Anti-cancer nuclear hormone receptor targeting compounds

Abstract

The present disclosure relates to anticancer compounds derived from nuclear steroid receptor binders, products containing the anticancer compounds, and methods of use and manufacture thereof.

Description

[0001] Cross-reference of related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 165,087, filed March 23, 2021, pursuant to 35 USC §119(e), which is hereby incorporated by reference in its entirety. Background Technology

[0003] Topoisomerase inhibitors are compounds that block the action of topoisomerases, which are classified into two main subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII). Topoisomerases play crucial roles in cell replication and DNA organization because they mediate the cutting of single-stranded and double-stranded DNA to unwind supercoils, unwind loops, and compress chromosomes in eukaryotic cells. Topoisomerase inhibitors affect these fundamental cellular processes. Some topoisomerase inhibitors prevent topoisomerases from performing DNA strand breaks, while others associate with the topoisomerase-DNA complex and prevent the rejoining step of the topoisomerase mechanism. These topoisomerase-DNA inhibitor complexes are cytotoxic because the unrepaired single-stranded and double-stranded DNA breaks they induce can lead to apoptosis and cell death. Due to this ability to induce apoptosis, topoisomerase inhibitors have attracted interest as a therapy targeting infected cells and cancer cells.

[0004] Camptothecin (CPT) is a topoisomerase poison. It is isolated from the bark and stem of the tree *Camptotheca acuminata* (of the genus *Camptotheca*, also known as the Happy Tree), a tree native to China, and is used in Traditional Chinese Medicine for cancer treatment. CPT has shown remarkable anticancer activity in preliminary clinical trials, particularly against breast, ovarian, colon, lung, and stomach cancers. However, its low solubility and reported adverse effects when used therapeutically have led synthetic and medicinal chemists to develop numerous synthesis methods for camptothecin and various derivatives to enhance the benefits of this chemical, with promising results. Currently, four CPT analogs (topotecan, irinotecan, beloteccan, and trastuzumab deruxtecan) are approved for use in cancer chemotherapy. In addition to its role as an antitumor agent, camptothecin has also shown anti-HIV activity by disrupting the self-association of viral infectious agents found in many retroviruses, including HIV.

[0005] There are likely to be many alternative uses for topoisomerase poisons in the future, including lupus, rare brain disorders, sepsis, and viral and trypanosomiasis infections. As additional roles for Top1 emerge (such as newly discovered regulatory functions), and as Top1 continues to be associated with disease states, efforts will continue in the coming years to discover new drugs (and repurposing them). Summary of the Invention

[0006] This article provides compounds comprising a nuclear payload (such as a topoisomerase inhibitor, topoisomerase poison, or analogue thereof) and a nuclear receptor-targeting epitope. The compounds described herein are engineered to bind to intracellular nuclear receptors, allowing the compounds and their nuclear payloads to accumulate in the cell nucleus. Not wishing to be bound by theory, a potential mode of enhanced utility is that this approach could provide compounds with cell-type selectivity rather than simply increased potency, thus striving for a higher therapeutic index. However, it is possible that the compounds could be active through other modes, such as, but not limited to, passive localization in the cell nucleus.

[0007] Furthermore, the compounds described herein provide targeted delivery of nuclear payloads. These compounds target and are localized within tumor tissue. The transport of these compounds, comprising at least one nuclear receptor-targeting epitope, such as a nuclear steroid receptor-targeting epitope, covalently attached to at least one nuclear payload, to the cell nucleus allows the nuclear payload to accumulate in the nucleus, thereby enhancing tumor cell death. In doing so, the compounds described herein can exhibit superior efficacy. Furthermore, the compounds described herein will exempt cells that do not express specific nuclear steroid receptors by accumulating in the nuclei of nuclear receptor-positive cells (such as steroid receptor-positive cells), and thus reduce side effects.

[0008] In some embodiments, a compound of formula I, II, or III, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof is provided.

[0009] A 1 -(L 1 -B 1 ) m’ I

[0010] A 1 -L 1 -(B 1 ) m’ II

[0011] A 1 -L 1 -B 1 III

[0012] in:

[0013] A 1 It is a nuclear payload (i.e., a topoisomerase inhibitor);

[0014] m' is 1, 2, or 3;

[0015] Each B 1 It is an independent nuclear receptor-targeting epitope; and

[0016] Each L 1 It is either a covalent bond or a connecting part.

[0017] In some embodiments, a compound of formula III, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, is provided.

[0018] A 1 -L 1 -B 1 III

[0019] in:

[0020] B 1 It is a nuclear receptor-targeting epitope;

[0021] L 1 It is a covalent bond or a connecting part; and

[0022] A 1 It is a topoisomerase inhibitor.

[0023] Also provided is a compound of Table 1, or a stereoisomer thereof, a mixture of stereoisomers thereof, a hydrate, a solvate, an isotopically enriched analog or a pharmaceutically acceptable salt thereof.

[0024] A pharmaceutical composition is also provided, comprising a compound as described herein, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0025] A method for treating or preventing cancer is also provided, the method comprising administering an effective amount of a compound or composition as described herein to an individual in need. The 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, nephroblastoma, cervical cancer, testicular cancer, soft tissue sarcoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, etc. 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 myeloid 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.

[0026] A method for treating or preventing cancer is also provided, the method 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 tumor, non-small cell lung cancer, colorectal cancer, breast cancer, non-Hodgkin's lymphoma, endometrial cancer, or oligodendroglioma.

[0027] A method for treating or preventing a neurogenetic disease or disorder is also provided, the method comprising administering an effective amount of a compound or composition as described herein to an individual in need. In some embodiments, the neurogenetic disease or disorder is Angelman syndrome.

[0028] A method for treating or preventing breast cancer is also provided, the method 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.

[0029] A method for treating or preventing prostate cancer is also provided, the method 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 metastatic castration-resistant prostate cancer (mCRPC).

[0030] A method for treating or preventing cancer is also provided, the method 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, in combination with another chemotherapeutic agent. Detailed Implementation

[0031] The following description illustrates exemplary embodiments of the present invention. However, it should be understood that this description is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0032] 1. Definition

[0033] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0034] The term “about” refers to a variation of ±1%, ±3%, ±5%, or ±10% of a specified value. For example, in some embodiments, “about 50” can include a range from 45 to 55. For integer ranges, the term “about” can include one or both integers greater than and / or less than the integers listed at both ends of the range. Unless otherwise indicated herein, the term “about” is intended to include values ​​close to the listed range, such as weight percentages, which are equivalent in terms of functionality of the individual ingredients, compositions, or embodiments. Furthermore, unless the context clearly specifies otherwise, the singular forms “an” and “the” include plural indicators. Thus, for example, reference to “the compound” includes a plurality of such compounds, and reference to “the determination” includes reference to one or more compounds and their equivalents known to those skilled in the art.

[0035] "alkyl" refers to and includes alkyl groups having a specified number of carbon atoms (i.e., C1-C2). 10 Or C 1-10 This refers to saturated straight-chain and branched monovalent hydrocarbon structures and combinations thereof (one to ten carbon atoms). Specifically, alkyl groups are those with 1 to 20 carbon atoms (“C1-C2”). 20 Alkyl group (“alkyl”). In one embodiment, the alkyl group has 1 to 12 carbon atoms (“C1-C1”). 12 Alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, and homologues and isomers of n-pentyl, n-hexyl, n-heptyl, and n-octyl.

[0036] As used herein, “alkenyl” refers to a group having at least one alkene unsaturated site (i.e., having at least one C=C moiety) and having a specified number of carbon atoms (i.e., C2-C). 10 Or C 2-10Alkenes are unsaturated, straight-chain or branched monovalent hydrocarbon chains or combinations thereof, consisting of two to ten carbon atoms. Alkenes can be in a "cis" or "trans" configuration, or alternatively, an "E" or "Z" configuration. Specifically, alkenes are those having 2 to 20 carbon atoms ("C2-C2"). 20 "Alkenyl" refers to those having 2 to 8 carbon atoms ("C2-C8 alkenyl"), 2 to 6 carbon atoms ("C2-C6 alkenyl"), or 2 to 4 carbon atoms ("C2-C4 alkenyl"). Examples of alkenyl groups include, but are not limited to, groups such as: vinyl (ethenyl or vinyl), propenyl, propenyl (or allyl), 2-methylpropenyl, butenyl, butenyl, butenyl, butenyl, butenyl, 1,3-dienyl, 2-methylbutenyl, 1,3-dienyl, their homologues and isomers, etc.

[0037] As used herein, “alkylene” refers to a residue that is identical to an alkyl group but has a divalent oxidation state. Specifically, alkylene groups are those having 1 to 6 carbon atoms (“C1-C6 alkylene”), 1 to 5 carbon atoms (“C1-C5 alkylene”), 1 to 4 carbon atoms (“C1-C4 alkylene”), or 1 to 3 carbon atoms (“C1-C3 alkylene”). Examples of alkylene groups include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), etc. Similarly, the terms “alkenylene,” “ynynylene,” “heteroalkylene,” “cycloalkylene,” “heterocyclylene,” “arylene,” and “heteroarylene” refer to alkenyl, ynynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl residues as defined herein, but which have a divalent oxidation state.

[0038] As used herein, "alkynyl" refers to a group 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-C). 10 Or C 2-10 Alkynes are unsaturated, straight-chain or branched monovalent hydrocarbon chains or combinations thereof, consisting of two to ten carbon atoms. Specifically, alkynyl groups are those having 2 to 20 carbon atoms ("C2-C2"). 20 The alkynyl group includes those having 2 to 8 carbon atoms ("C2-C8 alkynyl"), 2 to 6 carbon atoms ("C2-C6 alkynyl"), or 2 to 4 carbon atoms ("C2-C4 alkynyl"). Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (or acetylenyl), propynyl, propynyl-1-, propynyl (or propynyl), butynyl, butynyl-2-, butynyl, butynyl-3-, their homologues or isomers, etc.

[0039] "Amino" refers to the formula -N(R) N )2 amines, wherein each R N Independently, it is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is optionally substituted, such as by one or more (e.g., 1-5 or 1-3) substituents (e.g., haloyl, cyano, hydroxyl, -NH2, -NH(alkyl), -N(alkyl)2, alkyl, alkenyl, alkynyl, alkoxy, or haloalkoxy).

[0040] "Aryl" refers to and includes polyunsaturated aromatic hydrocarbon groups. Aryl groups may contain additional fused rings (e.g., 1 to 3 rings). In one variant, the aryl group contains 6 to 14 cyclic carbon atoms. In some embodiments, the aryl group has 6 to 20 cyclic carbon atoms (i.e., C64 to C14). 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl group) or 6 to 10 carbon ring atoms (i.e., C46, ​​C56, C6 ... 6-10 Aryl groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, etc. It should be understood that aryl groups do 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.

[0041] "Carbonyl" refers to the group C=O.

[0042] "Cycloalkyl" refers to and includes cyclic hydrocarbon structures that can be fully saturated, monounsaturated, or polyunsaturated, but are non-aromatic, and have a specified number of carbon atoms (e.g., C1-C1). 10 This refers to one to ten carbon atoms. A cycloalkyl group can consist of one ring (such as cyclohexyl) or multiple rings (such as adamantyl). A cycloalkyl group containing more than one ring can be fused, spiro- or bridged, or a combination thereof. In some embodiments, the cycloalkyl group has 3 to 20 cyclic carbon atoms (i.e., C64, C16, C2 ... 3-20 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12+ ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C14 and C24). 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-6 (Cycloalkyl). It should be understood that the term cycloalkyl is intended to cover any non-aromatic ring that can fused with an aryl ring, regardless of its attachment 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, norbornyl, etc.

[0043] "Halogroup" or "halogen" refers to a group 17 element having an atomic number from 9 to 85. In some embodiments, the halogen group includes fluorine, chlorine, bromine, and iodine. Where a residue is substituted by more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached; for example, dihaloaryl, dihaloalkyl, trihaloaryl, etc., refer to aryl and alkyl groups substituted by two ("di") or three ("tri") halogen groups (which may but not necessarily be the same halogen group); thus, 4-chloro-3-fluorophenyl falls within the dihaloaryl range. An alkyl group in which each hydrogen atom is substituted by a halogen group is called a "perhaloalkyl". In some embodiments, a perhaloalkyl is trifluoroalkyl (-CF3). Similarly, "perhaloalkoxy" refers to an alkoxy group in which each H atom in the alkyl moieties constituting the alkoxy group is substituted by a halogen. An example of a perhaloalkoxy is trifluoromethoxy (-OCF3).

[0044] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. The term "heteroalkyl" includes unbranched saturated chains or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NH-, -O-, -S-, -S(O)-, and -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.), sulfones (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.

[0045] "Heteroaryl" refers to and includes an unsaturated aromatic ring group having 1 to 10 ring carbon atoms and at least one ring heteroatom (including, but not limited to, heteroatoms such as nitrogen, oxygen, and sulfur), wherein the nitrogen and sulfur atoms are optionally oxidized, and one or more nitrogen atoms are optionally quaternized. In some embodiments, a heteroaryl comprises an unsaturated aromatic ring group having 1 to 10 ring carbon atoms and 1 to 4 ring heteroatoms. In some embodiments, a heteroaryl comprises a 5-12 membered ring system, a 5-10 membered ring system, or a 5-6 membered ring system, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, wherein the ring heteroatom is independently selected from nitrogen, oxygen, and sulfur. The heteroaryl may be attached to the rest of the molecule at a ring carbon or at a ring heteroatom. Any aromatic ring having a single or multiple fused rings containing at least one heteroatom is considered a heteroaryl, regardless of its attachment to the rest of the molecule (i.e., through any fused ring). Heteroaryl groups do not include aryl groups as defined above or overlap with aryl groups as defined above. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, thiopheneyl, furanyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, indole, benzothiazolyl, benzooxazolyl, benzoisooxazolyl, imidazopyridyl, etc.

[0046] "Heterocyclic" or "heterocyclic group" 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), wherein the nitrogen and sulfur atoms are optionally oxidized, and one or more nitrogen atoms are optionally quaternized. It should be understood that any non-aromatic ring containing at least one heteroatom is considered a heterocyclic group, regardless of the attachment (i.e., whether it can be bonded by carbon atoms or heteroatoms). Furthermore, the term heterocyclic group is intended to cover any non-aromatic ring containing at least one heteroatom, which may be fused with an aryl or heteroaryl ring, regardless of its attachment to the rest of the molecule. In some embodiments, heteroaryl groups comprise 3-12 membered ring systems, 3-10 membered ring systems, or 5-6 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, which are independently selected from nitrogen, oxygen, and sulfur. Heterocyclic groups comprising more than one ring can be fused, spirocyclic, or bridged, or any combination thereof. Examples of heterocyclic groups include, but are not limited to, tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazineyl, pyrrolylyl, thiazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrooxazolyl, dihydroisooxazolyl, dioxopentyl, morpholinyl, dioxalkyl, tetrahydrothiophenyl, etc.

[0047] "Oxide group" refers to a part that equals O.

[0048] Unless otherwise specified, "optionally substituted" means that the group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4, or 5) substituents listed for the group, wherein the substituents may be the same or different, provided that the normal valence of the group is not exceeded. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In another embodiment, the optionally substituted group has four substituents. In some embodiments, the optionally 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.

[0049] Stereoisomers, mixtures of stereoisomers, tautomers, hydrates, solvates, isotopically enriched analogs, and pharmaceutically acceptable salts of the compounds described herein are also provided.

[0050] The compounds disclosed herein, or their pharmaceutically acceptable salts, may include asymmetric centers, thus yielding enantiomers, diastereomers, and other stereoisomers, which, in absolute stereochemistry, may be defined as (R)- or (S)- or (D)- or (L)- for amino acids. This disclosure 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 chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, the compounds are intended to include both E and Z geometric isomers, unless otherwise specified.

[0051] "Stereoisomers" refer to compounds composed of identical atoms bonded by the same bonds but having different, non-interchangeable three-dimensional structures. This disclosure considers 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 that are not mirror images of each other). Therefore, all stereoisomers of the compounds of the present invention (e.g., geometric isomers, optical isomers, etc.) (including those of salts, solvates, and hydrates of the compounds) are considered, such as those that may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotational isomers, transasterisomers, and diastereomers.

[0052] A mixture of diastereomers can be separated into their respective 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 an enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosser's acyl chloride), converting the enantiomer mixture into a diastereomer mixture, separating the diastereomers, and converting (e.g., hydrolyzing) individual diastereomers into their respective pure enantiomers. Furthermore, some compounds can be transisomers and are considered part of this disclosure. Stereoisomers can also be separated using chiral HPLC.

[0053] Some compounds exist as tautomers. These tautomers are in equilibrium with each other. For example, compounds containing amides can exist in equilibrium with imine tautomers. Regardless of which tautomer is exhibited, and regardless of the equilibrium nature between the tautomers, those skilled in the art will understand that a compound includes both amide and imine tautomers. Therefore, compounds containing amides should be understood to include their imine tautomers. Similarly, compounds containing imines should be understood to include their amide tautomers.

[0054] The term "hydrate" refers to a complex formed by the combination of a compound and water as described herein.

[0055] "Solvate" means an association or complex of one or more solvent molecules with a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

[0056] Any compound or structure described herein is also intended to represent both unlabeled and isotopically labeled forms of the compound. These forms may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have the structures described herein, but 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… 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. Compounds with various isotope labels incorporated into this disclosure, such as those doped with radioactive isotopes, such as... 3 H and 14 Compounds of C. These isotope-labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques (e.g., positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays), or in the treatment of patients with radiotherapy. These compounds can exhibit increased metabolic resistance and are therefore used to increase the half-life of any compound when administered to mammals (particularly humans). Such compounds are synthesized using methods well known in the art, for example, by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0057] Some of the compounds disclosed herein contain one or more ionizable groups (from which protons can be removed (e.g., -COOH) or added (e.g., amines) or quaternizable (e.g., amines) groups). All possible ionic forms of such molecules and their salts are intended to be individually included in the disclosure text herein. Regarding salts of the compounds described herein, those skilled in the art can select suitable ones from a variety of available counterions. In a particular application, the selection of a given anion or cation to prepare the salt may result in an increase or decrease in the solubility of that salt.

[0058] As used herein, the term "biologically indivisible connective tissue" is intended to refer to a connective tissue that is not readily hydrolyzed under physiological conditions. As used herein, the term "biologically divisible connective tissue" is intended to refer to a connective tissue that is readily hydrolyzed under physiological conditions. In some embodiments, at least one connective tissue is hydrolyzed under intracellular conditions (e.g., low pH).

[0059] As used herein, the term “cancer” refers to a group of mammalian diseases characterized by uncontrolled cell growth. The term “cancer” is used interchangeably with the terms “tumor,” “solid tumor,” “malignant tumor,” “excessive proliferation,” and “vesicle.” Cancer encompasses all types of excessive proliferative growth, hyperplastic growth, neoplastic growth, carcinogenic growth or carcinogenic processes, metastatic tissue, or malignant transformation of cells, tissues, or organs, regardless of histopathological type or stage of invasion. Illustrative examples include lung cancer, prostate cancer, head and neck cancer, breast cancer and colorectal cancer, melanoma, and gliomas (such as high-grade gliomas, including glioblastoma multiforme (GBM), the most common and deadliest malignant primary brain tumor in adults).

[0060] The phrase "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 after 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 nomenclature, treatment for all types of solid tumors is within the scope of this disclosure.

[0061] "Chemotherapy agent" refers to any substance that can reduce or prevent the growth, proliferation, or spread of cancer cells, cancer cell clusters, tumors, or other malignant tissues. The term is also intended to cover radiation therapy or any antitumor or anticancer agent.

[0062] As used herein, “treatment” or “treating” is a method for obtaining a beneficial or desired outcome, such as a clinical outcome. For the purposes of this disclosure, a beneficial or desired clinical outcome includes, but is not limited to, relief of symptoms and / or reduction of the severity of symptoms and / or prevention of the worsening of symptoms associated with a disease or condition. In some embodiments, “treatment” or “treating” is a method for obtaining a beneficial or desired outcome, such as a clinical outcome. For the purposes of this disclosure, a beneficial or desired clinical outcome includes, but is not limited to, relief of symptoms and / or reduction of the severity of symptoms or the worsening of symptoms associated with a disease or condition. In one variant, a beneficial or desired clinical outcome includes, but is not limited to, relief of symptoms and / or reduction of the severity of symptoms and / or prevention of the worsening of symptoms associated with cognitive impairment, psychotic disorders, neurotransmitter-mediated disorders, and / or neuronal disorders. In some embodiments, treatment of a disease or condition with a compound of this disclosure or a pharmaceutically acceptable salt thereof is without side effects, or has fewer side effects than currently available therapies for said disease or condition, and / or improves an individual's quality of life.

[0063] The term "inhibit" ("inhibiting" and "inhibition") refers to slowing down, stopping, or reversing the growth or progression of a disease, infection, symptom, 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.

[0064] As used herein, “combination therapy” means a therapy comprising two or more different compounds. Therefore, in one aspect, combination therapies comprising the compounds detailed herein and another compound are provided. In some variations, the combination therapy optionally comprises one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and / or inert substances. In various embodiments, treatment with the combination therapy may result in additive or even synergistic (e.g., greater than additive) results compared to the administration of a single compound of this disclosure 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 a single therapy. In some embodiments, the combination therapy achieves the same or greater therapeutic benefit compared to the use of any single compound alone. In some embodiments, the combination therapy achieves the same or greater therapeutic benefit by using a smaller amount of compound (e.g., a lower dose or a less frequent dosing schedule) compared to the amount typically used for a single compound or therapy. In some embodiments, the use of a small amount of compound results in a reduction in the number, severity, frequency, and / or duration of one or more side effects associated with said compound.

[0065] As used herein, the term "effective amount" refers to an amount of the compound of this disclosure that, in conjunction with parameters of its efficacy and toxicity and based on the knowledge of a practicing professional, should be effective in a given therapeutic form. As understood in the art, an effective amount can be one or more doses; that is, a single or multiple doses may be required to achieve the desired therapeutic endpoint. An effective amount may be considered in the context of administration of one or more therapeutic agents, and administration of a single agent may be considered in an effective amount if combination with one or more other agents can achieve or realize a desired or beneficial result. The appropriate dose of any co-administered compound may optionally be reduced due to the combined effects of the compounds (e.g., additive or synergistic effects).

[0066] As used herein, the terms "antagonist" or "inhibitor" refer to compounds whose presence results in a reduction in the biological activity of a target protein or enzyme. For example, a "topoisomerase inhibitor" is any compound that inhibits the function of one or more topoisomerases.

[0067] As used in this article, IC 50 This refers to the amount, concentration, or dose of a specific test compound that achieves 50% inhibition of the maximum response in a assay measuring such a reaction (e.g., regulation of topoisomerase).

[0068] As used in this article, EC 50 This refers to the dose, concentration, or amount of a specific test compound that elicits a dose-dependent response when the maximum expression of a specific response induced, stimulated, or enhanced by the specific test compound is 50%.

[0069] As used in this article, the term "cancer" refers to the abnormal growth of cells that tend to proliferate uncontrollably and, in some cases, metastasize (spread). Types of cancer include, but are not limited to, solid tumors (such as those of the bladder, intestines, brain, breast, endometrium, heart, kidneys, lungs, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid)), prostate, skin (melanoma), or blood cancers (such as leukemia).

[0070] As used in this article, the term "carrier" refers to a relatively non-toxic compound or agent that facilitates the incorporation of the compound into cells or tissues.

[0071] As used herein, "unit dosage form" refers to a physically discrete unit suitable as a unit dose, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect associated with the desired drug carrier. Unit dosage forms may contain single or combination therapies.

[0072] As used herein, the term "controlled release" refers to a formulation or fraction containing a drug in which the release of the drug is not immediate; that is, administration of a "controlled release" formulation does not result in the immediate release of the drug into the absorption reservoir. The term encompasses long-acting formulations designed to gradually release the drug compound over an extended period of time. Controlled release formulations can include a variety of drug delivery systems and typically involve mixing the 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, etc.) and formulating the mixture according to a desired delivery route (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, etc.).

[0073] As used herein, "pharmaceuticalally acceptable" or "pharmacologically acceptable" means a material that is biologically or otherwise undesirable, for example, a material that can be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a harmful manner with any other component of the composition containing the material. In some embodiments, pharmaceutically acceptable carriers or excipients have met the required standards for toxicological and manufacturing testing and / or are included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0074] “Pharmaceutically acceptable salts” are those that retain at least some of the biological activity of the free (non-salt) compound and can be administered to an individual as a drug or pharmaceutical. Such salts include, for example: (1) acid addition salts formed from inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); or acid addition salts formed from organic acids (such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, etc.); (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth metal ions, or aluminum ions) or when they are combined with organic bases. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc. Other examples of pharmaceutically acceptable salts include those listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977 Jan; 66(1): 1-19. Pharmaceutically acceptable salts can be prepared in situ during manufacturing or by reacting the purified compound of this disclosure, in its free acid or base form, with a suitable organic or inorganic base or acid, and then separating the resulting salt during subsequent purification. It should be understood that references to pharmaceutically acceptable salts include their solvent-added form or crystalline form, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are typically formed during crystallization. Hydrates are formed when the solvent is water, or alcohols when the solvent is an alcohol. 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 lead to the dominance of the single-crystal form.

[0075] As used herein, the term "excipient" means an inert or inactive substance that can be used in the manufacture of a drug or pharmaceutical, such as a tablet containing a compound of this disclosure as an active ingredient. The term "excipient" can cover a variety of substances, including, but not limited to, any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or emulsion, lubricant, solution for parenteral 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 (directly compressible), honey DC, lactose (anhydrous or monohydrate; optionally combined with aspartame, cellulose or microcrystalline cellulose), starch DC, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, carboxymethyl starch sodium, etc.; creams or emulsions include... Examples of ingredients include maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearate fumarate, etc.; materials for chewable tablets include, for example, dextrose, fructose DC, lactose (monohydrate, optionally combined with aspartame or cellulose), etc.; suspending agents / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, 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.

[0076] compound

[0077] This article provides targeted compounds for the treatment of cancer. The compounds described herein are capable of targeting the cell nucleus through recognition, enabling nuclear receptors to bind to corresponding binding sites on epitopes, and delivering a nuclear payload to the cell nucleus. The nuclear payload can then bind to one or more target sites within the cell nucleus and / or disrupt one or more cellular processes, thereby inducing cell death.

[0078] In some embodiments, the nuclear payload is bonded to one or more nuclear acceptor target epitopes via a linker. In some embodiments, the linker provides a single link or a single connection, meaning that the linker is coupled to only one atom of each of the payload and the epitope.

[0079] Therefore, a compound of formula I, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, is provided:

[0080] A 1 -(L 1 -B 1 )m’ I

[0081] in:

[0082] A 1 It is a nuclear payload (i.e., a topoisomerase inhibitor);

[0083] m' is 1, 2, or 3;

[0084] Each B 1 It is an independent nuclear receptor-targeting epitope; and

[0085] Each L 1 It is either a covalent bond or a connecting part.

[0086] In some embodiments, one or more nuclear receptor-targeting epitopes are bonded to the nuclear payload via a single linker. Therefore, a compound of formula II, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, is also provided.

[0087] A 1 -L 1 -(B 1 ) m’ II

[0088] in:

[0089] A 1 It is a nuclear payload (i.e., a topoisomerase inhibitor);

[0090] m' is 1, 2, or 3;

[0091] Each B 1 It is an independent nuclear receptor-targeting epitope; and

[0092] L 1 It is the connecting part.

[0093] In some embodiments, a compound is provided comprising a nuclear payload optionally bonded to a nuclear receptor-targeting epitope via a linker portion. Thus, a compound of formula III, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, is provided.

[0094] A 1 -L 1 -B 1 III

[0095] in:

[0096] A 1 It is a nuclear payload (i.e., a topoisomerase inhibitor);

[0097] B 1 It is a nuclear receptor-targeting epitope; and

[0098] L 1 It is a covalent bond or a connecting part.

[0099] In some embodiments of Formula I, II, or III, A 1 yes:

[0100]

[0101]

[0102] The wavy line indicates a target epitope of at least one nuclear steroid receptor (optionally via a linker; e.g., -L). 1 -B 1 ) attachment point.

[0103] In some embodiments of Formula I, II, or III, A 1 yes:

[0104]

[0105] The tilde key refers to the key with L. 1 The connection point. In some implementations, A 1 yes:

[0106]

[0107] The tilde key refers to the key with L. 1 The connection point.

[0108] In some embodiments, any of the compounds disclosed herein (e.g., compounds of formulas I, II, and III) includes a topoisomerase inhibitor analog that, even after modification to obtain the compounds described herein, exhibits biological activity comparable to that observed in the original, unmodified topoisomerase inhibitor. In some embodiments, the topoisomerase inhibitor analog retains the ability to inhibit topoisomerases. In some embodiments, the topoisomerase inhibitor analog exhibits binding activity that 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.

[0109] In some embodiments, any compound disclosed herein (e.g., compounds of formula I, II, III), B 1It binds to estrogen receptors, glucocorticoid receptors, progesterone receptors, or androgen receptors. In some implementations, B... 1 Binds to estrogen receptors. In some implementations, B 1 Binds to glucocorticoid receptors. In some implementations, B... 1 Binds to the progesterone receptor. In some implementations, B... 1 Binding to androgen receptors. Exemplary estrogen receptors, glucocorticoid receptors, progesterone receptors, or androgen receptor binders are described in this article.

[0110] nuclear payload

[0111] In some embodiments, the nuclear payload (i.e., A) in the compound described herein 1 ) is a topoisomerase inhibitor. As used herein, the term "topoisomerase inhibitor" refers to a compound or portion that blocks the action of a topoisomerase (or DNA topoisomerase), which is an enzyme involved in the overrotation or underrotation of DNA.

[0112] Topoisomers (divided into two main subtypes, type I topoisomerases (TopI) and type II topoisomerases (TopII)) play crucial roles in cell replication and DNA organization because they mediate the cutting of single-stranded and double-stranded DNA to unwind supercoils, unwind loops, and compress chromosomes in eukaryotic cells. 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 poisons and bind to the topoisomerase-DNA complex to prevent the rejoining step of the topoisomerase mechanism. These topoisomerase-DNA inhibitor complexes are cytotoxic agents because the unrepaired single-stranded and double-stranded DNA breaks they induce can lead to apoptosis and cell death. Due to this ability to induce apoptosis, topoisomerase inhibitors have been used as therapeutic agents against infected cells and cancer cells.

[0113] In some embodiments, the nuclear payload of the compound described herein (i.e., A) 1 The compound is derived from camptothecin (CPT). Therefore, in some embodiments, the nuclear payload (i.e., A) of the compound described herein is... 1 ) is a camptothecin (CPT) analogue. In some embodiments, the core payload (i.e., A) of the compound described herein 1It is derived from topotecan, irinotecan (CPT-11), silatecan (DB-67, AR-67), cositecan (BNP-1350), eczetcan, letopotecan, gimatecan (ST1481), belotetcan (CKD-602) or rubitecan or their analogues.

[0114] In some implementations, such as those concerning nuclear payloads (i.e., A...) 1 The terms “derived from” or “analyte” as used refer to at most one non-hydrogen atom of the original, unmodified nuclear payload (i.e., a known topoisomerase inhibitor) being replaced by a covalent bond (optionally via a linker portion) to the nuclear acceptor targeting epitope. Exemplary non-hydrogen atoms include, but are not limited to, -CH3, -OH, =O, and -NH2. In some embodiments, as with respect to the nuclear payload (i.e., A…) 1 The term "derived from" as used here means that one or more atoms (e.g., hydrogen, methyl, or hydroxyl) of the original, unmodified nuclear payload (i.e., the topoisomerase inhibitor) are combined with L 1 Direct covalent bond substitution. Exemplary non-hydrogen atoms include, but are not limited to, -CH3, -OCH3, -OH, =O, -NH2, -N(CH3)2, etc. In some embodiments, a hydrogen atom is bonded to a heteroatom (e.g., N, O, or S) of the original, unmodified nuclear payload (i.e., a known topoisomerase inhibitor) and is then bonded to L. 1 The covalent bond substitution. In some embodiments, the term "derived from" means that one or more atoms (e.g., hydrogen, methyl, or hydroxyl) are replaced by L. 1 Direct covalent bond substitution.

[0115] In some implementations, in the nuclear payload (i.e., A) as disclosed herein 1 One or more atoms on the compound (e.g., hydrogen, methyl, hydroxyl, amino, etc.) are replaced to attach to the rest of the compound (e.g., part of -L). 1 -B 1 In some embodiments, the hydrogen atom on the nuclear acceptor targeting epitope disclosed herein is replaced to attach 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). Analogs are derived from known nuclear payloads described herein (e.g., topoisomerase inhibitors or A...). 1And modified to optionally conjugate to at least one nuclear hormone receptor targeting epitope via a linker portion. The analogues, even after modification to obtain the compounds described herein, retain biological activity comparable to that observed in the original, unmodified topoisomerase inhibitors. In some embodiments, the compounds exhibit binding activity or inhibition of 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 inhibitors. In some embodiments, the compounds as described herein exhibit IC50 values ​​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. 50 .

[0116] In some embodiments of Formula I, II, or III, A 1 It is a compound of formula IA:

[0117]

[0118] in:

[0119] Y is a bond, -CH2- or -CH2-CH2-;

[0120] Z represents a bond or an O;

[0121] R 1 R 2 R 3 and R 4 Each group independently consists of hydrogen, halogen, cyano, nitro, and -OR. 15 -SR 15 -NR 15 R 16 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R 15 -C(=O)OR 15 -OC(=O)R 15 -C(=O)NR 15 R 16 -NR 15 C(=O)R 16 -NR 15 C(=O)OR 16 -S (=O) 1-2 R 15 -S (=O)1- 2NR 15 R 16 -NR 15 S(=O) 1-2 R 16 、-Si(R 15 )3 or -C=NOR 15 When the valence is allowed, R 1 R 2 R 3 and R 4 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently and optionally bounded by one or more R groups. 10 replace;

[0122] or R 1 and R 2 With R 1 and R 2 The attached atoms together form C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups, optionally with one or more R groups when the valence allows. 10 replace;

[0123] or R 2 and R 3 With R 2 and R 3 The attached atoms together form C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups, optionally with one or more R groups when the valence allows. 10 replace;

[0124] Or R 3 and R 4 With R 3 and R 4 The attached atoms together form C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups, optionally with one or more R groups when the valence allows. 10 replace;

[0125] Each R 10 Independently, it is a halogenated group, cyano group, nitro group, or -OR group. 17 -SR 17 -SF5, -NR 17 R 18 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R 17 -C(=O)OR 17 -OC(=O)OR17 -OC(=O)R 17 -C(=O)NR 17 R 18 -OC(=O)NR 17 R 18 -NR 7 C(=O)NR 17 R 18 -S (=O) 1-2 R 17 -S (=O) 1- 2NR 17 R 18 -NR 17 S(=O) 1-2 R 18 -NR 17 S(=O) 1-2 NR 17 R 18 -NR 17 C(=O)R 18 -NR 17 C(=O)OR 18 、-Si(R 17 )3 or -C=NOR 17 When the valence is allowed, R 10 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently and optionally substituted with one or more halogroups or optionally with an oxogroup, halogroup, hydroxyl group, or amino group. 1-12 Alkyl substitution; and

[0126] Each R 15 and R 16 Independently, it is hydrogen and C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 Cycloalkyl, wherein, where the valence permits, each alkyl, alkenyl, ynyl or cycloalkyl group is optionally and independently substituted with an oxo group, a halo group, a hydroxyl group or an amino group; or R 15 and R 16 With R 15 and R 16 The attached atoms together form C atoms that are optionally substituted with a halogen group or optionally with an oxo group, halogen group, hydroxyl group, or amino group. 1-12 Alkyl-substituted heterocyclic groups; and

[0127] Each R 17 and R 18 Independently, it is hydrogen and C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C3-12 cycloalkyl, wherein each C, when valence permits, 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 The cycloalkyl group may optionally be substituted with an oxo group, a halogen group, a hydroxyl group, or an amino group; or R 17 and R 18 With R 17 and R 18 The attached atoms together form C atoms that are optionally substituted with a halogen group or optionally with an oxo group, halogen group, hydroxyl group, or amino group. 1-12 Alkyl-substituted heterocyclic groups;

[0128] One or more atoms of formula IA (e.g., hydrogen, methyl, or hydroxyl) are directly covalently bonded L 1 Replacement.

[0129] In L 1 In the implementation of the key, the phrase "is directly covalently bonded L" 1 "Substitution" means that the group is replaced by B. 1 Direct covalent bond substitution.

[0130] In some embodiments, the hydrogen atom of formula IA is combined with L 1 Direct covalent bond substitution.

[0131] In some implementations, in R 1 R 2 and R 3 One or more atoms in one of them (e.g., hydrogen, methyl, or hydroxyl) are combined with L 1 Direct covalent bond substitution.

[0132] In some implementations, Y is -CH2-.

[0133] In some implementations, Z is O.

[0134] In some implementations, Y is -CH2- and Z is O.

[0135] In certain embodiments of the various formulations described herein, the terms heterocyclic, aryl, or heteroaryl refer to 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0136] In some embodiments, a compound of formula IA-1, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof is provided.

[0137]

[0138] in:

[0139] R 1 R 2 R 3 and R 4 Each group independently consists of hydrogen, halogen, cyano, nitro, and -OR. 15 -SR 15 -NR 15 R 16 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R 15 -C(=O)OR 15 -OC(=O)R 15 -C(=O)NR 15 R 16 -NR 15 C(=O)R 16 -S (=O) 1-2 R 15 -S (=O) 1-2 NR 15 R 16 -NR 15 S(=O) 1- 2R 16 、-Si(R 15 )3 or -C=NOR 15 When the valence is allowed, R 1 R 2 R 3 and R 4 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently and optionally bounded by one or more R groups. 10 replace;

[0140] Or R 1 and R 2 With R 1 and R 2 The attached atoms together form C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups, optionally with one or more R groups when the valence allows. 10 replace;

[0141] Or R 2 and R 3 With R 2 and R 3 The attached atoms together form C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups, optionally with one or more R groups when the valence allows. 10 replace;

[0142] or R 3 and R 4 With R 3 and R 4 The attached atoms together form C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups, optionally with one or more R groups when the valence allows. 10 replace;

[0143] Each R 10 Independently, it is a halogenated group, cyano group, nitro group, or -OR group. 17 -SR 17 -SF5, -NR 17 R 18 C 1-12 Alkyl, C 2-12 alkenyl,

[0144] C 2-12 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R 17 -C(=O)OR 17 -OC(=O)OR 17 -OC(=O)R 17 -C(=O)NR 17 R 18 -OC(=O)NR 17 R 18 -NR 7 C(=O)NR 17 R 18 -S (=O) 1-2 R 17 -S (=O) 1-2 NR 17 R 18 -NR 17 S(=O) 1-2 R 18 -NR 17 S(=O) 1-2 NR 17 R 18 -NR 17 C(=O)R 18 -NR 17 C(=O)OR 18 、-Si(R 17 )3 or -C=NOR 17 When the valence is allowed, R 10 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently and optionally substituted with one or more halogroups or optionally with an oxogroup, halogroup, hydroxyl group, or amino group. 1-12Alkyl substitution; and

[0145] Each R 15 and R 16 Independently, it is hydrogen and C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 cycloalkyl, wherein each C, when valence permits, 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 The cycloalkyl group is optionally and independently substituted with an oxo group, a halogen group, a hydroxyl group, or an amino group; or R 15 and R 16 With R 15 and R 16 The attached atoms together form C atoms that are optionally substituted with a halogen group or optionally with an oxo group, halogen group, hydroxyl group, or amino group. 1-12 Alkyl-substituted heterocyclic groups; and

[0146] Each R 17 and R 18 Independently, it is hydrogen and C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 cycloalkyl, wherein each C, when valence permits, 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 The cycloalkyl group may optionally be substituted with an oxo group, a halogen group, a hydroxyl group, or an amino group; or R 17 and R 18 With R 17 and R 18 The attached atoms together form C atoms that are optionally substituted with a halogen group or optionally with an oxo group, halogen group, hydroxyl group, or amino group. 1-12 Alkyl-substituted heterocyclic groups;

[0147] One or more atoms (e.g., hydrogen, methyl, hydroxyl, etc.) are directly covalently bonded to at least one nuclear acceptor targeting epitope (optionally via a linker as defined herein; e.g., -L) 1 -B 1 ) is replaced. In some embodiments, the hydrogen atom of formula IA-1 is replaced with L 1 Direct covalent bond substitution.

[0148] In some embodiments of Formula I, II, or III, A 1 Compounds of formula IB:

[0149]

[0150] in:

[0151] R 1 It is hydrogen, -C=NOR 15 Or optionally by one or more R 10 Replacement C 1-6 alkyl;

[0152] R 2 It is hydrogen, C 1-6 Alkyl, -N(R) 17 R 18 )2、-NO2、-C 1-6 Alkylene-OC 1-6 Alkyl or -C 1-6 Alkylene-N(R) 17 R 18 )2; or

[0153] R 1 and R 2 With R 1 and R 2 The attached atoms together form an array optionally bound by one or more R 10 Replacement C 3-10 cycloalkyl;

[0154] R 3 It is hydrogen, hydroxyl, halogen, C 1-6 Alkyl or -OC 1-6 alkyl;

[0155] R 4 It is hydrogen, halogenated group, C 1-6 Alkyl or -OC 1-6 Alkyl; or

[0156] R 3 and R 4 Together they form -O-CH2-O- or -O-CH2CH2-O-;

[0157] Y is a bond, -CH2- or -CH2-CH2-; and

[0158] Z represents a bond or an O;

[0159] Among them, in R 1 R 2 and R 3 One or more atoms in one of them are with L 1 Direct covalent bond substitution.

[0160] In some implementations, the hydrogen atom of formula IB is combined with L 1 Direct covalent bond substitution.

[0161] In some embodiments, a compound of formula IB, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof is provided.

[0162]

[0163] in:

[0164] R 1 Is it hydrogen or -L? 1 -B 1 ;

[0165] R 2 It is hydrogen, NH2, NO2 or -L 1 -B 1 ;

[0166] R 3 It is hydrogen, halogroup, methyl, methoxy or -L 1 -B 1 ;

[0167] R 4 It is hydrogen, halogroup, methyl or methoxy; or

[0168] R 3 and R 4 Together they form -O-CH2-O- or -O-CH2CH2-O-;

[0169] Y is a bond, -CH2- or -CH2-CH2-; and

[0170] Z stands for bond or O.

[0171] In some implementations, R 1 R 2 or R 3 Only one of them is -L 1 -B 1 In some implementations, R 1 Yes -L 1 -B 1 In some implementations, R 2 Yes -L 1 -B 1 In some implementations, R 3 Yes -L 1 -B 1 .

[0172] In some embodiments, a compound of formula IC is provided, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof:

[0173]

[0174] in:

[0175] B 1 It is a nuclear receptor-targeting epitope as defined in this article;

[0176] n is 2, 3, or 4;

[0177] A is either O or NH;

[0178] R 3 It is hydrogen, halogroup, methyl or methoxy;

[0179] R 4 It is hydrogen, halogroup, methyl, methoxy; or

[0180] R 3 and R 4 Together they form -O-CH2-O- or -O-CH2CH2-O-;

[0181] Y is a bond, -CH2- or -CH2-CH2-; and

[0182] Z stands for bond or O.

[0183] In some embodiments, a compound of formula ID, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof is provided.

[0184]

[0185] in:

[0186] L 1 It is the connecting part;

[0187] B 1 It is a nuclear receptor-targeting epitope as defined in this article;

[0188] R 4 It is hydrogen, halogroup, methyl or methoxy;

[0189] R 17 and R 18 Each of them is independently hydrogen, C 1-12 Alkyl, C 2-12 alkenyl or C 2-12 Alkynyl group, wherein each C, when valence permits, 1-12 Alkyl, C 2-12 alkenyl or C 2-12 The alkynyl group may optionally be substituted with an oxo group, a halogen group, a hydroxyl group, or an amino group; or R 17 and R 18 With R 17 and R18 The attached atoms together form C atoms that are optionally substituted with a halogen group or optionally with an oxo group, halogen group, hydroxyl group, or amino group. 1-12 Alkyl-substituted heterocyclic groups;

[0190] Y is a bond, -CH2- or -CH2-CH2-; and

[0191] Z stands for bond or O.

[0192] In some embodiments, a compound of formula IE is provided, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof:

[0193]

[0194] in:

[0195] L 1 It is the connecting part;

[0196] B 1 It is a nuclear receptor-targeting epitope as defined in this article;

[0197] R 4 It is hydrogen, halogroup, methyl or methoxy;

[0198] R 17 It is hydrogen, C 1-12 Alkyl, C 2-12 alkenyl or C 2-12 Alkynyl group, wherein each C, when valence permits, 1-12 Alkyl, C 2-12 alkenyl or C 2-12 The alkynyl group may optionally be replaced by an oxo group, a halo group, a hydroxyl group, or an amino group;

[0199] Y is a bond, -CH2- or -CH2-CH2-; and

[0200] Z stands for bond or O.

[0201] In some embodiments, a compound of formula IF, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof is provided.

[0202]

[0203] in:

[0204] L 1 It is the connecting part;

[0205] B 1 It is a nuclear receptor-targeting epitope as defined in this article;

[0206] R 4 It is hydrogen, halogroup, methyl or methoxy;

[0207] Y is a bond, -CH2- or -CH2-CH2-; and

[0208] Z stands for bond or O.

[0209] In some embodiments, a compound of formula IG is provided, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof:

[0210]

[0211] in:

[0212] B 1 It is a nuclear receptor-targeting epitope as defined in this article;

[0213] A is N or CH;

[0214] R 3 It is hydrogen, halogroup, methyl or methoxy;

[0215] R 4 It is hydrogen, halogroup, methyl, methoxy; or

[0216] R 3 and R 4 Together they form -O-CH2-O- or -O-CH2CH2-O-;

[0217] Y is a bond, -CH2- or -CH2-CH2-; and

[0218] Z stands for bond or O.

[0219] In some embodiments, a compound of formula IH is provided, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof:

[0220]

[0221] in:

[0222] B 1 It is a nuclear receptor-targeting epitope as defined in this article;

[0223] A is N or CH;

[0224] R 4 It is hydrogen, halogroup, methyl, methoxy; or

[0225] Each R 10Independently, it is a halogenated group, cyano group, nitro group, or -OR group. 17 -SR 17 -SF5, -NR 17 R 18 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R 17 -C(=O)OR 17 -OC(=O)OR 17 -OC(=O)R 17 -C(=O)NR 17 R 18 -OC(=O)NR 17 R 18 -NR 7 C(=O)NR 17 R 18 -S (=O) 1-2 R 17 -S (=O) 1- 2NR 17 R 18 -NR 17 S(=O) 1-2 R 18 -NR 17 S(=O) 1-2 NR 17 R 18 -NR 17 C(=O)R 18 -NR 17 C(=O)OR 18 、-Si(R 17 )3 or -C=NOR 17 When the valence is allowed, R 10 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently and optionally substituted with one or more halogroups or optionally with an oxogroup, halogroup, hydroxyl group, or amino group. 1-12 Alkyl substitution;

[0226] Each R 17 and R 18 Independently, it is hydrogen and C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 cycloalkyl, wherein each C, when valence permits, 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12The cycloalkyl group may optionally be substituted with an oxo group, a halogen group, a hydroxyl group, or an amino group; or R 17 and R 18 With R 17 and R 18 The attached atoms together form C atoms that are optionally substituted with a halogen group or optionally with an oxo group, halogen group, hydroxyl group, or amino group. 1-12 Alkyl-substituted heterocyclic groups;

[0227] Y is a bond, -CH2- or -CH2-CH2-; and

[0228] Z stands for bond or O.

[0229] In some embodiments, a compound of formula IJ is provided, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof:

[0230]

[0231] in:

[0232] R 3 It is hydrogen, hydroxyl group, -CH2NH2 or -C(=O)H;

[0233] When R 3 When R is -CH2NH2 or -C(=O)H 2 It is hydrogen; or

[0234] When R 3 When it is hydrogen or hydroxyl, R 2 It is -C(=O)H or -CH2R 11 ;

[0235] R 11 Yes - OR 12 -SR 12 -CH2 NH2, -NR 12 R 13 or -N + R 12 R 13 R 14 ;

[0236] R 12 R 13 and R 14 Each is independently hydrogen, C 1-6 Alkyl, C 2-6 Hydroxyalkyl, C 1-6 Dialkylamino, C 1-6 Dialkylamino-C 2-6 Alkyl, C 1-6 Alkylamino-C 2-6 Alkyl, C2-6 Aminoalkyl or 3-7 membered unsubstituted or substituted rings; and

[0237] When R 11 Yes -NR 12 R 13 At that time, R 12 and R 13 Groups can react with R 12 and R 13 The nitrogen atoms bonded to the group combine together to form a heterocycle, provided that the heterocycle is selected from morpholino, N-methylpiperazino, or 4'-piperidinylpiperidino, each of which may contain additional heteroatoms;

[0238] Or its pharmaceutically acceptable salts, hydrates or solvates;

[0239] The atom (e.g., hydrogen, carbon, or heteroatom) is directly covalently bonded to at least one nuclear acceptor target epitope (optionally via a linker as defined herein; e.g., -L). 1 -B 1 (replace)

[0240] In some embodiments, the nuclear payload is derived from topotecan or an analogue thereof (i.e., a topotecan-containing analogue). In some embodiments, a compound of formula IK is provided:

[0241]

[0242] Among them B 1 It is a nuclear receptor-targeting epitope; and L 1 It is a covalent bond or a connecting part.

[0243] In some embodiments, the nuclear payload is derived from irinotecan (CPT-11) or an analogue thereof (i.e., an irinotecan-containing analogue). In some embodiments, a compound of the formula IL is provided:

[0244]

[0245] Among them B 1 It is a nuclear receptor-targeting epitope; and L 1 It is a covalent bond or linker. In some embodiments, a compound of formula IM is provided:

[0246]

[0247] Among them B 1 It is a nuclear receptor-targeting epitope; and L 1 It is a covalent bond or a connecting part.

[0248] In some embodiments, the nuclear payload is derived from cerettenac (DB-67, AR-67) or an analogue thereof (i.e., an analogue containing cerettenac). In some embodiments, a compound of formula IN is provided:

[0249]

[0250] Among them B 1 It is a nuclear receptor-targeting epitope; and L 1 It is a covalent bond or a connecting part.

[0251] In some embodiments, the nuclear payload is derived from cocitecan (BNP-1350) or an analogue thereof (i.e., a cocitecan-containing analogue). In some embodiments, a compound of formula 10 is provided:

[0252]

[0253] Among them B 1 It is a nuclear receptor-targeting epitope; and L 1 It is a covalent bond or a connecting part.

[0254] In some embodiments, the nuclear payload is derived from eczema or an analogue thereof (i.e., an analogue containing eczema). In some embodiments, a compound of formula IP is provided:

[0255]

[0256] Among them B 1 It is a nuclear receptor-targeting epitope; and L 1 It is a covalent bond or linker. In some embodiments, a compound of formula IQ is provided:

[0257]

[0258] Among them B 1 It is a nuclear receptor-targeting epitope; and L 1 It is a covalent bond or a connecting part.

[0259] In some embodiments, the nuclear payload is derived from letopecan or an analogue thereof (i.e., an analogue containing letopecan). In some embodiments, a compound of formula IR is provided:

[0260]

[0261] Among them B 1 It is a nuclear receptor-targeting epitope; and L 1 It is a covalent bond or a connecting part.

[0262] In some embodiments, the nuclear payload is derived from gimatecan (ST1481) or an analogue thereof (i.e., an analogue containing gimatecan). In some embodiments, a compound of formula IS is provided:

[0263]

[0264] Among them B 1 It is a nuclear receptor-targeting epitope; and L 1 It is a covalent bond or a connecting part.

[0265] In some embodiments, the nuclear payload is derived from belotecone (CKD-602) or an analogue thereof (i.e., an analogue containing belotecone). In some embodiments, a compound of formula IT is provided:

[0266]

[0267] Among them B 1 It is a nuclear receptor-targeting epitope; and L 1 It is a covalent bond or a connecting part.

[0268] In some embodiments, the nuclear payload is derived from rubitecan or an analogue thereof (i.e., an analogue containing rubitecan). In some embodiments, a compound of formula IU is provided:

[0269]

[0270] Among them B 1 It is a nuclear receptor-targeting epitope; and L 1 It is a covalent bond or a connecting part.

[0271] In some implementations, the nuclear payload (i.e., A) 1 Source:

[0272]

[0273]

[0274] In some implementations, the nuclear payload or A 1 Source:

[0275]

[0276]

[0277] In some implementations, the nuclear payload originates from:

[0278]

[0279] In some implementations, the nuclear payload originates from:

[0280]

[0281]

[0282] In some implementations, the nuclear payload originates from:

[0283]

[0284] In some implementations, the nuclear payload originates from:

[0285]

[0286]

[0287] In some implementations, the nuclear payload originates from:

[0288]

[0289] In some implementations, the nuclear payload originates from:

[0290]

[0291] In some implementations, the nuclear payload originates from:

[0292]

[0293] In some implementations, the nuclear payload originates from:

[0294]

[0295]

[0296] In some implementations, the nuclear payload originates from:

[0297]

[0298] nuclear receptor targeting epitopes

[0299] In some implementations, B 1 It is a nuclear hormone receptor-targeting epitope. In some implementations, B 1 It is a nuclear steroid receptor-targeting epitope. As used herein, "nuclear receptor-targeting epitope" refers to the following portion of the compounds described herein (e.g., B...). 1The portion of the compound is derived from nuclear-targeting agents 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-targeting epitopes are used to associate the compound with the target nuclear receptor (e.g., a nuclear steroid receptor), promoting the localization of the compound to cells expressing the nuclear steroid receptor and transporting the nuclear payload from the cytoplasm to the nucleus, thereby accumulating the compound in the nucleus. Accumulation levels can be controlled by selecting an appropriate nuclear receptor-targeting epitope. For example, through nuclear translocation of the nuclear steroid receptor following epitope binding to the receptor, the compounds described herein can accumulate in the nucleus to varying degrees, with high accumulation in the case of a full agonist (e.g., dihydrotestosterone (DHT)), moderate accumulation in the case of a partial agonist (e.g., bicalutamide), and low accumulation in the case of an antagonist (e.g., enzalutamide).

[0300] Steroid receptor targets can be any steroid receptor, including but not limited to those overexpressed on cancer cells. In some embodiments, at least one nuclear steroid receptor targeting epitope 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.

[0301] Exemplary nuclear steroid receptor-targeting epitopes include those derived from: 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.

[0302] Nuclear steroid receptor-targeting epitopes can typically bind to nuclear steroid receptors, and their IC50... 50 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 its EC 50 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 3400 nM, or less than about 200 nM, or less than about 100 nM.

[0303] In some embodiments, the nuclear hormone receptor binding affinity of the compounds of the present invention can be defined based on 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 compounds disclosed herein bind to human estrogen receptors with an affinity of at least 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of 17β-estradiol.

[0304] For example, some compounds of the present invention can bind to human androgen receptors. In some cases, the compounds disclosed herein bind to androgen receptors with an affinity of at least 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% for dihydrotestosterone (DHT).

[0305] For example, some compounds of the present invention can bind to human progesterone receptors. In some cases, the compounds disclosed herein bind to progesterone receptors with an affinity of at least 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of progesterone.

[0306] For example, some compounds of the present invention can bind to human glucocorticoid receptors. In some cases, the compounds disclosed herein bind to glucocorticoid receptors with an affinity of at least 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of cortisone.

[0307] In some implementations, nuclear steroid receptors target epitopes (e.g., B... 1 ( ) is an agonist of the androgen receptor. In some implementations, the nuclear steroid receptor targeting epitope is an antagonist of the androgen receptor.

[0308] In some implementations, nuclear steroid receptors target epitopes (e.g., B... 1 The target epitope is steroidal (or derived from steroidal compounds) (e.g., dihydrotestosterone). In some embodiments, the nuclear steroid receptor targeting epitope is nonsteroidal (or derived from nonsteroidal compounds) (e.g., enzalutamide, apalutamide, AZD9496, and bicalutamide).

[0309] Analogs are derived from known nuclear steroid receptor targeting epitopes described herein (e.g., B... 1And modified to optionally conjugate to at least one nucleosteroid payload via a linker portion. The analogues, even after modification to obtain the compounds described herein, retain biological activity comparable to that observed in the original, unmodified nucleosteroid receptor targeting epitopes. In some embodiments, the compounds exhibit binding activity or inhibition of 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 targeting epitopes.

[0310] In some implementations, the analogue is derived from a known nuclear receptor-targeting epitope (e.g., B...). 1 ), such as known nuclear steroid receptor targeting epitopes. In some embodiments, B 1 This involves binding to estrogen receptors, glucocorticoid receptors, progesterone receptors, or androgen receptors. In some embodiments, the term "derived from," as used with respect to nuclear receptor-targeting epitopes, means that at most one non-hydrogen atom of the original, unmodified nuclear receptor-targeting compound (i.e., a known nucleosteroid receptor-targeting compound) is replaced by a covalent bond (optionally via a linker portion) with the nuclear payload. Exemplary non-hydrogen atoms include, but are not limited to, -CH3, -OH, =O, and -NH2. In some embodiments, the term "derived from," as used with respect to nuclear receptor-targeting epitopes, means that at most one non-hydrogen atom of the original, unmodified nuclear receptor-targeting compound (i.e., a known nucleosteroid receptor-targeting compound) is replaced by a covalent bond (optionally via a linker portion) with the nuclear payload. In some embodiments, a hydrogen atom bonded to a heteroatom (e.g., N, O, or S) of the original, unmodified nuclear receptor-targeting compound (i.e., a known nucleosteroid receptor-targeting compound) is replaced by a covalent bond (optionally via a linker portion) with the nuclear payload. In some implementations, the term "derived from" means that one or more atoms (e.g., hydrogen, methyl, or hydroxyl) are derived from L 1 Direct covalent bond substitution.

[0311] In some implementations, nuclear steroid receptors target epitopes (e.g., B... 1This is an androgen receptor-targeting epitope. As used herein, the term "androgen receptor-targeting epitope" is intended to refer to the portion of a compound that binds to an androgen receptor and can be functionally an androgen receptor agonist or androgen receptor antagonist (including partial androgen receptor agonists or partial androgen receptor antagonists), and in some embodiments, is capable of binding to the receptor and facilitating the shuttle transfer of the ligand-receptor complex from the cytoplasm to the cell nucleus. An "androgen receptor" (AR)—also known as NR3C4 (member 4 of the nuclear receptor subfamily 3C)—is a type of nuclear receptor that, upon activation by binding an androgen receptor conjugate (e.g., androgens such as testosterone or dihydrotestosterone) in the cytoplasm, is capable of translocating androgens to the cell nucleus.

[0312] Exemplary androgen receptor targeting epitopes (e.g., B) that can be used with the compounds described herein 1 This includes, but is not limited to, androgen receptor agonists, selective androgen receptor modulators (SARMs) (e.g., enobosarm), androgen receptor antagonists (e.g., bicalutamide, flutamide, nilumethoxazole, or enzalutamide), selective estrogen receptor modulators (SERMs) (e.g., tamoxifen, toremifene, or raloxifene), estrogen receptor antagonists (e.g., fulvestrant), progestins (e.g., medroxyprogesterone acetate), estrogens (e.g., estrusstem), ketoconazole, abiraterone, dalolutamide, or analogues thereof.

[0313] In some implementations, nuclear steroid receptors target epitopes (e.g., B... 1This compound is a selective androgen receptor modulator (SARM). In some embodiments, the compound comprises at least one nuclear steroid receptor targeting epitope, which independently includes epitopes derived from: testosterone, testosterone esters (e.g., testosterone enanthate, propionate, cyclopentyl propionate, etc. or analogues thereof), embosamole, 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-40 503, S-23, testolone (RAD-140), acetothiolutamide, andarine (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 their analogues.

[0314] In some implementations, such as the nuclear receptor-targeting epitope (B) disclosed herein 1 Individual atoms on the ) are replaced to attach to the rest of the compound (e.g., part of -L) 1 -B 1 In some embodiments, the halogen atom on the nuclear acceptor targeting epitope disclosed herein is replaced to attach to the remainder of the compound. In some embodiments, the hydrogen atom on the nuclear acceptor targeting epitope disclosed herein is replaced to attach 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.

[0315] In some implementations, B 1 With formula IIA:

[0316]

[0317] in:

[0318] Tilde key refers to the key with L 1 The connection point;

[0319] R 30 It is hydrogen, C1-12 Alkyl, C 1-12 Haloalkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 cycloalkyl, wherein each C, when valence permits, 1-12 Alkyl, C 1-12 Haloalkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 The cycloalkyl group is optionally and independently surrounded by one to five R... 100 replace;

[0320] R 40 It is hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 cycloalkyl, wherein each C, when valence permits, 1-12 Alkyl, C 1-12 Haloalkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 The cycloalkyl group is optionally and independently surrounded by one to five R... 100 replace;

[0321] Each R 50 Independently, it is a halogenated group, cyano group, nitro group, or -OR group. 170 -SR 170 -NR 170 R 180 C 1-12 Alkyl, C 1-12 Haloalkyl, C 2-12 alkenyl or C 2-12 Alkynyl group; wherein, when valence permits, each C 1-12 Alkyl, C 1-12 Haloalkyl, C 2-12 alkenyl or C 2-12 The alkynyl group is independently and optionally substituted by one to five halogroups, hydroxyl groups or amino groups;

[0322] Each R 100 Independently, it can be an oxo group, a halogen group, a cyano group, a nitro group, or an -OR group. 170 -SR 170 -SF5, -NR 170 R 180 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R 170-C(=O)OR 170 -OC(=O)OR 170 -OC(=O)R 170 -C(=O)NR 170 R 180 -OC(=O)NR 170 R 180 -NR 170 C(=O)NR 170 R 180 -S (=O) 1-2 R 170 -S (=O) 1-2 NR 170 R 180 -NR 170 S(=O) 1-2 R 180 -NR 170 S(=O) 1-2 NR 170 R 180 -NR 170 C(=O)R 180 -NR 170 C(=O)OR 180 Or -C = NOR 17 When the valence is allowed, R 100 Each C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-10 C10 groups in which cycloalkyl, heterocyclic, aryl, and heteroaryl groups are independently and optionally substituted with one or more halogroups or optionally with oxo, halogroups, hydroxyl, or amino groups. 1-12 Alkyl substitution; and

[0323] Each R 170 and R 180 Independently hydrogen or, when valence permits, optionally substituted with an oxo group, a halogen group, a hydroxyl group, or an amino group. 1-12 Alkyl; or R 170 and R 180 With R 170 and R 180 The attached atoms together form C atoms that are optionally substituted with a halogen group or optionally with an oxo group, halogen group, hydroxyl group, or amino group. 1-12 Alkyl-substituted heterocyclic groups.

[0324] In some implementations, B 1 Formula IIB:

[0325]

[0326] in:

[0327] Tilde key refers to the key with L 1 The connection point;

[0328] R 60 It is hydrogen, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 cycloalkyl, wherein each C, when valence permits, 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 The cycloalkyl group is optionally and independently surrounded by one to five R... 100 replace;

[0329] R 80 It is hydrogen, hydroxyl, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy or C 3-12 cycloalkyl, wherein each C, when valence permits, 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, or C 1-12 Alkoxy, C 3-12 The cycloalkyl group is optionally and independently surrounded by one to five R... 100 replace;

[0330] R 81 It is hydrogen, hydroxyl, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy or C 3-12 cycloalkyl, wherein each C, when valence permits, 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy or C 3-12 The cycloalkyl group is optionally and independently surrounded by one to five R... 100 replace;

[0331] or R 80 and R 81 With R 80 and R 81 The attached atoms together form C atoms that are optionally substituted with a halogen group or optionally with an oxo group, halogen group, hydroxyl group, or amino group. 1-12 Alkyl-substituted heterocyclic groups;

[0332] Each R 100 Independently, it can be an oxo group, a halogen group, a cyano group, a nitro group, or an -OR group.170 -SR 170 -SF5, -NR 170 R 180 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R 170 -C(=O)OR 170 -OC(=O)OR 170 -OC(=O)R 170 -C(=O)NR 170 R 180 -OC(=O)NR 170 R 180 -NR 170 C(=O)NR 170 R 180 -S (=O) 1-2 R 170 -S (=O) 1-2 NR 170 R 180 -NR 170 S(=O) 1-2 R 180 -NR 170 S(=O) 1-2 NR 170 R 180 -NR 170 C(=O)R 180 -NR 170 C(=O)OR 180 Or -C = NOR 17 When the valence is allowed, R 100 Each C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-10 C10 groups in which cycloalkyl, heterocyclic, aryl, and heteroaryl groups are independently and optionally substituted with one or more halogroups or optionally with oxo, halogroups, hydroxyl, or amino groups. 1-12 Alkyl substitution; and

[0333] Each R 170 and R 180 Independently hydrogen or, when valence permits, optionally substituted with an oxo group, a halogen group, a hydroxyl group, or an amino group. 1-12 Alkyl; or R 170 and R 180 With R 170 and R 180The attached atoms together form C atoms that are optionally substituted with a halogen group or optionally with an oxo group, halogen group, hydroxyl group, or amino group. 1-12 Alkyl-substituted heterocyclic groups.

[0334] In some implementations, B 1 With IIC:

[0335]

[0336] in:

[0337] Tilde key refers to the key with L 1 The connection point;

[0338] R 60 It is hydrogen, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 cycloalkyl, wherein each C, when valence permits, 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 The cycloalkyl group is optionally and independently surrounded by one to five R... 100 replace;

[0339] Each R 100 Independently, it can be an oxo group, a halogen group, a cyano group, a nitro group, or an -OR group. 170 -SR 170 -SF5, -NR 170 R 180 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R 170 -C(=O)OR 170 -OC(=O)OR 170 -OC(=O)R 170 -C(=O)NR 170 R 180 -OC(=O)NR 170 R 180 -NR 170 C(=O)NR 170 R 180 -S (=O) 1-2 R 170 -S (=O) 1-2 NR 170 R 180 -NR 170 S(=O) 1-2 R180 -NR 170 S(=O) 1-2 NR 170 R 180 -NR 170 C(=O)R 180 -NR 170 C(=O)OR 180 Or -C = NOR 17 When the valence is allowed, R 100 Each C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-10 C10 groups in which cycloalkyl, heterocyclic, aryl, and heteroaryl groups are independently and optionally substituted with one or more halogroups or optionally with oxo, halogroups, hydroxyl, or amino groups. 1-12 Alkyl substitution; and

[0340] Each R 170 and R 180 Independently hydrogen or, when valence permits, optionally substituted with an oxo group, a halogen group, a hydroxyl group, or an amino group. 1-12 Alkyl; or R 170 and R 180 With R 170 and R 180 The attached atoms together form C atoms that are optionally substituted with a halogen group or optionally with an oxo group, halogen group, hydroxyl group, or amino group. 1-12 Alkyl-substituted heterocyclic groups.

[0341] In some implementations, B 1 Having IID:

[0342]

[0343] in:

[0344] Tilde key refers to the key with L 1 The connection point;

[0345] A” and A”' are each independently O or S;

[0346] R a and R b Each is independently CH3 or CH2CH3; or R a and R b With R a and R b The attached atoms together form C 3-5 cycloalkyl, ethylene oxide, oxetane, or tetrahydrofuran;

[0347] B、B 10 B2 B 3 B' B 1’ B 2’ and B 3’ Each is CR independently c Or N;

[0348] Each R c It can be hydrogen, fluorine, CN, or methyl independently;

[0349] D is NH, O, S, CH2 or C=O;

[0350] "X" represents CN, a halogenated group, or NO2;

[0351] "Y" represents CH3, CH2R d CHF2 or CF3;

[0352] R d It is a halogenated group;

[0353] Z”' is H, C 1-2 Alkyl, C2 alkenyl, or NO2; or

[0354] X and Y together form The dash indicates the key to the ring;

[0355] Or Y” and Z”' together form Each of them It is a single or double bond, and the hyphen indicates a bond with a ring; and

[0356] Z' is CH or N.

[0357] In some implementations, B 1 With IIE:

[0358]

[0359] in:

[0360] The tilde refers to the connection point with L;

[0361] Q is Where bond a is attached to ring a and bond b is attached to ring b;

[0362] R a and R b Each is independently -CH3 or -CH2CH3; or R a and R b With R a and R b The attached atoms together form C 3-5 Cycloalkyl, ethylene oxide, oxobutyric, or tetrahydrofuranyl;

[0363] A and A' are each independently O or S;

[0364] E, E 1 E 2 and E 3 Each is CR independently c Or N, and each R c It is independently hydrogen, halogroup, CN or methyl; E 4 Is it CF, CH, or N?

[0365] Q 1 It is a bond, CH2, C=O or (C=O)NH;

[0366] Q 2 It is NH, O, S, CH2, NH(C=O), C(=O)NH or C=O;

[0367] R 44 R 45 and R 46 Each is independently hydrogen, CN, or C. 1-2 alkyl;

[0368] t is 0, 1, 2, 3, or 4;

[0369] Each R e Independently, it is a halogenated group, a cyano group, or a C group. 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0370] R 41 It is a halogenated group, CN, or NO2;

[0371] R 42 It is a halogenated group, CH3, CH2F, CHF2, or CF3; or

[0372] R 41 and R 42 Together The dash indicates the key to ring a;

[0373] R 43 It is hydrogen, halogenated group, C 1-2 Alkyl, C2 alkenyl, NO2, CF3; or

[0374] R 42 and R 43 Together Each of them It is a single or double bond, and the dash indicates the bond with ring a.

[0375] In some implementations, B 1 yes:

[0376]

[0377] in:

[0378] R 30 It is hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 cycloalkyl, wherein each C, when valence permits, 1-12 Alkyl, C 1-12 Haloalkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 The cycloalkyl group is optionally and independently surrounded by one to five R... 100 replace;

[0379] R 40 It is hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 cycloalkyl, wherein each C, when valence permits, 1-12 Alkyl, C 1-12 Haloalkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 The cycloalkyl group is optionally and independently surrounded by one to five R... 100 replace;

[0380] Each R 50 Independently, it is a halogenated group, cyano group, nitro group, or -OR group. 170 -SR 170 -NR 170 R 180 C 1-12 Alkyl, C 1-12 Haloalkyl, C 2-12 alkenyl or C 2-12 Alkynyl group; wherein, when valence permits, each C 1-12 Alkyl, C 1-12 Haloalkyl, C 2-12 alkenyl or C 2-12 The alkynyl group is independently and optionally substituted by one to five halogroups, hydroxyl groups or amino groups;

[0381] R 60 It is hydrogen, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 cycloalkyl, wherein each C, when valence permits,1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 The cycloalkyl group is optionally and independently surrounded by one to five R... 100 replace;

[0382] Each R 100 Independently, it can be an oxo group, a halogen group, a cyano group, a nitro group, or an -OR group. 170 -SR 170 -SF5, -NR 170 R 180 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R 170 -C(=O)OR 170 -OC(=O)OR 170 -OC(=O)R 170 -C(=O)NR 170 R 180 -OC(=O)NR 170 R 180 -NR 170 C(=O)NR 170 R 180 -S (=O) 1-2 R 170 -S (=O) 1-2 NR 170 R 180 -NR 170 S(=O) 1-2 R 180 -NR 170 S(=O) 1-2 NR 170 R 180 -NR 170 C(=O)R 180 -NR 170 C(=O)OR 180 Or -C = NOR 17 When the valence is allowed, R 100 Each C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-10 C10 groups in which cycloalkyl, heterocyclic, aryl, and heteroaryl groups are independently and optionally substituted with one or more halogroups or optionally with oxo, halogroups, hydroxyl, or amino groups. 1-12 Alkyl substitution;

[0383] Each R170 and R 18 Independently hydrogen or, when valence permits, optionally substituted with an oxo group, a halogen group, a hydroxyl group, or an amino group. 1-12 Alkyl; or R 170 and R 180 With R 170 and R 180 The attached atoms together form C atoms that are optionally substituted with a halogen group or optionally with an oxo group, halogen group, hydroxyl group, or amino group. 1-12 Alkyl-substituted heterocyclic groups.

[0384] A” and A”' are each independently O or S;

[0385] R a and R b Each is independently CH3 or CH2CH3; or R a and R b With R a and R b The attached atoms together form C 3-5 cycloalkyl, ethylene oxide, oxetane, or tetrahydrofuran;

[0386] B、B 10 B 2 B 3 B' B 1’ B 2’ and B 3’ Each is CR independently c Or N;

[0387] Each R c It can be hydrogen, fluorine, CN, or methyl independently;

[0388] D is NH, O, S, CH2 or C=O;

[0389] "X" represents CN, a halogenated group, or NO2;

[0390] "Y" represents CH3, CH2R d CHF2 or CF3;

[0391] R d It is a halogenated group;

[0392] Z”' is H, C 1-2 Alkyl, C2 alkenyl, or NO2; or

[0393] X and Y together form

[0394] Or Y” and Z”' together form and

[0395] Z' is CH or N.

[0396] In some implementations, B 1 yes:

[0397]

[0398] The tilde key refers to the key with L. 1 The connection point.

[0399] In some implementations, B 1 yes:

[0400]

[0401] Or its stereoisomers or mixtures of stereoisomers or the like, wherein the wavy line indicates the attachment point with the nuclear payload (optionally via the connecting portion).

[0402] In some implementations, B 1 Derived from progesterone, embosamol, bicalutamide, apalutamide, testosterone, dihydrotestosterone, testosterone, 19-nortestosterone, progesterone, adaline, cortisol, prednisone, flutamide, nilumet, enzalutamide, tamoxifen, toremifene, raloxifene, bardoxifen, octopimiphene, megestrol acetate, estradiol, abiraterone, LGD-2941, BMS-564929, ostalin, urolipristal acetate, asoprilini (J867), mifepristone, telapristone (CDB-4124, Proellex, Progenta) or analogues thereof.

[0403] In some implementations, B 1 Derived from progesterone, embosamole, bicalutamide, apalutamide, testosterone, dihydrotestosterone, flutamide, nilumet, enzalutamide, tamoxifen, toremifene, raloxifene, bardoxifene, octopimiphene, megestrol acetate, abiraterone, LGD-2941, BMS-564929, ostalin or analogues thereof.

[0404] In some implementations, B 1 Including nuclear receptor-targeting epitopes derived from the following:

[0405]

[0406]

[0407]

[0408]

[0409] Or its stereoisomers or mixtures of stereoisomers or the like thereof, wherein at least one hydrogen atom is reacted with A 1 The direct covalent bond (optionally via the linker portion) is replaced.

[0410] These and others that can be described in this article are B 1 Selective androgen receptor modulators (SARMs) that target nuclear steroid receptor epitopes can be found in the following: US 6,462,038, US 6,777,427, WO 2001 / 027086, WO2004 / 013104, WO 2004 / 000816, WO 2004 / 0113309, US2006 / 0211756, US2006 / 0063819, US2005 / 245485, US2005 / 250741, US2005 / 277681, WO 2006 / 060108, WO 2004 / 041277, WO2003 / 034987, US2006 / 0148893, US2006 / 0142387, WO 2005 / 000795、WO 2005 / 085185、WO2006 / 133216、WO 2006 / 044707、WO 2006 / 124447、WO 2007 / 002181、WO 2005 / 108351, WO2005 / 115361 and US2006 / 0160845.

[0411] In some implementations, B 1 It is a selective estrogen receptor modulator (SERM). In some implementations, B... 1This includes epitopes derived from the following: diacetylene decarboxylates, bardoxifene, bromhexene (Acnestrol), clomiphene (clomiphene), cyclofennig (Sexovid), lasoxifene (Fablyn), olmexifen (Centron, Novex, Novex-DS, Sevista), octopimiphene (Osphena, deaminohydroxytoremifene), raloxifene (Evita), tamoxifen (Novades), toremifene (Falleton; 4-clotamoxifen), aziroxifene, afifixifene (4-hydroxytamoxifen; a metabolite of tamoxifen), allastrantrine, enclomiphene ((E)-clomiphene), indoxifene (4-hydroxy-N-demethyltamoxifen; a metabolite of tamoxifen). ), clomiphene ((Z)-clomiphene), bardoxifene, azoxiphene, burixiphene, oflomiphene (clomiphene N-oxide; a metabolite of clomiphene), droloxiphene (3-hydroxytamoxiphene), etacstil, fepemiphene, GW-7604 (4-hydroxyetestil), edoxifene (pyrrolidine-4-iodotamoxiphene), levomexiphene ((L)-olmexiphene), mipoxiphene, naproxen, nimiphene (CI-628), panomiphene, piperacixifene (ERA-923), trivoxiphene, raloxifene, LY117018, onassidone, taremexin (toremexin citrate) or cindoxiphene (D-16726) or their analogues.

[0412] In some implementations, SERMs are structurally classified as triphenylene (tamoxifen, clomiphene, toremifene, droloxifene, edoxifene, opemifene, nonpemiphene, afifoxifene, etc. or their analogues), benzothiophene (raloxifene, azoxifene, etc. or their analogues), indole (badoxifene, cindoxifen, piperonoxifene, etc. or their analogues), tetrahydronaphthalene (lasoxifene, naproxen, etc. or their analogues), or benzopyran (acobifene, omexifen, levomeloxifen, etc. or their analogues).

[0413] In some implementations, B 1 It is a selective estrogen receptor downregulator (SERD). In some embodiments, the compound contains at least one nuclear steroid receptor targeting epitope, which independently includes epitopes derived from: fulvestrant, bulistrant (ARN-810), atestradiol (GW5638), AZD9496, giredestrant (GDC-9545), or GW7604.

[0414] In some implementations, B 1It is a selective progesterone receptor modulator (SPRM). In some embodiments, B includes epitopes derived from: ulipristal acetate, asoprene (J867), mifepristone, terazosone (CDB-4124, Proellex, Progenta), or analogues thereof.

[0415] In some implementations, B 1 Including epitopes derived from the following: estrogen, estradiol, estriol, estrone, progesterone, enbosamole, bicalutamide, apalutamide, testosterone, dihydrotestosterone, estradiol, flutamide, nilumet, enzalutamide, tamoxifen, toremifene, raloxifene, bardoxifene, octopimiphene, megestrol acetate, estradiol, abiraterone, LGD-2941, BMS-564929, ostalin or analogues thereof.

[0416] In some embodiments, at least one nuclear steroid receptor-targeting epitope is an androgen receptor-targeting epitope, and includes:

[0417]

[0418] Or its stereoisomers or mixtures of stereoisomers or the like, wherein the wavy line indicates the attachment point with the nuclear payload (optionally via the connecting portion).

[0419] In some embodiments, at least one nuclear steroid receptor-targeting epitope is an estrogen receptor-targeting epitope, and includes:

[0420]

[0421] Or its stereoisomers or mixtures of stereoisomers or the like, wherein the wavy line indicates the attachment point with the nuclear payload (optionally via the connecting portion).

[0422] In some embodiments, at least one nuclear steroid receptor-targeting epitope is an estrogen receptor-targeting epitope, and includes:

[0423]

[0424]

[0425] Or its stereoisomers or mixtures of stereoisomers or the like, wherein the wavy line indicates the attachment point with the nuclear payload (optionally via the connecting portion).

[0426] In some embodiments, at least one nuclear steroid receptor targeting epitope includes:

[0427]

[0428]

[0429]

[0430] Or its stereoisomers or mixtures of stereoisomers or the like, wherein the wavy line indicates the attachment point with the nuclear payload (optionally via the connecting portion).

[0431] In some embodiments, at least one nuclear steroid receptor targeting epitope includes:

[0432]

[0433]

[0434] Or its stereoisomers or mixtures of stereoisomers or the like, wherein the wavy line indicates the attachment point with the nuclear payload (optionally via the connecting portion).

[0435] In some implementations, the nucleosteroid receptor targeting epitope is not or does not contain peptides, proteins, nanoparticles, or antibodies.

[0436] Connection part

[0437] The “linking moiety” of any compound described herein may be biocleavable (e.g., acid-labile) or biocleavable. The linking moiety may be linear, branched, saturated, unsaturated, all-carbon, or heteroatom-containing. The linking moiety may also contain one or more fused, saturated, unsaturated, and all-carbon or heteroatom-containing rings. In some embodiments, the linking moiety is a biocleavable linking moiety. In some embodiments, the linking moiety is a biocleavable linking moiety. In some embodiments, the nuclear payload is bonded to a nuclear steroid receptor targeting epitope via a biocleavable linking moiety and to one or more nuclear steroid receptor targeting epitopes via a biocleavable linking moiety. In some embodiments, the biocleavable linking moiety is an acid-labile linking moiety. In some embodiments, the linking moiety includes a hydrazone linker.

[0438] Imagine any linker that can be used in the compounds described herein, provided that it does not significantly interfere with or disrupt the desired binding of the nuclear payload or nuclear receptor targeting epitope.

[0439] In some embodiments, the linking portion is alkylene, heteroalkylene, alkenylene, heteroalkenylene, alynylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene; wherein each alkylene, heteroalkylene, alkenylene, heteroarylene, alynylene, or heteroarylene may optionally comprise an arylene, heteroarylene, cycloalkylene, or heterocycloalkylene; and further wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alynylene, heteroarylene, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is independently and optionally selected from one to five groups independently chosen from an oxo group, a halogen group, a C-group ... 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Substitution of alkyl halogens.

[0440] In some implementations, the connection portion L 1 It has the following formula:

[0441] -(L a ) q -,

[0442] in:

[0443] Each L a Yes -NR 110 -、-O-、-S(O) 0-2 -、-NR 110 C(O)-、-C(O)NR 110 -、-NR 110 C(O)NR 110 -、-NR 110 S(O)2-、-S(O)2NR 110 -、-NR 110 S(O)2NR 110 -、-CR 120 =N-NR 110 -、-NR 110 -N=CR 120 -, -C(O)-, -OC(O)-, -OC(O)O-, -C(O)O-, alkylene, alkenylene, ynylene, arylene, cycloalkylene, heterocyclic or heteroarylene, wherein each alkylene, alkenylene, ynylene, arylene, cycloalkylene, heterocyclic or heteroarylene is independently and optionally selected from one to five independently selected from oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Substitution of haloalkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic groups;

[0444] Each R 110 Independently, it is hydrogen and C 1-4Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, aryl, heteroaryl, cycloalkyl or heterocyclic groups;

[0445] Each R 120 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic groups; and

[0446] q is an integer from 0 to 20.

[0447] In some implementations, the connection portion L 1 It has the following formula:

[0448] -Y 10 -(CHR 130 ) n’ -Y 20 -(CHR 140 ) n” -Y 30 -(CHR 150 ) m” -Y 40 -

[0449] in:

[0450] Y 10 Y 20 Y 30 and Y 40 Each of them is an independent bond, -NR 110 -、-O-、-S(O) 0-2 -、-NR 110 C(O)-、-C(O)NR 110 -、-NR 110 C(O)NR 110 -、-NR 110 S(O)2-、-S(O)2NR 110 -、-NR 110 S(O)2NR 110 -、-CR 120 =N-NR 110 -、-NR 110 -N=CR 120 -, -C(O)-, -OC(O)-, -OC(O)O-, -(CH2CH2O) 1-5-, -C(O)O-, alkylene, alkenylene, ynylene, arylene, cycloalkylene, heterocyclic, and heteroarylene; wherein each alkylene, alkenylene, ynylene, arylene, cycloalkylene, heterocyclic, or heteroarylene is independently and optionally selected from one to five independently selected from oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Substituents of haloalkoxy groups;

[0451] Each R 110 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, aryl, heteroaryl, cycloalkyl or heterocyclic groups;

[0452] Each R 120 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, aryl, heteroaryl, cycloalkyl or heterocyclic groups;

[0453] Each R 130 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, aryl, heteroaryl, cycloalkyl or heterocyclic groups;

[0454] Each R 140 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, aryl, heteroaryl, cycloalkyl or heterocyclic groups;

[0455] Each R 150 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic groups; and

[0456] n', n” and m” are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0457] In some implementations, the connection portion L 1 It has the following formula:

[0458] -Y 10 -(CH2) n' -Y 20 -(CH2) p' -Y 30 -

[0459] Where Y 10 Y 20 and Y 30 Each of these is independently a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, -CR 110 R 120 -、-NR 110 -、-O-、-S(O) 0-2 -、-NR 110 C(O)-、-C(O)NR 110 -、-NR 110 S(O)2-、-S(O)2NR 110 -、-CR 120 =N-NR 110 -、-NR 110 -N=CR 120 -、-OC(O)- or -C(O)-;

[0460] Each R 110 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Halogenated alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic;

[0461] Each R 120 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Halogenated alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic groups; and

[0462] n' and p' are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0463] In some implementations, Y 10 Y 20 and Y 30 Each alkylene, alkenylene, ynylene, arylene, or heteroarylene is independently and optionally composed of one to five independently selected from oxo, halogen, C, ... 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Substituents of haloalkoxy groups.

[0464] In some implementations, the connecting portion has the following formula:

[0465] -Y 10 -(CH2) n’ -Y 20 -(CH2) m” -Y 30 -

[0466] in:

[0467] Y 10 Y 20 and Y 30 Each of them is independently -NR 110 -、-O-、-S(O) 0-2 -、-NR 110 C(O)-、-C(O)NR 110 -、-NR 110 S(O)2-、-S(O)2NR 110 -、-CR 120 =N-NR 110 -、-NR 110 -N=CR 120 -, -C(O)-, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene; wherein each alkylene, heteroalkylene, alkenyl, heteroalkenyl, alynyl, heteroalynyl, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is independently and optionally selected from one to five independently selected from oxo, halogen, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkyl groups;

[0468] Each R 110 C is independent 1-4 Alkyl, C 1-4 Halogenated alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic;

[0469] Each R 120 C is independent 1-4 Alkyl, C 1-4 Halogenated alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic groups; and

[0470] n' and m" are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0471] In some implementations, the connection portion is not a key. In some implementations, each R 110 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Halogenated alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; and each R 120 Independently, it is hydrogen and C 1-4 Alkyl, C1-4 Halogenated alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic.

[0472] In some implementations, the connecting portion has the following formula:

[0473] -Y 10 -(CH2) n' -Y 20 -(CH2) m” -Y 30 -

[0474] in:

[0475] Y 10 Y 20 and Y 30 Each of them is independently -NR 110 -、-O-、-S(O) 0-2 -、-NR 110 C(O)-、-C(O)NR 110 -、-NR 110 S(O)2-、-S(O)2NR 110 -、-CR 120 =N-NR 110 -、-NR 110 -N=CR 120 -, -C(O)-, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene; wherein each alkylene, heteroalkylene, alkenyl, heteroalkenyl, alynyl, heteroalynyl, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene is independently and optionally selected from one to five independently selected from oxo, halogen, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkyl groups;

[0476] Each R 110 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Halogenated alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic;

[0477] Each R 120 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Halogenated alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic groups; and

[0478] n' and m" are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0479] In some implementations, the connecting portion has the following formula:

[0480] -Y 10-(CH2) n' -Y 20 -(CH2) p' -Y 30 -

[0481] Where Y 10 Y 20 and Y 30 Each of these is independently a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, -CR 110 R 120 -、-NR 110 -、-O-、-S(O) 0-2 -、-NR 110 C(O)-、-C(O)NR 110 -、-NR 110 S(O)2-、-S(O)2NR 110 -、-CR 120 =N-NR 110 -、-NR 110 -N=CR 120 -or -C(O)-;

[0482] Each R 110 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Halogenated alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic;

[0483] Each R 120 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Halogenated alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic groups; and

[0484] n' and p' are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0485] In some implementations, L 1 This includes parts of organisms that cannot be cut.

[0486] In some implementations, L 1 Including optional substitution of C 4-7 Alkylene atoms of 1 atom, optionally substituted C 4-7 A heterocyclic group of one atom or an optionally substituted C 4-7 A heteroalkylene group of 1 atom.

[0487] In some implementations, L 1 Including optionally substituted heterocyclic groups and / or optionally substituted heteroalkyl groups.

[0488] In some implementations, L 1 C is an optional substitute 4-10 Atomized heteroalkylene.

[0489] In some implementations, L 1 It is a key.

[0490] In some implementations, L 1 It is a 4-12 atom alkylene or heteroalkylene linking moiety, containing CH2 and at most two heteroatoms, each independently selected from NH, O, or S, and optionally one C=O. In some embodiments, L 1 It is a 4-11 atom alkylene or heteroalkylene linking moiety, containing CH2 and at most two heteroatoms each independently selected from NH, O, or S, and optionally one C=O. In some embodiments, L 1 It is a 4-10 atom alkylene or heteroalkylene linking moiety, containing CH2 and at most two heteroatoms, each independently selected from NH, O, or S, and optionally one C=O. In some embodiments, L 1 It is a 4-9 atom alkylene or heteroalkylene linking moiety, containing CH2 and at most two heteroatoms, each independently selected from NH, O, or S, and optionally one C=O. In some embodiments, L 1 It is a 4-8 atom alkylene or heteroalkylene linking moiety, containing CH2 and at most two heteroatoms, each independently selected from NH, O, or S, and optionally one C=O. In some embodiments, L 1 It is a 4-7 atom alkylene or heteroalkylene linking moiety, containing CH2 and at most two heteroatoms, each independently selected from NH, O, or S, and optionally one C=O. In some embodiments, L 1 It is a 4-6 atom alkylene or heteroalkylene linkage containing CH2 and up to two heteroatoms each independently selected from NH, O or S, and optionally one C=O.

[0491] In some implementations, the connecting portion has the following formula:

[0492]

[0493] in

[0494] The ring C is a 3-10-membered cycloalkylene group or a 3-10-membered heterocyclic group; wherein each 3-10-membered cycloalkylene group or 3-10-membered heterocyclic group is independently and optionally composed of one to five independently selected oxo groups, halogen groups, C- groups, etc. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Substituents of haloalkoxy groups;

[0495] Y 50 and Y 60 Each of them is an independent bond, -NR 110 -、-O-、-S(O) 0-2 -、-NR 110 C(O)-、-C(O)NR 110 -、-NR 110 C(O)NR 110 -、-NR 110 S(O)2-、-S(O)2NR 110 -、-NR 110 S(O)2NR 110 -、-CR 120 =N-NR 110 -、-NR 110 -N=CR 120 -, -C(O)-, -OC(O)-, -OC(O)O-, -(CH2CH2O) 1-5 -, -C(O)O-, alkylene, alkenylene, ynylene, arylene, cycloalkylene, heterocyclic, and heteroarylene; wherein each alkylene, alkenylene, ynylene, arylene, cycloalkylene, heterocyclic, or heteroarylene is independently and optionally selected from one to five independently selected from oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Substituents of haloalkoxy groups;

[0496] Each R 110 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Halogenated alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic;

[0497] Each R 120 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Halogenated alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic groups; and

[0498] The asterisk (*) and wavy lines represent covalent bonds.

[0499] In some implementations, Y 50 and Y 60 Each alkylene, alkenylene, ynylene, arylene, cycloalkylene, heterocycloalkylene, or heteroarylene is independently and optionally composed of one to five independently selected from halogenated groups, C... 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4Substituents of haloalkoxy groups.

[0500] In some implementations, the connecting portion has the following formula:

[0501]

[0502] in

[0503] The ring C is a 3-10-membered cycloalkylene group or a 3-10-membered heterocyclic group; wherein each 3-10-membered cycloalkylene group or 3-10-membered heterocyclic group is independently and optionally composed of one to five independently selected oxo groups, halogen groups, C- groups, etc. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Substituents of haloalkoxy groups;

[0504] Y 50 and Y 60 Each of them is an independent bond, -NR 110 -、-O-、-S(O) 0-2 -、-NR 110 C(O)-、-C(O)NR 110 -、-NR 110 C(O)NR 110 -、-NR 110 S(O)2-、-S(O)2NR 110 -、-NR 110 S(O)2NR 110 -、-CR 120 =N-NR 110 -、-NR 110 -N=CR 120 -, -C(O)-, -OC(O)-, -OC(O)O-, -(CH2CH2O) 1-5 -, -C(O)O-, alkylene, alkenylene, ynylene, arylene, cycloalkylene, heterocyclic, and heteroarylene; wherein each alkylene, alkenylene, ynylene, arylene, cycloalkylene, heterocyclic, or heteroarylene is independently and optionally selected from one to five independently selected from oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Substituents of haloalkoxy groups;

[0505] Each R 110 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Halogenated alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic;

[0506] Each R120 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Halogenated alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic groups; and

[0507] The asterisk (*) and wavy lines represent covalent bonds.

[0508] In some implementations, Y 50 and Y 60 Each of them is an independent bond, -NR 110 -、-O-、-S(O) 0-2 -、-NR 110 C(O)-、-C(O)NR 110 -、-NR 110 C(O)NR 110 -、-NR 110 S(O)2-、-S(O)2NR 110 -、-NR 110 S(O)2NR 110 -、-CR 120 =N-NR 110 -、-NR 110 -N=CR 120 -, -C(O)-, -OC(O)-, -OC(O)O-, -(CH2CH2O) 1-5 -、-C(O)O-.

[0509] In some implementations, the connecting portion has the following formula:

[0510]

[0511] in:

[0512] L 2 Attached to ring b and L 3 Attached to A;

[0513] L 2 and L 3 Each is independently selected from the bond, CH2, CH2CH2, or C=O;

[0514] s is 1, 2, or 3; and

[0515] s' is 0 or 1.

[0516] In some implementations, the connecting portion has the following formula:

[0517]

[0518]

[0519]

[0520]

[0521] The asterisk (*) and wavy or dashed lines represent covalent bonds.

[0522] In some implementations, the connecting portion has the following formula:

[0523]

[0524]

[0525]

[0526] The asterisk (*) and wavy lines represent covalent bonds.

[0527] In some implementations, the connecting portion has the following formula:

[0528]

[0529]

[0530] The asterisk (*) and dashed or wavy lines represent covalent bonds.

[0531] In some embodiments, a compound as shown in Table 1, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, is provided.

[0532] Table 1

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540] Treatment

[0541] This invention provides compounds that can be used to treat, prevent, and / or delay the onset and / or development of cancer. Therefore, in some embodiments, a method for treating cancer is provided, the method comprising administering a therapeutically effective amount of the compound or composition described herein to a subject in need of treatment. Some embodiments provide a method for enhancing cytotoxic cancer therapy in a subject recognized as needing such treatment, the method comprising administering a therapeutically acceptable amount of the compound or composition described herein to the subject.

[0542] It is envisioned that patients suffering from any type of cancer could benefit from treatment using the compounds and compositions described herein. Therefore, in some embodiments, the cancers are 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, nephroblastoma, cervical cancer, testicular cancer, soft tissue sarcoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, small cell lung cancer. Cancer, stomach cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid, malignant melanoma, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid 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 thrombocytosis, adrenocortical carcinoma, skin cancer, trophoblastic tumor, or prostate cancer. In some embodiments, the cancer is bladder cancer, blood cancer (e.g., leukemia (e.g., chronic leukemia, chronic lymphocytic leukemia (CLL, etc.)) 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.

[0543] In some implementations, the cancer is chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, non-Hodgkin lymphoma, Waldenström macroglobulinemia, polycythemia vera, trophoblastic tumor, and ovarian cancer.

[0544] In some embodiments, the compounds and compositions described herein are tailored to target cancers that overexpress specific receptors (such as, but not limited to, androgen receptors, estrogen receptors, progesterone receptors, and / or glucocorticoid receptors) by comprising an epitope that targets that specific nuclear receptor. The epitope may be derived from steroid hormones or any non-steroidal drug that targets that particular receptor.

[0545] In some embodiments, a method for treating or preventing cancers that overexpress androgen receptors is provided, the method comprising administering to an individual in need an effective amount of a compound comprising at least one nuclear payload and at least one androgen receptor-targeting epitope, or a pharmaceutically acceptable salt or solvate thereof. Specific 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, the method 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.

[0546] In some embodiments, a method for treating or preventing cancers that overexpress androgen receptors is provided, the method comprising administering to an individual in need an effective amount of a compound comprising at least one nuclear payload and at least one androgen receptor-targeting epitope, or a pharmaceutically acceptable salt or solvate thereof. 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-targeting epitope 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-targeting epitope comprises embosamol, bicalutamide, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, estrustin, ketoconazole, abiraterone, dalolutamide, or analogues thereof. In some embodiments, the androgen receptor targeting epitopes include embosamole, bicalutamide, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, estrustin, ketoconazole, abiraterone, or analogues thereof. In some embodiments, the nuclear payload includes a topoisomerase inhibitor.

[0547] In some embodiments, a method for treating or preventing cancers that overexpress estrogen and / or progesterone receptors is provided, the method comprising administering to an individual in need an effective amount of a compound comprising at least one nuclear payload and at least one estrogen and / or progesterone receptor targeting epitope, or a pharmaceutically acceptable salt or solvate thereof. Specific cancers contemplated for treatment by such a method include, but are not limited to, breast cancer, uterine cancer, or ovarian cancer.

[0548] In some embodiments, a method for treating or preventing cancers that overexpress glucocorticoid receptors is provided, the method comprising administering to an individual in need an effective amount of a compound comprising at least one nuclear payload and at least one glucocorticoid receptor-targeting epitope, or a pharmaceutically acceptable salt or solvate thereof. Specific cancers contemplated for treatment by such a method include, but are not limited to, breast cancer, uterine cancer, or ovarian cancer. Specific cancers contemplated for treatment by such a method include, but are not limited to, prostate cancer, possibly breast cancer, uterine cancer, and ovarian cancer.

[0549] Breast cancer includes ductal carcinoma in situ (DCIS) and invasive breast cancer. Breast cancer can occur in the mammary ducts, lactiferous 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).

[0550] Prostate cancer is cancer that develops in the prostate gland (a gland in the male reproductive system). It occurs when the cells of the prostate gland mutate and begin to multiply uncontrollably. These cells can metastasize from the prostate to almost any other part of the body (metastatic prostate cancer), especially bones and lymph nodes, but also to the kidneys, bladder, and even the brain and other tissues. Prostate cancer can cause painful urination, difficulty urinating, problems during intercourse, and erectile dysfunction. Other symptoms may appear in the later stages of the disease. Detection rates of prostate cancer vary widely worldwide, with lower rates in South and East Asia than in Europe, and especially lower than in the United States. Prostate cancer most commonly occurs in men over 50 and is one of the most common types of cancer in men. However, many men who develop prostate cancer never experience symptoms, never receive treatment, and eventually die from other causes. This is because, in most cases, prostate cancer grows slowly, and because most of those affected are over 60. Therefore, they often die from causes unrelated to prostate cancer. The development of prostate cancer is related to many factors, including genetics and diet. The presence of prostate cancer can be indicated by symptoms, physical examination, prostate-specific antigen (PSA), or biopsy. People are concerned about the accuracy of the PSA test and its usefulness in screening. Suspected prostate cancer is usually confirmed by a prostate biopsy and microscopic examination. Further tests (such as CT scans and bone scans) can be performed to determine if the prostate cancer has spread. Combinations with surgery and radiation therapy or other treatments (such as hormone therapy, chemotherapy, proton therapy, cryosurgery, high-intensity focused ultrasound (HIFU)) are also considered.

[0551] Certain embodiments provide a method for inhibiting one or more topoisomerases in a subject recognized as needing such treatment, the method comprising administering to the subject a therapeutically acceptable amount of the compound or composition described herein. In one embodiment, this document provides a method for treating a disease improved by inhibiting one or more topoisomerases, the method comprising administering to a subject requiring treatment a therapeutically effective amount of the compound or composition described herein.

[0552] Some implementations provide a method of treating leukemia, colon cancer, glioblastoma, lymphoma, melanoma, breast cancer, or cervical cancer in a subject who is recognized as needing such treatment, the method comprising administering to the subject a therapeutically acceptable amount of the compound or composition described herein.

[0553] In some embodiments, this document provides a method for treating cancers lacking homologous recombination (HR)-dependent DNA double-strand break (DSB) repair pathways, the method comprising administering a therapeutically effective amount of the compound or composition described herein to a subject requiring treatment. In some embodiments, the cancer comprises one or more cancer cells that, relative to normal cells, have a reduced or eliminated ability to repair DNA DSB via HR. In some embodiments, the cancer cells have a BRCA1 or BRCA2 deficient phenotype. In some embodiments, the cancer cells lack BRCA1 or BRCA2. In some embodiments, the methods provided herein relate to the treatment of an individual who is heterozygous for mutations in genes encoding components of HR-dependent DNA DSB repair pathways. In some embodiments, the individual is heterozygous for mutations in BRCA1 and / or BRCA2. In some embodiments, the methods of treating cancer include treatment of breast cancer, ovarian cancer, pancreatic cancer, and / or prostate cancer. In some embodiments, the methods of treating cancer further include the administration of ionizing radiation or a chemotherapy agent.

[0554] 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 gain or loss of short repeat units within microsatellite sequences (also known as microsatellite instability (MSI)). At least six different MMR proteins are required. For mismatch recognition, depending on the type of lesion to be repaired (MSH6 is required for the correction of single-base mismatches, while both MSH3 and MSH6 can contribute to the correction of insertion-deletion loops), the MSH2 protein forms a heterodimer with either MSH6 or MSH3. 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 one or more helicases, 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 other proteins, MLH3 and PMS1. Recent observations suggest that PMS2 is required for correcting single-base mismatches, and both PMS2 and MLH3 contribute to the correction of insertion-deletion loops. Other homologs of human MMR proteins are known to be required for functions other than MMR. These proteins include MSH4 and MSH5, which are essential for meiotic (and possibly mitotic) recombination, but are not presumed to be involved in MMR.

[0555] Germline mutations in the human MMR gene result in susceptibility to hereditary nonpolyposis colorectal cancer (HNPCC), one of the most common cancer syndromes in humans. The syndrome is clinically defined as a large number of colorectal cancers and a defined range of extraintestinal cancers diagnosed early and transmitted as an autosomal dominant trait. MSI is a hallmark of HNPCC, which also occurs in approximately 15% to 25% of sporadic tumors of the colorectal and other organs. According to international standards, high MSI (MSI-H) is defined as instability at two or more of the five loci or at ≥30% to 40% of all microsatellite loci studied, while instability at fewer loci is termed low MSI (MSI-L). In non-HNPCC cancers (e.g., breast, prostate, and lung cancer), MSI occurs at a high rate (2% to 50% of tumors). Similar to HNPCC cancers, categories MSS, MSI-L, and MSI-H can be distinguished in these cancers based on the proportion of instability markers. In one implementation, a method for treating cancers lacking mismatch DNA repair pathways is provided. In another embodiment, it is a method for treating cancers exhibiting microsatellite instability due to reduced or impaired DNA repair pathways. In yet another embodiment, it is a method for treating cancers exhibiting genomic instability due to reduced or impaired DNA repair pathways.

[0556] In some embodiments, the compounds or compositions described herein can be used to prepare agents for cancers lacking homologous recombination (HR)-dependent DNA double-strand break (DSB) repair activity, or to treat patients with cancer lacking HR-dependent DNA DSB repair activity, said treatment comprising administering a therapeutically effective amount of said compound or composition to said patient.

[0557] The HR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via homology mechanisms to reform continuous DNA helices. 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), and XRCC3 (NM_007068). _005432), RAD52(NM_002879), RAD54L(NM_003579), RAD54B(NM_012415), BRCA1(NM_007295), BRCA2(NM_000059), RAD50(NM_005732), 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).

[0558] In some implementations, cancers lacking HR-dependent DNA DSB repair include one or more cancer cells that, relative to normal cells, have a reduced or eliminated ability to repair DNA DSB through this pathway, i.e., the activity of the HR-dependent DNA DSB repair pathway is reduced or eliminated in the one or more cancer cells.

[0559] In some implementations, 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.

[0560] In some embodiments, the cancer cells have a BRCA1 and / or BRCA2 deficient phenotype, i.e., BRCA1 and / or BRCA2 activity is reduced or eliminated in the cancer cells. In some embodiments, cancer cells with this phenotype lack BRCA1 and / or BRCA2, i.e., BRCA1 and / or BRCA2 expression and / or activity is reduced or eliminated in the cancer cells, for example through mutations or polymorphisms in the encoding nucleic acids, or through amplification, mutation, or polymorphism of genes encoding regulatory factors (e.g., the EMSY gene encoding a BRCA2 regulatory factor), or through epigenetic mechanisms (such as gene promoter methylation).

[0561] BRCA1 and BRCA2 are tumor suppressor factors, and their wild-type alleles are frequently lost in tumors of heterozygous 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)).

[0562] Vectors with mutations in BRCA1 and / or BRCA2 also have an increased risk of developing ovarian, prostate, and pancreatic cancer.

[0563] In some implementations, an individual is heterozygous for one or more variants (such as mutations and polymorphisms) in BRCA1 and / or BRCA2 or their regulators. The detection of variants in BRCA1 and BRCA2 is described in the following literature: e.g., 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.

[0564] In some cases, cancer-related mutations and polymorphisms are detected as follows: 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., mutant or allelic variant) peptides.

[0565] In some embodiments, the compounds described herein are envisioned for use in patients whose cancer has relapsed or become refractory. The term "relapse" refers to the recurrence or regrowth of a disease (or cancer) after a period of remission. The term "refractory" is used to describe a situation where cancer does not respond to treatment or the response to treatment does not last long. For example, the compounds described herein could be used to treat cancer in patients who have previously been treated with the cancer therapies described herein (e.g., enzalutamide).

[0566] Some embodiments provide a method of treating a viral infection in a subject who is recognized as needing such treatment, the method comprising administering to the subject a therapeutically acceptable amount of the compounds or compositions described herein. In some embodiments, the compounds and compositions described herein can be used to treat RNA viruses such as 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.

[0567] 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.

[0568] 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 subjects requiring such treatment.

[0569] In some embodiments, the compounds and compositions described herein can be used to treat autoimmune disorders, such as lupus, in subjects who require such treatment.

[0570] In some embodiments, the compounds and compositions described herein can be used to treat neurological or developmental disorders in subjects who require such treatment, such as Rett syndrome or Angelman syndrome.

[0571] Composition

[0572] This disclosure covers compositions of any compounds detailed herein, including pharmaceutical compositions. Therefore, this document provides pharmaceutical compositions comprising compounds of this disclosure or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions provided herein may be in forms suitable for oral, buccal, parenteral (e.g., intravenous, intramuscular, infusion, or subcutaneous), nasal, topical, or rectal administration, or in forms suitable for inhalation administration.

[0573] In one aspect, the compounds described herein may be in purified form. Compositions comprising the compounds described herein or salts thereof are provided, such as compositions of substantially pure compounds. In some embodiments, the compositions comprising the compounds described herein or salts thereof are in 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 salt thereof (which constitutes the majority of the composition). In one variant, a composition of substantially pure compounds or salts thereof is provided, wherein the composition contains no more than 25% impurities. In another variant, a composition of substantially pure compounds or salts thereof is provided, wherein the composition contains no more than 20% impurities. In yet another variant, a composition of substantially pure compounds or salts thereof is provided, wherein the composition contains no more than 10% impurities. In other variants, a composition of substantially pure compounds or salts thereof is provided, wherein the composition contains no more than 5% impurities. In yet another variant, a composition of substantially pure compounds or salts thereof is provided, wherein the composition contains no more than 3% impurities. In another variation, a composition of a substantially pure compound or a salt thereof is provided, wherein the composition contains no more than 1% impurities. In yet another variation, a composition of a substantially pure compound or a salt thereof is provided, wherein the composition contains no more than 0.5% impurities.

[0574] In some embodiments, the pharmaceutical composition is formulated in any manner, including using one or more physiologically acceptable carriers containing excipients and / or adjuvants that facilitate the processing of the active compound into the pharmaceutical composition. In some embodiments, the appropriate formulation depends on the chosen route of administration. In various embodiments, any technology, carrier, and excipient may be used appropriately.

[0575] This document provides pharmaceutical compositions comprising the compounds described herein and one or more pharmaceutically acceptable diluents, one or more excipients, and / or one or more carriers. Furthermore, in some embodiments, the compounds described herein are administered as pharmaceutical compositions in which the compounds are mixed with other active ingredients, as in combination therapies.

[0576] As used herein, a pharmaceutical composition refers to a mixture of the compound 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, implementing the treatment methods or uses provided herein includes administering or using a pharmaceutical composition containing a therapeutically effective amount of the compound provided herein. In specific embodiments, the treatment methods provided herein include administering such pharmaceutical composition 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 age and relative health of the subject, the potency of the compound used, and other factors. In various embodiments, the compound described herein is used alone or in combination with one or more therapeutic agents as components of a mixture.

[0577] In some embodiments, the pharmaceutical compositions provided herein are formulated for intravenous injection. In some aspects, the intravenous injection formulations provided herein are formulated as aqueous solutions, and in some embodiments, as formulated in physiologically compatible buffer solutions (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 aspects, the transmucosal formulations contain an permeabilizing agent suitable for the barrier to be penetrated. In some embodiments, the pharmaceutical compositions provided herein are formulated for other parenteral injections, with suitable formulations including aqueous or non-aqueous solutions, and in one embodiment, formulated with physiologically compatible buffer solutions or excipients.

[0578] In some embodiments, the pharmaceutical compositions provided herein are formulated for oral administration. In some aspects, the oral formulations provided herein comprise the compounds described herein formulated together with a pharmaceutically acceptable carrier or excipient. Such carriers enable the formulation of the compounds described herein into tablets, powders, pills, sugar-coated pills, capsules, liquids, gels, syrups, elixirs, pastes, suspensions, etc., for oral ingestion by a patient to be treated.

[0579] In some embodiments, a pharmaceutical composition for oral use is obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the mixture into granules after adding suitable excipients (if desired) to obtain tablets or sugar-coated pellet cores. Suitable excipients particularly include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, astragalus gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, a disintegrant, such as cross-linked croscarmellose sodium carboxymethylcellulose, polyvinylpyrrolidone, agar, or alginate or its salts, such as sodium alginate, may be added.

[0580] In some embodiments, this document provides a pharmaceutical composition formulated as a sugar-coated pellet core with a suitable coating. In some embodiments, a concentrated sugar solution is used to form a suitable coating and optionally contains gum arabic, talc, polyvinylpyrrolidone, carboplatin gel, polyethylene glycol and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. In some embodiments, dyes and / or pigments are added to the tablet, sugar-coated pellet, and / or its coating to, for example, identify or characterize different combinations of active compound dosages.

[0581] In some embodiments, the pharmaceutical composition for oral use comprises push-in capsules made of gelatin, and soft-sealable capsules made of gelatin and plasticizers such as glycerin or sorbitol. In some embodiments, the push-in capsules contain the active ingredient mixed with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or magnesium stearate), and optionally a stabilizer. In some embodiments, in the soft capsules, 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 optionally added. In some embodiments, the formulation for oral administration is prepared at a dose suitable for such administration.

[0582] 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 tablets, lozenges, or gels formulated in a conventional manner. In some embodiments, parenteral injection includes bolus injection or continuous infusion. In some embodiments, the formulation for injection is provided in unit dosage form, such as in ampoules; or in multi-dose containers in which preservatives are added. In some embodiments, the pharmaceutical compositions described herein are in a form suitable for parenteral injection, as a sterile suspension, solution, or emulsion in an oily or aqueous medium, and optionally contain formulations such as suspending agents, stabilizers, and / or dispersants. Pharmaceutical formulations for parenteral administration comprise aqueous solutions of the active compound in a water-soluble form. In some embodiments, the suspension of the active compound is prepared as a suitable oily injectable suspension. Suitable lipophilic solvents or media include fatty oils (e.g., sesame oil) or synthetic fatty acid esters (e.g., ethyl oleate, 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 dextran. Optionally, the suspension also contains 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 for reconstitution with a suitable medium (e.g., sterile, pyrogen-free water) prior to use.

[0583] In some embodiments, the compounds described herein are applied topically. In specific embodiments, the compounds described herein are formulated into a variety of topically applicable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compounds optionally contain solubilizers, stabilizers, tonic agents, buffers, and / or preservatives.

[0584] In some embodiments, the pharmaceutical compositions provided herein are formulated for transdermal administration of the compounds described herein. In some embodiments, the administration of such compositions employs transdermal delivery devices and transdermal delivery patches. In some embodiments, the compositions are lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in a polymer or binder. Such patches include those constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents. In some embodiments, transdermal delivery of the compounds described herein is accomplished using iontophoresis patches, etc. In some embodiments, the absorption rate is slowed by using a rate-controlled membrane or by trapping the compound within a polymer matrix or gel. Conversely, an absorption enhancer is optionally used to increase absorption. The absorption enhancer and carrier comprise 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 comprising a backing member, a reservoir containing the compound and optionally a carrier, an optional rate-controlled barrier for delivering the compound to the host skin over a prolonged period at a controlled and predetermined rate, and means for securing the device to the skin.

[0585] 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, atomized spray, or powder. In some embodiments, the pharmaceutical compositions described herein are conveniently delivered from a pressurized package or nebulizer in the form of an aerosol spray, wherein a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas, is used. In some aspects of pressurized aerosols, the dosage unit is determined by a valve that provides a delivery metering amount. In some embodiments, capsules and cartridges, such as those for use in inhalers or blowpipes, are formulated (by way of example only) to contain a powder mixture of the compounds described herein with a suitable powder matrix (e.g., lactose or starch).

[0586] 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 optionally contains a conventional suppository base (such as cocoa butter or other glycerides) and a synthetic polymer (such as polyvinylpyrrolidone, PEG, etc.). 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, optionally in combination with cocoa butter.

[0587] In the various embodiments provided herein, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, said one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically acceptable formulation. In some embodiments, the appropriate formulation depends on the chosen route of administration. In various embodiments, any of the techniques, carriers, and excipients is suitably used. In some embodiments, the pharmaceutical composition containing the compound described herein is manufactured in a conventional manner, such as (by way of example only) through conventional mixing, dissolving, granulation, pelleting, silylation, emulsification, encapsulation, embedding, or compression methods.

[0588] In some embodiments, the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, diluent, or excipient, and the compound described herein as an active ingredient, in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. Furthermore, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity. In some cases, the compounds described herein are present as tautomers. All tautomers are included within the scope of the compounds presented herein. Additionally, this document includes solvated and unsolvated forms of the compounds described herein. Solvated compounds include those solvated with pharmaceutically acceptable solvents (such as water, ethanol, etc.). The solvated forms of the compounds presented herein are also considered to be disclosed herein. In some embodiments, the pharmaceutical compositions described herein comprise other pharmaceutical or pharmaceutical formulations, 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.

[0589] Methods for preparing compositions containing compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form solid, semi-solid, or liquid formulations. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, pouches, and suppositories. Liquid compositions include solutions in which the compounds are dissolved, emulsions containing the compounds, or solutions containing liposomes, micelles, 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, in a solid form suitable for dissolving or suspending in a liquid prior to use, or in the form of emulsions. These compositions optionally contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc.

[0590] 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 applied in solution or suspension form, a first portion of the agent is present in solution form, and a second portion of the agent is present in particulate form in a suspension within a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0591] Useful aqueous suspensions optionally contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers (such as cellulose polymers, e.g., hydroxypropyl methylcellulose) and water-insoluble polymers (such as cross-linked carboxyl-containing polymers). Useful compositions optionally contain mucosal adhesive polymers selected from, for example, carboxymethyl cellulose, carbomer (acrylic polymer), poly(methyl methacrylate), polyacrylamide, polycarbofil, acrylic / butyl acrylate copolymer, sodium alginate, and dextran.

[0592] Useful compositions may optionally include a solubilizer, which contributes to the solubility of the compounds described herein. The term "sorcerer" generally includes agents that cause the formation of micellar solutions or true solutions of pharmaceutical agents. Solubilizers include certain acceptable nonionic surfactants, such as polysorbate 80, and ophthalmologically acceptable ethylene glycol, polyethylene glycol (e.g., polyethylene glycol 400), and ethylene glycol ethers.

[0593] Useful compositions optionally 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 trihydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0594] Useful compositions optionally contain one or more salts in amounts required to achieve an acceptable weight-molar osmotic concentration of the composition. Such salts include those 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.

[0595] Some useful compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as phenylmercuric borate and thimerosal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, hexadecyltrimethylammonium bromide, and hexadecylpyridine chloride.

[0596] Some useful compositions optionally contain one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octylphenyl polyol 10 and octylphenyl polyol 40.

[0597] Some useful compositions optionally contain one or more antioxidants to enhance chemical stability when needed. Suitable antioxidants include (by way of example only) ascorbic acid and sodium metabisulfite.

[0598] In some embodiments, the aqueous suspension composition is packaged in a single-dose, non-resealable container. In alternative embodiments, multi-dose, resealable containers are used, in which case a preservative is typically included in the composition.

[0599] In various embodiments, any delivery system for hydrophobic pharmaceutical compounds is used. Liposomes and emulsions are examples of delivery media or carriers for hydrophobic drugs. In some embodiments, certain organic solvents, such as N-methylpyrrolidone, are used. In some embodiments, sustained-release systems are employed to deliver the compound, such as a semi-permeable matrix of a solid hydrophobic polymer containing a therapeutic agent. Various sustained-release materials are utilized in the embodiments described herein. In some embodiments, sustained-release capsules release the compound for several weeks to more than 100 days. In some embodiments, depending on the chemical properties and biological stability of the therapeutic agent, additional strategies for protein stabilization are employed.

[0600] In some embodiments, the formulations or compositions described herein benefit from and / or optionally contain antioxidants, metal chelators, thiol-containing 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.

[0601] Dosage and treatment regimen

[0602] In some embodiments, a composition containing one or more of the compounds described herein is administered for preventative and / or therapeutic treatment. In some therapeutic applications, the composition is administered to a patient already suffering from the disease or condition in an amount sufficient to cure or at least partially stop the symptoms of the disease or condition. In some embodiments, the effective amount for such use will depend on the severity and course of the disease or condition, prior therapy, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. In some cases, it is deemed appropriate for the caregiver to determine such an effective therapeutic amount through routine experiments (including, but not limited to, dose-escalation clinical trials).

[0603] In certain preventative applications, compositions containing the compounds described herein are administered to patients who are susceptible to or otherwise at risk of developing a particular disease, disorder, or condition. In some embodiments, the amount administered is defined as a “preventatively effective amount or dose.” In some embodiments of such use, the precise amount of compound administered depends on the patient’s health condition, weight, etc. In some embodiments, caregivers are deemed fit to determine this preventatively effective amount through routine testing (e.g., dose-escalation clinical trials). In some embodiments, when used on a patient, the effective amount for such use will depend on the severity and duration of the disease, disorder, or condition, prior therapy, the patient’s health status and response to the medication, and the judgment of the treating physician.

[0604] 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 administration of the compounds may optionally be prolonged, i.e., for an extended period of time (including throughout the patient’s life), in order to improve or otherwise control or limit the symptoms of the patient’s disease or condition.

[0605] In certain cases where the patient's condition has indeed improved or not significantly improved, the compound may optionally be administered continuously at the physician's discretion; alternatively, the dosage of the drug being administered may optionally be temporarily reduced or temporarily suspended for a certain period of time (i.e., a "withdrawal period"). In some implementations, the length of the withdrawal period varies between 2 days and 1 year, including (by example only) 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 reductions during the withdrawal period range from approximately 10% to approximately 100%, including (for example only) reductions of 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%.

[0606] In some implementations, a maintenance dose is administered as needed after the patient's condition improves. In some implementations, the dose (e.g., maintenance dose) or frequency of administration, or both, is reduced as symptoms change to maintain the level of improvement in the disease, disorder, or condition. However, in some implementations, the patient may optionally receive long-term intermittent treatment based on any recurrence of symptoms.

[0607] In some embodiments, the amount of the agent administered corresponding to the effective dose varies based on factors such as the specific compound, the disease or condition and its severity, and the characteristics (e.g., weight) of the subject or host requiring treatment. However, in some embodiments, the effective dose is determined based on specific circumstances surrounding the case, including, for example, the specific agent administered, the route of administration, the condition being treated, and the subject or host being treated. However, in some embodiments, the dose for adult treatment ranges from about 0.02 mg to about 5000 mg daily, and in specific embodiments, from about 1 mg to about 1500 mg daily. In various embodiments, the desired dose is conveniently administered as a single dose or in divided doses simultaneously (or over a short period of time) or at appropriate intervals (e.g., two, three, four, or more sub-dose times daily).

[0608] In some embodiments, the pharmaceutical compositions described herein are in unit dosage forms suitable for precise single-dose administration. 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 in the form of packages containing discrete amounts of the formulation. Non-limiting examples are packaged tablets or capsules and powders in vials or ampoules. In some embodiments, aqueous suspension compositions are packaged in single-dose, non-resealable containers. In alternative embodiments, multi-dose, resealable containers are used, in which case preservatives are typically included in the composition. By way of example only, in some embodiments, formulations for parenteral injection are provided in unit dosage forms, including but not limited to ampoules; or in multi-dose containers in which preservatives are added.

[0609] In some embodiments, the suitable daily dose of the compound described herein is from about 0.01 mg / kg body weight to about 10 mg / kg body weight. In some embodiments, the indicated daily dose in larger subjects (including, but not limited to, humans) is in the range of about 0.5 mg to about 1,000 mg, conveniently administered in divided doses, including but not limited to up to four times daily or in an extended-release form. In some embodiments, a suitable unit dosage form for oral administration contains about 1 mg to about 50 mg of the active ingredient. The foregoing ranges are merely suggestive, as the number of variables associated with individual treatment regimens is large, and considerable deviations from these recommended values ​​are not 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 method of administration, the individual subject's needs, the severity of the disease or condition being treated, and the practitioner's judgment.

[0610] In some implementations, the toxicity and therapeutic efficacy of such treatment regimens are determined by standard drug procedures in cell cultures or laboratory animals, including but not limited to LD50. 50 (The dose that is lethal to 50% of the population) and ED 50 The determination of the dose (the amount that is therapeutically effective in 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, which can be expressed as LD50. 50 With ED 50 The ratio between. In some embodiments, compounds exhibiting high therapeutic indices are disclosed. In some embodiments, data obtained from cell culture assays and animal studies are used to formulate dosage ranges for human use. In specific embodiments, the dosage of such compounds is within a certain cyclic concentration range, said cyclic concentration including ED... 50 It also exhibits minimal toxicity. In some embodiments, the dosage varies within this range depending on the dosage form and route of administration used.

[0611] In some embodiments, the disclosed compounds exhibit increased affinity, increased potency, or increased therapeutic index to the nuclear target compared to unmodified nuclear payloads from which the compounds are 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, improving the therapeutic index, and reducing the overall cost of treatment. In some embodiments, the daily dose suitable for administering the compounds described herein is less than 100% of the recommended daily dose of an unmodified nuclear payload, 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 90%, or about 60% to 90%, or about 70% to 90%, or about 20% to 80%, or about 30% to 80%, or about 40% to 80%, or about 50% to 80%, or about 60% to 80%, or about 70% to 80%, or about 20% to 70%, or about 30% to 70%, or about 40% to 70%, or about 50% to 70%, or about 60% to 70%.

[0612] In some embodiments, the compounds described herein are used to prepare or manufacture a medicament for treating a disease or condition, said treatment being mediated by a topoisomerase inhibitor or wherein inhibition of one or more topoisomerases improves said disease or condition. In some embodiments, a method for treating any of the diseases or conditions described herein in a subject requiring such treatment involves administering a pharmaceutical composition to said subject in a therapeutically effective amount, said pharmaceutical composition containing at least one compound described herein or a pharmaceutically acceptable salt, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate thereof.

[0613] Combination therapy

[0614] The compounds described herein can 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 pharmacological properties of the combination. In one embodiment, this disclosure provides for the use of compounds as described herein in combination with another pharmaceutical agent or treatment method (such as another cancer treatment). For example, when treating cancer, the composition can be combined with other anticancer compounds (such as paclitaxel or rapamycin).

[0615] The compounds of this disclosure may also be combined with one or more other active ingredients in a single dosage form for simultaneous or sequential administration to a patient. Combination therapy may be administered concurrently or sequentially. When administered sequentially, the combination may be administered in two or more doses.

[0616] Combination therapy can provide “synergistic effects”, meaning that the combined effect of active ingredients is greater than the sum of the effects of using the compounds alone. Synergistic effects can be achieved when active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combination formulation; (2) delivered alternately or in parallel as separate formulations; or (3) administered or delivered via some other regimen. Synergistic effects can also be achieved when delivered in alternating therapy, or when compounds are administered or delivered sequentially, for example, in separate tablets, pills, or capsules, or by different injections in separate syringes. Typically, in alternating therapy, the effective doses of each active ingredient are administered sequentially (i.e., consecutively); however, in combination therapy, the effective doses of two or more active ingredients are administered together. Synergistic anticancer effects refer to anticancer effects greater than the predicted additive effect of the individual compounds in the combination.

[0617] Given the potential for toxicity (if any), administration of the compounds and compositions of this disclosure to patients will follow the general protocol for the administration of chemotherapeutic agents. Treatment cycles are expected to be repeated as needed. It is also conceivable that various standard or adjuvant cancer therapies, as well as surgical interventions, may be used in combination with one or more of the described active agents. These therapies include, but are not limited to, chemotherapy, radiotherapy, immunotherapy, gene therapy, and surgery.

[0618] In some embodiments, this document provides a method for treating cancer, the method comprising administering to a subject requiring treatment a therapeutically effective amount of a compound or composition described herein in combination 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.

[0619] In some embodiments, this document provides a method for treating cancer, the method comprising administering to a subject requiring treatment a therapeutically effective amount of a compound or composition described herein in combination with ionizing radiation and one or more chemotherapy agents. In some embodiments, the compound described herein is administered simultaneously with ionizing radiation and one or more chemotherapy agents. In other embodiments, the compound described herein is administered sequentially with ionizing radiation and one or more chemotherapy agents.

[0620] In some embodiments, this document provides a method for treating cancer, the method comprising administering to a subject requiring treatment a therapeutically effective amount of a combination of the compound or composition described herein and ionizing radiation. In some embodiments, radiation is administered at a dose 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 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, radiation is administered at a dose 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 approximately six times per week. It is conceivable that prostate-specific chemical prostatectomy can be achieved by administering radiation in combination with the compounds or compositions described herein, while avoiding harmful side effects such as impotence and incontinence associated with surgical prostatectomy due to damage to blood vessels and nerves.

[0621] Cancer treatment can also include various combinations of chemotherapy and radiation-based therapies. Combination chemotherapy includes the use of chemotherapeutic agents such as cisplatin, etoposide, irinotecan, campotexa, topotecan, paclitaxel, docetaxel, epothilone, paclitaxel, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, and BMS214662. (Gefitinib) (Erlotinib hydrochloride), anti-EGFR antibody, (Imatinib), Intron, ara-C, Doxorubicin, Cyclophosphamide, Gemcitabine, Uracil N-mustache, Nitrogen Mustard, Ifosfamide, Melphalan, Chlorobutyrate Mustard, Piperbromodiphenyltate, Triethylene melamine, Triethylene thiophosphamide, Busulfan, Carmustine, Lomustine, Streptozotocin, Dacarbazine, Fluorouracil, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine Phosphate, Pentostatin, Vincristine, Vincristine, Vincristine, Bleomycin, Doxorubicin, Doxycycline, Epirubicin, Idarubicin, Activamycin, Deoxycofromycin, Mitomycin-C, L-Asparaginase, Teniposide, 17α- Ethynyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoromethyltestosterone, drotaldoxaproate, testosterone lactone, medroxyprogesterone acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorestradiol, hydroxyprogesterone, aminoglutethimide, estradiol, medroxyprogesterone acetate, leuprorelin, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, acridine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrozole, letrozole, capecitabine, raloxifene, droxil, hexamethylmelamine, avastin, herceptin, cyclophosphamide, vesicosteroids, zevallin, arsenic trioxide, capecitabine, vinorelbine, porphyrin sodium. (Cetuximab), liposomes, thiotepa, hexamethylmelamine, melphalan, trastuzumab, leurozole, fulvestrant, exemestane, ifosfomide, rituximab, C225, camppas, carboplatin, procarbazine, nitrogen mustard, cyclophosphamide, camptothecin, ifosfomide, melphalan, chlorambucil, busulfan, nitrosourea, danomycin, doxorubicin, bleomycin, procainamide, mitomycin, etoposide (VP 16), tamoxifen, raloxifene, estrogen receptor conjugates, paclitaxel, gemcitabine, novibenten, farnesyltransferase inhibitors, antiplatinum, 5-fluorouracil, vincristine, vinblastine, and methotrexate, or any of the foregoing analogues or derivative variants.

[0622] In some embodiments, the compounds described herein are administered in combination with CDK inhibitors (e.g., CDK2, CDK4, CDK6 inhibitors, or CDK4 / 6 inhibitors).

[0623] Other factors that cause DNA damage (e.g., radiation therapy) have been widely used, including those commonly referred to as gamma rays, X-rays, and / or the targeted delivery of radioactive isotopes to tumor cells. Other forms of DNA damage factors, such as microwave and UV irradiation, have also been considered. Most likely, all of these factors cause extensive damage to DNA, DNA precursors, DNA replication and repair, and chromosome assembly and maintenance. X-ray doses range from daily doses of 50 to 200 roentgens over long durations (e.g., 3 to 4 weeks) to single doses of 2000 to 6000 roentgens. Radioactive isotope doses vary considerably and depend on the isotope's half-life, the intensity and type of emitted radiation, and the uptake by tumor cells. The terms "contact" and "exposure" as used herein, when applied to cells, describe the process of delivering therapeutic constructs and chemotherapy or radiotherapy agents to or in direct proximity to target cells. To achieve cell killing or arrest, two agents are delivered to cells in combined amounts to effectively kill or prevent cell division.

[0624] Immunotherapy agents typically rely on the use of immune effector cells and molecules that 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 serve as an effector of the therapy, or it can recruit other cells to actually influence cell killing. Antibodies can also be conjugated to drugs or toxins (chemotherapy agents, radioactive nucleotides, ricin A chain, cholera toxin, pertussis toxin, etc.) and used solely as a target. Alternatively, effectors can be lymphocytes carrying surface molecules that interact directly or indirectly with tumor cell targets. Various effector cells include cytotoxic T cells and NK cells.

[0625] Therefore, immunotherapy can be combined with gene therapy as part of a combination therapy. The general approach to combination therapy is discussed below. Typically, tumor cells must carry some easily targeted markers, i.e., those not present on most other cells. Many tumor markers exist, and any one of these markers may be suitable for targeting in the context of this disclosure. Common tumor markers include carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), urogenital tumor-associated antigen (uroTA), embryonic antigen (EGA), tyrosinase (p97), gp68, TAG-72, HMFG, sialylated Lewis antigen (SMA), MucA, MucB, PLAP, estrogen receptor, laminin receptor, erb B, and p155.

[0626] In yet another implementation, secondary treatment is secondary gene therapy, wherein a therapeutic polynucleotide is administered before, after, or simultaneously with the first chemotherapeutic agent. The combined delivery of the chemotherapeutic agent and a vector encoding the gene product will have a combined anti-excessive proliferation effect on the target tissue.

[0627] Approximately 60% of people diagnosed 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 those described in this disclosure, 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 include laser surgery, cryosurgery, electrosurgery, and microscopically controlled surgery (Moiré surgery). It is further envisioned that this disclosure can be used in conjunction with the removal of superficial cancer, primary cancer, or associated amounts of normal tissue.

[0628] The application of compounds or compositions as described herein can be performed before or after other anticancer agents or treatments, at intervals ranging from minutes to weeks. In another embodiment where the anticancer agent and expression construct are applied separately, it is generally ensured that no significant time intervals are consumed between each delivery, allowing the agent and expression construct to still exert a beneficial combined effect on the cells. For example, in such cases, it is conceivable that cells, tissues, or organisms having two, three, four, or more modalities can be contacted substantially simultaneously (i.e., within less than about one minute) with one or more active agents. In other respects, one or more agents may be applied for 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, or 45 hours to approximately 48 hours or longer before and / or after the application of one or more active agents. In some other embodiments, the agents may be applied for 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, or 20 days to approximately 21 days before and / or after the application of the one or more active agents. However, in some cases, it may be desirable to significantly extend the duration of treatment, with intervals of several weeks between each administration (e.g., about 1, about 2, about 3, about 4, about 6, or about 8 weeks or longer).

[0629] Reagent test kit

[0630] Kits for achieving anticancer effects are provided, the kits comprising the compounds or compositions described herein. In some embodiments, the kit comprises a unit dose of the compounds or compositions described herein and instructions for administration thereof. In some aspects, the kit further comprises a second drug suitable for anticancer therapy or instructions for co-administration of another anticancer therapy (such as radiation or gene therapy). In another aspect, the kit for achieving anticancer effects comprises 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 suitable for anticancer therapy. In yet another variation, the kit for achieving anticancer effects comprises a high dose (e.g., greater than about 500 mg / day) of the compounds or compositions described herein and a second drug suitable for anticancer therapy.

[0631] Methods of manufacturing pharmaceuticals

[0632] In another aspect of this disclosure, the use of the compounds and compositions described herein in the manufacture of pharmaceutical agents is provided. In particular, the manufacture of pharmaceutical agents for treating cancer or diseases or conditions is provided, said treatment being at least partially mediated by blocking DNA repair and / or transcriptional activation, such as by inhibiting one or more topoisomerases. Furthermore, pharmaceutical compositions of the compounds described herein are also intended for use in the manufacture of pharmaceutical agents for treating diseases or conditions, said treatment being at least partially mediated by inhibiting one or more topoisomerases.

[0633] Implementation plan with numbering

[0634] Implementation Scheme 1: A compound of Formula I, II, or III, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof:

[0635] A 1 -(L 1 -B 1 ) m’ I

[0636] A 1 -L 1 -(B 1 ) m’ II

[0637] A 1 -L 1 -B 1 III

[0638] in:

[0639] A 1It is a topoisomerase inhibitor or an analogue;

[0640] m' is 1, 2, or 3;

[0641] Each B 1 It is an independent nuclear receptor-targeting epitope; and

[0642] L 1 It is the connecting part.

[0643] Implementation Scheme 2: The compound according to Implementation Scheme 1, or its stereoisomers, mixtures of stereoisomers, hydrates, solvates, isotopically enriched analogs, or pharmaceutically acceptable salts, wherein A 1 Selected from:

[0644]

[0645]

[0646] The wavy line indicates -L 1 -B 1 Attachment point.

[0647] Implementation Scheme 3: The compound according to Implementation Scheme 1 or 2, wherein m' is 1.

[0648] Implementation Scheme 4: A compound of formula IA, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof:

[0649]

[0650] in:

[0651] R 1 R 2 R 3 and R 4 Each group independently consists of hydrogen, halogen, cyano, nitro, and -OR. 15 -SR 15 -NR 15 R 16 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R 15 -C(=O)OR 15 -OC(=O)R 15 -C(=O)NR 15 R 16 -NR 15 C(=O)R16 -NR 15 C(=O)OR 16 -S (=O) 1-2 R 15 -S (=O) 1- 2NR 15 R 16 -NR 15 S(=O) 1-2 R 16 、-Si(R 15 )3 or -C=NOR 15 When the valence is allowed, R 1 R 2 R 3 and R 4 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently and optionally bounded by one or more R groups. 10 replace;

[0652] Or R 1 and R 2 With R 1 and R 2 The attached atoms together form C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups, optionally with one or more R groups when the valence allows. 10 replace;

[0653] or R 2 and R 3 With R 2 and R 3 The attached atoms together form C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups, optionally with one or more R groups when the valence allows. 10 replace;

[0654] or R 3 and R 4 With R 3 and R 4 The attached atoms together form C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups, optionally with one or more R groups when the valence allows. 10 replace;

[0655] Each R 10 Independently, it is a halogenated group, cyano group, nitro group, or -OR group. 17 -SR 17 -SF5, -NR 17 R 18 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R 17 -C(=O)OR 17 -OC(=O)OR 17 -OC(=O)R 17 -C(=O)NR 17 R 18 -OC(=O)NR 17 R 18 -NR 7 C(=O)NR 17 R 18 -S (=O) 1-2 R 17 -S (=O) 1- 2NR 17 R 18 -NR 17 S(=O) 1-2 R 18 -NR 17 S(=O) 1-2 NR 17 R 18 -NR 17 C(=O)R 18 -NR 17 C(=O)OR 18 、-Si(R 17 )3 or -C=NOR 17 When the valence is allowed, R 10 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently and optionally substituted with one or more halogroups or optionally with an oxogroup, halogroup, hydroxyl group, or amino group. 1-12 Alkyl substitution; and

[0656] Each R 15 and R 16 Independently, it is hydrogen and C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 cycloalkyl, wherein each C, when valence permits, 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 The cycloalkyl group is optionally and independently substituted with an oxo group, a halogen group, a hydroxyl group, or an amino group; or R 15 and R 16 With R 15 and R 16The attached atoms together form a heterocyclic group optionally substituted with a halogenated group or a C group optionally substituted with an oxo group, a halogenated group, a hydroxyl group, or an amino group. 1-12 Alkyl; and

[0657] Each R 17 and R 18 Independently, it is hydrogen and C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 cycloalkyl, wherein each C, when valence permits, 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 The cycloalkyl group may optionally be substituted with an oxo group, a halogen group, a hydroxyl group, or an amino group; or R 17 and R 18 With R 17 and R 18 The attached atoms together form C atoms that are optionally substituted with a halogen group or optionally with an oxo group, halogen group, hydroxyl group, or amino group. 1-12 Alkyl-substituted heterocyclic groups;

[0658] One or more atoms (e.g., hydrogen, methyl, hydroxyl, etc.) are directly covalently bonded to at least one nuclear acceptor targeting epitope (optionally via a linker as defined herein; e.g., -L) 1 -B 1 (replace)

[0659] Implementation Scheme 5: A compound of Formula IB, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof:

[0660]

[0661] in:

[0662] R 1 Is it hydrogen or -L? 1 -B 1 ;

[0663] R 2 It is hydrogen, NH2, NO2 or -L 1 -B 1 ;

[0664] R 3 It is hydrogen, halogroup, methyl, methoxy or -L 1 -B 1 ;

[0665] R 4 It is hydrogen, halogroup, methyl or methoxy; or

[0666] R 3 and R 4 Together they form -O-CH2-O- or -O-CH2CH2-O-;

[0667] Y is a bond, -CH2- or -CH2-CH2-; and

[0668] Z stands for bond or O.

[0669] Implementation Scheme 6: The compound according to Implementation Scheme 5, wherein R 1 R 2 or R 3 Only one of them is -L 1 -B 1 .

[0670] Implementation Scheme 7: The compound according to Implementation Scheme 5, wherein R 2 Yes -L 1 -B 1 .

[0671] Implementation Scheme 8: The compound according to Implementation Scheme 5, wherein R 3 Yes -L 1 -B 1 .

[0672] Implementation Scheme 9: The compound according to any of the foregoing implementation schemes, wherein L 1 It has the following formula:

[0673] -Y 10 -(CH2) n' -Y 20 -(CH2) p' -Y 30 -

[0674] Where Y 10 Y 20 and Y 30 Each of these is independently a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, -CR 110 R 120 -、-NR 110 -、-O-、-S(O) 0-2 -、-NR 110 C(O)-、-C(O)NR 110 -、-NR 110 S(O)2-、-S(O)2NR 110 -、-CR 120 =N-NR 110 -、-NR110 -N=CR 120 -or -C(O)-;

[0675] Each R 110 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Halogenated alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic;

[0676] Each R 120 Independently, it is hydrogen and C 1-4 Alkyl, C 1-4 Halogenated alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic groups; and

[0677] n' and p' are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0678] Implementation Scheme 10: The compound according to any of the foregoing implementation schemes, wherein L 1 This includes parts of organisms that cannot be cut.

[0679] Implementation Scheme 11: The compound according to any of the foregoing implementation schemes, wherein L 1 It is an optionally substituted alkylene or an optionally substituted heteroalkylene.

[0680] Implementation Scheme 12: The compound according to any of the foregoing implementation schemes, wherein L 1 Including optional substitution of C 4-7 Alkylene atoms of 1 atom, optionally substituted C 4-7 A heterocyclic group of one atom or an optionally substituted C 4-7 A heteroalkylene group of 1 atom.

[0681] Implementation Scheme 13: The compound according to any of the foregoing implementation schemes, wherein L 1 C is an optional substitute 4-10 A heteroalkylene group of 1 atom.

[0682] Implementation Scheme 14: The compound according to any of the foregoing implementation schemes, wherein L 1 It is a 4-7 atom alkylene or heteroalkylene linkage containing CH2 and up to 2 heteroatoms each independently selected from NH, O or S and optionally a C=O.

[0683] Implementation Scheme 15: The compound according to any of the preceding embodiments, wherein the connecting portion has the following formula:

[0684]

[0685] The asterisk (*) and wavy lines represent covalent bonds.

[0686] Implementation Scheme 16: A compound according to any of the preceding embodiments, wherein the compound retains biological activity comparable to that observed in original, unmodified topoisomerase inhibitors.

[0687] Implementation Scheme 17: A compound according to any of the foregoing embodiments, wherein the compound is expressed at an IC50 concentration of less than about 5,000 nM. 50 Inhibits topoisomerases.

[0688] Implementation Scheme 18: The compound according to any one of the preceding implementation schemes, wherein the compound binds totopoisomerase I.

[0689] Implementation Scheme 19: A compound according to any one of the preceding embodiments, wherein the compound comprises a nuclear receptor-targeting epitope derived from:

[0690]

[0691]

[0692]

[0693] Or its stereoisomers or mixtures of stereoisomers or the like thereof, wherein at least one hydrogen atom is reacted with A 1 The direct covalent bond (optionally via the linker portion) is replaced.

[0694] Implementation Scheme 20: A compound 1, 2, 3, 4 or 5 as provided in Table 1, or a stereoisomer thereof, a mixture of stereoisomers, a hydrate, a solvate, an isotopically enriched analog or a pharmaceutically acceptable salt thereof.

[0695] Implementation Scheme 21: A pharmaceutical composition comprising a compound according to any of the preceding embodiments, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0696] Implementation Scheme 22: A method for treating or preventing cancer, the method comprising administering an effective amount of the pharmaceutical composition according to Implementation Scheme 21 to an individual in need.

[0697] Implementation Scheme 23: The method according to Implementation Scheme 21, wherein the administration includes oral administration.

[0698] Implementation Scheme 24: The method according to Implementation Scheme 21, the method further includes administering an additional chemotherapeutic agent.

[0699] Implementation Scheme 25: The method according to Implementation Scheme 24, wherein the additional chemotherapeutic agent is cisplatin, or etoposide, irinotecan, camptothecin, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778123, BMS214662, gefitinib, erlotinib hydrochloride, anti-EGFR antibody, matinib, intron, vidarabine, doxorubicin, cyclophosphamide, gemcitabine, uracil nitrogen mustard, nitrogen mustard, ifosfamide, melphalan, chlorambucil, piperobromane, ethylmelamine, ethylthiophosphamide, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, fluorouracil, cytarabine, 6-mercapto-1, 1-hydroxychloroquine. Purine, 6-thioguanine, fludarabine phosphate, pentostatin, vincristine, vinblastine, vindesine, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, photomycin, deoxycofromycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoromethesterone, drotaldophenone propionate, testrolide, medroxyprogesterone acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone Chlorpheniramine, Hydroxyprogesterone, Aminglutide, Estrogenus, Medroxyprogesterone Acetate, Leuprorelin, Flutamide, Toremifene, Goserelin, Carboplatin, Hydroxyurea, Acridine, Procarbazine, Mitotan, Mitoxantrone, Levamisole, Navelbene, Anastrozole, Capecitabine, Droloxifen, Hexamethylmelamine, Avastin, Herceptin, Bixamethasone, Velcade, Zevallin, Arsenic Trioxide, Xeloda, Vinorelbine, Porphyrin, Cetuximab, Liposomes, Thiotepa, Hexamethylmelamine Trastuzumab, letrozole, fulvestrant, exemestane, rituximab, C225, campas, carboplatin, procarbazine, nitrogen mustard, cyclophosphamide, camptothecin, melphalan, busulfan, nitrosourea, daunomycin, doxorubicin, bleomycin, procainoxam, mitomycin, etoposide (VP16), raloxifene, estrogen receptor binders, paclitaxel, gemcitabine, novibenten, farnesyltransferase inhibitors, antiplatinum and methotrexate or their analogues or derivatives.

[0700] Implementation Scheme 26: The method according to any one of Implementation Schemes 22-25, the method further comprising administering radiotherapy to the patient.

[0701] Implementation Scheme 27: The method according to any one of Implementation Schemes 22-26, wherein the cancer is a BRCA-positive cancer.

[0702] Implementation Scheme 28: The method according to any one of Implementation Schemes 22-27, wherein the cancer is a solid tumor.

[0703] Implementation Scheme 29: The method according to any one of Implementation Schemes 22-28, wherein the cancer is a cancer affecting B cells.

[0704] Implementation Scheme 30: The method according to any one of Implementation Schemes 22-29, 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, nephroblastoma, cervical cancer, testicular cancer, soft tissue sarcoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, or primary brain cancer. 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 myeloid 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 thrombocytosis, adrenocortical carcinoma, skin cancer, trophoblastic tumors, or prostate cancer.

[0705] Implementation Scheme 31: The method according to Implementation Scheme 22, wherein the cancer is neuroblastoma, brainstem glioma, Ewing's tumor, non-small cell lung cancer, colorectal cancer, breast cancer, non-Hodgkin's lymphoma, endometrial cancer, or oligodendroglioma.

[0706] Implementation Scheme 32: A method for treating or preventing neurogenetic diseases or disorders, the method comprising administering an effective amount of the pharmaceutical composition according to Implementation Scheme 21 to an individual in need.

[0707] Implementation Scheme 33: The method according to Implementation Scheme 32, wherein the neurogenetic disease or disorder is Angelman syndrome.

[0708] Example

[0709] The present disclosure is further illustrated by the following examples. These examples are not limiting and represent only various aspects of the present disclosure. The solid and dotted wedges within the structures disclosed herein illustrate relative stereochemistry, while absolute stereochemistry is depicted only where explicitly stated or indicated.

[0710] Compounds having the structure of any of the compounds, formulas, or subforms described herein can be synthesized using standard synthetic techniques known to those skilled in the art. The compounds of this disclosure can be synthesized using the general synthetic methods described in the general methods or synthetic examples.

[0711] In cases where it is desired to obtain a specific enantiomer of a compound, this can be achieved from a mixture of the respective enantiomers using any suitable conventional 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 chiral compound. The diastereomer can then be separated by any convenient means, such as crystallization and recovery of the desired enantiomer. In another resolution method, the racemic mixture can be separated using chiral high-performance liquid chromatography. Alternatively, if desired, the specific enantiomer can be obtained by using a suitable chiral intermediate in one of the methods.

[0712] Chromatography, recrystallization, and other conventional separation procedures can also be used with intermediates or final products where it is desirable to obtain a specific isomer of the compound or otherwise purify the reaction product.

[0713] Synthesis program

[0714] Example 1

[0715] (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-4-(6-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido

[0716] Synthesis of [3,4-b]indol-1-yl)phenoxy)hexanoyl)piperazine-1-carboxylate (compound 1)

[0717]

[0718] 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 equivalent) 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 equivalent) and ethyl 6-bromohexanoate (600 mg, 2.2 mmol, 1.1 equivalent) in DMF (200 mL) and stirred at room temperature for 16 h. The reaction progress was monitored by TLC analysis. After completion, the mixture was diluted with ice 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 silica gel column chromatography to give the title compound (900 mg, 85%).

[0719] 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 equivalent) 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 (265 mg, 0.5 mmol, 1.0 equivalent) in MeOH (10 mL). The reaction progress was monitored by TLC. 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.

[0720] Step 3: (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl 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)hexanoyl)piperazin-1-methyl Preparation of ester (1): HATU (141 mg, 0.37 mmol, 1.5 equivalent) 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-pyrido[3,4-b]indol-1-yl)phenoxy)hexanoic acid (125 mg, 0.25 mmol, 1.0 equivalent) in DMF (5 mL) and stirred at room temperature for 15 min. DIPEA (0.18 mL, 1.0 mmol, 2.0 equivalent) and (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl 4-(2,2,2-trifluoroacetyl)-4l4-piperazine-1-carboxylate (150 mg, 0.25 mmol, 1.0 equivalent) were added to the solution and stirred at room temperature for 2 h. After completion, the mixture was diluted with ice 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. This crude product was purified by silica gel column chromatography to obtain the desired product. The product was then ground with acetone / n-pentane (1:5) and dried to give the title compound (22 mg, 6%). LCMS: 989.5 [M + H] + ; 1H NMR (400MHz, DMSO-d6): δ10.52(s,1H),8.19(d,J=9.6Hz,1H),8.01(d,J=2.6Hz,1H),7.69(dd,J=9.2,2.2Hz ,H),7.38(d,J=7.0Hz,1H)7.32(s,1H),7.17(d,J=7.9Hz,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 = 7.7Hz, 4H), 1.22-1.03 (m, 6H), 0.88 (t, J = 7.2Hz, 3H).

[0721] Example 2

[0722] (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-4-(6-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido

[0723] Synthesis of [3,4-b]indol-1-yl)phenoxy)hexyl)piperazine-1-carboxylate (compound 2)

[0724]

[0725] 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 equivalent) 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 equivalent) and 6-bromohexyl-1-ol (396 mg, 2.2 mmol, 1.1 equivalent) 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 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 silica gel column chromatography to give the title compound (800 mg, 82%).

[0726] 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 equivalents) 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 equivalent) in DCM (50 mL) and stirred at room temperature for 2 h. 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.

[0727] Step 3: Preparation of (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrido[3',4':6,7]indolazino[1,2-b]quinolin-9-yl 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-carboxylate (2): To (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrido[3',4':6,7]indolazino[1,2-b]quinolin-9-yl 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-carboxylate (2) [3',4':6,7]indolazino[1,2-b]quinoline-9-yl 4-(2,2,2-trifluoroacetyl)-4l4-piperazine-1-carboxylate (240 mg, 0.4 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-pyridino[3,4-b]indol-1-yl)phenoxy)hexanal (389 mg, 0.8 mmol, 2.0 equivalent) were added to a stirred solution of IPA (20 mL) with acetic acid (0.1 mL) and stirred at room temperature for 15 min. Sodium cyanoborohydride (49 mg, 0.8 mmol, 2.0 equivalent) was added to this solution and the mixture was stirred at room temperature overnight. The reaction progress was monitored by TLC and LC-MS analysis. 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 the crude product, which was purified by reversed-phase chromatography to give the title compound (72 mg, 18%). LCMS: 975.4 [M + H] + ; 1H NMR (400MHz, DMSO-d6): δ10.53(s,1H),8.18(d,J=9.2Hz,1H),8.00(d,J=2.6Hz,1H),7.66(d,J=9.2Hz,1H) ,7.39(d,J=7.8Hz,1H),7.32(s,1H),7.18(d,J=7.8Hz,1H),6.86-7.05(m,2H),6.66(d,J=11.4Hz,1H),6.54 (s,1H),5.44(s,2H),5.34(s,2H),5.12(m,1H),3.96(m,2H),3.67-3.48(m,6H),3.19(d,J=6.6Hz,3H),2.8 6-2.20(m,8H),1.79-1.20(m,16H),1.16(m,2H),1.11(s,2H),1.04(d,J=6.1Hz,3H),0.88(t,J=7.2Hz,3H).

[0728] Example 3

[0729] (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]

[0730] Synthesis of Quinolin-9-yl 4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenten[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexanoyl)piperazine-1-carboxylate (compound 3)

[0731]

[0732] Step 1: Preparation of (S)-1-(tert-butyl)4-(4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)piperazine-1,4-dicarboxylate: DIPEA (0.34 mL, 1.91 mmol, 1.5 equivalence) was added to a stirred solution of 7-ethyl-10-hydroxycamptothecin (0.50 g, 1.27 mmol, 1.0 equivalence) in THF (10 mL), followed by the addition of p-nitrochlorocarboxylate (0.30 g, 1.53 mmol, 1.2 equivalence). The reaction was then allowed to proceed with stirring at room temperature for 2 h. After completion, the mixture was evaporated under reduced pressure to obtain a crude product, 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 equivalent) and N-Boc piperazine (467 mg, 2.5 mmol, 2.0 equivalent). The reaction was then allowed to proceed with stirring at room temperature for 16 h. 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 obtain the title compound (300 mg, 39%).

[0733] Step 3: Preparation of (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-ylpiperazine-1-carboxylate trifluoromethanesulfonate: At 0 °C, TFA (0.5 mL) was added dropwise to a stirred solution of (S)-1-(tert-butyl)-4-(4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)piperazine-1,4-dicarboxylate (0.30 g, 0.50 mmol, 1.0 equivalent) in DCM (5 mL). The resulting mixture was then stirred at room temperature for 30 min. After completion, the reactants were evaporated under reduced pressure to obtain a crude product, which was then purified by grinding with diethyl ether (2 × 25 mL) to obtain the title compound (220 mg, 90%).

[0734] Step 4: (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl 4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenteno[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexanoyl Preparation of piperazine-1-carboxylate (3): HATU (0.22 g, 5.8 mmol, 1.5 equivalent) was added to a stirred solution of 6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenteno[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexanoic acid (0.26 g, 0.46 mmol, 1.0 equivalent) in DMF (5 mL). The reaction was then allowed to proceed with stirring at 0 °C for 10 min. At 0 °C, (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-ylpiperazine-1-carboxylate trifluoromethanesulfonate (0.2 g, 3.9 mmol, 1.0 equivalence) dissolved in DMF (5 mL) and DIPEA (0.2 mL, 11.7 mmol, 3.0 equivalence) was added dropwise to the reactants. The reaction was then allowed to proceed with stirring at room temperature for 2 h. After completion, the reaction mixture was diluted with DCM (50 mL) and then washed with ice 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 reversed-phase HPLC to give the title compound (76 mg, 18%). LCMS: 1062 [M+H] + ; 1H NMR (400MHz, DMSO-d6): δ8.19(d,J=9.2Hz,1H),8.02(s,1H),7.70(d,J=9.2Hz,1H),7.33(s,1H),6.99(d,J =8.3Hz,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=16.0,7.24Hz,5H),2.83(s,6H),2.60-2.71(m,3H),2.34(d,J=9.6Hz,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=7.7Hz,7H),0.88(t,J=7.4Hz,3H).

[0735] Example 4

[0736] (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]

[0737] Synthesis of Quinolin-9-yl 4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenten[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylate (compound 4)

[0738]

[0739] Step 1: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(6-oxohexyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenten[a]phenanthrene-17-yl acetate: To (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-hydroxyhexyl)(methyl))phenyl) (Amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenteno[a]phenanthrene-17-yl acetate (281 mg, 0.5 mmol, 1.0 equivalent) was added to a solution of DCM (20 mL) with DMP (424 mg, 1.0 mmol, 2.0 equivalent), followed by the addition of water (18 mg, 1.0 mmol, 2.0 equivalent) and stirring at room temperature for 2 h. 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 for the next step without further purification.

[0740] Step 2: (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl 4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3 Preparation of (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylate (4): [3',4':6,7]Indolezido[1,2-b]quinoline-9-yl 4-(2,2,2-trifluoroacetyl)-4l4-piperazine-1-carboxylate trifluoromethanesulfonate (120 mg, 0.2 mmol, 1.0 equivalent) and (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(6-oxohexyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenten[a]phenanthrene-17-yl acetate (224 mg, 0.4 mmol, 2.0 equivalent) were added to a stirred solution of IPA (5 mL) with acetic acid (0.05 mL) and stirred at room temperature for 15 min. Sodium cyanoborohydride (25 mg, 0.4 mmol, 2.0 equivalence) was added to the solution and 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 the crude product, which was purified by reversed-phase chromatography to give the title compound (12 mg, 6%). LCMS: 1049.0 [M + H] + ; 1H NMR (400MHz, DMSO-d6): δ8.18(d,J=8.8Hz,1H),8.00(d,J=2.2Hz,1H),7.67( d,J=10.5Hz,1H),7.32(s,1H),6.98(d,J=8.2Hz,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=7.2Hz,3H).

[0741] Example 5

[0742] Synthesis of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl 4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecano-1H-cyclopenteno[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylate (compound 5)

[0743]

[0744] Step 1: Preparation of (S)-1-(tert-butyl)4-(10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)piperazine-1,4-dicarboxylate: At 0 °C, DIPEA (3.3 mL, 19 mmol, 4.0 equivalent) and triphosgene (2.8 g, 9.5 mmol, 2.0 equivalent) dissolved in DCM (15 mL) were added dropwise to a stirred solution of topotecan hydrochloride (2 g, 4.75 mmol, 1.0 equivalent) in anhydrous THF (100 mL): DCM (100 mL). The mixture was stirred at 0 °C for 30 min, followed by the addition of N-Boc piperazine (1.32 g, 7.12 mmol, 1.5 equivalence) dissolved in DCM (15 mL). The resulting mixture was stirred at room temperature for 3 h. 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%).

[0745] Step 2: Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-ylpiperazine-1-carboxylate trifluoromethanesulfonate: At 0°C, (S)-1-(tert-butyl)-4-(10-((dimethylamino)methyl) 4-Ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)piperazine-1,4-dicarboxylate (0.35 g, 0.55 mmol) was added dropwise to a stirred solution in DCM (5 mL) with 1 mL of trifluoroacetic acid and the resulting solution was stirred at room temperature for 3 h. The reaction was monitored by LC-MS. After completion, the mixture was concentrated under reduced pressure to give a crude product, which was then ground with diethyl ether to give the title compound (0.28 g, 95%).

[0746] Step 3: (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl) Preparation of (S)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopentenyl[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylate (5): ... 4,12,14-Tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-ylpiperazine-1-carboxylate trifluoromethanesulfonate (0.25 g, 0.46 mmol, 1.0 equivalent) and (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(6-oxohexyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenteno[a]phenanthrene-17-ylacetate (0.28 g, 0.50 mmol, 1.1 equivalent) were added to a stirred solution of acetic acid (0.2 mL) in MeOH (12 mL) and the mixture was stirred at room temperature for 15 min. Sodium cyanoborohydride (0.058 g, 0.92 mmol, 2.0 equivalence) was then added to the mixture, and the resulting 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 product, which was purified by reversed-phase HPLC to give the title compound (0.01 g, 2%). LCMS: 1078 [M + H] + ; 1H NMR (500MHz, DMSO-d6): δ8.94(s,1H),8.11(d,J=9.2Hz,1H),7.63(d,J=9.2Hz, 1H),7.34(s,1H),6.99(d,J=8.2Hz,2H),6.59(d,J=8.2Hz,2H),6.55(s,1H),5. 68(s,2H),5.43(s,4H),5.32(s,4H),4.40(d,J=7.0Hz,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).

[0747] Example 6

[0748] Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl 4-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidine-1-yl)-2-fluorobenzamido)hexyl)piperazine-1-carboxylate (compound 6)

[0749]

[0750] Step 1: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidine-1-yl)-2-fluoro-N-(6-hydroxyhexyl)benzamide

[0751] HATU (1.14 g, 3.0 mmol, 1.5 equivalence) was added to a stirred solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidine-1-yl)-2-fluorobenzoic acid (0.9 g, mmol, 2.0 mmol, 1.0 equivalence) in DMF (5 mL) and stirred at room temperature for 15 min. DIPEA (1.67 mL, 10.0 mmol, 5.0 equivalence) and 6-aminohexyl-1-ol (284 mg, 2.4 mmol, 1.2 equivalence) were added to this solution and stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture was diluted with ice water (30 mL) and extracted with DCM (50 mL × 2). The combined organic layers were washed with a saline solution (20 mL × 4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel column chromatography to give the desired product (700 mg, 63.5%). LCMS: 551.3 [M + H] + .

[0752] Step 2: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidine-1-yl)-2-fluoro-N-(6-oxohexyl)benzamide

[0753] 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-oxo-2-thiooxoimidazolidine-1-yl)-2-fluoro-N-(6-hydroxyhexyl)benzamide (275 mg, 0.5 mmol, 1.0 equivalent) in DCM (20 mL) and stirred at room temperature for 2 h. 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. LCMS: 549.4 [M + H] + .

[0754] Step 3: Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl 4-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidine-1-yl)-2-fluorobenzamido)hexyl)piperazine-1-carboxylate (compound 6)

[0755] Acetic acid (0.2 mL) was added to a stirred solution of compound 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidine-1-yl)-2-fluoro-N-(6-oxohexyl)benzamide (225 mg, 0.5 mmol, 1.0 equivalent) and intermediate 1 (315 mg, 0.5 mmol, 1.0 equivalent) in methanol (10 mL), and the mixture was stirred at room temperature for 15 min. Sodium cyanoborohydride (126 mg, 2.0 mmol, 4.0 equivalent) was 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 aqueous NaHCO3 solution (30 mL) and extracted with DCM (50 mL × 2). The combined organic layers were washed with a saline solution (20 mL × 4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by reversed-phase chromatography to obtain the desired product (18 mg, 3.4%) (formate).

[0756] 1 H NMR (400MHz, DMSO-d6): δ8.94(s,1H),8.48(br s,2H),8.40(d,J=7.89Hz,1H),8.29(s,1H),8.11(d,J=9.65Hz,2H),7.76(s ,1H),7.63(d,J=9.21Hz,1H),7.43(d,J=10.96Hz,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=13.59Hz,6H),2.20(s,6H),1.85(d,J=14.03Hz,2H),1.54(s,8H),1.36(br s,4H),1.23(br s,2H),0.89(t,J=7.24Hz,3H). LCMS:1067[M+H] + .

[0757] Example 7

[0758] Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-((5-(((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)oxy)pentyl)oxy)benzamide (compound 7)

[0759]

[0760] Step 1a: Preparation of methyl 4-(5-bromopentoxy)benzoate

[0761] At room temperature, 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), and the mixture was stirred at the same temperature for 30 min. Then, 1,5-dibromopentane (24.0 g, 105.2 mmol, 2.0 equivalent) 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 give a crude product, which was purified by CombiFlash chromatography to give the title compound (11.5 g, 73%). LCMS: 301 [M + H] + .

[0762] Step 1: Preparation of 4-(5-bromopentoxy)benzoic acid

[0763] A solution of methyl 4-(5-bromopentoxy)benzoate (6.6 g, 22.0 mmol, 1.0 equivalent) in THF:MeOH (30 mL:15 mL) was mixed with LiOH·H2O (9.0 g, 220.0 mmol, 10 equivalent) dissolved in H2O (5 mL) and the mixture was stirred at room temperature for 2 h. 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 approx. 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] + .

[0764] Step 2: Preparation of 4-(5-bromopentoxy)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)benzamide

[0765] HATU (2.3 g, 6.29 mmol, 1.2 equivalence) was added to a stirred solution of 4-(5-bromopentoxy)benzoic acid (1.5 g, 5.24 mmol, 1.0 equivalence) in DMF (15 mL) and the mixture was stirred at room temperature for 15 min. Then, DIPEA (4.8 mL, 26.22 mmol, 5.0 equivalence) and 4-((1r,4r)-4-aminocyclohexyloxy)-2-chlorobenzonitrile hydrochloride (1.4 g, 5.24 mmol, 1.0 equivalence) were added sequentially, and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LC-MS. After completion, the mixture was diluted with ice 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] + .

[0766] 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-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)oxy)pentyl)oxy)benzamide (compound 7)

[0767] Cs₂CO₃ (0.640 g, 1.96 mmol, 2.0 equivalence) was added to a stirred solution of topotecan hydrochloride (0.45 g, 0.98 mmol, 1.0 equivalence) in DMF (8 mL) and the mixture was stirred at room temperature for 20 min. Then, TBAI (0.072 g, 0.19 mmol, 0.2 equivalence) and 4-(5-bromopentoxy)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)benzamide (2.04 g, 3.93 mmol, 4.0 equivalence) 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 water (30 mL) and the resulting precipitate was filtered through a Buchner funnel to obtain a crude residue, which was purified by reversed-phase chromatography to give the title compound (0.065 g, 7%). 1H NMR (400MHz, DMSO-d6): δ8.80-8.78(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=8.77Hz,1H),6.97(d,J=8.33Hz,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,6H),1.77-1.75(m,2H),1.69-1.67(m,2H),1.51(d,J=7.89Hz,3H),1.24(m,2H),0.88(t,J=7.45Hz,3H). LCMS:860[M+H] + .

[0768] Example 8

[0769] (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl-4-(6-(((5R,8S,9R,10R,13R,14R,17R)-10,13-dimethyl-3-oxohexadecylhydro

[0770] Preparation of 1H-cyclopentenano[a]phenanthrene-17-yl)oxy)hexyl)piperazine-1-carboxylate (compound 8)

[0771] Step 1: Preparation of (5S,8R,9S,10S,13S,14S,17S)-17-(6-hydroxyhexyloxy)-10,13-dimethyltetradecano-1H-cyclopenten[a]phenanthrene-3(2H)-one

[0772] At room temperature, 6N HCl (13 mL) was added to a stirred solution of (5S,8R,9S,10S,13S,14S,17S)-10,13-dimethylhexadecylhydrospiro[cyclopenten[a]phenanthrene-3,2'-[1,3]dioxolane]-17-ol (0.86 g, 1.66 mmol, 1.0 equivalence) in THF (21 mL) and water (4.0 mL), and the resulting mixture was stirred at 0 °C for 2 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with saturated NaHCO3 (50 mL) (pH approx. 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] + .

[0773] Step 2: Preparation of 6-((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-oxohexadecylhydro-1H-cyclopenten[a]phenanthrene-17-yloxy)hexanal

[0774] DMP (1.39 mL, 2.41 mmol) was added to a stirred solution of (5S,8R,9S,10S,13S,14S,17S)-10,13-dimethylhexadecylhydrospiro[cyclopenten[a]phenanthrene-3,2'-[1,3]dioxolane]-17-ol (0.70 g, 1.61 mmol, 1.0 equivalence) in DCM (10 mL). The reaction mixture was allowed to be stirred at 0 °C for 1 h. 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 give the desired product (0.60 g, 99.99%). LCMS: 389.30 [M+H] + .

[0775] Step 3: Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl 4-(6-(((5R,8S,9R,10R,13R,14R,17R)-10,13-dimethyl-3-oxohexadecylhydro-1H-cyclopenteno[a]phenanthrene-17-yl)oxy)hexyl)piperazine-1-carboxylate (compound 8)

[0776] At 0 °C, topotecan (0.60 g, 1.80 mmol, 1.0 equivalent) and acetic acid (0.2 mL) were added to a stirred solution of 6-((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-oxohexadecylhydro-1H-cyclopenteno[a]phenanthrene-17-yloxy)hexanal (0.70 g, 1.80 mmol, 1.0 equivalent) in methanol (10 mL) for 1 h, followed by the addition of NaBH3CN (0.18 g, 3.60 mmol, 2.0 equivalent). The resulting mixture was stirred at room temperature for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was alkalized with NaHCO3 solution (100 mL) and extracted with DCM (200 mL). The organic layer was washed with water (200 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. The crude product was then purified by CombiFlash [silica gel 100-200 mesh, elution - 0-6% MeOH in DCM] to obtain the desired product (0.20 g, 13%). 1 HNMR (400MHz, DMSO-d6): δ8.95(s,1H),8.29(s,1H),8.11(d,J=8.77Hz,1H),7.63(d,J=8.77Hz,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=7.24Hz,4H),0.79-0.56(m,4H). LCMS:907.19[M+H] + .

[0777] Example 9

[0778] Preparation of (11R,13S,17R)-17-acetyl-11-(4-((6-(4-(((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)oxy)piperidin-1-yl)hexyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenteno[a]phenanthrene-17-yl acetate (compound 9)

[0779]

[0780] Step 1: Preparation of tert-butyl 4-hydroxypiperidine-1-carboxylate

[0781] Boc-anhydride (25.5 g, 118.8 mmol, 1.0 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 h. 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). 1 H NMR (400MHz, CDCl3): δ3.91-3.79(m,3H), 3.08-3.00(m,2H), 1.90-1.81(m,2H), 1.51-1.41(m,11H).

[0782] Step 2: Preparation of tert-butyl 4-iodopiperidine-1-carboxylate

[0783] Triphenylphosphine (32.2 g, 122.8 mmol, 1.3 equivalents) and imidazole (10.2 g, 151.2 mmol, 1.6 equivalents) were added to a stirred solution of N-Boc-4-hydroxypiperidine (19 g, 94.52 mmol, 1.0 equivalents) in DCM (200 mL), followed by the addition of iodine (23.81 g, 94.5 mmol, 1.0 equivalents) in portions at 0 °C. The resulting mixture was then stirred at ambient temperature for 4 h 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 give a crude residue, which was purified by CombiFlash chromatography to give the title compound (13.9 g, 47% yield). 1 H NMR (400MHz, CDCl3): δ4.43 (m, 1H), 3.57 (dt, J = 3.6, 13.6Hz, 2H), 3.26 (dt, J = 6.0, 3.6Hz, 2H), 2.01 (m, 4H), 1.44 (s, 9H).

[0784] Step 3: Preparation of (S)-tert-butyl 4-((10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)oxy)piperidine-1-carboxylate

[0785] Cs₂CO₃ (4.26 g, 13.11 mmol, 2.0 equivalent) was added to a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H,12H)-dione (3 g, 6.55 mmol, 1.0 equivalent) in DMF (25 mL), and the mixture was stirred at room temperature for 15 min. Then, TBAI (0.484 g, 1.31 mmol, 0.2 equivalent) and tert-butyl 4-iodopiperidine-1-carboxylate (8.2 g, 26.22 mmol, 4.0 equivalent) were added sequentially to the mixture, and the mixture was heated at 70 °C for 30 min. The reaction progress was monitored by TLC and LC-MS. After completion, the mixture was quenched with ice 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] + .

[0786] Step 4: Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-9-(piperidin-4-yloxy)-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H,12H)-dione

[0787] At 0 °C, trifluoroacetic acid (2 mL) was slowly added to a stirred solution of (S)-tert-butyl-4-((10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)oxy)piperidine-1-carboxylate (0.65 g, 1 mmol) in DCM (8 mL), and the resulting mixture was stirred at room temperature for 2 h. 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 ground with diethyl ether (10 mL × 2) to give the title compound (0.35 g, 64%). LCMS: 505 [M + H] + .

[0788] Step 5: Preparation of ((11R,13S,17R)-17-acetyl-11-(4-((6-(4-(((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)oxy)piperidin-1-yl)hexyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenteno[a]phenanthrene-17-yl acetate (compound 9)

[0789] At room temperature, (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-9-(piperidin-4-yloxy)-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H,12H)-dione (0.30 g, 0.48 mmol, 1.0 equivalent) and (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-1 1-(4-(methyl(6-oxohexyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecano-1H-cyclopenteno[a]phenanthrene-17-yl acetate (0.804 g, 1.44 mmol, 3.0 equivalents) was added to a stirred solution of anhydrous methanol (12 mL) with acetic acid (0.2 mL) 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 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 reversed-phase chromatography to give the title compound (25 mg, 4%). 1H NMR (400MHz, DMSO-d6): δ8.80(s,1H),8.18-8.01(m,1H),7.93-7.69(m,1H),7.29(s,1H),6.97(d,J=8.55H z,2H),6.58(d,J=8.55Hz,2H),6.50(s,2H),5.66(s,1H),5.42(s,2H),5.28(s,2H),4.39(d,J=6.80Hz,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=7.21Hz,3H). LCMS:1048[M+H] + .

[0790] Example 10

[0791] Preparation of (11R,13S,17R)-17-acetyl-11-(4-((7-(4-(((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)oxy)piperidin-1-yl)heptyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenteno[a]phenanthrene-17-yl acetate (compound 10)

[0792]

[0793] Step 1: Preparation of tert-butyl 4-hydroxypiperidine-1-carboxylate

[0794] Boc-anhydride (25.5 g, 118.8 mmol, 1.0 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 h. 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). 1 H NMR (400MHz, CDCl3): δ3.91-3.79(m,3H), 3.08-3.00(m,2H), 1.90-1.81(m,2H), 1.51-1.41(m,11H).

[0795] Step 2: Preparation of tert-butyl 4-iodopiperidine-1-carboxylate

[0796] Triphenylphosphine (32.2 g, 122.8 mmol, 1.3 equivalents) and imidazole (10.2 g, 151.2 mmol, 1.6 equivalents) were added to a stirred solution of N-Boc-4-hydroxypiperidine (19 g, 94.52 mmol, 1.0 equivalents) in DCM (200 mL), followed by the addition of iodine (23.81 g, 94.5 mmol, 1.0 equivalents) in portions at 0 °C. The resulting mixture was then stirred at ambient temperature for 4 h 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 give a crude residue, which was purified by CombiFlash chromatography to give the title compound (13.9 g, 47% yield). 1 H NMR (400MHz, CDCl3): δ4.43 (m, 1H), 3.57 (dt, J = 3.6, 13.6Hz, 2H), 3.26 (dt, J = 6.0, 3.6Hz, 2H), 2.01 (m, 4H), 1.44 (s, 9H).

[0797] Step 3: Preparation of (S)-tert-butyl 4-((10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)oxy)piperidine-1-carboxylate

[0798] Cs₂CO₃ (4.26 g, 13.11 mmol, 2.0 equivalent) was added to a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H,12H)-dione (3 g, 6.55 mmol, 1.0 equivalent) in DMF (25 mL), and the mixture was stirred at room temperature for 15 min. Then, TBAI (0.48 g, 1.31 mmol, 0.2 equivalent) and tert-butyl 4-iodopiperidine-1-carboxylate (8.2 g, 26.22 mmol, 4.0 equivalent) were added sequentially to the mixture, and the mixture was heated at 70 °C for 30 min. The reaction progress was monitored by TLC and LC-MS. After completion, the mixture was quenched with ice 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] + .

[0799] Step 4: Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-9-(piperidin-4-yloxy)-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H,12H)-dione

[0800] At 0 °C, trifluoroacetic acid (2 mL) was slowly added to a stirred solution of (S)-tert-butyl-4-((10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)oxy)piperidine-1-carboxylate (0.65 g, 1 mmol, 1.0 equivalent) in DCM (8 mL), and the resulting mixture was stirred at room temperature for 2 h. 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 ground with diethyl ether (10 mL × 2) to give the title compound (0.35 g, 64%). LCMS: 505 [M + H] + .

[0801] Step 4a: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((7-hydroxyheptyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenten[a]phenanthrene-17-yl acetate

[0802] NaHCO3 (pH approx. 8-9) was added to a stirred suspension of 7-bromoheptanol (3.17 g, 16.2 mmol, 3.0 equivalent) in EtOH:H2O (25 mL: 5 mL), followed by the addition of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methylamino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenteno[a]phenanthrene-17-yl acetate (2.5 g, 5.42 mmol, 1.0 equivalent) dissolved in EtOH (20 mL). The resulting mixture was heated at 80 °C for 16 h. 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 and concentrated under reduced pressure to obtain a crude residue, which was purified by CombiFlash chromatography to give the title compound (1.1 g, 35%). LCMS: 576 [M+H] + .

[0803] Step 4b: Synthesis of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(7-oxohepyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenten[a]phenanthrene-17-yl acetate ester. The ester was synthesized at 0 °C by oxidizing (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((7-hydroxy)-1H-)-(a]phenanthrene-17-yl acetate ester. (methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenteno[a]phenanthrene-17-ylacetate (1 g, 1.73 mmol, 1.0 equivalent) was added in portions to a stirred solution in EtOAc (100 mL) with 2-iodobenzoic acid (1.2 g, 4.34 mmol, 2.5 equivalent) and the mixture was allowed to be stirred at 80 °C for 2 h. After completion, the mixture was diluted with DCM (300 mL). The organic layer was washed with a saturated solution of Na2S2O3 (100 mL × 2), NaHCO3 solution (100 mL × 2), then with water (100 mL), and dried over anhydrous sodium sulfate. The solution was concentrated to give the title compound (0.9 g, 90%), which was used for the next step without further purification. LCMS: 574 [M+H] + .

[0804] Step 5: Preparation of (11R,13S,17R)-17-acetyl-11-(4-((7-(4-(((S)-10((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)oxy)piperidin-1-yl)heptyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenteno[a]phenanthrene-17-yl acetate (compound 10)

[0805] At room temperature, (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-9-(piperidin-4-yloxy)-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H,12H)-dione (0.3 g, 0.48 mmol, 1.0 equivalent) and (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-1 1-(4-(methyl(7-oxohepyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecano-1H-cyclopenteno[a]phenanthrene-17-yl acetate (0.80 g, 1.44 mmol, 3.0 equivalents) was added to a stirred solution of anhydrous methanol (12 mL) with acetic acid (0.2 mL), and the mixture was stirred at the same temperature for 30 min. Sodium cyanoborohydride (0.06 g, 0.96 mmol) was then slowly added to the mixture, and the resulting 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 reversed-phase chromatography to give the title compound (20 mg, 2%). 1H NMR (400MHz, DMSO-d6): δ8.78(s,1H),8.07(d,J=9.2Hz,1H),7.76(d,J=9.2Hz,1H),7.27(s,1H),7. 03-6.88(m,2H),6.56(d,J=8.8Hz,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=7.9Hz,2H),3.85(s,3H),3.22(d,J=7.0Hz,2H),2.80(s,6H),2.72(s,2H),2.20(s,3H),2.13(d,J=14.0Hz,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=7.5Hz,3H).LCMS:1062[M+H] + .

[0806] Example 11

[0807] Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazin-3-carboxamide (compound 11)

[0808]

[0809] Step 1: Preparation of (S)-1-(4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)-N,N,N-trimethylmethylammonium iodide

[0810] At room temperature, methyl iodine (2.60 g, 19.0 mmol, 4 equivalents) was added to a solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H,12H)-dione (2.0 g, 4.75 mmol, 1.0 equivalent) in MeOH (50 mL), and the mixture was stirred at the same temperature for 3 h. After 3 h, the mixture was concentrated under reduced pressure to give a quaternary ammonium salt, which was washed with diethyl ether and dried under reduced pressure to give the title compound (2.0 g, 76%).

[0811] Step 2: Preparation of (S)-tert-butyl 4-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazine-1-carboxylate

[0812] A solution of (S)-1-(4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)-N,N,N-trimethylammonium iodide (2.0 g, 3.55 mmol, 1.0 equivalent) and N-Boc-piperazine (1.18 g, 5.32 mmol, 1.5 equivalent) in Na₂HPO₄:KH₂PO₄ (pH ~ 7) (20 mL) was stirred at 100 °C for 3 h. The reaction was monitored by TLC. After completion, the mixture was diluted with NaHCO₃ (50 mL) and extracted with 10% MeOH in EtOAc (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue, which was purified by CombiFlash chromatography to give the title compound (0.25 g, 12%). LCMS: 563 [M+H] + .

[0813] Step 3: Preparation of (S)-4-ethyl-4,9-dihydroxy-10-(piperazin-1-ylmethyl)-1H-pyrano[3',4':6,7]indolazido[1,2-b]quinoline-3,14(4H,12H)-dione

[0814] At 0 °C, TFA (0.5 mL) was added dropwise to a stirred solution of (S)-tert-butyl-4-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazine-1-carboxylate (0.25 g, 0.44 mmol, 1.0 equivalent) in DCM (5 mL) and the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After completion, the mixture was quenched with saturated NaHCO3 solution (100 mL) and extracted with 10% MeOH in EtOAc (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] + .

[0815] Step 4a: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)pyridazine-3-carboxamide

[0816] 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)pyridazin-3-carboxamide (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 h. 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 give a crude product, which was purified by CombiFlash chromatography to give the title compound (0.5 g, 62%). LCMS: 468 [M + H] + .

[0817] Step 4: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazin-3-carboxamide (compound 11)

[0818] A catalytic amount of acetic acid (0.1 mL) was added to a solution of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)pyrazin-3-carboxamide (200 mg, 0.432 mmol, 1.0 equivalent) and (S)-4-ethyl-4,9-dihydroxy-10-(piperazin-1-ylmethyl)-1H-pyrano[3',4':6,7]indolazino[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 h. Sodium cyanoborohydride (0.07 g, 1.08 mmol, 2.5 equivalent) was then added to the mixture, and stirring was continued for 1 h. 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 give a crude residue, which was washed with methanol to give the title compound (0.06 g, 15%). 1 H NMR (400MHz, DMSO-d6): δ8.73(s,1H),8.58(d,J=8.33Hz,1H),7.98(d,J=9.21Hz,1H),7.85(d,J=8.77Hz,1H),7.79(d ,J=9.21Hz,1H),7.47-7.36(m,2H),7.32(d,J=9.65Hz,1H),7.26(s,1H),7.13(dd,J=8.77,2.19Hz,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=12.06Hz,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=11.84Hz,2H),0.88(t,J=7.45Hz,3H). LCMS:914[M+H] + .

[0819] Example 12

[0820] Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-((6-(4-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazin-1-yl)-6-oxohexyl)oxy)benzamide (compound 12)

[0821]

[0822] Step 1: Preparation of 4-hydroxybenzoic acid

[0823] A solution of 4N NaOH in 80 mL of water (13.1 g, 328 mmol, 10.0 equivalent) was added to a solution of methylparaben (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 h. The reaction was monitored by TLC. After completion, the mixture was concentrated under reduced pressure and the resulting residue was acidified to pH 3–2 with concentrated HCl. 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] + .

[0824] Step 2: Preparation of 4-(6-methoxy-6-oxohexyloxy)benzoic acid

[0825] 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 min. Ethyl 5-bromohexanoate (1.13 g, 5.43 mmol, 1.5 equivalent) was then added. The resulting mixture was stirred at 50 °C for 16 h. 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] + .

[0826] Step 3: Preparation of methyl 6-(4-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexylcarbamoyl)phenoxy)hexanoate

[0827] At 0 °C, HATU (750 mg, 1.97 mmol, 1.5 equivalent) was added to a solution of 4-(6-methoxy-6-oxohexyloxy)benzoic acid (350 mg, 1.31 mmol, 1.0 equivalent) in dry DMF (5 mL) and stirred for 30 min. 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 resulting mixture was stirred at room temperature for 2 h. 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 unpurified for the next step. LCMS: 499 [M+H] + .

[0828] Step 4: Preparation of 6-(4-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexylcarbamoyl)phenoxy)hexanoic acid. Methyl 6-(4-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexylcarbamoyl)phenoxy)hexanoate (600 mg, 1.20 mmol, 1.0 equivalent) in a solution of THF:MeOH (1:1, 10 mL) was added to 4 M NaOH (144 mg, 3.60 mmol, 3.0 equivalent) and stirred at room temperature for 1 h. The reaction progress was monitored using TLC. After completion, the mixture was concentrated under reduced pressure and acidified to pH 3-4 with concentrated HCl. The obtained solid was then filtered through a Buchner funnel and 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 further purification. LCMS: 485 [M+H] + .

[0829] Step 5: Preparation of (S)-1-(4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)-N,N,N-trimethylammonium iodide

[0830] MeI (0.9 mL) was added to a suspension of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolazino[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 h. After completion, the volatiles were removed under reduced pressure to give the title compound (240 mg, 96%).

[0831] Step 6: Preparation of (S)-tert-butyl 4-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazine-1-carboxylate

[0832] To a suspension of (S)-1-(4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[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), tert-butyl piperazine-1-carboxylate (670 mg, 3.60 mmol, 1.7 equivalent) was added, and the resulting mixture was heated at 80 °C for 16 h and monitored using LC-MS. After completion, the mixture was acidified to pH 6–6.5 with pure 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 further purification. LCMS: 563 [M+H] + .

[0833] Step 7: Preparation of (S)-4-ethyl-4,9-dihydroxy-10-(piperazin-1-ylmethyl)-1H-pyrano[3',4':6,7]indolazido[1,2-b]quinoline-3,14(4H,12H)-dione

[0834] TFA (2 mL) was added to a solution of (S)-tert-butyl-4-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazine-1-carboxylate (1.2 g, 2.13 mmol, 1.0 equivalent) in DCM (20 mL), and the mixture was stirred at room temperature for 16 h. After completion, the volatiles were removed under reduced pressure to give the title compound (700 mg, 71%). LCMS: 463 [M+H] + .

[0835] Step 8: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-((6-(4-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazin-1-yl)-6-oxohexyl)oxy)benzamide (compound 12)

[0836] At 0 °C, HATU (117 mg, 0.309 mmol, 1.5 equivalent) was added to a solution of 6-(4-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexylcarbamoyl)phenoxy)hexanoic acid (100 mg, 0.206 mmol, 1.0 equivalent) in dry DMF (5 mL) and stirred for 30 min. (S)-4-ethyl-4,9-dihydroxy-10-(piperazin-1-ylmethyl)-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H,12H)-dione (95 mg, 0.206 mmol, 1.0 equivalent) was added, followed by DIPEA (78 mg, 0.618 mmol, 3.0 equivalent). The resulting mixture was stirred at room temperature for 2 h. 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 by preparative HPLC to give the title compound (20 mg, 5%). 1H NMR (400MHz, DMSO-d6): δ8.77(s,1H),8.12(t,J=8Hz,1H),7.99(d,J=8Hz,1H),7.85(d,J=8Hz,1H),7.81(d,J =8Hz,2H),7.47(d,J=12Hz,1H),7.38(s,1H),7.26(s,1H),7.13(d,J=12Hz,1H),6.96(d,J=8Hz,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=6Hz ,2H),2.08(m,3H),1.88(m,4H),1.73(t,J=8Hz,2H),1.46(m,8H),0.88(t,J=8Hz,3H). LCMS:929[M+H] + .

[0837] Example 13

[0838] Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinolin-9-yl 4-(6-(3,5-difluoro-4-((1S,3S)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyridino[3,4-b]indol-1-yl)phenoxy)hexyl)piperazine-1-carboxylate (compound 13)

[0839]

[0840] Acetic acid (0.5 mL) was added to a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrido[3',4':6,7]indolazino[1,2-b]quinoline-9-ylpiperazine-1-carboxylate (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) and stirred at room temperature for 15 min. NaBH3CN (64 mg, 1.0 mmol, 2.0 equivalent) was added to the solution and stirred overnight at room temperature. The reaction progress 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 reversed-phase chromatography to obtain the desired product (24 mg, 5%). 1 H NMR (400MHz, DMSO-d6): δ10.51(s,1H),8.94(s,1H),8.18-8.07(m,2H),7.62(d,J=9.2Hz,1H) ,7.44-7.32(m,2H),7.18(d,J=7.9Hz,1H),7.05-6.91(m,2H),6.64(d,J=11.0Hz,1H),6.54(br s,1H),5.43(s,2H),5.31(s,2H),5.12(br s,1H),3.98(t,J=6.4Hz,2H),3.83-3.62(m,5H),2.93-2.76(m,2H),2.45-2.25(m,10H),2.20(s,6H),1.87(dt,J=1 4.0,7.0Hz,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=7.2Hz,3H). LCMS:1004[M+H] + .

[0841] Example 14

[0842] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazine-1-carbonyl)piperidine-1-

[0843] Preparation of pyridazine-3-carboxamide (compound 14)

[0844]

[0845] Step 1: Preparation of (S)-1-(4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)-N,N,N-trimethylmethylammonium iodide

[0846] At room temperature, methyl iodine (2.60 g, 19.0 mmol, 4 equivalents) was added to a solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H,12H)-dione (2.0 g, 4.75 mmol, 1.0 equivalent) in MeOH (50 mL), and the mixture was stirred at the same temperature for 3 h. After 3 h, the mixture was concentrated under reduced pressure to give the quaternary ammonium salt of the compound, which was washed with diethyl ether and dried under reduced pressure to give the title compound (2.0 g, 76%).

[0847] Step 2: Preparation of (S)-tert-butyl 4-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazine-1-carboxylate

[0848] A solution of (S)-1-(4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)-N,N,N-trimethylammonium iodide (2.0 g, 3.55 mmol, 1.0 equivalent) and Boc-piperazine hydrochloride (1.18 g, 5.32 mmol, 1.5 equivalent) in Na₂HPO₄:KH₂PO₄ (pH ~ 7) (20 mL) was heated at 100 °C for 3 h. The reaction was monitored by TLC. After completion, the mixture was diluted with NaHCO₃ (50 mL) and extracted with 10% MeOH in EtOAc (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue, which was purified by CombiFlash chromatography to give the title compound (0.25 g, 12%). LCMS: 563 [M+H] + .

[0849] Step 3: Preparation of (S)-4-ethyl-4,9-dihydroxy-10-(piperazin-1-ylmethyl)-1H-pyrano[3',4':6,7]indolazido[1,2-b]quinoline-3,14(4H,12H)-dione

[0850] At 0 °C, TFA (0.5 mL) was added dropwise to a stirred solution of (S)-tert-butyl-4-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazine-1-carboxylate (0.25 g, 0.44 mmol, 1.0 equivalent) in DCM (5 mL) and the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After completion, the mixture was quenched with saturated NaHCO3 solution (100 mL) and extracted with 10% MeOH in EtOAc (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] + .

[0851] Step 4: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazine-1-carbonyl)piperidin-1-yl)pyridazine-3-carboxamide (compound 14)

[0852] At 0 °C, HATU (0.401 g, 1.05 mmol, 3.0 equivalent) was added to a stirred solution of 1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carboxylic acid (0.170 g, 0.35 mmol, 1.0 equivalent) in DMF (8 mL) and the resulting mixture was stirred at the same temperature for 10 min. DIPEA (0.3 mL, 1.75 mmol, 5.0 equivalence) and (S)-4-ethyl-4,9-dihydroxy-10-(piperazin-1-ylmethyl)-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H,12H)-dione (0.325 g, 0.70 mmol, 1.2 equivalence) were then added sequentially to the mixture, and the mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC and LCMS. After completion, water (10 mL) was added, and the resulting 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%). 1 H NMR (400MHz, DMSO-d6): δ8.79(s,1H),8.59(d,J=8.33Hz,1H),8.00(d,J=9.21Hz,1H),7.86(s,1H),7.81(d,J=9.65Hz,1H),7.48( d,J=9.21Hz,1H),7.42-7.29(m,2H),7.26(s,1H),7.13(dd,J=8.77,2.19Hz,1H),6.49(m,1H),5.42(s,2H),5.26(s,2H),4.58-4.4 1(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),2.35-2.2 7(m,1H),2.10(d,J=10.09Hz,2H),1.94-1.78(m,4H),1.73(d,J=12.28Hz,2H),1.67-1.45(m,4H),1.23(s,2H),0.95-0.78(m,3H). LCMS:928[M+H] + .

[0853] Example 15

[0854] Preparation of (S)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidine-1-yl)-N-(6-(4-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazin-1-yl)hexyl)-2-fluorobenzamide (compound 15)

[0855] Step 1: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidine-1-yl)-2-fluoro-N-(6-hydroxyhexyl)benzamide

[0856] Add 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, 1.1 equivalent) to a stirred solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazol-1-yl) in DMF (10 mL) and allow the reaction mixture to be stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture (monitored by TLC analysis) was quenched with ice water (400 mL × 2) and extracted with EtOAc (200 mL × 2). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to obtain a crude residue, which was purified by CombiFlash chromatography to give the title compound (1.80 g, 75%). LCMS: 551.2 [M+H] + .

[0857] Step 2: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidine-1-yl)-2-fluoro-N-(6-oxohexyl)benzamide

[0858] DMP (0.77 g, 1.82 mmol, 1.67 equivalent) was added to a stirred solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidine-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 allowed to be stirred at room temperature for 1 h. (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] + .

[0859] Step 3: Preparation of tert-butyl 4-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidine-1-yl)-2-fluorobenzamido)hexyl)piperazine-1-carboxylate

[0860] To a stirred solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidine-1-yl)-2-fluoro-N-(6-oxohexyl)benzamide (0.40 g, 0.72 mmol, 1.0 equivalent) and piperazine-1-carboxylic acid tert-butyl ester (0.24 g, 1.08 mmol, 1.5 equivalent) in methanol (5 mL), acetic acid (0.02 mL) and NaCNBH3 (0.03 g, 0.54 mmol, 1.0 equivalent) were added, and the reaction mixture was allowed to be stirred at room temperature for 16 h. 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 with 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] + .

[0861] Step 4: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidine-1-yl)-2-fluoro-N-(6-(piperazin-1-yl)hexyl)benzamide

[0862] TFA (1.5 mL) was added to a stirred solution of 4-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidine-1-yl)-2-fluorobenzamido)hexyl)piperazine-1-carboxylic acid tert-butyl ester (0.30 g, 0.39 mmol, 1.0 equivalent) in DCM (10 mL), and the reaction mixture was allowed to be stirred at room temperature for 1 h. 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] + .

[0863] Step 5: Preparation of (S)-1-(4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)-N,N,N-trimethylammonium

[0864] Methyl iodine (5 mL) was added to a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolazino[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 allowed to be stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture (monitored by TLC analysis) was concentrated under reduced pressure and ground with diethyl ether (50 mL) to obtain the desired product (2.3 g, 92%). LCMS: 436.4 [M+H] + .

[0865] Step 6: Preparation of (S)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidine-1-yl)-N-(6-(4-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazin-1-yl)hexyl)-2-fluorobenzamide (compound 15)

[0866] Add 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiooxoimidazolidine-1-yl)-2-fluoro-N-(6-(piperazin-1-yl)hexyl)benzamide (0.30 g, 0.68 mmol, 1.0 equivalent) and (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H)-dione (0.42 g, 0.68 mmol, 1.0 equivalent) to a stirred solution of KHPO4 and NaHPO4 (20 mL). The reaction mixture is allowed to be stirred at 120 °C for 16 h. After the reaction was complete, the reaction mixture (monitored by TLC analysis) was quenched with Na₂HCO₃ (50 mL × 2) and extracted with 10% MeOH in DCM (20 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 reversed-phase chromatography to obtain the desired product (0.03 g, 6%). LCMS: 996.1 [M + H] + .

[0867] Example 16

[0868] Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(2R,6R)-4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenteno[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)-2,6-dimethylpiperazine-1-carboxylate (compound 16)

[0869]

[0870] Step 1: Preparation of tert-butyl (3R,5R)-4-(chlorocarbonyl)-3,5-dimethylpiperazine-1-carboxylate

[0871] At 0 °C, triphosgene (prepared dissolved in 15 mL DCM) (1.03 g, 3.49 mmol, 0.5 equivalent) was added dropwise to a stirred solution of (3R,5R)-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.5 g, 7.0 mmol, 1.0 equivalent) in DCM (30 mL) and pyridine (1.4 mL, 17.4 mmol, 2.5 equivalent). The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was acidified with 1 N 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%). 1 H NMR (400MHz, CDCl3): δ3.69-3.61(m,4H)3.48(m,2H)1.46(s,9H),1.4(m,6H).

[0872] Step 2: Preparation of 4-(tert-butyl)1-((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)(2R,6R)-2,6-dimethylpiperazine-1,4-dicarboxylate

[0873] DIPEA (2.7 mL, 15.4 mmol, 5.0 equivalence) and DMAP (0.094 g, 0.77 mmol, 0.25 equivalence) were added to a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H)-dione (1.30 g, 3.08 mmol, 1.0 equivalence) in DCM (50 mL). The mixture was stirred at room temperature for 5 min, followed by the slow addition of (3R,5R)-4-(chlorocarbonyl)-3,5-dimethylpiperazin-1-carboxylic acid tert-butyl ester (1.28 g, 4.63 mmol, 1.5 equivalence) dissolved in DCM (20 mL). The resulting mixture was stirred at room temperature for 16 h. 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 provide the desired product. The resulting solid was filtered, washed with pentane, and dried under vacuum (1.2 g, 59%). LCMS: 661.1 [M+H] + .

[0874] Step 3: Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(2R,6R)-2,6-dimethylpiperazine-1-carboxylate

[0875] At 0 °C, trifluoroacetic acid (2 mL) was added dropwise to a stirred solution of 4-(tert-butyl)-1-((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)(2R,6R)-2,6-dimethylpiperazine-1,4-dicarboxylate (1.2 g, 1.8 mmol) in DCM (20 mL), and the resulting solution was stirred at room temperature for 3 h. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure to give a crude product, which was then ground with diethyl ether (200 mL) to give the desired compound (0.95 g, 94%). LCMS: 561.2 [M+H] + .

[0876] Step 4: Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(2R,6R)-4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenteno[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)-2,6-dimethylpiperazine-1-carboxylate (compound 16)

[0877] To (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(2R,6R)-2,6-dimethylpiperazine-1-carboxylate (0.95 g, 1.4 mmol, 1.0 equivalent) and (8S,11R,13S,14S,17R)-1 7-Acetyl-13-methyl-11-(4-(methyl(6-oxohexyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenteno[a]phenanthrene-17-yl acetate (2.3 g, 4.2 mmol, 3.0 equivalent) was added to a stirred solution of methanol (10 mL) with acetic acid (0.5 mL) and stirred at room temperature for 16 h. 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 min. The reaction mixture was then warmed to room temperature and stirred for another 2 h. The reaction progress was monitored by TCL analysis. Water was added to the reactants, which were then filtered and dried to give the desired compound (0.013 g, 1%). 1 H NMR (500MHz, DMSO-d6): δ8.95(s,1H),8.24(s,1H),8.10(d,J=9.06Hz,1H),7.58(d,J=9.06Hz ,1H),7.34(s,1H),7.08-6.85(m,J=8.58Hz,2H),6.67-6.55(m,J=8.58Hz,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,5 H),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=6.20Hz,3H). LCMS:1106.3[M+H] + .

[0878] Example 17

[0879] Preparation of (S)-10-(tert-butoxymethyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl 4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenteno[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylate (compound 17)

[0880]

[0881] Step 1: Preparation of (S)-10-(tert-butoxymethyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H)-dione

[0882] A stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolazino[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 with Na2SO4 and concentrated under reduced pressure to obtain a crude residue, which was purified by silica gel column chromatography (Combiflash, elution: 0-3% MeOH in DCM) to obtain the desired product (0.110 g, 11%). LCMS:451.3[M+H] + .

[0883] Step 2: Preparation of (S)-1-(10-(tert-butoxymethyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)4-(tert-butyl)piperazine-1,4-dicarboxylate

[0884] To a stirred solution of (S)-10-(tert-butoxymethyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H)-dione (0.110 g, 0.24 mmol, 1.0 equivalent) in DCM (10 mL), DIPEA (0.6 mL, 1.21 mmol, 5.0 equivalent) and DMAP (0.0084 g, 0.06 mmol, 0.25 equivalent) were added. The reaction mixture was then allowed to stir at room temperature for 5 min, and tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate (0.026 g, 0.026 mmol, 1.2 equivalent) was added. The reaction mixture was allowed to stir at room temperature for 16 h. 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 silica gel column chromatography (Combiflash, elution: 0–3% MeOH in DCM) to obtain the desired product (0.140 g, 87%). LCMS: 663.1 [M + H] + .

[0885] Step 3: Preparation of (S)-10-(tert-butoxymethyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-ylpiperazine-1-carboxylate

[0886] TFA (0.5 mL) was added to a stirred solution of (S)-1-(10-(tert-butoxymethyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinolin-9-yl)-4-(tert-butyl)piperazine-1,4-dicarboxylate (0.140 g, 0.211 mmol, 1.0 equivalent) in DCM (10 mL), and the reaction mixture was allowed to be stirred at room temperature for 1 h. 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] + .

[0887] Step 4: Preparation of (S)-10-(tert-butoxymethyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl 4-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenteno[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylate (compound 17)

[0888] To (S)-10-(tert-butoxymethyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-ylpiperazine-1-carboxylate (0.090 g, 0.160 mmol, 1.0 equivalent) and (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl) (6-oxohexyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenten[a]phenanthrene-17-yl acetate (0.107 g, 0.192 mmol, 1.2 equivalents) was added to a stirred solution of methanol (10 mL) with acetic acid (0.2 mL) and NaCNBH3 (0.014 g, 0.32 mmol, 2.0 equivalents). The reaction mixture was allowed to be stirred at room temperature for 2 h. 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 with Na2SO4 and concentrated under reduced pressure to obtain a crude residue, which was purified by silica gel column chromatography (Combiflash, elution: 0-3% MeOH in DCM) to obtain the desired product (0.016 g, 9%). 1H NMR (400MHz, DMSO-d6): δ8.83(s,1H),8.14(d,J=9.1Hz,1H),7.65(d,J=9.1Hz,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=6.2Hz,1H),3.68(br s,2H),3.46(br s,3H),3.25(d,J=6.7Hz,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=7.6Hz,4H),1.73(d,J=19.6Hz,2H),1.45(br s, 4H), 1.39-1.26 (m, 18H), 1.22 (s, 3H), 0.89 (t, J = 7.2Hz, 3H), 0.24 (s, 3H). LCMS:1107.2[M+H] + .

[0889] Example 18

[0890] Preparation of 2-(((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-oxohexadecylhydro-1H-cyclopenteno[a]phenanthrene-17-yl)oxy)-N-(1-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperidin-4-yl)-N-methylacetamide (compound 18)

[0891]

[0892] Step 1: Synthesis of (S)-(1-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperidin-4-yl)(methyl)carbamate tert-butyl ester (intermediate 3)

[0893] At room temperature, a 37% formaldehyde solution (0.3 mL, 3.29 mmol, 1.5 equivalent) was added to a stirred solution of (S)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H)-dione (intermediate 1, 1.0 g, 2.74 mmol, 1.0 equivalent) and methyl(piperidin-4-yl)carbamate tert-butyl ester (intermediate 2, 881 mg, 4.12 mmol, 1.5 equivalent) in acetic acid (10 mL). The reaction mixture was heated to 80 °C and stirred for 3 h 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 pH 9, the solid was filtered and washed with water, and dried under vacuum to give intermediate 3 (1.1 g, 68%). 1 H NMR(400MHz, DMSO-d6)δ8.72(s,1H)7.97(d,J=9.39Hz,1H)7.41(d,J=9.00Hz,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=10.96Hz,2H)2.66(s,3H)2.24(br t,J=11.15Hz,2H)1.77-1.95(m,3H)1.68(br d,J=11.35Hz,2H)1.55(br (s, 2H) 1.39 (s, 9H) 0.87 (t, J = 7.24 Hz, 3H) (1H exchangeable hydrogen was not observed in the spectrum). LCMS: 591.2 [M+H] + .

[0894] Step 2: Synthesis of (S)-4-ethyl-4,9-dihydroxy-10-((4-(methylamino)piperidin-1-yl)methyl)-1,12-dihydro-14H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H)-dione TFA salt (intermediate 4)

[0895] TFA (1.8 mL, 18.6 mmol, 10 equivalence) was added to a stirred solution of (S)-(1-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperidin-4-yl)(methyl)carbamate (intermediate 3, 1.1 g, 1.86 mmol, 1.0 equivalence) in DCM (20 mL) at 0 °C under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. 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 intermediate 4 (900 mg, 98%) as a TFA salt. 1 H NMR(400MHz,DMSO-d6)δ11.36(br s,1H)9.70(br s,1H)8.85-8.90(m,2H)8.19(d,J=9.13Hz,1H)7.65(d,J=9.38Hz,1H)7.23-7.34(m,1H)6.50(brs,1H)5.43(s,2H)5.28(s,2H)4.71(br s,2H)3.65(br d,J=1.63Hz,2H)3.38(q,J=7.00Hz,1H)3.25(br s,2H)2.58(s,3H)2.19(br d,J=10.26Hz,2H)1.77-1.94(m,4H)0.89(t,J=7.32Hz,3H). LCMS:491.45[M+H] + .

[0896] Step 3: Synthesis of 2-(((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-oxohexadecylhydro-1H-cyclopenteno[a]phenanthrene-17-yl)oxy)-N-(1-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperidin-4-yl)-N-methylacetamide (18)

[0897] At room temperature, (S)-4-ethyl-4,9-dihydroxy-10-((4-(methylamino)piperidin-1-yl)methyl)-1,12-dihydro-14H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H)-dione TFA salt intermediate 4 (250 mg, 0.51 mmol, 1.0 equivalent) and 2-(((5S,9S,10S,13S,14) S,17S)-10,13-dimethyl-3-oxohexadecylhydro-1H-cyclopenteno[a]phenanthrene-17-yl)oxy)acetic acid intermediate 5 (195 mg, 0.56 mmol, 1.1 equivalents) was added to a stirred solution of DMF (5 mL) with HATU (273 mg, 0.76 mmol, 1.5 equivalents) and DIPEA (0.3 mL, 1.53 mmol, 3 equivalents) and stirred for 16 h. 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%). 1 H NMR(400MHz, DMSO-d6)δ8.74(br s,1H)7.98(d,J=9.13Hz,1H)7.43(dd,J=9.13,5.00Hz,1H)7.26(s,1H)6.47(br d,J=2.00Hz,1H)5.41(s,2H)5.26(s,2H)4.18-4.33(m,1H)4.09(brs,4H)3.70-3.83(m,1H)3.30-3.40(m,3H)3.05(br d,J=10.88Hz,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 was not observed in the spectrum). LCMS: 821.7 [M+H] + HPLC purity: 97.9%.

[0898] Example 19

[0899] (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-(4-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazin-1-yl)-6-oxohexyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecano-1H-cyclopenteno[a]

[0900] Preparation of phenanthrene-17-ylacetic acid ester (compound 19)

[0901]

[0902] Step 1: Synthesis of (S)-4-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 3)

[0903] At room temperature, under an inert atmosphere, a 37% formaldehyde solution (0.29 mL, 8.24 mmol, 1.2 equivalent) was added to a stirred solution of (S)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H)-dione HCl salt intermediate 1 (2.5 g, 6.86 mmol, 1.0 equivalent) and piperazine-1-carboxylic acid tert-butyl ester intermediate 2 (1.85 g, 10.3 mmol, 1.5 equivalent) in acetic acid (10 mL). The reaction mixture was heated to 80 °C and stirred for 2 h 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 (10 mL), and dried under vacuum to give intermediate 3 (1.9 g, 50%). LCMS: 463.46 (M-100, Boc group cleavage observed in LCMS) [M-Boc+H] + .

[0904] Step 2: Synthesis of (S)-4-ethyl-4,9-dihydroxy-10-(piperazin-1-ylmethyl)-1,12-dihydro-14H-pyrano[3',4':6,7]indolazido[1,2-b]quinoline-3,14(4H)-dione TFA salt (intermediate 4)

[0905] At 0 °C, under a nitrogen atmosphere, TFA (2.7 mL, 35 mmol, 10 equivalence) was added to a stirred solution of (S)-4-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 3, 2 g, 3.5 mmol, 1.0 equivalence) in DCM (20 mL). The mixture was warmed to room temperature and stirred for 2 h. 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 intermediate 4 (1.4 g, 83%). 1 H NMR(400MHz,DMSO-d6)δ8.86(br s,2H)8.10(d,J=9.25Hz,1H)7.58(d,J=9.25Hz,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=7.17Hz,3H).

[0906] Step 3: Synthesis of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methylamino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenten[a]phenanthrene-17-yl acetate (intermediate 5)

[0907] Potassium acetate (4.12 g, 4.2 mmol, 1.0 equivalent) and iodine (2.65 g, 21 mmol, 5 equivalent) were added to a stirred solution of ullistat acetate (2.0 g, 4.2 mmol, 1.0 equivalent) in methanol (30 mL) and THF (30 mL) and stirred for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, a saturated solution of sodium thiosulfate (100 mL) was added to the reaction mixture, the solid was filtered and washed with diethyl ether (30 mL), and dried under vacuum to give intermediate 5 (1.7 g, 87%). 1H NMR(400MHz, DMSO-d6)δ7.00(br d,J=8.31Hz,1H)6.91(br d,J=8.31Hz,1H)6.74(br d,J=8.80Hz,1H)6.44(br d,J=8.80Hz,1H)5.67(s,1H)4.66-4.75(m,1H)4.39(br dd,J=19.32,6.60Hz,1H)2.75(s,3H)2.61(br d,J=4.40Hz,2H)2.34(brdd,J=11.74,3.42Hz,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] + .

[0908] Step 4: Synthesis of 6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecano-1H-cyclopenten[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexanoic acid (intermediate 7)

[0909] Intermediate 6 (2.1 g, 10.8 mmol, 5 equivalents) and NaHCO3 (1.84 g, 21.6 mmol, 10 equivalents) were added to a stirred solution of intermediate 5 (1 g, 2.1 mmol, 1.0 equivalents) in ethanol (15 mL) and water (15 mL) at 0 °C. The reaction mixture was heated at 80 °C for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, 2 M HCl in ethanol (10 mL) was added to the reaction mixture until the pH reached 6. The mixture was then extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The obtained crude compound was purified by passing it through a Combiflash column using 5% methanol in dichloromethane to give intermediate 7 (250 mg, 20%). 1H NMR(400MHz,DMSO-d6)δ6.97(br d,J=8.22Hz,2H)6.57(br d,J=8.22Hz,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 was not seen in the spectrum).

[0910] Step 5: Synthesis of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-(4-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-10-yl)methyl)piperazin-1-yl)-6-oxohexyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecylhydro-1H-cyclopenteno[a]phenanthrene-17-yl acetate (19)

[0911] At room temperature, 6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecano-1H-cyclopenten[a]phenanthrene-11-yl)phenyl)(methyl)amino)hexanoic acid intermediate 7 (200 mg, 0.34 mmol, 1.0 equivalent) and (S)-4-ethyl-4,9-dihydroxy-10-( Piperazin-1-ylmethyl)-1,12-dihydro-14H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-3,14(4H)dione TFA salt (intermediate 4, 192 mg, 0.41 mmol, 1.2 equivalents) was added to a stirred solution of DMF (2 mL) with HATU (186 mg, 0.52 mmol, 1.5 equivalents) and DIPEA (0.090 mL, 0.52 mmol, 1.5 equivalents) and stirred for 4 h. 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 off and washed with water (10 mL) and dried under vacuum to obtain the crude compound. The obtained crude compound was purified by Combiflash column chromatography using 7% methanol in dichloromethane to give the desired product (60 mg, 16%). 1 H NMR(400MHz, DMSO-d6)δ11.35(br s,1H)9.65(br s,1H)8.94(s,1H)8.21(d,J=9.25Hz,1H)7.64(d,J=9.25Hz,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=6.94Hz,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=7.17Hz,3H)0.22(s,3H). LCMS:511.4[M / 2+H] + 1018.6 [MH] - HPLC purity: 95.1%.

[0912] Example 20

[0913] Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl(1-(2-(((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-oxohexadecylhydro-1H-cyclopenteno[a]phenanthrene-17-yl)oxy)acetyl)piperidin-4-yl)(methyl)carbamate (compound 21)

[0914] Step 1: Synthesis of tert-butyl 4-((chlorocarbonyl)(methyl)amino)piperidine-1-carboxylate (intermediate 2)

[0915] At 0 °C, pyridine (1.10 mL, 13 mmol, 1.5 equivalence) was added to a stirred solution of tert-butyl 4-(methylamino)piperidine-1-carboxylate (intermediate 1, 2.0 g, 9.3 mmol, 1.0 equivalence) in DCM (30 mL), followed by triphosgene (830 mg, 2.7 mmol, 0.3 equivalence). The mixture was warmed to room temperature and stirred for 2 h. 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 x 60 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give intermediate 2 (2.0 g, crude), which was used in the next step without further purification.

[0916] Step 2: Synthesis of (S)-4-((((10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)oxy)carbonyl)(methyl)amino)piperidine-1-carboxylic acid tert-butyl ester (intermediate 4)

[0917] At 0 °C, (S)-10-((dimethylamino)methyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 2, 2 g, 7.2 mmol, 1.0 equivalent) and DIPEA (8 mL, 38 mmol, 5 equivalent) were added to a stirred solution of 4-((chlorocarbonyl)(methyl)amino)piperidine-1-carboxylic acid tert-butyl ester (intermediate 2, 2 g, 7.2 mmol, 1.0 equivalent) in DMF (15 mL) and THF (15 mL). The mixture was heated to room temperature and stirred for 16 h. 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 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a crude compound. The obtained crude compound was purified by passing it through a Combiflash column using 5% methanol in dichloromethane to give intermediate 4 (690 mg, 24%). 1 HNMR(400MHz, DMSO-d6)δ8.94(s,1H)8.10(br d,J=9.29Hz,1H)7.62(br d,J=9.29Hz,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=7.34Hz,3H). LCMS:661.4[M+H] + .

[0918] Step 3: Synthesis of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-ylmethyl(piperidin-4-yl)carbamate (intermediate 5)

[0919] At 0 °C, under a nitrogen atmosphere, TFA (1.2 mL, 20 mmol, 20 equivalence) was added to a stirred solution of (S)-4-((((10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolazino[1,2-b]quinoline-9-yl)oxy)carbonyl)(methyl)amino)piperidine-1-carboxylic acid tert-butyl e...

Claims

1. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and 。 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 3. The compound according to claim 1, wherein the compound is 。 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 5. The compound according to claim 1, wherein the compound is 。 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 7. The compound according to claim 1, wherein the compound is 。 8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 9. The compound according to claim 1, wherein the compound is 。 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 11. The compound according to claim 1, wherein the compound is 。 12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is 。 13. The compound according to claim 1, wherein the compound is 。 14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 15. The compound according to claim 1, wherein the compound is 。 16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 。 17. The compound according to claim 1, wherein the compound is 。

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