,15,16-tetraoxabisspiro[5.2.59.26]hexadecane-3-yl(3-(benzyl(methyl)amino)propyl)carbamate (37e): 1 H NMR (500MHz, CDCl3) δ7.32–7.28(m,5H),5.75(br,1H),4.8(br,1H),3.48(s,2H),3.24–3.17(m,3H),2 .45–2.44(m,4H),2.19(s,3H),1.75–1.68(m,12H),1.50–1.44(m,2H),1.11–1.07(m,1H),0.87(s,9H). 13 C NMR (100MHz, CDCl3) δ156.19,138.93,129.12,128.5,127.34,108.54,107.56(dr),107.5(dr),69.88(dr),69.6(dr),6 2.83,56.01,55.93,47.56,42.23,40.52,32.47,32.07,29.84,28.30,27.73,27.13,26.42,25.66,25.41,23.31,22.83. C 28 H 45 N₂O₆[M+H] + ESI-HRMS: Calculated value 505.3199, measured value 505.3263.

[0450] 12-(tert-butyl)-7,8,15,16-tetraoxabispiro[5.2.59.26]hexadecane-3-ylpiperazine-1-carboxylic acid ester (37f): 1 H NMR (400MHz, CDCl3) δ4.86–4.84(m,1H),3.43(brs,5H),3.15(br,1H),2.82(brs,4H),2.4–2.31( m,2H),2.10–2.08(m,1H),1.83–1.63(m,10H),1.48–1.44(m,2H),1.1–1.06(m,1H),0.86(s,9H). 13CNMR(100MHz, CDCl3)δ154.86,108.59,107.46(dr),107.42(dr),70.62(dr),70.41(dr),47.54, 47.48,45.88,45.04,44.65,32.45,32.05,29.83,28.24,27.7,27.11,26.49,25.61,23.3,22.76. C21H37N2O6[M+H] + ESI-HRMS: Calculated value 413.2573, measured value 413.2631.

[0451] 3-(2,4-dimethyl-3,6-dioxane-1,4-dien-1-yl)-3-methylbutyric acid (43): 1 HNMR (300MHz, CDCl3) δ6.44(s,1H),3.03(s,2H),2.16(s,3H),1.97(s,3H),1.43(s,6H). 13 C NMR (75MHz, CDCl3) δ189.80,188.37,178.34,151.00,143.86,140.50,135.00,47.47,38.31,29.26,15.61,14.64.

[0452] 12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecane-3-yl-4-(3-(2,4-dimethyl-3,6-dioxane-1,4-dien-1-yl)-3-methylbutyryl)piperazine-1-carboxylic acid ester (37g): 1 H NMR(400MHz, CDCl3)δ6.42(s,1H),4.86(br,1H),3.5–3.38(m,8H),3.04(s,2H),2.39(br,1H), 2.16(s,3H),1.98(s,3H),1.85–1.6(m,7H),1.48–1.44(m,8H),1.11–1.07(m,1H),0.86(s,9H). 13CNMR(100MHz, CDCl3)δ190.21,188.42,170.78,154.74,153.32,143.87,138.14,134.99,108.65,107.33(dr),107.29(dr),71.25(dr),71.02(d r),47.54,47.49,47.34,45.44,43.69,41.3,38.22,32.46,32.06,29.8 3,29.25,28.3,27.71,27.11,26.45,25.71,23.29,22.78,15.78,14.64. ESI-HRMSC34H51N2O9[M+H] + Calculated value: 631.3516, measured value: 631.3566.

[0453] 4-(dibenzylamino)but-1-ol (44): 1 H NMR(400MHz, CDCl3)δ7.3–7.20(m,10H),4.60(s,2H),3.54(s,4H),3.49(t, J=5.8Hz,2H),2.42(t,J=6.2Hz,2H),1.62–1.57(m,2H),1.54–1.49(m,2H). 13 C NMR (100MHz, CDCl3) δ141.19,138.39,129.31,128.47,128.31,127.43,127.14,126.93,64.96,62.51,58.26,53.65,31.25,24.48. C 18 H 24 NO[M+H] + ESI-HRMS: Calculated value 270.1780, measured value 270.1851.

[0454] (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(4-aminobutoxy)tetrahydro-2H-pyran-3,4,5-triacetic acid triester (46): 1H NMR (500MHz, CDCl3) δ5.19(t,J=9.5Hz,1H),5.06(t,J=9.7Hz,1H),4.94(t,J=9.5Hz ,1H),4.50(d,J=8.0Hz,1H),4.24(dd,J=12.3,4.5Hz,1H),4.15(d,J=12.3Hz,1H),3. 89–3.85(m,1H),3.71–3.69(m,1H),3.56–3.53(m,1H),3.02(t,J=6.9Hz,2H),2.09( s,3H),2.07(s,3H),2.01(s,3H),1.99(s,3H),1.82–1.80(m,2H),1.72–1.71(m,2H). 13 C NMR (125MHz, CDCl3) δ 100.77, 72.85, 71.97, 71.41, 69.20, 68.51, 61.99, 39.69, 26.50, 24.46, 20.96, 20.72. ESI-HRMSC 18 H 30 NO 10 [M+H] + Calculated value: 420.1791, measured value: 420.1860.

[0455] (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(4-((((12-(tert-butyl)-7,8,15,16-tetraoxabispiro[5.2.59.26]hexadecane-3-yl)oxy)carbonyl)amino)butoxy)tetrahydro-2H-pyran-3,4,5-triacetic acid triester (37h): 1 H NMR (500MHz, CDCl3) δ5.19(t,J=9.5Hz,1H),5.08(t,J=9.7Hz,1H),4.97(dd,J=9.6,8.0Hz,1H),4.78(br, 1H),4.48(d,J=7.9Hz,1H),4.25(dd,J=12.3,4.7Hz,1H),4.16–4.09(m,1H),3.89–3.86(m,1H),3.68(ddd ,J=9.9,4.5,2.3Hz,1H),3.52–3.49(m,1H),3.18–3.17(m,2H),2.40–2.33(m,2H),2.08(s,3H),2.04–2.0 2(m,9H),1.80–1.54(m,14H),1.46(t,J=13.5Hz,2H),1.31–1.23(m,2H),1.10–1.05(m,1H),0.86(s,9H).13 CNMR(125MHz, CDCl3)δ170.82,170.43,169.55,169.49,156.13,108.56,107.47(dr),107.42(dr),100.96,72.96,71.97,71.49,70.22(dr), 69.98(dr),69.73,68.61,62.07,47.58,40.52,32.46,32.16,29.83,2 7.72,27.01,26.67,25.53,23.28,22.83,20.88,20.80,20.75,20.73. C 35 H 56 NO 16 [M+H] + ESI-HRMS: Calculated value 746.3521, measured value 746.3582.

[0456] 12-(tert-butyl)-7,8,15,16-tetraoxabisspiro[5.2.59.26]hexadecane-3-yl(4-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)butyl)carbamate (37i): 1 HNMR (500MHz, Acetone-d6) δ6.35(s,1H),4.74(s,1H),4.26(d,J=7.7Hz,1H),3.88–3.85(m,1H),3.82(dd,J=11.7,2.0Hz,1H),3.63(dd,J=11.7,5.2Hz, 1H),3.53–3.51(m,1H),3.37–3.26(m,3H),3.15(t,J=8.3Hz,3H),2.36(br, 2H),1.76–1.59(m,13H),1.48–1.43(m,2H),1.28–1.15(m,4H),0.87(s,9H). 13 C NMR (150MHz, Acetone-d6) δ156.91,108.81,107.97,104.02,77.80,77.42,74.75,71.52,70.09(dr),69.97(dr), 69.55,62.80,47.97,41.03,40.90,32.76,32.49,28.71,27.81,27.44,27.33,27.19,26.13,26.05,23.85,23.34. C 27 H 48 NO 12 [M+H]+ ESI-HRMS: Calculated value 578.3098, measured value 578.3158.

[0457] Bis(12-(tert-butyl)-7,8,15,16-tetraoxabispiro[5.2.59.26]hexadecane-3-yl)((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))dicarbamate (37j): 1 H NMR (400MHz, CDCl3) δ5.19(br,1H),4.82(br,1H),3.62(s,4H),3.57–3.55(m,4H),3.38–3.33(m,4H),3. 15(br,1H),2.44–2.33(m,3H),1.77–1.63(m,21H),1.48–1.44(m,4H),1.08–1.06(m,2H),0.86(s,18H). 13 CNMR(100MHz, CDCl3)δ156.13,108.56,107.45(dr),107.39(dr),70.48(CH2),70.37(dr),70.25(dr ),47.55,40.83(CH2),32.47,32.07,29.84,28.11,27.72,27.12,26.53,25.65,25.47,23.3,22.83. C 40 H 69 N2O 14 [M+H] + ESI-HRMS: Calculated value 801.4671, measured value 801.4714.

[0458] Bis(12-(tert-butyl)-7,8,15,16-tetraoxabispiro[5.2.59.26]hexadecane-3-yl)methyl phosphate (37k): 1 H NMR(500MHz, CDCl3)δ4.55(br,2H),3.75(d,J=15Hz,3H),3.15(br,2H),2.50–2.3 3(m,4H),1.88–1.58(m,20H),1.49–1.44(m,4H),1.11–1.06(m,2H),0.86(s,18H). 13 CNMR(125MHz, CDCl3)δ108.67,107.14(dr),107.08(dr),74.57(d, 1 J C-p =5.04Hz)(dr),74.39(d, 1 J C-p=6.3Hz)(dr),54.29(d, 1 J C-p =6.3Hz),32.47,32.08,29.85,28.43,27.72,25.08,23.29,22.78. 31 P NMR (160MHz, CDCl3) δ-1.22. C 33 H 58 O 12 P[M+H] + The calculated value of ESI-HRMS is 676.3588, and the measured value is 676.3638.

[0459] 2,2'-Dithiodimethylbis(ethanol-1-ol) (47): 1 H NMR (500MHz, CDCl3) δ3.85 (q, J = 5Hz, 4H), 2.84 (q, J = 6Hz, 4H). 13 C NMR (125MHz, CDCl3) δ60.42,41.25.

[0460] Bis(12-(tert-butyl)-7,8,15,16-tetraoxabispiro[5.2.59.26]hexadecane-3-yl)(dithionediylbis(ethane-2,1-diyl))bis(carbonate) (37l): 1 H NMR (600MHz, CDCl3) δ4.82–4.79(m,2H),4.38(t,J=6Hz,4H),3.15(br,2H),2.97(t,J=6Hz,4H ),2.45–2.35(m,4H),1.88–1.57(m,22H),1.49–1.44(m,4H),1.10–1.06(m,2H),0.86(s,18H). 13 C NMR(150MHz, CDCl3)δ154.48,108.64,107.20(dr),107.14(dr),74.34(dr),74.27(dr),74.13(dr),74.05 (dr),65.62,47.56,47.53,37.14,32.47,32.07,29.84,27.72,26.73,26.17,25.47,25.22,23.27,22.83. C 38 H 62 NaO 14 S2[M+Na] + ESI-HRMS: Calculated value 829.3479 [M+H] + The measured value was 829.3874.

[0461] N,N-dibenzyl-3-((((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)-N-methylpropan-1-aminium iodide)(48): 1 H NMR(600MHz, CDCl3)δ7.60(d,4H),7.50–7.43(m,6H),5.50(dt,J=25.4,6Hz,1H),4.93–4.88(br,4H),4.75(br,1H),3.43–3.40(m,2H),3.2 9(q,J=6Hz,2H),3.16(br,1H),3.04(s,3H),2.45–2.30(m,4H),1.78–1.64(m,11H),1.46(t,J=12Hz,2H),1.07(t,J=12Hz,1H),0.86(s,9H). 13 C NMR (150MHz, CDCl3) δ156.62,133.37,131.17,129.62,126.71,108.58,107.39(dr),107.31(dr),70.80(dr),70.51(d r),65.25,57.96,47.53,46.88,38.02,32.47,32.06,29.84,27.72,27.08,26.52,25.66,25.46,24.30,23.32,22.83. C 35 H 51 N₂O₆, [M] + ESI-HRMS: Calculated value 595.3742, measured value 595.3722.

[0462] Tributyl(3-((((12-(tert-butyl)-7,8,15,16-tetraoxabispiro[5.2.59.26]hexadecane-3-yl)oxy)carbonyl)amino)propyl)phosphonium bromide(56): 1H NMR(500MHz, CDCl3)δ6.08–5.99(m,1H),4.75(br,1H),3.33(q,J=11.4Hz,6H),3.14(br,1H),2.56–2.29 (m,11H),1.90–1.52(m,24H),1.44–1.42(m,2H),1.09–1.05(m,1H),0.97(t,J=6.7Hz,9H),0.85(s,9H). 13 C NMR (125MHz, CDCl3) δ156.63,108.37,107.32(dr),107.23(dr),70.45(dr),70.16(dr),47.42,40.95(d, 3 J c,p =16.4Hz),32.32,31.95,29.70,27.58,27.03,26.47,25.51,23.97(d, 2 J c,p =15.1Hz), 23.71(d, 3 J c,p =5Hz),23.12,22.69,22.05,19.00(d, 1 J c,p =47.9Hz), 16.88(d, 1 J c,p =49.1Hz), 13.45. 31 P NMR (160MHz, CDCl3) δ33.88. C 32 H 61 NO6P[M] + ESI-HRMS: Calculated value 586.4231, measured value 586.4212.

[0463] 4-(((((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)methyl)-1-methylpyridin-1-ium iodide(4-(((((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)methyl)-1-methylpyridin-1-ium iodide)(50): 1HNMR(500MHz, CDCl3)δ8.95(s,2H),8.06(s,2H),6.48–6.39(m,1H),4.83–4.38(m,6H) ,3.13–2.84(m,4H),2.33–2.17(m,2H),2.04–1.46(m,10H),1.08(m,1H),0.86(s,9H). 13 C NMR (125MHz, CDCl3) δ160.44,156.61,144.94,126.71,108.61,107.83,107.45(dr),107.35(dr),71.61(dr ),71.20(dr),49.40,47.54,44.21,32.47,32.07,29.84,29.17,27.73,27.06,25.53,23.80,23.44,22.83. C 24 H 37 N₂O₆, [M] + ESI-HRMS: Calculated value 449.2646, measured value 449.2627.

[0464] 4-(((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)-1,1-dimethylpiperazin-1-ium iodide(4-(((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)-1,1-dimethylpiperazin-1-ium iodide)(51): 1 H NMR(500MHz, CDCl3)δ4.85(br,1H),3.89–3.64(m,13H),3.13(br,1H),2.44–2.2 1(m,3H),1.96–1.81(m,10H),1.48–1.42(m,2H),1.11–1.05(m,1H),0.86(s,9H). 13 C NMR(125MHz, CDCl3)δ154.03,108.67,107.85,107.22(dr),107.12(dr),72.75(dr),72.40(dr),61.68,52.37 ,47.53(dr),47.51(dr),38.12,32.45,32.05,29.82,29.14,27.71,27.14,26.45,25.83,23.77,23.43,22.81. C23 H 41 N2O6[M] + ESI-HRMS: Calculated value 441.2959, measured value 441.2946.

[0465] 3-((((12-(tert-butyl)-7,8,15,16-tetraoxabisspiro[5.2.59.26]hexadecane-3-yl)oxy)carbonyl)amino)-N,N,N-trimethylpropane-1-ammonium iodide(49): 1 H NMR (500MHz, CDCl3) δ5.88–5.77(m,1H),4.78(br,1H),3.75(br,2H),3.41–3.33(m,10H ),3.14(br,1H),2.44–1.60(m,16H),1.47–1.42(m,2H),1.10–1.05(m,1H),0.86(s,9H). 13 C NMR (125MHz, CDCl3) δ156.46,108.49,108.44,107.44(dr),107.32(dr),70.39(dr),69.98(dr),65.09,54.06,47 .41(dr),47.38(dr),37.74,32.33,31.93,29.70,29.02,27.58,26.93,26.40,25.35,23.92,23.85,23.18,22.70. C 23 H 43 N2O6[M] + The calculated value of ESI-HRMS is 443.3116, and the measured value is 443.3093.

[0466] N1,N1-Dibutylpropane-1,3-diamine (52): 1 H NMR(500MHz, CDCl3)δ2.68(t,J=6.8Hz,2H),2.41–2.39(m,2H),2.35–2.32(m,4H) ,1.53(p,J=5Hz,2H),1.41–1.33(m,6H),1.28–1.21(m,4H),0.86(t,J=7.3Hz,6H). 13 C NMR (125MHz, CDCl3) δ54.00,52.09,41.01,31.07,29.32,20.82,14.16.

[0467] N-Butyl-N-(3-((((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)propyl)-N-methylbutan-1-aminium iodide(N-butyl-N-(3-((((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)propyl)-N-methylbutan-1-aminium iodide)(53): 1 H NMR(500MHz, CDCl3)δ6.04–5.89(brs,1H),4.76–4.73(br,1H),3.56–3.53(m,2H),3.39–3.31(m,6H),3.21(s,3H),3.11(br,1H),2 .41–2.29(m,2H),2.05–2.00(m,3H),1.76–1.56(m,12H),1.46–1.37(m,6H),1.05(t,J=10Hz,1H),0.97(t,J=5Hz,6H),0.83(s,9H). 13 C NMR (125MHz, CDCl3) δ156.51,108.46,108.42,107.43(dr),107.30(dr),70.39(dr),69.95(dr),62.08,60.17,4 9.33,47.45,37.76,32.36,32.05,29.72,27.62,27.53,26.99,26.47,24.45,23.31,23.27,22.72,19.75,13.78. C 29 H 55 N2O6[M] + ESI-HRMS: Calculated value 527.4055, measured value 527.4031.

[0468] N-Benzyl-3-((((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)-N,N-dimethylpropan-1-aminium iodide)(54):1 H NMR (500MHz, CDCl3) δ7.6–7.49(m,5H),5.67–5.61(m,1H),4.79(s,2H),3.70(br,2H),3.35(br,2H),3.22–3. 12(m,6H),2.34–2.02(m,4H),1.80–1.61(m,15H),1.46(t,J=12.1Hz,2H),1.08(t,J=15Hz,1H),0.86(s,9H). 13 CNMR(125MHz, CDCl3)δ156.69,133.23,131.43,129.74,128.77,127.49,126.51,108.59,107.45(dr),107.37(dr),70.80(dr) ,70.51(dr),68.55,62.74,50.37,47.56,38.07,32.47,32.07,29.85,29.51,27.73,27.04,26.62,23.98,23.95,23.28,22.84. C 29 H 47 N2O6[M] + ESI-HRMS: Calculated value 519.3429, measured value 519.3403.

[0469] N,N,N-tribenzyl-3-((((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)propan-1-aminium iodide)(57): 1 HNMR(500MHz, CDCl3)δ7.64–7.62(m,6H),7.56–7.52(m,9H),5.22(br,1H),4.72(s,7H),3.36–3.34(m,2H),3.19–3.1 8(m,3H),2.34–2.31(m,3H),2.04–2.00(m,3H),1.79–1.76(m,9H),1.49–1.44(m,2H),1.11–1.06(m,1H),0.87(s,9H). 13C NMR(125MHz, CDCl3)δ156.65,133.41,131.49,130.02,126.78,108.60,107.84,107.36(dr),107.30(dr),70.83(dr),70.60(dr), 64.26,58.15,47.58(dr),47.56(dr),38.29,32.47,32.07,29.84,29.18,27.73,27.05,26.62,26.57,25.50,23.45,23.28,22.83. C 41 H 55 N2O6[M] + ESI-HRMS: Calculated value 671.4055, measured value 671.4041.

[0470] 7,8,15,16-Tetraoxa-dispiro[5.2.59.26]hexadecane-3-ol(59): 1 H NMR (500MHz, CDCl3, 298K) δ3.84–3.83(m,1H),2.62(br,1H),2.26–2.13(m,3H),1.8–1.45(m,15H). 1 H NMR (500MHz, CDCl3, 320K) δ3.85–3.83(m,1H),2.57–1.46(m,19H). 13 C NMR (125MHz, CDCl3, 298K) δ108.49,107.57,67.81,31.87,30.37,29.58,28.37,25.70,25.45,22.28,21.99. 13 CNMR (125MHz, CDCl3, 320K) δ108.50, 107.61, 67.86, 30.10, 25.52, 22.17. C 12 H 20 O5Na[M+Na] + ESI-HRMS: Calculated value 267.1208, measured value 267.1200.

[0471] 3-((((7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecane-3-yl)oxy)carbonyl)amino)-N,N-dibenzyl-N-methylpropane-1-ammonium iodide (59a): 1H NMR(500MHz, CDCl3)δ7.62(d,J=7.1Hz,4H),7.46–7.40(m,6H),5.66(t,J=6.1Hz,1H),4.92(s,4H ),4.72(br,1H),3.37–3.27(m,4H),3.05(s,3H),2.32(br,5H),1.82–1.76(m,9H),1.46(br,5H). 13 C NMR (125MHz, CDCl3) δ156.60,133.42,131.06,129.56,126.99,108.58,107.35,70.62,65.26,58 .03,46.98,38.07,32.05,30.96,29.82,29.47,26.89,25.80,25.67,25.50,24.42,22.94,22.17. C 31 H 43 N2O6[M] + ESI-HRMS: Calculated value 539.3116, measured value 539.3100.

[0472] (3-((((7,8,15,16-tetraoxabispiro[5.2.59.26]hexadecane-3-yl)oxy)carbonyl)amino)propyl)triphenylphosphonium bromide(59b): 1 H NMR (500MHz, CDCl3) δ7.81–7.77(m,9H),7.70–7.68(m,6H),6.78(br,1H),4.70(br,1H),3.88–3.82 (m,2H),3.52–3.51(m,2H),2.47(br,1H),2.35–2.17(m,3H),1.86–1.68(m,13H),1.46–1.42(m,2H). 13 C NMR (125MHz, CDCl3) δ156.83,135.22(d, 4 J C,P =2.5Hz), 133.72(d, 3 J C,P =10Hz), 130.66(d, 2 J C,P =12.6Hz), 118.48(d, 1 J C,P =86.9Hz),108.47,107.49,70.36,40.46(d, 2 J C,P=18.9Hz),31.92,30.50,29.84,28.26,27.17,25.72,25.51,23.04,22.32,21.98,20.88(d, 1 J C,P =51.7Hz). 31 P NMR (160MHz, CDCl3) δ24.67ppm. C 34 H 41 NO6P[M] + ESI-HRMS: Calculated value 590.2666, measured value 590.2655.

[0473] Deferasirox (61): 1 H NMR (400MHz, DMSO-d6) δ8.07(d,J=7.6Hz,1H),8.01(d,J=8.3Hz,2H),7.58–7.54(m,3H),7.41–7.34(m,2H),7.04–6.96(m,3H),6.89(d,J=8.2Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ166.49,160.01,156.45,155.21,152.10,141.31,132.63,131.53, 131.13,130.58,130.39,126.86,123.37,119.76,119.56,117.12,116.20,114.48,113.71.

[0474] N1,N1-Dibenzyl-N3-(But-3-yn-1-yl)propane-1,3-diamine (alk-72): 1 H NMR (500MHz, CDCl3) δ7.36–7.29(m,8H),7.25–7.22(m,2H),3.54(s,4H),2.69(t,J=6.8Hz,2H),2.62(t,J =6.8Hz,2H),2.47(t,J=6.7Hz,2H),2.33(td,J=6.8,2.6Hz,2H),1.96(t,J=2.6Hz,1H),1.74–1.70(m,2H). 13 C NMR (125MHz, CDCl3) δ139.80,129.06,128.37,127.05,79.30,69.56,58.60,51.54,48.18,47.80,29.85,27.12,19.61. C 21 H 27N2[M+H] + ESI-HRMS: Calculated value 307.2096, measured value 307.2164.

[0475] N,N-dibenzyl-3-(but-3-yn-1-yl(((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)-N-methylpropan-1-ammonium iodide(N,N-dibenzyl-3-(but-3-yn-1-yl(((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)-N-methylpropan-1-ammonium iodide)(alk-R-48): 1 H NMR (500MHz, CDCl3, 320K) δ7.63 (d, J = 5Hz, 4H), 7.51–7.47 (m, 6H), 4.97 (brs, 4H), 4.82 (br, 1H), 3.47–3. 42(m,6H),3.09(s,3H),2.45(br,2H),2.33(br,2H),2.03–1.54(m,17H),1.12–1.08(m,1H),0.88(s,9H). 13 C NMR (125MHz, CDCl3, 320K) δ156.05,133.44,131.18,129.65,127.01,108.73,107.22,87.07,71.73(dr),70.78(dr), 65.41,57.88,47.69,47.10(dr),46.85(dr),45.69,32.49,32.08,30.32,29.85,29.49,27.74,26.94,23.13,22.82. C 39 H 55 N2O6[M] + ESI-HRMS: Calculated value 647.4055, measured value 647.4025.

[0476] (3-(But-3-yn-1-ylamino)propyl)triphenylphosphine bromide (alk-68): 1H NMR (500MHz, CDCl3, 320K) δ7.63 (d, J = 5Hz, 4H), 7.51–7.47 (m, 6H), 4.97 (brs, 4H), 4.82 (br, 1H), 3.47–3. 42(m,6H),3.09(s,3H),2.45(br,2H),2.33(br,2H),2.03–1.54(m,17H),1.12–1.08(m,1H),0.88(s,9H). 13 CNMR (125MHz, CDCl3, 320K) δ156.05,133.44,131.18,129.65,127.01,108.73,107.22,87.07,71.73(dr),70.78(dr) ,65.41,57.88,47.69,47.10(dr),46.85(dr),45.69,32.49,32.08,30.32,29.85,29.49,27.74,26.94,23.13,22.82. C 39 H 55 N2O6[M] + ESI-HRMS: Calculated value 647.4055, measured value 647.4025.

[0477] (3-(but-3-yn-1-yl(((12-(tert-butyl)-7,8,15,16-tetraoxabispiro[5.2.59.26]hexadecane-3-yl)oxy)carbonyl)amino)propyl)triphenylphosphonium bromide (alk-R-37b): 1 H NMR (500MHz, CDCl3, 320K) δ7.86–7.77(m,9H),7.70(br,6H),4.76(brs,1H),3.90(brs,2H),3.64(brs,2H) ,3.52(brs,2H),2.48–2.33(m,4H),2.16–2.03(m,3H),1.84–1.55(m,12H),1.12–1.10(m,1H),0.88(s,9H). 13 C NMR (126MHz, CDCl3, 320K) δ155.97,135.17,133.94(d, 3 J C,P =10.2Hz), 130.67(d, 2 J C,P =12.6Hz), 118.71(d, 1 J C,P=86.9Hz),108.63,107.34,81.99,71.08(dr),70.93(dr),70.06,48.35,47.68,32.50,32.09,29.85,27.74,26.94,23.13,22.83,20.54(d, 1 J C,P =51.7Hz). 31 P NMR (160MHz, CDCl3) δ24.74ppm. C 42 H 53 NO6P[M] + ESI-HRMS: Calculated value 698.3605, measured value 698.3584.

[0478] 2-Methyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)propane-1-ol (64): 1 H NMR (400MHz, CDCl3) δ3.90(s,4H),3.35(s,2H),1.77-1.66(m,5H),1.51-1.44(m,2H),1.34-1.29(m,3H),0.82(s,6H). 13 C NMR (101MHz, CDCl3) δ109.01,70.72,64.29,64.25,42.03,37.08,35.21,24.46,21.95. ESI-LRMS: m / z 215.25[M+H] + C 12 H 23 O3[M+H] + ESI-HRMS: Calculated value 214.1569, measured value 215.1641.

[0479] 4-(1-hydroxy-2-methylprop-2-yl)cyclohexane-1-one (65): 1 H NMR (400MHz, CDCl3) δ3.38 (s, 2H), 2.38–2.24 (m, 5H), 2.03 (ddd, J = 13.2, 5.8, 3.0 Hz, 2H), 1.76 (tt, J=12.1, 3.0Hz, 1H), 1.44 (qd, J=12.8, 5.1Hz, 2H), 0.84 (s, 6H). 13 C NMR (100MHz, CDCl3) δ212.96,70.48,41.44,41.34,37.15,27.27,21.90.

[0480] 2-Methyl-2-(4-oxocyclohexyl)propylbut-3-yn-1-ylcarbamate (37): 1 HNMR (500MHz, CDCl3) δ5.16 (br, 1H), 3.82 (s, 2H), 3.27 (q, J = 5Hz, 2H), 2.36–2.31 (m, 4H), 2.24 (td, J = 14. 1,5.8Hz,2H),2.00–1.96(m,3H),1.65(tt,J=12.1,3.0Hz,1H),1.41(qd,J=12.9,4.0Hz,2H),0.85(s,6H). 13 C NMR (125MHz, CDCl3) δ212.15,156.67,81.59,71.87,70.18,42.43,41.36,39.80,36.31,27.32,22.36,20.03. C 15 H 24 NO3[M+H] + ESI-HRMS: Calculated value 265.1678, measured value 266.1747.

[0481] 2-(12-hydroxy-7,8,15,16-tetraoxabispiro[5.2.59.26]hexadecane-3-yl)-2-methylpropylbut-3-yn-1-ylcarbamate (alk-L-37): 1 H NMR(400MHz, CDCl3)δ5.03(s,1H),3.84(brs,3H),3.31–3.15(m,3H),2.61( br,1H),2.39(brs,2H),2.15–2.00(m,2H),1.77–1.24(m,15H),0.86(s,6H). 13 C NMR (100MHz, CDCl3) δ156.76,108.19,107.68,81.58,71.93,70.14,67.83(dr),67.57(d r),42.94,39.74,36.11,31.91,30.17,29.62,28.27,25.69,25.44,22.85,22.18,19.98. C 21 H 33 NNaO7[M+Na] + ESI-HRMS: Calculated value 434.2155, measured value 434.2139.

[0482] N,N-Dibenzyl-3-((((12-(1-(((but-3-yn-1-ylcarbamoyl)oxy)-2-methylpropyl-2-yl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecane-3-yl)oxy)carbonyl)amino)-N-methylpropyl-1-ammonium iodide (alk-L-48): 1 H NMR (400MHz, CDCl3) δ7.61 (d, J = 4Hz, 4H), 7.45–7.39 (m, 6H), 5.72–5.65 (m, 1H), 5.03–4.89 (m, 5H), 4.72 (br, 1H), 3.84 (s, 2H), 3.33-3.26(m,6H),3.10-3.04(m,5H),2.41-2.32(m,6H),2.03-1.88(m,4H),1.69-1.42(m,4H),1.30-1.23(m,6H),0.86(s,6H). 13 CNMR(100MHz,CDCl3)δ156.73,156.57,133.36,130.89,129.50,126.87,108 .26,107.45(dr),107.36(dr),81.56,71.89,70.55,70.25(dr),70.13(dr), 67.24,65.08,57.79,46.89,42.99(dr),42.90(dr),39.74,37.92,36.11,31 .92,29.78,29.59,28.02,27.02,26.51,25.36,24.31,22.81,22.18,19.99. C 40 H 56 N3O8[M] + ESI-HRMS: Calculated value 706.4062, measured value 706.4031.

[0483] (3-((((12-(1-((but-3-yn-1-ylcarbamoyl)oxy)-2-methylpropyl-2-yl)-7,8,15,16-tetraoxabispiro[5.2.59.26]hexadecane-3-yl)oxy)carbonyl)amino)propyl)triphenylphosphonium bromide (alk-L-37b): 1H NMR (500MHz, CDCl3) δ7.79–7.68(m,15H),6.83–6.78(m,1H),5.02(br,1H),4.70(br,1H),3.84–3.80(m,4H),3.49–3.48(m,2H ),3.33–3.32(m,2H),3.15(br,1H),2.47–2.23(m,4H),2.03–1.77(m,11H),1.54–1.43(m,3H),1.30–1.24(m,4H),0.86(s,6H). 13 C NMR (125MHz, CDCl3) δ156.78,135.21(d, 4 J C,P =2.5Hz), 133.67(d, 3 J C,P =10.1Hz), 130.65(d, 2 J C,P =12.6Hz), 118.41(d, 1 J C,P =85.7Hz),108.15,107.59(dr),107.51(dr),81.59,71.92,70.33(dr),70.12(dr),43.00(dr),42.89(dr),40.46(d, 2 J C,P =17.6Hz),39.75,36.13,32.03,29.80,28.17,27.08,26.55,25.67,22.99,22.79,22.20,20.74(d, 1 J C,P =51.7Hz), 20.00. 31 P NMR (160MHz, CDCl3) δ24.70ppm. C 43 H 54 N₂O₈P[M] + ESI-HRMS: Calculated value 757.3580, measured value 757.3580.

[0484] (E)-2-(1-(pyridin-2-yl)ethylidene)hydrazine-1-carbodithioate (Methyl(E)-2-(1-(pyridin-2-yl)ethylidene)hydrazine-1-carbodithioate)(74): E-isomer: 1¹H NMR (400MHz, CDCl₃) δ 10.06 (s, 0.59H), 8.59 (d, J = 4.4Hz, 0.59H), 8.18 (d, J = 8.0Hz, 0.59H), 7.72 (t, J = 7.7Hz, 0.59H), 7.32–7.28 (m, 0.59H), 2.67 (s, 1.8H), 2.45 (s, 1.8H). Z-isomer: 1 H NMR (400MHz, CDCl3) δ8.74 (d, J=4.5Hz, 0.41H), 7.90 (t, J=7.9Hz, 0.41H), 7.5 9(d,J=8.1Hz,0.41H),7.40–7.38(m,0.41H),2.64(s,0.82H),2.44(s,0.82H). 13 C NMR(100MHz, CDCl3)δ201.80,201.19,154.35,152.52,149.99,148.81(E),148.05(Z),140.57,137.89(Z ),136.47(E),124.48(Z),124.41(E),124.12(Z),120.98(E),22.22(Z),17.93(E),17.34(Z),11.26(E).

[0485] N-(3-aminopropyl)-2-(1-(pyridin-2-yl)ethylidene)hydrazine-1-thiocarboxamide (75): E-isomer: 1 HNMR (400MHz, CD3OD) δ 8.57 (d, J = 4Hz, 0.69H), 8.18 (d, J = 8.1Hz, 0.69H), 7.83 (td, J = 7.9, 1.7Hz, 0.69H), 7.39 (dd, J = 7.4, 4.9Hz, 0.69H), 3.80 (t, J = 6.7Hz, 1.38H), 3.39 (t, J = 4H, 0.69H), 2.72 (t, J = 6.7Hz, 1.38H), 2.39 (s, 2.1H), 1.84 (p, J = 6.8Hz, 1.38H). Z-isomer: 1 ¹H NMR (400 MHz, CD₃OD) δ 8.45 (d, J = 4.2 Hz, 0.19 H), 8.07 (d, J = 8.2 Hz, 0.18 H), 7.76–7.72 (m, 0.19 H), 7.25 (dd, J = 6.8, 5.5 Hz, 0.19 H), 2.31 (s, 0.56 H), 2.00–1.92 (m, 0.38 H). Thiol form: 1H NMR (400MHz, CD3OD) δ8.74 (d, J=4.0Hz, 0.12H), 8.00 (td, J=7.9, 1.7Hz, 0.12H) ,7.49–7.46(m,0.12H),7.48(dd,J=7.6,4.9Hz,0.12H),2.00–1.92(m,0.24H). 13 CNMR(100MHz, CDCl3)δ178.35,154.55,148.93,148.09,136.54,124.22,120.89,41.27,29.48,11.37. LRMS(EI,20eV)m / z 251(M + ,5.37),121(100);C 11 H 17 HRMS(EI) of N5S: calculated value 251.1205, measured value 251.1209.

[0486] N-(3-(((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1”-cyclohexane]-4”-yl)amino)propyl)-2-(1-(pyridin-2-yl)ethylidene)hydrazine-1-thiocarboxamide (77): 1 HNMR (500MHz, DMSO-d6) δ10.33(s,1H),8.81(t,J=5.8Hz,1H),8.56(d,J=4.7Hz,1H),8.36(t,J=7.8Hz,1H),8.22(s,1H),7.82(t,J=7.7Hz, 1H),7.40–7.37(m,1H),3.37(t,J=5.8Hz,2H),3.08–2.88(m,4H),2.38–2.33(m,3H),1.98–1.88(m,5H),1.79–1.60(m,15H),1.47(br,2H). 13 CNMR(150MHz,CD3OD)δ180.24,156.01,149.81,149.48,138.33,138.28,125.40,122.82,111.67,107.51,56. 94,43.75,41.84,39.61,39.56,37.89,35.62,34.08,34.06,31.42,30.34,27.95,26.40,25.70,22.25,20.92. C 27 H 40 N5O4S[M+H] +The calculated value of ESI-HRMS is 530.2723, and the measured value is 530.2775.

[0487] result

[0488] These exemplary compounds demonstrate that the cytotoxicity of 1,2,4,5-tetraoxanes can be modulated by altering the targeting group. 1,2,4,5-tetraoxanes with urethane linkages exhibit better activity than amides. Furthermore, compounds with targeting groups show better anticancer activity and selectivity. If the targeting group contains a phosphonium or quaternary ammonium moiety, the cytotoxicity and selectivity of the present invention will be significantly enhanced. The biological characteristics of the exemplary compounds are as follows: Figure 1 As shown.

[0489] Typically, the formula "cyclic ring + 1,2,4,5-tetraoxane + targeting group" indicates that the ring provides lipophilicity for cell permeability, while the targeting group provides water solubility. For example, the tert-butylcyclohexyl ring has been identified as a component that maintains the killing effect on cancer cells, while phosphonium or quaternary ammonium groups are elements in the targeting group that provide cytotoxicity and selectivity.

[0490] Example 2. The compound exhibits anticancer activity.

[0491] Materials and methods

[0492] The anticancer activity of the exemplary compounds listed in Example 1 against human cervical HeLa cells, breast cancer MDA-MB-231 cells, human hepatocytes HepG2 cells, human colorectal HCT116 cells, mammary duct T47D cells, non-cancerous NIH3T3 cells, canine kidney MDCK cells, and mouse brain bEnd.3 cells was tested.

[0493] result

[0494] The viability test results of the compounds are summarized in Tables 1 to 12a. Overall, the tetraoxane compounds exhibited broad-spectrum anticancer activity against colon HCT116, breast MDA-MB-231 and MCF-7, ovarian HEYA8, leukemia HL-60, liver Huh7 and PLC, and bone U2OS cancer cells. Erastin, RSL3, and artesunate are known compounds. However, their performance in breast cancer MDA-MB-231 cells and non-cancerous NIH3T3 cells has not been previously reported. Table 12b summarizes some compounds that induced good selectivity between cancer and non-cancerous cell lines. Furthermore, this is the first report showing that 1,2,4,5-tetraoxane derivatives selectively eradicate cancer cells via the ferroptosis pathway. Table 13 summarizes the IC50 values ​​of compounds 37b and 48 compared to known drugs (i.e., OZ277, OZ439, and RKA 182). 50Value and selectivity. OZ422 and OZ439 (Vennerstrom et al.) belong to the 1,2,4-trioxopentane class, but they showed poor activity against MDA-MB-231, HCT116, and HL-60 cells (general IC50 values ​​and selectivity). 50 Value > 10 μM).

[0495] Tetraoxanes 37b, 48, 37f, 53, 56, and alk-R-48 generally target the IC50 of triple-negative breast cancer MDA-MB-231 cells. 50 Values ​​<4 μM. Their cytotoxicity against MDA-MB-231 cells is at least 10 times that of non-cancerous NIH3T3 and MDCK cells. For example, compound 48 is effective against breast cancer MDA-MB-231 cells (IC50, 100 μM). 50 =2.4±0.7μM), colonic HCT116 cells (IC) 50 =2.2±0.3μM) and HL-60 leukemia cells (IC50, 2.2±0.3μM) 50 The cytotoxicity of the 1.2 ± 0.9 μM (IC50) in non-cancerous NIH3T3 cells was 1.2 ± 0.9 μM. 50 =29.0±5.7μM) 12, 13, and 24 times that of cancer cells. Conversely, ellastatin and RSL3 showed higher cytotoxicity to non-cancer cells than to cancer cells, indicating a lack of selectivity.

[0496] Compounds reported in the literature, such as OZ422, OZ439, and FINO2, showed poor activity against MDA-MB-231 cells (IC50). 50 Values ​​are typically >10 μM). Compound 48 (IC50 for MDA-MB-231) 50 : 2.4±0.7μM) and 37b (IC for MDA-MB-231) 50 The cytotoxicity of compound 37b against the same breast cancer cell line was 10-fold and 64-fold, respectively, compared to the literature example OZ439. Compound 37b showed 87-fold cytotoxicity against breast cancer MDA-MB-231 cells compared to OZ277. Compound 48 (IC50-0.4±0.05 μM) showed 10-fold and 64-fold cytotoxicity against the same breast cancer cell line, respectively. 50 : 2.2±0.3μM) and 37b (IC50 for HCT116) 50The cytotoxicity of compounds 48 and 37b against the same colon cancer cell line was 29-fold and 106-fold, respectively, compared to the literature example OZ439. Furthermore, compounds 48 and 37b showed cytotoxicity to colon cancer HCT116 cells that were 44-fold and 113-fold, respectively, compared to OZ277. Compound 48 showed at least 9-fold cytotoxicity against leukemia HL-60 cells compared to OZ439. FINO2 (Woerpel et al.) belongs to the 1,2-dioxolane class, but it performed poorly in TNBC MDA-MB-231 cells (IC50, 0.6 ± 0.3 μM). 50 >10 μM). Compounds 48 and 37b were at least 4-fold and 25-fold more potent than FINO2 in eradicating MDA-MB-231 cells, respectively. FINO2 has been reported to induce ferroptosis, iron oxidation, and indirectly target GPX4. The compounds disclosed herein can induce ferroptosis and iron oxidation without protein targets. Furthermore, the compounds disclosed herein can kill CSCs and IC50 cells. 50 <2μM.

[0497] RKA182 (a compound reported in the literature) is the second example of a 1,2,4,5-tetraoxane that exhibits poor activity (IC50) against HL-60 cells. 50 =11.6±0.4 μM). Compared with 1,2,4,5-tetraoxane RKA182, compound 48 was 9 times more potent in HL-60 leukemia cells. The optimal selectivity index of RKA182 was 4 (PMBC: IC50). 50 =46.6±0.7μM compared to HL-60: IC 50 =11.6±0.4 μM). In comparison, compound 48 showed a selectivity up to 24-fold (NIH3T3: IC50). 50 =29.0±5.7μM compared to HL-60: IC 50 =1.2±0.9μM). Furthermore, RKA182 showed poor killing effects on cervical cancer HeLa cells, liver cancer HepG2 cells, and renal cancer HEK293 cells, with an overall IC50 of 1.2±0.9μM. 50 >12 μM. Conversely, the exemplary compound exhibited an overall IC50 of <3 μM in the aforementioned cancer cell lines. 50 In particular, for HepG2 cells, compound 37b showed 36 times the cytotoxicity of RKA182. Furthermore, RKA182 has been reported to induce apoptosis, rather than ferroptosis, in cancer. The O'Neill group has published reports on the use of second-generation RKA182 for the treatment of malaria, but no reports have been made regarding its anticancer activity. Tetraoxane E209 is another example targeting malaria; however, no anticancer activity has been reported.

[0498] Table 1. IC50 of tetraoxane against MDA-MB-231 cells 50 Value (μM)

[0499] compound <![CDATA[IC 50 (μM)]]> StdDev 6b 2.6 1.0 30a 14.4 1.1 37 7.4 0.5 37a 2.0 1.3 37b 0.38 0.049 30b 0.53 0.037 37f 2.9 0.8 37g 11.0 0.9 37i 24.3 3.3 37j 23.9 5.5 37d 31.7 7.0 37e 1.7 0.5 48 2.4 0.7 49 31.5 1.3 54 14.7 3.2 53 3.7 0.4 56 0.97 0.1 50 19.2 5.0 51 26.1 1.0 57 2.9 0.09 59a 10.4 0.8 59b 1.9 0.8 alk-R-37b 2.3 0.3 alk-R-48 0.8 0.2 alk-L-37b 2.1 0.3 alk-L-48 8.8 2.1 59 >50 Nil alk-L-37 24.5 1.4 Elastin 1.3 0.2 RSL3 0.041 0.015 Artesunate 20.3 3.5

[0500] a After incubation with the compound shown for 48 hours, IC 50 Values ​​were calculated based on the concentration-response curve measured by the MTT assay. Data represent the mean ± SD, n = 3.

[0501] Table 2. IC50 of tetraoxane against HeLa cells 50 Value (μM)

[0502]

[0503]

[0504] a After incubation with the indicated compound for 48 hours, IC 50 Values ​​were calculated based on the concentration-response curve measured by the MTT assay. Data represent the mean ± SD, n = 3.

[0505] Table 3. IC50 of tetraoxane against T47D cells 50 Value (μM)

[0506] compound <![CDATA[IC 50 (μM)]]> StdDev 6b 4.4 1.9 30a ND ND 37 6.1 0.9 37a 2.2 0.3 37b 0.62 0.11 30b ND ND 37f 1.3 0.6 37g 3.1 0.7 37i 13.2 2.8 37j 10.6 1.3 37d 10.4 4.1 37e 1.2 0.5 48 1.7 0.3

[0507] a After incubation with the indicated compound for 48 hours, IC 50 Values ​​were calculated based on concentration-response curves measured using the MTT assay. Data represent mean ± SD, n = 3. ND = Undetermined.

[0508] Table 4. IC50 of tetraoxane against HEK293 cells 50 Value (μM)

[0509] compound <![CDATA[IC 50 (μM)]]> StdDev 6b 1.6 0.8 30a 2.5 0.6 37 5.8 0.1 37a 0.8 0.2 37b 1.6 0.6 30b 1.0 0.2

[0510] a After incubation with the compound shown for 48 hours, IC 50 Values ​​were calculated based on the concentration-response curve measured by the MTT assay. Data represent the mean ± SD, n = 3.

[0511] Table 5. IC50 of tetraoxane against HepG2 cells 50 Value (μM)

[0512] compound <![CDATA[IC 50 (μM)]]> StdDev 37 4.8 0.5 37a 2.0 0.1 37b 0.7 0.5 30b 1.2 0.7

[0513] a After incubation with the compound shown for 48 hours, IC 50 Values ​​were calculated based on the concentration-response curve measured by the MTT assay. Data represent the mean ± SD, n = 3.

[0514] Table 6. IC50 of tetraoxane against Jurkat cells 50 Value (μM)

[0515] compound <![CDATA[IC 50 (μM)]]> StdDev 48 1.0 0.4

[0516] a After incubation with the compound shown for 48 hours, IC 50 Values ​​were calculated based on the concentration-response curve measured by the MTT assay. Data represent the mean ± SD, n = 3.

[0517] Table 7. IC50 of tetraoxane against NIH3T3 cells 50 Value (μM)

[0518] compound <![CDATA[IC 50 (μM)]]> StdDev 37 7.1 2.2 37a 1.7 0.7 37b 4.6 1.9 30b 5.8 0.5 37f 11.6 2.4 37g 26.6 2.6 37i >100 ND 37j >100 ND 37d 30.3 1.5 37e 1.9 0.9 48 29.0 5.7 49 >50 ND 54 >50 ND 53 33.7 3.4 56 11.1 0.6 50 44.9 7.3 51 >25 ND 57 9.8 1.4 alk-R-37b 9.7 3 alk-R-48 10.8 3.7 alk-L-37b 12.9 1.4 alk-L-48 18.2 3.8 Elastin 0.29 0.020 RSL3 0.028 0.0086 Artesunate 17.4 7.2

[0519] a After incubation with the compound shown for 48 hours, IC 50 Values ​​were calculated based on concentration-response curves measured using the MTT assay. Data represent mean ± SD, n = 3. ND = Undetermined.

[0520] Table 8. IC50 of tetraoxane against HCT116 cells 50 Value (μM)

[0521] compound <![CDATA[IC 50 (μM)]]> StdDev 37 14.4 5.6 37a 4.6 0.9 37b 0.6 0.3 30b 1.4 0.9 48 2.2 0.3 49 >50 ND 54 26.2 12.0 53 6.7 1.4 56 2.7 0.3 50 >25 ND 51 >50 ND

[0522] a After incubation with the compound shown for 48 hours, IC 50 Values ​​were calculated based on concentration-response curves measured using the MTT assay. Data represent mean ± SD, n = 3. ND = Undetermined.

[0523] Table 9. IC50 of tetraoxane against MDCK cells 50 Value (μM)

[0524] compound <![CDATA[IC 50 (μM)]]> StdDev 6b 18.1 1.7 30a 42.8 2.9 37 >50 ND 37a 23.7 4.5 37b 9.5 2.2 30b 5.8 0.5 37f 12.4 0.9 37g 22.3 2.1 37i >50 ND 37j >100 ND 37d >100 ND 37e 19.3 4.7 48 28.2 3.8

[0525] a After incubation with the compound shown for 48 hours, IC 50 Values ​​were calculated based on concentration-response curves measured using the MTT assay. Data represent mean ± SD, n = 3. ND = Undetermined.

[0526] Table 10. IC50 of tetraoxane against HL-60 cells 50 Value (μM)

[0527] compound <![CDATA[IC 50 (μM)]]> StdDev 48 1.2 0.9

[0528] a After incubation with the compound shown for 48 hours, IC 50Values ​​were calculated based on the concentration-response curve measured by the MTT assay. Data represent the mean ± SD, n = 3.

[0529] Table 11. IC50 of tetraoxane against bEnd.3 cells 50 Value (μM)

[0530] compound <![CDATA[IC 50 (μM)]]> StdDev 6b 12.3 1.4 37 >100 ND 37a 10.9 0.8 37b 5.2 0.3

[0531] a After incubation with the compound shown for 48 hours, IC 50 Values ​​were calculated based on concentration-response curves measured using the MTT assay. Data represent mean ± SD, n = 3. ND = Undetermined.

[0532] Table 12a. IC50 of tetraoxane against different cell lines 50 Value (μM)

[0533]

[0534] Table 12b. IC50 of various compounds against different cell lines 50 Value and selectivity

[0535]

[0536] a ND indicates undetermined. The value in parentheses refers to the selectivity index (IC50 of NIH 3T3). 50 Divided by IC50 for cancer cells 50 ). ND = Undetermined.

[0537] Table 13. IC50 of compounds 37b and 48 compared to OZ277, OZ439, and RKA182 for different cell lines. 50 Value and selectivity

[0538]

[0539] #Experimental Data

[0540] *Reported data for known compounds

[0541] After incubation with the compound shown for 48 hours, IC 50 Values ​​were calculated (μmol / L) based on concentration-response curves obtained from the MTT assay. Data represent mean ± SD, n = 3. ND = Undetermined. Values ​​in parentheses refer to the selectivity index (IC50 of NIH 3T3). 50 Divided by IC50 for cancer cells 50 ).

[0542] Example 3. Compounds exhibit anti-cancer stem cell activity

[0543] Materials and methods

[0544] The cytotoxicity of 1,2,4,5-tetraoxane 48 and 37b to HEY A8 CSC and mouse xenograft ovarian tumor cancer stem cell (CSC) models was examined. Figure 2 Using HEY A8 CSC cells (10) 6 Nude mice were subcutaneously injected and randomly assigned to one of six treatment groups (n=4): (i) DMSO; (ii) paclitaxel (PTX), 5 mg / kg; (iii) compound 37b, 5 mg / kg; (iv) compound 37b, 10 mg / kg; (v) compound 48, 5 mg / kg; and (vi) compound 48, 10 mg / kg. All animals were sacrificed and photographed when tumor ulceration began in the control animals (DMSO) at day 25. Paclitaxel was used as a negative control because ovarian CSCs are known to be resistant to paclitaxel.

[0545] result

[0546] Compounds 48 and 37b showed IC50 values ​​against adherent cancer cells HEY A8. 50 The values ​​were 2.3 ± 0.7 μM and 1.4 ± 0.07 μM, respectively (Table 14). Unlike paclitaxel, both peroxide compounds eradicated almost all CSC spheroids (i.e., more than 90%) at a concentration of 5 μM. Figure 3A and 3B Notably, neither 5 μM ellastatin nor 50 μM artesunate showed any cytotoxic effects on HEYA8 CSCs. This is the first report demonstrating that 1,2,4,5-tetraoxane derivatives can terminate cancer stem cell activity at the micromolar level (e.g., tetraoxane 48: IC50 against HEYA8 CSCs). 50 =1.2±0.5μM). 1,2,4,5-Tetraoxane derivatives simultaneously remove cancer and CSCs through the same small molecule.

[0547] Table 14. IC50 of compounds 48 and 37 against HeyA8 cells 50 Value (μM)

[0548]

[0549] a After incubation with the compound shown for 48 hours, IC 50 Value based on CellTiter- Calculation of concentration-response curve (μmol / L). Data represent mean ± SD, n = 3.

[0550] Pretreatment of adherent HEY A8 cells with the iron chelator DFO or ferrostatin-1 (Fer-1) reversed compound 48-induced cell death, rather than paclitaxel (Taxol). Figure 4 The lipophilic iron chelator deferasirox (DFX) was able to rescue some of the cell death in HEYA8 CSCs treated with compound 48, while most CSCs remained unaffected by co-treatment with compound 48 and Fer-1. Figure 5A and 5B This indicates that compound 48 exerts its cytotoxicity in cancer and CSCs through ferroptosis. Compound 37b also induced ferroptosis rather than apoptosis in HEYA8 CSCs. In contrast, known drugs such as cholic acids, deoxycholic acids, and steroid derivatives of 1,2,4,5-tetraoxane have been reported to exhibit anticancer activity. The cholic acid group carries some protected polar groups, which helps to improve the bioavailability of the compound. However, as shown in the figure, the cholic acid derivatives of tetraoxane induce apoptosis in cancer cells. Instead, the compounds disclosed herein generate hydroxyl radicals and lipid peroxides and induce ferroptosis in cancer cells. Structurally, the compounds disclosed herein differ from the cholic acids, deoxycholic acids, and steroid derivatives of 1,2,4,5-tetraoxane because the compounds here contain charged targeting groups, such as water-soluble phosphorus or quaternary ammonium moieties, and do not contain two or three protected polar groups.

[0551] Ellastin and RSL3 are selective drugs for tumor cells with carcinogenic RAS. However, their killing efficacy against CSCs has not been fully studied. Although both Ellastin and RSL3 can eradicate most adherent HEYA8 cells at 5 μM, high concentrations of artesunate are required to achieve near 50% cell death. Figure 6 Conversely, HEYA8 CSCs were almost insensitive to single doses of both ellastatin and artesunate, except for RSL3. Figure 6 GPX4 inhibition appears to effectively suppress CSC growth. However, considering the toxicity of RSL3 to NIH3T3 cells (IC50), the effect is less pronounced. 50 =28.3±8.6 nM), due to the loss of selectivity, using RSL3 as an anti-CSC agent offers no advantage. The compounds described herein not only have IC50 concentrations... 50 <3μM eradicates HEYA8 cancer cells, and also with IC50 50 <2 μM eradicates CSCs. In particular, compound 48 exhibits at least 24 times the cytotoxicity against HEYA8 CSCs compared to non-cancerous cells. The disclosed compounds demonstrate superior killing efficacy and selectivity against CSCs compared to alastin, RSL3, paclitaxel (Taxol), and artesunate.

[0552] The antitumor activity of the compound was then evaluated using xenografted ovarian tumors in mice. Compared with the vehicle control, treatment with compound 37b alone (5 mg / kg and 10 mg / kg) effectively inhibited tumor growth. Figure 7A and 7B Compound 48 (10 mg / kg) reduced tumor size. Generally, both compound 37b and 48 regimens were well tolerated in the test animals. No abnormal behavior or weight loss was observed throughout the experiment. Figure 7C In vivo experiments successfully demonstrated the use of tetraoxane compounds as anticancer agents and ensured their safety.

[0553] The antitumor activity of the compound was also evaluated using xenografted mammary tumors in mice. Compared with the vector control, treatment with compound 37b alone (10 mg / kg) effectively inhibited tumor growth. Figure 12A and 12B Compound 48 (5 mg / kg and 10 mg / kg) reduced tumor size. No abnormal behavior or weight loss was observed throughout treatment with compounds 48 and 37c. Figure 12C Compared with the control group, histopathological examination of the liver, heart, kidney, spleen, and lungs of the treated animals showed no histological changes. Figure 12D ).

[0554] Example 4. Targeted delivery of 1,2,4,5-tetraoxane to eradicate cancer cells via ferroptosis

[0555] Materials and methods

[0556] Fer-1 was used to investigate the cell death pathway induced by the compounds described in this paper. Liproxstatin-1 was used to further confirm whether 48 and 37b induced ferroptosis in MDA-MB-231 cells.

[0557] result

[0558] Viability results showed that Fer-1 disrupted cell death in MDA-MB-231 cells treated with various tetraoxanes, including 48 and 37b. Figure 8A and 8C Liproxstatin-1 was used to further confirm whether 48 and 37b induced ferroptosis in MDA-MB-231 cells. Figure 9 As shown, pretreatment of cells with this inhibitor prevents cell death induced by two tetraoxanes.

[0559] Reactive oxygen species (ROS) are associated with ferroptosis and other cell death events. Oxidative stress induced by 48 and 37b can be indicated by the fluorescent probe HKOH-1r, which emits at 520 nm after oxidation by cytoplasmic hydroxyl radicals. By using HKOH-1r, the type of ROS produced by tetraoxane in MDA-MB-231 cells can be specified.

[0560] Confocal images of MDA-MB-231 cells after tetraoxane treatment were captured, and the relative mean fluorescence intensity of cells with HKOH-1r was quantified. Figure 10 The results showed that a large number of hydroxyl radicals were observed approximately 5.5 hours after the addition of 48 and 37b, followed by significant cell death. This phenomenon is consistent with one of the characteristics of ferroptosis.

[0561] Since lipid peroxidation is evidence of ferroptosis, the C11-BODIPY probe was used to verify lipid ROS generated by tetraoxane. It is a ratiometric membrane-targeted probe that modulates the emission wavelength from 590 nm to 510 nm when detecting lipid ROS. Here, MDA-MB-231 cells were treated with 48, 37b, and RSL3, respectively. Lipid ROS levels were quantified by flow cytometry. The untreated group emitted a weak signal in the FL1 channel. Figure 11 This indicates that most of the C11-BODIPY conjugation system was intact and did not react with lipid ROS. Enhanced fluorescence of FL1 was observed in the RSL3-treated group. Similar to RSL3, lipid ROS were generated in cells treated with 48 or 37b.

[0562] Some cancer cells can evade the cytotoxicity of anticancer drugs by upregulating certain anti-apoptotic proteins, thereby developing resistance to apoptotic cell death. Conversely, ferroptosis is an iron-dependent and reactive oxygen species (ROS)-dependent cell death pathway. Cancer cells are known to have elevated iron levels, which favors ferroptosis to induce harmful lipid peroxidation and irreversible cell death, bypassing anti-apoptotic pathways, and is therefore advantageous. The data shown above have demonstrated that the tetraoxane compounds described herein eradicate cancer cells and CSCs through ferroptosis.

[0563] The tetraoxane compounds described in this article generate reactive oxygen species (ROS) within cancer cells for therapeutic purposes. Unlike photodynamic therapy, these tetraoxane compounds do not rely on any external irradiation to generate ROS, thus eliminating the problems associated with shallow laser penetration. Furthermore, the effectiveness of the treatment is not affected by intracellular pH. For example, tetraoxane compounds generate hydroxyl radicals and lipid peroxides in breast cancer MDA-MB-231. This is advantageous because chemokinetic therapy (CDT) is known to rely heavily on the acidity of the tumor microenvironment and high levels of intracellular hydrogen peroxide to generate hydroxyl radicals as strong oxidants. CDT is sometimes ineffective if the tumor site is highly vascularized and the pH is neutral. The intracellular H2O2 concentration in cancer cells is insufficient to generate lethal levels of hydroxyl radicals for therapeutic purposes.

[0564] Furthermore, the tetraoxane compounds described herein are small molecules that can be used for ferroptosis therapy, which eliminates the need for complex nanoparticle formulations that encapsulate multiple components used to generate oxidative stress to ablate cancer cells (such as enzymes that catalyze the production of hydrogen peroxide and iron oxide).

[0565] Industrial applicability

[0566] This invention provides an anticancer compound that can be used to treat cancer, alleviate cancer symptoms, or treat or improve one or more cancer-related symptoms. Therefore, it can be formulated into a corresponding pharmaceutical product with industrial applicability.

Claims

1. A compound having the structure ###0001### (a) wherein a is 1 ; (b) wherein a' is 1 ; (c) wherein Z' is hydrogen; (d) wherein X' is O; (e) wherein R5 is hydrogen or alkynyl having 2 to 24 carbon atoms, R8 is substituted or unsubstituted alkyl having 10 or fewer carbon atoms, or R5 and R8 together with the nitrogen to which they are attached form a substituted or unsubstituted heterocycloalkyl having 3-10 ring atoms; (f) wherein the substituents of the alkyl are amino, phosphonium, or glycosyl, the substituents of the heterocycloalkyl are alkyl having 10 or fewer carbon atoms.

3. The compound of claim 1, wherein (e) R5 and R8 together with the nitrogen to which they are attached form a substituted or unsubstituted piperazinyl.

6. A compound having the structure ###0002### 7. A compound having the structure ###0003### (a) wherein A' and A" are independently substituted or unsubstituted cyclohexyl; (b) wherein a and a" are 1 ; (c) wherein Z' and Z" are hydrogen; (d) wherein X' and X" are O; (e) wherein W' and W" are C; (f) wherein Y' and Y" are independently NR8 or O; (g) wherein R8 is hydrogen; (h) wherein L' is disulfide or polyether; and (i) wherein the substituents are independently alkyl having 10 or fewer carbon atoms.

8. The compound of claim 7 having the structure ###0004### 9. A pharmaceutical composition comprising a compound of any one of claims 1-8; and a pharmaceutically acceptable excipient, wherein the compound is in an effective amount to treat, reduce, or treat or ameliorate one or more symptoms associated with cancer in a subject. (f) wherein R 10 is wherein G' is and p is 0; wherein R 11 is hydrogen or and R 12 and R 13 are independently hydrogen or alkynyl having 2 to 24 carbon atoms, and e is 0 or 1 ; d is 0; and 10. The pharmaceutical composition of claim 9, further comprising a second active agent, optionally more than one second active agent.

2. The compound according to claim 1, wherein the (g) substituent is independently an amino group represented by, a phosphonium represented by, or a glucosyl group, wherein E is absent, R x , R xi , R xii , R vi , R vii and R viii each independently represent an alkyl group having 10 or less carbon atoms, a benzyl group, or an aryl group having a 5- to 10-membered ring.

11. The pharmaceutical composition of claim 10, wherein the second active agent is an anti-cancer agent.

4. The compound of claim 1, wherein R 12 is hydrogen and R 13 is alkynyl having 2 to 24 carbon atoms.

5. The compound of any one of claims 1-4, wherein R5 is hydrogen and R8 is wherein h and i are independently integers from 0 to 3; wherein R 15 - R 20 is independently alkyl having 10 or fewer carbon atoms, aryl having 5 to 10 membered rings, or benzyl.

12. Use of a compound of any one of claims 1-8 in the manufacture of a medicament for treating, reducing, or treating or ameliorating one or more symptoms associated with cancer.

13. The use of claim 12, wherein the medicament is prepared in a dosage form suitable for administration by oral administration, parenteral administration, inhalation, mucosal administration, topical administration, or a combination thereof.

14. The use of claim 12 or 13, wherein the cancer is colon cancer, breast cancer, ovarian cancer, cervical cancer, lung cancer, rectal cancer, kidney cancer, liver cancer, brain cancer or leukemia, or a combination thereof. ​ ​ ​ ​ ​ (g) wherein R 22 and R' 22 are independently and j is an integer from 0 to 3; ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​

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