Anti-cancer nuclear hormone receptor-targeting compounds

Abstract

This invention relates to anticancer compounds derived from nuclear steroid receptor binders, products containing such anticancer compounds, and methods for their use and preparation.

Description

[Technical Field]

[0001] This invention relates to anticancer nuclear hormone receptor targeted compounds. [Previous Technology]

[0002] Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which break down into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII). Topoisomerases play important roles in cell proliferation and DNA organization because they mediate the cleavage of single-stranded and double-stranded DNA in eukaryotic cells, thereby relaxing supercoils, unwinding loops, and condensing chromosomes. Topoisomerase inhibitors affect these fundamental cellular processes. Some topoisomerase inhibitors prevent topoisomerases from carrying out DNA strand breaks, while others associate with topoisomerase-DNA complexes and prevent the reconnection step of the topoisomerase mechanism. These topoisomerase-DNA-inhibitor complexes are cytotoxic because unrepaired single-stranded and double-stranded DNA breaks induced by these complexes can lead to apoptosis and cell death. Due to this ability to induce apoptosis, topoisomerase inhibitors have gained attention as therapeutic agents against infected and cancerous cells.

[0003] Camptothecin (CPT) is a topoisomerase poison. It is isolated from the bark and branches of the tree *Camptotheca acuminata* (Camptotheca, Happy Tree), a tree native to China, which is used in traditional Chinese medicine for cancer treatment. CPT has shown significant anticancer activity in preliminary clinical trials, particularly against breast cancer, ovarian cancer, colon cancer, lung cancer, and gastric cancer. However, CPT has low solubility and adverse effects have been reported in its therapeutic use. Therefore, synthetic and medicinal chemists have developed numerous synthetic methods for camptothecin and its derivatives to increase the benefits of the chemicals, with good results. Currently, four CPT analogs are approved for use in cancer chemotherapy: topotecan, irinotecan, beloteccan, and trastuzumab deruxtecan. In addition to its role as an antitumor agent, camptothecin also exhibits anti-HIV activity because it interrupts the self-association of viral infectious agents present in many retroviruses, including HIV.

[0004] Many alternative uses for topoisomerase toxins may also emerge in the future, including lupus, rare brain disorders, sepsis, and viral and trypanosomiasis infections. As additional roles of Top1 (such as newly discovered regulatory functions) become apparent and Top1 continues to be involved in disease conditions, new drug discovery (and drug reuse) will continue in the coming years. [Summary of the Invention]

[0005] This document provides compounds comprising a nuclear payload such as a topoisomerase inhibitor, a topoisomerase toxin, or an analogue thereof, and a nuclear receptor-targeting antigenic determinant. The compounds described herein are designed to bind to intracellular nuclear receptors, allowing the compounds and their nuclear payload to accumulate in the cell nucleus. Not wishing to be bound by theory, one potential mode of enhancing efficacy is that this approach can provide compounds with cell type selectivity, rather than merely improving potency towards a higher therapeutic index. However, it is possible that the compounds could act via other modes, such as, but not limited to, passive localization in the nucleus.

[0006] Furthermore, the compounds described herein provide targeted delivery of nuclear payloads. The compounds target and localize within tumor tissue. Delivery of a compound comprising at least one nuclear receptor target antigenic determinant (such as a nuclear steroid receptor target antigenic determinant) covalently linked to at least one nuclear payload to the nucleus allows for the accumulation of the nuclear payload in the nucleus, thereby promoting tumor cell death. In this way, the compounds described in this invention can exhibit superior efficacy. Additionally, the compounds described in this invention, by accumulating in the nuclei of nuclear receptor-positive cells (such as steroid receptor-positive cells), displace cells that do not express specific nuclear steroid receptors, and thus reduce side effects.

[0007] In some embodiments, a compound of formula I, II or III, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog or pharmaceutically acceptable salt thereof is provided: A1-(L1-B1)m'I A1-L1-(B1)m'II A1-L1-B1III Wherein: A1 is a nuclear effective load (i.e., a topoisomerase inhibitor); m' is 1, 2 or 3; each B1 is independently a nuclear receptor target antigen determinant; and each L1 is independently a covalent bond or linker.

[0008] In some embodiments, a compound of formula III, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog or pharmaceutically acceptable salt thereof, is provided: A1-L1-B1III wherein: B1 is a nuclear receptor target antigen determinant; L1 is a covalent bond or linker; and A1 is a topoisomerase inhibitor.

[0009] Also provided is a compound of Table 1, or a stereoisomer, a mixture of stereoisomers, a hydrate, a solvate, an isotope-enriched analog or a pharmaceutically acceptable salt thereof.

[0010] A composition is also provided comprising a compound as described herein, or a stereoisomer thereof, a mixture of stereoisomers thereof, a hydrate, a solvate, an isotope-enriched analog or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] A method for treating or preventing cancer is also provided, comprising administering to an individual in need an effective amount of a compound or composition as described herein. Cancer may be leukemia, lung cancer, breast cancer, fallopian tube cancer, brain cancer, head and neck cancer, esophageal cancer, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer, or skin cancer, such as, but not limited to, liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, chronic lymphoblastic leukemia, Waldenström's macroglobulinemia. Macroglobulinemia, primary macroglobulinemia, bladder cancer, chronic granulocytic leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid, malignant melanoma, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urogenital cancer, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, skin cancer, trophoblastic tumor, or prostate cancer.

[0012] A method for treating or preventing cancer is also provided, comprising administering to an individual in need an effective amount of a compound or composition as described herein. In some embodiments, the cancer is neuroblastoma, brainstem glioma, Ewing's disease, non-small cell lung cancer, colorectal cancer, breast cancer, non-Hodgkin's lymphoma, endometrial cancer, or oligodendroglioma.

[0013] A method for treating or preventing neurogenetic diseases or conditions is also provided, comprising administering to an individual in need an effective amount of a compound or composition as described herein. In some embodiments, the neurogenetic disease or condition is Angelman syndrome.

[0014] A method for treating or preventing breast cancer is also provided, comprising administering to an individual in need an effective amount of a compound or composition as described herein. In some embodiments, the breast cancer is hormone receptor-positive metastatic breast cancer.

[0015] A method for treating or preventing prostate cancer is also provided, comprising administering to an individual in need an effective amount of a compound or composition as described herein. In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0016] A method for treating or preventing cancer is also provided, comprising administering to an individual in need an effective amount of a compound or composition as described herein, or a medically acceptable salt or solvate thereof, and additional chemotherapeutic agents.

Implementation Method

[0017] Cross-reference to related applications This application claims the benefit of U.S. Provisional Application No. 63 / 165,087, filed March 23, 2021, pursuant to 35 USC §119(e), the entire contents of which are incorporated herein by reference.

[0018] The following description illustrates exemplary embodiments of the technology of the present invention. However, it should be understood that this description is not intended to limit the scope of the present invention, but is instead provided as an exemplary embodiment.

[0019] 1. Definitions as used in this specification, unless otherwise indicated by the context, the following words, phrases and symbols are generally intended to have the meanings set forth below.

[0020] The term "about" refers to a variation of ±1%, ±3%, ±5%, or ±10% of the specified value. For example, "about 50" may include a range of 45 to 55 in some embodiments. For integer ranges, the term "about" may include one or both integers greater than and / or less than the stated integers at each end of the range. Unless otherwise indicated herein, the term "about" is intended to include values ​​close to the stated range that are functionally equivalent in relation to the individual ingredient, composition, or embodiment, such as weight percentage. Furthermore, unless the context clearly specifies otherwise, the singular forms "a" and "the" include a plurality of references. Thus, for example, a reference to "the compound" includes a plurality of such compounds, and a reference to "the analysis" includes references to one or more compounds and their equivalents known to those skilled in the art.

[0021] "alkyl" refers to and includes saturated straight-chain and branched monovalent hydrocarbon structures and combinations thereof having a specified number of carbon atoms (i.e., C1-C10 or C1-10 means one to ten carbon atoms). A specific alkyl group is an alkyl group having 1 to 20 carbon atoms ("C1-C20 alkyl"). In one embodiment, the alkyl group is an alkyl group having 1 to 12 carbon atoms ("C1-C12 alkyl"), an alkyl group having 1 to 8 carbon atoms ("C1-C8 alkyl"), an alkyl group having 3 to 8 carbon atoms ("C3-C8 alkyl"), an alkyl group having 1 to 6 carbon atoms ("C1-C6 alkyl"), an alkyl group having 1 to 5 carbon atoms ("C1-C5 alkyl"), or an alkyl group having 1 to 4 carbon atoms ("C1-C4 alkyl"). Examples of alkyl groups include (but are not limited to) groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, tert-butyl, homologues and isomers thereof, such as n-pentyl, n-hexyl, n-heptyl, n-octyl and similar groups.

[0022] As used herein, "alkenyl" refers to an unsaturated straight-chain or branched monovalent hydrocarbon chain or combination thereof having at least one alkene unsaturated site (i.e., having at least one C=C portion) and having a specified number of carbon atoms (i.e., C2-C10 or C2-10 means two to ten carbon atoms). Alkenyl groups may be in a "cis" or "trans" configuration, or alternatively in an "E" or "Z" configuration. Specific alkenyl groups are alkenyl groups having 2 to 20 carbon atoms ("C2-C20 alkenyl"), alkenyl groups having 2 to 8 carbon atoms ("C2-C8 alkenyl"), alkenyl groups having 2 to 6 carbon atoms ("C2-C6 alkenyl"), or alkenyl groups having 2 to 4 carbon atoms ("C2-C4 alkenyl"). Examples of alkenyl groups include (but are not limited to) groups such as ethenyl, propyl-1-enyl, propyl-2-enyl (or allyl), 2-methylpropyl-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-dienyl, their homologues and isomers, and similar groups.

[0023] As used herein, "alkylene" refers to a residue that is the same as an alkyl group but has a divalent oxidation state. Specific alkylene groups are alkylene groups having 1 to 6 carbon atoms ("C1-C6 alkylene groups"), alkylene groups having 1 to 5 carbon atoms ("C1-C5 alkylene groups"), alkylene groups having 1 to 4 carbon atoms ("C1-C4 alkylene groups"), or alkylene groups having 1 to 3 carbon atoms ("C1-C3 alkylene groups"). Examples of alkylene groups include (but are not limited to) groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), and similar groups. Similarly, the terms "alkenyl", "alkynyl", "heteroalkyl", "cycloalkyl", "heterocyclic", "aryl" and "heteroaryl" refer to alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl residues that are divalent as defined herein.

[0024] As used herein, "alkynyl" refers to an unsaturated straight-chain or branched monovalent hydrocarbon chain or combination thereof having at least one alkynyl unsaturated site (i.e., having at least one part of the formula C≡C) and having a specified number of carbon atoms (i.e., C2-C10 or C2-10 means two to ten carbon atoms). Specific alkynyl groups are alkynyl groups having 2 to 20 carbon atoms ("C2-C20 alkynyl"), alkynyl groups having 2 to 8 carbon atoms ("C2-C8 alkynyl"), alkynyl groups having 2 to 6 carbon atoms ("C2-C6 alkynyl"), or alkynyl groups having 2 to 4 carbon atoms ("C2-C4 alkynyl"). Examples of alkynyl groups include (but are not limited to) groups such as ethynyl, propynyl, propargyl (or propargyl), butynyl, butynyl, butynyl, butynyl, butynyl, their homologues and isomers, and similar groups.

[0025] "Amino" refers to an amine of the formula -N(RN)2, wherein each RN is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein each is substituted as appropriate, such as by one or more (e.g. 1 to 5 or 1 to 3) substituents (e.g., halo, cyano, hydroxyl, -NH2, -NH(alkyl), -N(alkyl)2, alkyl, alkenyl, alkynyl, alkoxy or haloalkoxy).

[0026] "Aryl" refers to and includes polyunsaturated aromatic hydrocarbon groups. An aryl group may contain other fused rings (e.g., 1 to 3 rings). In one variation, the aryl group contains 6 to 14 ring carbon atoms. In some embodiments, the aryl group has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 ring carbon atoms (i.e., C6-12 aryl), or 6 to 10 ring carbon atoms (i.e., C6-10 aryl). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and similar groups. It should be understood that aryl does not in any way encompass or overlap with heteroaryl groups as defined below. It should be understood that if one or more aryl groups are fused with a heteroaryl group, the resulting ring system is a heteroaryl group. It should be understood that if one or more aryl groups are fused with a heterocyclic group, the resulting ring system is a heterocyclic group.

[0027] "Carbonyl" refers to the group C=O.

[0028] "Cycloalkyl" refers to and includes cyclic hydrocarbon structures that may be fully saturated, monounsaturated, or polyunsaturated, but are non-aromatic, and have a specified number of carbon atoms (e.g., C1-C10 means one to ten carbons). A cycloalkyl group may consist of one ring (such as cyclohexyl) or multiple rings (such as adamantyl). Cycloalkyl groups containing more than one ring may be fused, helicaled, or bridged, or combinations thereof. In some embodiments, the cycloalkyl group has 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). It should be understood that the term cycloalkyl is intended to cover any non-aromatic ring that can fused with an aromatic ring, regardless of its connection to the rest of the molecule. Examples of cycloalkyl groups include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, noryl and similar groups.

[0029] “halo” or “halogen” refers to an element in Group 17 with atomic numbers 9 to 85. In some embodiments, halo includes fluorine, chlorine, bromine, and iodine. Where a residue is substituted by more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, such as dihaloaryl, dihaloalkyl, trihaloaryl, etc., which refer to aryl and alkyl groups substituted by two (“di”) or three (“tri”) halogen groups, which may be (but are not necessarily) the same halogen group; thus, 4-chloro-3-fluorophenyl falls within the category of dihaloaryl. An alkyl group in which all hydrogens are substituted by halogen groups is called a “perhaloalkyl”. In some embodiments, a perhaloalkyl is a trifluoroalkyl (-CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which each H of the alkyl moieties constituting the alkoxy group in the halogen-substituted hydrocarbon is an alkoxy group. An example of a perhaloalkoxy is trifluoromethoxy (-OCF3).

[0030] "Heteroalkyl" means an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are independently substituted with the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. By way of example, one, two, or three carbon atoms may be independently substituted with the same or different heteroatom groups. Heteroatom groups include (but are not limited to) -NH-, -O-, -S-, -S(O)-, -S(O)2-. Examples of heteroalkyl groups include, for example, ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3, -CH2CH2SCH2CH2SCH3, etc.), alkyl groups (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2OCH3, etc.) and amines (e.g., -CH2NHCH3, -CH(CH3)NHCH3, -CH2CH2NHCH3, -CH2CH2NHCH2CH2NHCH3, etc.). As used herein, heteroalkyl groups include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0031] "Heteroaryl" refers to and includes an unsaturated aromatic cyclic group having 1 to 10 cyclic carbon atoms and at least one cyclic heteroatom, such cyclic heteroatoms including (but not limited to) heteroatoms such as nitrogen, oxygen, and sulfur, wherein the nitrogen and sulfur atoms are oxidized as appropriate, and the nitrogen atom is quaternized as appropriate. In some embodiments, a heteroaryl group includes an unsaturated aromatic cyclic group having 1 to 10 cyclic carbon atoms and 1 to 4 cyclic heteroatoms. In some embodiments, a heteroaryl group includes a 5 to 12-membered ring system, a 5 to 10-membered ring system, or a 5 to 6-membered ring system, each independently having 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatom independently selected from nitrogen, oxygen, and sulfur. The heteroaryl group may be attached to the rest of the molecule at the cyclic carbon or at the cyclic heteroatom. Any aromatic ring having one or more fused rings and containing at least one heteroatom is considered a heteroaryl, regardless of its connection to the rest of the molecule (i.e., via any of the fused rings). A heteroaryl does not encompass or overlap with aryl groups as defined above. Examples of heteroaryl groups include (but are not limited to) pyridinyl, pyrimidinyl, phenylthio, furanyl, thiazolyl, pyrazolyl, acezolyl, isoacezolyl, imidazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, indole, benzothiazolyl, benzoacezolyl, benzoisoacezolyl, imidazopyridyl, and similar groups.

[0032] "Heterocycle" or "heterocyclyl" refers to a saturated or unsaturated non-aromatic group having 1 to 10 ring carbon atoms and 1 to 4 ring heteroatoms, such as nitrogen, sulfur, or oxygen and the like, wherein the nitrogen and sulfur atoms are oxidized as appropriate, and the nitrogen atom is quaternized as appropriate. It should be understood that any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl group, regardless of its connection (i.e., it may be bonded via carbon atoms or heteroatoms). Furthermore, the term heterocyclyl is intended to cover any non-aromatic ring containing at least one heteroatom that may be fused with an aryl or heteroaryl ring, regardless of its connection with the rest of the molecule. In some embodiments, heteroaryl groups include 3 to 12-membered ring systems, 3 to 10-membered ring systems, or 5 to 6-membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Heterocycles comprising more than one ring may be fused, screwed, or bridged, or any combination thereof. Examples of heterocyclic groups include (but are not limited to) tetrahydropiperanyl, dihydropiperanyl, piperidinyl, piperidinyl, pyrrolidinyl, thiazolinyl, thiazolinyl, tetrahydrofuranyl, dihydroisoazolyl, dihydroisoazolyl, dioxacyclopentyl, piperanyl, dioxacyclohexyl, tetrahydrophenylthio, and similar groups.

[0033] "Side group" refers to the part = O.

[0034] Unless otherwise specified, "substituted as appropriate" means that the group may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents listed for the group, wherein such substituents may be the same or different, provided that they do not exceed the normal valence of the group. In one embodiment, the substituted group has one substituent. In another embodiment, the substituted group has two substituents. In another embodiment, the substituted group has three substituents. In another embodiment, the substituted group has four substituents. In some embodiments, the substituted group has 0 to 2, 0 to 5, 1 to 2, 2 to 5, 3 to 5, 2 to 3, 2 to 4, 3 to 4, 1 to 3, 1 to 4, or 1 to 5 substituents.

[0035] Also provided are stereoisomers, mixtures of stereoisomers, tautomers, hydrates, solvates, isotope-enriched analogs and pharmaceutically acceptable salts of the compounds described herein.

[0036] The compounds disclosed herein, or their pharmaceutically acceptable salts, may include asymmetric centers and thus may produce enantiomers, diastereomers, and other stereoisomers, which may be defined, in absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids. This invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using pachysynthetic agents or pachysynthetic reagents, or resolved using conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for preparing / separating individual enantiomers include pachysynthesis from suitable optically pure precursors or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, pachyhigh-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, and unless otherwise stated, the compounds are intended to include E and Z geometric isomers.

[0037] "Stereoisomers" refers to compounds consisting of identical atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. This invention covers various stereoisomers and mixtures thereof, including "enantiomers," which are two stereoisomers whose molecules are non-overlapping mirror images of each other; and "diastereomers," which are stereoisomers having at least two asymmetric atoms but not being mirror images of each other. Therefore, it covers all stereoisomers of the compounds of this invention (e.g., geometric isomers, optical isomers, and the like) (including stereoisomers of salts, solvates, and hydrates of the compounds), such as stereoisomers that may exist due to asymmetric carbons on various substituents, including enantiomers (which may even exist in the absence of asymmetric carbons), rotational isomers, hysteresis isomers, and diastereoisomers.

[0038] A mixture of diastereomers can be separated into their individual diastereomers based on their physicochemical differences using methods well known to those skilled in the art (such as, for example, chromatography and / or fractional crystallization). Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a palmitic auxiliary, such as a palmitic alcohol or Mosher's acid chloride) to convert the enantiomer mixture into a diastereomer mixture, separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into their corresponding pure enantiomers. Furthermore, some compounds may be lag isomers and are considered part of this invention. Stereoisomers can also be separated using palmitic HPLC.

[0039] Some compounds exist as tautomers. These tautomers are in equilibrium with each other. For example, acetylamine-containing compounds can exist in equilibrium with imine tautomers. Regardless of the type of tautomers exhibited or the nature of the equilibrium between them, those skilled in the art generally understand a compound to include both acetylamine and imine tautomers. Therefore, acetylamine-containing compounds are understood to include their imine tautomers. Similarly, imine-containing compounds should be understood to include their acetylamine tautomers.

[0040] The term "hydrate" refers to a complex formed by combining the compounds described herein with water.

[0041] "Solvate" refers to an association or complex of one or more solvent molecules with the compound of the present invention. Examples of solvents that form solvates include (but are not limited to): water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

[0042] Any compound or structure given herein is intended to represent both unlabeled and isotopically labeled forms of such compounds. Such forms of compounds may also be referred to as "isotopically enriched analogs." Isotopically labeled compounds have the structures described herein, except that one or more atoms are replaced by atoms having selected atomic masses or mass numbers. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. The various isotopically labeled compounds of the present invention are, for example, those compounds containing radioactive isotopes such as 3H and 14C. Such isotopically labeled compounds are suitable for metabolic studies, reaction kinetic studies, detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or matrix tissue distribution analysis), or for use in the radiotherapy of patients. These compounds can exhibit increased metabolic resistance and are therefore suitable for increasing the half-life of any compound when administered to mammals, particularly humans. These compounds are synthesized using methods well-known in this art, for example, by employing starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0043] Certain compounds disclosed herein contain one or more ionizable groups (from proton-removable groups (e.g., -COOH), proton-adding groups (e.g., amines), or quaternary ammoniation-compatible groups (e.g., amines)). All possible ionic forms of such molecules and their salts are intended to be individually included in the disclosure herein. Regarding salts of the compounds described herein, those skilled in the art can select appropriate relative ions from a wide variety of available relative ions. In particular applications, the selection of a given anion or cation for preparing the salt can increase or decrease the solubility of the salt.

[0044] As used herein, the term "non-biodegradable linker" means a linker that is not readily hydrolyzed under physiological conditions. As used herein, the term "biodegradable linker" means a linker that is readily hydrolyzed under physiological conditions. In some embodiments, at least one linker is hydrolyzed under intracellular conditions (e.g., low pH).

[0045] As used herein, the term "cancer" refers to a class of mammalian diseases characterized by uncontrolled cell growth. The term "cancer" may be used interchangeably with the terms "tumor," "solid tumor," "malignant tumor," "excessive proliferation," and "necrotic tumor." Cancer includes all types of excessive proliferative growth, proliferative growth, neoplastic growth, carcinogenic growth or carcinogenic processes, metastatic tissue or malignantly transformed cells, tissues, or organs, regardless of the type or stage of aggressive histopathology. Illustrative examples include lung cancer, prostate cancer, head and neck cancer, breast cancer and colorectal cancer, melanoma, and gliomas (such as advanced gliomas, including glioblastoma multiforme (GBM), the most common and deadliest malignant primary brain tumor in adult humans).

[0046] The term "solid tumor" includes, for example, lung cancer, head and neck cancer, brain cancer, oral cancer, colorectal cancer, breast cancer, prostate cancer, pancreatic cancer, and liver cancer. Other types of solid tumors are named according to the specific cells that form them, such as sarcomas formed by connective tissue cells (e.g., bone, cartilage, fat), carcinomas formed by epithelial tissue cells (e.g., breast, colon, pancreas), and lymphomas formed by lymphoid tissue cells (e.g., lymph nodes, spleen, thymus). Regardless of the naming conventions, the treatment of all types of solid tumors is within the scope of this invention.

[0047] "Chemotherapy agent" means any substance that can reduce or prevent the growth, proliferation or spread of cancer cells, cancer cell populations, tumors or other malignant tissues. The term is also intended to cover radiotherapy or any antitumor or anticancer agent.

[0048] As used herein, "treatment" is a method for obtaining a beneficial or desired outcome (such as a clinical outcome). For the purposes of this invention, a beneficial or desired clinical outcome includes (but is not limited to) relieving symptoms and / or reducing the severity of symptoms and / or preventing the worsening of symptoms associated with a disease or condition. In some embodiments, "treatment" is a method for obtaining a beneficial or desired outcome (such as a clinical outcome). For the purposes of this invention, a beneficial or desired clinical outcome includes (but is not limited to) relieving symptoms and / or reducing the severity of symptoms and / or preventing the worsening of symptoms associated with a disease or condition. In a variation, a beneficial or desired clinical outcome includes (but is not limited to) relieving symptoms and / or reducing the severity of symptoms and / or preventing the worsening of symptoms associated with cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders, and / or neuronal disorders. In some embodiments, treatment of a disease or condition with the compounds of this invention or their medically acceptable salts has no side effects, or the accompanying side effects are fewer than those associated with currently available therapies for the disease or condition, and / or improves the individual's quality of life.

[0049] The term "inhibit / inhibiting / inhibition" refers to slowing down, stopping, or reversing the growth or progression of a disease, infection, condition, or cell population. For example, inhibition can be greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99% compared to growth or progression that occurs in the absence of treatment or exposure.

[0050] As used herein, "combination therapy" means a therapy comprising two or more different compounds. Thus, in one embodiment, a combination therapy is provided comprising the compounds detailed herein and another compound. In some variations, the combination therapy may include one or more pharmaceutically acceptable carriers or excipients, non-medically active compounds, and / or inert substances. In various embodiments, treatment with the combination therapy may produce additive or even synergistic (e.g., greater than additive) results compared to administration of a single compound of the invention alone. In some embodiments, a lower amount of each compound is used as part of the combination therapy compared to the amount typically used in an individual therapy. In some embodiments, the combination therapy achieves the same or greater therapeutic benefit compared to using any one of the individual compounds alone. In some embodiments, the combination therapy achieves the same or greater therapeutic benefit using a smaller amount (e.g., a lower dose or less frequent dosing schedule) of the compound compared to the amount typically used in an individual compound or therapy. In some embodiments, using a small amount of the compound reduces the number, severity, frequency, and / or duration of one or more compound-related side effects.

[0051] As used herein, the term "effective amount" is intended to be effective in a given therapeutic manner, in combination with the efficacy and toxicity parameters of the compounds of the present invention and based on the knowledge of a practitioner. As understood in the art, an effective amount can be one or more doses; that is, achieving the desired therapeutic endpoint may require a single dose or multiple doses. Therefore, an "effective amount" may be considered in the case of administration of one or more therapeutic agents, and a single agent may be considered to be administered at an effective amount if desired or favorable results can be obtained or have been obtained in combination with one or more other agents. The appropriate dose of any co-administered compound may be reduced as appropriate due to the combined effects of the compounds (e.g., additive or synergistic effects).

[0052] As used herein, the terms "antagonist" or "inhibitor" refer to compounds whose presence reduces the bioactivity of a target protein or enzyme. For example, a "topoisomerase inhibitor" is any compound that inhibits the function of one or more topoisomerases.

[0053] As used herein, IC50 refers to the amount, concentration, or dose of a specific test compound that achieves 50% inhibition of the maximum response (such as topoisomerase regulation) in an analysis measuring this response.

[0054] As used herein, EC50 refers to a dose, concentration or amount at which the dose-dependent response induced by a particular test compound is 50% of the maximum performance of the particular response induced, caused or enhanced by the particular test compound.

[0055] As used herein, the term "cancer" refers to the abnormal growth of cells that tend to proliferate in an uncontrolled manner and, in some cases, tend to metastasize (spread). Types of cancer include (but are not limited to) solid tumors (such as solid tumors of the bladder, intestines, brain, breast, endometrium, heart, kidneys, lungs, lymphoid tissue (lymphoma), ovaries, pancreas, or other endocrine organs (thyroid), etc.), prostate tumors, skin tumors (melanoma), or hematologic malignancies (such as leukemia).

[0056] As used herein, the term “carrier” refers to a relatively non-toxic compound or agent that promotes the incorporation of a compound into cells or tissues.

[0057] As used herein, "unit dosage form" means a physically discrete unit suitable for use as a unit dose, each unit containing a predetermined amount of active ingredient and required pharmaceutical carrier calculated to produce the desired therapeutic effect. Unit dosage forms may contain single or combination therapies.

[0058] As used herein, the term "controlled release" refers to a formulation containing a drug or a portion thereof, wherein the drug is not released immediately; that is, with respect to a "controlled release" formulation, administration does not result in the immediate release of the drug into the absorption tank. This term encompasses reservoir-type formulations designed to release the drug compound gradually over an extended period of time. Controlled release formulations can include a wide variety of drug delivery systems, which typically involve mixing a drug compound with a carrier, polymer, or other compound having the desired release characteristics (e.g., pH-dependent or pH-independent solubility, varying degrees of water solubility, and the like), and formulating the mixture according to the desired delivery route (e.g., coated capsules, implantable reservoirs, biodegradable capsules containing injectable solutions, and the like).

[0059] As used herein, "medically acceptable" or "pharmacologically acceptable" means a material that has no adverse effects on biology or otherwise, that is, a material that can be incorporated into a pharmaceutical composition administered to a patient without causing any significant adverse biological effects or interacting in a harmful manner with any other component in the composition containing it. In some embodiments, a pharmaceutically acceptable carrier or excipient meets the required standards for toxicological and manufacturing testing and / or is included in the Inactive Ingredient Guide developed by the U.S. Food and Drug Administration.

[0060] "Pharmaceutically acceptable salts" are salts that retain at least some of the biological activity of a free (non-salt) compound and can be administered to an individual as a drug or medicine. Such salts include, for example: (1) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids, such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in a parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion) or coordinated with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like. Other examples of pharmaceutically acceptable salts include those listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. January 1977; 66(1):1-19. Pharmaceutically acceptable salts can be manufactured in situ during a preparation process or prepared by reacting the purified compound of the invention, in its free acid or free base form, separately with a suitable organic or inorganic base or acid, and separating the resulting salt during subsequent purification. It should be understood that references to pharmaceutically acceptable salts include their solvation or crystalline forms, specifically, solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are typically formed during a crystallization process. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholic compound is formed. Polymorphs comprise different crystalline arrangements of the same elemental composition of the compound. Polymorphs typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Various factors, such as recrystallization solvents, crystallization rates, and storage temperatures, can promote the dominance of single-crystal forms.

[0061] As used herein, the term "excipient" means an inert or inactive substance that can be used in the manufacture of a drug or pharmaceutical product, such as a tablet containing the compound of the present invention as an active ingredient. The term "excipient" can cover a variety of substances, including (but not limited to) any of the following: binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solution for non-enterovenous administration, material for chewable tablets, sweetener or flavoring agent, suspending / gelling agent, or wet granulation agent. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coatings include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coating, etc.; compression / encapsulation aids include, for example, calcium carbonate, dextrose, fructose DC. Materials for chewable tablets include: (directly compressible), honey DC, lactose (anhydrous or monohydrate; combined with aspartame, cellulose, or microcrystalline cellulose as appropriate), starch DC, sucrose, etc.; disintegrants include, for example, sodium croscarmellose, gellan gum, sodium glycolate starch, etc.; creams or lotions include, for example, maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, for example, dextrose, fructose DC, lactose (monhydrate, combined with aspartame or cellulose as appropriate), etc.; suspending / gelling agents include, for example, carrageenan, sodium glycolate starch, saccharin, etc.; sweeteners include, for example, aspartame, dextrose, fructose DC, sorbitol, sucrose DC, etc.; and wet granulation agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0062] Compounds This document provides targeted compounds for the treatment of cancer. The compounds described herein are capable of targeting the cell nucleus by recognizing and binding nuclear receptor target antigen determinants to individual binding sites and delivering a nuclear payload to the cell nucleus. The nuclear payload can then bind to one or more target sites within the nucleus and / or disrupt one or more cellular processes, thereby causing cell death.

[0063] In some embodiments, the nuclear payload is bonded to the nuclear receptor target antigenic determinant via a linker portion. In some embodiments, the linker portion provides a single bond or a single bond, meaning that the linker binds to only one atom of each of the payload and the antigenic determinant.

[0064] Therefore, a compound of formula I, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog or pharmaceutically acceptable salt thereof, is provided: A1-(L1-B1)m'I where: A1 is a nuclear effective load (i.e., a topoisomerase inhibitor); m' is 1, 2 or 3; each B1 is independently a nuclear receptor target antigen determinant; and each L1 is independently a covalent bond or linker.

[0065] In some embodiments, one or more nuclear receptor target antigen determinants are bonded to the nuclear payload via a single linker. Thus, a compound of formula II, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog, or pharmaceutically acceptable salt thereof, is also provided: A1-L1-(B1)m'II Wherein: A1 is the nuclear payload (i.e., a topoisomerase inhibitor); m' is 1, 2, or 3; each B1 is independently a nuclear receptor target antigen determinant; and L1 is a linker.

[0066] In some embodiments, a compound is provided comprising, where appropriate, a nuclear payload bound to a nuclear receptor target antigenic determinant via a linker portion. Thus, a compound of formula III, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog, or pharmaceutically acceptable salt thereof, is provided: A1-L1-B1III Wherein: A1 is the nuclear payload (i.e., a topoisomerase inhibitor); B1 is the nuclear receptor target antigenic determinant; and L1 is a covalent bond or linker portion.

[0067] In some embodiments of Formula I, II or III, A1 is:; wherein the wavy line indicates, as appropriate, a connection point via a connecting portion (e.g. -L1-B1) to at least one nuclear steroid receptor target antigen determinant.

[0068] In some embodiments of Formula I, II, or III, A1 is: , where the tilde refers to the connection point with L1. In some embodiments, A1 is: , where the tilde refers to the connection point with L1.

[0069] In some embodiments, any of the compounds disclosed herein (e.g., compounds of formula I, II, or III) comprises a topoisomerase inhibitor analog that, even after modification to obtain the compounds described herein, exhibits biological activity equivalent to that observed in the original, unmodified topoisomerase inhibitor. In some embodiments, the topoisomerase inhibitor analog maintains its ability to inhibit topoisomerases. In some embodiments, the binding activity exhibited by the topoisomerase inhibitor analog is at least about 98%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% of the binding activity observed in the original, unmodified topoisomerase inhibitor.

[0070] In some embodiments, any of the compounds disclosed herein (e.g., compounds of formula I, II, or III) binds B1 to an estrogen receptor, a glucocorticoid receptor, a progesterone receptor, or an androgen receptor. In some embodiments, B1 binds to an estrogen receptor. In some embodiments, B1 binds to a glucocorticoid receptor. In some embodiments, B1 binds to a progesterone receptor. In some embodiments, B1 binds to an androgen receptor. Exemplary estrogen receptor, glucocorticoid receptor, progesterone receptor, or androgen receptor binders are described herein.

[0071] Nuclear payload In some embodiments, the nuclear payload (i.e., A1) in the compounds described herein is a topoisomerase inhibitor. As used herein, the term "topoisomerase inhibitor" refers to a chemical compound or portion that blocks the action of topoisomerases (or DNA topoisomerases) that are involved in the overrotation or underrotation of DNA.

[0072] Topoisomerases, which break down into two broad subtypes (Type I topoisomerase (TopI) and Type II topoisomerase (TopII)), play important roles in cell proliferation and DNA organization because they mediate the cleavage of single-stranded and double-stranded DNA in eukaryotic cells, thereby relaxing supercoils, unwinding loops, and condensing chromosomes. Topoisomerase inhibitors affect these fundamental cellular processes. In some embodiments, topoisomerase inhibitors prevent topoisomerases from performing DNA strand breaks. In some embodiments, topoisomerase inhibitors are referred to as topoisomerase toxins and associate with topoisomerase-DNA complexes to prevent the reconnection step of the topoisomerase mechanism. These topoisomerase-DNA-inhibitor complexes are cytotoxic agents because unrepaired single-stranded and double-stranded DNA breaks induced by these complexes can lead to apoptosis and cell death. Due to this ability to induce apoptosis, topoisomerase inhibitors have been used as therapeutic agents against infectious and cancerous cells.

[0073] In some embodiments, the core effective load (i.e., A1) of the compounds described herein is derived from camptothecin (CPT). Therefore, in some embodiments, the core effective load (i.e., A1) of the compounds described herein is an analogue of camptothecin (CPT). In some embodiments, the core effective load (i.e., A1) of the compounds described herein is derived from topotecan, irinotecan (CPT-11), silatecan (DB-67, AR-67), cositecan (BNP-1350), exatecan, lurtotecan, gimatecan (ST1481), belotetcan (CKD-602), or rubitecan or an analogue thereof.

[0074] In some embodiments, the terms "derived from" or "likely" used when referring to the nuclear payload (i.e., A1) mean that at most one non-hydrogen atom of the original unmodified nuclear payload (i.e., a known topoisomerase inhibitor) is replaced by a covalent bond to the nuclear receptor target antigen determinant via a linker, as appropriate. Exemplary non-hydrogen atoms include, but are not limited to, -CH3, -OH, =O, and -NH2. In some embodiments, the term "derived from" used when referring to the nuclear payload (i.e., A1) means that one or more atoms (e.g., hydrogen, methyl, or hydroxyl) of the original unmodified nuclear payload (i.e., a topoisomerase inhibitor) are replaced by a direct covalent bond to L1. Exemplary non-hydrogen atoms include, but are not limited to, -CH3, -OCH3, -OH, =O, -NH2, -N(CH3)2, and the like. In some embodiments, a hydrogen atom (e.g., N, O, or S) bonded to a heteroatom (i.e., a known topoisomerase inhibitor) of the original, unmodified nuclear payload is replaced by a covalent bond linked to L1. In some embodiments, the term "derived from" means that one or more atoms (e.g., hydrogen, methyl, or hydroxyl) are replaced by a direct covalent bond linked to L1.

[0075] In some embodiments, one or more atoms (e.g., hydrogen, methyl, hydroxyl, amino, etc.) on the nuclear payload (i.e., A1) disclosed herein are substituted for attachment to the remainder of the compound (e.g., partially -L1-B1). In some embodiments, hydrogen atoms on the nuclear receptor target antigenic determinant disclosed herein are substituted for attachment to the remainder of the compound. In some embodiments, the hydrogen atom is on a heteroatom. In some embodiments, the hydrogen atom is on a halogen. In some embodiments, the hydrogen atom is on nitrogen. In some embodiments, the hydrogen atom is on oxygen. In some embodiments, the hydrogen atom is on carbon (e.g., methyl). The analogues are derived from known nuclear payloads (e.g., topoisomerase inhibitors or A1) described herein and modified, where appropriate, to bind to at least one nuclear hormone receptor target antigenic determinant via a linker. Even after modification to obtain the compounds described herein, the analogues maintain biological activity equivalent to that observed in the original unmodified topoisomerase inhibitors. In some embodiments, the binding activity or inhibition exhibited by the compound is at least about 98%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% or about 5-50% of the binding activity or inhibition observed in the original, unmodified topoisomerase inhibitor. In some embodiments, the compound as described herein exhibits an IC50 of less than about 500 nM, or less than about 400 nM, or less than about 350 nM, or less than about 300 nM, or less than about 200 nM, or less than about 100 nM, or less than about 50 nM.

[0076] In some embodiments of formula I, II, or III, A1 is a compound of formula IA: wherein: Y is a bond, -CH2- or -CH2-CH2-; Z is a bond or O; R1, R2, R3, and R4 are each independently hydrogen, halogroup, cyanogroup, nitrogroup, -OR15, -SR15, -NR15R16, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R15, -C(=O)OR15, -OC(=O)R15, -C(=O)NR15R16, -NR15C ... O)R16, -NR15C(=O)OR16, -S(=O)1-2R15, -S(=O)1-2NR15R16, -NR15S(=O)1-2R16, -Si(R15)3 or -C=NOR15, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group of R1, R2, R3 and R4 is independently substituted by one or more R10 groups as the valence number allows; Or R1 and R2 together with the atoms they are attached to form C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups substituted with one or more R10 groups, as permitted by the valence; or R2 and R3 together with the atoms they are attached to form C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups substituted with one or more R10 groups, as permitted by the valence; or R3 and R4 together with the atoms they are attached to form C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups substituted with one or more R10 groups, as permitted by the valence. Each R10 is independently a halogen, cyano, nitro, -OR17, -SR17, -SF5, -NR17R18, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R17, -C(=O)OR17, -OC(=O)OR17, -OC(=O)R17, -C(=O)NR17R18, -OC(=O)NR17R18, -NR7C(=O)NR17R18, -S(=O)1-2R 17. -S(=O)1-2NR17R18, -NR17S(=O)1-2R18, -NR17S(=O)1-2NR17R18, -NR17C(=O)R18, -NR17C(=O)OR18, -Si(R17)3 or -C=NOR17, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group of R10 is independently substituted by one or more halogen groups or C1-12 alkyl groups (which are substituted by side oxygen, halogen, hydroxyl or amino groups as appropriate) when the valence number allows;Furthermore, each of R15 and R16 is independently hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl, wherein each alkyl, alkenyl, alkynyl, or cycloalkyl group is independently substituted with a side-oxygen group, halogen group, hydroxyl group, or amino group as permitted by valence; or R15 and R16 together with the atoms they are attached to form heterocyclic groups substituted with halogen groups or C1-12 alkyl groups (substituted with side-oxygen groups, halogen groups, hydroxyl groups, or amino groups as permitted by valence); and each of R17 and R1 8 is independently hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 ynyl or C3-12 cycloalkyl, wherein each of the C1-12 alkyl, C2-12 alkenyl, C2-12 ynyl or C3-12 cycloalkyl groups is substituted with a side-oxygen group, halogen group, hydroxyl group or amino group as the valence allows; or R17 and R18 together with the atoms they are attached to form a heterocyclic group substituted with a halogen group or a C1-12 alkyl group (which is substituted with a side-oxygen group, halogen group, hydroxyl group or amino group as appropriate); wherein one or more atoms of formula IA (e.g. hydrogen, methyl or hydroxyl) are directly covalently substituted with L1.

[0077] In embodiments where L1 is a bond, the phrase "substituted by direct covalent bond L1" means that the group is substituted by a direct covalent bond connected to B1.

[0078] In some embodiments, the hydrogen atom of formula IA is replaced by a direct covalent bond to L1.

[0079] In some embodiments, one or more atoms (e.g., hydrogen, methyl or hydroxyl) of one of R1, R2 and R3 are replaced by direct covalent bonds to L1.

[0080] In some embodiments, Y is -CH2-.

[0081] In some embodiments, Z is 0.

[0082] In some embodiments, Y is -CH2- and Z is O.

[0083] In some embodiments of the various forms described herein, the terms heterocyclic, aryl or heteroaryl refer to 3 to 10-membered heterocyclic, 6 to 10-membered aryl or 5 to 10-membered heteroaryl.

[0084] In some embodiments, a compound of formula IA-1, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog, or pharmaceutically acceptable salt thereof, is provided: wherein: R1, R2, R3, and R4 are each independently hydrogen, halogroup, cyanogroup, nitrogroup, -OR15, -SR15, -NR15R16, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R15, -C(=O)OR15, -OC(=O)R15, -C(=O)NR15R16, - NR15C(=O)R16, -S(=O)1-2R15, -S(=O)1-2NR15R16, -NR15S(=O)1-2R16, -Si(R15)3 or -C=NOR15, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group of R1, R2, R3 and R4 is independently substituted by one or more R10 groups as the valence number allows; Or R1 and R2 together with the atoms they are attached to form C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups substituted with one or more R10 groups, as permitted by the valence; or R2 and R3 together with the atoms they are attached to form C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups substituted with one or more R10 groups, as permitted by the valence; or R3 and R4 together with the atoms they are attached to form C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups substituted with one or more R10 groups, as permitted by the valence. Each R10 is independently a halogen, cyano, nitro, -OR17, -SR17, -SF5, -NR17R18, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R17, -C(=O)OR17, -OC(=O)OR17, -OC(=O)R17, -C(=O)NR17R18, -OC(=O)NR17R18, -NR7C(=O)NR17R18, -S(=O)1-2R 17. -S(=O)1-2NR17R18, -NR17S(=O)1-2R18, -NR17S(=O)1-2NR17R18, -NR17C(=O)R18, -NR17C(=O)OR18, -Si(R17)3 or -C=NOR17, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group of R10 is independently substituted by one or more halogen groups or C1-12 alkyl groups (which are substituted by side oxygen, halogen, hydroxyl or amino groups as appropriate) when the valence number allows;Furthermore, each of R15 and R16 is independently hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl, wherein each of the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl is independently substituted with a side-oxygen group, a halogen group, a hydroxyl group, or an amino group, as the valence allows; or R15 and R16 together with the atoms they are attached to form heterocycles substituted with a halogen group or a C1-12 alkyl group (which is substituted with a side-oxygen group, a halogen group, a hydroxyl group, or an amino group, as appropriate). The group consists of a hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl group, wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl group is substituted with a side-oxygen group, halogen group, hydroxyl group, or amino group as permitted by valence; or R17 and R18 together with the atoms to which they are attached form a heterocyclic group substituted with a halogen group or a C1-12 alkyl group (which is substituted with a side-oxygen group, halogen group, hydroxyl group, or amino group as permitted); wherein one or more atoms (e.g., hydrogen, methyl, hydroxyl, etc.) are directly covalently substituted to at least one nuclear receptor target antigen determinant via a linker portion (e.g., -L1-B1) as defined herein. In some embodiments, the hydrogen atom of formula IA-1 is directly covalently substituted to L1.

[0085] In some embodiments of formula I, II or III, A1 is a compound of formula IB: wherein: R1 is hydrogen, -C=NOR15 or, as appropriate, a C1-6 alkyl group substituted with one or more R10s; R2 is hydrogen, a C1-6 alkyl group, -N(R17R18)2, -NO2, -C1-6 alkyl-O-C1-6 alkyl or -C1-6 alkyl-N(R17R18)2; or R1 and R2 together with the atoms to which they are attached form, as appropriate, a C3-10 cycloalkyl group substituted with one or more R10s; R3 is hydrogen, hydroxyl, halogen, C1-6 alkyl or -O-C1-6 alkyl; R4 is hydrogen, halogen, C1-6 alkyl or -O-C1-6 alkyl; or R3 and R4 together form -O-CH2-O- or -O-CH2CH2-O-; Y is a bond, -CH2- or -CH2-CH2-; and Z is a bond or O; wherein one or more atoms of one of R1, R2 and R3 are replaced by direct covalent bonds to L1.

[0086] In some embodiments, the hydrogen atoms of formula IB are replaced by direct covalent bonds to L1.

[0087] In some embodiments, a compound of formula IB, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog, or pharmaceutically acceptable salt thereof, is provided: wherein: R1 is hydrogen or -L1-B1; R2 is hydrogen, NH2, NO2, or -L1-B1; R3 is hydrogen, a halogen, methyl, methoxy, or -L1-B1; R4 is hydrogen, a halogen, methyl, or methoxy; or R3 and R4 together form -O-CH2-O- or -O-CH2CH2-O-; Y is a bond, -CH2-, or -CH2-CH2-; and Z is a bond or O.

[0088] In some embodiments, only one of R1, R2, or R3 is -L1-B1. In some embodiments, R1 is -L1-B1. In some embodiments, R2 is -L1-B1. In some embodiments, R3 is -L1-B1.

[0089] In some embodiments, a compound of formula IC, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog, or pharmaceutically acceptable salt thereof, is provided: wherein: B1 is a nuclear receptor target antigen determinant as defined herein; n is 2, 3, or 4; A is O or NH; R3 is hydrogen, halo, methyl, or methoxy; R4 is hydrogen, halo, methyl, or methoxy; or R3 and R4 together form -O-CH2-O- or -O-CH2CH2-O-; Y is a bond, -CH2-, or -CH2-CH2-; and Z is a bond or O.

[0090] In some embodiments, a compound of formula ID, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog, or pharmaceutically acceptable salt thereof, is provided: wherein: L1 is the linking moiety; B1 is a nuclear receptor target antigen determinant as defined herein; R4 is hydrogen, a halogroup, a methyl group, or a methoxy group; each of R17 and R18 is independently hydrogen, a C1-12 alkyl, a C2-12 alkenyl, or a C2-12 alkynyl, wherein each C1-12 alkyl, C2-12 alkenyl, or C2-12 alkynyl is substituted with a side-oxygen group, a halogroup, a hydroxyl group, or an amino group as the valence permits; or R17 and R18 together with the atom to which they are linked form a heterocyclic group substituted with a halogroup or a C1-12 alkyl group (which is substituted with a side-oxygen group, a halogroup, a hydroxyl group, or an amino group as the case may be) as the case may be; Y is a bond, -CH2-, or -CH2-CH2-; and Z is a bond or O.

[0091] In some embodiments, a compound of formula IE, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog, or pharmaceutically acceptable salt thereof, is provided: wherein: L1 is a linking moiety; B1 is a nuclear receptor target antigen determinant as defined herein; R4 is hydrogen, a halogroup, a methyl group, or a methoxy group; R17 is hydrogen, a C1-12 alkyl group, a C2-12 alkenyl group, or a C2-12 alkynyl group, wherein each C1-12 alkyl group, C2-12 alkenyl group, or C2-12 alkynyl group is substituted with a side-oxygen group, a halogroup, a hydroxyl group, or an amino group as permitted by valence; Y is a bond, -CH2-, or -CH2-CH2-; and Z is a bond or O.

[0092] In some embodiments, a compound of formula IF, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog or pharmaceutically acceptable salt thereof, is provided: wherein: L1 is a linking moiety; B1 is a nuclear receptor target antigen determinant as defined herein; R4 is hydrogen, halogroup, methyl or methoxy; Y is a bond, -CH2- or -CH2-CH2-; and Z is a bond or O.

[0093] In some embodiments, an IG compound, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog, or pharmaceutically acceptable salt thereof, is provided: wherein: B1 is a nuclear receptor target antigen determinant as defined herein; A is N or CH; R3 is hydrogen, halogroup, methyl, or methoxy; R4 is hydrogen, halogroup, methyl, or methoxy; or R3 and R4 together form -O-CH2-O- or -O-CH2CH2-O-; Y is a bond, -CH2-, or -CH2-CH2-; and Z is a bond or O.

[0094] In some embodiments, a compound of formula IH, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog or pharmaceutically acceptable salt thereof, is provided: wherein: B1 is a nuclear receptor target antigen determinant as defined herein; A is N or CH; R4 is hydrogen, halogen, methyl, or methoxy; or each R10 is independently halogen, cyano, nitro, -OR17, -SR17, -SF5, -NR17R18, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R17, -C(=O)OR17, -OC(=O)OR17, -OC(=O)R17, -C(=O)NR17R18, -OC(=O)NR17R18, -NR7C(=O)NR17R18, -S =O)1-2R17, -S(=O)1-2NR17R18, -NR17S(=O)1-2R18, -NR17S(=O)1-2NR17R18, -NR17C(=O)R18, -NR17C(=O)OR18, -Si(R17)3 or -C=NOR17, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group of R10 is independently substituted by one or more halogen groups or C1-12 alkyl groups (which are substituted by side oxygen, halogen, hydroxyl or amino groups as appropriate) when the valence number allows; Each R17 and R18 is independently hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl, wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl is substituted with a side-oxygen group, halogen group, hydroxyl group, or amino group as the valence allows; or R17 and R18 together with the atom to which they are attached form a heterocyclic group substituted with a halogen group or a C1-12 alkyl group (which is substituted with a side-oxygen group, halogen group, hydroxyl group, or amino group as the valence allows); Y is a bond, -CH2-, or -CH2-CH2-; and Z is a bond or O.

[0095] In some embodiments, a compound of formula IJ, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog, or pharmaceutically acceptable salt thereof, is provided: wherein: R3 is hydrogen, hydroxyl, -CH2NH2, or -C(=O)H; when R3 is -CH2NH2 or -C(=O)H, R2 is hydrogen; or when R3 is hydrogen or hydroxyl, R2 is -C(=O)H or -CH2R11; R11 is -OR12, -SR12, -CH2NH2, -NR12R13, or -N+R12R13R14; R12, R13, and R14 are each independently hydrogen, C1-6 alkyl, C2-6 hydroxyalkyl, C1-6 dialkylamino, C1-6 dialkylamino-C2-6 alkyl, C1-6 alkylamino-C2-6 alkyl, C2-6 aminoalkyl, or 3 to 7 unsubstituted or substituted rings; and when R11 is -NR12R13, the R12 and R13 groups may combine with their bonded nitrogen atoms to form a heterocycle, subject to the restriction that the heterocycle is selected from N-hydroxyl, N-methylpiperidyl, or 4'-piperidinidinyl, each of which may contain additional heteroatoms; or a pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein the atoms (e.g., hydrogen, carbon, or heteroatoms) are, where appropriate, directly covalently substituted to at least one nuclear receptor target antigen determinant via a linker (e.g., -L1-B1) as defined herein.

[0096] In some embodiments, the nuclear payload is derived from topotecan or its analogues (i.e., analogues containing topotecan). In some embodiments, a compound of formula IK is provided: wherein B1 is a nuclear receptor target antigen determinant; and L1 is a covalent bond or linker.

[0097] In some embodiments, the nuclear payload is derived from irinotecan (CPT-11) or its analogues (i.e., irinotecan-containing analogues). In some embodiments, an IL compound is provided, wherein B1 is a nuclear receptor target antigenic determinant; and L1 is a covalent bond or linker. In some embodiments, an IM compound is provided, wherein B1 is a nuclear receptor target antigenic determinant; and L1 is a covalent bond or linker.

[0098] In some embodiments, the nuclear payload is derived from slatecan (DB-67, AR-67) or its analogues (i.e., analogues containing slatecan). In some embodiments, a compound of formula IN is provided: wherein B1 is a nuclear receptor target antigen determinant; and L1 is a covalent bond or linker.

[0099] In some embodiments, the nuclear payload is derived from costatec (BNP-1350) or its analogues (i.e., costatec-containing analogues). In some embodiments, a compound of formula 10 is provided: wherein B1 is a nuclear receptor target antigen determinant; and L1 is a covalent bond or linker.

[0100] In some embodiments, the nuclear payload is derived from ethatecan or an analogue thereof (i.e., an ethatecan-containing analogue). In some embodiments, an IP compound is provided, wherein B1 is a nuclear receptor target antigenic determinant; and L1 is a covalent bond or linker. In some embodiments, an IQ compound is provided, wherein B1 is a nuclear receptor target antigenic determinant; and L1 is a covalent bond or linker.

[0101] In some embodiments, the nuclear payload is derived from letopecan or an analogue thereof (i.e., an analogue containing letopecan). In some embodiments, an IR compound of formula IR is provided: wherein B1 is a nuclear receptor target antigen determinant; and L1 is a covalent bond or linker.

[0102] In some embodiments, the nuclear payload is derived from gematecan (ST1481) or its analogues (i.e., gematecan-containing analogues). In some embodiments, a compound of formula IS is provided: wherein B1 is a nuclear receptor target antigen determinant; and L1 is a covalent bond or linker.

[0103] In some embodiments, the nuclear payload is derived from belotecone (CKD-602) or its analogues (i.e., belotecone-containing analogues). In some embodiments, an IT compound of formula is provided: wherein B1 is a nuclear receptor target antigen determinant; and L1 is a covalent bond or linker.

[0104] In some embodiments, the nuclear payload is derived from rubotecan or an analogue thereof (i.e., an analogue containing rubotecan). In some embodiments, a compound of formula IU is provided: wherein B1 is a nuclear receptor target antigen determinant; and L1 is a covalent bond or linker.

[0105] In some embodiments, the core payload (i.e., A1) is derived from:

[0106] In some embodiments, the core payload or A1 series is derived from:

[0107] In some embodiments, the core payload is derived from:

[0108] In some embodiments, the core payload is derived from:

[0109] In some embodiments, the core payload is derived from:

[0110] In some embodiments, the core payload is derived from:

[0111] In some embodiments, the core payload is derived from:

[0112] In some embodiments, the core payload is derived from:

[0113] In some embodiments, the core payload is derived from:

[0114] In some embodiments, the core payload is derived from:

[0115] In some embodiments, the core payload is derived from:

[0116] Nuclear Receptor Target Antigen Determinant In some embodiments, B1 is a nuclear hormone receptor target antigen determinant. In some embodiments, B1 is a nuclear steroid receptor target antigen determinant. As used herein, "nuclear receptor target antigen determinant" refers to a portion of the compound described herein (e.g., B1) that is derived from a nuclear target agent as disclosed herein and interacts with the ligand-binding domain of the target nuclear receptor (i.e., the portion of the compound that drives the ligand-binding interaction). Nuclear receptor target antigen determinants are used to associate the compound with a target nuclear receptor (e.g., a nuclear steroid receptor), facilitating the localization of the compound to cells expressing the nuclear steroid receptor and allowing the nuclear payload to translocate from the cytosol to the nucleus, thereby allowing the compound to accumulate in the nucleus. The accumulation level can be controlled by selecting an appropriate nuclear receptor target antigen determinant. For example, the compounds described herein can accumulate in the nucleus to varying degrees via nuclear translocation of nuclear steroid receptors (which occurs after the antigenic determinant binds to the receptor), with higher levels in the case of full agonists (e.g., dihydrotestosterone (DHT)), moderate levels in the case of partial agonists (e.g., bicalutamide), and lower levels in the case of antagonists (e.g., enzalutamide).

[0117] The steroid receptor target can be any steroid receptor, including but not limited to steroid receptors overexpressed on cancer cells. In some embodiments, at least one nuclear steroid receptor target antigenic determinant is capable of binding to the ligand-binding domain of a nuclear steroid receptor, such as the ligand-binding domain of an estrogen receptor, glucocorticoid receptor, progesterone receptor, or androgen receptor.

[0118] Exemplary nuclear steroid receptor target antigenic determinants include those derived from the following antigenic determinants: androgen receptor agonists, androgen receptor antagonists, selective androgen receptor modulators (SARMs), estrogen receptor agonists, estrogen receptor antagonists, selective estrogen receptor modulators (SERMs), glucocorticoid receptor antagonists, glucocorticoid receptor agonists, selective glucocorticoid receptor modulators (SGRMs), progesterone receptor antagonists, progesterone receptor agonists, selective progesterone receptor modulators (SPRMs), or combinations thereof.

[0119] Nuclear steroid receptor target antigenic determinants are typically able to bind to nuclear steroid receptors at IC50 of less than about 500 nM, or less than about 400 nM, or less than about 300 nM, or less than about 200 nM or less than about 100 nM, or at EC50 of less than about 1 µM, or less than about 900 nM, or less than about 800 nM, or less than about 700 nM, or less than about 600 nM, or less than about 500 nM, or less than about 400 nM, or less than about 300 nM, or less than about 200 nM or less than about 100 nM.

[0120] In some embodiments, the nuclear hormone receptor binding affinity of the compounds of the present invention may be defined according to their affinity relative to a reference nuclear hormone receptor binding compound. For example, some compounds of the present invention can bind to estrogen receptors. In some cases, the affinity of the compounds disclosed herein for binding to human estrogen receptors is at least 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of their affinity for 17β-estradiol.

[0121] By way of additional examples, some of the compounds of the present invention can bind to human androgen receptors. In some cases, the affinity of the compounds disclosed herein for binding to androgen receptors is at least 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of their affinity for binding to dihydrotestosterone (DHT).

[0122] By way of additional examples, some of the compounds of the present invention can bind to human progesterone receptors. In some cases, the affinity of the compounds disclosed herein for binding to the progesterone receptor is at least 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of their affinity for binding to progesterone.

[0123] By way of additional examples, some of the compounds of the present invention can bind to human glucocorticoid receptors. In some cases, the affinity of the compounds disclosed herein for binding to glucocorticoid receptors is at least 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of their affinity for cortisone.

[0124] In some embodiments, the nucleosteroid receptor target antigenic determinant (e.g., B1) is a agonist at the androgen receptor. In some embodiments, the nucleosteroid receptor target antigenic determinant is an antagonist at the androgen receptor.

[0125] In some embodiments, the nuclear steroid receptor target antigenic determinant (e.g., B1) is a steroid (or a steroid-derived compound) (e.g., dihydrotestosterone). In some embodiments, the nuclear steroid receptor target antigenic determinant is a non-steroid (or a non-steroid-derived compound) (e.g., enzalutamide, apalutamide, AZD9496, and bicalutamide).

[0126] The analogues are derived from known nucleosteroid receptor target antigenic determinants (e.g., B1) described herein and modified, where appropriate, to bind to at least one nucleosteroid payload via a linker. Even after modification to obtain the compounds described herein, the analogues retain biological activity equivalent to that observed in the original unmodified nucleosteroid receptor target antigenic determinant. In some embodiments, the binding activity or inhibition exhibited by the compounds is at least about 98%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% or about 5-50% of the binding activity or inhibition observed in the original unmodified nucleosteroid receptor target antigenic determinant.

[0127] In some embodiments, the analogue is derived from a known nuclear receptor target antigenic determinant (e.g., B1), such as a known nuclear steroid receptor target antigenic determinant. In some embodiments, B1 binds to an estrogen receptor, glucocorticoid receptor, progesterone receptor, or androgen receptor. In some embodiments, the term "derived from," as used when referring to a nuclear receptor target antigenic determinant, means that at most one non-hydrogen atom of the original unmodified nuclear receptor target compound (i.e., a known nuclear steroid receptor target compound) is covalently substituted to the nuclear payload via a linker, as appropriate. Exemplary non-hydrogen atoms include, but are not limited to, -CH3, -OH, =O, and -NH2. In some embodiments, the term "derived from," as used when referring to a nuclear receptor target antigenic determinant, means that at most one non-hydrogen atom of the original unmodified nuclear receptor target compound (i.e., a known nuclear steroid receptor target compound) is covalently substituted to the nuclear payload via a linker, as appropriate. In some embodiments, a hydrogen atom (e.g., N, O, or S) bonded to a heteroatom of the original, unmodified nuclear receptor target compound (i.e., a known nuclear steroid receptor target compound) is replaced by a covalent bond, as appropriate, connected to the nuclear payload via a linker. In some embodiments, the term "derived from" means that one or more atoms (e.g., hydrogen, methyl, or hydroxyl) are replaced by a direct covalent bond connected to L1.

[0128] In some embodiments, the nuclear steroid receptor target antigenic determinant (e.g., B1) is an androgen receptor target antigenic determinant. As used herein, the term "androgen receptor target antigenic determinant" is intended to refer to a portion of a compound that binds to an androgen receptor and can function as an androgen receptor agonist or androgen receptor antagonist (including partial androgen receptor agonists or partial androgen receptor antagonists), and in some embodiments, it is capable of binding to the receptor and the ligand-receptor complex moving from the cytoplasm into the cell nucleus. An "androgen receptor" (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that, upon activation by binding to an androgen receptor binder (e.g., androgen hormones such as testosterone or dihydrotestosterone) in the cytoplasm, translocates androgens to the cell nucleus.

[0129] Exemplary androgen receptor target antigen determinants (e.g., B1) that can be used in the compounds described herein include (but are not limited to) androgen receptor agonists, selective androgen receptor modulators (SARMs) (e.g., enobosarm), androgen receptor antagonists (e.g., bicalutamide, flutamide, nilutamide, or enzalutamide), selective estrogen receptor modulators (SERMs) (e.g., tamoxifen, toremifene, or raloxifene), estrogen receptor antagonists (e.g., fulvestrant), progestins (e.g., megestrol acetate), estrogens (e.g., estramustine), ketoconazole, abiraterone, darolutamide, or analogues thereof.

[0130] In some embodiments, the nuclear steroid receptor target antigen determinant (e.g., B1) is a selective androgen receptor modulator (SARM). In some embodiments, the compound comprises at least one nuclear steroid receptor target antigenic determinant, independently comprising antigenic determinants derived from: testosterone, testosterone esters (e.g., testosterone heptaate, testosterone propionate, testosterone cyclopentylpropionate, etc., or analogs thereof), enoxaparin, BMS-564929, PS178990, LGD-4033 (ligandrol), LGD-2941, AC-262,356, JNJ-28330835, JNJ-37654032, JNJ-26146900, LGD-2226, LGD-3303, LGD-121071, LG-120907, S-40503, S-23, testolone (RAD-140), acetylthiouracil, and andaline. (S-4), LG-121071, TFM-4AS-1, YK-11, MK-0773 (PF-05314882), GSK2849466, GSK2881078, GSK8698, GSK4336, ACP-105, TT701, LY2452473 (TT-701), 1-(2-hydroxy-2-methyl-3-phenoxypropionyl)-indoline-4-carboxynitrile derivatives (J Med Chem. 2014, 57(6), 2462-71) or analogues thereof.

[0131] In some embodiments, a single atom on the nuclear receptor target antigenic determinant (B1) as disclosed herein is substituted for attachment to the remainder of the compound (e.g., partially -L1-B1). In some embodiments, a halogen atom on the nuclear receptor target antigenic determinant as disclosed herein is substituted for attachment to the remainder of the compound. In some embodiments, a hydrogen atom on the nuclear receptor target antigenic determinant as disclosed herein is substituted for attachment to the remainder of the compound. In some embodiments, the hydrogen atom is on a heteroatom. In some embodiments, the hydrogen atom is on nitrogen. In some embodiments, the hydrogen atom is on oxygen. In some embodiments, the hydrogen atom is on carbon.

[0132] In some embodiments, B1 has formula IIA: wherein: the wavy bond refers to the connection point with L1; R30 is hydrogen, C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, C2-12 ynyl or C3-12 cycloalkyl, wherein each C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, C2-12 ynyl or C3-12 cycloalkyl is independently substituted by one to five R100 as the valence number allows; R40 is hydrogen, C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, C2-12 ynyl or C3-12 cycloalkyl, wherein each C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, C2-12 ynyl or C3-12 cycloalkyl is independently substituted by one to five R100 as the valence number allows; Each R50 is independently a halogen, cyano, nitro, -OR170, -SR170, -NR170R180, C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, or C2-12 alkynyl; wherein each C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, or C2-12 alkynyl is independently substituted with one to five halogen, hydroxyl, or amino groups as the valence allows; Each R100 is independently a side-oxygen group, halogen group, cyano group, nitro group, -OR170, -SR170, -SF5, -NR170R180, C1-12 alkyl group, C2-12 alkenyl group, C2-12 alkynyl group, C3-10 cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -C(=O)R170, -C(=O)OR170, -OC(=O)OR170, - OC(=O)R170, -C(=O)NR170R180, -OC(=O)NR170R180, -NR170C(=O)NR170R180, - S(=O)1-2R170, -S(=O)1-2NR170R180, -NR170S(=O)1-2R180, -NR170S(=O)1-2NR 170R180, -NR170C(=O)R180, -NR170C(=O)OR180 or -C=NOR17, wherein each of the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl groups of R100 is independently substituted with one or more halogens or C1-12 alkyl groups (which are substituted with oxy, halogen, hydroxy or amino groups as appropriate), and each of R170 and R180 is independently hydrogen or a C1-12 alkyl group substituted with oxy, halogen, hydroxy or amino groups as appropriate, or R170 and R180 together with the atoms to which they are attached form a heterocyclic group substituted with halogens or C1-12 alkyl groups (which are substituted with oxy, halogen, hydroxy or amino groups as appropriate).

[0133] In some embodiments, B1 has the formula IIB: wherein: the wavy bond refers to the connection point with L1; R60 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C3-12 cycloalkyl, wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C3-12 cycloalkyl is independently substituted by one to five R100 as the valence number allows; R80 is hydrogen, hydroxyl, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy or C3-12 cycloalkyl, wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C1-12 alkoxy or C3-12 cycloalkyl is independently substituted by one to five R100 as the valence number allows; R81 is hydrogen, hydroxyl, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, or C3-12 cycloalkyl, wherein each of the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, or C3-12 cycloalkyl groups may be independently substituted by one to five R100 groups, as the valence allows; or R80 and R81 together with the atoms they are attached to form heterocyclic groups substituted by halogens or C1-12 alkyl groups (which may be substituted by oxy, halogen, hydroxyl, or amino groups, as appropriate); Each R100 is independently a side-oxygen group, halogen group, cyano group, nitro group, -OR170, -SR170, -SF5, -NR170R180, C1-12 alkyl group, C2-12 alkenyl group, C2-12 alkynyl group, C3-10 cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -C(=O)R170, -C(=O)OR170, -OC(=O)OR170, - OC(=O)R170, -C(=O)NR170R180, -OC(=O)NR170R180, -NR170C(=O)NR170R180, - S(=O)1-2R170, -S(=O)1-2NR170R180, -NR170S(=O)1-2R180, -NR170S(=O)1-2NR 170R180, -NR170C(=O)R180, -NR170C(=O)OR180 or -C=NOR17, wherein each of the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl groups of R100 is independently substituted with one or more halogens or C1-12 alkyl groups (which are substituted with oxy, halogen, hydroxy or amino groups as appropriate), and each of R170 and R180 is independently hydrogen or a C1-12 alkyl group substituted with oxy, halogen, hydroxy or amino groups as appropriate, or R170 and R180 together with the atoms to which they are attached form a heterocyclic group substituted with halogens or C1-12 alkyl groups (which are substituted with oxy, halogen, hydroxy or amino groups as appropriate).

[0134] In some embodiments, B1 has the formula IIC: wherein: the wavy bond refers to the connection point with L1; R60 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C3-12 cycloalkyl, wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C3-12 cycloalkyl is independently substituted by one to five R100 as the valence allows; each R100 is independently a side-oxygen group, halogroup, cyanogroup, nitrogroup, -OR170, -SR170, -SF5, -NR170R180, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclic group, aryl group, heteroaryl group, -C(=O)R170, -C(=O)OR170, -OC(=O)OR170, - OC(=O)R170, -C(=O)NR170R180, -OC(=O)NR170R180, -NR170C(=O)NR170R180, - S(=O)1-2R170, -S(=O)1-2NR170R180, -NR170S(=O)1-2R180, -NR170S(=O)1-2NR 170R180, -NR170C(=O)R180, -NR170C(=O)OR180 or -C=NOR17, wherein each of the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl groups of R100 is independently substituted with one or more halogens or C1-12 alkyl groups (which are substituted with oxy, halogen, hydroxy or amino groups as appropriate), and each of R170 and R180 is independently hydrogen or a C1-12 alkyl group substituted with oxy, halogen, hydroxy or amino groups as appropriate, or R170 and R180 together with the atoms to which they are attached form a heterocyclic group substituted with halogens or C1-12 alkyl groups (which are substituted with oxy, halogen, hydroxy or amino groups as appropriate).

[0135] In some embodiments, B1 has the formula IID: wherein: the wavy bond refers to the connection point with L1; A'' and A''' are each independently O or S; Ra and Rb are each independently CH3 or CH2CH3; or Ra and Rb together with the atoms they are attached to form a C3-5 cycloalkyl, ethylene oxide, oxetane or tetrahydrofuran; B, B10, B2, B3, B', B1', B2' and B3' are each independently CRc or N; each Rc is independently hydrogen, fluorine, CN or methyl; D is NH, O, S, CH2 or C=O; X'' is CN, a halogroup or NO2; Y'' is CH3, CH2Rd, CHF2 or CF3; Rd is a halogroup; Z''' is H, C1-2 alkyl, C2 alkenyl or NO2; or X'' and Y'' are formed together, wherein the dashed line indicates the bond to the ring; It can be formed by Y'' and Z''' together, each of which is a single bond or a double bond, and the dashed line indicates the bond connected to the ring; and Z' is CH or N.

[0136] In some embodiments, B1 has the formula IIE: wherein: the wavy bond refers to the connection point with L; Q is; wherein bond a is connected to ring a and bond b is connected to ring b; Ra and Rb are each independently -CH3 or -CH2CH3; or Ra and Rb together with the atoms they are connected to form a C3-5 cycloalkyl, ethylene oxide, oxacyclobutyl or tetrahydrofuranyl; A and A' are each independently O or S; E, E1, E2 and E3 are each independently CRc or N, and each Rc is independently hydrogen, halogroup, CN or methyl; E4 is CF, CH or N; Q1 is bond, CH2, C=O or (C=O)NH; Q2 is NH, O, S, CH2, NH(C=O), C(=O)NH or C=O; R44, R45 and R46 are each independently hydrogen, CN or C1-2 alkyl; t is 0, 1, 2, 3 or 4; Each Re is independently a halogroup, cyanogroup, C1-4 alkyl group, or C1-4 haloalkyl group; R41 is a halogroup, CN group, or NO2 group; R42 is a halogroup, CH3 group, CH2F group, CHF2 group, or CF3 group; or R41 and R42 are formed together, wherein the dashed line indicates the bond to ring a; R43 is hydrogen, halogroup, C1-2 alkyl group, C2 alkenyl group, NO2 group, or CF3 group; or R42 and R43 are formed together, wherein each is a single or double bond, and wherein the dashed line indicates the bond to ring a.

[0137] In some embodiments, B1 is: ; wherein: R30 is hydrogen, C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, C2-12 ynyl or C3-12 cycloalkyl, wherein each C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, C2-12 ynyl or C3-12 cycloalkyl is independently substituted by one to five R100 as the valence number allows; R40 is hydrogen, C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, C2-12 ynyl or C3-12 cycloalkyl, wherein each C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, C2-12 ynyl or C3-12 cycloalkyl is independently substituted by one to five R100 as the valence number allows; Each R50 is independently a halogroup, cyanogroup, nitrogroup, -OR170, -SR170, -NR170R180, C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, or C2-12 ynyl; wherein each C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, or C2-12 ynyl is independently substituted by one to five halogroups, hydroxyl groups, or amino groups as permitted by the valence number; R60 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 ynyl, or C3-12 cycloalkyl, wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 ynyl, or C3-12 cycloalkyl is independently substituted by one to five R100 groups as permitted by the valence number; Each R100 is independently a side-oxygen group, halogen group, cyano group, nitro group, -OR170, -SR170, -SF5, -NR170R180, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -C(=O)R170, -C(=O)OR170, -OC(=O)OR170, -OC(=O)R170, -C(=O)NR170R180, -OC(=O)NR170R180, -NR170C(=O)NR170R180, -S(=O)1-2R1 70, -S(=O)1-2NR170R180, -NR170S(=O)1-2R180, -NR170S(=O)1-2NR170R180, -NR170C(=O)R180, -NR170C(=O)OR180 or -C=NOR17, wherein each of the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl and heteroaryl groups of R100 is independently substituted with one or more halogens or C1-12 alkyl groups (which are substituted with lateral oxygen, halogen, hydroxyl or amino groups as appropriate, where the valence allows); each of R170 and R180 is independently hydrogen or a C1-12 alkyl group substituted with lateral oxygen, halogen, hydroxyl or amino groups as appropriate, where the valence allows;Alternatively, R170 and R180, together with the atoms they are attached to, form heterocyclic groups that are substituted with a halogen or C1-12 alkyl group (which may be substituted with a side oxygen, halogen, hydroxyl, or amino group, depending on the case); A'' and A''' are each independently O or S; Ra and Rb are each independently CH3 or CH2CH3; or Ra and Rb, together with the atoms they are attached to, form C3-5 cycloalkyl, ethylene oxide, oxetane, or tetrahydrofuran; B, B10, B2, B3, B', B1', B2', and B3' are each independently CRc or N; each Rc is independently hydrogen, fluorine, CN, or methyl; D is NH, O, S, CH2, or C=O; X'' is CN, a halogen, or NO2; Y'' is CH3, CH2Rd, CHF2, or CF3; Rd is a halogen; Z''' is H, C1-2 alkyl, C2 alkenyl, or NO2; or X'' and Y'' are formed together; or Y'' and Z''' are formed together; and Z' is CH or N.

[0138] In some embodiments, B1 is: where the tilde refers to the connection point with L1.

[0139] In some embodiments, B1 is: , or a stereoisomer or mixture of stereoisomers or the like, wherein the wavy line indicates the connection point with the core payload via the connection portion as appropriate.

[0140] In some embodiments, B1 is derived from progesterone, enoxaparin, bicalutamide, apalutamide, testosterone, dihydrotestosterone, testosterone, 19-nortestosterone, progesterone, adalin, cortisol, prednisone, flutamide, niludamide, enzalutamide, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, megestrol acetate, estradiol, abiraterone, LGD-2941, BMS-564929, ostarine, ulipristal acetate, asopridine (J867), mifepristone, telapristone (CDB-4124, Proellex, Progenta) or analogues thereof.

[0141] In some embodiments, B1 is derived from progesterone, enoxaparin, bicalutamide, apalutamide, testosterone, dihydrotestosterone, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bardoxifene, octopimiphene, medroxyprogesterone acetate, abiraterone, LGD-2941, BMS-564929, ostalin, or analogues thereof.

[0142] In some embodiments, B1 comprises a nuclear receptor target antigen determinant derived from:, or a stereoisomer or mixture of stereoisomers thereof or the like thereof, wherein at least one hydrogen atom is replaced by a direct covalent bond to A1 via a linker portion, as appropriate.

[0143] These and other selective androgen receptor modulators (SARMs) that can be used as nuclear steroid receptor target antigen determinants in B1 as described herein are found in US 6,462,038, US 6,777,427, WO2001 / 027086, WO2004 / 013104, WO2004 / 000816, WO2004 / 0113309, US2006 / 0211756, US2006 / 0063819, US2005 / 245485, US2005 / 250741, US2005 / 277681, WO2006 / 060108, WO2004 / 041277, WO Among them are 2003 / 034987, US2006 / 0148893, US2006 / 0142387, WO2005 / 000795, WO2005 / 085185, WO2006 / 133216, WO2006 / 044707, WO2006 / 124447, WO2007 / 002181, WO2005 / 108351, WO2005 / 115361 and US2006 / 0160845.

[0144] In some embodiments, B1 is a selective estrogen receptor modulator (SERM). In some embodiments, B1 comprises antigenic determinants derived from: aordrin, badoxifene, broparestrol, clomiphene, cyclofenil, lasofoxifene, ormeloxifene (Centron, Novex, Novex-DS, Sevista), oxifene (Osphena, desaminoglycantoremifene), raloxifene (Evista), tamoxifen (Nolvadex), toremifene (Fareston; 4-chlorotamoxifen), acolbifene, afimoxifene (4-hydroxytamoxifen; a metabolite of tamoxifen), elacestrant, and enclomifene. (E)-Cromiphene, Endoxifen (4-hydroxy-N-demethyltamoxifen; a metabolite of tamoxifen), Zuclomifene ((Z)-Cromiphene), Bardoxifene, Arzoxifene, Brilanestrant, Clomifenoxide (clomifen N-oxide; a metabolite of clomiphene), Droloxifen (3-hydroxytamoxifen), Etastil, Fispemifene, GW-7604 (4-hydroxyentastil), Idoxifen ((N-pyrrolidyl)-4-iodotamoxifen), Levomeloxifene ((L)-Omexifen), miproxifene, naproxen, nitromifene (CI-628), panomifene, pipendoxifene (ERA-923), trioxifene, keoxifene hydrochloride, LY117018, onapristone, fareston (toremifene citrate), or zindoxifene (D-16726), or analogues thereof.

[0145] In some embodiments, SERMs are structurally classified as triphenylene (tamoxifen, clomiphene, toremifene, traloxifen, edoxifene, opemifene, nonpemiphene, afifoxifene, etc. or their analogues), benzothiophene (raloxifene, azoxifen, etc. or their analogues), indole (bardoxifene, cindoxifen, piperonoxifene, etc. or their analogues), tetrahydronaphthalene (lasoxifene, naphthoxidine, etc. or their analogues) or benzopiperanone (acobifene, omexifen, levomexifen, etc. or their analogues).

[0146] In some embodiments, B1 is a selective estrogen receptor downregulator (SERD). In some embodiments, the compound comprises at least one nuclear steroid receptor target antigenic determinant, independently comprising antigenic determinants derived from: fulvestrant, bryanestrant (ARN-810), entastista (GW5638), AZD9496, giredestrant (GDC-9545), or GW7604.

[0147] In some embodiments, B1 is a selective progesterone receptor modulator (SPRM). In some embodiments, B comprises an antigenic determinant derived from uretol acetate, asolinib (J867), mifepristone, terazosone (CDB-4124, Proellex, Progenta), or analogues thereof.

[0148] In some embodiments, B1 comprises antigenic determinants derived from: estrogen, estradiol, estriol, estrone, progesterone, enoxaparin, bicalutamide, apalutamide, testosterone, dihydrotestosterone, estradiol, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bardoxifene, octopimiphene, megestrol acetate, estmustine, abiraterone, LGD-2941, BMS-564929, ostalin, or analogues thereof.

[0149] In some embodiments, at least one nuclear steroid receptor target antigen determinant is an androgen receptor target antigen determinant and comprises: , or a stereoisomer or mixture of stereoisomers or the like thereof, wherein the wavy line indicates, as appropriate, the connection point with the nuclear payload via the connecting portion.

[0150] In some embodiments, at least one nuclear steroid receptor target antigen determinant is an estrogen receptor target antigen determinant and comprises: or a stereoisomer or mixture of stereoisomers thereof or the like thereof, wherein the wavy line indicates, as appropriate, the connection point with the nuclear payload via the connecting portion.

[0151] In some embodiments, at least one nuclear steroid receptor target antigen determinant is an estrogen receptor target antigen determinant and comprises:; or a stereoisomer or mixture of stereoisomers thereof or the like thereof, wherein the wavy line indicates, as appropriate, the connection point with the nuclear payload via the connecting portion.

[0152] In some embodiments, at least one nuclear steroid receptor target antigen determinant comprises: , or a stereoisomer or mixture of stereoisomers thereof or the like thereof, wherein the wavy line indicates, as appropriate, the connection point with the nuclear payload via the connecting portion.

[0153] In some embodiments, at least one nuclear steroid receptor target antigen determinant comprises:; or a stereoisomer or mixture of stereoisomers thereof or the like thereof, wherein the wavy line indicates, as appropriate, the connection point with the nuclear payload via the connecting portion.

[0154] In some embodiments, the nuclear steroid receptor target antigen determinant is not or does not contain peptides, proteins, nanoparticles or antibodies.

[0155] Linking Membrane The "linking membrane" of any compound described herein may be biodegradable (e.g., acid-labile) or non-biodegradable. The linking membrane may be straight-chain, branched-chain, saturated, unsaturated, all-carbon, or heteroatom. The linking membrane may also contain one or more rings that are fused, saturated, unsaturated, all-carbon, or heteroatom. In some embodiments, the linking membrane is a non-biodegradable linking membrane. In some embodiments, the linking membrane is a biodegradable linking membrane. In some embodiments, the nuclear payload is bonded to a nuclear steroid receptor target antigenic determinant via a non-biodegradable linking membrane and to one or more nuclear steroid receptor target antigenic determinants via biodegradable linking membranes. In some embodiments, the biodegradable linking membrane is an acid-labile linking membrane. In some embodiments, the linking membrane comprises a hydrazone bond.

[0156] It is considered that any linker may be used in the compounds described herein, provided that the linker does not significantly interfere with or disrupt the desired binding of the nuclear payload or nuclear receptor target antigen determinant.

[0157] In some embodiments, the linking portion is an alkyl group, azaalkyl group, anenyl group, anenylene group, anynyl group, anynylene group, an aryl group, anynylene group, ancycloalkyl group, or anynylene group; wherein each alkyl group, azaalkyl group, anenyl group, anenylene group, anynylene group, anynylene group, or anynylene group may, as appropriate, include an aryl group, anynylene group, anynylene group, or anynylene group; and furthermore, each alkyl group, azaalkyl group, anenylene group, anenylene group, anynylene group, anynylene group, anynylene group, or anynylene group is independently, as appropriate, substituted by one to five independently selected substituents from the following: syloxy group, halogen group, C1-4 alkyl group, C1-4 alkoxy group, and C1-4 haloalkyl group.

[0158] In some embodiments, the connecting portion L1 has the following formula: -(La)q-, where: each La is -NR110-, -O-, -S(O)0-2-, -NR110C(O)-, -C(O)NR110-, -NR110C(O)NR110-, -NR110S(O)2-, -S(O)2NR110-, -NR110S(O)2NR110-, -CR120=N-NR110-, -NR110-N=CR120-, -C(O-), -OC(O-, - OC(O)O-, -C(O)O-, alkyl, alkenyl, alkyne, aryl, cycloalkyl, heterocyclic or heterocyclic, wherein each alkyl, alkenyl, alkyne, aryl, cycloalkyl, heterocyclic or heterocyclic is independently substituted, as appropriate, by one to five independently selected substituents from: syloxy, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic; Each R110 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic; each R120 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic; and q is an integer from 0 to 20.

[0159] In some embodiments, the connection portion L1 has the following formula: -Y10-(CHR130)n'-Y20-(CHR140)n''-Y30-(CHR150)m''-Y40- Wherein: each of Y10, Y20, Y30 and Y40 is independently a bond, -NR110-, -O-, -S(O)0-2-, -NR110C(O)-, -C(O)NR110-, -NR110C(O)NR110-, -NR110S(O)2-, -S(O)2NR110-, -NR110S(O)2NR110-, -CR120=N-NR110-, -NR110-N=CR120-, -C(O) -、-OC(O)-、-OC(O)O-、-(CH2CH2O)1-5-、-C(O)O-、extrinyl、extrinyl, extrinylaryl、extrincycloalkyl、extrinheterocyclic and extrinheteroaryl; wherein each extrinyl, extrinyl, extrinyl, extrinylaryl, extrincycloalkyl, extrinheterocyclic or extrinheteroaryl is independently substituted, as appropriate, by one to five independently selected substituents from the following: syloxy, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or C1-4 haloalkoxy; Each R110 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic; each R120 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic; each R130 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic; each R140 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic. Each R150 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic; and n', n'', and m'' are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0160] In some embodiments, the connecting portion L1 has the following formula: -Y10-(CH2)n'-Y20-(CH2)p'-Y30- where each of Y10, Y20 and Y30 is independently a bond, a substituted alkyl group, a substituted heteroalkyl group, a substituted aryl group, a substituted heteroaryl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, -CR110R120-, -NR110-, -O-, -S(O)0-2-, -NR110C(O)-, -C(O)NR110-, -NR110S(O)2-, -S(O)2NR110-, -CR120=N-NR110-, -NR110-N=CR120-, -OC(O)- or -C(O)-; Each R110 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; each R120 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; and n' and p' are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0161] In some embodiments, each of the alkyl, alkenyl, alkynyl, aryl or heteroaryl groups of Y10, Y20 and Y30 is independently substituted by one to five independent substituents selected from the following: syloxy, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or C1-4 haloalkoxy.

[0162] In some embodiments, the connecting portion has the following formula: -Y10-(CH2)n'-Y20-(CH2)m''-Y30- Wherein: Each of Y10, Y20 and Y30 is independently -NR110-, -O-, -S(O)0-2-, -NR110C(O)-, -C(O)NR110-, -NR110S(O)2-, -S(O)2NR110-, -CR120=N-NR110-, -NR110-N=CR120-, -C(O)-, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; wherein each aryl, heteroalkyl, alkenyl, alkenyl, alkyne, alkyne, aryl, alkyne, cycloalkyl or heterocycloalkyl is independently substituted, as appropriate, by one to five independently selected substituents from the following: syloxy, halogen, C1-4 alkyl, C1-4 alkoxy and C1-4 haloalkyl; Each R110 is independently C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; each R120 is independently C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; and n' and m'' are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0163] In some embodiments, the connecting portion is not a bond. In some embodiments, each R110 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; and each R120 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic.

[0164] In some embodiments, the connecting portion has the following formula: -Y10-(CH2)n'-Y20-(CH2)m''-Y30- Wherein: Each of Y10, Y20 and Y30 is independently -NR110-, -O-, -S(O)0-2-, -NR110C(O)-, -C(O)NR110-, -NR110S(O)2-, -S(O)2NR110-, -CR120=N-NR110-, -NR110-N=CR120-, -C(O)-, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; wherein each aryl, heteroalkyl, alkenyl, alkenyl, alkyne, alkyne, aryl, alkyne, cycloalkyl or heterocycloalkyl is independently substituted, as appropriate, by one to five independently selected substituents from the following: syloxy, halogen, C1-4 alkyl, C1-4 alkoxy and C1-4 haloalkyl; Each R110 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; each R120 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; and n' and m'' are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0165] In some embodiments, the connecting portion has the following formula: -Y10-(CH2)n'-Y20-(CH2)p'-Y30- where each of Y10, Y20 and Y30 is independently a bond, a substituted alkyl group, a substituted heteroalkyl group, a substituted aryl group, a substituted heteroaryl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, -CR110R120-, -NR110-, -O-, -S(O)0-2-, -NR110C(O)-, -C(O)NR110-, -NR110S(O)2-, -S(O)2NR110-, -CR120=N-NR110-, -NR110-N=CR120- or -C(O)-; Each R110 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; each R120 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; and n' and p' are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0166] In some embodiments, L1 includes a non-biologically degradable portion.

[0167] In some embodiments, L1 comprises, as appropriate, a substituted C4-7 atom alkyl group, a substituted C4-7 atom heterocyclic group, or a substituted C4-7 atom heteroalkyl group.

[0168] In some embodiments, L1 comprises, as appropriate, a substituted acycloyl group and / or, as appropriate, a substituted acycloyl group.

[0169] In some embodiments, L1 is a C4-10 atom alkyl group that has been substituted, as appropriate.

[0170] In some embodiments, L1 is a key.

[0171] In some embodiments, L1 is a alkyl or heteroalkyl linking portion of 4 to 12 atoms, containing CH2 and at most two heteroatoms each independently selected from NH, O, or S, and optionally containing one C=O. In some embodiments, L1 is a alkyl or heteroalkyl linking portion of 4 to 11 atoms, containing CH2 and at most two heteroatoms each independently selected from NH, O, or S, and optionally containing one C=O. In some embodiments, L1 is a alkyl or heteroalkyl linking portion of 4 to 10 atoms, containing CH2 and at most two heteroatoms each independently selected from NH, O, or S, and optionally containing one C=O. In some embodiments, L1 is a alkyl or heteroalkyl linking portion of 4 to 9 atoms, containing CH2 and at most two heteroatoms each independently selected from NH, O, or S, and optionally containing one C=O. In some embodiments, L1 is a 4- to 8-atom alkyl or heteroalkyl linking portion, containing CH2 and at most two heteroatoms each independently selected from NH, O, or S, and optionally containing a C=O. In some embodiments, L1 is a 4- to 7-atom alkyl or heteroalkyl linking portion, containing CH2 and at most two heteroatoms each independently selected from NH, O, or S, and optionally containing a C=O. In some embodiments, L1 is a 4- to 6-atom alkyl or heteroalkyl linking portion, containing CH2 and at most two heteroatoms each independently selected from NH, O, or S, and optionally containing a C=O.

[0172] In some embodiments, the connecting portion has the following formula:; wherein the ring C is a 3 to 10-membered cycloalkyl or a 3 to 10-membered heterocyclic group; wherein each 3 to 10-membered cycloalkyl or 3 to 10-membered heterocyclic group is independently substituted by one to five independently selected substituents as appropriate: syloxy, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or C1-4 haloalkoxy; Each of Y50 and Y60 is independently a bond, -NR110-, -O-, -S(O)0-2-, -NR110C(O-), -C(O)NR110-, -NR110C(O)NR110-, -NR110S(O)2-, -S(O)2NR110-, -NR110S(O)2NR110-, -CR120=N-NR110-, -NR110-N=CR120-, -C(O-), -O C(O)-, -OC(O)O-, -(CH2CH2O)1-5-, -C(O)O-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic, or heteroaryl is independently substituted, as appropriate, by one to five independently selected substituents: oxy, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy; each R110 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; each R120 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; and wherein "*" and wavy lines indicate covalent bonds.

[0173] In some embodiments, each of the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic or heteroaryl groups of Y50 and Y60 is independently substituted by one to five independently selected substituents: halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or C1-4 haloalkoxy.

[0174] In some embodiments, the linking portion has the following formula: wherein the ring C is a 3 to 10-membered cycloalkyl or a 3 to 10-membered heterocyclic group; wherein each 3 to 10-membered cycloalkyl or 3 to 10-membered heterocyclic group is independently substituted by one to five independently selected substituents as appropriate: syloxy, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy or C1-4 haloalkoxy; Each of Y50 and Y60 is independently a bond, -NR110-, -O-, -S(O)0-2-, -NR110C(O-), -C(O)NR110-, -NR110C(O)NR110-, -NR110S(O)2-, -S(O)2NR110-, -NR110S(O)2NR110-, -CR120=N-NR110-, -NR110-N=CR120-, -C(O-), -O C(O)-, -OC(O)O-, -(CH2CH2O)1-5-, -C(O)O-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic, or heteroaryl is independently substituted, as appropriate, by one to five independently selected substituents: oxy, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy; each R110 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; each R120 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; and wherein "*" and wavy lines indicate covalent bonds.

[0175] In some embodiments, each of Y50 and Y60 is independently a bond, -NR110-, -O-, -S(O)0-2-, -NR110C(O)-, -C(O)NR110-, -NR110C(O)NR110-, -NR110S(O)2-, -S(O)2NR110-, -NR110S(O)2NR110-, -CR120=N-NR110-, -NR110-N=CR120-, -C(O)-, -OC(O)-, -OC(O)O-, -(CH2CH2O)1-5-, -C(O)O-.

[0176] In some embodiments, the connection portion has the following formula: , where: L2 is connected to ring b and L3 is connected to A; L2 and L3 are each independently selected from bond, CH2, CH2CH2 or C=O; s is 1, 2 or 3; and s' is 0 or 1.

[0177] In some embodiments, the connection portion has the following formula:; where "*" and wavy lines or dashed lines represent covalent bonds.

[0178] In some embodiments, the connection portion has the following formula:; where "*" and wavy lines represent covalent bonds.

[0179] In some embodiments, the connection portion has the following formula:; where "*" and dashed or wavy lines represent covalent bonds.

[0180] In some embodiments, compounds as shown in Table 1, or stereoisomers, mixtures of stereoisomers, hydrates, solvates, isotope-enriched analogs, or pharmaceutically acceptable salts thereof are provided. Table 1

[0181] Treatment Methods This document provides compounds that can be used to treat, prevent, and / or delay the onset and / or progression of cancer. Therefore, in some embodiments, a method for treating cancer is provided, comprising administering to an individual in need of treatment a therapeutically effective amount of a compound or composition described herein. Some embodiments provide a method for enhancing cytotoxic cancer therapy in an individual deemed in need of such treatment, comprising administering to that individual a therapeutically acceptable amount of a compound or composition described herein.

[0182] It is considered that patients with any cancer may benefit from treatment with the compounds and compositions described herein. Therefore, in some embodiments, the cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, chronic lymphoblastic leukemia, Waldenström's macroglobulinemia, primary macroglobulinemia, bladder cancer, chronic granulocytic leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, etc. Lung cancer, stomach cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid, malignant melanoma, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urogenital cancer, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, skin cancer, trophoblastic tumor, or prostate cancer. In some embodiments, the cancer is bladder cancer; blood cancer, such as leukemia (e.g., chronic leukemia, chronic lymphocytic leukemia (CLL)) or lymphoma (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, low-grade lymphoma, high-grade lymphoma); lung cancer (e.g., small cell lung cancer); breast cancer; fallopian tube cancer; glioblastoma multiforme; head and neck cancer; esophageal cancer; ovarian cancer; pancreatic cancer; peritoneal cancer; prostate cancer; testicular cancer; skin cancer (e.g., melanoma); or uterine cancer. In some embodiments, the cancer is bladder cancer, breast cancer, fallopian tube cancer, ovarian cancer, prostate cancer, peritoneal cancer, testicular cancer, endometrial cancer, or uterine cancer.

[0183] In some embodiments, the cancer is chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenström's macroglobulinemia, polycythemia vera, trophoblastoma, and ovarian cancer.

[0184] In some embodiments, compounds and compositions as described herein are modified by including antigenic determinants that target the specific nuclear receptor to target cancers that overexpress a specific receptor (such as, but not limited to, androgen receptors, estrogen receptors, progesterone receptors, and / or glucocorticoid receptors). The antigenic determinants may be derived from steroid hormones or any nonsteroidal drugs that target the specific receptor.

[0185] In some embodiments, a method for treating or preventing cancers that overexpress androgen receptors is provided, comprising administering to an individual in need an effective amount of a compound or a pharmaceutically acceptable salt or solvate thereof, the compound comprising at least one nuclear payload and at least one androgen receptor target antigen determinant. Certain cancers contemplated for treatment by such a method include, but are not limited to, prostate cancer, breast cancer, triple-negative breast cancer, bladder cancer, or liver cancer. A method for treating or preventing metastatic castration-resistant prostate cancer (mCRPC) is also provided, comprising administering to an individual in need an effective amount of a compound or composition as described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0186] In some embodiments, a method of treating or preventing cancers that overexpress androgen receptors is provided, comprising administering to an individual in need an effective amount of a compound or a pharmaceutically acceptable salt or solvate thereof, the compound comprising at least one nuclear payload and at least one androgen receptor target antigen determinant. In some embodiments, the cancer is prostate cancer, breast cancer, triple-negative breast cancer, bladder cancer, or liver cancer. In some embodiments, the androgen receptor target antigen determinant comprises an androgen receptor agonist, a selective androgen receptor modulator (SARM), an androgen receptor antagonist, a selective estrogen receptor modulator (SERM), an estrogen receptor antagonist, a progesterone, or an estrogen. In some embodiments, the androgen receptor target antigen determinant comprises enoxaparin, bicalutamide, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, estradiol, ketoconazole, abiraterone, dalutamide, or an analogue thereof. In some embodiments, the androgen receptor target antigen determinant comprises enoxaparin, bicalutamide, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, fulvestrant, medroxyprogesterone acetate, estradiol, ketoconazole, abiraterone, or analogues thereof. In some embodiments, the nuclear payload comprises a topoisomerase inhibitor.

[0187] In some embodiments, a method for treating or preventing cancers that overexpress estrogen and / or progesterone receptors is provided, comprising administering to an individual in need an effective amount of a compound or a medically acceptable salt or solvate thereof, the compound comprising at least one nuclear payload and at least one estrogen and / or progesterone receptor target antigen determinant. Specific cancers intended to be treated by such a method include, but are not limited to, breast cancer, uterine cancer, or ovarian cancer.

[0188] In some embodiments, a method for treating or preventing cancers that overexpress glucocorticoid receptors is provided, comprising administering to an individual in need an effective amount of a compound or a medically acceptable salt or solvate thereof, the compound comprising at least one nuclear payload and at least one glucocorticoid receptor target antigenic determinant. Specific cancers intended to be treated by such a method include, but are not limited to, breast cancer, uterine cancer, or ovarian cancer. Specific cancers intended to be treated by such a method include (but are not limited to) prostate cancer, and possibly breast cancer, uterine cancer, and ovarian cancer.

[0189] Breast cancer includes ductal carcinoma in situ (DCIS) and invasive breast cancer. Breast cancer can occur in the mammary ducts, lobules, and connective tissue. Breast cancer includes estrogen receptor (ER) negative and hormone receptor (HR) negative types, and can also be classified as group 3 (HER-2 positive) or group 4 (basal-like).

[0190] Prostate cancer is a cancer that develops in the prostate gland (a gland in the male reproductive system). It occurs when prostate cells mutate and begin to multiply uncontrollably. These cells can metastasize from the prostate (metastatic prostate cancer) to almost any other part of the body, specifically bones and lymph nodes, and among other tissues, the kidneys, bladder, and even the brain. Prostate cancer can cause pain, difficulty urinating, problems during intercourse, and erectile dysfunction. Other symptoms may occur in the later stages of the disease. The detection rate of prostate cancer varies widely throughout the world, with lower detection rates in South and East Asia than in Europe, and especially in the United States. Prostate cancer most commonly occurs in men over the age of fifty and is one of the most prevalent types of cancer in men. However, many men with prostate cancer never experience symptoms, do not receive treatment, and eventually die from other causes. This is because prostate cancer grows slowly in most cases, and because most of those affected are over 60 years of age. Therefore, these men often die from causes unrelated to prostate cancer. Many factors, including genetics and diet, are involved in the development of prostate cancer. The presence of prostate cancer can be indicated by symptoms, physical examination, prostate-specific antigen (PSA) test, or biopsy. There are concerns regarding the accuracy of the PSA test and its usefulness in screening. Suspected prostate cancer is usually confirmed by obtaining a biopsy of the prostate and examining it under a microscope. Other tests (such as CT scans and bone scans) can be performed to determine if the prostate cancer has spread. Combinations with primary surgery and radiation therapy or other treatments (such as hormone therapy, chemotherapy, proton therapy, cryosurgery, and high-intensity focused ultrasound (HIFU)) are also considered.

[0191] Certain embodiments provide a method of inhibiting one or more topoisomerases in an individual deemed to require such treatment, comprising administering to the individual a therapeutically acceptable amount of a compound or composition described herein. In one embodiment, this document provides a method of treating a disease that is improved by inhibiting one or more topoisomerases, comprising administering to the individual requiring treatment a therapeutically effective amount of a compound or composition described herein.

[0192] Certain embodiments provide a method of treating leukemia, colon cancer, glioblastoma, lymphoma, melanoma, breast cancer, or cervical cancer in an individual deemed to require such treatment, comprising administering to the individual a therapeutically acceptable amount of a compound or composition described herein.

[0193] In some embodiments, this document provides a method for treating cancers lacking homologous recombination (HR)-dependent DNA double-strand break (DSB) repair pathways, comprising administering a therapeutically effective amount of a compound or composition described herein to an individual requiring treatment. In some embodiments, the cancer includes one or more cancer cells that, relative to normal cells, have a reduced or absent ability to repair DNA DSB via HR. In some embodiments, the cancer cells have a BRCA1 or BRCA2 deletion phenotype. In some embodiments, the cancer cells lack BRCA1 or BRCA2. In some embodiments, the method provided herein relates to treating an individual who is heterozygous for mutations in a gene encoding a component of an HR-dependent DNA DSB repair pathway. In one embodiment, the individual is heterozygous for mutations in BRCA1 and / or BRCA2. In some embodiments, the method of treating cancer includes treating breast cancer, ovarian cancer, pancreatic cancer, and / or prostate cancer. In some embodiments, the method of treating cancer further includes administering ionizing radiation or a chemotherapy agent.

[0194] The primary function of the DNA mismatch repair (MMR) system is to eliminate single-base mismatches and insertion / deletion loops that may occur during DNA replication. Insertion / deletion loops are caused by the addition or loss of short repeat units within small satellite sequences (also known as small satellite instability (MSI)). At least six different MMR proteins are required. For mismatch recognition, the MSH2 protein forms a heterodimer with either MSH6 or MSH3, depending on the type of lesion to be repaired (MSH6 is required to correct single-base mismatches, while both MSH3 and MSH6 can help correct insertion / deletion loops). The heterodimers of MLH1 and PMS2 coordinate the interaction between the mismatch recognition complex and other proteins required for MMR. These additional proteins may include at least exonuclease 1 (EXO1), possibly a helicase, proliferating cell nuclear antigen (PCNA), single-stranded DNA-binding protein (RPA), and DNA polymerases δ and ε. In addition to PMS2, MLH1 may also heterodimerize with two additional proteins, MLH3 and PMS1. Recent observations indicate the need for PMS2 to correct single-base mismatches, and that both PMS2 and MLH3 contribute to the correction of insertion / deletion loops. Additional homologs of human MMR proteins required for functions other than MMR are known. These proteins include MSH4 and MSH5, which are essential for meiotic (and possibly mitotic) recombination, but are assumed not to be involved in MMR.

[0195] Germline mutations in the human MMR gene cause susceptibility to hereditary nonpolyposis colorectal cancer (HNPCC), one of the most common cancer syndromes in humans. Early diagnosis and the spread of excessive colorectal cancer as an autosomal dominant trait, along with the defined extracoloral cancer spectrum, constitute the clinical definition of the syndrome. MSI (a marker of HNPCC) also occurs in approximately 15% to 25% of incidental tumors in the colorectal region and other organs. According to international guidelines, higher MSI (MSI-H) is defined as instability at two or more of the five loci or at ≥30% to 40% of all small satellite loci studied, while instability at fewer loci is termed MSI-Low (MSI-L). MSI occurs in a considerable proportion (2% to 50% of tumors) of non-HNPCC cancers (e.g., breast, prostate, and lung cancer). Based on the proportion of instability markers, categories MSS, MSI-L, and MSI-H can be distinguished from HNPCC cancers. In one embodiment, it is a method for treating cancers with missing mismatch DNA repair pathways. In another embodiment, it is a method for treating cancers exhibiting small satellite instability due to reduced or damaged DNA repair pathways. In yet another embodiment, it is a method for treating cancers exhibiting genomic instability due to reduced or damaged DNA repair pathways.

[0196] In some embodiments, the compounds or compositions described herein may be used to prepare agents for treating cancers lacking homologous recombination (HR)-dependent DNA double-strand break (DSB) repair activity, or for treating patients with cancers lacking HR-dependent DNA DSB repair activity, the treatment comprising administering a therapeutically effective amount of the compound or composition to the patient.

[0197] The HR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA through homology mechanisms to reform continuous DNA helices. The components of the HR-dependent DNA DSB repair pathway include (but are not limited to) ATM (NM_000051), RAD51 (NM_002875), RAD51L1 (NM_002877), RAD51C (NM_002876), RAD51L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), and MRE11A. (NM_005590) and NBS11M_00248_5). Other proteins involved in the HR-dependent DNA DSB repair pathway include regulators such as EMSY (Wood et al., Science, 291, 1284-1289 (2001); Khanna et al., Nat. Genet. 27(3): 247-254 (2001); and Hughes-Davies et al., Cell, 115, pp. 523-535).

[0198] In some embodiments, cancers lacking HR-dependent DNA DSB repair include one or more cancer cells whose ability to repair DNA DSB via this pathway is reduced or absent (relative to normal cells), that is, the activity of the HR-dependent DNA DSB repair pathway is reduced or eliminated in one or more cancer cells.

[0199] In some embodiments, the activity of one or more components of the HR-dependent DNA DSB repair pathway is eliminated in one or more cancer cells of an individual suffering from cancer lacking HR-dependent DNA DSB repair. Components of the HR-dependent DNA DSB repair pathway include those listed above.

[0200] In some embodiments, cancer cells exhibit a BRCA1 and / or BRCA2 deletion phenotype, meaning that BRCA1 and / or BRCA2 activity is reduced or eliminated in cancer cells. In some embodiments, cancer cells with this phenotype lack BRCA1 and / or BRCA2, that is, the expression and / or activity of BRCA1 and / or BRCA2 are reduced or eliminated in cancer cells, for example, by means of mutations or polymorphism in the encoding nucleic acids, or by means of amplification, mutation, or polymorphism in genes encoding regulatory factors (e.g., the EMSY gene encoding a BRCA2 regulatory factor), or by means of post-natal mechanisms (such as gene promoter methylation).

[0201] BRCA1 and BRCA2 are tumor suppressor factors, and their wild-type pairs are frequently lost in tumors with xenogeneic conjugation vectors. BRCA1 and / or BRCA2 mutations are associated with breast cancer. Amplification of the EMSY gene, which encodes the BRCA2 binding factor, is associated with breast and ovarian cancer (Jasin M., Oncogene, 21(58), 8981-93 (2002); Tutt et al., Trends Mol. Med., 8(12), 571-6, (2002); and Radice, PJ, Exp Clin Cancer Res., 21(3 Supplement), 9-12 (2002)).

[0202] Vectors with mutations in BRCA1 and / or BRCA2 also have a higher risk of ovarian cancer, prostate cancer and pancreatic cancer.

[0203] In some embodiments, individuals heterosynthesize to one or more variations (such as mutations and polymorphisms) in BRCA1 and / or BRCA2 or their regulators. Detection of variations in BRCA1 and BRCA2 is described, for example, in EP 699 754; EP 705 903; Neuhausen, SL and Ostrander, EA, Genet. Test, 1, 75-83 (1992); Janatova M. et al., Neoplasia, 50(4), 246-50 (2003). The determination of amplification of the BRCA2 binding factor EMSY is described in Hughes-Davies et al., Cell, 115, 523-535.

[0204] In some cases, cancer-related mutations and polymorphisms are detected at the nucleic acid level by detecting the presence of variant nucleic acid sequences, or at the protein level by detecting the presence of variant (i.e., mutated or paired gene variant) polypeptides.

[0205] In some embodiments, the compounds described herein are considered suitable for patients with relapsed or refractory cancer. The term "relapsed" means the recurrence or regrowth of a disease (or cancer) after a period of remission. The term "refractory" is used to describe a cancer that does not respond to treatment or whose response to treatment is not long-lasting. For example, the compounds herein may be suitable for treating cancer in patients previously treated with cancer therapies described herein (e.g., enzalutamide).

[0206] Certain embodiments provide a method of treating a viral infection in an individual deemed to require such treatment, comprising administering to the individual a therapeutically acceptable amount of a compound or composition described herein. In some embodiments, the compounds and compositions described herein can be used to treat enterovirus 71 (the pathogen of hand-foot-mouth disease), Kaposi's sarcoma-associated herpesvirus, HIV infection, Ebola virus, simian virus 40, parvovirus, adenovirus, herpesvirus, and other DNA viruses.

[0207] In some embodiments, the compounds and compositions described herein can be used to enhance the effects of cancer immunotherapy. In some embodiments, the compounds and compositions described herein can be used to stimulate or attenuate immune responses outside of cancer.

[0208] In some embodiments, the compounds and compositions described herein can be used to prevent the expression of pathogen-associated inflammatory genes. In some embodiments, the compounds and compositions described herein can be used to treat Staphylococcus aureus infection in individuals requiring such treatment.

[0209] In some embodiments, the compounds and compositions described herein can be used to treat autoimmune diseases, such as lupus, in individuals who require such treatment.

[0210] In some embodiments, the compounds and compositions described herein can be used to treat neurological or developmental disorders in individuals who require such treatment, such as Rett Syndrome or Angelman Syndrome.

[0211] Compositions This invention encompasses compositions of any of the compounds detailed herein, including pharmaceutical compositions. Therefore, pharmaceutical compositions are provided herein that comprise compounds of the present invention or their pharmaceutically acceptable salts, and pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions provided herein may be administered orally, buccally, non-enterically (e.g., intravenously, intramuscularly, infusion, or subcutaneously), nasally, topically, or rectally, or by inhalation.

[0212] In one embodiment, the compound as described herein may be in a purified form. Compositions comprising the compound as described herein or its salts are provided, such as compositions of substantially pure compounds. In some embodiments, compositions comprising the compound as described herein or its salts are in a substantially pure form. Unless otherwise stated, "substantially pure" means a composition containing no more than 35% impurities, wherein impurities represent compounds other than the desired compound or its salt, which constitutes the majority of the composition. In one variation, a composition of substantially pure compounds or their salts is provided, wherein the composition contains no more than 25% impurities. In another variation, a composition of substantially pure compounds or their salts is provided, wherein the composition contains 20% or no more than 20% impurities. In yet another variation, a composition of substantially pure compounds or their salts is provided, wherein the composition contains 10% or no more than 10% impurities. In yet another variation, a composition of substantially pure compounds or their salts is provided, wherein the composition contains 5% or no more than 5% impurities. In another variation, a composition of substantially pure compound or its salt is provided, wherein the composition contains 3% or no more than 3% impurities. In yet another variation, a composition of substantially pure compound or its salt is provided, wherein the composition contains 1% or no more than 1% impurities. In yet another variation, a composition of substantially pure compound or its salt is provided, wherein the composition contains 0.5% or no more than 0.5% impurities.

[0213] In some embodiments, the pharmaceutical composition is formulated in any manner, including using one or more physiologically acceptable carriers that contain excipients and / or adjuvants that facilitate the processing of the active compound into the pharmaceutical composition. In some embodiments, appropriate formulation depends on the chosen route of administration. In various embodiments, any suitable technology, carrier, and excipient is used.

[0214] This document provides pharmaceutical compositions comprising the compounds described herein and pharmaceutically acceptable diluents, excipients, and / or carriers. Additionally, in some embodiments, the compounds described herein are administered as pharmaceutical compositions, wherein the compounds described herein are mixed with other active ingredients, as in combination therapy.

[0215] As used herein, a pharmaceutical composition refers to a mixture of the compounds described herein with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In some embodiments, the pharmaceutical composition facilitates the administration of the compound to a living organism. In some embodiments, practicing the treatments or methods of use provided herein includes administering or using a pharmaceutical composition containing a therapeutically effective amount of the compounds provided herein. In certain embodiments, the treatment methods provided herein include administering such pharmaceutical compositions to a mammal suffering from a disease or condition to be treated. In one embodiment, the mammal is a human. In some embodiments, the therapeutically effective amount varies widely depending on the severity of the disease, the individual's age and relative health status, the potency of the compound used, and other factors. In various embodiments, the compounds described herein are used alone or in combination with one or more therapeutic agents as components of a mixture.

[0216] In some embodiments, the pharmaceutical compositions provided herein are formulated for intravenous injection. In some embodiments, the intravenous injection formulations provided herein are formulated as aqueous solutions, and in some embodiments, they are formulated in physiologically compatible buffers such as Hank's solution, Ringer's solution, or saline buffer. In some embodiments, the pharmaceutical compositions provided herein are formulated for transmucosal administration. In some embodiments, transmucosal formulations include permeabilizing agents suitable for permeation barriers. In some embodiments, the pharmaceutical compositions provided herein are formulated for other non-intestinal injections, suitable formulations including aqueous or non-aqueous solutions, and in one embodiment, formulation is performed using physiologically compatible buffers or excipients.

[0217] In some embodiments, the pharmaceutical compositions provided herein are formulated for oral administration. In some embodiments, the oral formulations provided herein comprise compounds described herein formulated with pharmaceutically acceptable carriers or excipients. Such carriers enable the compounds described herein to be formulated as tablets, powders, pills, sugar-coated pills, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like for oral administration to a patient to be treated.

[0218] In some embodiments, a pharmaceutical composition for oral use is obtained by mixing one or more solid excipients with one or more of the compounds described herein, grinding the resulting mixture as appropriate, and processing the mixture into granules after adding suitable adjuvants as needed, to obtain a tablet or sugar-coated pill core. Specifically, suitable excipients include fillers such as sugars (including lactose, sucrose, mannitol, or sorbitol); cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other excipients such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Disintegrants such as croscarmellose sodium, polyvinylpyrrolidone, agar, or alginate or its salts, such as sodium alginate, may be added as needed.

[0219] In some embodiments, this document provides a pharmaceutical composition formulated to have a sugar-coated pill core suitable for coating. In some embodiments, a concentrated sugar solution is used to form a suitable coating and, where appropriate, contains gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, a paint solution, and a suitable organic solvent or solvent mixture. In some embodiments, dyes and / or pigments are added to the tablets, sugar-coated pills, and / or their coatings for purposes such as identifying or characterizing different combinations of active compound dosages.

[0220] In some embodiments, the pharmaceutical composition used includes, orally, a push-in formulation made of gelatin and a sealed soft capsule made of gelatin and a plasticizer (such as glycerin or sorbitol). In some embodiments, the push-in formulation contains an active ingredient blended with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or magnesium stearate), and, where applicable, a stabilizer. In some embodiments, in the soft capsule, the active compound is dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, a stabilizer is added, where applicable. In some embodiments, the formulation for oral administration is in a dosage suitable for such administration.

[0221] In some embodiments, the pharmaceutical compositions provided herein are formulated for buccal or sublingual administration. In some embodiments, the buccal or sublingual compositions are in the form of lozenges, oral tablets, or gels formulated in a conventional manner. In some embodiments, non-enteral injection involves bolus injection or continuous infusion. In some embodiments, the formulation for injection is in a unit dosage form, such as in an ampoule or multi-dose container with added preservatives. In some embodiments, the pharmaceutical compositions described herein are in a form suitable for non-enteral injection, such as a sterile suspension, solution, or emulsion in an oily or aqueous medium; and, where appropriate, contain formulation agents such as suspending agents, stabilizers, and / or dispersants. Pharmaceutical formulations for non-enteral administration include aqueous solutions of active compounds in an aqueous form. In some embodiments, the suspension of the active compound is prepared as a suitable oily injectable suspension. Suitable lipophilic solvents or mediums include fatty oils, such as sesame oil; or synthetic fatty acid esters, such as ethyl oleate or triglycerides; or liposomes. In some embodiments, the aqueous injectable suspension contains substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or polydextrose. Depending on the application, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions. In alternative embodiments, the active ingredient is in powder form reconstituted with a suitable mediator (e.g., sterile, pyrogen-free water) prior to use.

[0222] In some embodiments, the compounds described herein are topically administered. In particular embodiments, the compounds described herein are formulated into a variety of topically administerable compositions, such as solutions, suspensions, emulsions, gels, pastes, sticks, balms, creams, or ointments. Such pharmaceutical compounds may contain, where appropriate, solubilizers, stabilizers, tonicants, buffers, and / or preservatives.

[0223] In some embodiments, the pharmaceutical compositions provided herein are formulated for transdermal administration of the compounds described herein. In some embodiments, administration of such compositions employs transdermal delivery devices and transdermal delivery patches. In some embodiments, the composition is a lipophilic emulsion or buffered aqueous solution dissolved and / or dispersed in a polymer or adhesive. Such patches include those constructed for continuous, pulsed, or on-demand delivery of pharmaceutical agents. In some embodiments, transdermal delivery of the compounds described herein is achieved using iontophoresis patches and the like. In some embodiments, the absorption rate is slowed by using a rate-control membrane or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers are used, as appropriate, to increase absorption. Absorption enhancers and carriers include absorbable, pharmaceutically acceptable solvents that facilitate the penetration of the compound through the skin. For example, a transdermal device is in the form of a bandage and includes a substrate component, a reservoir containing a compound and, if applicable, a carrier, a rate control barrier that, if applicable, delivers the compound to the host skin at a controlled and predetermined rate over an extended period of time, and components that make the device safe for the skin.

[0224] In some embodiments, the pharmaceutical compositions provided herein are formulated for administration by inhalation. In some embodiments, in such pharmaceutical compositions formulated for inhalation, the compounds described herein are in the form of an aerosol, mist, or powder. In some embodiments, the pharmaceutical compositions described herein are preferably delivered in the form of an aerosol spray from a pressurized package or nebulizer, using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In some forms of pressurized aerosols, the dosage unit is determined by providing a valve to deliver a metering amount. In some embodiments, capsules and cartridges having gelatin, such as (by way of example only) for inhalers or blowpipes, are formulated as a powder mixture containing the compounds described herein and a suitable powder matrix (such as lactose or starch).

[0225] In some embodiments, the compounds described herein are formulated in rectal compositions, such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, gel suppositories, or retention enemas. In some embodiments, the rectal composition may contain, where appropriate, a conventional suppository base (such as cocoa butter or other glycerides); and a synthetic polymer, such as polyvinylpyrrolidone, PEG, and the like. In some suppository forms of the composition, a low-melting-point wax, such as, but not limited to, a mixture of fatty acid glycerides, is first melted and combined with cocoa butter, where appropriate.

[0226] In the various embodiments provided herein, the pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, such carriers comprising excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically acceptable formulation. In some embodiments, appropriate formulation depends on the chosen route of administration. In various embodiments, any suitable technology, carrier, and excipient is used. In some embodiments, the pharmaceutical compositions comprising the compounds described herein are manufactured in a conventional manner, such as (by way of example only) by means of conventional mixing, dissolving, granulation, sugar-coated pill making, water milling, emulsification, encapsulation, coating, or compression processes.

[0227] In some embodiments, the pharmaceutical composition includes at least one pharmaceutically acceptable carrier, diluent, or excipient, and the compound described herein in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt, as an active ingredient. Additionally, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of such compounds having the same type of activity. In some cases, the compounds described herein are present in tautomer form. All tautomers are included within the scope of the compounds presented herein. Furthermore, this document includes both solvated and non-solvated forms of the compounds described herein. Solvated compounds include those solvated with pharmaceutically acceptable solvents (such as water, ethanol, and the like). The solvated forms of the compounds presented herein are also considered to be those disclosed herein. In some embodiments, the pharmaceutical compositions described herein include other medical or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts and / or buffers for adjusting osmotic pressure. In other embodiments, the pharmaceutical compositions described herein also contain other therapeutically valuable substances.

[0228] Methods for preparing compositions containing compounds described herein include formulation of the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form solid, semi-solid, or liquid forms. Solid compositions include (but are not limited to) powders, tablets, dispersible granules, capsules, pouches, and suppositories. Liquid compositions include solutions containing dissolved compounds, emulsions containing compounds, or solutions containing liposomes, microcells, or nanoparticles containing compounds as disclosed herein. Semi-solid compositions include (but are not limited to) gels, suspensions, and creams. In various embodiments, the compositions are in the form of liquid solutions or suspensions, solid forms suitable for dissolving or suspending in a liquid prior to use, or emulsions. Such compositions may contain small amounts of non-toxic adjuvants, such as wetting agents or emulsifiers, pH buffers, etc., as appropriate.

[0229] In some embodiments, the composition comprising the compounds described herein is in liquid form, wherein the agent is present in solution, suspension, or both. In some embodiments, when the composition is administered in solution or suspension form, a first portion of the agent is present in solution, and a second portion of the agent is present in particulate form in a suspension in a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is an aqueous solution.

[0230] Suitable aqueous suspensions may contain one or more polymers in suspending form, depending on the application. Suitable polymers include water-soluble polymers, such as cellulose polymers, for example hydroxypropyl methylcellulose, and water-insoluble polymers, such as crosslinked carboxyl-containing polymers. Suitable compositions may contain mucosal adhesive polymers selected from, for example, the following: carboxymethyl cellulose, carbomer (acrylic polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylate / butyl acrylate copolymer, sodium alginate, and polydextrose.

[0231] Applicable compositions may include, where applicable, a solubilizer that helps dissolve the compounds described herein. The term "sourcerizer" generally includes agents that cause the formation of a microcellular solution or a true solution of the reagent. Solubilizers include certain acceptable nonionic surfactants (e.g., polysorbate 80) and ophthalmologically acceptable glycols, polyethylene glycols (e.g., polyethylene glycol 400), and glycol ethers.

[0232] Suitable compositions may include one or more pH adjusters or buffers, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. The amounts of such acids, bases, and buffers required to maintain the pH of the composition within an acceptable range are included.

[0233] The applicable composition may include one or more salts in an amount required to achieve an acceptable weight molar osmotic concentration of the composition. Such salts include salts having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0234] Certain applicable compositions may include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances, such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds, such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0235] Some applicable compositions may include one or more surfactants, as appropriate, to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyethylene glycol fatty acid glycerides and vegetable oils, such as polyethylene glycol (60) hydrogenated castor oil; and polyethylene glycol alkyl ethers and alkyl phenyl ethers, such as octoxynol 10 and octoxynol 40.

[0236] Certain applicable compositions may include one or more antioxidants to enhance the desired chemical stability. Suitable antioxidants include (by way of example only) ascorbic acid and sodium metabisulfite.

[0237] In some embodiments, the aqueous suspension composition is packaged in a single-dose, non-reclosable container. In alternative embodiments, a multi-dose, reclosable container is used, in which case a preservative is typically included in the composition.

[0238] In various embodiments, any delivery system for hydrophobic pharmaceutical compounds is employed. Liposomes and emulsions are examples of delivery media or carriers for hydrophobic drugs. In some embodiments, certain organic solvents, such as N-methylpyrrolidone, are employed. In some embodiments, sustained-release systems, such as a semi-permeable matrix containing a solid hydrophobic polymer of a therapeutic agent, are used to deliver the compound. Various sustained-release materials are utilized in the embodiments herein. In some embodiments, sustained-release capsules release the compound for several weeks up to more than 100 days. In some embodiments, additional strategies for protein stabilization are employed, depending on the chemical properties and biological stability of the therapeutic agent.

[0239] In some embodiments, the formulations or compositions described herein benefit from and / or, where appropriate, include antioxidants, metal chelators, thiol compounds and other general stabilizers. Examples of such stabilizers include (but are not limited to): (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (i) pentosan polysulfate and other heparin-like substances, (m) divalent cations (such as magnesium and zinc) or (n) combinations thereof.

[0240] Dosing and Treatment Regimens In some embodiments, a composition containing the compounds described herein is administered for prophylactic and / or therapeutic treatment. In some therapeutic applications, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially suppress the symptoms of the disease or condition. In some embodiments, the effective amount for this purpose depends on the severity and course of the disease or condition, prior therapy, the patient's health status, weight, and response to the drug, and the judgment of the treating physician. In some cases, it is considered appropriate for caregivers to determine such an effective amount for treatment through routine experiments (including, but not limited to, dose-escalation clinical trials).

[0241] In certain preventative applications, a composition containing a compound described herein is administered to a patient who is susceptible to or otherwise at risk of a particular disease, condition, or illness. In some embodiments, the amount administered is defined as a "preventative effective amount or dose." In some embodiments of this use, the precise amount of the compound administered depends on the patient's health condition, weight, and the like. In some embodiments, it is considered appropriate for caregivers to determine such preventative effective amounts through routine testing (e.g., dose-escalation clinical trials). In some embodiments, the effective amount used for this purpose, when administered to a patient, will depend on the severity and duration of the disease, condition, or illness, prior therapy, the patient's health condition and response to the drug, and the judgment of the treating physician.

[0242] In some cases, after administration of the compounds or compositions described herein, the patient’s condition does not improve or does not improve significantly, and the physician may, at his discretion, administer the compounds for an extended period of time, including throughout the patient’s life, in order to alleviate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0243] In certain cases where the patient's condition has improved or not substantially improved, the administration of the compound may be continued as appropriate, at the physician's judgment; alternatively, the dosage of the drug may be temporarily reduced or temporarily suspended for a certain period of time (i.e., a "withdrawal period"). In some embodiments, the length of the withdrawal period varies between 2 days and 1 year, including, for example, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dosage reduction during the withdrawal period includes a reduction of approximately 10% to approximately 100%, for example only, including approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 95%, or approximately 100%.

[0244] In some embodiments, a maintenance dose may be administered as necessary after the patient's condition has improved. In some embodiments, the dose or frequency of administration, or both, of the maintenance dose may be reduced, depending on the symptoms, to a level that allows the improvement in the disease, symptom, or condition to be maintained. However, in some embodiments, the patient may be given long-term intermittent treatment as appropriate in the event of any recurrence of symptoms.

[0245] In some embodiments, the amount of a given agent corresponding to an effective amount varies depending on factors such as the specific compound, the disease or condition and its severity, and the characteristics (e.g., weight) of the individual or host requiring treatment. In some embodiments, the effective amount is still determined based on the specific circumstances surrounding the case, including, for example, the specific agent administered, the route of administration, the condition being treated, and the individual or host being treated. However, in some embodiments, the dose used for adult treatment is from about 0.02 to about 5000 mg per day, and in one particular embodiment, it is in the range of about 1 to about 1500 mg per day. In various embodiments, the desired dose is preferably presented as a single dose or as multiple doses administered simultaneously (or over a short period of time) or at appropriate time intervals (e.g., as sub-dose twice, three, four, or more times per day).

[0246] In some embodiments, the pharmaceutical compositions described herein are presented in unit dosage forms suitable for single-dose administration of precise doses. In some cases, in unit dosage forms, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. In some embodiments, the unit doses are presented in packaged forms containing discrete amounts of the formulation. Non-limiting examples include packaged tablets or capsules and powders in vials or ampoules. In some embodiments, aqueous suspension compositions are packaged in single-dose, non-reclosable containers. In alternative embodiments, multi-dose, reclosable containers are used, in which case preservatives are typically included in the composition. By way of example only, in some embodiments, formulations for non-enteric injection are presented in unit dosage forms including (but not limited to) ampoules, or in multi-dose containers with added preservatives.

[0247] In some embodiments, the daily dose suitable for the compounds described herein is from about 0.01 to about 10 mg per kilogram of body weight. In some embodiments, the indicated daily dose in larger individuals (including (but not limited to) humans) is in the range of from about 0.5 mg to about 1,000 mg, which is preferably administered in divided doses (including (but not limited to) up to four times a day) or in an extended release form. In some embodiments, suitable unit dosage forms for oral administration contain about 1 to about 50 mg of the active ingredient. The foregoing ranges are merely illustrative, as there are a great many variables relating to individual treatment regimens, and large deviations from such recommended values ​​are uncommon. In some embodiments, the dose varies depending on many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the individual's needs, the severity of the disease or condition to be treated, and the physician's diagnosis.

[0248] In some embodiments, the toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or laboratory animals, including but not limited to determining the LD50 (the 50% lethal dose in a population) and ED50 (the 50% therapeutically effective dose in a population). The dose ratio between toxicity and therapeutic effect is the therapeutic index and can be expressed as the ratio between LD50 and ED50. In some embodiments, compounds exhibiting high therapeutic indices are disclosed. In some embodiments, data obtained from cell culture analysis and animal studies are used to formulate dosage ranges for human use. In certain embodiments, the dosage of such compounds is within a range that includes the cyclic concentration of the ED50 with minimal toxicity. In some embodiments, the dosage varies within this range depending on the dosage form and route of administration used.

[0249] In some embodiments, the disclosed compounds exhibit increased affinity, potency, or therapeutic index to the nuclear target compared to the unmodified nuclear payload from which the compound is derived. In some embodiments, this higher affinity, potency, or therapeutic index can provide benefits such as allowing for lower doses and thus reducing the likelihood of toxicity, increasing the therapeutic index, and reducing the overall cost of treatment. In some embodiments, the daily dose of the compound described herein is suitable to be less than 100% of the recommended daily dose of the unmodified nuclear load, or less than about 90%, or less than about 80%, or less than about 70%, or less than about 60%, or less than about 50%, or less than about 40%, or about 20% to about 90%, or about 30% to about 90%, or about 40% to about 90%, or about 50% to about 90%, or about 60% to about 90%, or about 70% to about 90%, or about 20% to about 80%, or about 30% to about 80%, or about 40% to about 80%, or about 50% to about 80%, or about 60% to about 80%, or about 70% to about 80%, or about 20% to about 70%, or about 30% to about 70%, or about 40% to about 70%, or about 50% to about 70%, or about 60% to about 70%.

[0250] In some embodiments, the compounds described herein are used to prepare or manufacture medicaments for treating diseases or conditions mediated by topoisomerase inhibitors or whose improvement is achieved by inhibition of one or more topoisomerases. In some embodiments, a method for treating any of the diseases or conditions described herein in an individual requiring such treatment involves administering to the individual in a therapeutically effective amount a pharmaceutical composition comprising: at least one compound described herein or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable precursor, or a pharmaceutically acceptable solvate.

[0251] Combination Therapy The compounds described herein may also be used in combination with other active ingredients. Such combinations are selected based on the condition to be treated, the cross-reactivity of the ingredients, and the pharmaceutical properties of the combination. In one embodiment, the present invention provides a use of a compound as described herein in combination with another agent or treatment method (such as another cancer treatment). For example, when treating cancer, the composition may be combined with other anticancer compounds (such as paclitaxel or rapamycin).

[0252] It is also possible to combine the compounds of the present invention with one or more other active ingredients in a single dosage form for simultaneous or sequential administration to a patient. Combination therapy can be administered simultaneously or sequentially. When administered sequentially, the combination can be administered in two or more doses.

[0253] Combination therapy can provide “synergistic effect” and “synergy”, meaning that the effect achieved when active ingredients are used together is greater than the sum of the effects produced by using the compounds separately. Synergistic effect can be achieved when active ingredients are: (1) co-formulated and simultaneously administered or delivered in combination formulations; (2) delivered alternately or in parallel in the form of individual formulations; or (3) by some other regimen. When delivered in alternating therapy, synergistic effect can be achieved when compounds are administered or delivered sequentially, for example in separate tablets, pills or capsules, or by different injections using separate syringes. Generally, in alternating therapy, effective doses of each active ingredient are administered sequentially (i.e., consecutively), however, in combination therapy, effective doses of two or more active ingredients are administered together. Synergistic anticancer effect means an anticancer effect greater than the predicted purely additive effect of the individual compounds in the combination.

[0254] Administration of the compounds and compositions of the present invention to patients, taking into account toxicity (if present), will follow general protocols for the administration of chemotherapeutic agents. Repeated treatment cycles are anticipated as needed. It has also been considered that various standard or adjuvant cancer therapies and surgical interventions may be administered in combination with the described active agents. These therapies include (but are not limited to) chemotherapy, radiotherapy, immunotherapy, gene therapy, and surgery.

[0255] In some embodiments, this document provides a method for treating cancer, comprising administering to an individual in need of treatment a therapeutically effective amount of a compound or composition described herein, along with ionizing radiation or one or more chemotherapeutic agents. In some embodiments, the compound described herein is administered simultaneously with ionizing radiation or one or more chemotherapeutic agents. In other embodiments, the compound described herein is administered sequentially with ionizing radiation or one or more chemotherapeutic agents.

[0256] In some embodiments, this document provides a method for treating cancer, comprising administering to an individual in need of treatment a therapeutically effective amount of a compound or composition described herein, along with ionizing radiation and one or more chemotherapeutic agents. In some embodiments, the compound described herein is administered simultaneously with ionizing radiation and one or more chemotherapeutic agents. In other embodiments, the compound described herein is administered sequentially with ionizing radiation and one or more chemotherapeutic agents.

[0257] In some embodiments, this document provides a method for treating cancer, comprising administering to an individual in need of treatment a therapeutically effective amount of a compound or composition described herein and ionizing radiation. In some embodiments, the radiation is administered at a dose of less than about 2.5 Gy per day, or about 2.0 Gy per day, or about 1.8 Gy per day, or about 1.6 Gy per day, or about 1.4 Gy per day, or about 1.2 Gy per day. In some embodiments, a dose of less than about 2.5 Gy, or about 2.0 Gy, or about 1.8 Gy, or about 1.6 Gy, or about 1.4 Gy, or about 1.2 Gy is administered about five times per week. In some embodiments, the radiation is administered at a dose of less than about 2.5 Gy per day, or about 2.0 Gy per day, or about 1.8 Gy per day, or about 1.6 Gy per day, or about 1.4 Gy per day, or about 1.2 Gy per day. In some embodiments, doses of less than about 2.5 Gy, or about 2.0 Gy, or about 1.8 Gy, or about 1.6 Gy, or about 1.4 Gy, or about 1.2 Gy are administered approximately six times per week. It has been considered that by administering radiation in combination with the compounds or compositions described herein, prostate-specific chemical prostatectomy can be achieved while avoiding harmful side effects such as impotence and incontinence following surgical prostatectomy due to vascular rupture and nerve severance.

[0258] Cancer therapy may also include multiple combination therapies with chemotherapy and radiation-based treatments. Combination chemotherapy includes the use of chemotherapeutic agents such as cisplatin, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, taxotere, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA® (gefitinib), TARCEVAR® (erlotinib hydrochloride). Hydrochloride, antibodies against EGFR, GLEEVEC® (imatinib), introns, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, nitrogen mustard, ifosfamide, melphalan, chlorambucil, pipebroman, triethyl melamine, triethylthiophosphatidylcholine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, fluxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate Phosphate), pentostatin, vinblastine, vincristine, vindesine, bleomycin, doxorubicin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-aspartate aminotransferase, teniposide, 17α-ethinylestradiol, diethylstilbestrol, testosterone, presbyronone, fluoromethathone, dromostanolone propionatePropionate, testosterone, medroxyprogesterone acetate, methylprednisolone, methyltestosterone, triamcinolone, chlorestrin, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrozole, letrazole, capecitabine, remdesivir Salfen (reloxafine), droloxafine, hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, vinorelbine, Porfimer, Erbitux® (cetuximab), lipids Thiotepa, hexamethylmelamine, melphalan, trastuzumab, letrozole, fulvestrant, exemestane, ifosfomide, rituximab, C225, camppas, carboplatin, procarbazine, methyldi(chloroethyl)amine, cyclophosphamide, camptothecin, ifosfomide, melphalan, chlorambucil, busulfan, nitrosourea, actinomycin D, donomycin, cranberry, bleomycin, mitomycin, etoposide (VP 16), tamoxifen, ranoxifene, estrogen receptor binders, paclitaxel, gemcitabine, vinorelbine, farnesyltransferase inhibitors, transplatinum, 5-fluorouracil, vincristine, vinblastine, and methotrexate, or any analogues or derivatives thereof.

[0259] In some embodiments, the compounds described herein are administered in combination with CDK inhibitors (e.g., CDK2, CDK4, CDK6 inhibitors or CDK4 / 6 inhibitors).

[0260] Other widely used factors causing DNA damage (such as radiotherapy) include what are commonly referred to as gamma rays, X-rays, and / or factors that deliver radioactive isotopes directly to tumor cells. Other forms of DNA damage are also included, such as microwave and UV irradiation. Most likely, all of these factors cause various forms of disruption to DNA, DNA precursors, DNA replication and repair, and chromosome assembly and maintenance. X-ray doses range from 50 to 200 roentgens per day over a prolonged period (e.g., 3 to 4 weeks) to 2000 to 6000 roentgens per single dose. Radioactive isotope doses vary considerably and depend on the isotope's half-life, the intensity and type of radiation emitted, and the uptake by the proliferating cells. When applied to cells, the terms "contact" and "exposure" are used herein to describe the process by which therapeutic constructs and chemotherapy or radiotherapy agents are delivered to or placed directly and in parallel with target cells. To achieve cell killing or inhibition, both agents are delivered to cells in a combination of doses that are effective in killing cells or preventing their division.

[0261] Immunotherapy agents typically rely on the use of immune effector cells and molecules to target and destroy cancer cells. Immune effectors can be, for example, antibodies specific to certain markers on the surface of tumor cells. An antibody alone can act as an effector of the therapy, or it can recruit other cells to actually influence cell killing. Antibodies can also bind to drugs or toxins (chemotherapy agents, radioactive nucleotides, ricin A chain, cholera toxin, pertussis toxin, etc.) and act solely as a target. Alternatively, effectors can be lymphocytes carrying surface molecules that interact directly or indirectly with the tumor cell target. Various effector cells include cytotoxic T cells and NK cells.

[0262] Therefore, immunotherapy can be combined with gene therapy as part of a combination therapy. A general approach for combination therapies is discussed below. Generally, tumor cells must carry markers suitable for targeting (i.e., not present on most other cells). Many tumor markers exist, and any one of these markers can be used for targeting in the context of this invention. Common tumor markers include carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), urinary tract tumor-associated antigen (UTC), embryonic antigen (ETA), tyrosinase (p97), gp68, TAG-72, HMFG, sialylated Lewis antigen (SIA), MucA, MucB, PLAP, estrogen receptor, laminin receptor, erb B, and p155.

[0263] In another embodiment, the adjuvant therapy is adjuvant gene therapy, wherein the therapeutic polynucleotide is administered before, after, or simultaneously with the first chemotherapeutic agent. Delivery of the chemotherapeutic agent via a vector encoding the gene product will have a combined anti-overproliferative effect on the target tissue.

[0264] Approximately 60% of people with cancer will undergo some type of surgery, including preventative, diagnostic or staging, curative, and palliative surgeries. Curative surgeries are cancer treatments that can be combined with other therapies, such as the treatment of this invention, chemotherapy, radiation therapy, hormone therapy, gene therapy, immunotherapy, and / or alternative therapies. Curative surgeries include resection, in which all or part of the cancerous tissue is physically removed, excised, and / or destroyed. Tumor resection refers to the physical removal of at least a portion of a tumor. In addition to tumor resection, surgical treatments also include laser surgery, cryosurgery, electrosurgery, and microscopically controlled surgery (Mohs' surgery). Upon further consideration, this invention can be used in conjunction with the removal of superficial cancer, primary cancer, or associated normal tissue.

[0265] Administration of a compound or composition as described herein may precede or follow another anticancer agent or treatment at intervals ranging from minutes to weeks. In embodiments where another anticancer agent and expression construct are administered separately, we generally ensure that no significant time period has elapsed between the delivery times so that the agent and expression construct will still be able to exert a beneficial combined effect on the cells. For example, in such cases, we consider that cells, tissues, or organisms having two, three, four, or more modalities may be substantially simultaneously (i.e., within less than about one minute) exposed to one or more active agents. In other embodiments, one or more agents may be administered within approximately 1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 9 hours, 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 28 hours, 31 hours, 35 hours, 38 hours, 42 hours, 45 hours to 48 hours or longer before and / or after administration of the active agent. In some other embodiments, the agent may be administered within approximately 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 8 days, 9 days, 12 days, 15 days, 16 days, 18 days, 20 days to 21 days before and / or after administration of the active agent. In some cases, it may be necessary to extend the time period for significant treatment, however, several weeks may have passed between individual administrations (e.g., about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, or about 8 weeks or more).

[0266] Kits are provided to achieve an anticancer effect and include the compounds or compositions described herein. In some embodiments, the kit includes a unit dose of the compounds or compositions described herein and instructions for administering such compounds or compositions. In some embodiments, the kit further includes a second drug for anticancer therapy, or instructions for co-administration with additional anticancer therapies (such as radiation or gene therapy). In another embodiment, the kit for achieving an anticancer effect includes a low dose (e.g., less than about 500 mg / day, or less than about 400 mg / day, or less than about 300 mg / day, or less than about 200 mg / day) of the compounds or compositions described herein and a second drug for anticancer therapy. In yet another variation, the kit for achieving an anticancer effect includes a high dose (e.g., greater than about 500 mg / day) of the compounds or compositions described herein and a second drug for anticancer therapy.

[0267] Method of Manufacturing a Pharmaceutical Agent In another aspect of the invention, the use of the compounds and compositions described herein in the manufacture of a pharmaceutical agent is provided. Specifically, the manufacture of a pharmaceutical agent for treating cancer or diseases or conditions mediated at least partially by blocking DNA repair and / or transcriptional activation (such as by inhibiting one or more topoisomerases) is provided. Furthermore, pharmaceutical compositions of the compounds described herein are also intended for use in the manufacture of a pharmaceutical agent for treating diseases or conditions mediated at least partially by inhibiting one or more topoisomerases.

[0268] Example 1: A compound of formula I, II or III, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog or pharmaceutically acceptable salt thereof: A1-(L1-B1)m'I A1-L1-(B1)m'II A1-L1-B1III Wherein: A1 is a topoisomerase inhibitor or an analog thereof; m' is 1, 2 or 3; each B1 is an independent nuclear receptor target antigen determinant; and L1 is a linker.

[0269] Example 2: The compound of Example 1, or its stereoisomers, mixtures of stereoisomers, hydrates, solvates, isotope-enriched analogs or pharmaceutically acceptable salts, wherein A1 is selected from:; wherein the wavy line indicates the connection point with -L1-B1.

[0270] Example 3: The compound as in Example 1 or 2, wherein m' is 1.

[0271] Example 4: A compound of formula IA, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog, or pharmaceutically acceptable salt thereof, wherein: R1, R2, R3, and R4 are each independently hydrogen, halogroup, cyanogroup, nitrogroup, -OR15, -SR15, -NR15R16, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R15, -C(=O)OR15, -OC(=O)R15, -C(=O)NR15R16, -NR15C ... O)R16, -NR15C(=O)OR16, -S(=O)1-2R15, -S(=O)1-2NR15R16, -NR15S(=O)1-2R16, -Si(R15)3 or -C=NOR15, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group of R1, R2, R3 and R4 is independently substituted by one or more R10 groups as the valence number allows; Or R1 and R2 together with the atoms they are attached to form C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups substituted with one or more R10 groups, as permitted by the valence; or R2 and R3 together with the atoms they are attached to form C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups substituted with one or more R10 groups, as permitted by the valence; or R3 and R4 together with the atoms they are attached to form C3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl groups substituted with one or more R10 groups, as permitted by the valence. Each R10 is independently a halogen, cyano, nitro, -OR17, -SR17, -SF5, -NR17R18, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R17, -C(=O)OR17, -OC(=O)OR17, -OC(=O)R17, -C(=O)NR17R18, -OC(=O)NR17R18, -NR7C(=O)NR17R18, -S(=O)1-2R 17. -S(=O)1-2NR17R18, -NR17S(=O)1-2R18, -NR17S(=O)1-2NR17R18, -NR17C(=O)R18, -NR17C(=O)OR18, -Si(R17)3 or -C=NOR17, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group of R10 is independently substituted by one or more halogen groups or C1-12 alkyl groups (which are substituted by side oxygen, halogen, hydroxyl or amino groups as appropriate) when the valence number allows;Furthermore, each of R15 and R16 is independently hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl, wherein each of the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl is independently substituted with a side-oxygen group, a halogen group, a hydroxyl group, or an amino group, as the valence allows; or R15 and R16 together with the atoms they are attached to form heterocycles substituted with a halogen group or a C1-12 alkyl group (which is substituted with a side-oxygen group, a halogen group, a hydroxyl group, or an amino group, as appropriate). R17 and R18 are independently hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl, wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, or C3-12 cycloalkyl is, where valence permits, substituted with a side-oxygen group, a halogen group, a hydroxyl group, or an amino group; or R17 and R18 together with the atoms to which they are attached form a heterocyclic group, substituted with a halogen group or a C1-12 alkyl group (which is, where appropriate, substituted with a side-oxygen group, a halogen group, a hydroxyl group, or an amino group); wherein one or more atoms (e.g., hydrogen, methyl, hydroxyl, etc.) are, where appropriate, directly covalently substituted via a linker portion (e.g., -L1-B1) as defined herein to at least one nuclear receptor target antigen determinant.

[0272] Example 5: A compound of formula IB, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog or pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen or -L1-B1; R2 is hydrogen, NH2, NO2 or -L1-B1; R3 is hydrogen, halogroup, methyl, methoxy or -L1-B1; R4 is hydrogen, halogroup, methyl or methoxy; or R3 and R4 together form -O-CH2-O- or -O-CH2CH2-O-; Y is a bond, -CH2- or -CH2-CH2-; and Z is a bond or O.

[0273] Example 6: The compound as in Example 5, wherein only one of R1, R2 or R3 is -L1-B1.

[0274] Example 7: The compound as in Example 5, wherein R2 is -L1-B1.

[0275] Example 8: The compound as in Example 5, wherein R3 is -L1-B1.

[0276] Example 9: A compound as described in any of the preceding examples, wherein L1 has the following formula: -Y10-(CH2)n'-Y20-(CH2)p'-Y30- wherein each of Y10, Y20 and Y30 is independently a bond, a substituted alkyl group, a substituted heteroalkyl group, a substituted aryl group, a substituted heteroaryl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, -CR110R120-, -NR110-, -O-, -S(O)0-2-, -NR110C(O)-, -C(O)NR110-, -NR110S(O)2-, -S(O)2NR110-, -CR120=N-NR110-, -NR110-N=CR120- or -C(O)-; Each R110 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; each R120 is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; and n' and p' are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0277] Example 10: The compound as described in any of the preceding examples, wherein L1 comprises a non-biologically cleavable portion.

[0278] Example 11: The compound as described in any of the preceding examples, wherein L1 is, as appropriate, a substituted alkyl group or a substituted heteroalkyl group.

[0279] Example 12: The compound of any of the preceding examples, wherein L1 comprises, as appropriate, a substituted C4-7 atom alkyl group, a substituted C4-7 atom heterocyclic group, or a substituted C4-7 atom heteroalkyl group.

[0280] Example 13: A compound as described in any of the preceding examples, wherein L1 is a substituted C4-10 atom alkyl group, as appropriate.

[0281] Example 14: The compound of any of the preceding examples, wherein L1 is a 4 to 7-atom alkyl or heteroalkyl linking portion, containing CH2 and at most 2 heteroatoms each independently selected from NH, O or S and, if applicable, a C=O.

[0282] Example 15: The compound of any of the preceding examples, wherein the connecting portion has the following formula: where "*" and wavy lines represent covalent bonds.

[0283] Example 16: A compound as described in any of the preceding examples, wherein the compound maintains biological activity equivalent to that observed in the original unmodified topoisomerase inhibitor.

[0284] Example 17: The compound of any of the preceding examples, wherein the compound inhibits the topoisomerase with an IC50 of less than about 5,000 nM.

[0285] Example 18: A compound as described in any of the preceding examples, wherein the compound is bound to topoisomerase I.

[0286] Example 19: A compound as described in any of the preceding examples, wherein the compound comprises a nuclear receptor target antigen determinant derived from:, or a stereoisomer or mixture of stereoisomers thereof or the like thereof, wherein at least one hydrogen atom is replaced by a direct covalent bond to A1 via a linker portion, as appropriate.

[0287] Example 20: Compound 1, 2, 3, 4 or 5 as provided in Table 1, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog or pharmaceutically acceptable salt thereof.

[0288] Example 21: A pharmaceutical composition comprising a compound or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotope-enriched analog or pharmaceutically acceptable salt and a pharmaceutically acceptable excipient as described in any of the preceding examples.

[0289] Example 22: A method of treating or preventing cancer, comprising administering to an individual in need an effective amount of a pharmaceutical composition as described in Example 21.

[0290] Example 23: The method of Example 21, wherein the feeding includes oral feeding.

[0291] Example 24: The method of Example 21, further comprising administering an additional chemotherapeutic agent.

[0292] Example 25: The method as in Example 24, wherein the additional chemotherapeutic agent is cisplatin or etoposide, irinotecan, captotocin, topotecan, docetaxel, epothilone, ketoconazole, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778123, BMS 214662, Gefitinib, Erlotinib Hydrochloride, Antibody against EGFR, Matinib, Intron, Cytarabine, Adriamycin, Cancer-Singleton Agent, Gemcitabine, Uracil Mustard, Nitrogen Mustard, Ifosfamide, Melphalan, Chlorbutamol Mustard, Piperbromophenazine, Triethylmelamine, Triethylthiophosphatidylcholine, Busulfan, Carmustine, Lomustine, Streptozotocin, Dacarbazine, Fluorouracil, Cytarabine, 6-Mercaptopurine 6-Thioguanine, Fludarabine Phosphate, Pentostatin, Vincristine, Vincristine, Vincristine, Bleomycin, Cranberry, Actinomycin D, Donomycin, Epirubicin, Idamycin, Photomycin, Deoxymethimazole, Mitomycin-C, L-Aspartame, Teniposide, 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Presson, Flumethasone, Drotahistamine Propionate, Testrolide, Medroxyprogesterone Acetate, Methyl Pressonetine, Methyltestosterone, Pressonetine, Triamcinolone, Chlorestrin, Hydroxyprogesterone, Aminolamide, Estrogenus, Medroxyprogesterone Acetate, Leuprolide, Flutamide, Toremiphene, Goserelin, Carboplatin, Hydroxyurea, Acridine, Procarbazine, Mitotan, Mitoxantrone, Levamisole, Noviben, Anastrozole, Capecitabine, Droloxifene, Hexamethylmelamine, Avastin, Hexamethasone, Bixamethasone, Velcade, Zevallin, Terlison Leukostatin, vinorelbine, porphyrin, cetuximab, liposomes, thiotepa, hexamethylmelamine, trastuzumab, letrozole, fulvestrant, exemestane, rituximab, C225, camppas, carboplatin, procarbazine, methyldi(chloroethyl)amine, cyclophosphamide, camptothecin, melphalan, busulfan, nitrosourea, actinomycin D, donomycin, cranberry, bleomycin, mitomycin, etoposide (VP 16), raloxifene, estrogen receptor binders, paclitaxel, gemcitabine, vinoxifene, farnesyltransferase inhibitors, transplatin and methotrexate, or their analogues or derivatives.

[0293] Example 26: The method of any one of Examples 22 to 25 further includes administering radiation therapy to the patient.

[0294] Example 27: The method of any one of Examples 22 to 26, wherein the cancer is a BRCA-positive cancer.

[0295] Example 28: The method of any one of Examples 22 to 27, wherein the cancer is a solid tumor.

[0296] Example 29: The method of any one of Examples 22 to 28, wherein the cancer is a cancer affecting B cells.

[0297] Example 30: The method of any one of Examples 22 to 29, wherein the cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, chronic lymphoblastic leukemia, Waldenström's macroglobulinemia, primary macroglobulinemia, bladder cancer, chronic granulocytic leukemia, or primary... Primary brain cancer, malignant melanoma, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urogenital cancer, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, skin cancer, trophoblastic tumor, or prostate cancer.

[0298] Example 31: The method of Example 22, wherein the cancer is neuroblastoma, brainstem glioma, Ewing's disease, non-small cell lung cancer, colorectal cancer, breast cancer, non-Hodgkin's lymphoma, endometrial cancer or oligodendroglioma.

[0299] Example 32: A method for treating or preventing neurogenetic diseases or conditions, comprising administering an effective amount of a pharmaceutical composition as described in Example 21 to an individual in need.

[0300] Example 33: The method of Example 32, wherein the neurogenetic disease or condition is Angelman's syndrome.

[0301] Examples The invention is further illustrated by the following examples. The following examples are non-limiting and only represent various aspects of the invention. The solid lines and dotted wedges in the structures disclosed herein illustrate relative stereochemistry, while absolute stereochemistry is only depicted in the specific statements or descriptions.

[0302] Compounds having the structure of any compound, formula, or subform described herein can be synthesized using standard synthetic techniques known to those skilled in the art. Compounds of the present invention can be synthesized using common methods or common synthetic procedures illustrated in the synthetic examples.

[0303] When it is necessary to obtain a specific enantiomer of a compound, this can be accomplished from the corresponding mixture of enantiomers using any suitable known procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives can be produced by reacting a mixture of enantiomers (e.g., a racemic mixture) with a suitable antimeric compound. The diastereomeric derivatives can then be separated by any suitable means, such as crystallization, and the desired enantiomer can be recovered. In another analytical method, antimeric high-performance liquid chromatography can be used to separate the racemic mixture. Alternatively, if necessary, the specific enantiomer can be obtained by using a suitable antimeric intermediate from one of the described methods.

[0304] Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products when necessary to obtain specific isomers of the compound or products of other purification reactions.

[0305] Synthetic Procedure Example 1: Synthesis of 4-(6-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)hexyl)piperazon-1-carboxylic acid (S)-4,11-diethyl-4-hydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (Compound 1)

[0306] Step-1: Preparation of ethyl 6-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)hexanoate: K2CO3 (550 mg, 4.0 mmol, 2.0 eq) was added to a mixture of 3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenol (776 mg, 2.0 mmol, 1.0 eq) and ethyl 6-bromohexanoate (600 mg, 2.2 mmol, 1.1 eq) in DMF (200 mL) and stirred at room temperature for 16 hours. The reaction progress was monitored by TLC analysis. After completion, the mixture was diluted with ice-cold water (30 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (20 mL × 4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by silicone column chromatography to give the title compound (900 mg, 85%).

[0307] Step-2: Preparation of 6-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)hexanoic acid: LiOH·H₂O (95 mg, 2.5 mmol, 5.0 eq) and water (2 mL) were added to a solution of ethyl 6-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)hexanoate in MeOH (10 mL). The reaction progress was monitored by TLC analysis. After completion, the mixture was concentrated and acidified to pH approximately 3 with an aqueous citric acid solution (20 mL), and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine (20 mL × 4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (150 mg, 60%), which was used without further purification.

[0308] Step-3: 4-(6-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridino[3,4-b]indol-1-yl)phenoxy)hexyl)piperazine-1-carboxylic acid(S)-4,11-diethyl-4-hydroxy-3,14-disideloxy-3,4 Preparation of ,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (1): HATU (141 mg, 0.37 mmol, 1.5 eq) was added to a stirred solution of 6-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridino[3,4-b]indol-1-yl)phenoxy)hexanoic acid (125 mg, 0.25 mmol, 1.0 eq) in DMF (5 mL) and stirred at room temperature for 15 minutes. Add DIPEA (0.18 mL, 1.0 mmol, 2.0 eq) and 4-(2,2,2-trifluoroacetyl)-4l4-piperazine-1-carboxylic acid (S)-4,11-diethyl-4-hydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (150 mg, 0.25 mmol, 1.0 eq) to this solution and stir at room temperature for 2 hours. After completion, dilute the mixture with ice-cold water (30 mL) and extract with DCM (50 mL × 2). The combined organic layers were washed with brine (20 mL × 4), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by silicone column chromatography to obtain the desired product. The product was then wet-milled again with acetone / n-pentane (1:5) and dried to give the title compound (22 mg, 6%).LCMS: 989.5 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ10.52 (s, 1H), 8.19 (d,J= 9.6 Hz, 1H), 8.01 (d,J= 2.6 Hz, 1H), 7.69 (dd,J= 9.2, 2.2 Hz, H), 7.38 (d,J= 7.0 Hz, 1H) 7.32 (s, 1H), 7.17 (d,J= 7.9 Hz, 1H), 7.04-6.88 (m, 2H), 6.64 (s, 1H), 6.67 (s, 1H), 6.53 (s, 1H), 5.44 (s, 2H), 5.34 (s, 2H), 5.12 (m, 1H), 4.04-3.90 (m, 2H), 3.69-3.45 (m, 10H), 3.26-2.56 (m., 6H), 2.21-2.45 (m, 3H), 1.98-1.43 (m, 8H), 1.29 (t,J= 7.7 Hz, 4H), 1.22-1.03 (m, 6H), 0.88 (t,J= 7.2 Hz, 3H).

[0309] Example 2 Synthesis of 4-(6-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)hexyl)piperazine-1-carboxylic acid (S)-4,11-diethyl-4-hydroxy-3,14-di-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (Compound 2)

[0310] Step-1: Preparation of 6-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)hexyl-1-ol: K2CO3 (552 mg, 4.0 mmol, 2.0 eq) was added to a mixture of 3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenol (776 mg, 2.0 mmol, 1.0 eq) and 6-bromohexyl-1-ol (396 mg, 2.2 mmol, 1.1 eq) in DMF (10 mL) and stirred overnight at room temperature. The reaction progress was monitored by TLC analysis. After completion, the reaction mixture was diluted with ice-cold water (30 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (20 mL × 4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silicone column chromatography to give the title compound (800 mg, 82%).

[0311] Step-2: Preparation of 6-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)hexanal: DMP (510 mg, 1.2 mmol, 1.2 eq) was added to a solution of 6-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)hexanal (489 mg, 1.0 mmol, 1.0 eq) in DCM (50 mL) and stirred at room temperature for 2 hours. The reaction mixture was then diluted with DCM (50 mL), washed with sodium thiosulfate solution (20 mL × 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was used in the next step without further purification.

[0312] Step-3: 4-(6-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)hexyl)piperyl-1-carboxylic acid (S)-4,11-diethyl-4-hydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H Preparation of 4-(2,2,2-trifluoroacetyl)-4l4-piperano-1-carboxylic acid (S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (240) 389 mg, 0.8 mmol, 2.0 eq) of 6-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)hexanal (20 mL) in IPA were added to a stirred solution, and acetic acid (0.1 mL) was added and the mixture was stirred at room temperature for 15 minutes. Sodium cyanoborohydride (49 mg, 0.8 mmol, 2.0 eq) was added to this solution, and the mixture was stirred overnight at room temperature. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with saturated NaHCO3 aqueous solution (30 mL) and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine (20 mL × 4), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase chromatography to give the title compound (72 mg, 18%).LCMS: 975.4[M+H]+; 1H NMR (400 MHz, DMSO-d6): δ10.53 (s, 1H), 8.18 (d,J= 9.2 Hz, 1H), 8.00 (d,J= 2.6 Hz, 1H), 7.66 (d,J= 9.2 Hz, 1H), 7.39 (d,J= 7.8 Hz, 1H), 7.32 (s, 1H), 7.18 (d,J= 7.8 Hz, 1H), 6.86-7.05 (m, 2H), 6.66 (d,J= 11.4 Hz, 1H), 6.54 (s, 1H), 5.44 (s, 2H), 5.34 (s, 2H), 5.12 (m, 1 H), 3.96 (m, 2H), 3.67-3.48 (m, 6H), 3.19 (d,J= 6.6 Hz, 3H), 2.86-2.20 (m, 8H), 1.79-1.20 (m, 16H), 1.16 (m, 2H), 1.11 (s, 2H), 1.04 (d,J= 6.1 Hz, 3H), 0.88 (t,J= 7.2 Hz, 3H).

[0313] Example 3 Synthesis of 4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)piperazo-1-carboxylic acid (S)-4,11-diethyl-4-hydroxy-3,14-disideoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (compound 3)

[0314] Step-1: Preparation of piperato-1,4-dicarboxylic acid (S)-1-(tert-butyl) ester 4-(4,11-diethyl-4-hydroxy-3,14-di-side-oxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl) ester: DIPEA (0.34 mL, 1.91 mmol, 1.5 eq) was added to a stirred solution of 7-ethyl-10-hydroxycamptothecin (0.50 g, 1.27 mmol, 1.0 eq) in THF (10 mL), followed by the addition of p-nitrochloroformate (0.30 g, 1.53 mmol, 1.2 eq). The reaction mixture was then stirred at room temperature for 2 hours. After completion, the mixture was evaporated under reduced pressure to obtain a crude substance, which was then treated with diethyl ether to obtain a crude residue (700 mg). This crude residue was dissolved in DCM (15 mL), followed by the addition of DMAP (153 mg, 1.25 mmol, 1.0 eq) and N-Boc piperazine (467 mg, 2.5 mmol, 2.0 eq). The reaction mixture was then stirred at room temperature for 16 hours. After completion, the mixture was diluted with DCM (50 mL) and then washed with brine (2 × 50 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain a crude residue, which was purified by CombiFlash chromatography to give the title compound (300 mg, 39%).

[0315] Step-3: Preparation of piperato-1-carboxylic acid (S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester trifluoromethanesulfonate: TFA (0.5 mL) was added dropwise to a stirred solution of piperato-1,4-dicarboxylic acid (S)-1-(tert-butyl) ester 4-(4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl) ester (0.30 g, 0.50 mmol, 1.0 eq) in DCM (5 mL) at 0 °C. The mixture was then stirred at room temperature for 30 minutes. After that, the reactants were evaporated under reduced pressure to give a crude product, which was purified by wet milling with diethyl ether (2 × 25 mL) to give the title compound (220 mg, 90%).

[0316] Step-4: 4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylic acid (S)-4,11-diethyl-4-hydroxy-3,14-sideoxy-3,4, Preparation of 12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (3): HATU (0.22 g, 5.8 mmol, 1.5 eq) was added to a stirred solution of 6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetoxy-13-methyl-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadienano[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexanoic acid (0.26 g, 0.46 mmol, 1.0 eq) in DMF (5 mL). The reaction mixture was then stirred at 0 °C for 10 min. At 0 °C, piperato-1-carboxylic acid (S)-4,11-diethyl-4-hydroxy-3,14-di-sideoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester trifluoromethanesulfonate (0.2 g, 3.9 mmol, 1.0 eq) and DIPEA (0.2 mL, 11.7 mmol, 3.0 eq) dissolved in DMF (5 mL) were added dropwise to the reactants. The mixture was then stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with DCM (50 mL) and washed with ice-cold water (2 × 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give a crude residue, which was purified by reverse-phase HPLC to give the title compound (76 mg, 18%).LCMS: 1062 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 8.19 (d,J= 9.2 Hz, 1H), 8.02 (s, 1H), 7.70 (d,J= 9.2 Hz, 1H), 7.33 (s, 1H), 6.99 (d,J= 8.3 Hz, 2H), 6.48-6.67 (m, 3H), 5.67 (s, 1H), 5.44 (s, 2H), 5.35 (s, 2H), 4.40 (m, 1H) 3.58 (m, 8H), 3.21 (dd,J= 16.0, 7.24 Hz, 5H), 2.83 (s, 6H), 2.60-2.71 (m, 3H), 2.34 (d,J= 9.6 Hz, 4H), 2.06-2.15 (m, 3H), 2.00 (s, 3H), 1.83-1.93 (m, 4H), 1.75 (s, 3H), 1.70 (m, 3H), 1.54 (m, 4H), 1.29 (t,J= 7.7 Hz, 7H), 0.88 (t,J= 7.4 Hz, 3H).

[0317] Example 4 Synthesis of 4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)piperazo-1-carboxylic acid (S)-4,11-diethyl-4-hydroxy-3,14-disideoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (compound 4).

[0318] Step-1: Acetic acid (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(6-sideoxyhexyl)amino)phenyl)-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-17-yl Preparation of the ester: DMP (424 mg, 1.0 mmol, 2.0 eq) was added to a solution of acetic acid (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-hydroxyhexyl)(methyl)amino)phenyl)-13-methyl-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-17-yl ester (281 mg, 0.5 mmol, 1.0 eq) in DCM (20 mL), followed by the addition of water (18 mg, 1.0 mmol, 2.0 eq), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with DCM (50 mL) and washed with sodium thiosulfate solution (20 mL × 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was used in the next step without further purification.

[0319] Step-2: 4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylic acid (S)-4,11-diethyl-4-hydroxy-3,14-diside Preparation of 4-(2,2,2-trifluoroacetyl)-4l4-piperano[3',4':6,7]inno[1,2-b]quinoline-9-yl ester trifluoromethanesulfonate (4): 4-(2,2,2-trifluoroacetyl)-4l4-piperano-1-carboxylic acid (S)-4,11-diethyl-4-hydroxy-3,14-di-side-oxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]inno[1,2-b]quinoline-9-yl ester trifluoromethanesulfonate (120 224 mg, 0.4 mmol, 1.0 eq) of acetic acid (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(6-sideoxyhexyl)amino)phenyl)-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecyl-1H-cyclopentadien[a]phenanthrene-17-yl ester (224 mg, 0.4 mmol, 2.0 eq) in IPA (5 mL) was stirred with acetic acid (0.05 mL) and stirred at room temperature for 15 minutes. Sodium cyanoborohydride (25 mg, 0.4 mmol, 2.0 eq) was added to this solution, and the mixture was stirred overnight at room temperature. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with saturated NaHCO3 aqueous solution (30 mL) and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine (20 mL × 4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by reverse-phase chromatography to give the title compound (12 mg, 6%).LCMS: 1049.0[M+H]+; 1H NMR (400 MHz, DMSO-d6): δ8.18 (d,J= 8.8 Hz, 1H), 8.00 (d,J= 2.2 Hz, 1H), 7.67 (d,J= 10.5 Hz, 1H), 7.32 (s, 1H), 6.98 (d,J= 8.2 Hz, 2H), 6.46-6.70 (m, 3H), 5.67 (s, 1H), 5.44 (s, 2H), 5.34 (s, 2H), 4.39 (m, 1H), 3.65 (m, 2H), 3.46 (m, 2H), 3.04-3.27 (m, 6H), 2.8-2.62 (m, 8H), 2.27-1.23 (m, 36H), 0.88 (t,J= 7.2 Hz, 3H).

[0320] Example 5 Synthesis of 4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)piperano-1-carboxylic acid(S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disideoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (compound 5).

[0321] Step-1: Preparation of piperato-1,4-dicarboxylic acid (S)-1-(tert-butyl) ester 4-(10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl) ester: DIPEA (3.3 mL, 19 mmol, 4.0 eq) and triphosgene (2.8 g, 9.5 mmol, 2.0 eq) dissolved in DCM (15 mL) were added dropwise to a stirred solution of topotecan hydrochloride (2 g, 4.75 mmol, 1.0 eq) in anhydrous THF (100 mL):DCM (100 mL) at 0 °C. The mixture was stirred at 0°C for 30 minutes, followed by the addition of N-Boc piperazine (1.32 g, 7.12 mmol, 1.5 eq) dissolved in DCM (15 mL). The mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the mixture was diluted with water (50 mL) and extracted with DCM (50 mL × 5). The combined organic layers were washed with saturated NaHCO3 (50 mL), water (50 mL), and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by CombiFlash chromatography to give the desired compound (0.35 g, 12%).

[0322] Step-2: Preparation of piperano-1-carboxylic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester trifluoromethanesulfonate: Piperano-1,4-dicarboxylic acid (S)-1-(tributyl) ester 4-(10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl) ester (0.35 g, 0.55 mmol) was prepared at 0 °C in DCM (5 Trifluoroacetic acid (1 mL) was added dropwise to a stirred solution and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by LC-MS. After completion, the mixture was concentrated under reduced pressure to give a crude product, which was wet-milled with diethyl ether to give the title compound (0.28 g, 95%).

[0323] Step-3: 4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylic acid(S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy Preparation of 3,14-disidero-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (5): Piperano-1-carboxylic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disidero-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester trifluoromethanesulfonate (0.25 Acetic acid (0.2 mL) was added to a stirred solution of 0.28 g (0.46 mmol, 1.0 eq) of acetic acid (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(6-sideoxyhexyl)amino)phenyl)-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecyl-1H-cyclopentadien[a]phenanthrene-17-yl ester (0.28 g, 0.50 mmol, 1.1 eq) in MeOH (12 mL), and the mixture was stirred at room temperature for 15 min. Then, sodium cyanoborohydride (0.058 g, 0.92 mmol, 2.0 eq) was added to the mixture, and the mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC and LCMS. After completion, the mixture was diluted with water (30 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with saturated NaHCO3 (20 mL), water (20 mL), and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude substance, which was purified by reverse-phase HPLC to give the title compound (0.01 g, 2%).LCMS: 1078 [M+H]+; 1H NMR (500 MHz, DMSO-d6): δ8.94 (s, 1H), 8.11 (d,J= 9.2 Hz, 1H), 7.63 (d,J= 9.2 Hz, 1H), 7.34 (s, 1H), 6.99 (d,J= 8.2 Hz, 2H), 6.59 (d,J= 8.2 Hz, 2H), 6.55 (s, 1H), 5.68 (s, 2H), 5.43 (s, 4H), 5.32 (s, 4H), 4.40 (d,J= 7.0 Hz, 2H), 3.75 (s, 4H), 3.70 (s, 4H), 3.46 (s, 4H), 3.25 (s, 2H), 2.82 (s, 6H), 2.43-0.81 (m, 32H), 0.24 (s, 3H).

[0324] Example 6 Preparation of 4-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionoylimidazolidine-1-yl)-2-fluorobenzoamino)hexyl)piperazine-1-carboxylic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disideoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (compound 6)

[0325] Step-1: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionylimidazodin-1-yl)-2-fluoro-N-(6-hydroxyhexyl)benzoamide HATU (1.14 g, 3.0 mmol, 1.5 equivalent) was added to a stirred solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionylimidazodin-1-yl)-2-fluorobenzoic acid (0.9 g, 2.0 mmol, 1.0 equivalent) in DMF (5 mL), and the mixture was stirred at room temperature for 15 minutes. DIPEA (1.67 mL, 10.0 mmol, 5.0 equivalents) and 6-aminohexane-1-ol (284 mg, 2.4 mmol, 1.2 equivalents) were added to this solution, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with ice-cold water (30 mL) and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine (20 mL × 4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silicone column chromatography to give the desired product (700 mg, 63.5%). LCMS: 551.3 [M+H]+.

[0326] Step-2: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionoylimidazodin-1-yl)-2-fluoro-N-(6-sideoxyhexyl)benzamide DMP (255 mg, 0.6 mmol, 1.2 equivalents) was added to a solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionoylimidazodin-1-yl)-2-fluoro-N-(6-hydroxyhexyl)benzamide (275 mg, 0.5 mmol, 1.0 equivalent) in DCM (20 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with DCM (50 mL) and washed with sodium thiosulfate solution (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was used as is in the next step. LCMS: 549.4 [M+H]+.

[0327] Step-3: Preparation of 4-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionoylimidazolidin-1-yl)-2-fluorobenzoylamino)hexyl)piperazine-1-carboxylic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disideoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (compound 6) to compound 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionoylimidazolidin-1-yl)-2-fluoro-N-(6-sideoxyhexyl)benzoylamine (225 Acetic acid (0.2 mL) was added to a stirred solution of INT-1 (315 mg, 0.5 mmol, 1.0 equivalent) in methanol (10 mL), and the mixture was stirred at room temperature for 15 minutes. Sodium cyanoborohydride (126 mg, 2.0 mmol, 4.0 equivalent) was then added to this solution, and the mixture was stirred overnight at room temperature. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was diluted with saturated NaHCO3 aqueous solution (30 mL) and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine (20 mL × 4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by reverse-phase chromatography to give the desired product (18 mg, 3.4%) (formate).

[0328] 1H NMR (400 MHz, DMSO-d6): δ 8.94 (s, 1H), 8.48 (br s, 2H), 8.40 (d,J= 7.89 Hz, 1H), 8.29 (s, 1H), 8.11 (d,J= 9.65 Hz, 2H), 7.76 (s, 1H), 7.63 (d,J= 9.21 Hz, 1H), 7.43 (d,J= 10.96 Hz, 1H), 7.34 (s, 2H), 6.54 (br s, 1H), 5.43 (s, 2H), 5.31 (s, 2H), 3.75 (br s, 4H), 3.48 (br s, 3H), 2.34 (d,J= 13.59 Hz, 6H), 2.20 (s, 6H), 1.85 (d,J= 14.03 Hz, 2H), 1.54 (s, 8H), 1.36 (br s, 4H), 1.23 (br s, 2H), 0.89 (t,J= 7.24 Hz, 3H). LCMS: 1067 [M+H]+.

[0329] Example 7 Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-((5-(((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]inno[1,2-b]quinoline-9-yl)oxy)pentyl)oxy)benzamide (compound 7)

[0330] Step-1a: Preparation of methyl 4-(5-bromopentoxy)benzoate K₂CO₃ (21.7 g, 157.8 mmol, 3 equivalents) was added to a stirred solution of methyl 4-hydroxybenzoate (8 g, 52.63 mmol, 1.0 equivalent) in acetonitrile (80 mL) at room temperature, and the mixture was stirred for 30 min at the same temperature. Then, 1,5-dibromopentane (24.0 g, 105.2 mmol, 2.0 equivalents) was added, and the resulting reaction mixture was heated at 90 °C for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the mixture was diluted with H₂O (150 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with water (100 mL × 3) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude substance, which was purified by CombiFlash chromatography to give the title compound (11.5 g, 73%). LCMS: 301[M+H]+.

[0331] Step-1: Preparation of 4-(5-bromopentoxy)benzoic acid LiOH·H₂O (9.0 g, 220.0 mmol, 1.0 equivalent) dissolved in H₂O (5 mL) was added to a solution of methyl 4-(5-bromopentoxy)benzoate (6.6 g, 22.0 mmol, 1.0 equivalent) in THF:MeOH (30 mL:15 mL), and the mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion, the mixture was concentrated under reduced pressure, and the resulting residue was acidified with 2N-HCl (pH approximately 3) under ice-cold conditions to form a precipitate, which was then filtered through a Buchner funnel to give the title compound (5 g, 79%). LCMS: 287.0 [M+H]⁺.

[0332] Step-2: Preparation of 4-(5-bromopentoxy)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)benzoamide HATU (2.3 g, 6.29 mmol, 1.2 equivalents) was added to a stirred solution of 4-(5-bromopentoxy)benzoic acid (1.5 g, 5.24 mmol, 1.0 equivalent) in DMF (15 mL), and the mixture was stirred at room temperature for 15 minutes. Then, DIPEA (4.8 mL, 26.22 mmol, 5.0 equivalents) and 4-((1r,4r)-4-aminocyclohexyloxy)-2-chlorobenzonitrile hydrochloride (1.4 g, 5.24 mmol, 1.0 equivalent) were added sequentially, and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the mixture was diluted with ice-cold water (30 mL), and the resulting precipitate was filtered through a Buchner funnel and washed with water (100 mL) and n-pentane (100 mL) to give the title product (2 g, 74%). LCMS: 519 [M+H]+.

[0333] Step-3: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-((5-(((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-di-side-oxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinolin-9-yl)oxy)pentyl)oxy)benzamide (compound 7) Cs2CO3 (0.640 g, 1.96 mmol, 2.0 equivalent) was added to a stirred solution of topotecan hydrochloride (0.45 g, 0.98 mmol, 1.0 equivalent) in DMF (8 mL), and the mixture was stirred at room temperature for 20 minutes. Next, TBAI (0.072 g, 0.19 mmol, 0.2 equivalents) and 4-(5-bromopentoxy)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)benzamide (2.04 g, 3.93 mmol, 4.0 equivalents) were added to the mixture, and the resulting mixture was heated at 70 °C for 30 min. The reaction progress was monitored by TLC and LC-MS. After completion, the mixture was diluted with ice-cold water (30 mL), and the resulting precipitate was filtered through a Buchner funnel to obtain a crude residue, which was purified by reverse-phase chromatography to give the title compound (0.065 g, 7%). 1H NMR (400 MHz, DMSO-d6): δ 8.80 - 8.78 (m, 1H), 8.12 - 8.09 (m, 2H), 7.90 - 7.60 (m, 3H), 7.41 - 7.38 (m., 1H), 7.29 (s, 1H), 7.14 (d,J= 8.77 Hz, 1H), 6.97 (d,J= 8.33 Hz, 2H), 6.49 (s, 1H), 5.51 - 5.43 (m, 2H), 5.29 - 5.27 (m, 2H), 4.55 - 5.52 (m., 2H), 4.24 - 4.22 (m, 2H), 4.09 - 4.06 (m, 2H), 3.85 - 3.82 (m., 3H), 2.34 - 2.32 (m, 2H), 2.2 - 2.18 (m, 4H), 2.13 - 2.11 (m, 1H), 2.07 - 1.87 (m, 6 H), 1.77 - 1.75 (m, 2H), 1.69 - 1.67 (m, 2H), 1.51 (d,J= 7.89 Hz, 3H), 1.24 (m, 2H), 0.88 (t,J= 7.45 Hz, 3H).LCMS: 860 [M+H]+.

[0334] Example 8 Preparation of 4-(6-(((5R,8S,9R,10R,13R,14R,17R)-10,13-dimethyl-3-sideoxyhexadecyl-1H-cyclopentadieno[a]phenanthrene-17-yl)oxy)hexyl)piperano-1-carboxylic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disideoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (compound 8)

[0335] Step-1: Preparation of (5S,8R,9S,10S,13S,14S,17S)-17-(6-hydroxyhexyloxy)-10,13-dimethyltetradecano-1H-cyclopentadieno[a]phenanthrene-3(2H)-one At room temperature, 6 N-HCl (13 mL) was added to a stirred solution of (5S,8R,9S,10S,13S,14S,17S)-10,13-dimethylhexadecanospiro[cyclopentadieno[a]phenanthrene-3,2'-[1,3]dioxacyclopentane]-17-ol (0.86 g, 1.66 mmol, 1.0 equivalent) in THF (21 mL) and water (4.0 mL), and the mixture was stirred at 0°C for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with saturated NaHCO3 (50 mL) (pH approximately 8). The aqueous layer was extracted with EtOAc (50 mL). The organic layer was washed with NaHCO3 (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the desired product (0.7 g, 42%). LCMS: 391.5 [M+H]+.

[0336] Step-2: Preparation of 6-((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-sideoxyhexadecylhydro-1H-cyclopentadieno[a]phenanthrene-17-yloxy)hexanal To a stirred solution of (5S,8R,9S,10S,13S,14S,17S)-10,13-dimethylhexadecylhydrospiro[cyclopentadieno[a]phenanthrene-3,2'-[1,3]dioxacyclopentane]-17-ol (0.70 g, 1.61 mmol, 1.0 equivalent) in DCM (10 ml), DMP (1.39 mL, 2.41 mmol) was added. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the desired product (0.60 g, 99.99%). LCMS: 389.30 [M+H]+.

[0337] Step-3: 4-(6-(((5R,8S,9R,10R,13R,14R,17R)-10,13-dimethyl-3-sideoxyhexadecyl-1H-cyclopentadienyl[a]phenanthrene-17-yl)oxy)hexyl)piperyl-1-carboxylic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disideoxy-3 Preparation of 4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (compound 8): 6-((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-sideoxyhexadecyl-1H-cyclopentadieno[a]phenanthrene-17-yloxy)hexanal (0.70 g, 1.80 mmol, 1.0 equivalent) in methanol (10 mL) was stirred at 0 °C. Topotecan (0.60 g, 1.80 mmol, 1.0 equivalent) and acetic acid (0.2 mL) were then added and the mixture was maintained for 1 hour. NaBH3CN (0.18 g, 3.60 mmol, 2.0 equivalent) was then added. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was alkalized with 100 mL of NaHCO3 solution and extracted with 200 mL of DCM. The organic layer was washed with 200 mL of water, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was then purified by CombiFlash [silicone 100 to 200 mesh, dissolution: 0-6% MeOH / DCM] to give the desired product (0.20 g, 13%). 1H NMR (400 MHz, DMSO-d6): δ 8.95 (s, 1H), 8.29 (s, 1H), 8.11 (d,J= 8.77 Hz, 1H), 7.63 (d,J= 8.77 Hz, 1H), 7.34 (s, 1H), 6.52 (s, 1H), 5.43 (s, 2H), 5.32 (br s, 2H), 3.76 (br s, 2H), 3.70 (br s, 2H), 3.47 (br s, 2H), 3.38 (br s, 1H), 2.26 (br s, 1H), 2.20 - 1.16 (d, 37H), 0.97 (s, 3H), 0.89 (t,J=7.24 Hz, 4H), 0.79 - 0.56 (m, 4H). LCMS: 907.19 [M+H]+.

[0338] Example 9 Preparation of (11R,13S,17R)-17-acetyl-11-(4-((6-(4-(((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]inno[1,2-b]quinolin-9-yl)oxy)piperidin-1-yl)hexyl)(methyl)amino)phenyl)-13-methyl-3-sideloxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-17-yl ester (compound 9)

[0339] Step-1: Preparation of tert-butyl 4-hydroxypiperidine-1-carboxylate Boc-anhydride (25.5 g, 118.8 mmol, 1.2 equivalent) and TEA (16.52 mL, 118.8 mmol, 1.2 equivalent) were added sequentially to a stirred solution of 4-hydroxypiperidine (10 g, 99.01 mmol, 1.0 equivalent) in DCM (200 mL), and the mixture was stirred at room temperature for 18 hours. The reaction was monitored by TLC and LC-MS. After completion, the mixture was diluted with H2O (100 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with water (100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (19 g, 95% yield). 1H NMR (400 MHz, CDCl3): δ 3.91-3.79 (m, 3H), 3.08-3.00 (m, 2H), 1.90-1.81 (m, 2H), 1.51-1.41 (m, 11H).

[0340] Step-2: Preparation of terbutyl 4-iodopiperidine-1-carboxylate Triphenylphosphine (32.2 g, 122.8 mmol, 1.3 equivalent) and imidazole (10.2 g, 151.2 mmol, 1.6 equivalent) were added to a stirred solution of N-Boc-4-hydroxypiperidine (19 g, 94.52 mmol, 1.0 equivalent) in DCM (200 mL). Iodine (23.81 g, 94.5 mmol, 1.0 equivalent) was then added fractionally at 0 °C. The resulting mixture was then stirred at ambient temperature for 4 hours and monitored by TLC. After completion, the mixture was diluted with water (100 mL) and extracted with diethyl ether (150 mL). The organic layer was washed with water (300 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude residue, which was purified by CombiFlash chromatography to give the title compound (13.9 g, 47% yield). ¹H NMR (400 MHz, CDCl₃): δ 4.43 (m, 1H), 3.57 (dt, J = 3.6, 13.6 Hz, 2H), 3.26 (dt, J = 6.0, 3.6 Hz, 2H), 2.01 (m, 4H), 1.44 (s, 9H).

[0341] Step-3: Preparation of 4-((10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl)oxy)piperidine-1-carboxylic acid (S)-tert-butyl ester To a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H,12H)-dione (3 g, 6.55 mmol, 1.0 equivalent) in DMF (25 mL), Cs2CO3 (4.26 g, 13.11 mmol) was added (4.26 g, 13.11 mmol) to the solution. The mixture was stirred at room temperature for 15 minutes. Then, TBAI (0.484 g, 1.31 mmol, 0.2 equivalence) and tributyl 4-iodopiperidin-1-carboxylate (8.2 g, 26.22 mmol, 4.0 equivalence) were added sequentially to the mixture, and the mixture was heated at 70 °C for 30 minutes. The reaction progress was monitored by TLC and LC-MS. After completion, the mixture was quenched with ice-cold water, and the resulting precipitate was filtered through a Buchner funnel, washed with H2O (100 mL), and dried under vacuum to obtain a crude residue, which was purified by CombiFlash chromatography to give the title compound (0.65 g, 15%). LCMS: 605 [M+H]+.

[0342] Step-4: Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-9-(piperidin-4-yloxy)-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H,12H)-dione: Trifluoroacetic acid (2 mL) was slowly added to a stirred solution of 4-((10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl)oxy)piperidin-1-carboxylic acid (S)-tert-butyl ester (0.65 g, 1 mmol) in DCM (8 mL) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC and LC-MS. After completion, the mixture was concentrated under reduced pressure to obtain a crude residue, which was wet-milled with diethyl ether (10 mL × 2) to give the title compound (0.35 g, 64%). LCMS: 505 [M+H]+.

[0343] Step-5: Acetic acid ((11R,13S,17R)-17-acetyl-11-(4-((6-(4-(((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]inno[1,2-b]quinoline-9-yl)oxy)piperidin-1-yl)hexyl)(methyl)amino)phenyl)-13-methyl Preparation of -3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadieno[a]phenanthrene-17-yl ester (compound 9) at room temperature to (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-9-(piperidin-4-yloxy)-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H,12H)-dione (0.30) 0.804 g (0.48 mmol, 1.0 equivalent) and acetic acid (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(6-sideoxyhexyl)amino)phenyl)-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-17-yl ester (0.804 g, 1.44 mmol, 3.0 equivalent) in anhydrous methanol (12 mL) were stirred. Acetic acid (0.2 mL) was added to the stirred solution, and the mixture was stirred at the same temperature for 30 min. Sodium cyanoborohydride (0.06 g, 0.96 mmol) was then slowly added, and the resulting reaction mixture was stirred at room temperature for 6 h. The reaction was monitored by TLC and LC-MS. After completion, the mixture was rinsed with H2O (30 mL). The organic layer was diluted with 20 mL of sodium hydroxide solution and extracted with DCM (30 mL × 3). The combined organic layers were washed with saturated NaHCO3 (20 mL), water (20 mL), and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude residue, which was purified by reverse-phase chromatography to give the title compound (25 mg, 4%).1H NMR (400 MHz, DMSO-d6): δ 8.80 (s, 1H), 8.18 - 8.01 (m, 1H), 7.93 - 7.69 (m, 1H), 7.29 (s, 1H), 6.97 (d,J= 8.55 Hz, 2H), 6.58 (d,J= 8.55 Hz, 2H), 6.50 (s, 2H), 5.66 (s, 1H), 5.42 (s, 2H), 5.28 (s, 2H), 4.39 (d,J= 6.80 Hz, 2H), 4.28 (m, 2H), 3.86 (s, 3H), 3.27 - 3.16 (m, 3H), 2.82 (s, 7H), 2.74 - 2.64 (m, 9H), 2.38 - 2.25 (m, 8H), 2.25 - 2.12 (m, 13H), 2.05 - 1.93 (m, 6H), 1.93 - 1.76 (m, 3H), 1.76 - 1.55 (m, 2H), 1.41 (m, 1H), 0.88 (t,J= 7.21 Hz, 3H). LCMS: 1048 [M+H]+.

[0344] Example 10 Preparation of (11R,13S,17R)-17-acetylated-11-(4-((7-(4-(((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-di-e-oxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl)oxy)piperidin-1-yl)heptyl)(methyl)amino)phenyl)-13-methyl-3-e-e-oxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-17-yl ester (compound 10)

[0345] Step-1: Preparation of tert-butyl 4-hydroxypiperidine-1-carboxylate Boc-anhydride (25.5 g, 118.8 mmol, 1.2 equivalent) and TEA (16.5 mL, 118.8 mmol, 1.2 equivalent) were added sequentially to a stirred solution of 4-hydroxypiperidine (10 g, 99.01 mmol, 1.0 equivalent) in DCM (200 mL), and the mixture was stirred at room temperature for 18 hours. The reaction was monitored by TLC and LC-MS. After completion, the mixture was diluted with H2O (100 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with water (100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (19 g, 95% yield). 1H NMR (400 MHz, CDCl3): δ 3.91 - 3.79 (m, 3H), 3.08 - 3.00 (m, 2H), 1.90 - 1.81 (m, 2H), 1.51 - 1.41 (m, 11H).

[0346] Step-2: Preparation of terbutyl 4-iodopiperidine-1-carboxylate Triphenylphosphine (32.2 g, 122.8 mmol, 1.3 equivalent) and imidazole (10.2 g, 151.2 mmol, 1.6 equivalent) were added to a stirred solution of N-Boc-4-hydroxypiperidine (19 g, 94.52 mmol, 1.0 equivalent) in DCM (200 mL), followed by the addition of iodine (23.81 g, 94.5 mmol, 1.0 equivalent) at 0 °C. The resulting mixture was then stirred at ambient temperature for 4 hours and monitored by TLC. After completion, the mixture was diluted with water (100 mL) and extracted with diethyl ether (150 mL). The organic layer was washed with water (300 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude residue, which was purified by CombiFlash chromatography to give the title compound (13.9 g, 47% yield). ¹H NMR (400 MHz, CDCl₃): δ 4.43 (m, 1H), 3.57 (dt, J = 3.6, 13.6 Hz, 2H), 3.26 (dt, J = 6.0, 3.6 Hz, 2H), 2.01 (m, 4H), 1.44 (s, 9H).

[0347] Step-3: Preparation of 4-((10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl)oxy)piperidine-1-carboxylic acid (S)-tert-butyl ester To a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H,12H)-dione (3 g, 6.55 mmol, 1.0 equivalent) in DMF (25 mL), Cs2CO3 (4.26 g, 13.11 mmol) was added (4.26 g, 13.11 mmol). The mixture was stirred at room temperature for 15 minutes. Then, TBAI (0.48 g, 1.31 mmol, 0.2 equivalence) and tributyl 4-iodopiperidin-1-carboxylate (8.2 g, 26.22 mmol, 4.0 equivalence) were added sequentially to the mixture, and the mixture was heated at 70 °C for 30 minutes. The reaction progress was monitored by TLC and LC-MS. After completion, the mixture was quenched with ice-cold water, and the resulting precipitate was filtered through a Buchner funnel, washed with H2O (100 mL), and dried under vacuum to obtain a crude residue, which was purified by CombiFlash chromatography to give the title compound (0.65 g, 15%). LCMS: 605 [M+H]+.

[0348] Step-4: Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-9-(piperidin-4-yloxy)-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H,12H)-dione: Trifluoroacetic acid (2 mL) was slowly added to a stirred solution of 4-((10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl)oxy)piperidin-1-carboxylic acid (S)-tert-butyl ester (0.65 g, 1 mmol, 1.0 equivalent) in DCM (8 mL) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC and LC-MS. After completion, the mixture was concentrated under reduced pressure to obtain a crude residue, which was wet-milled with diethyl ether (10 mL × 2) to give the title compound (0.35 g, 64%). LCMS: 505 [M+H]+.

[0349] Step-4a: Preparation of acetic acid (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((7-hydroxyheptyl)(methyl)amino)phenyl)-13-methyl-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-17-yl ester. NaHCO3 (pH approximately 8 to 9) was added to a stirred suspension of 7-bromoheptanol (3.17 g, 16.2 mmol, 3.0 equivalents) in EtOH:H2O (25 mL:5 mL), followed by the addition of NaHCO3 dissolved in EtOH (20 mL). Acetic acid (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methylamino)phenyl)-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-17-yl ester (2.5 g, 5.42 mmol, 1.0 equivalent) was added to the mixture, and the resulting mixture was heated at 80 °C for 16 hours. After completion, the mixture was diluted with water (100 mL) and extracted with DCM (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a crude residue was obtained, which was purified by CombiFlash chromatography to give the title compound (1.1 g, 35%). LCMS: 576 [M+H]+.

[0350] Step-4b: Acetic acid (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(7-sideoxyheptyl)amino)phenyl)-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-17-yl The ester was synthesized by adding 2-iodooxybenzoic acid (1.2 g, 4.34 mmol, 2.5 equivalents) participle to a stirred solution of acetic acid (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((7-hydroxyheptyl)(methyl)amino)phenyl)-13-methyl-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-17-yl ester (1 g, 1.73 mmol, 1.0 equivalent) in EtOAc (100 mL) while stirring the mixture at 80 °C for 2 hours. After completion, the mixture was diluted with DCM (300 mL). The organic layer was washed with saturated Na₂S₂O₃ solution (100 mL × 2) and NaHCO₃ solution (100 mL × 2), followed by washing with water (100 mL), drying over anhydrous sodium sulfate, and concentrated to give the title compound (0.9 g, 90%), which was used in the next step without further purification. LCMS: 574 [M+H]⁺.

[0351] Step-5: Acetic acid (11R,13S,17R)-17-acetyl-11-(4-((7-(4-(((S)-10((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]inno[1,2-b]quinoline-9-yl)oxy)piperidin-1-yl)heptyl)(methyl)amino)phenyl)-13-methyl- Preparation of 3-Symoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadieno[a]phenanthrene-17-yl ester (compound 10) at room temperature by oxidizing (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-9-(piperidin-4-yloxy)-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H,12H)-dione (0.3g) Acetic acid (0.2 mL) was added to a stirred solution of 17-17-acetylated-13-methyl-11-(4-(methyl(7-hepta-methyl)amino)phenyl)-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecyl-1H-cyclopentadien[a]phenanthrene-17-yl ester (0.80 g, 1.44 mmol, 3.0 equivalent) in anhydrous methanol (12 mL), and the mixture was stirred for 30 min at the same temperature. Then, sodium cyanoborohydride (0.06 g, 0.96 mmol) was slowly added to the mixture, and the mixture was stirred at room temperature for 6 h. The reaction was monitored by TLC and LC-MS. After completion, the mixture was diluted with H2O (30 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with saturated NaHCO3 (20 mL), water (20 mL), and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude residue, which was purified by reverse-phase chromatography to give the title compound (20 mg, 2%).1H NMR (400 MHz, DMSO-d6): δ 8.78 (s, 1H), 8.07 (d,J= 9.2 Hz, 1H), 7.76 (d,J= 9.2 Hz, 1H), 7.27 (s, 1H), 7.03-6.88 (m, 2H), 6.56 (d,J= 8.8 Hz, 2H), 6.48 (s, 1H), 5.65 (s, 1H), 5.40 (s, 2H), 5.26 (s, 2H), 4.66 (br s, 1H), 4.37 (d,J= 7.9 Hz, 2H), 3.85 (s, 3H), 3.22 (d,J= 7.0 Hz, 2H), 2.80 (s, 6H), 2.72 (s, 2H), 2.20 (s, 3H), 2.13 (d,J= 14.0 Hz, 3H), 2.08 (s, 3H), 1.97 (s, 3H), 1.93 - 1.78 (m, 7H), 1.73 (s, 3H), 1.71 - 1.52 (m, 8H), 1.42 (s, 8H), 1.26 (s, 8H), 0.86 (t,J= 7.5 Hz, 3H). LCMS: 1062 [M+H]+.

[0352] Example 11 Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)pyridine-3-methylamine (compound 11)

[0353] Step-1: Preparation of (S)-1-(4-ethyl-4,9-dihydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)-N,N,N-trimethylammonium iodide: At room temperature, 2.0 g, 4.75 mmol, 1.0 equivalent of iodomethane (2.60 g, 19.0 mmol, 4 equivalents) was added to a solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H,12H)-dione (50 mL) in MeOH, and the mixture was stirred for 3 hours at the same temperature. After 3 hours, the mixture was concentrated under reduced pressure to obtain a quaternary salt, which was washed with diethyl ether and dried under reduced pressure to give the title compound (2.0 g, 76%).

[0354] Step-2: Preparation of 4-((4-ethyl-4,9-dihydroxy-3,14-dilateraloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperano-1-carboxylic acid (S)-tertiary butyl ester: Iodide (S)-1-(4-ethyl-4,9-dihydroxy-3,14-dilateraloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)-N,N,N-trimethylmethylammonium (2.0 g, 3.55 mmol, 1.0 equivalent) and N-Boc-piperano (1.18 g, 5.32 mmol, 1.0 equivalent) were prepared. A solution of 1 mmol (1.5 equivalents) in Na₂HPO₄:KH₂PO₄ (pH approx. 7) (20 mL) was stirred at 100 °C for 3 hours. The reaction was monitored by TLC. After completion, the mixture was diluted with NaHCO₃ (50 mL) and extracted with EtOAc (200 mL × 3) containing 10% MeOH. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by CombiFlash chromatography to give the title compound (0.25 g, 12%). LCMS: 563 [M+H]⁺.

[0355] Step-3: Preparation of (S)-4-ethyl-4,9-dihydroxy-10-(piperazine-1-ylmethyl)-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H,12H)-dione TFA (0.5 mL) was added dropwise to a stirred solution of (S)-((4-ethyl-4,9-dihydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperazine-1-carboxylic acid (S)-tert-butyl ester (0.25 g, 0.44 mmol, 1.0 equivalent) in DCM (5 mL) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After completion, the mixture was quenched with saturated NaHCO3 solution (100 mL) and extracted with EtOAc containing 10% MeOH (100 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.200 g, 97%). LCMS: 463 [M+H]+.

[0356] Step-4a: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-methoxypiperidin-1-yl)tazo-3-methamide DMP (1.44 g, 3.41 mmol, 2.0 equivalent) was added to a solution of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)tazo-3-methamide (0.8 g, 1.7 mmol, 1.0 equivalent) in DCM (20 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After completion, the mixture was diluted with DCM (100 mL) and washed with saturated NaHCO3 (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude substance, which was purified by CombiFlash chromatography to give the title compound (0.5 g, 62%). LCMS: 468 [M+H]+.

[0357] Step-4: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)tadala-3-methylamine (compound 11) A catalytic amount of acetic acid (0.1 mL) was added to a solution of (S)-4-ethyl-4,9-dihydroxy-10-(piperazo-1-ylmethyl)-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H,12H)-dione (0.3 g, 0.65 mmol, 1.0 equivalent) in methanol:THF (5:2) (14 mL), and the reaction mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (0.07 g, 1.08 mmol, 2.5 equivalent) was then added to the mixture, and stirring was continued for 1 hour. The reaction was monitored by TLC. After completion, the mixture was concentrated under reduced pressure, diluted with H2O (50 mL), and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with water (100 mL × 2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude residue, which was washed with methanol to give the title compound (0.06 g, 15%).1H NMR (400 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.58 (d,J= 8.33 Hz, 1H), 7.98 (d,J= 9.21 Hz, 1H), 7.85 (d,J= 8.77 Hz, 1H), 7.79 (d,J= 9.21 Hz, 1H), 7.47 - 7.36 (m, 2H), 7.32 (d,J= 9.65 Hz, 1H), 7.26 (s, 1H), 7.13 (dd,J= 8.77, 2.19 Hz, 1H), 6.48 - 6.38 (br s, 1H), 5.41 (s, 2H), 5.25 (s, 2H) 4.61 - 4.40 (m, 3H), 4.10 (s, 3H), 2.99 (t,J= 12.06 Hz, 3H), 2.67 (m, 3H), 2.61 (m, 3H), 2.03 - 2.21 (m, 4H), 1.95 - 1.72 (m, 7H), 1.71 - 1.57 (m, 4H), 1.57 - 1. 43 (m, 2H), 1.10 (d,J= 11.84 Hz, 2H), 0.88 (t,J= 7.45 Hz, 3H). LCMS: 914 [M+H]+.

[0358] Example 12 Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-((6-(4-(((S)-4-ethyl-4,9-dihydroxy-3,14-di-side-oxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperano-1-yl)-6-side-oxyhexyl)oxy)benzamide (compound 12)

[0359] Step-1: Preparation of 4-Hydroxybenzoic acid A solution of 4N NaOH (13.1 g, 328 mmol, 1.0 equivalent) in water (80 mL) was added to a solution of methyl p-hydroxybenzoate (5 g, 32.89 mmol, 1.0 equivalent) in THF:MeOH (1:1, 100 mL), and the mixture was stirred at room temperature for 16 hours. The reaction was monitored using TLC. After completion, the mixture was concentrated under reduced pressure, and the resulting residue was acidified with concentrated HCl to pH 3 to 2. The precipitated solid was filtered through a Buchner funnel, washed with cold water, and dried to give the title compound (2.5 g, 55%). LCMS: 139 [M+H]+.

[0360] Step-2: Preparation of 4-(6-methoxy-6-hexyloxy)benzoic acid 4-hydroxybenzoic acid (500 mg, 3.62 mmol, 1.0 equivalent) was added to a solution of sodium methoxide (410 mg, 7.60 mmol, 2.1 equivalent) in methanol (30 mL), and the mixture was stirred at room temperature for 5 minutes. Then, ethyl 5-bromohexanoate (1.13 g, 5.43 mmol, 1.5 equivalent) was added. The mixture was stirred at 50 °C for 16 hours. The reaction was monitored using TLC. After completion, the volatiles were removed under reduced pressure, and the residue was dissolved in water. The aqueous layer was washed with diethyl ether (50 mL) and then acidified to pH 3-4 with dilute hydrochloric acid. The precipitated solid was collected by filtration, washed with water, and dried to give the title compound (463 mg, 48%). LCMS: 267 [M+H]+.

[0361] Step-3: Preparation of methyl 6-(4-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexylaminomethoxy)phenoxy)hexanoate: HATU (750 mg, 1.97 mmol, 1.5 equivalent) was added to a solution of 4-(6-methoxy-6-thiocyclohexyloxy)benzoic acid (350 mg, 1.31 mmol, 1.0 equivalent) in anhydrous DMF (5 mL) at 0 °C and the mixture was stirred for 30 minutes. 4-((1r,4r)-4-aminocyclohexyloxy)-2-chlorobenzonitrile (327 mg, 1.31 mmol, 1.0 equivalent) was added to this mixture, followed by DIPEA (247 mg, 1.97 mmol, 1.5 equivalent). The mixture was stirred at room temperature for 2 hours. After completion, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with water (30 mL × 2) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give the title compound (600 mg), which was used as is in the next step without purification. LCMS: 499 [M+H]+.

[0362] Step-4: Preparation of 6-(4-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexylaminomethyl)phenoxy)hexanoic acid Methyl 6-(4-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexylaminomethyl)phenoxy)hexanoate (600 mg, 1.20 mmol, 1.0 equivalent) in THF:MeOH (1:1, 10 mL) was added to a solution and stirred at room temperature for 1 hour. The reaction progress was monitored using TLC. After completion, the mixture was concentrated under reduced pressure and acidified with concentrated HCl to pH 3 to 4. The resulting solid was then filtered through a Buchner funnel, washed with water, diethyl ether, and pentane, and dried under vacuum to give the title compound (500 mg, 86%), which was used directly in the next step without purification. LCMS: 485 [M+H]+.

[0363] Step-5: Preparation of (S)-1-(4-ethyl-4,9-dihydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)-N,N,N-trimethylmethylammonium MeI (0.9 mL) was added to a suspension of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H,12H)-dione (190 mg, 0.451 mmol, 1.0 equivalent) in MeOH (5 mL), and the mixture was stirred at room temperature for 16 hours. After completion, the volatiles were removed under reduced pressure to give the title compound (240 mg, 96%).

[0364] Step-6: Preparation of 4-((4-ethyl-4,9-dihydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperano-1-carboxylic acid (S)-tert-butyl ester iodide was prepared by dissolving (S)-1-(4-ethyl-4,9-dihydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)-N,N,N-trimethylammonium iodide (1.2 g, 2.13 mmol, 1.0 equivalent) in 0.1 M KH2PO4 (22 mL) and 0.1 M Na2HPO4 (34 mL) in 0.1 M KH2PO4 (22 mL). Tributyl piperatocyanate (670 mg, 3.60 mmol, 1.7 equivalents) was added to the suspension in mL, and the resulting mixture was heated at 80 °C for 16 h, monitored by LCMS. After completion, the mixture was acidified to pH 6 to 6.5 with dilute HCl and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to give the title compound (1.2 g, 99%), which was used directly in the next step without purification. LCMS: 563 [M+H]+.

[0365] Step-7: Preparation of (S)-4-ethyl-4,9-dihydroxy-10-(piperazine-1-ylmethyl)-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H,12H)-dione TFA (2 mL) was added to a solution of (S)-tert-butyl(4-ethyl-4,9-dihydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperazine-1-carboxylic acid (1.2 g, 2.13 mmol, 1.0 equivalent) in DCM (20 mL), and the mixture was stirred at room temperature for 16 hours. After completion, the volatiles were removed under reduced pressure to obtain the title compound (700 mg, 71%). LCMS: 463 [M+H]+.

[0366] Step-8: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-((6-(4-(((S)-4-ethyl-4,9-dihydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperano-1-yl)-6-sideloxyhexyl)oxy)benzylamine (compound 12) was prepared by adding HATU (117) to a solution of 6-(4-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexylaminemethyl)phenoxy)hexanoic acid (100 mg, 0.206 mmol, 1.0 equivalent) in anhydrous DMF (5 mL) at 0 °C. (S)-4-ethyl-4,9-dihydroxy-10-(piperazine-1-ylmethyl)-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H,12H)-dione (95 mg, 0.206 mmol, 1.0 equivalent) was added to this reaction mixture, followed by DIPEA (78 mg, 0.618 mmol, 3.0 equivalent). The mixture was stirred at room temperature for 2 hours. After completion, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with water (30 mL × 2) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and evaporated to give a crude product, which was purified preparatively to give the title compound (20 mg, 5%). 1H NMR (400 MHz, DMSO-d6): δ8.77 (s, 1H), 8.12 (t,J= 8 Hz, 1H), 7.99 (d,J= 8 Hz, 1H), 7.85 (d,J= 8 Hz, 1H), 7.81 (d,J= 8 Hz, 2H), 7.47 (d,J= 12 Hz, 1H), 7.38 (s, 1H), 7.26 (s, 1H), 7.13 (d,J= 12 Hz, 1H), 6.96 (d,J= 8 Hz, 2H), 6.49 (br s, 1H), 5.41 (s, H), 5.25 (s, 2H), 4.53 (m, 1H), 4.02 (m, 4H), 3.80 (m, 2H), 2.33 (t,J= 6 Hz, 2H), 2.08 (m, 3H), 1.88 (m, 4H), 1.73 (t,J= 8 Hz, 2H), 1.46 (m, 8H), 0.88 (t,J= 8 Hz, 3H).LCMS: 929 [M+H]+.

[0367] Example 13 Preparation of 4-(6-(3,5-difluoro-4-((1S,3S)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)hexyl)piperano-1-carboxylic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (compound 13)

[0368] A solution of piperato-1-carboxylic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-di-di-oxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (266 mg, 0.5 mmol, 1.0 equivalent) and 6-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)hexanal (243 mg, 0.5 mmol, 1.0 equivalent) in MeOH (5 mL) was stirred and acetic acid (0.5 mmol) was added. The solution was stirred at room temperature for 15 minutes. NaBH3CN (64 mg, 1.0 mmol, 2.0 equivalent) was added to this solution and stirred overnight at room temperature. The reaction was monitored by TLC and LC-MS. After the reaction was complete, the reaction mixture was diluted with saturated NaHCO3 aqueous solution (30 mL) and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine (20 mL × 4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by reverse-phase chromatography to give the desired product (24 mg, 5%). 1H NMR (400 MHz, DMSO-d6): δ 10.51 (s, 1H), 8.94 (s, 1H), 8.18-8.07 (m, 2H), 7.62 (d,J= 9.2 Hz, 1H), 7.44-7.32 (m, 2H), 7.18 (d,J= 7.9 Hz, 1H), 7.05-6.91 (m, 2H), 6.64 (d,J= 11.0 Hz, 1H), 6.54 (br s, 1H), 5.43 (s, 2H), 5.31 (s, 2H), 5.12 (br s, 1H), 3.98 (t,J= 6.4 Hz, 2H), 3.83-3.62 (m, 5H), 2.93-2.76 (m, 2H), 2.45-2.25 (m, 10 H), 2.20 (s, 6H), 1.87 (dt,J= 14.0, 7.0 Hz, 2H), 1.76-1.62 (m, 3H), 1.54-1.44 (m, 8H), 1.44-1.29 (m, 2H), 1.22-1.04 (m, 6H), 0.88 (t,J= 7.2 Hz, 3H). LCMS: 1004 [M+H]+.

[0369] Example 14 Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-(((S)-4-ethyl-4,9-dihydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)pyridine-3-methylamine (compound 14)

[0370] Step-1: Preparation of (S)-1-(4-ethyl-4,9-dihydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)-N,N,N-trimethylmethylammonium iodide was prepared by adding iodomethane (2.60 g, 19.0 mmol, 4 equivalents) to a solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H,12H)-dione (2.0 g, 4.75 mmol, 1.0 equivalent) in MeOH (50 mL) at room temperature and stirring the mixture for 3 hours at the same temperature. After 3 hours, the mixture was concentrated under reduced pressure to obtain the quaternary salt of the compound, which was washed with diethyl ether and dried under reduced pressure to give the title compound (2.0 g, 76%).

[0371] Step-2: Preparation of 4-((4-ethyl-4,9-dihydroxy-3,14-dilateraloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperano-1-carboxylic acid (S)-tertiary butyl ester: Iodide (S)-1-(4-ethyl-4,9-dihydroxy-3,14-dilateraloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)-N,N,N-trimethylammonium (2.0 g, 3.55 mmol, 1.0 equivalent) and Boc-piperano hydrochloride (1.18 g, 5.32 mmol, 1.0 equivalent) were prepared. A solution of 1 mmol (1.5 equivalents) in Na₂HPO₄:KH₂PO₄ (pH approx. 7) (20 mL) was heated at 100 °C for 3 hours. The reaction was monitored by TLC. After completion, the mixture was diluted with NaHCO₃ (50 mL) and extracted with EtOAc (200 mL × 3) containing 10% MeOH. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by CombiFlash chromatography to give the title compound (0.25 g, 12%). LCMS: 563 [M+H]⁺.

[0372] Step-3: Preparation of (S)-4-ethyl-4,9-dihydroxy-10-(piperazine-1-ylmethyl)-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H,12H)-dione TFA (0.5 mL) was added dropwise to a stirred solution of (S)-((4-ethyl-4,9-dihydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperazine-1-carboxylic acid (0.25 g, 0.44 mmol, 1.0 equivalent) in DCM (5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After completion, the mixture was quenched with saturated NaHCO3 solution (100 mL) and extracted with EtOAc containing 10% MeOH (100 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.200 g, 97%). LCMS: 463 [M+H]+.

[0373] Step-4: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-(((S)-4-ethyl-4,9-dihydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)piperidin-3-carboxylic acid (compound 14) at 0°C to 1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)aminomethyl)piperidin-3-yl)piperidin-4-carboxylic acid (0.170 g, 0.35 g) HATU (0.401 g, 1.05 mmol, 3.0 equivalent) was added to a stirred solution of DMF (8 mL), and the mixture was stirred at the same temperature for 10 minutes. DIPEA (0.3 mL, 1.75 mmol, 5.0 equivalent) and (S)-4-ethyl-4,9-dihydroxy-10-(piperazine-1-ylmethyl)-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H,12H)-dione (0.325 g, 0.70 mmol, 1.2 equivalent) were then added sequentially to the mixture, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC and LCMS. After completion, water (10 mL) was added, and the precipitate was filtered through a Buchner funnel. The obtained solid was washed with water (5 mL × 2) and n-pentane (5 mL × 2), dried under vacuum to obtain a crude product, which was purified by Combiflash chromatography to give the title compound (0.055 g, 16%).1H NMR (400 MHz, DMSO-d6): δ 8.79 (s, 1 H), 8.59 (d,J= 8.33 Hz, 1H), 8.00 (d,J= 9.21 Hz, 1H), 7.86 (s, 1H), 7.81 (d,J= 9.65 Hz, 1H), 7.48 (d,J= 9.21 Hz, 1H), 7.42-7.29 (m, 2H), 7.26 (s, 1H), 7.13 (dd,J= 8.77, 2.19 Hz, 1H), 6.49 (m, 1H), 5.42 (s, 2H), 5.26 (s, 2H), 4.58-4.41 (m, 3H), 4.03 (m, 2H), 3.87 (m, 1H), 3.57 (m, 2H), 3.46 (m, 3H), 3.16-3.08 (m, 2H), 3.02 (m, 1H), 2.67 (m, 1H), 2.58 (m, 2H), 2.35-2.27 (m, 1H), 2.10 (d,J= 10.09 Hz, 2H), 1.94-1.78 (m, 4H), 1.73 (d,J= 12.28 Hz, 2H), 1.67-1.45 (m, 4H), 1.23 (s, 2H), 0.95-0.78 (m, 3H). LCMS: 928 [M+H]+.

[0374] Example 15 Preparation of (S)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionylimidazolidine-1-yl)-N-(6-(4-((4-ethyl-4,9-dihydroxy-3,14-sideoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperano-1-yl)hexyl)-2-fluorobenzoamide (compound 15)

[0375] Step-1: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionylimidazodin-1-yl)-2-fluoro-N-(6-hydroxyhexyl)benzamide To a stirred solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionylimidazodin-1-yl)-2-fluorobenzoic acid (2.0 g, 4.43 mmol, 1.0 equivalent) in DMF (10 mL), EDC.HCl (1.27 g, 6.64 mmol, 1.5 equivalent), HOBT (1.01 g, 6.64 mmol, 1.5 equivalent) and 6-aminohexyl-1-ol (0.56 g, 4.87 mmol, 1.0 mmol, 1.0 mmol, 1.5 equivalent) was added to the stirred solution. The reaction mixture was stirred at room temperature for 1 hour (mmol, 1.1 equivalents). After the reaction was complete, the reaction mixture (monitored by TLC analysis) was quenched with ice-cold water (400 mL × 2) and extracted with EtOAc (200 mL × 2). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and a crude residue was obtained, which was purified by CombiFlash chromatography to give the title compound (1.80 g, 75%). LCMS: 551.2 [M+H]+.

[0376] Step-2: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionoylimidazolidin-1-yl)-2-fluoro-N-(6-sideoxyhexyl)benzamide DMP (0.77 g, 1.82 mmol, 1.67 equivalents) was added to a stirred solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionoylimidazolidin-1-yl)-2-fluoro-N-(6-hydroxyhexyl)benzamide (0.60 g, 1.09 mmol, 1.0 equivalent) in DCM (10 mL), and the reaction mixture was stirred at room temperature for 1 hour. (The reaction was monitored by TLC). After completion, the mixture was diluted with H2O (200 mL × 2) and extracted with DCM (50 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the desired product (400 mg, 67%). LCMS: 549.2 [M+H]+.

[0377] Step-3: Preparation of 4-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionoylimidazolidin-1-yl)-2-fluorobenzylamino)hexyl)piperazine-1-carboxylic acid tributyl ester. Acetic acid (0.02 g) was added to a stirred solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionoylimidazolidin-1-yl)-2-fluoro-N-(6-sideoxyhexyl)benzylamino (0.40 g, 0.72 mmol, 1.0 equivalent) and piperazine-1-carboxylic acid tributyl ester (0.24 g, 1.08 mmol, 1.5 equivalent) in methanol (5 mL). The reaction mixture was stirred at room temperature for 16 hours with NaCNBH3 (0.03 g, 0.54 mmol, 1.0 equivalent) for 10 mL. After the reaction was complete, the reaction mixture (monitored by TLC analysis) was quenched with Na2HCO3 (200 mL × 2) and extracted with DCM (50 mL × 2). The combined organic layers were washed with H2O (50 mL × 2) and dried over Na2SO4, and concentrated under reduced pressure to obtain a crude residue, which was purified by CombiFlash chromatography to obtain the desired product (0.30 g, 76%). LCMS: 719.8 [M+H]+.

[0378] Step-4: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionoylimidazolidin-1-yl)-2-fluoro-N-(6-(piperazinyl-1-yl)hexyl)benzamide TFA (1.5 mL) was added to a stirred solution of 4-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionoylimidazolidin-1-yl)-2-fluorobenzamide)hexyl)piperazinyl-1-carboxylic acid tributyl ester (0.30 g, 0.39 mmol, 1.0 equivalent) in DCM (10 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture (monitored by TLC analysis) was quenched with water (100 mL × 2) and extracted with DCM (50 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the desired product (0.25 g, 96%). LCMS: 620.2 [M+H]+.

[0379] Step-5: Preparation of (S)-1-(4-ethyl-4,9-dihydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)-N,N,N-trimethylmethylammonium Iodimethane (5 mL) was added to a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H)-dione (2.5 g, 5.93 mmol, 1.0 equivalent) in methanol (50 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture (monitored by TLC analysis) was concentrated under reduced pressure and wet-milled with diethyl ether (50 mL) to obtain the desired product (2.3 g, 92%). LCMS: 436.4 [M+H]+.

[0380] Step-6: (S)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionylimidazolidine-1-yl)-N-(6-(4-((4-ethyl-4,9-dihydroxy-3,14-sideoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]) Preparation of indo[1,2-b]quinoline-10-yl)methyl)piperazol-1-yl)hexyl)-2-fluorobenzamide (compound 15) to 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-sideoxy-2-thionylimidazolidin-1-yl)-2-fluoro-N-(6-(piperazol-1-yl)hexyl)benzamide (0.30) A stirred solution containing (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H)-dione (0.42 g, 0.68 mmol, 1.0 equivalent) was added to KHPO4 and NaHPO4 (20 mL). The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the reaction mixture (monitored by TLC analysis) was quenched with Na2HCO3 (50 mL × 2) and extracted with DCM containing 10% MeOH (20 mL × 2). The combined organic layers were washed with H2O (50 mL × 2) and dried over Na2SO4, then concentrated under reduced pressure to obtain a crude residue, which was purified by reverse-phase chromatography to obtain the desired product (0.03 g, 6%). LCMS: 996.1 [M+H]+.

[0381] Example 16 Preparation of (2R,6R)-4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)-2,6-dimethylpiperazine-1-carboxylic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disideoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (compound 16)

[0382] Step-1: Preparation of tributyl (3R,5R)-4-(chlorocarbonyl)-3,5-dimethylpiperyl-1-carboxylate Tributyl tributyl (3R,5R)-3,5-dimethylpiperyl-1-carboxylate (1.5 g, 7.0 mmol, 1.0 equivalent) was added dropwise to a stirred solution of (3R,5R)-3,5-dimethylpiperyl-1-carboxylate (1.5 g, 7.0 mmol, 1.0 equivalent) in DCM (30 mL) and pyridine (1.4 mL, 17.4 mmol, 2.5 equivalent) at 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was acidified with 1N HCl (40 mL) and extracted with DCM (30 mL × 5). The combined organic layers were washed with H2O (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the desired compound (1.28 g, 67.3%). ¹H NMR (400 MHz, CDCl3): δ 3.69 - 3.61 (m, 4H) 3.48 (m, 2H) 1.46 (s, 9H), 1.4 (m, 6H).

[0383] Step-2: Preparation of (2R,6R)-2,6-dimethylpiperazine-1,4-dicarboxylic acid 4-(tert-butyl) ester 1-((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl) ester To (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H)-dione (1.30 g, 3.08 mmol, 1.0 equivalent) in DCM (50 DIPEA (2.7 mL, 15.4 mmol, 5.0 equivalent) and DMAP (0.094 g, 0.77 mmol, 0.25 equivalent) were added to a stirred solution in DCM (20 mL). The mixture was stirred at room temperature for 5 minutes, followed by the slow addition of tributyl (3R,5R)-4-(chlorocarbonyl)-3,5-dimethylpiperyl-1-carboxylic acid (1.28 g, 4.63 mmol, 1.5 equivalent) dissolved in DCM (20 mL). The mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated on a rotary evaporator and water was added to give the desired product. The resulting solid was filtered, washed with pentane, and dried under vacuum (1.2 g, 59%). LCMS: 661.1 [M+H]+.

[0384] Step-3: Preparation of (2R,6R)-2,6-dimethylpiperano-1-carboxylic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disideoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester at 0°C. Trifluoroacetic acid (2 mL) was added dropwise to a stirred solution (1.8 mmol) in DCM (20 mL), and the solution was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure to give a crude product, which was wet-milled with diethyl ether (200 mL) to give the desired compound (0.95 g, 94%). LCMS: 561.2 [M+H]+.

[0385] Step-4: (2R,6R)-4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)-2,6-dimethylpiperazine-1-carboxylic acid(S)-10-((dimethylamino)methyl)-4-ethyl-4 Preparation of 16-hydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (compound 16) To (2R,6R)-2,6-dimethylpiperano-1-carboxylic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (0.95 A mixture of 17-acetylated-13-methyl-11-(4-(methyl(6-sideoxyhexyl)amino)phenyl)-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecyl-1H-cyclopentadien[a]phenanthrene-17-yl ester (2.3 g, 4.2 mmol, 3.0 equivalent) in methanol (10 mL) was stirred with acetic acid (0.5 mL) and stirred at room temperature for 16 hours. The reaction mixture was cooled to 0 °C and sodium cyanoborohydride (0.176 g, 2.8 mmol, 2.0 equivalent) was added and stirred for 30 minutes. The reaction mixture was then warmed to room temperature and stirred for another 2 hours. The reaction progress was monitored by TCL analysis. Water was added to the reactants, which were then filtered and dried to obtain the desired compound (0.013 g, 1%).1H NMR (500 MHz, DMSO-d6): δ 8.95 (s, 1H), 8.24 (s, 1H), 8.10 (d,J= 9.06 Hz, 1H), 7.58 (d,J= 9.06 Hz, 1H), 7.34 (s, 1H), 7.08 - 6.85 (m,J= 8.58 Hz, 2H), 6.67 - 6.55 (m,J= 8.58 Hz, 3H), 5.67 (s, 1H), 5.43 (s, 2H), 5.31 (s, 2H), 4.39 (m, 1H), 4.10 (m, 2H), 3.77 (m, 2H), 3.20 (m, 3H), 2.90 - 2.77 (m, 5H), 2.76 - 2.66 (m, 6H), 2.48 - 2.23 (m, 19H), 2.20 (s, 6H), 2.17 - 2.02 (m, 5H), 2.00 (s, 5H), 1.95 -1.77 (m, 5H), 1.77 - 1.62 (m, 3H), 1.41 (d,J= 6.20 Hz, 3H). LCMS: 1106.3 [M+H]+.

[0386] Example 17 Preparation of 4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)piperazo-1-carboxylic acid (S)-10-(tributoxymethyl)-4-ethyl-4-hydroxy-3,14-disideoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (compound 17)

[0387] Step-1: Preparation of (S)-10-(tributoxymethyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H)-dione A stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H)-dione (1.0 g, 2.19 mmol, 1.0 equivalent) in t-BuOH (10 mL) was stirred at 140 °C for 5 min under MW irradiation. After completion, the mixture was diluted with H2O (50 mL × 2) and extracted with DCM (50 mL × 2). The combined organic layers were washed with H2O (50 mL × 2) and dried over Na2SO4, then concentrated under reduced pressure to obtain a crude residue, which was purified by silicone column chromatography (Combiflash, dissolution: 0-3% MeOH / DCM) to obtain the desired product (0.110 g, 11%). LCMS: 451.3 [M+H]+.

[0388] Step-2: Preparation of 4-(tertiary butyl) ester of piperano-1,4-dicarboxylic acid (S)-1-(10-(tri-butoxymethyl)-4-ethyl-4-hydroxy-3,14-di-side-oxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl) ester. Add DIPEA (0.6 mL, 1.21 mmol) to a stirred solution of (S)-10-(tri-butoxymethyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H)-dione (0.110 g, 0.24 mmol, 1.0 equivalent) in DCM (10 mL). 0.0084 g, 0.06 mmol, 0.25 equivalents) and DMAP (0.0084 g, 0.06 mmol, 0.25 equivalents). The reaction mixture was then stirred at room temperature for 5 minutes, and tributyl 4-(chlorocarbonyl)piperazine-1-carboxylic acid (0.026 g, 0.026 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture (monitored by TLC analysis) was diluted with H2O (50 mL × 2) and extracted with DCM (50 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain a crude residue, which was purified by silicone column chromatography (Combiflash, dissolution: 0-3% MeOH / DCM) to obtain the desired product (0.140 g, 87%). LCMS: 663.1 [M+H]+.

[0389] Step-3: Preparation of piperato-1-carboxylic acid (S)-10-(tri-butoxymethyl)-4-ethyl-4-hydroxy-3,14-di-side-oxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester To a stirred solution of (S)-1-(10-(tri-butoxymethyl)-4-ethyl-4-hydroxy-3,14-di-side-oxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl)-4-(tri-butyl)piperano-1,4-dicarboxylic acid ester (0.140 g, 0.211 mmol, 1.0 equivalent) in DCM (10 mL), TFA (0.5 g) was added (5 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture (monitored by TLC analysis) was quenched with Na₂HCO₃ (50 mL × 2) and extracted with DCM (50 mL × 2). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to obtain the desired product (0.090 g, 76%). LCMS: 563.2 [M+H]⁺.

[0390] Step-4: 4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylic acid(S)-10-(tert-butoxymethyl)-4-ethyl-4- Preparation of hydroxy-3,14-disideroxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (compound 17): Piperano-1-carboxylic acid (S)-10-(tert-butoxymethyl)-4-ethyl-4-hydroxy-3,14-disideroxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (0.090) A solution of acetic acid (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(6-sideoxyhexyl)amino)phenyl)-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-17-yl ester (0.107 g, 0.192 mmol, 1.2 equivalents) in methanol (10 mL) was stirred, and then acetic acid (0.2 mL) and NaCNBH3 (0.014 g, 0.32 mmol, 2.0 equivalents) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture (monitored by TLC analysis) was quenched with Na₂HCO₃ (50 mL × 2) and extracted with DCM (50 mL × 2). The combined organic layers were washed with H₂O (50 mL × 2) and dried over Na₂SO₄, then concentrated under reduced pressure to obtain a crude residue, which was purified by silicone column chromatography (Combiflash, dissolution: 0-3% MeOH / DCM) to obtain the desired product (0.016 g, 9%).1H NMR (400MHz, DMSO-d6): δ 8.83 (s, 1H), 8.14 (d,J= 9.1 Hz, 1H), 7.65 (d,J= 9.1 Hz, 1H), 7.34 (s, 1H), 6.98 (d,J= 8.6 Hz, 2H), 6.64 - 6.49 (m, 3H), 5.67 (s, 1H), 5.43 (s, 2H), 5.34 (s, 2H), 4.77 (s, 2H), 4.40 (d,J= 6.2 Hz, 1H), 3.68 (br s, 2H), 3.46 (br s, 3H), 3.25 (d,J= 6.7 Hz, 3H), 2.82 (s, 3H), 2.33 (br s, 3H), 2.22 (br s, 1H), 2.19 -2.00 (m, 10H), 1.88 (d,J= 7.6 Hz, 4H), 1.73 (d,J= 19.6 Hz, 2H), 1.45 (br s, 4H), 1.39 - 1.26 (m, 18H), 1.22 (s, 3H), 0.89 (t,J= 7.2 Hz, 3H), 0.24 (s, 3H). LCMS: 1107.2 [M+H]+.

[0391] Example 18 Preparation of 2-(((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-sideoxyhexadecyl-1H-cyclopentadien[a]phenanthrene-17-yl)oxy)-N-(1-(((S)-4-ethyl-4,9-dihydroxy-3,14-sideoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperidin-4-yl)-N-methylacetamide (compound 18)

[0392] Step-1: Synthesis of (S)-(1-((4-ethyl-4,9-dihydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperidin-4-yl)(methyl)aminocarbamate tributyl ester (Int-3) at room temperature to (S)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H)-dione (Int-1, 1.0 g, 2.74 mmol, 1.0 equivalent) and methyl(piperidin-4-yl)aminocarbamate tributyl ester (Int-2, 881 mg, 4.12 mg) 37% formaldehyde solution (0.3 mL, 3.29 mmol, 1.5 equivalents) was added to a stirred solution of acetic acid (10 mL). The reaction mixture was heated to 80 °C and stirred for 3 hours in a sealed tube. The reaction progress was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure to give the crude product. The crude product was alkalized with aqueous ammonia solution until the pH reached 9, the solid was filtered, washed with water, and dried under vacuum to give Int-3 (1.1 g, 68%). 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H) 7.97 (d,J= 9.39 Hz, 1H) 7.41 (d,J= 9.00 Hz, 1H) 7.25 (s, 1H) 6.37 (br s, 1H) 5.41 (s, 2H) 5.19 - 5.29 (m, 2H) 4.08 (s, 2H) 3.03 (br d,J= 10.96 Hz, 2H) 2.66 (s, 3H) 2.24 (br t,J =11.15 Hz, 2H) 1.77 - 1.95 (m, 3H) 1.68 (br d,J =11.35 Hz, 2H) 1.55 (br s, 2H) 1.39 (s, 9H) 0.87 (t, J = 7.24 Hz, 3H) (1H exchangeable hydrogen is not visible in the spectrum). LCMS: 591.2 [M+H]+.

[0393] Step-2: Synthesis of (S)-4-ethyl-4,9-dihydroxy-10-((4-(methylamino)piperidin-1-yl)methyl)-1,12-dihydro-14H-piperano[3',4':6,7]inno[1,2-b]quinoline-3,14(4H)-dione.TFA salt (Int-4) was synthesized at 0°C under a nitrogen atmosphere to (S)-(1-((4-ethyl-4,9-dihydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]inno[1,2-b]quinoline-10-yl)methyl)piperidin-4-yl)(methyl)aminocarbamate tributyl ester (Int-3, 1.1 g, 1.86 mmol, 1.0 equivalent) in DCM (20 TFA (1.8 mL, 18.6 mmol, 10 equivalents) was added to the stirred solution. The reaction mixture was heated to room temperature and stirred for 2 hours. The reaction progress was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, washed with diethyl ether (10 mL) and dried under vacuum to give Int-4 (900 mg, 98%) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 11.36 (br s, 1H) 9.70 (br s, 1H) 8.85-8.90 (m, 2H) 8.19 (d,J =9.13 Hz, 1H) 7.65 (d,J =9.38 Hz, 1H) 7.23 - 7.34 (m, 1H) 6.50 (br s, 1H) 5.43 (s, 2H) 5.28 (s, 2H) 4.71 (br s, 2H) 3.65 (br d,J =1.63 Hz, 2H) 3.38 (q,J =7.00 Hz, 1H) 3.25 (br s, 2H) 2.58 (s, 3H) 2.19 (br d,J =10.26 Hz, 2H) 1.77 - 1.94 (m, 4H) 0.89 (t,J =7.32 Hz, 3H). LCMS: 491.45 [M+H]+.

[0394] Step-3: 2-(((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-sideoxyhexadecyl-1H-cyclopentadien[a]phenanthrene-17-yl)oxy)-N-(1-(((S)-4-ethyl-4,9-dihydroxy-3,14-sideoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo) Synthesis of [1,2-b]quinoline-10-yl)methyl)piperidin-4-yl)-N-methylacetamide (18) at room temperature to (S)-4-ethyl-4,9-dihydroxy-10-((4-(methylamino)piperidin-1-yl)methyl)-1,12-dihydro-14H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H)-dione. TFA salt Int-4(250 In a stirred solution of 195 mg, 0.51 mmol, 1.0 equivalent of 5S,9S,10S,13S,14S,17S)-10,13-dimethyl-3-sideoxyhexadecyl-1H-cyclopentadienyl[a]phenanthrene-17-yl)oxy)acetic acid Int-5 (195 mg, 0.56 mmol, 1.1 equivalent) in DMF (5 mL), HATU (273 mg, 0.76 mmol, 1.5 equivalent) and DIPEA (0.3 mL, 1.53 mmol, 3 equivalent) was added and stirred for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, water (20 mL) was added to the reaction mixture, the solid was filtered and washed again with water (50 mL), and dried under vacuum to give the desired product (80 mg, 20%).1H NMR (400 MHz, DMSO-d6) δ 8.74 (br s, 1H) 7.98 (d,J =9.13 Hz, 1H) 7.43 (dd,J =9.13, 5.00 Hz, 1H) 7.26 (s, 1H) 6.47 (br d,J =2.00 Hz, 1H) 5.41 (s, 2H) 5.26 (s, 2H) 4.18 - 4.33 (m, 1H) 4.09 (br s, 4H) 3.70 - 3.83 (m, 1H) 3.30 - 3.40 (m, 3H) 3.05 (br d,J =10.88 Hz, 2H) 2.81 (s, 2H) 2.55 (s, 3H) 2.23 - 2.34 (m, 3H) 2.08 (br d, J = 14.01 Hz, 1H) 1.92-1.85 (m, 6H) 1.67 - 1.73 (m, 1H) 1.58 - 1.66 (m, 2H) 1.35 - 1.56 (m, 6H) 1.16 - 1.33 (m, 6H) 0.97 (s, 3H) 0.88 (br t, J = 7.32 Hz, 3H) 0.72 (s, 3H) (1H exchangeable hydrogen is not visible in the spectrum). LCMS: 821.7 [M+H]+. HPLC purity 97.9%.

[0395] Example 19 Preparation of acetic acid (8S,11R,13S,14S,17R)-17-acetylated-11-(4-((6-(4-(((S)-4-ethyl-4,9-dihydroxy-3,14-di-epoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperano-1-yl)-6-epoxyhexyl)(methyl)amino)phenyl)-13-methyl-3-epoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-17-yl ester (compound 19)

[0396] Step-1: Synthesis of (S)-4-((4-ethyl-4,9-dihydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)terylpiperano-1-carboxylic acid (Int-3) at room temperature under an inert atmosphere to (S)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H)-dione.HCl salt Int-1 (2.5 g, 6.86 mmol, 1.0 equivalent) and tributylpiperano-1-carboxylic acid Int-2 (1.85 g, 10.3 mmol, 1.0 equivalent) salt.HCl. 37% formaldehyde solution (0.29 mL, 8.24 mmol, 1.2 equivalents) was added to a stirred solution of acetic acid (10 mL). The reaction mixture was heated to 80 °C and stirred for 2 hours in a sealed tube. The reaction progress was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure to give a crude compound, which was alkalized with aqueous ammonia solution until pH 9. The solid was filtered, washed with water (10 mL), and dried under vacuum to give Int-3 (1.9 g, 50%). LCMS: 463.46 (M-100, Boc group cleavage observed in LCMS) [M-Boc+H]+.

[0397] Step-2: Synthesis of (S)-4-ethyl-4,9-dihydroxy-10-(piperazine-1-ylmethyl)-1,12-dihydro-14H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H)-dione.TFA salt (Int-4) was performed at 0°C under a nitrogen atmosphere by adding TFA (2.7 g, 3.5 mmol, 1.0 equivalent) to a stirred solution of (S)-4-((4-ethyl-4,9-dihydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperazine-1-carboxylic acid tributyl ester (Int-3, 2 g, 3.5 mmol, 1.0 equivalent) in DCM (20 mL). The solution was heated to room temperature and stirred for 2 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, washed with diethyl ether (10 mL) and dried under vacuum to give Int-4 (1.4 g, 83%). 1H NMR (400 MHz, DMSO-d6) δ 8.86 (br s, 2H) 8.10 (d,J =9.25 Hz, 1H) 7.58 (d,J =9.25 Hz, 1H) 7.21 - 7.32 (m, 2H) 6.97 - 7.15 (m, 1H) 6.34 - 6.64 (m, 1H) 5.42 (s, 2H) 5.26 (s, 2H) 4.40 (s, 2H) 3.10-3.30 (m, 8H) 1.85-1.89 (m, 2H) 0.88 (t,J =7.17 Hz, 3H).

[0398] Step-3: Synthesis of acetic acid (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methylamino)phenyl)-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-17-yl ester (Int-5): Potassium acetate (4.12 g, 4.2 mmol, 10 equivalents) and iodine (2.65 g, 21 mmol, 5 equivalents) were added to a stirred solution of uritol acetate (2.0 g, 4.2 mmol, 1.0 equivalents) in methanol (30 mL) and THF (30 mL) at 0 °C and stirred for 3 hours. The reaction progress was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and a saturated sodium thiosulfate solution (100 mL) was added to the reaction mixture. The solid was filtered, washed with diethyl ether (30 mL), and dried under vacuum to give Int-5 (1.7 g, 87%). 1H NMR (400 MHz, DMSO-d6) δ 7.00 (br d,J =8.31 ​​Hz, 1H) 6.91 (br d,J =8.31 ​​Hz, 1H) 6.74 (br d,J =8.80 Hz, 1H) 6.44 (br d,J =8.80 Hz, 1H) 5.67 (s, 1H) 4.66 - 4.75 (m, 1H) 4.39 (br dd,J =19.32, 6.60 Hz, 1H) 2.75 (s, 3H) 2.61 (br d,J =4.40 Hz, 2H) 2.34 (br dd,J =11.74, 3.42 Hz, 2H) 2.13 - 2.24 (m, 3H) 2.10 (s, 3H) 1.99-2.05 (m, 3H) 1.91 (s, 3H) 1.61 - 1.78 (m, 3H) 1.24 - 1.47 (m, 3H) 0.23 (s, 3H). LCMS: 462.15 [M+H]+.

[0399] Step-4: Synthesis of 6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetoxy-13-methyl-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexanoic acid (Int-7) was performed at 0 °C by adding Int-6 (2.1 g, 10.8 mmol, 5 equivalents) and NaHCO3 (1.84 g, 21.6 mmol, 10 equivalents) to a stirred solution of Int-5 (1 g, 2.1 mmol, 1.0 equivalents) in ethanol (15 mL) and water (15 mL). The reaction mixture was heated at 80 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, 10 mL of ethanol containing 2 M HCl was added to the reaction mixture until the pH reached 6, and the mixture was extracted with ethyl acetate (2 × 100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The crude compound was purified by Combiflash column chromatography using 5% methanol / dichloromethane to give Int-7 (250 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ 6.97 (br d,J =8.22 Hz, 2H) 6.57 (br d,J =8.22 Hz, 2H) 5.57 - 5.79 (m, 1H) 3.90 - 4.18 (m, 4H) 3.48-3.50 (m, 1H) 2.67 - 2.90 (m, 3H) 2.75 (s, 3H) 2.45 - 2.59 (m, 5H) 2.20 (s, 3H) 1.94 - 2.18 (m, 6H) 1.95 (s, 3H) 1.62 - 1.80 (m, 2H) 1.34 - 1.60 (m, 2H) 1.18 - 1.31 (m, 2H) 1.15-1.20 (m, 1H) 0.30 (s, 3H) (1H exchangeable hydrogen is not visible in the spectrum).

[0400] Step-5: Acetic acid (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-(4-(((S)-4-ethyl-4,9-dihydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)piperano-1-yl)-6-sideloxyhexyl)(methyl)amino)phenyl)-13-methyl-3-sideloxy-2,3,6,7,8 The synthesis of 6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-sideoxy-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentadien[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexanoic acid Int-7 at room temperature HATU (186 mg, 0.52 mmol, 1.5 equivalent) and DIPEA (0.090 mL, 0.52 mmol, 1.5 equivalent) were added to a stirred solution of (S)-4-ethyl-4,9-dihydroxy-10-(piperazine-1-ylmethyl)-1,12-dihydro-14H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H)dione. The TFA salt (Int-4, 192 mg, 0.41 mmol, 1.2 equivalent) in DMF (2 mL) and stirred for 4 hours. The reaction was monitored by TLC. After the reaction was complete, water (20 mL) was added to the reaction mixture, the solid was filtered, washed with water (10 mL), and dried under vacuum to obtain the crude compound. The crude compound was purified by Combiflash column chromatography using 7% methanol / dichloromethane to obtain the desired product (60 mg, 16%).1H NMR (400 MHz, DMSO-d6) δ 11.35 (br s, 1H) 9.65 (br s, 1H) 8.94 (s, 1H) 8.21 (d,J =9.25 Hz, 1H) 7.64 (d,J =9.25 Hz, 1H) 7.30 (s, 1H) 7.02 (br s, 2H) 6.67 (br s, 2H) 5.67 (s, 1H) 5.43 (s, 2H) 5.30 (s, 2H) 4.76 (br s, 2H) 4.41 (br d,J =6.94 Hz, 3H) 3.98 - 4.08 (m, 10H) 3.49-3.45 (br s, 4H) 3.25 (br s, 2H) 2.85 (s, 3H) 2.56 (br s, 2H) 2.28 - 2.42 (m, 3H) 2.13 (s, 3H) 2.00 (s, 3H) 1.82 - 1.94 (m, 2H) 1.63 - 1.80 (m, 4H) 1.20 - 1.56 (m, 7H) 0.88 (t,J =7.17 Hz, 3H) 0.22 (s, 3H). LCMS: 511.4 [M / 2+H]+, 1018.6 [MH]-. HPLC purity 95.1%.

[0401] Example 20 Preparation of (1-(2-(((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-sideoxyhexadecyl-1H-cyclopentadien[a]phenanthrene-17-yl)oxy)acetyl)piperidin-4-yl)(methyl)aminocarbamic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disideoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (compound 21)

[0402] Step-1: Synthesis of Tributyl 4-((chlorocarbonyl)(methyl)amino)piperidine-1-carboxylate (Int-2) Pyridine (1.10 mL, 13 mmol, 1.5 equivalent) was added to a stirred solution of tributyl 4-(methylamino)piperidine-1-carboxylate (Int-1, 2.0 g, 9.3 mmol, 1.0 equivalent) in DCM (30 mL), followed by the addition of triphosgene (830 mg, 2.7 mmol, 0.3 equivalent). The mixture was heated to room temperature and stirred for 2 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was washed with water (60 mL) and extracted with DCM (2 × 60 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated under vacuum to obtain Int-2 (2.0 g, crude material), which was used in the next step without further purification.

[0403] Step-2: Synthesis of (S)-4-((((10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-di-side-oxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl)oxy)carbonyl)(methyl)amino)piperidine-1-carboxylic acid tributyl ester (Int-4) was prepared at 0°C by reacting 4-((chlorocarbonyl)(methyl)amino)piperidine-1-carboxylic acid tributyl ester (Int-2, 2 g, 7.2 mmol, 1.0 equivalent) with DMF (15 mL) and THF (15 mL). (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H)-dione·HCl salt (Int-3, 1.71 g, 3.6 mmol, 0.5 equivalents) and DIPEA (8 mL, 38 mmol, 5 equivalents) were added to a stirred solution. The mixture was heated to room temperature and stirred for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was washed with water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The crude compound was purified by Combiflash column chromatography using 5% methanol / dichloromethane to give Int-4 (690 mg, 24%). 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H) 8.10 (br d,J =9.29 Hz, 1H) 7.62 (br d,J =9.29 Hz, 1H) 7.30-7.33(m, 1H) 6.52 (br s, 1H) 5.42 (s, 2H) 5.30 (s, 2H) 3.87 - 4.19 (m, 4H) 3.75 (br s, 2H) 3.01-3.05 (m, 4H) 2.66 - 2.94 (m, 3H) 2.25 (s, 3H) 1.66 (s, 6H) 1.41 (s, 9H) 0.88 (br t,J =7.34 Hz, 3H). LCMS: 661.4 [M+H]+.

[0404] Step-3: Synthesis of methyl(piperidin-4-yl)aminocarboxylic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]inno[1,2-b]quinoline-9-yl ester (Int-5) at 0°C under a nitrogen atmosphere to (S)-4-((((10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]inno[1,2-b]quinoline-9-yl)oxy)carbonyl)(methyl)amino)piperidin-1-carboxylic acid tributyl ester (Int-4, 700 mg, 1 TFA (1.2 mL, 20 mmol, 20 equivalents) was added to a stirred solution in DCM (15 mL). The solution was heated to room temperature and stirred for 4 hours. The reaction progress was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, washed with diethyl ether (10 mL), and dried under vacuum to give Int-5 (570 mg, 98%) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 10.15 (br s, 1H) 9.11 (s, 1H) 8.41 - 9.01 (m, 1H) 8.32 (d,J =8.80 Hz, 1H) 7.81 (d,J =8.80 Hz, 1H) 7.37 (s, 1H) 6.56 (br s, 1H) 5.40 (s, 2H) 5.32 (br s, 2H) 4.80-482 (m, 1H) 4.22-428 (s, 2H) 3.50-3.58 (m, 4H) 3.13 (s, 3H) 2.81 (s, 6H) 2.03 (br d,J =13.21 Hz, 2H) 1.79 - 1.95 (m, 4H) 0.89 (br t,J =7.09 Hz, 3H). LCMS: 560.2 [M+H]+.

[0405] Step-4: (1-(2-(((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-sideoxyhexadecyl-1H-cyclopentadien[a]phenanthrene-17-yl)oxy)acetyl)piperidin-4-yl)(methyl)aminocarboxylic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disideoxy-3,4,12,14-tetrahydro- Synthesis of 1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (21) at room temperature to methyl(piperidin-4-yl)aminocarboxylic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-disideloxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester TFA salt (Int-5, 300) HATU (406 mg, 10.6 mmol, 2.0 equivalent) and NaHCO3 (225 mg, 26.5 mmol, 3.0 equivalent) were added to a stirred solution of 2-(((5S,9S,10S,13S,14S,17S)-10,13-dimethyl-3-sideoxyhexadecyl-1H-cyclopentadien[a]phenanthrene-17-yl)oxy)acetic acid (Int-6, 183 mg, 5.3 mmol, 1.0 equivalent) in DMF (15 mL) and stirred for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, water (20 mL) was added to the reaction mixture, the solid was filtered, washed with water (50 mL), and dried under vacuum to obtain the crude compound. The crude compound was purified by preparative HPLC to obtain the desired product (142 mg, 29%).1H NMR (400 MHz, DMSO-d6) δ 9.83 (br s, 1H) 9.15 (s, 1H) 8.39 (d,J =9.26 Hz, 1H) 7.89 (d,J =9.26 Hz, 1H) 7.44 (s, 1H) 6.61 (br s, 1H) 5.51 (s, 2H) 5.40 (s, 2H) 4.89 (br s, 2H) 4.54 (br dd,J =9.69, 1.56 Hz, 1H) 4.35 - 4.50 (m, 1H) 4.17 (d,J =5.38 Hz, 2H) 4.02 - 4.11 (m, 1H) 3.44 (br d,J =8.13 Hz, 1H) 3.11 (s, 3H) 2.80-2.90 (m, 2H) 2.92 (s, 6H) 2.64 - 2.77 (m, 1H) 2.42 - 2.52 (m, 1H) 2.31 - 2.41 (m, 1H) 2.09 - 2.19 (m, 1H) 1.78 - 2.05 (m, 10H) 1.64 - 1.73 (m, 2H) 1.55 - 1.63 (m, 2H) 1.41 - 1.54 (m, 4H) 1.23 - 1.39 (m, 6H) 1.05 (s, 3H) 0.96 (br t,J =7.32 Hz, 3H) 0.80 (s, 3H). LCMS: 893.0 [M+H]+. HPLC purity 97.90%.

[0406] Example 21 Preparation of 2-(((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-sideoxyhexadecyl-1H-cyclopentadien[a]phenanthrene-17-yl)oxy)-N-(((S)-4-ethyl-4,9-dihydroxy-3,14-sideoxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-10-yl)methyl)-N-methylacetamide (compound 25)

[0407] Step-1: Synthesis of (S)-4-ethyl-4,9-dihydroxy-10-((methylamino)methyl)-1,12-dihydro-14H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H)-dione (Int-2) at room temperature: 37% formaldehyde solution (197 mg, 6.59 mmol, 1.2 equivalent) was added to a stirred solution of (S)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H)-dione (Int-1, 2.0 g, 5.4 mmol, 1.0 equivalent) and methylamine hydrochloride (255 mg, 8.2 mmol, 1.5 equivalent) in acetic acid (20 mL). The reaction mixture was heated to 80°C and stirred for 2 hours in a sealed tube. The reaction progress was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain the crude compound. The crude compound was alkalized with aqueous ammonia solution until the pH reached 9, the solid was filtered, washed with water, and dried under vacuum to give Int-2 (1.7 g, 50%). 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H) 7.97 (d,J =9.29 Hz, 1H) 7.40 (d,J =9.29 Hz, 1H) 7.24 (s, 1H) 5.41 (s, 2H) 5.22 (s, 2H) 5.20 (br s, 1H) 4.37 (s, 2H) 2.46 (s, 3H) 1.82 - 1.93 (m, 3H) 0.88 (br t,J =6.85 Hz, 3H). LCMS: 408.4 [M+H]+.

[0408] Step-2: 2-(((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-sideoxyhexadecyl-1H-cyclopentadieno[a]phenanthrene-17-yl)oxy)-N-(((S)-4-ethyl-4,9-dihydroxy-3,14-sideoxy-3,4,12,14-tetrahydro-1H-piperano[3', Synthesis of (S)-4-ethyl-4,9-dihydroxy-10-((methylamino)methyl)-1,12-dihydro-14H-piperano[3',4':6,7]inno[1,2-b]quinoline-3,14(4H)-dione (Int-2,500) at room temperature HATU (879 mg, 2.45 mmol, 2.0 equivalent) and DIPEA (0.64 mL, 3.68 mmol, 3.0 equivalent) were added to a stirred solution of 2-(((5S,9S,10S,13S,14S,17S)-10,13-dimethyl-3-sideoxyhexadecyl-1H-cyclopentadieno[a]phenanthrene-17-yl)oxy)acetic acid (Int-3, 427 mg, 1.22 mmol, 1.0 equivalent) in DMF (5 mL). The reaction mixture was heated to 50 °C and stirred for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was washed with water (100 mL) and extracted with DCM containing 10% methanol (2 × 100 mL). The combined organic extracts were concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by Combiflash column using 10% methanol / DCM to obtain the desired product (160 mg, 16%).1H NMR (400 MHz, DMSO-d6)δ 10.67 (s, 1H) 8.76 (s, 1H) 8.04 (d,J =9.26 Hz, 1H) 7.58 (d,J =9.26 Hz, 1H) 7.28 (s, 1H) 6.30 (s, 1H) 5.37 (d,J =5.50 Hz, 2H) 5.20 - 5.34 (m, 2H) 5.07 (d,J =19.26 Hz, 1H) 4.81 (d,J =14.01 Hz, 1H) 4.29 (d,J =13.76 Hz, 1H) 4.00 (d,J =13.63 Hz, 1H) 2.80 (m, 3H) 2.23 - 2.39 (m, 2H) 2.02 - 2.18 (m, 2H) 1.80 - 1.98 (m, 3H) 1.68 - 1.78 (m, 1H) 1.54 - 1.67 (m, 1H) 0.91 - 1.33 (m, 13H) 0.87 (t, J = 7.25 Hz, 3H) 0.77 (s, 3H) 0.46 (s, 3H) 0.05 - 0.13 (m, 3H). LCMS: 738.35 [M+H]+. HPLC purity 97.5%.

[0409] Example 22 Preparation of 4-(1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)aminomethyl)tadal-3-yl)piperidine-4-carbonyl)piperidine-1-carboxylic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-di-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester (compound 26)

[0410] Step-1: Synthesis of Tributyl Piperazine-1-carboxylate (Int-2) Pyridine (2.97 g, 37.6 mmol, 1.4 equivalent) and triphosgene (3.19 g, 10.7 mmol, 0.4 equivalent) were added to a stirred solution of tributyl piperazine-1-carboxylate (Int-1, 5 g, 26.8 mmol, 1.0 equivalent) in DCM (100 mL) at 0 °C. The mixture was then heated to room temperature and stirred for 2 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was washed with water (100 mL) and extracted with DCM (2 × 100 mL). The combined organic extracts were washed again with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give Int-2 (6.0 g, 90%). 1H NMR (400 MHz, DMSO-d6)δ 3.64 (br d,J =4.40 Hz, 2H) 3.52 (br s, 2H) 3.27 - 3.47 (m, 3H) 2.93 - 3.21 (m, 1H) 1.41 (s, 9H).

[0411] Step-2: Synthesis of piperano-1,4-dicarboxylic acid (S)-1-(tert-butyl) ester 4-(10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl) ester (Int-4) To the (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-piperano[3',4':6,7]indo[1,2-b]quinoline-3,14(4H)-dione HCl salt (Int-3, 10 g, 23.7 mmol, 1.0 equivalent) in a stirred solution in DCM (250 mL) DIPEA (15.3 g, 118 mmol, 5 equivalents) and DMAP (724 mg, 5.9 mmol, 0.25 equivalents) were added dropwise over 10 minutes at 0 °C with DCM (mL) containing tributyl 4-(chlorocarbonyl)piperazine-1-carboxylate (Int-2, 5.89 g, 23.7 mmol, 1 equivalent), and the mixture was stirred for 16 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was washed with water (100 mL) and extracted with DCM (3 × 100 mL). The combined organic extracts were washed again with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude compound. The crude compound was purified by Combiflash column chromatography using 7% methanol / DCM to give Int-4 (10 g, 66%). 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H) 8.11 (d,J =9.29 Hz, 1H) 7.65 (d,J =9.29 Hz, 1H) 7.34 (s, 1H) 6.53 (s, 1H) 5.43 (s, 2H) 5.31 (s, 2H) 3.67 - 3.79 (m, 4H) 3.41 - 3.55 (m, 6H) 2.20 (s, 6H) 1.80 - 1.93 (m, 2H) 1.44 (s, 9H) 0.89 (br t,J =7.34 Hz, 3H). LCMS: 634.2 [M+H]+.

[0412] Step-3: Synthesis of piperano-1-carboxylic acid (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl ester TFA salt (Int-5) at 0°C under a nitrogen atmosphere to piperano-1,4-dicarboxylic acid (S)-1-(tributyl) ester 4-(10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-piperano[3',4':6,7]indo[1,2-b]quinoline-9-yl) ester (Int-4, 1 g, 15 g) TFA (3 mL) was added to a stirred solution in DCM (20 mL) at a concentration of 1 mmol (1.0 equivalent). The mixture was heated to room temperature and stirred for 16 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, washed with diethyl ether (20 mL), and dried under vacuum to obtain Int-5 (1.02 g, crude substance) as a TFA salt, which was used in the next step wit...

Claims

1. A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: , or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: , or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: , or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: , or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: , or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: , or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: , or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: , or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

18. A pharmaceutical composition comprising a compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.