Phospholipid ether conjugates as drug carriers targeting cancer.

Description

1 / 92 Phospholipid ether conjugates as vehicles for Drugs targeted at cancer Divided from patent application BR 11 2022 004482 8, filed on September 11, 2020. CROSS-REFERENCE TO RELATED REQUESTS

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 899,611, filed September 12, 2019, U.S. Provisional Patent Application No. 62 / 899,615, filed September 12, 2019, U.S. Provisional Patent Application No. 62 / 899,618, filed September 12, 2019, U.S. Provisional Patent Application No. 62 / 946,870, filed December 11, 2019, U.S. Provisional Patent Application No. 62 / 956,844, filed January 3, 2020, and U.S. Provisional Patent Application No. 62 / 956,907, filed January 3, 2020, the contents of which are incorporated herein by Reference in its entirety. FIELD OF THE INVENTION

[0002] This disclosure relates to therapeutic compounds capable of targeting a wide range of tumor cells. This disclosure is further directed to compositions comprising the therapeutic compounds, methods of manufacturing the therapeutic compounds and methods of cancer treatment comprising the administration of the therapeutic compounds. INTRODUCTION

[0003] In 2018, 18 million people were diagnosed with cancer worldwide and 9.6 million died from cancer. In the United States, about 40% of all people will be diagnosed with cancer during their lifetime. Petition 870260042444, dated 06 / 05 / 2026, page 11 / 143 2 / 92 As of 2018, lung cancer (2.09 million cases), breast cancer (2.09 million cases), colorectal cancer (1.80 million cases), prostate cancer (1.28 million cases), skin cancer (non-melanoma) (1.04 million cases), and stomach cancer (1.03 million cases) are the most common types of cancer. Despite many treatments available, cancer remains the second leading cause of death worldwide.

[0004] Cancer is the result of unlimited cell division. Healthy cells have checkpoints that prevent unlimited cell division. Some examples of these checkpoints are nutrient availability, DNA damage, and contact inhibition (i.e., one cell comes into contact with another cell). In addition, most cells can only replicate a finite number of times and are therefore programmed to die after a certain number of cell divisions.

[0005] Cancer is the result of a cell overcoming these built-in checkpoints and proliferating out of control. This uncontrolled proliferation leads to the formation of a tumor. There are two types of tumors, benign and malignant. Benign tumors are unable to cross the natural boundaries between tissue types. Malignant tumors, on the other hand, are able to invade nearby tissues or enter the bloodstream and metastasize to a different location. Only malignant tumors are considered cancerous. It is this ability to infiltrate and metastasize that makes cancer such a deadly disease. Furthermore, lipid metabolism can play a profound role in cancer metastasis. Petition 870260042444, dated 06 / 05 / 2026, page 12 / 143 3 / 92 Cancer cells often exhibit fundamentally altered cellular metabolism. However, the role of lipid metabolism in the development of malignant cancers remains unclear.

[0006] To further complicate the fight against cancer, malignant tumors present distinct cell types. One particularly problematic type is cancer stem cells (CSCs). CSCs are capable of self-renewal and differentiation into the different types of cancer cells found in a malignant tumor. Thus, CSCs are a primary factor in a tumor's metastatic capacity. CSCs often survive radiation and chemotherapy. It is assumed that cancer recurrence after radiation and chemotherapy is the result of the inability of radiation and chemotherapy to kill all CSCs combined with the ability of CSCs to establish a new tumor.

[0007] Chemotherapy is a term used to describe a particular type of cancer treatment that includes the use of cytotoxic anticancer drugs. Cytotoxic drugs used during chemotherapy can be divided into several main categories, including alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, and mitotic inhibitors. Cytotoxic anticancer drugs typically cause cell division to cease and thus affect both healthy and cancerous tissue. Alkylating agents interrupt the division of cancer cells by damaging the cancer cell's DNA. Some common alkylating agents used to treat cancer are nitrogen mustards (for Petition 870260042444, dated 06 / 05 / 2026, page 13 / 143 4 / 92 For example, cyclophosphamide (Cytoxan®; Cytoxan is a registered trademark of Baxter International), nitrosoureas, alkyl sulfonates, triazeins, and ethyleneimines. Platinum drugs, such as cisplatin and carboplatin, function similarly to alkylating agents. Antimetabolites stop the division of cancer cells by inhibiting DNA and RNA synthesis. Some common antimetabolites used to treat cancer are 6-mercaptopurine, gemcitabine (Gemzar®; Gemzar is a registered trademark of Eli Lilly and Company), methotrexate, and pemetrexed (Alimta®; Alimta is a registered trademark of Eli Lilly and Company). Topoisomerase inhibitors stop the division of cancer cells by inhibiting topoisomerase enzymes from separating DNA for replication. Some common topoisomerase inhibitors are topotecan, irinotecan, etoposide, and teniposide. Mitotic inhibitors interrupt cancerous cell division by inhibiting key cell division enzymes.Some common mitotic inhibitors are taxanes (e.g., paclitaxel (Taxol®; Taxol is a registered trademark of Bristol-Myers Squibb Company) and docetaxel (Taxotere®; Taxotere is a registered trademark of Aventis Pharma SA)), epothilones, and vinca alkaloids.

[0008] One drawback of all these anticancer drugs is the damage they cause to healthy tissue. Because the drugs treat cancer by inhibiting normal cell function, healthy tissue that also depends on constant cell division, such as blood cells, mucous surfaces, and skin, can also be severely damaged. This damage results in significant morbidity and Petition 870260042444, dated 06 / 05 / 2026, page 14 / 143 5 / 92 may limit the amount of chemotherapy that can be safely administered. Examples of side effects that occur during chemotherapy treatment include low blood count, hair loss, muscle and joint pain, nausea, vomiting, diarrhea, mouth sores, fever, and chills. To overcome this problem, new agents continue to be developed with unique mechanisms of action designed to provide greater targeting and that affect proteins and cellular functions that occur only in cancer cells. For example, antibody-drug conjugates (ADCs) have been designed to bind to specific epitopes on the surface of tumor cells and offer an alternative method to target tumor cells in an effort to reduce associated toxicities.Although highly selective, very few ADCs are therapeutically useful because they achieve only modest cellular uptake (<1% of the infused drug) and have limited cell-killing activity. Some cancer-specific drugs are imatinib (Gleevec®; Gleevec is a registered trademark of Novartis AG), gefitinib (Iressa®; Iressa is a registered trademark of AstraZeneca UK Limited), sunitinib (Sutent®; Sutent is a registered trademark of CP Pharmaceuticals, International CV), and bortezomib (Velcade®; Velcade is a registered trademark of Millennium Pharmaceuticals, Inc.). However, these drugs are not approved for the treatment of all types of cancer and are universally associated with the development of treatment resistance. Furthermore, many of these compounds still lack absolute tumor selectivity and remain limited in their application. Petition 870260042444, dated 06 / 05 / 2026, page 15 / 143 6 / 92 its therapeutic use due to off-target effects.

[0009] Recently, phospholipid ether (PLE) analogs have been shown to be an effective molecular platform for the delivery of anticancer drugs. See U.S. Patent No. 9,480,754 and Weichert et al. (Sei Transi Med, 2014, 6(240), 240ra75), each of which is incorporated herein by reference in its entirety. As can be seen, most anticancer drugs in clinical use have limited utility due to their toxicity to all proliferating cells and / or the inability to exert their effect on all tumor cells. Thus, a need remains in the art for alternative anticancer drug delivery vehicles that can deliver potent, effective, and broad-spectrum anticancer drugs to cancer cells, including CSCs, while avoiding substantial drug uptake by healthy cells. Furthermore, the vehicle for delivering anticancer drugs must be able to cross barriers, such as the blood-brain barrier (BBB). SUMMARY OF THE INVENTION

[00010] In one aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, where n is 2-20; Petition 870260042444, dated 06 / 05 / 2026, page 16 / 143 7 / 92 halogen. Q2 is a self-immolating link or spacer; and Z is an anticancer drug.

[00011] In another embodiment, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering an effective amount of a compound as described in this descriptive report, or a pharmaceutically acceptable salt thereof.

[00012] The disclosure provides other aspects and concretizations that will be apparent in light of the following detailed description and attached drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[00013] FIGS. 1A-1B show the uptake of phospholipid drug conjugates (PDCs) in cell lines Petition 870260042444, dated 06 / 05 / 2026, page 17 / 143 8 / 92 tumor cells. FIG. 1A shows the green fluorescence, which is indicative of phospholipid ether (PLE) plus a BODIPY. FIG. 1B shows the MFI to autofluorescence ratio for CLR1502 absorption.

[00014] FIGS. 2A-2B show the uptake of PDCs in tumor cell lines (cell lines A375 and A549). FIG. 2A shows the concentration of complete conjugated PLE in the cytoplasm. FIG. 2B shows the concentration of payload released in the cytoplasm.

[00015] FIG. 3 shows the uptake of CLR1502 and CLR1501 through lipid rafts in tumor cells and primary tumor samples, respectively. CLR1502 is the near-infrared molecule bound to PLE and is white. Blue is Hoechst's nuclear stain. Red is the B subunit of cholera toxin and indicative of lipid rafts.

[00016] FIG. 4 shows the in vitro efficacy of PDC-SM2 against melanoma cells (A375) and lung cancer cells (A549).

[00017] FIG. 5 shows cytotoxic PDCs that are tolerated in vivo. For the payload dose of 0.5 mg / kg, the circles indicate when the mice died or were sacrificed. The arrows indicate when the doses were administered.

[00018] FIG. 6 shows the in vitro uptake of CLR2000045 in MCF-7 and NHDF cell lines.

[00019] FIG. 7 shows the in vitro cytotoxicity of CLR2000045 in breast cancer cell lines.

[00020] FIG. 8 shows the in vivo antitumor activity in a chicken embryo chorioallantoic membrane model (MCF-7). Petition 870260042444, dated 06 / 05 / 2026, page 18 / 143 9 / 92

[00021] FIG. 9 shows the in vivo antitumor efficacy in the implanted TNBC (HCC70) xenograft model.

[00022] FIG. 10 shows the Kaplan-Meier survival curve in the TNBC mouse xenograft model (HCC70).

[00023] FIGS. 11A-11B show changes in the body weight post-treatment mouse xenograft model (HCC70). FIG. 11A is 1 mg / kg administered 3 times per week. FIG. 11B is 1 mg / kg administered 2 times per week.

[00024] FIG. 12 shows the in vitro uptake of CLR180099A and CLR180099B in A549 and NHDF cells.

[00025] FIG. 13 shows the in vitro uptake of CLR180095 in A549 (black line) and HCT 116 (gray line) cells. The cells were incubated for 48 hours and the initial incubation concentration was 100 nM. Uptake was evaluated by LC / LC / MS.

[00026] FIG. 14 shows the in vitro release of payload in A549 cells.

[00027] FIG. 15 shows the in vitro cytotoxicity of CLR180099A in lung cancer, breast cancer and melanoma cells.

[00028] FIG. 16 shows the in vivo antitumor efficacy of CLR180099A in an implanted colorectal cancer xenograft model.

[00029] FIG. 17 shows the Kaplan-Meier survival curve in the colorectal cancer xenograft model for CLR180099A.

[00030] FIG. 18 shows the in vivo tolerability of CLR180099A. Petition 870260042444, dated 06 / 05 / 2026, page 19 / 143 10 / 92

[00031] FIGS. 19A-19F show the selective uptake of CLR1502 in intestinal tumors. FIG. 19A is the entire colon that was removed at necropsy 96 hours after administration of 50 pg of CLR1502 per mouse. FIG. 19B is the distal segment of the small intestine that was removed at necropsy 96 hours after administration of 50 pg of CLR1502 per mouse. Areas of higher signal intensity were observed using the I VIS Spectrum. These areas are non-invasive (colon FIG. 19C; distal small intestine FIG. 19F) and invasive (colon FIG. 19D; distal small intestine FIG. 19E). FIG. 19C, FIG. 19D, FIG. 19E and FIG. Figures 19F are enlarged as shown by the black box. The arrows point to malignant glands within the intestinal musculature. Bars: 1mm.

[00032] FIGS. 20A-20F show CLR1501 uptake in the brain. FIGS. 20A, 20B, and 20C show a U251-derived orthotopic brain tumor verified by magnetic resonance imaging (MRI; FIG. 20A, T2-weighted) and labeled with CLR1501 (FIG. 20C) with ToPro3 nuclear contrast (FIG. 20B). FIGS. 20D, 20E, and 20F are histological analyses of the brain tumor interface in a CLR1501-labeled 22T glioblastoma multiforme-derived orthotopic xenograft (green). FIG. 20D is an epifluorescent visualization of the xenograft-brain boundary with blue DAPI nuclear counterstaining. Figure 20E is a confocal view of a CLR1501-labeled xenograft. Figure 20F is a confocal, bright-field view of the xenograft and adjacent normal brain. N indicates normal brain; RFU indicates relative fluorescent units; T indicates tumor. Petition 870260042444, dated 06 / 05 / 2026, p. 20 / 143 11 / 92

[00033] FIG. 21A shows brain treated with CLR1502 in vivo with visible light (left) and fluorescence of CLR1502 from an orthotopic xenograft derived from 22CSC in vivo (right).

[00034] FIG. 21B shows brain and tumor treated with CLR1502 ex vivo with visible light (upper left) and fluorescence of CLR1502 from a 22CSC-derived xenograft ex vivo demonstrating excellent macroscopic delineation of the tumor from the normal brain (upper right). The figure also shows tumor verification (T) by histology (hematoxylin and eosin; lower left) and normal brain verification (N) by histology (hematoxylin and eosin; lower right).

[00035] FIG. 22 shows that tumor thickness is not responsible for the increased signal intensity observed in bowel cancers. FIG. 22A shows layers of the colon. FIG. 22B shows the total radiant efficiency for each layer.

[00036] FIG. 23 shows the in vivo optical scan of CLR1502 uptake in a colorectal carcinoma model. Fluorescence intensity (indicated by the colored bar) and biodistribution were determined in vivo over time.

[00037] FIG. 24 shows the in vivo optical scan of CLR1502 uptake in a breast cancer model. An athymic nude mouse with an orthotopic breast cancer xenograft (MDA-MB-231) was photographed daily for seven days (168 hours) using the Fluoptics Fluobeam® and I VIS® Spectrum systems (yellow and green arrows for Fluobeam and I VIS). Petition 870260042444, dated 06 / 05 / 2026, page 21 / 143 12 / 92 Spectrum, respectively).

[00038] FIG. 25 shows an athymic nude mouse with a lung cancer xenograft (H226 lung) on ​​each flank injected intravenously with CLR1502 that was photographed using the I VIS Spectrum. At 96 hours, the difference in radiant efficiency between malignant and normal tissue creates sufficient contrast for illumination of the tumor margin, as indicated by the black arrows. DETAILED DESCRIPTION OF THE INVENTION

[00039] This descriptive report describes therapeutic compounds capable of targeting a wide range of tumor cells. The compounds disclosed in this descriptive report can target specialized structures in tumor cell membranes, such as lipid rafts. Consequently, the compounds disclosed in this descriptive report can be used to target tumor cells with high specificity. In particular, the compounds disclosed in this descriptive report can be used for the treatment of cancer. 1. Definitions

[00040] Unless otherwise defined, all technical and scientific terms used in this descriptive report have the same meaning commonly understood by a person skilled in the art. In case of conflict, this document, including definitions, shall prevail. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described in this descriptive report may be used in the practice or testing of the present invention. All publications, Petition 870260042444, dated 06 / 05 / 2026, page 22 / 143 13 / 92 patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods and examples disclosed in this descriptive report are for illustrative purposes only and are not intended to be limiting.

[00041] The terms comprise(s), include(s), having, has, may, contains and their variants, as used in this descriptive report, are intended to be open transitional phrases, terms or words that do not exclude the possibility of additional acts or structures. The singular forms a, eeo include plural references, unless the context clearly indicates otherwise. This disclosure also contemplates other embodiments comprising, consisting of and consisting essentially of, or elements presented herein, whether explicitly stated or not.

[00042] For the recitation of numerical intervals in this descriptive report, each intermediate number between them with the same degree of precision is explicitly contemplated. For example, for the interval 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the interval 6.0-7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitly contemplated.

[00043] The term about or approximately as used in this descriptive report as applied to one or more values ​​of interest, refers to a value that is similar to a stated reference value or within an acceptable range of error for the specific value as determined by a person skilled in the art, which Petition 870260042444, dated 06 / 05 / 2026, page 23 / 143 14 / 92 will depend in part on how the value is measured or determined, such as the limitations of the measurement system. In certain respects, the term approximately refers to a range of values ​​that fall within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in any direction (greater than or less than) the stated reference value, unless otherwise indicated or evident from the context (except when such a number exceeds 100% of a possible value). Alternatively, approximately may mean within 3 or more standard deviations, according to practice in the art. Alternatively, as with regard to biological systems or processes, the term "about" can mean within an order of magnitude, preferably within 5 times, and more preferably within 2 times, of a value.

[00044] Definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this publication, chemical elements are identified according to the Periodic Table of Elements, CAS version, Chemistry and Physics Handbook, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, the general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Petition 870260042444, dated 06 / 05 / 2026, page 24 / 143 15 / 92 Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[00045] As used in this descriptive report, the term cancer refers to any disease resulting from the uncontrolled division of cells capable of metastasizing. The term cancer, as used in this descriptive report, refers to, but is not limited to, a variety of cancer types, including breast cancer, including male breast cancer; digestive / gastrointestinal cancers, including anal cancer, appendix cancer, extrahepatic bile duct cancer, gastrointestinal carcinoid tumor, colon cancer, esophageal cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumors (main point), islet cell tumors, adult primary liver cancer, childhood liver cancer, pancreatic cancer, rectal cancer, small bowel cancer, and stomach (gastric) cancer;Endocrine and neuroendocrine cancers including pancreatic adenocarcinoma, adrenocortical carcinoma, pancreatic neuroendocrine tumors, Merkel cell carcinoma, non-small cell neuroendocrine tumor of the lung, small cell neuroendocrine tumor of the lung, parathyroid cancer, pheochromocytoma, pituitary tumor and thyroid cancer; eye cancers including intraocular melanoma and retinoblastoma; genitourinary cancer including bladder cancer, kidney cancer (renal cells), penile cancer, prostate cancer, renal pelvis and ureter cancer of transitional cells, testicular cancer, urethral cancer and tumor; Petition 870260042444, dated 06 / 05 / 2026, page 25 / 143 16 / 92 Wilms; germ cell cancers including childhood central nervous system cancer, childhood extracranial germ cell tumor, extragonadal germ cell tumor, ovarian germ cell tumor and testicular cancer; gynecological cancers including cervical cancer, endometrial cancer, gestational trophoblastic tumor, epithelial ovarian cancer, ovarian germ cell tumor, uterine sarcoma, vaginal cancer and vulvar cancer; head and neck cancer, including hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, metastatic squamous neck cancer with occult primary cancer, mouth cancer, nasopharyngeal cancer, oropharyngeal cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, pharyngeal cancer, salivary gland cancer and throat cancer;Leukemias, including adult acute lymphoblastic leukemia, childhood acute lymphoblastic leukemia, adult acute myeloid leukemia, childhood acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia; multiple myeloma, including malignant plasma cells; lymphomas, including AIDS-related lymphoma, cutaneous T-cell lymphoma, adult Hodgkin lymphoma, childhood Hodgkin lymphoma, Hodgkin lymphoma during pregnancy, mycosis fungoides, adult non-Hodgkin lymphoma, childhood non-Hodgkin lymphoma, non-Hodgkin lymphoma during pregnancy, adult non-Hodgkin lymphoma, childhood non-Hodgkin lymphoma, non-Hodgkin lymphoma during pregnancy, nervous system lymphoma, Sézary syndrome, and Waldenstrom's macroglobulinemia; cancers; Petition 870260042444, dated 06 / 05 / 2026, page 26 / 143 17 / 92 musculoskeletal cancers, including Ewing's sarcoma, osteosarcoma and malignant fibrous histocytoma of bone, infantile rhabdomyosarcoma and soft tissue sarcoma; neurological cancers including adult brain tumor, infantile brain tumor, astrocytomas, brainstem glioma, atypical teratoid / rhabdoid tumor of the central nervous system, embryonal tumors of the central nervous system, craniopharyngioma, ependymoma, neuroblastoma, primary lymphoma of the central nervous system (CNS); respiratory / thoracic cancers including non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, thymoma and thymic carcinoma; and skin cancers including Kaposi's sarcoma, melanoma and squamous cell carcinoma.

[00046] As used in this descriptive report, the term cancer stem cell refers to a cancer cell capable of self-renewal and differentiation into the distinct types of cancer cells found in a malignant tumor.

[00047] The terms chemotherapeutic drug, anticancer drug, and antitumor drug are used interchangeably throughout the descriptive report.

[00048] In general, reference to a circulating tumor cell is intended to refer to a single cell, while reference to circulating tumor cells or a group of circulating tumor cells is intended to refer to more than one cancerous cell. However, a person skilled in the art would understand that reference to circulating tumor cells is intended to include a population of cells. Petition 870260042444, dated 06 / 05 / 2026, page 27 / 143 18 / 92 circulating tumor cells including one or more circulating tumor cells, while the reference to a circulating tumor cell may include more than one circulating tumor cell. The term circulating tumor cell or circulating tumor cells, as used in this descriptive report, refers to any cancerous cell or cluster of cancerous cells that are found in the blood or blood serum sample of a subject. CTCs may also contain or consist of a cancerous stem cell or cluster of cancerous stem cells that are found in the blood or blood serum sample of a subject.

[00049] As used in this descriptive report, the term composition is intended to encompass a product comprising the specified ingredients in the specified quantities, as well as any product that results, directly or indirectly, from a combination of the specified ingredients in the specified quantities.

[00050] The terms control, reference level, and reference are used interchangeably in this descriptive report. The reference level may be a predetermined value or range that is used as a reference to evaluate the measured outcome. Control group, as used in this descriptive report, refers to a group of control subjects. The predetermined level may be a cutoff value of a control group. The predetermined level may be an average of a control group. Cutoff values ​​(or predetermined cutoff values) may be determined by the Adaptive Index Model methodology. Petition 870260042444, dated 06 / 05 / 2026, page 28 / 143 19 / 92 (AIM). Cutoff values ​​(or predetermined cutoff values) can be determined by a receptor operating curve (ROC) analysis from biological samples of the patient group. ROC analysis, as generally known in the biological arts, is a determination of the ability of a test to discriminate one condition from another, for example, to determine the performance of each marker in identifying an ideal patient to receive IL-1Ra therapy. A description of ROC analysis is provided in PJ Heagerty et al. (Biometrics 2000, 56, 337-44), the disclosure of which is incorporated herein by reference in its entirety. Alternatively, cutoff values ​​can be determined by a quartile analysis of biological samples from a patient group.For example, a cutoff value can be determined by selecting a value that corresponds to any value in the 25th-75th percentile range, preferably a value that corresponds to the 25th percentile, 50th percentile, or 75th percentile, and most preferably the 75th percentile. Such statistical analyses can be performed using any method known in the art and can be implemented through any number of commercially available software packages (e.g., from Analyse-it Software Ltd., Leeds, UK; StataCorp LP, College Station, TX; SAS Institute Inc., Cary, NC). Healthy or normal levels or ranges for a target or for a protein activity can be defined according to standard practice. A control can be a subject or a tumor-free cell as detailed in this descriptive report. A control can be a subject or a sample. Petition 870260042444, dated 06 / 05 / 2026, page 29 / 143 20 / 92 of him, whose disease status is known. The subject, or a sample of him, may be healthy, ill, ill before treatment, ill during treatment, or ill after treatment, or a combination thereof.

[00051] The term dose, as used in this descriptive report, denotes any form of the formulation or composition of the active ingredient that contains a sufficient amount to produce a therapeutic effect with at least a single administration. Formulation and compound are used interchangeably in this descriptive report.

[00052] The term dosage, as used in this descriptive report, refers to the administration of any quantity, number and frequency of doses over a specified period of time.

[00053] The terms effective amount or therapeutically effective amount, as used in this descriptive report, refer to any amount of a pharmaceutically acceptable agent or composition or compound being administered that will alleviate to some extent one or more of the symptoms of the disease or condition being treated. The result may be the reduction and / or relief of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an effective amount for therapeutic uses is the amount of the composition comprising a compound as disclosed in this descriptive report required to provide a clinically significant decrease in the symptoms of the disease. An appropriate “effective” amount in any individual case may be determined using techniques such as a scaling study. Petition 870260042444, dated 06 / 05 / 2026, page 30 / 143 21 / 92 dose.

[00054] The term halogen, as used in this descriptive report, means Cl, Br, I, F, At, or synthetic halogens such as tennessine (Ts).

[00055] As used in this descriptive report, the term heterocycloalkyl refers to a cyclic group of 3 to 24 atoms (C3-C24) selected from carbon, nitrogen, sulfur, phosphate, and oxygen in which at least one atom is carbon.

[00056] As defined in this descriptive report, the term isomer includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like. In one embodiment, this disclosure covers the use of different optical isomers as detailed in this descriptive report. It will be appreciated by those skilled in the art that the anticancer compounds useful in the present invention may contain at least one stereogenic center. Consequently, the compounds used in the methods of the present invention may exist and be isolated in optically active or racemic forms. Some compounds may also exhibit polymorphism.

[00057] The terms malignant tumor cell, tumor cell, and cancerous cell are used interchangeably throughout the descriptive report. The terms malignant tumor stem cell, tumor stem cell, and cancerous stem cell are used interchangeably throughout the descriptive report.

[00058] Sample or test sample, as used Petition 870260042444, dated 06 / 05 / 2026, page 31 / 143 22 / 92 in this descriptive report may mean any sample in which the presence and / or level of a target is to be detected or determined. Samples may include liquids, solutions, emulsions, or suspensions. Samples may include a medical sample. Samples may include any biological fluid or tissue, such as blood, whole blood, blood fractions such as plasma and serum, cartilage, ligaments, tendons, muscle, interstitial fluid, sweat, saliva, urine, tears, synovial fluid, synovial membrane, meniscus, bone marrow, cerebrospinal fluid, nasal secretions, sputum, amniotic fluid, bronchoalveolar lavage fluid, gastric lavage, vomit, fecal matter, lung tissue, peripheral blood mononuclear cells, total leukocytes, lymph node cells, spleen cells, tonsil cells, cancer cells, tumor cells, bile, digestive fluid, skin, or combinations thereof. In some embodiments, the sample comprises an aliquot.In other embodiments, the sample comprises a biological fluid. Samples may be obtained by any means known in the art. The sample may be used directly as obtained from a patient or may be pre-treated, such as by filtration, distillation, extraction, concentration, centrifugation, inactivation of interfering components, addition of reagents and the like, to modify the character of the sample in some way, as discussed in this descriptive report or otherwise, as is known in the state of the art.

[00059] Subject and patient as used herein refer interchangeably to any vertebrate, including but not limited to a mammal that desires or needs the Petition 870260042444, dated 06 / 05 / 2026, page 32 / 143 23 / 92 compositions or methods described in this descriptive report. The subject may be human or non-human. The subject may be a vertebrate. The subject may be a mammal. The mammal may be a primate or a non-primate. The mammal may be a non-primate such as, for example, a cow, pig, camel, llama, hedgehog, anteater, platypus, elephant, alpaca, horse, goat, rabbit, sheep, hamster, guinea pig, cat, dog, mouse, and rat. The mammal may be a primate, such as a human. The mammal may be a non-human primate such as, for example, a monkey, cynomolgus monkey, rhesus monkey, chimpanzee, gorilla, orangutan, and gibbon. The subject may be of any age or stage of development, such as, for example, an adult, an adolescent, or an infant. The subject may be male. The subject may be female. In some embodiments, the subject has a specific cancer. The individual may be undergoing other forms of treatment.

[00060] As used in this descriptive report, the term therapeutic compound refers to any chemical compound capable of providing treatment for cancer.

[00061] To treat or treat or treatment means to suppress, repress, reverse, alleviate, improve or inhibit the deterioration of a disease or to eliminate the disease completely. A treatment can be carried out acutely or chronically. The term also refers to reducing the severity of a disease or symptoms associated with such a disease.

[00062] Unless otherwise defined in this descriptive report, the scientific and technical terms used in connection with this disclosure will have the Petition 870260042444, dated 06 / 05 / 2026, page 33 / 143 24 / 92 meanings that are commonly understood by those skilled in the art. For example, any nomenclature used in connection with cell and tissue culture techniques, molecular biology, immunology, microbiology, genetics, and chemistry and hybridization of proteins and nucleic acids described herein are those that are well known and commonly used in the state of the art. The meaning and scope of terms should be clear; in the case of any latent ambiguity, the definitions provided in this descriptive report take precedence over any dictionary or extrinsic definition. Furthermore, unless otherwise required by the context, singular terms should include plurals and plural terms should include singulars. 2. Compounds

[00063] In one aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, Me3N 1—L—q2_z' ' n (I) where n is 2-20 Q1 is a connection or where m is 0100; Petition 870260042444, dated 06 / 05 / 2026, p. 34 / 143 25 / 92 Q2 is a self-immolating link or spacer; and Z is an anticancer drug.

[00064] The number n can be any integer from 2 to 20. In some realizations, n is 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20. In particular realizations, n is 18.

[00065] The number m can be any integer from 0 to 100. In some realizations, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some realizations, m is an integer from 10 to 20, from 10 to 40, from 10 to 60, or from 10 to 80. In some realizations, m is 0 and Q1 is a link or

[00066] Q2 can be any known self-immolating spacer, including, for example, paraaminobenzyloxycarbonyl (PABC).

[00067] In some realizations, Rxé H. In some realizations, Rxé Cl. Petition 870260042444, dated 06 / 05 / 2026, p. 35 / 143 26 / 92

[00068] In some realizations, n is 2-20, Q1 is a Rx is H, or halogen, and Z is an anticancer drug.

[00069] Z can be any anticancer drug, including several known chemotherapy drugs.

[00070] In some embodiments, Z is a pole-type kinase 1 (PLK-1) inhibitor. Suitable PLK-1 inhibitors include, for example, BI2536, BI6727 (volasertib), diaminopyrimidine (DAP) derivatives such as DAP-81 and DAP-83, as well as the compounds disclosed in Kumar et al. (Biomed Res Int. 2015, 2015: 705745) and Peters et al. (Nat Chern Biol. 2006, 2(11):618-26), the contents of which are incorporated herein by reference in their entirety.

[00071] In some embodiments, Z is a tubulin polymerase inhibitor, just like nocodazole.

[00072] In some embodiments, Z is a tubulin stabilizer, as are tacalonolides.

[00073] In some embodiments, Z is an agent Petition 870260042444, dated 06 / 05 / 2026, page 36 / 143 27 / 92 antineoplastic, such as monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), monomethyl auristatin D (MMAD).

[00074] In some embodiments, Z is an inhibitor of eukaryotic translation initiation factor 4 (EIF4), such as EIF4A and EIF4E inhibitors. In some embodiments, Z is an EIF4E inhibitor. Suitable EIF4 inhibitors include, for example, ribavirin and the compounds disclosed in D'Abronzo et al. (Neoplasia, 2018, 20(6), 563-573) and US Patent No. 10,577,378, the contents of which are incorporated herein by reference in their entirety.

[00075] In some embodiments, Z is an analogue of combretastatin A-4, such as combretastatin A4 phosphate or ombrabulin. Suitable analogues of combretastatin A-4 also include, for example, the compounds disclosed in Beilina et al. (Bioorganic & Medicinal Chemistry Letters 2006, 16(22), 5757-5762), the contents of which are incorporated herein by reference in their entirety.

[00076] In some embodiments, Z is an analog of flavaglin. Suitable flavaglin analogs include, for example, the compounds disclosed in US Patent Application Publication 2018 / 0086729, the contents of which are incorporated herein by reference in their entirety.

[00077] In certain embodiments, Z is one of the other known anticancer drugs, including, for example, (i) other antiproliferative / antineoplastic drugs, such as alkylating agents, antimetabolites, antitumor antibiotics, antimitotic agents; and topoisomerase inhibitors; (ii) Petition 870260042444, dated 06 / 05 / 2026, page 37 / 143 28 / 92 cytostatic agents, such as antiestrogens, antiandrogens, LHRH antagonists or LHRH agonists, progestogens and aromatase inhibitors; (iii) anti-invasion agents (e.g., c-Src kinase family inhibitors); (iv) growth factor function inhibitors, such as tyrosine kinase inhibitors; (v) antiangiogenic agents; (vi) vascular damage agents; and (vii) endothelin receptor antagonists.

[00078] Examples of suitable anticancer drugs include, but are not limited to, paclitaxel, irinotecan, topotecan, gemcitabine, cisplatin, geldanamycin, mertansine, abiraterone, afatinib, aminolevulinic acid, aprepitant, axitinib, azacitidine, belinostat, bendamustine, bexarotene, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, cabozantinib, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, cetuximab, chlorambucil, clofarabine, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin, decitabine, docetaxel, dolastatins (e.g., monomethyl auristatin E), doxorubicin, enzalutamide, epirubicin, eribulin mesylate, erlotinib, etoposide, everolimus, floxuridine, fludarabine phosphate, fluorouracil, ganetespib, gefitinib, gemtuzumab ozogamicin, hexamethylmelamine, hydroxyurea, ibritumomab tiuxetan, ibrutinib, hydroxyurea, ibritumomab tiuxetan, ifosfamide, imatinib, ipilimumabixabepilone, lapatinib, leucovorin calcium, lomus tina, maitansinoids, mechlorethamine, melphalan, mercaptopurine, mesna, methotrexate, mitomycin C, mitotane, mitoxantrone, Petition 870260042444, dated 06 / 05 / 2026, page 38 / 143 29 / 92 Nelarabine, nelfinavir, nilotinib, obinutuzumab, ofatumumab, omacetaxine mepesuccinate, oxaliplatin, panitumumab, Pazopanib, pegaspargase, pemetrexed, pentostatin, pertuzumab, pertuzumab plicaniccin, pomalidomide, ponatinib hydrochloride, pralatrexate, procarbazine, radium 223 dichloride, ramucirumab, regorafenib, retaspimycin, ruxolitinib, semustine, siltuximab, sorafenib, streptozocin, sunitinib malate, tanespimycin, temozolomide, temsirolimus, teniposide, toremifenemide, thiotepaposide, toremifenemide, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vincristine, vinorelbine, vismodegib, vorinostat and zivaflibercept.

[00079] In some embodiments, compounds of formula (I) have a formula structure (Ia), or a pharmaceutically acceptable salt thereof, wherein Q1 is L-Q2 ' and is a PLK-1 inhibitor, a tubulin polymerase inhibitor, a tubulin stabilizer, an antineoplastic agent, or an inhibitor of eukaryotic translation initiation factor 4 (EIF4). Specifically, formula (Ia) may be Petition 870260042444, dated 06 / 05 / 2026, page 39 / 143 30 / 92 pharmaceutically acceptable form thereof, wherein n is 2-20 and Z is a PLK-1 inhibitor, a tubulin polymerase inhibitor, a tubulin stabilizer, an antineoplastic agent, or an inhibitor of eukaryotic translation initiation factor 4 (EIF4).

[00080] In some embodiments, the compound has a formula structure (Ia), wherein Z is a PLK-1 inhibitor or an antineoplastic agent. In some embodiments, the compound has a formula structure (Ia-1), (Ia-2), or (Ia-3), or a pharmaceutically acceptable salt thereof, wherein Z is a PLK-1 inhibitor. For example, Z may Petition 870260042444, dated 06 / 05 / 2026, p. 40 / 143 31 / 92

[00081] In some embodiments, the compound has a formula structure (Ia-1), (Ia-2), or (Ia-3), or a pharmaceutically acceptable salt thereof, wherein Z is an antineoplastic agent selected from the group consisting of monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), and monomethyl auristatin E (MMAD). In some embodiments, the compound has a formula structure (Ia-3), or a pharmaceutically acceptable salt thereof, wherein Z is MMAE, MMAF, or MMAD (shown below).

[00082] In some embodiments, compounds of formula (I) have a structure of formula (Ib) or a salt Petition 870260042444, dated 06 / 05 / 2026, p. 41 / 143 32 / 92 pharmaceutically acceptable of the same, where n is 18, Q1 is OH OIU i QP-0-P-í11 I * 0 OH OH 0 pPOP—o HO, Specifically II THE OH or a combretastatin analogue (formula db) may be OH II Me3N MejN· 9' P<-O(CH2)1ê OPOP--Z II O OH OH OPOP—OH íl-b-Ξ), or Petition 870260042444, dated 06 / 05 / 2026, p. 42 / 143 33 / 92 pharmaceutically acceptable of the same, where Z is an analogue of combretastatin A-4.

[00083] In some embodiments, the compound has a formula structure (Ib-1), (Ib-2), or (Ib-3), or a pharmaceutically acceptable salt thereof, where Z is an analogue UN II of combretastatin A-4, such as

[00084] In some embodiments, formula (I) have a pharmaceutically acceptable formula structure of the same, in HC fj] the compounds of (Ic) , or a salt that né 18, Q1 is the a link or 0 r / xt Specifically, ÔH HN^O ', L-Q2 is 'or and Z is a flavaglin analog. the formula (Ic) can be Petition 870260042444, dated 06 / 05 / 2026, p. 43 / 143 34 / 92 O HO ho2c HO, OR or a pharmaceutically acceptable salt thereof, where Z is an analogue of flavaglin.

[00085] In some embodiments, the compound has a formula structure (Ic-1), (Ic-2) or (Ic-3), or a pharmaceutically acceptable salt thereof where Z is a flavaglin analogue, such as

[00086] Suitable compounds as disclosed in this descriptive report include: Petition 870260042444, dated 06 / 05 / 2026, p. 44 / 143 35 / 92 A ' ο θ Φ 'CÕ 1 Η II 0 3 Ρ Λ-ο(οη3)18 ® / ~Ο □ MejN—' θ ΐ? _ J Υη ( ΜΜΑΕ) = 'Ν' 1 ο 1 hn. χ Υ * Νγ^ η hi ο 4 τ „ ''' Ν a τ 0 X (CLR2208), ο^νη φ ΗΝ^Ν. Ν·ψ^ΝΟϊ OH 0 fin ι ι .-X. OFOpO - f^ _f ui 1 / — 0 OH A. NH || (CLR22D6), 0 HN^· O^NHj 0¾¾ m Petition 870260042444, de 06 / 05 / 2026, pág. 45 / 143 36 / 92 (CLR2013), (CLR20C0045), (CLR2010), Petition 870260042444, de 06 / 05 / 2026, pág. 46 / 143 37 / 92 © (CLR180099B), ou um seu sal pharmaceuticamente aceitável.

[00087] The disclosed compounds may exist as pharmaceutically acceptable salts. The term pharmaceutically acceptable salt refers to salts or zwitterions of compounds that are soluble in water or oil or dispersible, suitable for the treatment of disorders without undue toxicity, irritation and allergic response, proportionate to a reasonable benefit / risk ratio and efficacy for the intended use.Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds can also be quaternized with alkyl chlorides, bromides, and iodides, such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, and stearyl. Petition 870260042444, dated 06 / 05 / 2026, page 47 / 143 38 / 92 and similar.

[00088] Basic addition salts can be prepared during the isolation and final purification of disclosed compounds by reacting a carboxyl group with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a metallic cation, such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or a primary, secondary, or tertiary organic amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-phenamine, and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[00089] The compound can exist as a stereoisomer, in which asymmetric or chiral centers are present. The stereoisomer is R or S depending on the configuration of the substituents around the chiral carbon atom. The terms R and S used in this descriptive report are configurations as defined in the 1974 LUPAC Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The disclosure covers several stereoisomers and mixtures thereof, and these are specifically included within the scope of this disclosure. Stereoisomers include enantiomers and diastereomers and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds can be prepared synthetically from materials of Petition 870260042444, dated 06 / 05 / 2026, page 48 / 143 39 / 92 commercially available batches containing asymmetric or chiral centers or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) fixing a mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography and optionally releasing the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith and Tatchell, “Vogel's Textbook of Practical Organic Chemistry”, 5th edition (1989), Longman Scientific & Technical, Essex CM202JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns or (3) fractional recrystallization methods. It should be understood that the compound may possess tautomeric forms as well as geometric isomers, and that these also constitute an aspect of the present disclosure.

[00090] This disclosure also includes an isotopically labeled compound, which is identical to those described in formula (I), but in that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes suitable for inclusion in the compounds of this disclosure are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as, but not limited to, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36Cl, respectively. Substitution by heavier isotopes, such as deuterium, i.e., 2H, may provide certain therapeutic advantages. Petition 870260042444, dated 06 / 05 / 2026, page 49 / 143 40 / 92 resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. The compound can incorporate positron-emitting isotopes for medical imaging studies and positron emission tomography (PET) to determine receptor distribution. Suitable positron-emitting isotopes that can be incorporated into compounds of formula (I) are 11C, 13N, 150 and 18F. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically labeled reagent in place of unlabeled reagent.

[00091] The compounds can be prepared by the synthesis schemes detailed herein. The compounds and intermediates can be isolated and purified by methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds may include, but are not limited to, chromatography on solid supports such as silica gel, alumina or silica derivatives with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum and trituration, as described, for example, in Vogel's Textbook of Practical Organic Chemistry, 5th edition (1989), by Furniss, Hannaford, Smith and Tatchell, pub. Longman Scientific & Technical, Essex CM202JE, England. Petition 870260042444, dated 06 / 05 / 2026, page 50 / 143 41 / 92

[00092] The reaction conditions and reaction times for each individual step may vary depending on the particular reagents employed and substituents present in the reagents used. Specific procedures are provided in the Examples section. The reactions may be processed in the conventional manner, e.g., by removing the solvent from the residue and further purified according to methodologies generally known in the state of the art, such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise described, the starting materials and reagents are commercially available or may be prepared by a person skilled in the art from commercially available materials using methods described in the chemical literature.Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the schemes described above or to the procedures described in the synthetic examples section.

[00093] Routine experimentation, including appropriate manipulation of reaction conditions, reagents, and the sequence of the synthetic pathway, protection of any chemical functionality that may not be compatible with the reaction conditions, and deprotection at an appropriate point in the reaction sequence of the method are included within the scope of the invention. Suitable protecting groups and methods for protecting and deprotecting different substituents using Petition 870260042444, dated 06 / 05 / 2026, page 51 / 143 42 / 92 Such suitable protective groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene's book entitled Protective Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. The synthesis of the compounds of the invention can be carried out by methods analogous to those described in the synthesis schemes and specific examples. 3. Pharmaceutical Compositions

[00094] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound as disclosed in this descriptive report, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[00095] The present pharmaceutical compositions can be manufactured by processes known in the state of the art, for example, by conventional processes of mixing, dissolution, granulation, coating of dragees, levigation, emulsification, encapsulation, trapping or lyophilization.

[00096] As described in this descriptive report, a pharmaceutically acceptable vehicle includes any and all solvents, diluents or other liquid vehicles, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as appropriate for the particular dosage form desired. Various vehicles used in the formulation of pharmaceutically acceptable compositions and techniques for the Petition 870260042444, dated 06 / 05 / 2026, page 52 / 143 43 / 92 their preparation are known in the state of the art (e.g., Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980)).

[00097] A pharmaceutically acceptable vehicle may be a functional molecule, such as a carrier, adjuvant, or diluent. A pharmaceutically acceptable carrier may be a filler, diluent, encapsulating material, or formulation aid of any type, non-toxic, inert solid, semi-solid, or liquid. Pharmaceutically acceptable vehicles include, for example, diluents, lubricants, binders, disintegrants, colorants, flavorings, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, emollients, propellants, humectants, powders, pH adjusting agents, and combinations thereof.

[00098] Some examples of materials that may serve as pharmaceutically acceptable compounds include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid or potassium sorbate, partial mixtures of glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, wool fat, sugars (such as lactose, glucose and sucrose), starches (such as Petition 870260042444, dated 06 / 05 / 2026, page 53 / 143 44 / 92 corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate), tragacanth powder, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil), glycols (such as propylene glycol or polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, compatible non-toxic lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, mold release agents, coating agents, emulsifying agents, sweeteners, flavorings, fragrance agents, preservatives, antioxidants may also be present in the composition, according to the formulator's judgment.

[00099] In some embodiments, the pharmaceutical composition consists essentially of a therapeutically effective amount of a compound as disclosed in this descriptive report, or a pharmaceutically acceptable salt thereof. [000100] Liquid dosage forms include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. Solid dosage forms include, but are not limited to, capsules, tablets, pills, powders, cements, pastes, and granules. Dosage forms for topical or transdermal administration of the present compounds include, but are not limited to, ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. Petition 870260042444, dated 06 / 05 / 2026, page 54 / 143 45 / 92 [000101] A liquid carrier or vehicle may be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycols and the like), vegetable oils, non-toxic glyceryl esters and suitable mixtures thereof. [000102] The pharmaceutical composition may be in a dosage form suitable for injection or infusion, such as sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient(s) that are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. The final dosage form must be sterile, fluid, and stable under manufacturing and storage conditions. Sterile injectable solutions may be prepared by incorporating at least one compound as disclosed in this descriptive report, or a pharmaceutically acceptable salt thereof in the required amount in the appropriate solvent with various other ingredients as needed, optionally followed by filter sterilization.In the case of sterile powders for the preparation of sterile injectable solutions, preparation methods may include vacuum drying and lyophilization techniques, which produce a powder of the active ingredient(s) plus any desired additional ingredients present in the sterile solutions. [000103] In some embodiments, the composition is a solution, such as a solution suitable for administration by infusion or injection. Solutions may be prepared in water, optionally mixed with a non-toxic surfactant. Petition 870260042444, dated 06 / 05 / 2026, page 55 / 143 46 / 92 Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin and mixtures thereof, and in oils. These preparations may contain a preservative to prevent the growth of microorganisms. Prevention of microorganism action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. [000104] Injectable forms can be made by forming microcapsule matrices of the compound(s) as disclosed in this descriptive report, or a pharmaceutically acceptable salt thereof, in biodegradable polymers, such as polylactide-polyglycolide. Depending on the compound-to-polymer ratio and the nature of the particular polymer employed, the drug release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable formulations are also prepared by trapping the drug in liposomes or microemulsions that are compatible with body tissues. [000105] In some embodiments, the composition may comprise at least one compound as described in this descriptive report and at least one additional anticancer drug. Anticancer drugs that are useful for the present disclosure include, but are not limited to, paclitaxel, irinotecan, topotecan, gemcitabine, cisplatin, geldanamycin, mertansine, abiraterone, afatinib, aminolevulinic acid, aprepitant, axitinib, azacitidine, belinostat, bendamustine, bexarotene, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, Petition 870260042444, dated 06 / 05 / 2026, page 56 / 143 47 / 92 cabozantinib, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, cetuximab, chlorambucil, clofarabine, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubin, decitabineb, denosuicin, dexrazoxane, docetaxel, dolastatins (e.g., monomethyl auristatin E), doxorubicin, enzalutamide, epirubicin, eribulin mesylate, erlotinib, etoposide, everolimus, floxuridine, fludarabine phosphate, fluorouracil, ganetespib, gefitinib, gemtuzumab ozogamicin, hexamethylmelamine, hydroxyurea, ibritumomab tietan, ibrutinib idelalisib, ifosfamide, imatinib, ipilimumab, ixabepilone, lapatinib, leucovorin calcium, lomustine, maitansinoids, mechlorethamine, melphalan, mercaptopurine, mesna, methotrexate, mitomycin C, mitotane, mitoxantrone, nelarabine, nelfinavir, nilotinib, obinutuzumab, ofatumumab, omacetaxine mepesuccinate, oxaliplatin, panitumumab, pazopanib, pegaspargase, pembrolizumab, penexed, pertuzumab, plicanicin,pomalidomide, ponatinib hydrochloride, pralatrexate, procarbazine, radium-223 dichloride, ramucirumab, regorafenib, retaspimycin, ruxolitinib, semustine, siltuximab, sorafenib, streptozocin, sunitinib malate, tanespimycin, temozolomide, temsirolimus, tenipaside, thalidolimus, toremifene, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vincristine, vinorelbine, vismodegib, vorinostat, and ziv-aflibercept. Any compounds that are currently known or capable of acting as anticancer drugs are also useful for this disclosure. Petition 870260042444, dated 06 / 05 / 2026, page 57 / 143 48 / 92 4. Methods [000106] The basis for the selective tumor targeting of the compounds detailed herein lies in the differences between the plasma membranes of cancer cells compared to those of most normal cells. Phospholipid ether (PLE) molecules take advantage of the metabolic change that tumor cells undergo to generate the energy needed for rapid cell division. Tumors increase the use of the beta-oxidative pathway to convert long-chain fatty acids (LCFAs) into energy. To increase LCFA uptake, tumor cells alter the cell membrane, forming specialized microdomains known as “lipid rafts.” Lipid rafts form due to metabolic changes and the need for phospholipids. Within tumor cells, these regions have become overabundant and stabilized, allowing them to be potential specific tumor targets.Specifically, cancer cell membranes are highly enriched in lipid rafts. In normal tissue, the presence of lipid rafts is limited and transient (~2 nanoseconds). In tumors, lipid rafts are present in increased amounts and are stabilized (up to 10 days). Cancer cells have five to ten times more lipid rafts than healthy cells. Furthermore, lipid rafts have been shown to be highly abundant in almost all tumor types and in 100% of individual cancer cells tested. Lipid rafts are highly organized and specialized regions of the phospholipid bilayer of the membrane, which... Petition 870260042444, dated 06 / 05 / 2026, page 58 / 143 49 / 92 lipid rafts contain high concentrations of various signaling molecules, sphingolipids, glycosphingolipids, and cholesterol, and serve to organize the cell surface and intracellular signaling molecules (e.g., growth factors and cytokine receptors, the phosphatidylinositol 3-kinase (PI3K) / Akt survival pathway). Data suggest that lipid rafts serve as entry portals for phospholipid ethers (PLEs). The marked selectivity of these compounds for cancer cells versus non-cancerous cells is attributed to the high affinity of PLEs for cholesterol and the abundance of cholesterol-rich lipid rafts in cancer cells. The fundamental role played by lipid rafts is highlighted by the fact that disruption of the lipid raft architecture suppresses the uptake of PLEs in cancer cells. It has been shown that the absorption of PLEs is reduced by 60% when lipid rafts are prevented from forming.These features, combined with lipid rafts that provide rapid internalization of phospholipid drug conjugates, make them an ideal target. [000107] The compounds as disclosed in this descriptive report, such as PLE analogs, may be LCFA mimetics. The molecules disclosed here have undergone extensive structure-activity relationship (SAR) analysis related to targeting lipid rafts in tumor cells and have been shown to bind specifically to these regions. The molecules disclosed here provide direct entry into the cytoplasm and Petition 870260042444, dated 06 / 05 / 2026, page 59 / 143 50 / 92 transit to the endoplasmic reticulum and mitochondria along the Golgi apparatus network within the cell cytoplasm. In some embodiments, the phospholipid drug conjugates (PDCs), as disclosed in this descriptive report, include a uniquely designed phospholipid ether conjugated to a novel combretastatin A (CBA) analog via a cleavable linker. CBAs are potent cytotoxins that inhibit tubulin polymerization within the tumor cell, as well as a demonstrated ability to disrupt the local vasculature around / within a tumor. In some embodiments, the compounds disclosed in this descriptive report include a uniquely designed phospholipid ether conjugated to a flavaglin analog (FLV) via a cleavable linker. FLVs are potent cytotoxins that inhibit translation, cell cycle progression, and induce apoptosis. [000108] The compounds as detailed in this descriptive report, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound as detailed in this descriptive report, may be used to treat cancer. In one aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering an effective amount of a compound as detailed in this descriptive report, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound as detailed in this descriptive report. [000109] In another aspect, the present disclosure provides pharmaceutically acceptable compounds, or salts of Petition 870260042444, dated 06 / 05 / 2026, page 60 / 143 51 / 92 same, as disclosed in this descriptive report for use in the treatment of cancer in a subject in need. [000110] In another aspect, the present disclosure provides the use of compounds, or pharmaceutically acceptable salts thereof, as disclosed in this descriptive report, for the manufacture of a medicament for the treatment of cancer in a subject in need. [000111] Cancers that can be treated with the compounds as detailed in this descriptive report, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound as detailed in this descriptive report include, but are not limited to: breast cancer including male breast cancer; digestive / gastrointestinal cancers, including anal cancer, appendix cancer, extrahepatic bile duct cancer, gastrointestinal carcinoid tumor, colon cancer, esophageal cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumors (essence), islet cell tumors, adult primary liver cancer, childhood liver cancer, pancreatic cancer, rectal cancer, small bowel cancer and stomach (gastric) cancer;Endocrine and neuroendocrine cancers including pancreatic adenocarcinoma, adrenocortical carcinoma, pancreatic neuroendocrine tumors, Merkel cell carcinoma, non-small cell neuroendocrine tumor of the lung, small cell neuroendocrine tumor of the lung, parathyroid cancer, pheochromocytoma, pituitary tumor and thyroid cancer; eye cancers including intraocular melanoma and retinoblastoma; genitourinary cancer; Petition 870260042444, dated 06 / 05 / 2026, page 61 / 143 52 / 92 including bladder cancer, kidney cancer (renal cells), penile cancer, prostate cancer, renal pelvis and transitional cell ureter cancer, testicular cancer, urethral cancer and Wilms' tumor; germ cell cancers including childhood central nervous system cancer, childhood extracranial germ cell tumor, extragonadal germ cell tumor, ovarian germ cell tumor and testicular cancer; gynecological cancers including cervical cancer, endometrial cancer, gestational trophoblastic tumor, epithelial ovarian cancer, ovarian germ cell tumor, uterine sarcoma, vaginal cancer and vulvar cancer;Head and neck cancer, including hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, metastatic squamous neck cancer with occult primary cancer, mouth cancer, nasopharyngeal cancer, oropharyngeal cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, pharyngeal cancer, salivary gland cancer, and throat cancer; leukemias including adult acute lymphoblastic leukemia, childhood acute lymphoblastic leukemia, adult acute myeloid leukemia, childhood acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia; Lymphomas, including AIDS-related lymphoma, cutaneous T-cell lymphoma, adult Hodgkin lymphoma, childhood Hodgkin lymphoma, Hodgkin lymphoma during pregnancy, mycosis fungoides, adult non-Hodgkin lymphoma, childhood non-Hodgkin lymphoma, non-Hodgkin lymphoma during pregnancy, primary central lymphoma, lymphoma of the nervous system; Petition 870260042444, dated 06 / 05 / 2026, p. 62 / 143 53 / 92 Sézary syndrome and Waldenstrom's macroglobulinemia; musculoskeletal cancers, including Ewing's sarcoma, osteosarcoma and malignant fibrous histocytoma of bone, infantile rhabdomyosarcoma and soft tissue sarcoma; neurological cancers including adult brain tumor, infantile brain tumor, astrocytomas, brainstem glioma, atypical teratoid / rhabdoid tumor of the central nervous system, embryonal tumors of the central nervous system, craniopharyngioma, ependymoma, neuroblastoma, primary lymphoma of the central nervous system (CNS); respiratory / thoracic cancers including non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, thymoma and thymic carcinoma; and skin cancers including Kaposi's sarcoma, melanoma and squamous cell carcinoma. In particular embodiments, the cancer may be melanoma, lung cancer, colorectal cancer, breast cancer or a combination thereof. [000112] In another embodiment, cancer may comprise one or more CTCs. The one or more CTCs may be selected from the group consisting of breast cancer, lung cancer, thyroid cancer, cervical cancer, melanoma, squamous cell carcinoma, prostate cancer, pancreatic cancer, colorectal cancer, and a cancer stem cell and a malignant plasma cell. [000113] In another embodiment, cancer can be metastatic. In particular embodiments, metastatic cancer can be selected from the group consisting of breast cancer, lung cancer, melanoma, and colorectal cancer. Petition 870260042444, dated 06 / 05 / 2026, page 63 / 143 54 / 92 [000114] In another embodiment, cancer can be a cancerous stem cell. In particular embodiments, the cancerous stem cell can be derived from the group consisting of breast cancer, lung cancer, melanoma, and colorectal cancer. [000115] In some embodiments, lung cancer may comprise small cell lung cancer, non-small cell lung cancer, or a combination thereof. [000116] In some embodiments, melanoma may comprise superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma, amelanotic melanoma, nevoid melanoma, squamous melanoma, desmoplastic melanoma, or a combination thereof. [000117] In some embodiments, colorectal cancer may include adenocarcinoma. [000118] In some embodiments, a compound of formula (Ia), (Ia-1), (Ia-2) or (Ia-3) as detailed in this descriptive report, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound as detailed herein may be used to treat melanoma, lung cancer, colorectal cancer or a combination thereof. [000119] In some embodiments, breast cancer may comprise invasive ductal carcinoma of the breast, metastatic breast cancer, inflammatory breast cancer, triple-negative breast cancer, ductal carcinoma in situ, or a combination thereof. In other embodiments, cancer is Petition 870260042444, dated 06 / 05 / 2026, page 64 / 143 55 / 92 breast cancer, the subject may be estrogen receptor positive, estrogen receptor negative, and progesterone receptor negative, express HER2 (HER2+), do not express HER2 (HER2-), or a combination thereof. In some embodiments, a compound of formula (Ib), (Ib-1), (Ib-2), or (Ib-3) as detailed in this descriptive report, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound as detailed in this descriptive report may be used to treat breast cancer. [000120] In some embodiments, a compound of formula (lc), (lc-1), (lc-2) or (lc-3) as detailed in this descriptive report, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound as detailed herein may be used to treat melanoma, lung cancer, colorectal cancer, breast cancer or a combination thereof. [000121] In some embodiments, the subject is a human, such as an adult or a baby. In some embodiments, the subject is an animal, such as a mammal. [000122] The methods may include administering a compound as detailed in this descriptive report, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound as detailed in this descriptive report in amounts as detailed in this descriptive report. In some embodiments, the methods include administering from about 0.0001 to about 1000 mg / kg of a compound as detailed in this descriptive report, or a pharmaceutically acceptable salt thereof. Petition 870260042444, dated 06 / 05 / 2026, page 65 / 143 56 / 92 [000123] The useful dosages of the compound(s) in the composition can be determined by comparing their in vitro activity and in vivo activity in their animal models. Methods for extrapolating effective dosages from rodents, pigs, and other animals to humans are known in the state of the art; for example, see Pat. No. 4,938,949. [000124] The actual dosage levels of the compounds in the therapeutic compositions as detailed in this descriptive report may be varied in order to obtain an amount of the compound(s) that is effective in achieving the desired therapeutic response for a given patient, composition, and route of administration. The selected dosage level and amount of the present compounds, or their pharmaceutically acceptable salts, for use in treatment may vary with the specific compound or salt selected, the route of administration, the disease or condition to be treated, the age and condition of the subject to be treated, the severity of the condition to be treated, and the patient's prior medical history and condition. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as free base.However, it is within the knowledge of the state of the art to initiate doses of the compound at levels lower than those necessary to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In certain situations, the disclosed compounds may be administered in amounts exceeding the dosage ranges described herein to effectively and aggressively treat particularly aggressive diseases or conditions. Petition 870260042444, dated 06 / 05 / 2026, page 66 / 143 57 / 92 [000125] In some embodiments, the compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as disclosed in this descriptive report may be administered by oral or intravenous administration. In general, however, an adequate dose will often be in the range of about 0.0001 mg / kg to about 1000 mg / kg, such as from about 0.001 mg / kg to about 10.0 mg / kg. For example, an appropriate dose may be in the range of approximately 0.001 mg / kg to approximately 5.0 mg / kg of body weight per day, such as approximately 0.01 mg / kg to approximately 1.0 mg / kg of the recipient's body weight per day, approximately 0.01 mg / kg to approximately 3.0 mg / kg of the recipient's body weight per day, approximately 0.1 mg / kg to approximately 5.0 mg / kg of the recipient's body weight per day, and approximately 0.2 mg / kg to 4.0 mg / kg of the recipient's body weight per day.The compound can be administered in unit dose form; for example, containing 1 to 100 mg, 10 to 100 mg, or 5 to 50 mg of active ingredient per unit dose form. [000126] The desired dose can be conveniently presented as a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more subdoses per day. The subdose itself can be further divided, for example, into several discrete, spaced administrations. [000127] The appropriate in vivo dosages to be administered and the particular mode of administration may vary depending on the age, weight, severity of the affliction and species of mammals treated, the particular compounds employed and the specific use for which these compounds are intended. Petition 870260042444, dated 06 / 05 / 2026, page 67 / 143 58 / 92 are employed. Determining effective dosage levels to achieve the desired result can be done by known methods, for example, clinical trials in humans, in vivo studies, and in vitro studies. For example, the effective dosages of the compounds disclosed in this descriptive report, or their pharmaceutically acceptable salts, can be determined by comparing their in vitro activity and in vivo activity in animal models. Such a comparison can be made by comparison with an established drug. [000128] The dosage amount and interval can be individually adjusted to provide plasma levels of the active fraction that are sufficient to maintain modulating effects or minimum effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and / or in vitro data. The dosages required to achieve the MEC will depend on individual characteristics and the route of administration. However, FIPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using the MEC value. Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10–90% of the time, preferably between 30–90%, and more preferably between 50–90%. In cases of local administration or selective uptake, the effective local drug concentration may not be related to the plasma concentration. [000129] The compounds, salts and compositions disclosed herein may be evaluated for efficacy and toxicity. Petition 870260042444, dated 06 / 05 / 2026, page 68 / 143 59 / 92 using known methods. For example, the toxicology of a particular compound, or a subset of compounds sharing certain chemical moieties, can be established by determining in vitro toxicity in relation to a cell line, such as a mammalian cell line, and preferably a human one. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, dogs, or monkeys, can be determined using known methods. The efficacy of a particular compound can be established using various recognized methods, such as in vitro methods, animal models, or clinical trials in humans. When selecting a model to determine efficacy, the person skilled in the art can be guided by the state of the art to choose an appropriate model, dose, route of administration, and / or regimen. [000130] The compound(s) as detailed in this descriptive report, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound(s) as detailed in this descriptive report, may be administered to humans and other mammals by a variety of known routes, including, without limitation, orally, rectally, parenterally, intracisternally, intravaginally, transdermally (e.g., using a patch), transmucosally, sublingually, pulmonaryly, intraperitoneally, topically (as by powders, ointments or drops), buccally or as an oral or nasal spray. The terms parenteral or Petition 870260042444, dated 06 / 05 / 2026, page 69 / 143 60 / 92 parenterally, as used in this descriptive report, refers to modes of administration that include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intra-articular injection and infusion. [000131] The compositions described herein may be administered with additional compositions to prolong the stability, distribution and / or activity of the compositions, or combined with additional therapeutic agents, or given before or after the administration of additional therapeutic agents. Combination therapy includes the administration of a single pharmaceutical dosage formulation containing one or more of the compounds described in this descriptive report and one or more additional pharmaceutical agents, as well as the administration of the compounds and each additional pharmaceutical agent in its own separate pharmaceutical dosage formulation. For example, the compounds as detailed in this descriptive report may be administered to a subject with an additional anticancer drug as detailed in this descriptive report. [000132] The compounds as detailed in this descriptive report, or their pharmaceutically acceptable salts, may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by hydrated mono- or multilamellar liquid crystals that are dispersed in an aqueous medium. Any physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present compositions in the form of liposomes may contain, Petition 870260042444, dated 06 / 05 / 2026, page 70 / 143 61 / 92 In addition to a compound described herein, anticancer drugs, stabilizers, preservatives, excipients, and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins) used separately or in combination. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33 et seq. Such compositions will influence the physical state, solubility, stability, in vivo release rate, and in vivo release rate. [000133] In one method of the present disclosure, a pharmaceutical composition can be delivered in a controlled-release system. For example, the agent can be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump can be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled-release system can be placed close to the therapeutic target, for example, the liver, thus requiring only a fraction of the systemic dose (see, for example, Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled-release systems are discussed in Langer's review (Science 249:1527-1533 (1990)). Petition 870260042444, dated 06 / 05 / 2026, page 71 / 143 62 / 92 5. Examples [000134] The foregoing may be better understood by reference to the following examples, which are presented for illustrative purposes only and are not intended to limit the scope of the invention. The present disclosure has several aspects and embodiments, illustrated by the attached non-limiting examples. Example 1. Materials and Methods [000135] The in vitro uptake of CLR2000045 was evaluated using MCF-7 breast cancer cells and normal human dermal fibroblast (NHDF) cells and was measured via LC / MS / MS. Breast cancer cells were maintained in minimum essential medium supplemented with 10% FBS. All cells were maintained at 37°C and 5% CO2. Cells were incubated with 1 μM of drug and the reported values ​​are the average of triplicate assessments. In vitro cytotoxicity was determined by the Cell Titer-Glo® assay using MCF-7 breast cancer cells and Hs578T triple-negative breast cancer cells. [000136] The in vitro uptake and release of CLR180099 were evaluated using A549 tumor cells, HCT 116 tumor cells, and normal human dermal fibroblast (NHDF) cells and measured via LC / MS / MS. Cells were incubated with 1 μM of drug, and the reported values ​​were the average of triplicate assessments. In vitro cytotoxicity was determined by the Cell Titer-Glo® assay. [000137] In an efficacy screening model using in vivo chicken embryos, 72 μM of CLR2000045 were administered to determine efficacy against tumors. MCFPetition 870260042444, 06 / 05 / 2026, p. 72 / 143 63 / 92 and compared with vehicle control and paclitaxel positive control at 50 μM. CLR2000045 was applied topically to the embryo envelope. Fertilized White Leghorn eggs were incubated at 37.5°C with 50% relative humidity for 9 days. At this time (E9), the chorioallantoic membrane (CAM) was lowered by making a small hole through the eggshell into the air sac, and a 1 cm² window was cut in the eggshell above the CAM. At least 20 eggs (depending on the embryo survival rate after 9 days of development, there may be more than 20 eggs per group) were used for each group. As some embryo deaths may occur after tumor grafting or may be related to a defective tumor graft, data may be collected with fewer than 20 eggs per group (minimum of 15 eggs per group). Tumor cells were cultured in DMEM supplemented with 10% FBS and 1% penicillin / streptomycin.On day E9, cells were detached with trypsin, washed with complete medium, and suspended in graft medium. An inoculum of 3 x 10⁶ cells was added to the CAM of each egg (E10) per group as appropriate, and then the eggs were randomized into groups. [000138] Embryo viability was checked daily. The number of dead embryos was also counted on day E18, in combination with the observation of any visible macroscopic abnormalities, to assess treatment-induced embryo toxicity. The final death rate and a Kaplan-Meyer curve were calculated for all groups. Any visible abnormalities observed were also noted. On day E18, the upper portion Petition 870260042444, dated 06 / 05 / 2026, page 73 / 143 64 / 92 of the CAM (with tumor) was removed from all viable embryos with tumors, washed with PBS buffer, and then transferred directly into PFA (fixation for 48 h). After that, the tumors were carefully sectioned from the normal CAM tissue and weighed. [000139] In vivo efficacy was further evaluated in R2G2 mice with HCC70 triple-negative breast cancer (TNBC) xenografts. Three doses (1 mg / kg) of CLR2000045 were evaluated, administered once, twice, or three times per week for two weeks. CLR2000045 was administered systemically by injection into the tail vein. Each group contained 10 mice. Tumor volume was monitored for efficacy and body weight for tolerability. Survival was also monitored. [000140] CLR180099 was administered intravenously (IV) to healthy C57BL / 6 mice to determine the maximum tolerated dose (MTD) compared to the FLV molecule alone. The vehicle used to administer CLR180099 was PBS in this case; however, any pharmaceutically suitable vehicle can be used. Each group contained 5 mice. In vivo efficacy was evaluated in athymic nude mice with HCT 116 xenografts. The mice were flank models that were developed by injecting the rear flank of the mice with approximately 1 x 10⁶ of the cells resuspended in 5 ml of 1.2% methylcellulose. The study was initiated when the mean tumor volume reached approximately 120 mm³. Tumor volume was measured using calipers – measurements of tumor length, width, and depth were used to calculate tumor volume. Two doses (2 Petition 870260042444, dated 06 / 05 / 2026, page 74 / 143 Doses of CLR180099 (65 / 92 mg / kg administered twice or 2 mg / kg administered three times) were evaluated. Each group contained 10 mice. Tumor volume was monitored for efficacy and body weight for tolerability. Total conjugated CLR180099 and free FLV were determined by mass spectrometry. Example 2. The phospholipid ether delivery vehicle shows specificity for a wide range of tumor cells. [000141] To demonstrate the uptake of PDCs in various tumor cell lines, several tumor cell lines, such as MCT-116, MeS SA / Dx5, Mia PaCa-2, Ovcar3, and U-87MG, were incubated with 5 mM CLR1501 (PLE plus a BODIPY fluorescent payload) for 24 hours at 37°C in complete medium. Each cell line may have a slightly different medium to optimize growth; any suitable medium known in the art can be used for each cell line. All cells were maintained at 37°C in an appropriate medium supplemented with 10% FBS and 5% CO2. CLR1501 was excited and then detected with an AlexaFluor 488 filter. CLR1501 was highly localized in all different tumor cell lines (FIG. 1A and FIG. 1B). This was repeated in more than 100 tumor cell lines, such as MM. IS, MM.IR, RPM 18226, U266 and NCIH929, Panc-1, A375, PC-3, Caki-2, HCT-116, A549, metastatic PC-3, MDA-MB-231, HT-29, SV-40, CNS-1, BxPC3, MCF-7, LuCap, LNCap, MES SA / Dx5, Capanl, HTB-77, Lan5, CHLA-20, NB1691 and SK-N-AS, with similar results. CLR1501 was administered to different cancer cell lines and one cell line of... Petition 870260042444, dated 06 / 05 / 2026, p. 75 / 143 66 / 92 normal human skin fibroblasts in vitro. Twenty-four hours later, CLR1501 exhibited preferential uptake of five to nine times in these cancer cell lines in vitro compared to normal fibroblasts. The retained CLR1501 was associated with plasma membranes and organelles. [000142] In vitro uptake and release with a cytotoxic payload was measured in A375 and A54 cell lines 9 by incubating them with 2 μM of a small cytotoxic PDC molecule with a semi-stable ligand (CLR2208, PDC-SM1) for 48 hours at 37°C in complete medium. PDC-SM1 uptake was measured by LC / MS / MS. PDC-SM1 demonstrated the onset of uptake within 30 minutes. 20-40% of the conjugate exposed to the cells was measured in the tumor cell cytoplasm within 24 hours (FIG. 2A). CLR2206 (PDC-SM2, the same as PDC-SM1 except with a cleavable ligand) was then used to measure payload release within tumor cells. CLR2200 (PDC-SM3) was also studied. Measurable payload release from the small molecule occurred between 1 and 2 hours after incubation (FIG. 2B). Insignificant payload release occurred in the media (<1 nM).These results indicated that phospholipid ether molecules have the ability to target a wide range of tumors, and PDCs have the ability to achieve 20-40% absorption of the exposed drug in tumor cell lines. [000143] To measure absorption through lipid rafts in tumor cells, multiple myeloma cells were incubated with CLR1502 (near the infrared molecule bound to PLE) for 24 hours at 37°C. The following day, the cells were washed and co-stained with staining. Petition 870260042444, dated 06 / 05 / 2026, p. 76 / 143 67 / 92 nucleus (Hoescht 33342). Using the B subunit of cholera toxin, they were further stained for the presence of lipid rafts. The cells were incubated with the B subunit of cholera toxin for 24 hours. In addition, to measure uptake through lipid rafts in primary tumor samples, patient-derived multiple myeloma cells were stained with Hoescht 33342 and incubated with CLR1501 (FIG. 3). These results demonstrate that PDC uptake was linked to lipid rafts in the membranes of tumor cells in both cell lines and primary tumor samples. [000144] In vitro efficacy with cytotoxic payloads was measured. PDC-SM2 demonstrated submicromolar activity (concentration measured based on the total concentration of the conjugate incubated in the cells) against melanoma (A375) and lung cancer (A549) cells. PDC-SM2 showed less activity against melanoma than lung cancer (IC50s 0.131 vs 0.016), but was more potent (0% vs 12% of viable cells remaining, FIG. 4). PDC-SM2 also showed similar activity and potency against colorectal cancer cells (HCT-116) as lung cancer without activity against normal fibroblast cells. Therefore, PDCs show payload release and strong nanomolar activity against tumor cells. [000145] To determine if cytotoxic PDCs are tolerated in vivo, C57BL / 6 mice were dosed as follows: PDC-SM2 was dosed on days 0, 3, and 7 at dose levels of 0.5 mg / kg, 1.0 mg / kg, or 2.0 mg / kg; the payload alone was measured on day 0 only at 0.25 mg / kg, 0.4 mg / kg, 1.0 mg / kg, or 2.0 mg / kg. Petition 870260042444, dated 06 / 05 / 2026, p. 77 / 143 68 / 92 mg / kg or 0.5 mg / kg; the vehicle was dosed on days 0, 3, and 7. The PDCs and the vehicle control showed no toxicity or adverse events during repeated dosing as measured by changes in weight (no weight loss). Payload doses of 0.25 and 0.4 mg / kg were tolerated, although some toxicity was observed in the skin and coat of the mice. The payload dose of 0.5 mg / kg was not tolerated; two mice died on day 4 after a single infusion, and all mice were sacrificed on day 5 (FIG. 5). These PDCs showed good plasma stability in human plasma. Plasma stability was measured using the Cyprotex plasma stability assay. Samples were at a concentration of 1 mM and were incubated for 0, 15, 30, 60, and 120 minutes. A positive control compound that degrades in plasma was used. The percentage of the compound remaining at each incubation time point was measured.PDC-SM2 showed some instability in mouse plasma which may result in some toxicity (TABLE 1). The present PDCs are well tolerated in vivo. Overall, PDCs offer a novel and unique approach to targeting small molecules to tumor cells. TABLE 1. Plasma stability assessment Compound ID Human Ti^ (min) Mouse Tia (min) PDG-SM2 >400 199 PDC-SM3 >400 >400 Propantheline 54 85 [000146] The selective uptake of CLR1502 was also measured in vivo in intestinal tumors. The entire colon and the distal segment of the small intestine were removed in Petition 870260042444, dated 06 / 05 / 2026, page 78 / 143 69 / 92 necropsy 96 hours after administration of 50 pg of CLR1502 (FIG. 19A and FIG. 19B). CLR1502 was administered via injection into the tail vein. Areas of highest signal intensity were observed using the I VIS Spectrum, which allows direct visualization of CLR1502 through the animal's skin. Subsequently, after euthanasia of the animal, the tissues identified by the I VIS system were excised by microdissection and histology was performed to see tumor tissue versus non-tumor tissue and where near-infrared staining occurred. These areas showed non-invasive tumors (colon FIG. 19C; distal small intestine FIG. 19F) and invasive tumors (colon FIG. 19D; distal small intestine FIG. 19E). [000147] In other studies, CLR1502 accumulates in metastases and regional lymph nodes. After bowel removal, mesenteric fat, pancreas, and spleen were isolated en bloc. In one case, two metastatic tumor deposits of ~4 mm in size were observed in the mesentery. These lesions were easily visualized with the Fluobeam near-infrared imager. These lesions were confirmed as metastatic malignant lesions in H&E. Regional lymphadenopathy also demonstrated CLR1502 accumulation using Fluobeam. No malignant cells were observed within these hyperplastic lymph nodes. [000148] Tumor thickness is not responsible for the increased signal intensity observed in intestinal cancers (FIG. 22A and FIG. 22B). Necropsy was performed 96 hours after injection of mice with 50 pg of CLR1502 per mouse. To examine the effect of tumor thickness Petition 870260042444, dated 06 / 05 / 2026, page 79 / 143 70 / 92 tissue, sections of normal-appearing colon were layered on top of each other. Radiant efficiency was measured to compare signal intensity between one, two, and three layers of normal colon and intestinal tumors. Note that a layer of normal colon is approximately 1 mm thick. Tissue thickness may explain the increased intensity observed in adenomas, but does not explain the differences observed in adenocarcinomas. [000149] In vivo optical scanning of CLR1502 uptake in a colorectal carcinoma model demonstrated preferential retention in malignant tissues compared to normal tissues. An athymic nude mouse bearing a colorectal carcinoma xenograft (HCT-116) was intravenously injected with 1 mg of CLR1502 and photographed using the Li-COR Pearl® Impulse system (FIG. 23). Fluorescence intensity (indicated by the colored bar) and biodistribution were determined in vivo over time. [000150] In vivo optical scanning of CLR1502 uptake in a breast cancer model demonstrated preferential retention in malignant tissues compared to normal tissues. An athymic nude mouse bearing an orthotopic breast cancer xenograft (MDA-MB-231) was intravenously injected with approximately 80 pg of CLR1502 and photographed daily in vivo for seven days (168 h) using the Fluoptics Fluobeam® and IVIS® Spectrum systems (FIG. 24). The study results showed selective uptake and prolonged retention within the tumor (yellow and green arrows for Fluobeam and IVIS Spectrum, respectively) and a relative increase in tissue clearance. Petition 870260042444, dated 06 / 05 / 2026, page 80 / 143 71 / 92 normal over time. [000151] An athymic nude mouse with a lung cancer xenograft (H226 lung) on ​​each flank was intravenously injected with approximately 50 pg of CLR1502 and photographed in epifluorescence mode with the IVIS Spectrum (FIG. 25). Note that at 96 hours the difference in radiant efficiency between malignant and normal tissue creates sufficient contrast for illumination of the tumor margin, as indicated by the black arrows. Example 3. CLR2000045 with a combretastatin A-4 analogue improves breast cancer therapy. [000152] CLR2000045 shows significant uptake in tumor cells with minimal uptake in normal tissue. The warhead release showed approximately 50% release at each time point. A steady state between uptake and warhead release was reached between 24 and 48 hours (FIG. 6). CLR2000045 shows excellent activity and potency against two breast cancer cell lines (MCF-7 and Hs578T) with IC50s of 76 nM and 51 nM, respectively (FIG. 7). The molecule also demonstrated activity against several other solid tumors, including lung cancer, melanoma, and colorectal cancer. Half the maximum inhibitory concentration (IC50) was measured in the cell lines (TABLE 2). The plasma stability of CLR2000045 was also measured (TABLE 3). TABLE 2. IC50 Assessment Petition 870260042444, dated 06 / 05 / 2026, page 81 / 143 72 / 92 Compound ID for cell lines A375, A549, HCT116, MCF7, NHDF, CLR2013: 0.443, 0, 445, 0, 451, 0.282, >50; CLR2000045: 0.610, 1.592, 1.886, 1.082, >50; CLR2010: 0.365, 0.457, 0.449, 0.356, >50 TABLE 3. Plasma stability evaluation Compound ID for human, Camundoncro, tlZ2 (min), (min), CLR2013: >400, 77; CLR2000045: >400, >400; Pronantelina: 77, 57 [000153] Fertilized white Leghorn chicken eggs (20 / dose group) were incubated at 37.5 °C for 9 days. MCF-7 cells were cultured under standard conditions before implantation. An inoculum of 3x106 MCF-7 cells was added to the chorioallantoic membrane on day 10. The eggs were then randomized into treatment groups and treated 4 times (on days 11, 13, 15, and 17) under the following conditions: vehicle, paclitaxel 50 mM per dose, and CLR2000045 72 pM per dose. CLR2000045 showed activity similar to paclitaxel in this screening model (FIG. 8). [000154] The study was initiated when the mean tumor volume of the group reached -200 mm3 (Day 4). CLR2000045 was administered IV at the following doses: 1 mg / kg on days 5 and 12 or on days 5, 8, 12 and 15 or on days 5, 7, 9, 12, 14 and 16. CLR2000045 demonstrated a dose-response reduction in tumor volume from dose group 1 to dose group 3 (3 times a week for 2 weeks) and the highest dose tested showed almost 100% tumor eradication. The 2 highest dose groups showed a reduction Petition 870260042444, dated 06 / 05 / 2026, p. 82 / 143 73 / 92 statistically significant increase in tumor volume compared to the vehicle control (pãQ,Q5 and pãQ,Q1 respectively) (FIG. 9). The Kaplan-Meier curve shows that treatment with CLR2QQQQ45 at 1 mg / kg three times a week for 2 weeks resulted in a significant increase in survival compared to the vehicle dosage and once a week (pãQ,QQ1, pãQ,Q5, respectively). 1 mg / kg twice a week for two weeks resulted in a significant increase compared to the vehicle (pãQ,Q5; FIG. 1Q). Changes in body weight after treatment were measured in the mouse xenograft model (HCC7Q) (FIG. 11A and FIG. 11B). [QQQ155] CLR2QQQQ45 demonstrates significant uptake and payload release (2Q-4Q% of exposed drug) in tumor cell lines, while minimal uptake occurs in normal cells. CLR2QQQQ45 shows potent in vitro activity against multiple breast cancer cell lines. CLR2000045 demonstrated potent in vivo activity against a triple-negative breast cancer model (HCC7Q) and a metastatic adenocarcinoma breast cancer model (MCF-7). CLR2QQQQ45 provided a statistically significant survival benefit in the TNBC (HCC7Q) model, and the two highest doses were shown to be well tolerated, as measured by body weight loss. Together, these data demonstrate the potent in vitro and in vivo activity of CLR2QQQQ45 against a variety of breast cancer cell lines and animal models and warrant the continued development of this PDC. Petition 870260042444, dated 06 / 05 / 2026, page 83 / 143 74 / 92 Example 4. CLR180099 Improves the Safety and Efficacy of Antitumor Drugs Against Colorectal Tumors [000156] CLR180099 showed excellent activity and potency against breast cancer and lung cancer with IC50s of 0.024 and 0.011, respectively (FIG. 12). The compound also demonstrated activity against several other solid tumors, including melanoma and colorectal cancer. The plasma stability of CLR1800095, CLR180099A and CLR180099B was measured in mice and humans (TABLE 4). CLR1800095 showed some instability in mouse plasma that may result in some toxicity. TABLE 4. Plasma stability assessment Compound ID Human Mouse t1 / 2 (min) t1 / 2 (min) CLR<1600095>400 199 CLR180099A >400 >400 CLR<1800990>400 >400 ProDantelina 54 85 [000157] The study was initiated when the mean tumor volume of the group reached -120 mm3 (Day 1). CLR180099 was administered IV at 2 mg / kg on days 1 and 4 or on days 1, 3, and 5. Docetaxel was administered at 10 mg / kg on days 1 and 4. CLR180099 demonstrated a similar or better reduction in tumor volume than docetaxel and demonstrated a dose-dependent effect. The docetaxel arm experienced several deaths beginning on day 18 and ending on day 26 (FIG. 16). The Kaplan-Meier curve shows that treatment with CLR180099 at 2 mg / kg on days 1 and 4 or days 1, 3, and 5 resulted in a significant increase in survival compared with docetaxel (FIG. 16). Petition 870260042444, dated 06 / 05 / 2026, page 84 / 143 75 / 92 17, log-rank test, p < 0.001). As measured by body weight loss, all mice treated with CLR180099 (both doses) demonstrated normal body weight growth throughout the study (FIG. 18). Five mice per group were dosed at each dose level. Both PDCs were tolerated up to a dose of 10 mg / kg with all mice alive and without end-organ toxicity (TABLE 5). Payload alone was not tolerated at doses above 0.5 mg / kg (all mice died at 0.5 mg / kg). TABLE 5. In vivo tolerability mg / kg 0.1 0.5 1 5 10 FLV 5 0 □ 0 0 CLR180099A 5 5 5 5 5 CLR180099B 5 5 5 5 5 [000158] CLR180099 demonstrated significant uptake and release of payload (20-40% of exposed drug) in tumor cell lines, while minimal uptake occurred in normal cells. CLR180099 showed potent in vitro activity against several solid tumors, including lung cancer (A549), breast cancer (MCF7), and melanoma (A375), as well as other tumor types. In vivo, two or three doses of CLR180099 showed similar or better activity than docetaxel in colorectal cancer. Furthermore, CLR180099 demonstrated significantly improved survival benefit at both doses compared to docetaxel. Tolerability assessment demonstrated that CLR180099 was well tolerated in both tumor-bearing and normal animals, and the FLV payload was toxic in both normal and tumor-bearing mice. CLR180099 showed no toxic effects compared to the payload of the analogue of Petition 870260042444, dated 06 / 05 / 2026, page 85 / 143 76 / 92 FLV alone, demonstrating that this payload can benefit from targeted delivery with a phospholipid ether (PLE). Example 5. Synthesis of Compounds [000159] The chemical synthesis steps were carried out as follows. The products were isolated using known techniques such as HPLC, and the resulting structures were verified by NMR and MS. Petition 870260042444, dated 06 / 05 / 2026, page 86 / 143 77 / 92 [000161] CLR2206 was synthesized according to Scheme 2. Hypophosphate chloride IA (2.5 eq.) was used in EtaN (10 eq.) and THF at -40°C for 3 hours to prepare compound 2 from compound 1. Compound 2 was reacted with 2A (1 eq.) in EtaN (1 eq.), GDI (1.5 eq.), ZnCh (2.6 eq.), and DMF at 15°C for 12 hours to produce compound 3. Deprotection of compound 3 in piperidine (5 eq. DMF, 15°C for 3 hours) yielded compound 4. Compound 4 was reacted with 4A (1 eq.) in Et3N (4 eq.), COMU (1.15 eq.), and CHCl3 at 15°C for 2 hours to produce CLR2206. Scheme 2 Φ HN N Ύ' *| hypophosOhata üh.nridB, 1A jf O ho-p—σ' u 1 CJÍ^NH ιφ ftp™, OH O JT T ,, 4 ÒH CLR22OÓ ^NH Ò Y pPO 8 2A Π Ί rmocHN_________2 hr * CDI.ZnClj J^jAo 0 ϊ Μ'·γΝθϊ ^χ,ΝΗ OH Ο Ρ L / Ο ΟΗ 1 ÍI Ί Ο^ΜΗ Φ UN Ν ΤΙ Ί Í? JULo 0'Ρ-Ο-Ρ—Ο _______ / ιι ι 1 7 — 0 ΟΗ ,λ -NH [| ^ Petition 870260042444, dated 06 / 05 / 2026, p. 87 / 143 78 / 92 [000162] CLR2200 was synthesized according to Scheme 3. Compound 5 reacted with MMAE (0.8 eq.) in pyridine (Py, 20 eq.), HOBt (0.5 eq.) and DMF at room temperature for 12 hours to produce compound 6. The decomposition of compound 6 in piperidine (10 eq.) and DCM:AcN (1:1) at room temperature for 12 hours yielded compound 7. Compound 7 was reacted with 7A (1 eq.), TEA (4.5 eq.), COMU (1.2 eq.) and CHCl3 at room temperature for 12 hours to produce CLR2200. Scheme 3 CLR2200 [000163] CLR200045 was prepared according to the Scheme 4, or alternatively according to Scheme 5. Petition 870260042444, dated 06 / 05 / 2026, p. 88 / 143 79 / 92 Scheme 4 CDI, ZnCfe, EMF OH O CLR2000045 Petition 870260042444, dated 06 / 05 / 2026, p. 89 / 143 80 / 92 Scheme 5 CLR2000D45 [000164] CLR2013 was prepared according to the Scheme 6. Scheme 6 OH O A. CLR1410. DIG, DMAP. CHCI^-BuOH B. CLR141D. COi / U, NEK CHC^-BuOH [000165] CLR1800095 was prepared in accordance with Diagram 7. Petition 870260042444, dated 06 / 05 / 2026, pp. 90 / 143 81 / 92 Scheme 7 ........”-----------.pyridine, D^P; rt 12h.29% rtdeSCkCI. NEti. DCM Z. LiBf, W*C? 4, teat S ' σΛO1 P^CiumaM í. TFA, DCí? íl&s, SKI.f Scheme 8 (LCMS purity 97%). Scheme 8 Petition 870260042444, dated 06 / 05 / 2026, pp. 91 / 143 82 / 92 OAC ϊ Ag / }. MeCK AcO^V^^V^^V'MeOH CAc MO;. THE N+ifmic EEDO rt,4h, 93% ΗΝ^^^,ΝΚί^ OPÉA. &CM, Õ rt, overnight, 60% CG^i 0 AoO^' / '^O' ÜAi OíOJlRüHb FLV^ DAz ttKj xr o Conditions: NEts, DMF, rt, overnight; DIPEA, DCM, rt, overnight. CLR10OO99B [000167] CLR180099A was prepared in accordance with Diagram 9. Petition 870260042444, dated 06 / 05 / 2026, p. 92 / 143 83 / 92 Scheme 9 CLR180099A [000168] For completeness, various aspects of the invention are set out in the following numbered clauses: [000169] Clause 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, Me3N OG içOP^O^C Hj)—Q1— L—Q2—Z ' n (I) where n is 2-20 Q1 is a connection or where m is 0100; Petition 870260042444, dated 06 / 05 / 2026, pp. 93 / 143 84 / 92 Q2 is a self-immolating link or spacer; and Z is an anticancer drug. [000170] Clause 2. The compound of clause 1, or a pharmaceutically acceptable salt thereof, wherein Is Q1 a connection or Petition 870260042444, dated 06 / 05 / 2026, pp. 94 / 143 85 / 92 O -^s^cAí. [000171] Clause 3. The compound of any of clauses 1-2, or a pharmaceutically acceptable salt thereof, wherein Z is a pole-like kinase 1 (PLK-1) inhibitor, a tubulin polymerase inhibitor, a tubulin stabilizer, an antineoplastic agent, an inhibitor of eukaryotic translation initiation factor 4 (EIF4), a combretastatin A-4 analogue or a flavaglin analogue. [000172] Clause 4. The compound of any of clauses 1-3, having a formula structure (Ia), or a pharmaceutically acceptable salt thereof, wherein N i V opop-^HOH0 H-nh L-Q2é ' 'or Z is a PLK-1 inhibitor, a tubulin polymerase inhibitor, a tubulin stabilizer, an antineoplastic agent, or an inhibitor of eukaryotic translation initiation factor 4 (EIF4). [000173] Clause 5. The compound of clause 4, in which Petition 870260042444, dated 06 / 05 / 2026, p. 95 / 143 86 / 92 Z is a PLK-1 inhibitor or an antineoplastic agent selected from the group consisting of monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), and monomethyl auristatin E (MMAD). [000174] Clause 6. The compound of any of clauses 1-3, having a formula structure (Ib), or a pharmaceutically acceptable salt thereof, where n is 18; Z is an analogue of combretastatin A-4. [000175] Clause 7. The compound of any of clauses 1-3, having a formula structure (Ic), or a pharmaceutically acceptable salt thereof, where n is 18; Is Q1 a connection or Petition 870260042444, dated 06 / 05 / 2026, p. 96 / 143 87 / 92 HOjC 0 XOY ÕH HN^O 1 -Í—ς HN'7 L-Q2 is or Z is an analogue of flavaglin. [000176] Clause 8. The compound selected from the group consisting of O 1 and clause 1, which is O^NH c (CLR2206). Petition 870260042444, dated 06 / 05 / 2026, p. 97 / 143 88 / 92 OH O (CLR2000045), (CLR2010), Petition 870260042444, dated 06 / 05 / 2026, pp. 98 / 143 OMe (CLR180095), (GLR1800099B), or a pharmaceutically acceptable salt thereof. [000177] Clause 9. A pharmaceutical composition comprising a compound of any of the clauses 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [000178] Clause 10. A method of treating cancer in a subject in need thereof, comprising administering an effective amount of a compound of Petition 870260042444, dated 06 / 05 / 2026, page 99 / 143 90 / 92 any of clauses 1-8, or a pharmaceutically acceptable salt thereof. [000179] Clause 11. The method of clause 10, where the cancer is melanoma, lung cancer, colorectal cancer, breast cancer or a combination thereof. [000180] Clause 12. The method of any of clauses 10-11, wherein lung cancer comprises small cell lung cancer, non-small cell lung cancer or a combination thereof; Melanoma includes superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma, amelanotic melanoma, nevus melanoma, squamous melanoma, desmoplastic melanoma, or a combination thereof; Colorectal cancer includes adenocarcinoma; or breast cancer includes invasive ductal carcinoma of the breast, metastatic breast cancer, inflammatory breast cancer, triple-negative breast cancer, ductal carcinoma in situ, or a combination thereof. [000181] Clause 13. The method of any of clauses 10-12, wherein cancer comprises cancerous stem cells. [000182] Clause 14. The method of any of clauses 10-13, wherein cancer comprises metastatic cancer cells. [000183] Clause 15. The method of any of clauses 10-14, wherein cancer comprises circulating tumor cells. Petition 870260042444, dated 06 / 05 / 2026, pages 100 / 143 91 / 92 [000184] Clause 16. The method of any of clauses 10-15, wherein the cancer is melanoma, lung cancer, colorectal cancer or a combination thereof, and wherein the compound is a compound of formula (Ia), or an acceptable salt thereof. [000185] Clause 17. The method of any of clauses 10-15, wherein the cancer is breast cancer, wherein the subject (1) is estrogen receptor positive, (2) is estrogen receptor negative and progesterone receptor negative, (3) expresses HER2 (HER2+), (4) does not express HER2 (HER2-), or a combination thereof. [000186] Clause 18. The method of any of clauses 10-15 and 17, wherein the cancer is breast cancer, and wherein the compound is a compound of formula (Ib), or a pharmaceutically acceptable salt thereof. [000187] Clause 19. The method of any of clauses 10-15, wherein cancer is melanoma, lung cancer, colorectal cancer, breast cancer or a combination thereof, and wherein the compound is a compound of formula (Ic), or a pharmaceutically acceptable salt thereof. [000188] The preceding description of the specific aspects will reveal the general nature of the invention so completely that others, applying knowledge of the art, may readily modify and / or adapt such specific aspects for various applications without undue experimentation and without departing from the general concept of the present disclosure. Therefore, such adaptations and modifications are intended to be within the meaning and scope of equivalents of the aspects. Petition 870260042444, dated 06 / 05 / 2026, pp. 101 / 143 92 / 92 disclosed, based on the teachings and guidance presented herein. It should be understood that the phraseology or terminology used herein is for descriptive purposes only and not for limitation, so the terminology or phraseology of this descriptive report should be interpreted by those skilled in the art in light of the teachings and guidance. [000189] The scope and extent of this disclosure shall not be limited by any of the exemplary aspects described above, but shall be defined only in accordance with the following claims and their equivalents. [000190] All publications, patents, patent applications and / or other documents cited in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application and / or other document were individually indicated to be incorporated by reference for all purposes. Petition 870260042444, dated 06 / 05 / 2026, pp. 102 / 143

Claims

1 / 6 CLAIMS 1. Compound of formula (I), or a pharmaceutically acceptable salt thereof, characterized in that it is: © θ Me3N^ \ .„ 3 OO—PChM—Q1—L—Q2-Z '7 (I) where: n is 2 -20; Q1 is a linkage or where m is 0 - 100; or HNX , where Rx is H or halogen; Q2 is a linkage, Z is an analogue of flavaglin.

2. A pharmaceutically acceptable compound or salt of Petition 870260042444, dated 06 / 05 / 2026, page 103 / 143 2 / 6, according to claim 1, characterized in that: Q1 is an OH or L-Q2 bond.

3. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, characterized in that n is 16-20.

4. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, characterized in that Rx is H or halogen.

5. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, Petition 870260042444, dated 06 / 05 / 2026, p. 104 / 143 3 / 6, characterized in that n is 18; Q1 is an L-Q2 and Rx is H or halogen.

6. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, characterized in that it is represented by formula (Ia) or formula (Ib), formula (Ia) is formula (Ib), wherein Z is an analogue of flavaglin. Petition 870260042444, dated 06 / 05 / 2026, p. 105 / 143 4 / 6 7. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, characterized in that the flavaglin analogue is 8. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, characterized in that it is selected from the group consisting of: Petition 870260042444, dated 06 / 05 / 2026, page 106 / 143 5 / 6 (CLR1800099B).

9. Pharmaceutical composition characterized in that it comprises a pharmaceutically acceptable compound or salt thereof as defined by any one of claims 1 to 8, and a pharmaceutically acceptable carrier.

10. Use of an effective amount of a compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 8, characterized in that it is for the manufacture of a medicament for the treatment of cancer in a patient who needs it.

11. Use according to claim 10, characterized in that the cancer is melanoma, lung cancer, colorectal cancer, breast cancer, or a combination thereof.

12. Use, according to any one of claims 10 to 11, characterized in that Lung cancer comprises small cell lung cancer, non-small cell lung cancer, or a combination thereof; Melanoma comprises superficial spreading melanoma, nodular melanoma, malignant lentiginous melanoma, acral lentiginous melanoma, amelanotic melanoma, nevoid melanoma, squamous cell melanoma, desmoplastic melanoma, or a combination thereof; Colorectal cancer comprises adenocarcinoma; or Breast cancer comprises invasive ductal carcinoma of the breast, metastatic breast cancer, inflammatory breast cancer, triple-negative breast cancer, ductal carcinoma in situ, or a combination thereof. Petition 870260042444, dated 06 / 05 / 2026, pp. 107 / 143 6 / 6 13. Use, according to any one of claims 10 to 12, characterized in that the cancer comprises cancerous stem cells.

14. Use, according to any one of claims 10 to 13, characterized in that the cancer comprises metastatic cancer cells.

15. Use, according to any one of claims 10 to 14, characterized in that the cancer comprises circulating tumor cells.

16. Use, according to any one of claims 10 to 15, characterized in that the cancer is breast cancer, wherein the subject (1) is estrogen receptor positive, (2) is estrogen receptor negative and progesterone receptor negative, (3) expresses HER2 (HER2+), (4) does not express HER2 (HER2-), or a combination thereof. Petition 870260042444, dated 06 / 05 / 2026, pp. 108 / 143

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