Anti-cancer nuclear hormone receptor targeting compounds

Abstract

Provided herein is a composition comprising nuclear payload (comprising topoisomerase inhibitor, topoisomerase poison or its analogue) and nuclear receptor targeting epitope.The compounds described herein are designed to bind to intracellular nuclear receptor, and allow the compound with its nuclear payload to accumulate in the nucleus.Without wishing to be bound by theory, one of the potential ways of enhancing utility is that this approach can provide compounds that not only have improved efficacy, but also have cell type selectivity and work towards a higher therapeutic index.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 377,511, filed September 28, 2022, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] background Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are divided into two broad subtypes: topoisomerase type I (TopI) and topoisomerase type II (TopII). Topoisomerases mediate the cleavage of single- and double-stranded DNA in eukaryotic cells, relaxing supercoils, uncoiling catenanes, and condensing chromosomes, thus playing a critical role in cellular reproduction and DNA organization. Topoisomerase inhibitors affect these essential cellular processes. Some topoisomerase inhibitors prevent topoisomerases from making DNA strand breaks, while others associate with the topoisomerase-DNA complex and block the religation step of the topoisomerase mechanism. These complexes are cytotoxic agents because the unrepaired single- and double-stranded DNA breaks caused by these topoisomerase-DNA-inhibitor complexes can lead to apoptosis and cell death. Because of their ability to induce apoptosis, topoisomerase inhibitors are of great interest as therapeutic agents against infected and cancerous cells.

[0003] Camptothecin (CPT) is a topoisomerase-blocking poison. It was isolated from the bark and stem of Camptotheca acuminata (Happy Tree), a native Chinese tree used as a cancer treatment in traditional Chinese medicine. In preliminary clinical trials, CPT demonstrated significant anticancer activity, particularly against breast, ovarian, colon, lung, and stomach cancers. However, camptothecin has poor solubility and reported adverse effects when used therapeutically. Therefore, synthetic and medicinal chemists have developed numerous syntheses of camptothecin and various derivatives with increasing chemical benefits, with good results. Four CPT analogs, namely topotecan, irinotecan, belotecan, and trastuzumab derxitecan, have been approved and are currently used in cancer chemotherapy. In addition to being an antitumor agent, camptothecin also exhibits anti-HIV activity by interfering with the self-association of viral infectivity factors found in many retroviruses, including HIV.

[0004] In the future, numerous alternative uses for topoisomerase poisons are likely, including lupus, rare brain disorders, sepsis, and viral and trypanosome infections. As additional roles for Top1 (such as newly discovered regulatory functions) emerge and Top1 continues to be implicated in disease states, novel drug discovery (and off-label use of drugs) efforts will likely continue for many years to come. Summary of the Invention [Means for solving the problem]

[0005] summary Provided herein is a compound comprising a nuclear payload (e.g., a topoisomerase inhibitor, a topoisomerase poison, or its analog) and a nuclear receptor targeting epitope.The compounds described herein are designed to bind to intracellular nuclear receptors, allowing the compound with its nuclear payload to accumulate in the nucleus.Without wishing to be bound by theory, one potential mode of enhanced utility is that this approach can provide compounds that not only have improved efficacy, but also have cell type selectivity and work toward a higher therapeutic index.However, the compounds may be activated by other modes, such as, but not limited to, passive localization in the nucleus.

[0006] Furthermore, the compounds described herein provide targeted delivery of nuclear payloads. The compounds target tumor tissue and are localized therein. The transport of a compound comprising at least one nuclear receptor targeting epitope, such as a nuclear steroid receptor targeting epitope, covalently linked to at least one nuclear payload into the nucleus allows the nuclear payload to accumulate in the nucleus, enhancing tumor cell death. By doing so, the compounds described herein can exhibit excellent efficacy. Furthermore, the compounds described herein can accumulate in the nucleus of nuclear receptor-positive cells, such as steroid receptor-positive cells, sparing cells that do not express certain nuclear steroid receptors, thereby reducing side effects.

[0007] In certain embodiments, there is provided a compound of Formula I, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, A 1 -L 1 -B 1 I During the ceremony, B 1 is a nuclear receptor targeting epitope, L 1 is a covalent bond or linking moiety, A 1 is represented by formula IA: [ka] It is of During the ceremony, R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, halo, cyano, nitro, -OR 15 , -SR 15 , -NR 15 R 16 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -C(=O)R 15 , -C(=O)OR 15 , -OC(=O)R 15 , -OC(=O)NR 15 R 16 , -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) 1~2 NR 15 R 16 , -NR 15 S(=O) 1~2 R 16 , -Si(R 15 )3 or -C=NOR 15 and each of them may contain, as valence permits, one or more R 10 or independently and optionally replaced by or R 1 and R 2 together with the atoms to which they are attached, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12aryl or 5- to 12-membered heteroaryl, each of which, valence permitting, may be joined by one or more R 10 or independently and optionally replaced by or R 2 and R 3 together with the atoms to which they are attached, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 aryl or 5- to 12-membered heteroaryl, each of which, valence permitting, may be joined by one or more R 10 or independently and optionally replaced by or R 3 and R 4 together with the atoms to which they are attached, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 aryl or 5- to 12-membered heteroaryl, each of which, valence permitting, may be joined by one or more R 10 and independently and optionally substituted by Each R 10 are independently halo, cyano, nitro, -OR 17 , -SR 17 , -SF5, -NR 17 R 18 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered 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 and each of them is halo, cyano, nitro, hydroxyl, amino, C, as far as valence allows. 1~12 Alkoxy, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 is optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R 15 and R 16 are independently hydrogen, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 aryl or 5- to 12-membered heteroaryl, each of which, as valence permits, is selected from halo, cyano, nitro, hydroxyl, amino, C 1~12 Alkoxyl, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; or R 15 and R 16together with the atom to which they are attached, valence permitting, halo, cyano, nitro, hydroxyl, amino, C 1~12 Alkoxyl, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 forming a 5- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R 17 and R 18 are independently hydrogen, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 aryl or 5- to 12-membered heteroaryl, each of which, as valence permits, is selected from halo, cyano, nitro, hydroxyl, amino, C 1~12 Alkoxyl, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; or R 17 and R 18 together with the atom to which they are attached, valence permitting, halo, cyano, nitro, hydroxyl, amino, C 1~12 Alkoxyl, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 forming a 5- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; One or more atoms of formula IA (e.g., hydrogen, methyl, or hydroxyl) may be L 1 is replaced by a direct covalent bond to

[0008] Similarly, provided are compounds of Table 1, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof.

[0009] Also provided are compositions comprising a compound described herein, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0010] Also provided are methods of treating or preventing cancer, including administering an effective amount of a compound or composition described herein to an individual in need thereof. Cancers include, but are not limited to, liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft tissue sarcoma, chronic lymphocytic leukemia, Wandenstrom's macroglobulinemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small cell lung carcinoma, gastric carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid ... The cancer may be chromoma, choriocarcinoma, mycosis fungoides, head and neck carcinoma, osteosarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenocortical carcinoma, skin cancer, trophoblastic neoplasm, or blood cancer such as prostate carcinoma, 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.

[0011] Similarly, methods for treating or preventing cancer are provided, comprising administering to an individual in need thereof an effective amount of a compound or composition described herein. DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description The following description describes exemplary embodiments of the present technology, but it should be recognized that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

[0013] 1.Definition As used herein, the following words, phrases, and symbols are intended to have the meanings generally set forth below, except to the extent that the context in which they are used indicates otherwise.

[0014] The term "about" refers to a variation of ±1%, ±3%, ±5%, or ±10% of the specified value. For example, "about 50" may, in some embodiments, include a range of 45 to 55. In the case of integer ranges, the term "about" may include one or two integers greater than and / or less than the recited integers at either end of the range. Unless otherwise indicated herein, the term "about" is intended to include values ​​adjacent to the recited range, e.g., weight percent, that are equivalent in terms of the function of the individual component, composition, or embodiment. Also, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "the compound" includes a plurality of such compounds, and a reference to "the assay" includes a reference to one or more compounds and equivalents thereof known to those of skill in the art.

[0015] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 12 carbon atoms ("C 1~12 alkyl"), 1 to 10 carbon atoms (i.e., C 1~10alkyl), 1 to 8 carbon atoms (i.e., C 1~8 alkyl), 1 to 6 carbon atoms (i.e., C 1~6 alkyl) or 1 to 4 carbon atoms (i.e., C 1~4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by a chemical name or specified by a molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0016] "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more hydrogen atoms are replaced by halogen. For example, if a residue is substituted with more than one halogen, the residue may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which may, but need not, be the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0017] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced with the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NH-, -O-, -S-, -S(O)-, -S(O)2-, and the like. As used herein, heteroalkyl includes 1 to 8 carbon atoms or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced with the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NH-, -O-, -S-, -S(O)-, and -S(O)-. Examples of heteroalkyl groups include, for example, ethers (e.g., -CHOCH, -CH(CH)OCH, -CHCHOCH, -CHCHOCH, -CHCHOCHCHOCH, etc.), thioethers (e.g., -CHSCH, -CH(CH)SCH, -CHCHSCH, -CHCHSCH, -CHCHSCHCHSCH, etc.), sulfones (e.g., -CHS(O)CH, -CH(CH)S(O)CH, -CHCHS(O) and amines (e.g., -CHNHCH, -CH(CH)NHCH, -CHCHNHCH, -CHCHNHCH, -CHCHNHCHNHCH. As used herein, heteroalkyl includes 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.

[0018] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2~4 It refers to an alkyl group having an alkenyl group. Examples of alkenyl groups include, for example, ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0019] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2~4 The term "alkynyl" refers to an alkyl group having one triple bond and one double bond.

[0020] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0021] "Alkoxyalkyl" refers to the group "alkyl-O-alkyl."

[0022] "Amino" means -NR y R z refers to the group, where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0023] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to an aromatic carbocyclic group having 6 to 20 ring carbon atoms (i.e., C 6~20 aryl), 6 to 12 ring carbon atoms (i.e., C 6~12 aryl), or 6 to 10 ring carbon atoms (i.e., C 6~10 aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. When one or more aryl groups are fused to a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused to a heterocyclyl, the resulting ring system is a heterocyclyl.

[0024] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and cyclic groups having at least one sp 3 As used herein, cycloalkyl includes carbocyclic fused ring systems having 3 to 20 ring carbon atoms (i.e., at least one non-aromatic ring). 3~20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3~6Cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring that can be fused to an aryl ring, regardless of attachment to the rest of the molecule. Furthermore, cycloalkyl also includes "spirocycloalkyl" when there are two substitution positions on the same carbon atom.

[0025] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to an aromatic group having 1 to 20 ring carbon atoms (i.e., C 1~20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3~12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3~8Heteroaryl) and contains 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain cases, heteroaryl includes 5- to 10-membered, 5- to 7-membered, or 5- to 6-membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, and isoquinolyl. , isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, thiophenyl (i.e., thienyl), triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl (wherein the heteroaryl can be attached via either ring of the fused system). Any aromatic ring having single or multiple fused rings and containing at least one heteroatom is considered heteroaryl, regardless of attachment to the rest of the molecule (i.e., via any one of the fused rings).Heteroaryl does not encompass or overlap with aryl as defined above.

[0026] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. A heterocyclyl may be a single ring or multiple rings, where the multiple rings may be fused, bridged, or spiro, and may contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O). - ) moiety. Any non-aromatic ring containing at least one heteroatom is considered heterocyclyl, regardless of attachment (i.e., whether bonded through a carbon atom or a heteroatom). Additionally, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, and may be fused to an aryl or heteroaryl ring, regardless of attachment to the remainder of the molecule. As used herein, heterocyclyl refers to a ring having 2 to 20 ring carbon atoms (i.e., C 2~20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2~12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2~10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2~8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3~12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3~8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3~6Heterocyclyl) has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. The term "heterocyclyl" also includes "spiroheterocyclyl" when there are two substitution positions on the same carbon atom. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindoline, and the like.

[0033] Heterocyclyl includes aryl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term "heterocyclyl" also includes "spiroheterocyclyl" when there are two substitution positions on the same carbon atom. Examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as, for example, oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl (wherein the heterocyclyl may be attached via either ring of the fused system).

[0027] "Alkylene" refers to a divalent alkyl group, as defined above.

[0028] "Alkenylene" refers to a divalent alkenyl group, as defined above.

[0029] "Alkynylene" refers to a divalent alkynyl group, as defined above.

[0030] "Arylene" refers to a divalent aryl group, as defined above.

[0031] "Cycloalkylene" refers to a divalent cycloalkyl group, as defined above.

[0032] "Heterocyclylene" refers to a divalent heterocyclyl group, as defined above.

[0033] "Heteroarylene" refers to a divalent heteroaryl group, as defined above.

[0034] "Oxo" refers to =O.

[0035] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo.

[0036] The term "optionally" or "optionally" means that the event or circumstance described below may or may not occur. The term "optionally substituted" refers to the fact that any one or more hydrogen atoms on the specified atom or group may or may not be replaced with a non-hydrogen moiety.

[0037] As used herein, "substituted" means that one or more hydrogen atoms of a group are replaced with a substituting atom or substituent commonly used in pharmaceutical chemistry. Each substituent may be the same or different. Examples of suitable substituents include hydrazide, halo, -CN, -NO, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR, and the like. 56 , -C(O)OR 56 , -C(O)R 56 , -O-alkyl-OR 56 , -alkyl-OR 56 , haloalkyl, haloalkoxy, SR 56 , S(O)R 56 , SO2R 56 , N.R. 56 R 57 , -C(O)NR 56 R 57 , N.R. 56 C(O)R 57 (including seleno and thio derivatives thereof), where each R 56 and R 57 is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkyl-alkyl-, heterocyclyl, heterocyclyl-alkyl-, aryl, aryl-alkyl-, heteroaryl, or heteroaryl-alkyl-, and wherein each substituent may be further optionally substituted.

[0038] Also provided are stereoisomers, mixtures of stereoisomers, tautomers, hydrates, solvates, isotopically enriched analogs, and pharmaceutically acceptable salts of the compounds described herein.

[0039] The compounds disclosed herein, or their pharmaceutically acceptable salts, may contain asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined with respect to absolute stereochemistry as (R)- or (S)-, or for amino acids, as (D)- or (L)-. The present disclosure is intended to include all such possible isomers, as well as their racemates 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, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-performance liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0040] "Stereoisomer" refers to a compound composed of the same atoms bonded by the same bonds but with different, incompatible three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another, and "diastereomers," which refer to stereoisomers that have at least two asymmetric atoms but are not mirror images of one another. Thus, all stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the present compounds (including salts, solvates, and hydrates of the present compounds), including those that may exist due to asymmetric carbons on various substituents (including enantiomeric forms (which may exist even when asymmetric carbons are absent), rotamer forms, atropisomers, and diastereomeric forms), are contemplated.

[0041] Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers (e.g., by hydrolysis). Some of the compounds may also be atropisomers, and are considered part of this disclosure. Stereoisomers can also be separated using chiral HPLC.

[0042] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, the compound is understood by those skilled in the art to include both the amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0043] The term "hydrate" refers to a complex formed by combining a compound described herein with water.

[0044] "Solvate" refers to 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.

[0045] Any formula or structure described herein is also intended to represent unlabeled and isotopically labeled forms of compounds.These forms of compounds are sometimes referred to as "isotopically enriched analogs."Isotopically labeled compounds have the structure shown herein, except that one or more atoms are replaced by atoms with selected atomic masses or mass numbers.Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, for example, 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. Various isotopically labeled compounds of the present disclosure, such as 3 H and 14 Those incorporating a radioactive isotope such as C. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) (including drug or substrate tissue distribution assays), or in radiotherapy of patients. Such compounds may exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound when administered to mammals, particularly humans. Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0046] Certain compounds disclosed herein contain one or more ionizable groups (groups that can remove a proton (e.g., —COOH) or add a proton (e.g., an amine), or groups that can be quaternized (e.g., an amine)). All possible ionic forms of such molecules and salts thereof are intended to be included individually in the disclosure herein. With respect to salts of the compounds described herein, one of skill in the art can select an appropriate counterion from among a wide variety of available counterions. In certain applications, the selection of a given anion or cation for the preparation of a salt can increase or decrease the solubility of the salt.

[0047] As used herein, the term "non-biocleavable linking moiety" is intended to refer to a linking moiety that is not readily hydrolyzed under physiological conditions. As used herein, the term "biocleavable linking moiety" is intended to refer to a linking moiety that is readily hydrolyzed under physiological conditions. In certain embodiments, at least one linking moiety is hydrolyzed under intracellular conditions (e.g., low pH). In some embodiments, biocleavability is self-cleaving and does not require physiological hydrolysis; in other embodiments, cleavage of a biocleavable linker is initiated by metabolic activation, such as oxidation, or pH-dependent cleavage without hydrolysis, such as by base- or acid-induced elimination. More broadly, biocleavable linkers can, in some instances, be similar to prodrugs, where one or more drugs are released upon cleavage. In this sense, there are numerous mechanisms for cleaving a prodrug to release the active entity or a precursor to the active entity, and there are also numerous and varied cleavage moieties known in the prodrug art and are included in our definition herein.

[0048] As used herein, the term "cancer" refers to a class of mammalian diseases characterized by uncontrolled cell growth. The term "cancer" is used interchangeably with the terms "tumor," "solid tumor," "malignant tumor," "hyperproliferative," and "neoplasm." Cancer includes all types of hyperproliferative, hyperplastic, neoplastic, cancerous growths, or oncogenic processes, metastatic tissues, or malignantly transformed cells, tissues, or organs, regardless of histopathological type or stage of invasion. 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 most lethal malignant primary brain tumor in adults).

[0049] 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 for the particular cells that form them, such as sarcomas formed from connective tissue cells (e.g., bone, cartilage, fat), carcinomas formed from epithelial tissue cells (e.g., breast, colon, pancreas), and lymphomas formed from lymphatic tissue cells (e.g., lymph nodes, spleen, and thymus). Regardless of the naming convention, treatment of all types of solid tumors is within the scope of this disclosure.

[0050] "Chemotherapeutic agent" refers to any substance that can reduce or prevent the growth, proliferation, or spread of cancer cells, populations of cancer cells, tumors, or other malignant tissue. The term is also intended to encompass radiation therapy or any anti-tumor or anti-cancer agent.

[0051] As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired results, such as clinical results. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms associated with a disease or condition, and / or reduction in the severity of symptoms, and / or prevention of worsening of symptoms. In one variation, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms associated with cognitive disorders, psychiatric disorders, neurotransmitter-mediated disorders, and / or neurological disorders, and / or reduction in the severity of symptoms, and / or prevention of worsening of symptoms. In one embodiment, treatment of a disease or condition with a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, achieves no or fewer side effects associated with currently available treatments for the disease or condition and / or improves the quality of life of the individual.

[0052] The terms "inhibit," "inhibiting," and "inhibition" refer to slowing, stopping, or reversing the growth or progression of a disease, infection, condition, or group of cells. Inhibition can be, for example, greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99% compared to growth or progression that occurs in the absence of treatment or contact.

[0053] As used herein, "combination therapy" refers to a therapy comprising two or more different compounds. Thus, in one aspect, a combination therapy comprising a compound detailed herein and anther compound is provided. In some variations, the combination therapy optionally includes one or more pharmaceutically acceptable carriers or additives, non-pharmaceutically active compounds, and / or inactive substances. In various embodiments, treatment with a combination therapy may produce additive or even synergistic (e.g., greater than additive) results compared to administration of a single compound of the present 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 the individual therapy. In one embodiment, the same or greater therapeutic effect is achieved by using the combination therapy than by using any of the individual compounds alone. In some embodiments, the same or greater therapeutic effect is achieved by using a lower amount of the compound in the combination therapy (e.g., a lower dose or a less frequent administration schedule) than the amount typically used for the individual compound or therapy. Preferably, the use of lower amounts of the compound results in a reduction in the number, severity, frequency, and / or duration of one or more side effects associated with the compound.

[0054] As used herein, the term "effective amount" refers to the amount of a compound of the present disclosure that should be effective in a given treatment regimen, based on efficacy and toxicity parameters and the knowledge of the practitioner.As understood in the art, an effective amount can be one or more doses, i.e., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint.An effective amount can be considered in the context of administering one or more therapeutic agents, and a single agent can be considered to be given in an effective amount if a desired or beneficial result can be achieved or is achieved in conjunction with one or more other agents.The appropriate dose of any co-administered compound can be lowered as necessary due to the combined effects (e.g., additive or synergistic effects) of the compounds.

[0055] As used herein, IC 50 refers to the amount, concentration, or dosage of a particular test compound that achieves 50% inhibition of a maximal response, such as modulation of PARP, in an assay that measures such response.

[0056] As used herein, EC 50 refers to the dose, concentration, or amount of a particular test compound that elicits a dose-dependent response at 50% of the maximal expression of the particular response induced, elicited, or potentiated by the particular test compound.

[0057] The term "cancer," as used herein, refers to an abnormal growth of cells that tend to proliferate uncontrolled and, in some cases, metastasize (spread). Types of cancer include, but are not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas, or other endocrine organs (thyroid)), prostate, skin (melanoma), or blood tumors (such as leukemia).

[0058] As used herein, the term "carrier" refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.

[0059] As used herein, "unit dosage form" refers to physically discrete units suitable as unitary dosage forms, each unit containing a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may include monotherapy or combination therapy.

[0060] As used herein, the term "controlled release" refers to a drug-containing formulation or fraction thereof in which the release of the drug is not immediate; i.e., in a "controlled release" formulation, administration does not result in the immediate release of the drug into an absorption pool. The term also encompasses depot formulations designed to gradually release a drug compound over an extended period of time. Controlled release formulations can include a wide variety of drug delivery systems, generally involving mixing a drug compound with a carrier, polymer, or other compound having the desired release characteristics (e.g., pH-dependent or pH-independent solubility, varying degrees of water solubility, etc.) and formulating the mixture according to the desired delivery route (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, etc.).

[0061] As used herein, "pharmaceutically acceptable" or "pharmacologically acceptable" intends a material that is not biologically or otherwise undesirable, e.g., 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 deleterious manner with any of the other components of the composition in which it is contained. A pharmaceutically acceptable carrier or excipient preferably meets the required standards of toxicological and manufacturing testing and / or is included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0062] A "pharmaceutically acceptable salt" is a salt that retains 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. Examples of such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, and tartaric acid; and (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Further 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 the manufacturing process or by separately reacting the purified compounds of the present disclosure in their free or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification. Reference to a pharmaceutically acceptable salt should be understood to include its solvent addition or crystalline forms, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are often formed during the crystallization process. They form hydrates when the solvent is water, or alcoholate salts when the solvent is alcohol. Polymorphs include different crystalline packing arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Various factors, such as the recrystallization solvent, crystallization rate, and storage temperature, can cause a single crystalline form to predominate.

[0063] As used herein, the term "excipient" refers to an inactive or non-active substance that may be used in the manufacture of a drug or pharmaceutical preparation, such as a tablet, containing a compound of the present disclosure as an active ingredient. The term excipient encompasses a variety of substances, including, but not limited to, binders, disintegrants, coatings, compression / encapsulation aids, creams or lotions, lubricants, solutions for parenteral administration, chewable tablet materials, sweeteners or flavorings, suspending / gelling agents, or any substance used as a wet granulator. Binders include, for example, carbomer, povidone, xanthan gum, and the like. Coatings include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coatings, and the like. Compression / encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = directly compressible), honey dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, and the like. Disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc. Creams or lotions include, for example, maltodextrin, carrageenan, etc. Lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc. Chewable tablet materials include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc. Suspending / 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 granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0064] compound Provided herein is a targeting compound for treating cancer.The compound described herein can recognize and bind to nuclear receptor targeting epitopes with their respective binding sites, thereby targeting the nucleus of cell, and deliver nuclear payload to the nucleus of cell.Then, nuclear payload can bind to one or more target sites in nucleus, and / or disrupt one or more cellular processes, causing cell death.

[0065] In certain embodiments, the nuclear payload is linked to the nuclear receptor targeting epitope(s) via a linking moiety. In certain embodiments, the linking moiety provides a single link, meaning that the linker is conjugated to only one atom of each of the payload and the epitope.

[0066] Thus, there is provided a compound of formula I, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, A 1 -L 1 -B 1 I During the ceremony, B 1 is a nuclear receptor targeting epitope, L 1 is a covalent bond or linking moiety, A 1 is represented by formula IA: [ka] It is of During the ceremony, R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halo, cyano, nitro, -OR 15 , -SR 15 , -NR 15 R 16 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -C(=O)R 15 , -C(=O)OR 15 , -OC(=O)R 15 , -OC(=O)NR 15 R 16 , -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) 1~2 NR 15 R 16 , -NR 15 S(=O) 1~2 R 16 , -Si(R 15 )3 or -C=NOR 15 and each of them may contain, as valence permits, one or more R 10 or independently and optionally replaced by or R 1 and R 2 together with the atoms to which they are attached, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 aryl or 5- to 12-membered heteroaryl, each of which, valence permitting, may be joined by one or more R 10 or independently and optionally replaced by or R 2 and R 3 together with the atoms to which they are attached, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 aryl or 5- to 12-membered heteroaryl, each of which, valence permitting, may be joined by one or more R 10 or independently and optionally replaced by or R 3 and R 4 together with the atoms to which they are attached, C3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 aryl or 5- to 12-membered heteroaryl, each of which, valence permitting, may be joined by one or more R 10 and independently and optionally substituted by R 5 is hydrogen or -C(=O)R 15 and Each R 10 are independently halo, cyano, nitro, -OR 17 , -SR 17 , -SF5, -NR 17 R 18 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered 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 17and each of them is halo, cyano, nitro, hydroxyl, amino, C, as far as valence allows. 1~12 Alkoxy, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 is optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R 15 and R 16 are independently hydrogen, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 aryl or 5- to 12-membered heteroaryl, each of which, as valence permits, is selected from halo, cyano, nitro, hydroxyl, amino, C 1~12 Alkoxyl, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; or R 15 and R 16 together with the atom to which they are attached, valence permitting, halo, cyano, nitro, hydroxyl, amino, C 1~12 Alkoxyl, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 forming a 5- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R 17 and R18 are independently hydrogen, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 aryl or 5- to 12-membered heteroaryl, each of which, as valence permits, is selected from halo, cyano, nitro, hydroxyl, amino, C 1~12 Alkoxyl, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; or R 17 and R 18 together with the atom to which they are attached, valence permitting, halo, cyano, nitro, hydroxyl, amino, C 1~12 Alkoxyl, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 forming a 5- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; One or more atoms of formula IA (e.g., hydrogen, methyl, or hydroxyl) may be L 1 is replaced by a direct covalent bond to

[0067] In certain embodiments, the compound is not a compound selected from the group of compounds in Table 1X, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof. [Table 1X-1] [Table 1X-2] [Table 1X-3] [Table 1X-4] [Table 1X-5] [Table 1X-6] [Table 1X-7]

[0068] In certain embodiments, R 1 is hydrogen.

[0069] In certain embodiments, R 1 is one or more R 10 C, which is replaced as needed by 1~12 It is alkyl.

[0070] In certain embodiments, R 1 is one or more R 10 optionally substituted with -Si(R 15 )3.

[0071] In certain embodiments, R 1 is one or more R 10 optionally substituted with -C=NOR 15 is.

[0072] In certain embodiments, R 1 is ethyl.

[0073] In certain embodiments, R 1 teeth, [ka] is.

[0074] In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 teeth, [ka] is.

[0075] In certain embodiments, R 1 teeth, [ka] is.

[0076] In certain embodiments, R 1 teeth, [ka] is.

[0077] In certain embodiments, R 2 is hydrogen.

[0078] In certain embodiments, R 2 is one or more R 10 C, which is replaced as needed by 1~12 It is alkyl.

[0079] In certain embodiments, R 2 teeth, [ka] is.

[0080] In certain embodiments, R 2 is nitro.

[0081] In certain embodiments, R 2 teeth, [ka] is.

[0082] In certain embodiments, R 1 and R 2 together with the atoms to which they are attached form one or more R 10 C, which is replaced as needed by 3~12 Forms a cycloalkyl.

[0083] In certain embodiments, R 1 and R 2 together with the atoms to which they are attached, [ka] Form.

[0084] In certain embodiments, R 3 is one or more R 10 -OR is replaced as needed by 15 is.

[0085] In certain embodiments, R 3 is one or more R 10 C, which is replaced as needed by 1~12 It is alkyl.

[0086] In certain embodiments, R 3 is one or more R 10 optionally substituted with -OC(=O)NR 15 R 16 is.

[0087] In certain embodiments, R 3 is -OH.

[0088] In certain embodiments, R 3 is methyl.

[0089] In certain embodiments, R 3 teeth, [ka] is.

[0090] In certain embodiments, R 3 teeth, [ka] is.

[0091] In certain embodiments, R 3 teeth, [ka] is.

[0092] In certain embodiments, R 3 teeth, [ka] is.

[0093] In certain embodiments, R 3 teeth, [ka] is.

[0094] In certain embodiments, R 3 is methoxy.

[0095] In certain embodiments, R 3 is hydrogen.

[0096] In certain embodiments, R 4 is hydrogen.

[0097] In certain embodiments, R 4 is a halo.

[0098] In certain embodiments, R 3 and R 4 together with the atoms to which they are attached form one or more R 10 to form an optionally substituted 5- to 12-membered heterocyclyl.

[0099] In certain embodiments, R 3 and R 4 together with the atoms to which they are attached, [ka] Form.

[0100] In certain embodiments, R 5 is hydrogen.

[0101] In certain embodiments, R 5 is one or more R 10 optionally substituted with -C(=O)R 15 is.

[0102] In certain embodiments, R 5 teeth, [ka] In certain embodiments, R 5 teeth, [ka] is.

[0103] In certain embodiments, A 1 teeth, [ka] [ka] [ka] It comes from.

[0104] In certain embodiments, A 1 teeth, [ka] [ka] It comes from.

[0105] In certain embodiments, the hydrogen atom of formula IA is L 1 In certain embodiments, the methyl of formula IA is replaced by a direct covalent bond to L 1 In certain embodiments, the hydroxyl of formula IA is replaced by a direct covalent bond to L 1 In certain embodiments, L is replaced by a direct covalent bond to 1 is A 1 In certain embodiments, nL 1 is A 1 is connected to the oxygen atom of

[0106] In certain embodiments, A 1 teeth, [ka] [ka] is.

[0107] In certain embodiments, A 1 teeth, [ka] [ka] is.

[0108] In certain embodiments, any of the compounds disclosed herein (e.g., compounds of Formula I) include topoisomerase inhibitor analogs, which, even after modification to arrive at the compounds described herein, exhibit biological activity equivalent to that observed in the original, unmodified topoisomerase inhibitor. In certain embodiments, topoisomerase inhibitor analogs maintain the ability to inhibit topoisomerase. In certain embodiments, topoisomerase inhibitor analogs exhibit 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] Nuclear payload In certain embodiments, the nuclear payload (i.e., A 1 ) is a topoisomerase inhibitor. As used herein, the term "topoisomerase inhibitor" refers to a chemical compound or moiety that blocks the action of topoisomerase (or DNA topoisomerase), an enzyme responsible for over- or under-coiling of DNA.

[0110] In certain embodiments, the nuclear payload (i.e., A 1 ) is derived from camptothecin (CPT). Thus, in certain embodiments, the nuclear payload (i.e., A 1 ) is a camptothecin (CPT) analog. In certain embodiments, the nuclear payload (i.e., A 1 ) are derived from topotecan, irinotecan (CPT-11), ciratecan (DB-67, AR-67), cositecan (BNP-1350), exatecan, lurtotecan, gimatecan (ST1481), belotecan (CKD-602) or rubitecan, or analogs thereof.

[0111] In certain embodiments, the nuclear payload (i.e., A 1 The term "derived from" or "analogue" as used with respect to the nuclear payload (i.e., a known topoisomerase inhibitor) means that at most one non-hydrogen atom of the original, unmodified nuclear payload (i.e., a known topoisomerase inhibitor) is replaced by a covalent bond to a nuclear receptor targeting epitope, optionally via a linking moiety. Exemplary non-hydrogen atoms include, but are not limited to, -CH3, -OH, =O, and -NH2. In certain embodiments, the nuclear payload (i.e., A 1 The term "derived from" as used with respect to the topoisomerase inhibitor refers to the fact that one or more atoms (e.g., hydrogen, methyl, or hydroxy) of the original unmodified nuclear payload (i.e., the topoisomerase inhibitor) have been modified by L 1

[0023] Exemplary non-hydrogen atoms include, but are not limited to, -CH, -OCH, -OH, =O, -NH, -N(CH), and the like. In certain embodiments, one hydrogen atom bonded to a heteroatom (e.g., N, O, or S) of the original unmodified nuclear payload (i.e., a known topoisomerase inhibitor) is replaced by a direct covalent bond to L. 1 In certain embodiments, the term "derived from" refers to a group in which one or more atoms (e.g., hydrogen, methyl, or hydroxy) are replaced by a covalent bond to L. 1 This means that the group is replaced by a direct covalent bond to

[0112] In certain embodiments, the nuclear payloads disclosed herein (i.e., A 1 ) one or more atoms (e.g., hydrogen, methyl, hydroxy, amino, etc.) on the remainder of the compound (e.g., the moiety -L 1 -B 1) is replaced with a bond to the remainder of the compound. In certain embodiments, a hydrogen atom on a nuclear receptor targeting epitope disclosed herein is replaced with a bond to the remainder of the compound. In certain embodiments, the hydrogen atom is on a heteroatom. In certain embodiments, the hydrogen atom is on a halogen. In certain embodiments, the hydrogen atom is on a nitrogen. In certain embodiments, the hydrogen atom is on an oxygen. In certain embodiments, the hydrogen atom is on a carbon (e.g., a methyl group). Analogs can be used in combination with known nuclear payloads (e.g., topoisomerase inhibitors or A) described herein. 1 ), and are optionally modified, via a linking moiety, to be conjugated to at least one nuclear hormone receptor targeting epitope. The analogs maintain biological activity comparable to that observed with the original, unmodified topoisomerase inhibitor, even after modification to arrive at the compounds described herein. In certain embodiments, the compounds exhibit binding activity or inhibition 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%, or about 5-50% of that observed with the original, unmodified topoisomerase inhibitor. In certain embodiments, the compounds described herein have an IC 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 Shows.

[0113] In certain embodiments, the nuclear payload (i.e., A 1 )teeth, [ka] [ka] It comes from.

[0114] In certain embodiments, the nuclear payload or A 1 teeth, [ka] [ka] It comes from.

[0115] Nuclear receptor targeting epitopes In certain embodiments, B 1 is a nuclear hormone receptor targeting epitope. In certain embodiments, B 1 B binds to the estrogen receptor, the glucocorticoid receptor, the progesterone receptor, or the androgen receptor. 1 In certain embodiments, B 1 B binds to the glucocorticoid receptor. In certain embodiments, B 1 B binds to the progesterone receptor. In certain embodiments, B 1 binds to the androgen receptor. Exemplary estrogen receptor, glucocorticoid receptor, progesterone receptor or androgen receptor binding agents are described herein.

[0116] In certain embodiments, B 1 is a nuclear steroid receptor targeting epitope. As used herein, a "nuclear receptor targeting epitope" refers to a portion of a compound described herein (e.g., B) derived from a nuclear targeting agent disclosed herein that interacts with the ligand binding domain of a target nuclear receptor. 1), i.e., the portion of a compound that drives ligand binding interactions. A nuclear receptor targeting epitope associates a compound with a target nuclear receptor, such as a nuclear steroid receptor, facilitates localization of the compound in nuclear steroid receptor-expressing cells, translocates the nuclear payload from the cytosol to the nucleus, and serves to accumulate the compound in the nucleus. The level of accumulation can be controlled by selecting an appropriate nuclear receptor targeting epitope. For example, the compounds described herein can accumulate in the nucleus to various degrees via nuclear translocation of the nuclear steroid receptor that occurs after epitope binding to the receptor: high for full agonists (e.g., dihydrotestosterone (DHT)), moderate for partial agonists (e.g., bicalutamide), and low for antagonists (e.g., enzalutamide).

[0117] The target of steroid receptor can be any steroid receptor, including but not limited to those that are overexpressed in cancer cells.In certain embodiments, at least one nuclear steroid receptor targeting epitope can bind to the ligand binding domain of nuclear steroid receptor, for example, the ligand binding domain on estrogen receptor, glucocorticoid receptor, progesterone receptor or androgen receptor.

[0118] 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.

[0119] Nuclear steroid receptor targeting epitopes typically have an IC of less than about 500 nM, or less than about 400 nM, or less than about 300 nM, or less than about 200 nM, or less than about 100 nM. 50 or an EC of less than about 1 μM, or less than about 900 nM, or less than about 800 nM, or less than about 700 nM, or less than about 600 nM, or 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. 50 It can bind to nuclear steroid receptors having the formula:

[0120] In certain embodiments, the nuclear hormone receptor binding affinity of the compounds of the present invention can be defined based on its affinity to a reference nuclear hormone receptor binding compound.For example, some compounds of the present invention can bind to estrogen receptor.In some examples, the compounds disclosed herein bind to human estrogen receptor with at least 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of the affinity of 17b-estradiol.

[0121] As an additional example, some compounds of the present invention can bind to the human androgen receptor. In some examples, the compounds disclosed herein bind to the androgen receptor with an affinity that is at least 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the affinity of dihydrotestosterone (DHT).

[0122] As an additional example, some compounds of the present invention can bind to the human progestin receptor. In some examples, the compounds disclosed herein bind to the progestin receptor with an affinity that is at least 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the affinity of progesterone.

[0123] As an additional example, some compounds of the present invention can bind to the human glucocorticoid receptor. In some examples, the compounds disclosed herein bind to the glucocorticoid receptor with an affinity that is at least 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the affinity of cortisone.

[0124] In certain embodiments, a nuclear steroid receptor targeting epitope (e.g., B 1 ) is an agonist at the androgen receptor. In certain embodiments, the nuclear steroid receptor targeting epitope is an antagonist at the androgen receptor.

[0125] In certain embodiments, a nuclear steroid receptor targeting epitope (e.g., B 1 ) is steroidal (or derived from a steroidal compound) (e.g., dihydrotestosterone). In certain embodiments, the nuclear steroid receptor targeting epitope is non-steroidal (or derived from a non-steroidal compound) (e.g., enzalutamide, apalutamide, AZD9496, and bicalutamide).

[0126] The analogs may be directed to known nuclear steroid receptor targeting epitopes described herein (e.g., B 1 ), and modified, optionally via a linking moiety, to be conjugated to at least one nuclear steroid payload. Even after modification to arrive at the compounds described herein, the analogs maintain biological activity that is comparable to that observed with the original, unmodified nuclear steroid receptor targeting epitope. In certain embodiments, the compounds exhibit binding activity or inhibition 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%, or about 5-50%, of that observed with the original, unmodified nuclear steroid receptor targeting epitope.

[0127] In certain embodiments, the analog is a known nuclear receptor targeting epitope, such as a known nuclear steroid receptor targeting epitope (e.g., B 1 In certain embodiments, B 1 binds to estrogen receptor, glucocorticoid receptor, progesterone receptor, or androgen receptor. In certain embodiments, when used in reference to a nuclear receptor targeting epitope, the term "derived from" means that at most one non-hydrogen atom of the original unmodified nuclear receptor targeting compound (i.e., a known nuclear steroid receptor targeting compound) is replaced by a covalent bond to a nuclear payload, optionally via a linking moiety. Exemplary non-hydrogen atoms include, but are not limited to, -CH, -OH, =O, and -NH. In certain embodiments, when used in reference to a nuclear receptor targeting epitope, the term "derived from" means that at most one non-hydrogen atom of the original unmodified nuclear receptor targeting compound (i.e., a known nuclear steroid receptor targeting compound) is replaced by a covalent bond to a nuclear payload, optionally via a linking moiety. In certain embodiments, one hydrogen atom bonded to a heteroatom (e.g., N, O, or S) of the original, unmodified nuclear receptor targeting compound (i.e., a known nuclear steroid receptor targeting compound) is replaced by a covalent bond to a nuclear payload, optionally via a linking moiety. In certain embodiments, the term "derived from" refers to a compound in which one or more atoms (e.g., hydrogen, methyl, or hydroxy) are replaced by a covalent bond to a nuclear payload. 1 is replaced by a direct covalent bond to

[0128] In certain embodiments, a nuclear steroid receptor targeting epitope (e.g., B 1) is an androgen receptor targeting epitope. As used herein, the term "androgen receptor targeting epitope" is intended to refer to a compound moiety that binds to an androgen receptor and may be functionally an androgen receptor agonist or androgen receptor antagonist (including a partial androgen receptor agonist or partial androgen receptor antagonist), and in some embodiments, can bind to the receptor and the ligand-receptor complex that shuttles from the cytoplasm to the nucleus of the cell. The "androgen receptor" (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that can translocate androgen hormones into the nucleus when activated by binding to an androgen receptor binder (e.g., an androgen hormone such as testosterone or dihydrotestosterone) in the cytoplasm.

[0129] In certain embodiments, the nuclear receptor targeting epitopes (B 1 ) to the rest of the compound (e.g., -L 1 -B 1 In certain embodiments, a halogen atom on a nuclear receptor targeting epitope disclosed herein is replaced for attachment to the remainder of the compound. In certain embodiments, a hydrogen atom on a nuclear receptor targeting epitope disclosed herein is replaced for attachment to the remainder of the compound. In certain embodiments, the hydrogen atom is on a heteroatom. In certain embodiments, the hydrogen atom is on a nitrogen. In certain embodiments, the hydrogen atom is on an oxygen. In certain embodiments, the hydrogen atom is on a carbon.

[0130] In certain embodiments, B 1 is represented by formula IIA: [ka] It is of During the ceremony, The wavy line bond is L 1represents a connection point to R 30 is hydrogen, C 1~12 Alkyl, C 1~12 Haloalkyl, C 2~12 Alkenyl, C 2~12 Alkynyl or C 3~12 is cycloalkyl, C 1~12 Alkyl, C 1~12 Haloalkyl, C 2~12 Alkenyl, C 2~12 Alkynyl or C 3~12 Each cycloalkyl may be optionally substituted with one or more R 100 and optionally independently substituted by R 40 is hydrogen, C 1~12 Alkyl, C 1~12 Haloalkyl, C 2~12 Alkenyl, C 2~12 Alkynyl or C 3~12 is cycloalkyl, C 1~12 Alkyl, C 1~12 Haloalkyl, C 2~12 Alkenyl, C 2~12 Alkynyl or C 3~12 Each cycloalkyl may be optionally substituted with one or more R 100 and optionally independently substituted by Each R 50 and R 51 are independently halo, cyano, nitro, -OR 170 , -SR 170 , -NR 170 R 180 , C 1~12 Alkyl, C 1~12 Haloalkyl, C 2~12 Alkenyl or C 2~12 Alkynyl, C 1~12 Alkyl, C 1~12 Haloalkyl, C 2~12 Alkenyl or C 2~12 each alkynyl is independently optionally substituted with one or more halo, hydroxyl, or amino, as valence allows; Each R 100are independently oxo, halo, cyano, nitro, -OR 170 , -SR 170 , -SF5, -NR 170 R 180 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered 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 , or -NR 170 C(=O)OR 180 and each of them is halo, cyano, nitro, hydroxyl, amino, C, as far as valence allows. 1~12 Alkoxy, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 is optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R 170 and R 180are independently hydrogen or optionally substituted with oxo, halo, hydroxyl, or amino, where valence allows. 1~12 Is it alkyl? or R 170 and R 180 C, together with the atoms to which they are attached, optionally substituted by halo, or by oxo, halo, hydroxyl, or amino. 1~12 Forms a heterocyclyl optionally substituted by alkyl.

[0131] In certain embodiments, B 1 teeth, [ka] is.

[0132] In certain embodiments, B 1 is of formula IIB' or IIB": [ka] It is of During the ceremony, The wavy line bond is L 1 represents a connection point to R N is H or C 1~12 is alkyl, R 60 is hydrogen, -OR 101 , -NR 101 R 102 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -C(=O)R 101 , -C(=O)OR 101 , -OC(=O)R 101 , -OC(=O)NR 101 R 102 , -C(=O)NR 101 R 102, -NR 101 C(=O)R 102 , -NR 101 C(=O)OR 102 and each of them may contain, as valence permits, one or more R 100 and optionally independently substituted by R 80 is hydrogen, -OR 101 , -NR 101 R 102 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -C(=O)R 101 , -C(=O)OR 101 , -OC(=O)R 101 , -OC(=O)NR 101 R 102 , -C(=O)NR 101 R 102 , -NR 101 C(=O)R 102 , -NR 101 C(=O)OR 102 and each of them may contain, as valence permits, one or more R 100 and optionally independently substituted by R 81 is hydrogen, -OR 101 , -NR 101 R 102 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -C(=O)R 101 , -C(=O)OR 101 , -OC(=O)R 101 , -OC(=O)NR 101 R 102 , -C(=O)NR 101 R 102 , -NR 101 C(=O)R102 , -NR 101 C(=O)OR 102 and each of them may contain, as valence permits, one or more R 100 or independently substituted as needed by or R 80 and R 81 C, together with the atoms to which they are attached, optionally substituted by halo, or by oxo, halo, hydroxyl, or amino. 1~12 forming a heterocyclyl optionally substituted by alkyl, R 82 is hydrogen, -OR 101 , -NR 101 R 102 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -C(=O)R 101 , -C(=O)OR 101 , -OC(=O)R 101 , -OC(=O)NR 101 R 102 , -C(=O)NR 101 R 102 , -NR 101 C(=O)R 102 , -NR 101 C(=O)OR 102 and each of them may contain, as valence permits, one or more R 100 and optionally independently substituted by Each R 101 and R 102 are independently hydrogen, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 aryl or 5- to 12-membered heteroaryl, each of which, as valence permits, is selected from halo, cyano, nitro, hydroxyl, amino, C 1~12Alkoxyl, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 is optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R 100 are independently oxo, halo, cyano, nitro, -OR 170 , -SR 170 , -SF5, -NR 170 R 180 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered 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 , or -NR 170 C(=O)OR 180 and each of them is halo, cyano, nitro, hydroxyl, amino, C, as far as valence allows. 1~12 Alkoxy, C 1~12 Alkyl, C2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 is optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R 170 and R 180 are independently hydrogen or optionally substituted with oxo, halo, hydroxyl, or amino, where valence allows. 1~12 Is it alkyl? or R 170 and R 180 C, together with the atoms to which they are attached, optionally substituted by halo, or by oxo, halo, hydroxyl, or amino. 1~12 Forms a heterocyclyl optionally substituted by alkyl.

[0133] In certain embodiments, B 1 is of formula IIB'. In certain embodiments, B 1 is of formula IIB"

[0134] In certain embodiments, R N is methyl.

[0135] In certain embodiments, B 1 is represented by formula IIB: [ka] It is of During the ceremony, The wavy line bond is L 1 represents a connection point to R 60 is hydrogen, -OR 101 , -NR 101 R 102 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -C(=O)R 101 , -C(=O)OR 101 , -OC(=O)R 101 , -OC(=O)NR 101 R 102 , -C(=O)NR 101 R 102 , -NR 101 C(=O)R 102 , -NR 101 C(=O)OR 102 and each of them may contain, as valence permits, one or more R 100 and optionally independently substituted by R 80 is hydrogen, -OR 101 , -NR 101 R 102 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -C(=O)R 101 , -C(=O)OR 101 , -OC(=O)R 101 , -OC(=O)NR 101 R 102 , -C(=O)NR 101 R 102 , -NR 101 C(=O)R 102 , -NR 101 C(=O)OR 102 and each of them may contain, as valence permits, one or more R 100 and optionally independently substituted by R 81 is hydrogen, -OR 101 , -NR 101 R 102 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C6~12 Aryl, 5-12 membered heteroaryl, -C(=O)R 101 , -C(=O)OR 101 , -OC(=O)R 101 , -OC(=O)NR 101 R 102 , -C(=O)NR 101 R 102 , -NR 101 C(=O)R 102 , -NR 101 C(=O)OR 102 and each of them may contain, as valence permits, one or more R 100 or independently substituted as needed by or R 80 and R 81 C, together with the atoms to which they are attached, optionally substituted by halo, or by oxo, halo, hydroxyl, or amino. 1~12 forming a heterocyclyl optionally substituted by alkyl, R 82 is hydrogen, -OR 101 , -NR 101 R 102 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -C(=O)R 101 , -C(=O)OR 101 , -OC(=O)R 101 , -OC(=O)NR 101 R 102 , -C(=O)NR 101 R 102 , -NR 101 C(=O)R 102 , -NR 101 C(=O)OR 102 and each of them may contain, as valence permits, one or more R 100 and optionally independently substituted by Each R 101 and R 102are independently hydrogen, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 aryl or 5- to 12-membered heteroaryl, each of which, as valence permits, is selected from halo, cyano, nitro, hydroxyl, amino, C 1~12 Alkoxyl, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 is optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R 100 are independently oxo, halo, cyano, nitro, -OR 170 , -SR 170 , -SF5, -NR 170 R 180 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered 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 , or -NR 170 C(=O)OR 180 and each of them is halo, cyano, nitro, hydroxyl, amino, C, as far as valence allows. 1~12 Alkoxy, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 is optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R 170 and R 180 are independently hydrogen or optionally substituted with oxo, halo, hydroxyl, or amino, where valence allows. 1~12 Is it alkyl? or R 170 and R 180 C, together with the atoms to which they are attached, optionally substituted by halo, or by oxo, halo, hydroxyl, or amino. 1~12 Forms a heterocyclyl optionally substituted by alkyl.

[0136] In certain embodiments, R 82 is hydrogen. In certain embodiments, R 82 is C 1~12 In certain embodiments, R 82 is methyl.

[0137] In certain embodiments, B 1 teeth, [ka] is.

[0138] In certain embodiments, B1 teeth, [ka] is.

[0139] In certain embodiments, B 1 teeth, [ka] is.

[0140] In certain embodiments, B 1 teeth, [ka] is.

[0141] In certain embodiments, B 1 teeth, [ka] is.

[0142] In certain embodiments, B 1 teeth, [ka] is.

[0143] In certain embodiments, B 1 is represented by formula IIC': [ka] It is of During the ceremony, The wavy line bond is L 1 represents a connection point to A" and A'" are each independently O or S; R a and R b are each independently CH3 or CH2CH3, or R a and R btogether with the atoms to which they are attached, C 3~6 forming a cycloalkyl, oxirane, oxetane or tetrahydrofuran, B, B 10 , B 2 , B 3 , B', B 1’ , B 2’ and B 3’ are each independently c or N, Each R c are independently hydrogen, fluoro, CN, or methyl; D is absent, NH, O, S, CH, —NH(C═O)—, —(C═O)NH—, or C═O; X" is CN, halo, or NO2; Y” is CH3, CH2R d , CHF2 or CF3, R d is a halo, Z” is H, C 1~2 alkyl, C2 alkenyl, or NO2, or X" and Y" come together, [ka] and the dashed line indicates a bond to the ring, or Or Y" and Z" together, [ka] Form each [ka] is a single or double bond, the dashed line indicates the bond to the ring, Z' is CH or N.

[0144] In certain embodiments, D is NH, O, S, CH, —NH(C═O)—, —(C═O)NH—, or C═O.

[0145] In certain embodiments, B1 is represented by formula IIC: [ka] It is of During the ceremony, The wavy line bond is L 1 represents a connection point to A" and A'" are each independently O or S; R a and R b are each independently CH3 or CH2CH3, or R a and R b together with the atoms to which they are attached, C 3~6 forming a cycloalkyl, oxirane, oxetane or tetrahydrofuran, B, B 10 , B 2 , B 3 , B', B 1’ , B 2’ and B 3’ are each independently c or N, Each R c are independently hydrogen, fluoro, CN, or methyl; D is NH, O, S, CH, -NH(C=O)-, -(C=O)NH- or C=O; X" is CN, halo, or NO2; Y” is CH3, CH2R d , CHF2 or CF3, R d is a halo, Z” is H, C 1~2 alkyl, C2 alkenyl, or NO2, or X" and Y" come together, [ka] and the dashed line indicates a bond to the ring, or Or Y" and Z" together, [ka] Form each [ka] is a single or double bond, the dashed line indicates the bond to the ring, Z' is CH or N.

[0146] In certain embodiments, B 1 teeth, [ka] is.

[0147] In certain embodiments, B 1 teeth, [ka] is.

[0148] In certain embodiments, B 1 teeth, [ka] is.

[0149] In certain embodiments, B 1 is the formula IID': [ka] It is of During the ceremony, W is O, S or NH; each [ka] are independently a double bond or a single bond; Each R 61 and R 62 are independently hydrogen, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl or C 3~12 is cycloalkyl, C1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl or C 3~12 Each cycloalkyl may be optionally substituted with one or more R 100 and optionally independently substituted by Each R 100 are independently oxo, halo, cyano, nitro, -OR 170 , -SR 170 , -SF5, -NR 170 R 180 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered 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 , or -NR 170 C(=O)OR 180 and each of them is halo, cyano, nitro, hydroxyl, amino, C, as far as valence allows. 1~12 Alkoxy, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 is optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R 170 and R 180 are independently hydrogen or optionally substituted with oxo, halo, hydroxyl, or amino, where valence allows. 1~12 Is it alkyl? or R 170 and R 180 C, together with the atoms to which they are attached, optionally substituted by halo, or by oxo, halo, hydroxyl, or amino. 1~12 Forms a heterocyclyl optionally substituted by alkyl. In certain embodiments, B 1 is the formula IID: [ka] It is of During the ceremony, W is O, S or NH; [ka] is a double or single bond, Each R 61 and R 62 are independently hydrogen, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl or C 3~12 is cycloalkyl, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl or C 3~12 Each cycloalkyl may be optionally substituted with one or more R 100 and optionally independently substituted by Each R 100 are independently oxo, halo, cyano, nitro, -OR 170, -SR 170 , -SF5, -NR 170 R 180 , C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered 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 , or -NR 170 C(=O)OR 180 and each of them is halo, cyano, nitro, hydroxyl, amino, C, as far as valence allows. 1~12 Alkoxy, C 1~12 Alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, 5-12 membered heterocyclyl, C 6~12 is optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R 170 and R 180are independently hydrogen or optionally substituted with oxo, halo, hydroxyl, or amino, where valence allows. 1~12 Is it alkyl? or R 170 and R 180 C, together with the atoms to which they are attached, optionally substituted by halo, or by oxo, halo, hydroxyl, or amino. 1~12 Forms a heterocyclyl optionally substituted by alkyl.

[0150] In certain embodiments, B 1 teeth, [ka] is.

[0151] In certain embodiments, B 1 teeth, [ka] is.

[0152] In certain embodiments, B 1 is represented by formula IIE: [ka] It is of During the ceremony, The wavy bond indicates the connection point to L, Q is [ka] wherein bond a is bonded to ring a and bond b is bonded to ring b; R a and R b are each independently -CH3 or -CH2CH3, or R a and R b together with the atoms to which they are attached, C 3~5forming a cycloalkyl, oxiranyl, oxetanyl or tetrahydrofuranyl, A and A' are each independently O or S; E, E 1 , E 2 and E 3 are each independently c or N, and each R c are independently hydrogen, halo, CN, or methyl; E 4 is CF, CH or N, Q 1 is a bond, CH, C=O or (C=O)NH, Q 2 is NH, O, S, CH, NH(C=O), C(=O)NH or C=O, R 44 , R 45 and R 46 are each independently hydrogen, CN, or C 1~2 is alkyl, t is 0, 1, 2, 3, or 4; Each R e and R f are independently halo, cyano, C 1~4 Alkyl or C 1~4 is haloalkyl, R 41 is halo, CN or NO2, R 42 is halo, CH3, CH2F, CHF2 or CF3, or R 41 and R 42 Let's get together and [ka] and the dashed line indicates the bond to ring a, R 43 is hydrogen, halo, C 1~2 alkyl, C2 alkenyl, NO2, CF3, or R 42 and R 43 Let's get together and [ka] Form each [ka] is a single or double bond, and the dashed line indicates the bond to ring a.

[0153] In certain embodiments, B 1 teeth, [ka] is.

[0154] In certain embodiments, B 1 teeth, [ka] is.

[0155] In certain embodiments, B 1 teeth, [ka] is.

[0156] In certain embodiments, B 1 teeth, [ka] is.

[0157] In certain embodiments, B 1is derived from progesterone, enobosarm, bicalutamide, apalutamide, testosterone, dihydrotestosterone, testosterone, 19-nortestosterone, progesterone, andarine, cortisol, prednisone, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, megestrol acetate, estramustine, abiraterone, LGD-2941, BMS-564929, ostarine, ulipristal acetate, asoprisnil (J867), mifepristone, telapristone (CDB-4124, Proellex, Progenta) or their analogs.

[0158] In certain embodiments, B 1 teeth, [ka] [ka] [ka] or a stereoisomer or mixture of stereoisomers thereof, or an analog thereof, wherein at least one hydrogen atom is bonded to A, optionally via a linking moiety. 1 is replaced by a direct covalent bond to

[0159] B as described herein 1These and other selective androgen receptor modulators (SARMs) that can be used as nuclear steroid receptor targeting epitopes in the present invention are disclosed in US 6,462,038, US 6,777,427, WO2001 / 027086, WO2004 / 013104, WO2004 / 000816, WO2004 / 0113309, US2006 / 0211756, US2006 / 0063819, US2005 / 245485, US2005 / 250741, US2005 / 2 77681, WO2006 / 060108, WO2004 / 041277, WO2003 / 034987, US2006 / 0148893, US2006 / 0142387, WO2005 / 000795, WO2005 / 085185, WO2006 / 133216, WO2006 / 044707, WO2006 / 124447, WO2007 / 002181, WO2005 / 108351, WO2005 / 115361 and US2006 / 0160845.

[0160] In certain embodiments, B 1 is a selective estrogen receptor modulator (SERM). In certain embodiments, B 1These include anordrin, bazedoxifene, broparestrol (Acnestrol), clomiphene (Clomid), cyclophen (Sexovid), lasofoxifene (Fablyn), ormeloxifene (Centron, Novex, Novex-DS, Sevista), ospemifene (Osphena, deaminohydroxytoremifene), raloxifene (Evista), tamoxifen (Nolvadex), toremifene (Fareston; 4-chlorotamoxifen), acolbifene, affimoxifen (4-hydroxytamoxifen; a metabolite of tamoxifen), elaxestrant, enclomiphene ((E)-clomiphene), endoxifen (4-hydroxy-N-desmethyltamoxifen; a metabolite of tamoxifen), and zuclomiphene. The epitopes include epitopes derived from phen ((Z)-clomiphene), bazedoxifene, arzoxifene, brilanestrant, clomiphene oxide (clomiphene N-oxide; a metabolite of clomiphene), droloxifene (3-hydroxytamoxifene), etacstil, fispemifene, GW-7604 (4-hydroxyetaxtil), idoxifene (pyrrolidino-4-iodotamoxifen), levormeloxifene ((L)-olmeloxifene), miproxifene, nafoxidine, nitromiphene (CI-628), panomiphene, pipendoxifene (ERA-923), toroxifene, keoxifene, LY117018, onapristone, fareston (toremifine citrate), or zindoxifene (D-16726), or analogs thereof.

[0161] In certain embodiments, the SERM is structurally classified as a triphenylethylene (such as tamoxifen, clomiphene, toremifene, droloxifene, idoxifene, ospemifene, fispemifene, afimoxifene, or an analog thereof), a benzothiophene (such as raloxifene, arzoxifene, or an analog thereof), an indole (such as bazedoxifene, zindoxifene, pipendoxifene, or an analog thereof), a tetrahydronaphthalene (such as lasofoxifene, nafoxidine, or an analog thereof), or a benzopyran (such as acolbifene, ormeloxifene, levormeloxifene, or an analog thereof).

[0162] In certain embodiments, B 1 is a selective estrogen receptor downregulator (SERD). In certain embodiments, the compound comprises at least one nuclear steroid receptor targeting epitope, independently comprising an epitope derived from fulvestrant, brilanestrant (ARN-810), etaxtil (GW5638), AZD9496, giredestrant (GDC-9545), or GW7604.

[0163] In certain embodiments, B 1 is a selective progesterone receptor modulator (SPRM). In certain embodiments, B comprises an epitope derived from ulipristal acetate, asoprisnil (J867), mifepristone, telapristone (CDB-4124, Proellex, Progenta), or an analog thereof.

[0164] In certain embodiments, B 1comprises an epitope derived from estrogen, estetrol, estriol, estrone, progesterone, enobosarm, bicalutamide, apalutamide, testosterone, dihydrotestosterone, estradiol, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, megestrol acetate, estramustine, abiraterone, LGD-2941, BMS-564929, ostarine, or an analog thereof.

[0165] In certain embodiments, the at least one nuclear steroid receptor targeting epitope is an androgen receptor targeting epitope; [ka] or a stereoisomer or mixture of stereoisomers thereof, or analogs thereof, where the wavy line indicates the point of attachment to the nuclear payload, optionally via a linking moiety.

[0166] In certain embodiments, at least one nuclear steroid receptor targeting epitope is an estrogen receptor targeting epitope; [ka] or a stereoisomer or mixture of stereoisomers thereof, or analogs thereof, where the wavy line indicates the point of attachment to the nuclear payload, optionally via a linking moiety.

[0167] In certain embodiments, at least one nuclear steroid receptor targeting epitope is an estrogen receptor targeting epitope; [ka] [ka] or a stereoisomer or mixture of stereoisomers thereof, or analogs thereof, where the wavy line indicates the point of attachment to the nuclear payload, optionally via a linking moiety.

[0168] In certain embodiments, the at least one nuclear steroid receptor targeting epitope is [ka] [ka] [ka] or a stereoisomer or mixture of stereoisomers thereof, or analogs thereof, where the wavy line indicates the point of attachment to the nuclear payload, optionally via a linking moiety.

[0169] In certain embodiments, the at least one nuclear steroid receptor targeting epitope is [ka] or a stereoisomer or mixture of stereoisomers thereof, or analogs thereof, where the wavy line indicates the point of attachment to the nuclear payload, optionally via a linking moiety.

[0170] In certain embodiments, the nuclear steroid receptor targeting epitope is not or does not comprise a peptide, protein, nanoparticle, or antibody.

[0171] connecting part The "linking moiety" of any compound described herein can be biocleavable (e.g., acid labile) or non-biocleavable. A linking moiety can be linear, branched, saturated, unsaturated, or all carbon or heteroatoms. A linking moiety can also be fused, saturated, unsaturated, and contain one or more rings that are all carbon or heteroatoms. In certain embodiments, a linking moiety is a non-biocleavable linking moiety. In certain embodiments, a linking moiety is a biocleavable linking moiety. In certain embodiments, a nuclear payload is linked to one nuclear steroid receptor targeting epitope via a non-biocleavable linking moiety and to one or more nuclear steroid receptor targeting epitope(s) via a biocleavable linking moiety. In certain embodiments, a biocleavable linking moiety is an acid labile linking moiety. In some embodiments, a linking moiety comprises a hydrazone linking group.

[0172] It is contemplated that any linking moiety may be used in the compounds described herein, provided that it does not significantly interfere with or prevent the desired binding of the nuclear payload or nuclear receptor targeting epitope.

[0173] In certain embodiments, L 1 is the expression: -(L a ) q - It is of During the ceremony, Each L a are independently, W, -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)NR 110 -, -CR 120 =N-NR 110 -, -NR 110 -N=CR 120-, -C(O)-, -OC(O)-, -OC(O)O-, -C(O)O-, C 1~12 Alkylene, C 2~12 Alkenylene, C 2~12 Alkynylene, C 6~12 Arylene, C 3~12 cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12-membered heteroarylene, each of which is selected from -OH, -NH2, -CN, oxo, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 is independently optionally substituted with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl; Each W is independently [ka] and R n For each occurrence, independently, H, C 1~4 Alkyl or C 1~4 haloalkyl, and R w For each occurrence, independently, H, C 3~12 Cycloalkyl, C 6~12 aryl (optionally substituted with one or more of halo or OH) or C 1~4 alkyl (one or more independently selected halo, OH, —SH, —S(C 1~4 alkyl), -CONH2, -COOH, -NHC(=NH)NH2, -NH2, -NHCOCH3, -NHCHO, -NHCONH2, C 6~12 optionally substituted by aryl, 5-12 membered heterocycle, or 5-12 membered heteroaryl; Each R 110 are independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12Aryl, 5-12 membered heteroaryl, C 3~12 cycloalkyl or 5- to 12-membered heterocyclyl; Each R 120 are independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 cycloalkyl or 5- to 12-membered heterocyclyl; q is an integer from 0 to 40. 1 One end of A 1 It is understood that the compound can be bound to

[0174] In certain embodiments, L 1 is the expression: -(L a ) q - It is of During the ceremony, Each L a are independently -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)NR 110 -, -CR 120 =N-NR 110 -, -NR 110 -N=CR 120 -, -C(O)-, -OC(O)-, -OC(O)O-, -C(O)O-, C 1~12 Alkylene, C 2~12 Alkenylene, C 2~12 Alkynylene, C 6~12 Arylene, C 3~12 cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12-membered heteroarylene, each of which is selected from oxo, halo, C 1~4Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 is independently optionally substituted with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl; Each R 110 are independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 cycloalkyl or 5- to 12-membered heterocyclyl; Each R 120 are independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 cycloalkyl or 5- to 12-membered heterocyclyl; q is an integer of 0 to 20.

[0175] In certain embodiments, L 1 is the expression: -Y 10 -(CHR 130 ) n’ -Y 20 -(CHR 140 ) n” -Y 30 -(CHR 150 ) m” -Y 40 -(CHR 160 ) p -Y 50 -(CHR 170 ) p’ -Y 60 - It is of During the ceremony, Each Y 10 , Y20 , Y 30 , Y 40 , Y 50 and Y 60 are independently -(W) s -, 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)NR 110 -, -CR 120 =N-NR 110 -, -NR 110 -N=CR 120 -, -C(O)-, -OC(O)-, -OC(O)O-, -(CH2CH2O) 1~5 -, -C(O)O-, C 1~12 Alkylene, C 2~12 Alkenylene, C 2~12 Alkynylene, C 6~12 Arylene, C 3~12 cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12-membered heteroarylene, each of which is selected from -OH, -NH2, -CN, oxo, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 is independently optionally substituted with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl; Each W is independently [ka] and R n For each occurrence, independently, H, C 1~4 Alkyl or C 1~4 haloalkyl, and R w For each occurrence, independently, H, C3~12 Cycloalkyl, C 6~12 aryl (optionally substituted with one or more of halo or OH) or C 1~4 alkyl (one or more independently selected halo, OH, —SH, —S(C 1~4 alkyl), -CONH2, -COOH, -NHC(=NH)NH2, -NH2, -NHCOCH3, -NHCHO, -NHCONH2, C 6~12 optionally substituted by aryl, 5-12 membered heterocycle, or 5-12 membered heteroaryl; Each R 110 , R 120 , R 130 , R 140 , R 150 , R 160 and R 170 are independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 cycloalkyl or 5- to 12-membered heterocyclyl, which are -OH, -NH2, -CN, oxo, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 is independently optionally substituted with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl; n', n'', m'', s, p and p' are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0176] In certain embodiments, L 1 is the expression: -Y 10 -(CHR 130 ) n’ -Y 20 -(CHR140 ) n” -Y 30 -(CHR 150 ) m” -Y 40 - It is of During the ceremony, Each Y 10 , Y 20 , Y 30 and Y 40 are independently a 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)NR 110 -, -CR 120 =N-NR 110 -, -NR 110 -N=CR 120 -, -C(O)-, -OC(O)-, -OC(O)O-, -(CH2CH2O) 1~5 -, -C(O)O-, C 1~12 Alkylene, C 2~12 Alkenylene, C 2~12 Alkynylene, C 6~12 Arylene, C 3~12 cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12-membered heteroarylene, each of which is selected from oxo, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 and independently optionally substituted with one or more substituents independently selected from haloalkoxy; Each R 110 are independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12cycloalkyl or 5- to 12-membered heterocyclyl; Each R 120 are independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 cycloalkyl or 5- to 12-membered heterocyclyl; Each R 130 are independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 cycloalkyl or 5- to 12-membered heterocyclyl; Each R 140 are independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 cycloalkyl or 5- to 12-membered heterocyclyl; Each R 150 are independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 cycloalkyl or 5- to 12-membered heterocyclyl; n', n" and m" are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0177] In certain embodiments, at least one W is Val. In certain embodiments, at least one W is Cit. In certain embodiments, s is 2. In certain embodiments, -(W)s - is -Val-Cit-.

[0178] In certain embodiments, L 1 is the expression: [ka] It is of During the ceremony, Each L 2 , L 3 and L 4 are independently bonded, C 1~12 alkylene, —NHC(═O)—, —C(═O)NH—, —C(═O)—O—, —OC(═O)—, or C═O; Each R 200 and R 201 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 cycloalkyl and 5- to 12-membered heterocyclyl; Each s and s' is independently 0, 1, 2, 3, or 4.

[0179] In certain embodiments, L 1 is the expression: -L 2 -L 3 -Cy1-L 4 -Cy2-L 5 -L 6 - It is of During the ceremony, Each L 2 , L 3 , L 4 L 5 and L 6 are independently bonded, C 1~12 alkylene, -O-, -NHC(=O)-, -C(=O)NH-, -C(=O)-O-, -OC(=O)- or C=O, and C 1~12one or more carbon atoms in the alkylene are optionally replaced by oxygen; Cy1 and Cy2 each independently represent a bond, C 6~12 Arylene, C 3~12 cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12-membered heteroarylene, each of which is selected from -OH, -NH2, -CN, oxo, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 It is independently optionally substituted with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl.

[0180] In certain embodiments, Cy1 is -OH, -NH2, -CN, oxo, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 and 5- to 12-membered heterocyclylene optionally substituted with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl.

[0181] In certain embodiments, Cy1 is -OH, -NH2, -CN, oxo, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 optionally substituted with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl [ka] In certain embodiments, Cy1 is -OH, -NH2, -CN, oxo, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 optionally substituted with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl [ka] In certain embodiments, Cy1 is [ka] In certain embodiments, Cy1 is [ka] In certain embodiments, Cy1 is a bond. In certain embodiments, Cy1 is [ka] or a bond.

[0182] In certain embodiments, Cy2 is -OH, -NH2, -CN, oxo, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 and 5- to 12-membered heterocyclylene optionally substituted with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl.

[0183] In certain embodiments, Cy2 is -OH, -NH2, -CN, oxo, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 optionally substituted with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl [ka] In certain embodiments, Cy2 is -OH, -NH2, -CN, oxo, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 optionally substituted with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl [ka] In certain embodiments, Cy2 is [ka] In certain embodiments, Cy2 is [ka] In certain embodiments, Cy2 is a bond. In certain embodiments, Cy2 is [ka] or a bond.

[0184] In certain embodiments, the linking moiety is of the formula: [ka] During the ceremony, Ring C is a 3- to 12-membered cycloalkylene or a 3- to 12-membered heterocyclylene, each of which is oxo, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 and independently optionally substituted with one or more substituents independently selected from haloalkoxy; Each Y 50 and Y 60 are independently a 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)NR 110 -, -CR 120 =N-NR 110 -, -NR 110 -N=CR 120 -, -C(O)-, -OC(O)-, -OC(O)O-, -(CH2CH2O) 1~5 -, -C(O)O-, C 1~12 Alkylene, C 2~12 Alkenylene, C 2~12 Alkynylene, C 6~12 Arylene, C 3~12 cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12-membered heteroarylene, each of which is selected from oxo, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 and independently optionally substituted with one or more substituents independently selected from haloalkoxy; Each R 110 are independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12Aryl, 5-12 membered heteroaryl, C 3~12 cycloalkyl or 5- to 12-membered heterocyclyl; Each R 120 are independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 cycloalkyl or 5- to 12-membered heterocyclyl; " * " and wavy lines represent covalent bonds.

[0185] In certain embodiments, Y 50 and Y 60 Each C 1~12 Alkylene, C 2~12 Alkenylene, C 2~12 Alkynylene, C 6~12 Arylene, C 3~12 Cycloalkylene, 5- to 12-membered heterocyclylene or 5- to 12-membered heteroarylene may be substituted with halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 and independently optionally substituted with 1 to 5 substituents independently selected from haloalkoxy.

[0186] In certain embodiments, the linking moiety is of the formula: [ka] During the ceremony, Ring C is a 3- to 12-membered cycloalkylene or a 3- to 12-membered heterocyclylene, each of which is oxo, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 and independently optionally substituted with one or more substituents independently selected from haloalkoxy; Each Y50 and Y 60 are independently a 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)NR 110 -, -CR 120 =N-NR 110 -, -NR 110 -N=CR 120 -, -C(O)-, -OC(O)-, -OC(O)O-, -(CH2CH2O) 1~5 -, -C(O)O-, C 1~12 Alkylene, C 2~12 Alkenylene, C 2~12 Alkynylene, C 6~12 Arylene, C 3~12 cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12-membered heteroarylene, each of which is selected from oxo, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 and independently optionally substituted with one or more substituents independently selected from haloalkoxy; Each R 110 are independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12 Aryl, 5-12 membered heteroaryl, C 3~12 cycloalkyl or 5- to 12-membered heterocyclyl; Each R 120 are independently hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 6~12Aryl, 5-12 membered heteroaryl, C 3~12 cycloalkyl or 5- to 12-membered heterocyclyl; " * " and wavy lines represent covalent bonds.

[0187] In certain embodiments, the linking moiety is of the formula: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] " * " and wavy or dashed lines represent covalent bonds. One end is A 1 It is understood that the compound can be bound to

[0188] In certain embodiments, the linking moiety is of the formula: [ka] [ka] [ka] [ka] [ka] [ka] " * " and wavy or dashed lines represent covalent bonds. * Or either the wavy line or the dashed line is A 1 It is understood that the compound can be bound to

[0189] In certain embodiments, provided are compounds as in Table 1, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14]

[0190] Treatment method Provided herein are compounds that can be used to treat, prevent, and / or delay the onset and / or development of cancer.Therefore, in certain embodiments, provided are methods for treating cancer, comprising administering a therapeutically effective amount of the compound or composition described herein to a subject in need of treatment.Certain embodiments provide a method for enhancing cytotoxic cancer therapy in a subject who has a recognized need for such treatment, comprising administering a therapeutically acceptable amount of the compound or composition described herein to the subject.

[0191] It is contemplated that any cancer patient may benefit from treatment with the compound and composition described herein.Therefore, in certain embodiments, cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft tissue sarcoma, chronic lymphocytic leukemia, Wandenstrom's macroglobulinemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small intestine carcinoma, etc. cell lung carcinoma, gastric carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosis fungoides, head and neck carcinoma, osteosarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenocortical carcinoma, skin cancer, trophoblastic neoplasm, or prostate carcinoma. In certain embodiments, the cancer is bladder cancer, a blood cancer such as leukemia (e.g., chronic leukemia, chronic lymphocytic leukemia (CLL), or lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's 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 certain embodiments, the cancer is bladder cancer, breast cancer, fallopian tube cancer, ovarian cancer, prostate cancer, peritoneal cancer, testicular cancer, endometrial cancer, or uterine cancer.

[0192] In certain embodiments, the cancer is chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, Wandenstrom's macroglobulinemia, polycythemia vera, trophoblastic neoplasm, and ovarian cancer.

[0193] In certain embodiments, the compounds and compositions described herein are tailored to target cancers that overexpress a specific receptor, such as, but not limited to, the androgen receptor, the estrogen receptor, the progesterone receptor, and / or the glucocorticoid receptor, by including an epitope that targets that specific nuclear receptor. The epitope may be derived from a steroid hormone or any non-steroidal drug that targets that specific receptor.

[0194] composition Any composition (including pharmaceutical compositions) of the compounds detailed herein is encompassed by the present disclosure.Therefore, provided herein is a pharmaceutical composition comprising the compound of the present disclosure or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or additive.The pharmaceutical compositions provided herein can be in a form suitable for oral, buccal, parenteral (for example, intravenous, intramuscular, infusion, or subcutaneous injection), nasal, topical, or rectal administration, or in a form suitable for administration by inhalation.

[0195] kit A kit for use in achieving anti-cancer effects is provided, which includes a compound or composition described herein. In certain embodiments, the kit includes a unit dose of the compound or composition described herein and instructions for administering it. In certain aspects, the kit further includes instructions for co-administering a second drug suitable for anti-cancer therapy, or an additional anti-cancer therapy (such as radiation or gene therapy). In another aspect, the kit for use in achieving anti-cancer effects includes a low dose (e.g., less than about 500 mg / day, or less than about 400 mg / day, or less than about 300 mg / day, or less than about 200 mg) of the compound or composition described herein and a second drug suitable for anti-cancer therapy. In yet another variation, the kit for use in achieving anti-cancer effects includes a high dose (e.g., more than about 500 mg / day) of the compound or composition described herein and a second drug suitable for anti-cancer therapy.

[0196] Drug manufacturing methods In another aspect of the present disclosure, the use of the compounds and compositions described herein in the manufacture of medicines is provided.In particular, the manufacture of medicines for use in the treatment of cancer or diseases or conditions that can be mediated at least in part by blocking DNA repair and / or transcription activation, such as by inhibiting one or more topoisomerases is provided.In addition, the pharmaceutical compositions of the compounds described herein are also intended to be used in the manufacture of medicines for use in the treatment of diseases or conditions that can be mediated at least in part by inhibiting one or more topoisomerases. [Example]

[0197] The present disclosure is further illustrated by the following examples, which are non-limiting and merely representative of various aspects of the present disclosure. Solid and dotted wedges in the structures disclosed herein indicate relative stereochemistry; absolute stereochemistry is indicated only where specifically stated or depicted.

[0198] Compounds having the structure of any compound, formula, or any subformula described herein can be synthesized using standard synthetic techniques known to those skilled in the art. Compounds of the present disclosure can be synthesized using the general methods or general synthetic procedures described in the synthetic examples.

[0199] If it is desired to obtain a specific enantiomer of a compound, this can be achieved from the corresponding mixture of enantiomers by 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., racemate) with an appropriate chiral compound.The diastereomers can then be separated by any convenient means, for example, by crystallization, and the desired enantiomer can be recovered.In another resolution process, racemate can be separated using chiral high-performance liquid chromatography.Alternatively, if desired, a specific enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described.

[0200] Chromatography, recrystallization, and other conventional separation procedures may be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify the product of a reaction.

[0201] (Example S1) Preparation of (S)-10-((4-(1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carbonyl)piperazin-1-yl)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl diisopropylcarbamate (Compound No. 1) [ka]

[0202] Step-1: Preparation of tert-butyl (S)-4-((9-((diisopropylcarbamoyl)oxy)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)piperazine-1-carboxylate (Intermediate-A1)

[0203] To a stirred solution of tert-butyl (S)-4-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)piperazine-1-carboxylate (Intermediate-3, 300 mg, 0.53 mmol, 1.0 equiv.) in DCM (5 mL) was added DIPEA (0.5 mL, 3.8 mmol, 5 equiv.) and DMAP (20 mg, 0.16 mmol, 0.25 equiv.) at room temperature, followed by diisopropylcarbamic acid chloride (Starting Material-1, 132 mg, 0.80 mmol, 1.5 equiv.) in DCM (2 mL) and stirring for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, water (100 mL) was added, and the aqueous reaction mixture was extracted with DCM (2 x 200 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column eluted with 4% methanol in DCM to give the product as a pale yellow solid (Intermediate-A1, 240 mg, 65%).

[0204] 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.14 - 8.16 (m, 1H), 7.60 - 7.63 (m, 1H), 7.38 (s, 1H), 6.54 (s, 1H), 5.46 (s, 2H), 5.32 (s, 2H), 3.88 (s, 2H), 3.26 - 3.42 (m, 7H), 2.40-2.45 (m, 3H), 1.84 - 1.92 (m, 2H), 1.39 (s, 9H), 1.33(d, J = 7.5 Hz, 12H), 1.09 (t, J = 7.09 Hz, 3H).LCMS:690.7 [M+H] + .

[0205] Step-2: Preparation of (S)-4-ethyl-4-hydroxy-3,14-dioxo-10-(piperazin-1-ylmethyl)-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl diisopropylcarbamate trifluoroacetate (Intermediate-A2)

[0206] Under a nitrogen atmosphere, to a stirred solution of tert-butyl (S)-4-((9-((diisopropylcarbamoyl)oxy)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)piperazine-1-carboxylate (Intermediate-A1, 240 mg, 0.35 mmol, 1.0 equiv.) in DCM (5 mL) was added TFA (0.2 mL, 1.05 mmol, 3 equiv.) at 0°C. The reaction mixture was stirred and allowed to warm to room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure, washed with diethyl ether (20 mL), and dried under vacuum to give Intermediate-A2 (220 mg, 94%) as an off-white solid.

[0207] 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.52 (br s, 2H), 8.13 (d, J = 9.29 Hz, 1H), 7.58 (d, J = 9.29 Hz, 1H), 7.34 (s, 1H), 6.50 (br s, 1H), 5.44 (s, 2H), 5.31 (s, 2H), 4.23 (br s, 2H), 3.90-3.96 (m, 4H), 3.05-3.15 (m, 4H), 2.62-2.67 (m, 2H), 1.81 - 1.95 (m, 2H), 1.37 (d, J = 6.85 Hz, 6H), 1.29 (d, J = 6.36 Hz, 6H), 0.84 - 0.97 (d, J = 8.5 Hz, 3H).LCMS:590.2 [M+H] + .

[0208] Step-3: Preparation of (S)-10-((4-(1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carbonyl)piperazin-1-yl)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl diisopropylcarbamate

[0209] To a stirred DMF (5 mL) solution of Intermediate-A2 (200 mg, 0.33 mmol, 1.0 equiv.) and Intermediate-13 (CAS Registry Number 2740523-67-3; 164 mg, 0.33 mmol, 1.0 equiv.) was added HATU (194 mg, 0.51 mmol, 1.5 equiv.) and DIPEA (0.09 mL, 0.66 mmol, 2 equiv.) at room temperature, and the resulting reaction mixture was stirred for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, water (100 mL) was added, and the aqueous mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by combiflash® column chromatography eluting with 3% methanol in DCM to afford the title compound (125 mg, 48%) as a pale yellow solid.

[0210] 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (br s, 1H), 8.57 (d, J = 8.25 Hz, 1H), 8.16 - 8.36 (m, 1H), 7.79 - 7.88 (m, 2H), 7.68 (br dd, J = 6.63, 4.50 Hz, 1H), 7.35 - 7.40 (m, 3H), 7.13 (dd, J = 8.82, 2.44 Hz, 1H), 6.39-6.68 (m, 1H), 5.44 (s, 2H), 5.35 (s, 2H), 4.46-4.56 (m, 3H), 4.26 - 4.35 (m, 4H), 3.78 - 3.96 (m, 4H), 3.33 - 3.63 (m, 3H), 2.92 - 3.20 (m, 4H), 2.04 - 2.16 (m, 2H), 1.84 - 1.97 (m, 4H), 1.46 - 1.77 (m, 9H), 1.33 (br dd, J = 12.57, 6.32 Hz, 12H), 0.90 (t, J = 7.32 Hz, 3H).LCMS:1055.4 [M+H] + . HPLC purity 98.9%.

[0211] (Example S2) Preparation of (S)-10-((4-(1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carbonyl)piperazin-1-yl)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylmethyl(phenyl)carbamate (Compound No. 2) [ka]

[0212] Step-1: Preparation of tert-butyl (S)-4-((4-ethyl-4-hydroxy-9-((methyl(phenyl)carbamoyl)oxy)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)piperazine-1-carboxylate (Intermediate-A3)

[0213] To a stirred solution of tert-butyl (S)-4-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)piperazine-1-carboxylate (Intermediate-3, 300 mg, 0.53 mmol, 1.0 equiv.) in DCM (15 mL) was added DIPEA (0.3 mL, 1.60 mmol, 3 equiv.) and DMAP (20 mg, 0.16 mmol, 0.25 equiv.) at room temperature, followed by the addition of methyl(phenyl)carbamyl chloride (Starting Material-1, 135 mg, 0.80 mmol, 1.5 equiv.) in DCM (5 mL). The resulting reaction mixture was then stirred for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with DCM (2 x 200 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column using 6% methanol in DCM to give Intermediate-A3 (260 mg, 70%) as an off-white solid.

[0214] 1H NMR (400 MHz, DMSO-d6) δ 8.96 (br s, 1H), 8.06 - 8.19 (m, 2H), 7.74 (d, J = 9.13 Hz, 1H), 7.55 (br d, J = 7.63 Hz, 1H), 7.44-7.46 (m, 1H), 7.28 - 7.35 (m, 2H), 6.57 - 6.62 (m, 1H), 6.48 - 6.54 (m, 1H), 5.42 (s, 2H), 5.29 (s, 2H), 3.69 - 3.82 (m, 1H), 3.38-3.40 (m, 3H), 3.16-3.19 (m, 3H), 2.95 (s, 3H), 2.65 (d, J = 5.13 Hz, 1H), 2.12 - 2.27 (m, 3H), 1.85-1.90 (m, 1H), 1.41 (s, 9H), 0.88 (t, J = 7.32 Hz, 3H).LCMS:696.2 [M+H] + .

[0215] Step-2: Preparation of (S)-4-ethyl-4-hydroxy-3,14-dioxo-10-(piperazin-1-ylmethyl)-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylmethyl(phenyl)carbamate trifluoroacetate (Intermediate-A4)

[0216] To a stirred solution of tert-butyl (S)-4-((4-ethyl-4-hydroxy-9-((methyl(phenyl)carbamoyl)oxy)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)piperazine-1-carboxylate (Intermediate-A3, 250 mg, 0.35 mmol, 1.0 equiv) in DCM (10 mL) was added TFA (0.27 mL, 3.5 mmol, 10 equiv) at 0° C. under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure, washed with diethyl ether (20 mL) and dried under vacuum to give Intermediate-A4 (210 mg, 98%) as an off-white solid.

[0217] 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (br s, 1H), 8.56 (br s, 2H), 8.15 (br d, J = 9.29 Hz, 1H), 7.75 (br d, J = 8.80 Hz, 1H), 7.53 - 7.58 (m, 3H), 7.49 (br t, J = 7.58 Hz, 1H), 7.34 (s, 1H), 6.50 (br s, 1H), 5.43 (s, 2H), 5.29 (br s, 2H), 3.81 - 3.96 (m, 3H), 3.42 (br s, 3H), 2.98-3.01 (m, 5H), 2.52-2.56 (m, 3H), 1.80 - 1.96 (m, 2H), 0.89 (br t, J = 7.09 Hz, 3H).

[0218] Step-3: Preparation of (S)-10-((4-(1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carbonyl)piperazin-1-yl)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylmethyl(phenyl)carbamate

[0219] (S)-4-Ethyl-4-hydroxy-3,14-dioxo-10-(piperazin-1-ylmethyl)-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylmethyl(phenyl)carbamate trifluoroacetate (Intermediate-A4, 200 mg, 0.33 mmol, 1.0 equiv.) and 1-(6-(((1r To a stirred solution of 4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carboxylic acid (Intermediate-13, 200 mg, 0.40 mmol, 1.2 equiv.) in DMF (5 mL) was added HATU (240 mg, 0.67 mmol, 1.5 equiv.) and DIPEA (0.17 mL, 1 mmol, 3 equiv.) at room temperature. The resulting reaction mixture was stirred for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was washed with water (20 mL) and extracted with 10% methanol in DCM (2 x 50 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The resulting crude material was purified by preparative HPLC with an ammonium bicarbonate in water / acetonitrile mobile phase to afford the title compound (75 mg, 21%) as an off-white solid.

[0220] 1H NMR (400 MHz, DMSO-d6) δ 8.99 (br s, 1H), 8.59 (d, J = 8.25 Hz, 1H), 8.14 (d, J = 9.13 Hz, 1H), 7.84 (dd, J = 10.94, 9.19 Hz, 2H), 7.76 (d, J = 9.26 Hz, 1H), 7.55 (br d, J = 7.75 Hz, 2H), 7.47 (t, J = 7.75 Hz, 2H), 7.31 - 7.41 (m, 4H), 7.13 (dd, J = 8.76, 2.38 Hz, 1H), 6.51 (s, 1H), 5.43 (s, 2H), 5.30 (s, 2H), 4.44 - 4.57 (m, 3H), 3.72 - 3.94 (m, 3H), 3.42 (s, 3H), 3.38-3.41(m, 4H), 3.07 - 3.18 (m, 2H), 2.91 - 3.01 (m, 1H), 2.07 - 2.29 (m, 5H), 1.80 - 1.97 (m, 4H), 1.43 - 1.76 (m, 9H), 0.89 (t, J = 7.32 Hz, 3H).LCMS:1061.4 [M+H] + . HPLC purity 98.2%.

[0221] (Example S3) Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 3-(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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (Compound No. 3) [ka] Step-1: Preparation of tert-butyl 6-(chlorocarbonyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (Intermediate-14)

[0222] To a stirred solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (starting material-1, 1.0 g, 5.05 mmol, 1.0 equiv.) in DCM (10 mL) at 0 °C, a solution of triphosgene (0.45 g, 1.51 mmol, 0.3 equiv.) in pyridine (0.81 mL, 10.10 mmol, 2 equiv.) and DCM (5 mL) was added dropwise over 10 min. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction progress was monitored by TLC (a nonpolar spot was observed). After completion of the reaction, the reaction mixture was poured into ice-cold water (20 mL) and extracted with DCM (2 × 15 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford Intermediate-14 (1.0 g, crude) as a light yellow solid, which was used in the next step without further purification.

[0223] 1 H NMR (400 MHz, DMSO-d6) δ 4.63 - 4.76 (m, 2H), 3.57 - 3.84 (m, 4H), 2.91 - 2.99 (m, 1H), 1.70 - 1.78 (m, 1H), 1.44 (s, 9H).

[0224] Step-2: Preparation of 3-(tert-butyl) 6-((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl) 3,6-diazabicyclo[3.1.1]heptane-3,6-dicarboxylate (Intermediate-15)

[0225] To a stirred solution of tert-butyl 6-(chlorocarbonyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (Intermediate-16, 0.92 g, 3.56 mmol, 1.5 equiv.) and (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione HCl salt (Starting Material-2, 1 g, 2.37 mmol, 1 equiv.) in THF (10 mL) and DMF (10 mL) was added DIPEA (2.12 mL, 11.87 mmol, 5 equiv.) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product. The crude product was purified by combiflash column chromatography eluted with 6% methanol in DCM to give Intermediate-15 (650 mg, 42%) as a light yellow solid.

[0226] 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.10 (d, J = 8.63 Hz, 1H), 7.51 (d, J = 9.01 Hz, 1H), 7.34 (s, 1H), 6.51 (s, 1H), 5.43 (s, 2H), 5.31 (s, 2H), 3.70 - 3.87 (m, 2H), 3.55 - 3.66 (m, 6H), 2.69 - 2.77 (m, 1H), 2.12 - 2.24 (m, 6H), 1.81 - 1.93 (m, 2H), 1.54 - 1.59 (m, 1H), 1.47 (s, 9H), 0.89 (t, J = 7.38 Hz, 3H).LCMS:646.50 [M+H] + .

[0227] 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]indolizino[1,2-b]quinolin-9-yl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate trifluoroacetate (Intermediate-16)

[0228] To a stirred solution of 3-(tert-butyl) 6-((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl) 3,6-diazabicyclo[3.1.1]heptane-3,6-dicarboxylate (Intermediate-17, 650 mg, 1.0 mmol, 1.0 equiv) in DCM (10 mL) was added TFA (0.57 mL, 7.55 mmol, 7.5 equiv) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure to give the crude product, which was triturated with ethyl acetate (30 mL), filtered and the collected solid was dried under vacuum to give Intermediate-16 (500 mg, 75%) as a yellow solid.

[0229] 1 H NMR (400 MHz, D2O) δ 8.99 (s, 1H), 8.33 (d, J = 9.38 Hz, 1H), 7.95 (d, J = 9.26 Hz, 1H), 7.63 (s, 1H), 5.29 - 5.60 (m, 4H), 4.92 - 5.00 (m, 2H), 3.97 - 4.24 (m, 3H), 3.72 - 3.88 (m, 3H), 3.19 - 3.31 (m, 2H), 3.05 (s, 3H), 3.02 (s, 4H), 1.93 - 2.09 (m, 3H), 0.98 (t, J = 7.19 Hz, 3H).LCMS: 546.2 and 547.2 [M+H] + .

[0230] Step-C1: Preparation 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-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-17)

[0231] To a stirred solution of starting material-1 (10 g, 21 mmol, 1.0 equiv.) in methanol (150 mL) and THF (150 mL) at 0 °C, KOAc (20.6 g, 210 mmol, 10 equiv.) and iodine (13.1 g, 105 mmol, 5 equiv.) were added. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with sodium thiosulfate (NaSO) solution (50 g in 30 mL of water) and extracted with ethyl acetate (2 × 200 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give intermediate-17 (8.0 g, 82%) as an off-white solid, which was used in the next step without further purification.

[0232] 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (br s, 1H), 6.91 (d, J = 8.31 Hz, 2H), 6.44 (d, J = 8.31 Hz, 2H), 5.67 (s, 1H), 4.37 (m, 1H), 2.75 (s, 2H), 2.61 (d, J = 4.40 Hz, 3H), 2.30 - 2.40 (m, 1H), 2.07 - 2.16 (s, 5H), 1.99 (s, 6H), 1.63 - 1.77 (m, 2H), 1.21 - 1.45 (m, 5H), 0.86 (t, J = 6.60 Hz, 1H), 0.16 - 0.28 (m, 3H).LCMS:462.28 [M+H] + .

[0233] Step-C2: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-hydroxyhexyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-18)

[0234] To a solution 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-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-17, 4 g, 8.67 mmol, 1.0 equiv.) and 6-bromohexan-1-ol (Starting Material-2, 7.81 g, 43.38 mmol, 5 equiv.) in ethanol (40 mL) and water (40 mL) was added NaHCO (7.37 g, 86.76 mmol, 10 equiv.) at room temperature. The reaction mixture was heated to 80 °C and stirred for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite bed and washed with ethyl acetate (40 mL). The filtrate was concentrated under reduced pressure, diluted with water (120 mL), and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by combiflash® chromatography eluted with 70% ethyl acetate in heptane to give Intermediate-18 (2.6 g, 53%) as an off-white solid.

[0235] 1H NMR (400 MHz, DMSO-d6) δ 6.98 (d, J = 7.89 Hz, 2H), 6.58 (d, J = 7.89 Hz, 2H), 5.67 (br s, 1H), 4.24 - 4.51 (m, 2H), 3.36 (d, J = 5.70 Hz, 2H), 3.23 (d, J = 6.58 Hz, 2H), 2.69 - 2.86 (m, 4H), 2.55 (s, 3H), 2.29 - 2.44 (m, 1H), 2.05 - 2.26 (m, 5H), 1.87 - 2.04 (m, 6H), 1.63 - 1.77 (m, 2H), 1.34 - 1.49 (m, 6H), 1.27 (br s, 6H), 0.23 (br s, 3H).LCMS:562.40 [M+H] + .

[0236] Step-C3: 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-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-C)

[0237] To a stirred solution of Intermediate-18 (500 mg, 0.891 mmol, 1 equiv.) in ethyl acetate (40 mL) at 0 °C, Dess-Martin periodinane (DMP) (1.1 g, 2.67 mmol, 3 equiv.) was added portionwise. The reaction mixture was heated to 80 °C for 2 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 50% aqueous NaSO (10 mL), saturated NaHCO (15 mL), and extracted with ethyl acetate (2 × 25 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give Intermediate-C (450 mg, 92%) as a brown solid.

[0238] 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 6.98 (d, J = 8.31 Hz, 2H), 6.58 (d, J = 8.80 Hz, 2 H), 5.67 (s, 1H), 4.39 (d, J = 5.87 Hz, 1H), 3.22 (t, J = 6.60 Hz, 2H), 2.55 - 2.80 (m, 5H), 2.51 - 2.54 (m, 2H), 2.40 (t, J = 7.09 Hz, 2H), 1.96 - 2.15 (m, 12H), 1.56-1.69 (m, 2H), 1.11 - 1.59 (m, 10H), 0.23 (s, 3H).LCMS:560.4 [M+H] + .

[0239] 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]indolizino[1,2-b]quinolin-9-yl 3-(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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)-hexyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0240] (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-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-C, 350 mg, 0.531 mmol, 1 equiv.) and (S)-10-((dimethylamino)methyl)-4- To a stirred solution of ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate trifluoroacetate (Intermediate-16, 296 mg, 0.531 mmol, 1 equiv.) in methanol (7 mL) was added glacial acetic acid (0.1 mL) at room temperature and stirred for an additional 2 hours. Sodium cyanoborohydride (65.8 mg, 1.06 mmol, 2 equiv.) was then added at 0°C, and the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure, quenched with ice-cold water (20 mL), and extracted with 10% methanol in DCM (2 × 20 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC purification eluted with mobile phase A: 0.1% FA in water and mobile phase B: acetonitrile to give the title compound (20 mg, 3%) as an off-white solid.

[0241] 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.13 (d, J = 9.26 Hz, 1H), 7.70 (d, J = 9.13 Hz, 1H), 7.35 (s, 1H), 6.97 (d, J = 8.63 Hz, 2H), 6.58 (d, J = 8.63 Hz, 2H), 6.52 (s, 1H), 5.62 - 5.70 (m, 1H), 5.43 (s, 2H), 5.32 (s, 2H), 4.35 - 4.43 (m, 1H), 3.88 - 3.97 (m, 1H), 3.72 - 3.85 (m, 2H), 3.52 - 3.71 (m, 4H), 3.34 - 3.42 (m, 1H), 3.21 - 3.28 (m, 2H), 2.82 (s, 3H), 2.65 - 2.79 (m, 2H), 2.54 - 2.64 (m, 2H), 2.28 - 2.39 (m, 1H), 2.19 (s, 6H), 2.11 - 2.17 (m, 3H), 2.09 (s, 3H), 1.96 - 2.01 (m, 4H), 1.83 - 1.93 (m, 3H), 1.63 - 1.77 (m, 2H), 1.54 - 1.61 (m, 1H), 1.42 - 1.53 (m, 2H), 1.21 - 1.41 (m, 11H), 0.89 (t, J = 7.32 Hz, 3H), 0.22 (s, 3H), -0.06 (s, 2H).LCMS:1089.57 [M+H] + . HPLC purity 86.1%

[0242] (Example S4) Preparation of 2-(2-(((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)oxy)-N-methylacetamido)-N-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)-N,2-dimethylpropanamide (Compound No. 4) [ka]

[0243] Step-1: Preparation of 2-methyl-2-(methylamino)propanoic acid trifluoroacetate (Intermediate-19)

[0244] To a stirred solution of 2-((tert-butoxycarbonyl)(methyl)amino)-2-methylpropanoic acid (starting material-1, 500 mg, 2.30 mmol, 1.0 equiv.) in DCM (10 mL) was added TFA (1.7 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure, and the reaction mixture was washed with diethyl ether (2×20 mL) and dried under vacuum to give Intermediate-19 (450 mg, 93%) as an off-white solid.

[0245] 1 H NMR (400 MHz, DMSO-d6) δ 14.125 (br s, 1H), 9.09 (br s, 2H), 2.51 (d, J = 11.25 Hz, 3H), 1.40 (s, 6H).LCMS:118.08 [M+H] + .

[0246] Step-2: Preparation of (S)-N-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-10-yl)methyl)-N,2-dimethyl-2-(methylamino)propanamide (Intermediate-20)

[0247] To a stirred solution of (S)-4-ethyl-4,9-dihydroxy-10-((methylamino)methyl)-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Intermediate-2, 400 mg, 0.98 mmol, 1.0 equiv.) and 2-methyl-2-(methylamino)propanoic acid trifluoroacetate (Intermediate-19, 137 mg, 1.17 mmol, 1.2 equiv.) in DMF (2 mL) was added HATU (703 mg, 1.96 mmol, 2.0 equiv.) and DIPEA (0.5 mL, 2.94 mmol, 3 equiv.) at room temperature, and the resulting reaction mixture was stirred for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was washed with water (60 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column eluted with 6% methanol in DCM to give Intermediate-20 (210 mg, 42%) as an off-white solid.

[0248] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (br s, 1H), 8.27 (br d, J = 7.83 Hz, 2H), 8.04 (br d, J = 8.80 Hz, 1H), 7.60 (br d, J = 9.29 Hz, 1H), 7.18 - 7.36 (m, 1H), 6.50 (br s, 1H), 5.41 (br s, 2H), 5.23 (br s, 2H), 5.09 (br s, 2H), 3.33 - 3.40 (m, 2H), 3.00 (br s, 3H), 2.33 (br s, 3H), 1.40 (s, 6H), 0.87 (t, J = 7.32 Hz, 3H).LCMS:507.45 [M+H] + .

[0249] Step-3: Preparation of 2-(2-(((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)oxy)-N-methylacetamido)-N-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)-N,2-dimethylpropanamide

[0250] (S)-N-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)-N,2-dimethyl-2-(methylamino)propenamide (Intermediate-20, 150 mg, 0.29 mmol, 1.0 equiv.) and 2-(((5S,8R,9S,10S,1 To a stirred solution of (3S,14S,17S)-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)oxy)acetic acid intermediate-4 (113 mg, 0.32 mmol, 1.1 equiv.) in DMF (2 mL) at room temperature was added HATU (212 mg, 0.59 mmol, 2.0 equiv.) and DIPEA (0.15 mL, 0.88 mmol, 3 equiv.). The reaction mixture was heated to 50° C. and stirred for 4 h. The reaction progress was monitored by TLC. After completion of the reaction, water (10 mL) was added, and the aqueous reaction mixture was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The resulting crude material was purified by preparative HPLC with ammonium bicarbonate / acetonitrile in water as the mobile phase to afford the title compound (7 mg, 3%) as an off-white solid.

[0251] 1H NMR (400 MHz, DMSO-d6) δ 10.50 (d, J = 4.38 Hz, 1H), 8.57 (s, 1H), 7.99 (d, J = 9.13 Hz, 1H), 7.52 (d, J = 9.13 Hz, 1H), 7.27 (s, 1H), 6.46 (s, 1H), 5.41 (br s, 2H), 5.30 (br s, 2H), 5.09 (br d, J = 12.38 Hz, 1H), 4.90 (br d, J = 12.38 Hz, 1H), 3.79 - 3.93 (m, 2H), 2.81 (s, 3H), 2.59 (s, 3H), 2.25 (br d, J = 14.13 Hz, 1H), 2.12 (br d, J = 15.26 Hz, 1H), 1.79 - 1.93 (m, 4H), 1.48 - 1.50 (m, 3H), 1.45 (s, 6H), 1.21 - 1.33 (m, 4H), 1.06 - 1.20 (m, 4H), 0.92 - 1.03 (m, 2H), 0.91 (s, 3H), 0.75 - 0.90 (m, 6H), 0.40 - 0.52 (m, 1H), 0.22 - 0.39 (m, 2H), 0.17 (s, 3H).LCMS:837.35 [M+H] + . HPLC purity 98.8%.

[0252] (Example S5) Preparation of (S)-4-ethyl-4-hydroxy-10-((4-methylpiperazin-1-yl)methyl)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylate (Compound No. 5) [ka]

[0253] Step-1: Preparation of (S)-4-ethyl-4,9-dihydroxy-10-((4-methylpiperazin-1-yl)methyl)-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Intermediate-1)

[0254] To a stirred solution of (S)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione hydrochloride (starting material-1, 10 g, 27.47 mmol, 1.0 equiv.) in AcOH (100 mL, 10 vol.) was added formaldehyde (3.95 mL, 41.20 mmol, 1.5 equiv., 37% in HO) and 1-methylpiperazine (starting material-2, 4.12 g, 41.20 mmol, 1.5 equiv.) under an argon atmosphere at ambient temperature. The resulting reaction mixture was stirred at 80 °C until complete consumption of the starting material was confirmed by TLC. The reaction mixture was then diluted with ice-cold water (250 mL) and extracted with 10% MeOH in DCM (2 × 250 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was washed with diethyl ether (100 mL) and dried to give (S)-4-ethyl-4,9-dihydroxy-10-((4-methylpiperazin-1-yl)methyl)-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Intermediate-1, 6 g, 46%) as an off-white solid.

[0255] 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.95 - 8.00 (m, 1H), 7.39 - 7.44 (m, 1H), 7.24 - 7.27 (m, 1H), 6.43 - 6.52 (m, 1H), 5.39 - 5.44 (m, 2H), 5.22 - 5.26 (m, 2H), 4.07 - 4.12 (m, 2H), 2.72 - 2.78 (m, 1H), 2.57 - 2.64 (m, 2H), 2.25 - 2.38 (m, 4H), 2.12 - 2.19 (m, 4H), 1.82 - 1.91 (m, 3H), 0.85 - 0.92 (m, 3H).LCMS:477.3 [M+H] + .

[0256] Step-2: Preparation of (S)-1-(tert-butyl) 4-(4-ethyl-4-hydroxy-10-((4-methylpiperazin-1-yl)methyl)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-2)

[0257] To a stirred solution of tert-butyl piperazine-1-carboxylate (starting material-3, 5 g, 26.88 mmol, 1.0 equiv.) in DCM (50 mL, 10 volumes) under an argon atmosphere was added pyridine (5.47 mL, 67.2 mmol, 2.5 equiv.) and triphosgene (3.99 g, 13.44 mmol, 0.5 equiv.) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 1N HCl (approximately 200 mL) and extracted with DCM (2×200 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate as a semi-solid. To a second flask charged with (S)-4-ethyl-4,9-dihydroxy-10-((4-methylpiperazin-1-yl)methyl)-1,12-dihydro-14H-pyrano[3',4':6,7]-indolizino[1,2-b]quinoline-3,14(4H)-dione (Intermediate-1, 6.3 g, 13.44 mmol, 0.5 equiv.) in DCM (25 mL, 10 volumes), DIPEA (6.19 mL, 33.6 mmol, 2.5 equiv.) and DMAP (327 mg, 2.68 mmol, 0.1 equiv.) were added under an argon atmosphere at 0° C. The carbonyl chloride was dissolved in DCM (25 mL) and added dropwise to the reaction mixture under an argon atmosphere at 0° C. The resulting reaction mixture was then stirred at ambient temperature until TLC indicated complete consumption of the starting material. The reaction mixture was then concentrated under reduced pressure and diluted with ice-cold water (100 mL), the resulting precipitate was filtered, and the crude product was dried and purified by flash column (silica gel, 100-200 mesh) eluted with 2-5% MeOH in DCM.The pure fractions were combined and concentrated under reduced pressure to give (S)-1-(tert-butyl) 4-(4-ethyl-4-hydroxy-10-((4-methylpiperazin-1-yl)methyl)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]-indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-2, 1.56 g, 26%) as an off-white solid.

[0258] 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.12 (d, J = 9.29 Hz, 1H), 7.65 (d, J = 9.17 Hz, 1H), 7.34 (s, 1H), 5.75 (s, 1H), 5.42 (s, 2H), 5.30 (s, 2H), 3.66 - 3.88 (m, 4H), 3.40 - 3.56 (m, 6H), 2.51 - 2.57 (m, 2H), 2.46 - 2.49 (m, 1H), 2.14 - 2.29 (m, 4H), 1.85 - 1.91 (m, 1H), 1.82 - 1.93 (m, 1H), 1.40 - 1.46 (m, 11H), 0.89 (t, J = 7.27 Hz, 3H).LCMS:689.4 [M+H] + .

[0259] Step-3: Preparation of (S)-4-ethyl-4-hydroxy-10-((4-methylpiperazin-1-yl)methyl)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-3)

[0260] To a stirred solution of (S)-1-(tert-butyl) 4-(4-ethyl-4-hydroxy-10-((4-methylpiperazin-1-yl)methyl)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-2, 1.5 g, 2.18 mmol, 1.0 equiv.) in DCM (15 mL, 10 vol.) was added TFA (1.66 mL, 21.8 mmol, 10 equiv.) at ambient temperature. The reaction mixture was stirred at ambient temperature until TLC indicated complete consumption of the starting material. The reaction mixture was then concentrated under reduced pressure, saturated sodium bicarbonate solution (100 mL) was added, and the aqueous mixture was extracted with 10% MeOH in DCM (2 x 250 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and triturated with diethyl ether (100 mL) to afford (S)-4-ethyl-4-hydroxy-10-((4-methylpiperazin-1-yl)methyl)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-3, 700 mg, 54%) as an off-white solid.

[0261] 1H NMR (400 MHz, DMSO-d6) δ 8.91 - 8.99 (m, 1H), 8.04 - 8.13 (m, 1H), 7.59 - 7.64 (m, 1H), 7.30 - 7.35 (m, 1H), 6.48 - 6.53 (m, 1H), 5.38 - 5.46 (m, 2H), 5.26 - 5.33 (m, 2H), 3.81 - 3.86 (m, 2H), 3.56 - 3.68 (m, 3H), 3.36 - 3.42 (m, 2H), 3.12 - 3.18 (m, 2H), 2.74 - 2.85 (m, 5H), 2.16 - 2.34 (m, 4H), 2.07 - 2.13 (m, 4H), 1.81 - 1.92 (m, 2H), 0.83 - 0.91 (m, 3H).LCMS:589.2 [M+H] + .

[0262] Step-4: Preparation of (S)-4-ethyl-4-hydroxy-10-((4-methylpiperazin-1-yl)methyl)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylate

[0263] To a stirred solution of (S)-4-ethyl-4-hydroxy-10-((4-methylpiperazin-1-yl)methyl)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-3, 2.0 g, 3.40 mmol, 1.0 equiv) in MeOH (20 mL, 10 vol) was added under an argon atmosphere at 0°C. (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-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-C, 3.8 g, 6.80 mmol, 2.0 equiv.) and acetic acid (1 mL, catalytic amount) were added. The reaction mixture was stirred at room temperature for 1 h, and then NaCNBH (428 mg, 6.80 mmol, 2.0 equiv.) was added at 0 °C under an argon atmosphere. The reaction mixture was then stirred at room temperature until TLC showed complete consumption of the starting material. The reaction mixture was then quenched with saturated sodium bicarbonate solution (250 mL) and extracted with ethyl acetate (2 x 500 mL), and the combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: spherical-C18, 40 uM, 100A; mobile phase A: 0.1% FA in water; mobile phase B: acetonitrile; flow rate: 25 mL / min, diluent: THF+DMSO).The pure fractions were lyophilized under reduced pressure to give (S)-4-ethyl-4-hydroxy-10-((4-methylpiperazin-1-yl)methyl)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)-hexyl)piperazine-1-carboxylate (486 mg, 12%) as an off-white solid.

[0264] 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.14 - 8.15 (m, 2H), 8.09 - 8.13 (m, 1H), 7.63 (d, J = 9.26 Hz, 1H), 7.34 (s, 1H), 6.96 - 7.00 (m, 2H), 6.58 - 6.62 (m, 3H), 6.48 - 6.54 (m, 2H), 5.66 - 5.69 (m, 1H), 5.42 - 5.44 (m, 2H), 5.28 - 5.33 (m, 2H), 4.38 - 4.42 (m, 1H), 4.38 - 4.42 (m, 1H), 3.82 - 3.86 (m, 2H), 3.66 - 3.72 (m, 2H), 3.44 - 3.50 (m, 4H), 3.22 - 3.27 (m, 5H), 2.29 - 2.37 (m, 7H), 2.08 - 2.18 (m, 11H), 1.42 - 1.51 (m, 5H), 1.26 - 1.35 (m, 7H), 0.86 - 0.91 (m, 3H), 0.22 - 0.25 (m, 3H).LCMS:1133.7 [M+H] + . HPLC purity 91.5%.

[0265] (Example S6) Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(7-((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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)heptyl)piperazine-1-carboxylate (Compound No. 6) [ka]

[0266] Step-1: 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-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-1)

[0267] To a stirred solution 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-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (starting material-1, 5.0 g, 10.84 mmol, 1.0 equiv.) in EtOH (50 mL, 10 vol.) and HO (25 mL, 5 vol.) under an argon atmosphere at 0 °C was added 7-bromoheptan-1-ol (starting material-2, 10.56 g, 54.2 mmol, 5.0 equiv.) and NaHCO (2.73 g, 32.52 mmol, 3.0 equiv.). The resulting reaction mixture was stirred at 80°C until TLC showed complete consumption of the starting material. The reaction mixture was then diluted with ice-cold water (250 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash column (silica gel, 100-200 mesh) eluted with 20-50% EtOAc in hexanes. The pure fractions were combined and concentrated under reduced pressure to give (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-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-1, 2 g, 32%) as an off-white solid.

[0268] H NMR (400 MHz, DMSO-d6) δ 6.97 (d, J = 8.31 Hz, 2H), 6.57 (d, J = 8.31 Hz, 2H), 5.64 - 5.70 (m, 1H), 4.36 - 4.41 (m, 1H), 4.27 - 4.32 (m, 1H), 3.33 - 3.38 (m, 3H), 3.18 - 3.26 (m, 2H), 2.78 - 2.82 (m, 3H), 2.64 - 2.77 (m, 2H), 2.54 - 2.64 (m, 2H), 2.30 - 2.41 (m, 1H), 2.19 - 2.24 (m, 1H), 2.11 - 2.15 (m, 1H), 2.06 - 2.11 (m, 3H), 1.97 - 2.03 (m, 4H), 1.85 - 1.93 (m, 1H), 1.64 - 1.75 (m, 2H), 1.35 - 1.50 (m, 6H), 1.19 - 1.32 (m, 8H), 0.17 - 0.26 (m, 3H).LCMS:576.96 [M+H] + .

[0269] Step-2: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(7-oxoheptyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-2)

[0270] Under an argon atmosphere, to a stirred solution 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-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-1, 3 g, 5.2 mmol, 1.0 equiv.) in EtOAc (60 mL, 20 vol.) was added DMP (4.4 g, 10.4 mmol, 2.0 equiv.) at 0° C. The resulting reaction mixture was stirred at 80° C. until TLC showed complete consumption of the starting material. The reaction mixture was then quenched with a mixture of NaSO and saturated sodium bicarbonate solution (1:1, 250 mL), extracted with EtOAc (2 × 500 mL), and the combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(7-oxoheptyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-2, 3 g, crude) as an off-white solid, which was used in the next step without further purification.

[0271] 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 6.97 (d, J = 7.82 Hz, 1H), 6.58 (d, J = 8.80 Hz, 1H), 5.67 (s, 1H), 4.39 (d, J = 6.36 Hz, 1H), 4.03 (q, J = 6.85 Hz, 1H), 3.17 - 3.26 (m, 2H), 2.65 - 2.84 (m, 4H), 2.52 - 2.65 (m, 2H), 2.28 - 2.44 (m, 3H), 2.05 - 2.25 (m, 6H), 1.84 - 2.04 (m, 7H), 1.62 - 1.76 (m, 2H), 1.34 - 1.54 (m, 5H), 1.21 - 1.31 (m, 5H), 1.15 - 1.20 (m, 2H), 0.21 - 0.26 (m, 3H).LCMS:574.72 [M+H] + .

[0272] 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]indolizino[1,2-b]quinolin-9-yl 4-(7-((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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)heptyl)piperazine-1-carboxylate

[0273] To a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-A, 3.0 g, 5.62 mmol, 1.0 equiv.) in MeOH (30 mL, 10 vol.) was added (8S) under an argon atmosphere at 0°C. ,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(7-oxoheptyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-2, 3.2 g, 5.62 mmol, 1.0 equiv.) and acetic acid (1 mL, catalytic amount) were added. The reaction mixture was stirred at room temperature for 1 h, after which NaCNBH (705 mg, 11.24 mmol, 2.0 equiv.) was added at 0 °C under an argon atmosphere. The reaction mixture was then stirred at room temperature until TLC showed complete consumption of the starting material. The reaction mixture was then quenched with saturated sodium bicarbonate solution (250 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: spherical-C18, 40 μM, 100 A; mobile phase A: 0.1% FA in water; mobile phase B: acetonitrile; flow rate: 25 mL / min, diluent: THF + DMSO).Pure fractions were combined and lyophilized under reduced pressure to give (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(7-((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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)heptyl)piperazine-1-carboxylate (2.35 g, 38%) as an off-white solid.

[0274] 1 H NMR (400 MHz, DMSO-d6) δ 8.96 - 9.00 (m, 1H), 8.09 - 8.16 (m, 1H), 7.60 - 7.65 (m, 1H), 7.32 - 7.36 (m, 1H), 6.97 - 7.01 (m, 2H), 6.57 - 6.62 (m, 2H), 6.49 - 6.51 (m, 1H), 5.66 - 5.70 (m, 1H), 5.42 - 5.44 (m, 2H), 5.30 - 5.32 (m, 2H), 4.37 - 4.42 (m, 1H), 3.80 - 3.87 (m, 2H), 3.64 - 3.73 (m, 2H), 3.42 - 3.51 (m, 2H), 3.24 - 3.25 (m, 3H), 2.80 - 2.84 (m, 4H), 2.41 - 2.43 (m, 2H), 2.31 - 2.34 (m, 4H), 2.08 - 2.15 (m, 12H), 1.99 - 2.01 (m, 5H), 1.85 - 1.92 (m, 4H), 1.65 - 1.73 (m, 3H), 1.41 - 1.51 (m, 5H), 1.27 - 1.34 (m, 6H), 0.86 - 0.91 (m, 4H), 0.23 - 0.26 (m, 3H).LCMS: 1091.1 [M+H] + .

[0275] (Example S7) Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(8-((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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)octyl)piperazine-1-carboxylate (Compound No. 7) [ka]

[0276] Step-1: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((8-hydroxyoctyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-1)

[0277] To a stirred solution 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-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (starting material-1, 10.0 g, 21.69 mmol, 1.0 equiv.) in EtOH (100 mL, 10 vol.) and HO (50 mL, 5 vol.) was added 8-bromooctan-1-ol (starting material-2, 22.66 g, 108.45 mmol, 5.0 equiv.) and NaHCO (5.46 g, 61.07 mmol, 3.0 equiv.) under an argon atmosphere at 0 °C. The resulting reaction mixture was stirred at 80°C until TLC showed complete consumption of the starting material. The reaction mixture was then diluted with ice-cold water (250 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash column (silica gel, 100-200 mesh) eluted with 20-50% EtOAc in hexanes. The pure fractions were combined and concentrated under reduced pressure to give (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((8-hydroxyoctyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-1, 5 g, 39%) as an off-white solid.

[0278] 1H NMR (400 MHz, DMSO-d6) δ 6.97 (d, J = 7.83 Hz, 2H), 6.57 (d, J = 7.83 Hz, 2H), 5.74 - 5.77 (m, 1H), 5.65 - 5.69 (m, 1H), 4.36 - 4.42 (m, 1H), 4.26 - 4.35 (m, 2H), 3.33 - 3.40 (m, 6H), 3.18 - 3.26 (m, 1H), 2.80 (s, 3H), 2.67 - 2.77 (m, 1H), 2.54 - 2.64 (m, 2H), 2.31 - 2.41 (m, 1H), 2.12 - 2.24 (m, 2H), 2.10 (s, 3H), 1.89 - 2.04 (m, 3H), 1.61 - 1.78 (m, 1H), 1.35 - 1.45 (m, 6H), 1.21 - 1.30 (m, 10H), 0.23 (s, 3H).LCMS:590.5 [M+H] + .

[0279] Step-2: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(8-oxooctyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-17-yl acetate (Intermediate-2)

[0280] To a stirred solution of ((8S,11R,13S,14S,17R)-17-acetyl-11-(4-((8-hydroxyoctyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-1, 4 g, 6.79 mmol, 1.0 equiv.) in EtOAc (80 mL, 20 vol.) was added DMP (5.75 g, 13.5 mmol, 2.0 equiv.) under an argon atmosphere at 0 °C. The resulting reaction mixture was stirred at 80 °C until TLC indicated complete consumption of the starting material. This reaction mixture was then diluted with NaSO and saturated bicarbonate. The mixture was quenched with a 1:1 mixture of HCl and HCl (250 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(8-oxooctyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-2, 4 g, crude) as an off-white solid, which was used in the next step without further purification.

[0281] 1H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 6.97 (d, J = 7.82 Hz, 1H), 6.57 (d, J = 7.82 Hz, 1H), 5.66 - 5.70 (m, 1H), 4.35 - 4.45 (m, 1H), 3.99 - 4.06 (m, 2H), 3.21 (d, J = 6.36 Hz, 1H), 2.79 - 2.82 (m, 2H), 2.66 - 2.78 (m, 2H), 2.54 - 2.64 (m, 2H), 2.37 - 2.44 (m, 3H), 2.29 - 2.36 (m, 1H), 2.18 - 2.26 (m, 1H), 2.09 - 2.17 (m, 4H), 1.97 - 2.01 (m, 5H), 1.85 - 1.92 (m, 1H), 1.66 - 1.74 (m, 1H), 1.41 - 1.56 (m, 6H), 1.22 - 1.28 (m, 8H), 1.17 (t, J = 7.09 Hz, 3H), 0.20 - 0.25 (m, 2H).LCMS:588.66 [M+H] + .

[0282] 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]indolizino[1,2-b]quinolin-9-yl 4-(8-((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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)octyl)piperazine-1-carboxylate

[0283] To a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-A, 4.0 g, 7.50 mmol, 1.0 equiv.) in MeOH (40 mL, 10 vol.) was added (8S) under an argon atmosphere at 0°C. ,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(8-oxooctyl)amino)-phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-2, 4.4 g, 7.50 mmol, 1.0 equiv.) and acetic acid (1 mL, catalytic amount) were added. The reaction mixture was stirred at room temperature for 1 h, after which NaCNBH (945 mg, 15.0 mmol, 2.0 equiv.) was added at 0 °C under an argon atmosphere. The reaction mixture was then stirred at room temperature until complete consumption of the starting material was indicated by TLC, quenched with saturated sodium bicarbonate solution (250 mL), and extracted with ethyl acetate (2 × 500 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: spherical-C18, 40 μM, 100 A; mobile phase A: 0.1% FA in water; mobile phase B: acetonitrile; flow rate: 25 mL / min, diluent: THF+DMSO).Pure fractions were combined and lyophilized under reduced pressure to give (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(8-((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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)octyl)piperazine-1-carboxylate (1.19 g, 14%) as an off-white solid.

[0284] 1 H NMR (400 MHz, DMSO-d6) δ 8.92 - 8.97 (m, 1H), 8.08 - 8.15 (m, 2H), 7.61 - 7.66 (m, 1H), 7.33 - 7.35 (m, 1H), 6.96 - 7.00 (m, 2H), 6.57 - 6.61 (m, 2H), 6.49 - 6.54 (m, 1H), 5.66 - 5.69 (m, 1H), 5.42 - 5.45 (m, 2H), 5.30 - 5.33 (m, 2H), 4.38 - 4.41 (m, 1H), 3.67 - 3.78 (m, 4H), 3.44 - 3.51 (m, 2H), 3.20 - 3.27 (m, 4H), 2.82 (s, 3H), 2.39 - 2.46 (m, 3H), 2.31 - 2.37 (m, 3H), 2.19 - 2.21 (m, 7H), 2.08 - 2.10 (m, 4H), 1.98 - 2.01 (m, 4H), 1.98 - 2.02 (m, 4H), 1.83 - 1.93 (m, 3H), 1.62 - 1.78 (m, 1H), 1.42 - 1.51 (m, 5H), 1.28 (br s, 10H), 0.86 - 0.92 (m, 4H), 0.24 - 0.25 (m, 3H).LCMS: 1105.5 [M+H] + .

[0285] (Example S8) Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(5-((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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)pentyl)piperazine-1-carboxylate (Compound No. 8) [ka]

[0286] Step-1: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((5-hydroxypentyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-1)

[0287] To a stirred solution 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-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (starting material-1, 9.0 g, 19.52 mmol, 1.0 equiv.) in EtOH (90 mL, 10 vol.) and HO (45 mL, 5 vol.) was added 5-bromopentan-1-ol (starting material-2, 16.29 g, 97.6 mmol, 5.0 equiv.) and NaHCO (4.91 g, 58.56 mmol, 3.0 equiv.) under an argon atmosphere at 0 °C. The resulting reaction mixture was stirred at 80°C until TLC showed complete consumption of the starting material. The reaction mixture was then diluted with ice-cold water (250 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash column (silica gel, 100-200 mesh) eluted with 20-50% EtOAc in hexanes. The pure fractions were combined and concentrated under reduced pressure to give (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((5-hydroxypentyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-1, 2.2 g, 20%) as an off-white solid.

[0288] 1H NMR (400 MHz, DMSO-d6) δ 6.98 (d, J = 8.31 Hz, 2H), 6.55 - 6.60 (m, 2H), 5.67 (s, 1H), 4.29 - 4.42 (m, 2H), 4.00 - 4.07 (m, 1H), 3.36 (q, J = 5.87 Hz, 2H), 3.19 - 3.24 (m, 2H), 2.81 (s, 3H), 2.66 - 2.77 (m, 2H), 2.54 - 2.64 (m, 2H), 2.31 - 2.40 (m, 1H), 2.19 - 2.24 (m, 1H), 2.12 - 2.18 (m, 2H), 2.07 - 2.10 (m, 3H), 1.94 - 2.02 (m, 5H), 1.86 - 1.94 (m, 1H), 1.65 - 1.75 (m, 2H), 1.39 - 1.49 (m, 5H), 1.23 - 1.33 (m, 2H), 1.17 (t, J = 7.09 Hz, 1H), 0.23 (s, 3H).LCMS:548.4 [M+H] + .

[0289] Step-2: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(5-oxopentyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-2)

[0290] To a stirred solution of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((5-hydroxypentyl)(methyl)amino)-phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-1, 2 g, 3.65 mmol, 1.0 equiv.) in EtOAc (40 mL, 20 vol.) was added DMP (3.09 g, 7.3 mmol, 2.0 equiv.) under an argon atmosphere at 0° C. The resulting reaction mixture was stirred at 80° C. until TLC indicated complete consumption of the starting material. The reaction mixture was then quenched with a mixture of NaSO and saturated sodium bicarbonate solution (1:1, 250 mL), extracted with EtOAc (2 x 500 mL), and the combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(5-oxopentyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-17-yl acetate (Intermediate-2, 2 g, crude) as an off-white solid, which was used in the next step without further purification.

[0291] 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 6.98 (d, J = 8.31 Hz, 2H), 6.59 (d, J = 8.31 Hz, 2H), 5.67 (s, 1H), 4.36 - 4.43 (m, 1H), 3.98 - 4.07 (m, 1H), 3.19 - 3.27 (m, 2H), 2.81 (s, 3H), 2.53 - 2.78 (m, 5H), 2.29 - 2.49 (m, 3H), 2.12 - 2.25 (m, 3H), 2.10 (s, 3H), 1.84 - 2.05 (m, 7H), 1.59 - 1.80 (m, 2H), 1.42 - 1.56 (m, 3H), 1.17 (t, J = 7.09 Hz, 1H), 0.23 (s, 3H).LCMS:546.68 [M+H] + .

[0292] 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]indolizino[1,2-b]quinolin-9-yl 4-(5-((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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)pentyl)piperazine-1-carboxylate

[0293] To a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-A, 4.0 g, 7.50 mmol, 1.0 equiv.) in MeOH (40 mL, 10 vol.) was added (8S) under an argon atmosphere at 0°C. ,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(5-oxopentyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-2, 4.1 g, 7.50 mmol, 1.0 equiv.) and acetic acid (1 mL, catalytic amount) were added. The reaction mixture was stirred at room temperature for 1 h, and NaCNBH (945 mg, 15.0 mmol, 2.0 equiv.) was added at 0 °C under an argon atmosphere. The reaction mixture was then stirred at room temperature until TLC showed complete consumption of the starting material. The reaction mixture was then quenched with saturated sodium bicarbonate solution (250 mL) and extracted with ethyl acetate (2 × 500 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: spherical-C18, 40 μM, 100 A; mobile phase A: 0.1% FA in water; mobile phase B: acetonitrile; flow rate: 25 mL / min, diluent: THF+DMSO).Pure fractions were combined and lyophilized under reduced pressure to give (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(5-((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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)-pentyl)piperazine-1-carboxylate (1.12 g, 14%) as an off-white solid.

[0294] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.94 (s, 1H), 8.16 (s, 2H), 8.11 (d, J = 9.29 Hz, 1H), 7.63 (d, J = 8.80 Hz, 1H), 7.34 (s, 1H), 6.99 (d, J = 7.82 Hz, 2H), 6.60 (d, J = 7.83 Hz, 2H), 5.66 - 5.69 (m, 1H), 5.43 (s, 2H), 5.31 (br s, 2H), 4.37 - 4.42 (m, 1H), 3.76 (br s, 2H), 3.67 - 3.72 (m, 2H), 3.44 - 3.48 (m, 3H), 3.21 - 3.30 (m, 5H), 2.83 (s, 3H), 2.52 - 2.79 (m, 5H), 2.29 - 2.44 (m, 6H), 2.20 (s, 6H), 2.10 (s, 3H), 2.00 (s, 3H), 1.80 - 1.94 (m, 3H), 1.64 - 1.77 (m, 1H), 1.39 - 1.57 (m, 4H), 1.24 - 1.38 (m, 3H), 0.89 (t, J = 6.85 Hz, 3H), 0.21 - 0.27 (m, 3H).LCMS:1063.2 [M+H] + .

[0295] (Example S9) Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexanoyl)piperazine-1-carboxylate (Compound No. 9) [ka]

[0296] Step-1: Preparation of 4-((2-carboxypropan-2-yl)amino)-2-fluorobenzoic acid (Intermediate-1)

[0297] To a stirred solution of 4-bromo-2-fluorobenzoic acid (starting material-1, 10.0 g, 45.66 mmol, 1.0 equiv.) in DMF (100 mL, 10 vol.) and water (10 mL, 1 vol.) was added 2-amino-2-methylpropanoic acid (starting material-2, 14.1 g, 136.98 mmol, 3.0 equiv.), N,N-dimethylglycine (2.35 g, 22.83 mmol, 0.5 equiv.), KCO (31.5 g, 228.3 mmol, 5.0 equiv.), Cu powder (575 mg, 9.13 mmol, 0.2 equiv.), and copper iodide (1.73 g, 9.13 mmol, 0.2 equiv.) at room temperature. The reaction mixture was stirred at 110 °C until TLC showed complete consumption of the starting material. The reaction mixture was then diluted with ice-cold water (500 mL) and acidified with 6 N HCl to a pH of about 4. The resulting aqueous solution was then extracted with ethyl acetate (2×1 L) and the combined organic layers were washed with brine solution (300 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized with DCM to give 4-((2-carboxypropan-2-yl)amino)-2-fluorobenzoic acid (Intermediate-1, 6.2 g, 56%) as an off-white solid.

[0298] 1 H NMR (400 MHz, DMSO-d6) δ 12.52 (br s, 2H), 7.59 (t, J = 8.79 Hz, 1H), 6.96 (s, 1H), 6.33 (dd, J = 8.79, 1.85 Hz, 1H), 6.15 (dd, J = 14.57, 1.62 Hz, 1H), 1.44 (s, 6H).LCMS:242.15 [M+H] + .

[0299] Step-2: Preparation of methyl 2-fluoro-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)benzoate (Intermediate-2)

[0300] To a stirred solution of 4-((2-carboxypropan-2-yl)amino)-2-fluorobenzoic acid (Intermediate-1, 6.2 g, 25.72 mmol, 1.0 equiv.) in DMF (70 mL, 10 vol.) at room temperature was added MeI (3.1 mL, 51.45 mmol, 2.0 equiv.), KCO (53.1 g, 385.5 mmol, 15.0 equiv.). The reaction mixture was stirred at ambient temperature until TLC showed complete consumption of the starting material. The reaction mixture was then diluted with ice-cold water (500 mL), filtered, and dried to give methyl 2-fluoro-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)benzoate (Intermediate-2, 4.82 g, 69%) as an off-white solid.

[0301] 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (t, J = 8.80 Hz, 1H), 7.11 (s, 1H), 6.29 (dd, J = 8.80, 2.45 Hz, 1H), 6.14 (dd, J = 14.67, 1.96 Hz, 1H), 3.74 (s, 3H), 3.63 (s, 3H), 1.48 (s, 6H).LCMS:270.10 [M+H] + .

[0302] Step-3: Preparation of methyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoate (Intermediate-3)

[0303] To a stirred solution of methyl 2-fluoro-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)benzoate (Intermediate-2, 4.8 g, 17.84 mmol, 1.0 equiv.) in DMSO (7.2 mL, 1.5 vol.) at room temperature was added 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (Starting Material-3, 8.5 g, 37.59 mmol, 2.1 equiv.). The reaction mixture was stirred at 90 °C until TLC showed complete consumption of the starting material. The reaction mixture was then diluted with ice-cold water (500 mL) and extracted with ethyl acetate (2 × 1 L). The combined organic layers were washed with brine solution (300 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, 100-200 mesh) eluted with 20-30% ethyl acetate in hexane. The pure fractions were combined and concentrated under reduced pressure to give methyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoate (Intermediate-3, 5 g, 60%) as an off-white solid.

[0304] 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 8.31 Hz, 1H), 8.29 (d, J = 1.47 Hz, 1H), 8.06 - 8.11 (m, 2H), 7.51 (dd, J = 11.25, 1.96 Hz, 1H), 7.41 (dd, J = 8.31, 1.96 Hz, 1H), 3.90 (s, 3H), 1.55 (s, 6H).LCMS:466.50 [M+H] + .

[0305] Step-4: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoic acid (Intermediate-4)

[0306] To a flask charged with methyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoate (Intermediate-3, 3 g, 6.45 mmol, 1.0 equiv.) in MeOH:THF:HO (1:1:1, 30 mL, 10 volumes) was added LiOH (810 mg, 19.35 mmol, 3.0 equiv.) under an argon atmosphere at ambient temperature. The reaction mixture was stirred at ambient temperature until TLC indicated complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure, diluted with water (10 mL), acidified to pH 3 with citric acid, and the resulting solid was filtered and dried to give 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoic acid (Intermediate-4, 2.6 g, 89%) as an off-white solid.

[0307] 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 8.31 Hz, 1H), 8.29 (s, 1H), 8.08 (d, J = 8.31 Hz, 1H), 7.94 (t, J = 8.07 Hz, 1H), 7.36 (d, J = 10.76 Hz, 1H), 7.29 (d, J = 8.31 Hz, 1H), 1.54 (s, 6H).LCMS:452.20 [M+H] + .

[0308] Step-5: Preparation of ethyl 6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexanoate (Intermediate-5)

[0309] To a stirred solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoic acid (Intermediate-4, 2.6 g, 5.76 mmol, 1.0 equiv.) in DMF (26 mL, 10 vol.) was added ethyl 6-aminohexanoate hydrogen chloride (Starting Material-4, 1.68 g, 8.64 mmol, 1.5 equiv.), EDC HCl (1.65 g, 8.64 mmol, 1.5 equiv.), HOBt (1.67 g, 8.64 mmol, 1.5 equiv.), DMAP (70 mg, 0.57 mmol, 0.1 equiv.), and DIPEA (3.18 mL, 17.28 mmol, 3.0 equiv.) at room temperature. The reaction mixture was stirred at ambient temperature until TLC showed complete consumption of the starting material, diluted with ice-cold water (100 mL), and extracted with ethyl acetate (2 × 250 mL). The combined organic layers were washed with brine solution (200 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (silica gel, 100-200 mesh) eluting with 40-60% ethyl acetate / hexanes. Pure fractions were combined and concentrated under reduced pressure to give ethyl 6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexanoate (Intermediate-5, 2.39 g, 70%) as an off-white solid.

[0310] 1H NMR (400 MHz, DMSO-d6) δ 8.48 (t, J = 5.38 Hz, 1H), 8.39 (d, J = 8.31 Hz, 1H), 8.28 (d, J = 1.22 Hz, 1H), 8.07 (dd, J = 8.31, 1.47 Hz, 1H), 7.74 (t, J = 8.07 Hz, 1H), 7.41 (dd, J = 10.64, 1.59 Hz, 1H), 7.31 (dd, J = 8.07, 1.71 Hz, 1H), 4.04 (q, J = 7.09 Hz, 2H), 3.24 (q, J = 6.60 Hz, 2H), 2.28 (t, J = 7.34 Hz, 2H), 1.55 - 1.59 (m, 2H), 1.53 (s, 6H), 1.47 - 1.52 (m, 2H), 1.28 - 1.38 (m, 2H), 1.16 (t, J = 7.09 Hz, 3H).LCMS:593.2 [M+H] + .

[0311] Step-6: Preparation of 6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexanoic acid (Intermediate-6)

[0312] To a flask charged with ethyl 6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexanoate (Intermediate-5, 2.4 g, 4.05 mmol, 1.0 equiv) in EtOH:THF:HO (1:1:1, 24 mL, 10 volumes) was added LiOH (509 mg, 12.15 mmol, 3.0 equiv) at ambient temperature under an argon atmosphere. The reaction mixture was stirred at ambient temperature until TLC indicated complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure, diluted with water (10 mL), acidified to pH ∼3 with citric acid, and the resulting solid was filtered and dried to give 6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexanoic acid (Intermediate-6, 2.0 g, 87%) as an off-white solid.

[0313] 1 H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.49 (t, J = 5.38 Hz, 1H), 8.40 (d, J = 8.31 Hz, 1H), 8.29 (s, 1H), 8.08 (d, J = 8.31 Hz, 1H), 7.75 (t, J = 8.07 Hz, 1H), 7.42 (d, J = 10.27 Hz, 1H), 7.33 (dd, J = 8.07, 1.22 Hz, 1H), 3.26 (q, J = 6.36 Hz, 2H), 2.22 (t, J = 7.34 Hz, 2H), 1.47 - 1.59 (m, 10H), 1.29 - 1.39 (m, 2H).LCMS:565.10 [M+H] + .

[0314] Step-7: Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexanoyl)piperazine-1-carboxylate

[0315] A flask was charged with 6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexanoic acid (Intermediate-6, 1.0 g, 1.77 mmol, 1.0 equiv.) in DMF (10 mL), and (S)-10-((dimethylamino)methyl)-4-ethyl-4-methyl ... -Hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-A, 945 mg, 1.77 mmol, 1.0 equiv.), HATU (1.0 g, 2.65 mmol, 1.5 equiv.), and DIPEA (0.97 mL, 3.98 mmol, 3.0 equiv.) were added. The reaction mixture was stirred at ambient temperature until complete consumption of the starting material was indicated by TLC, diluted with ice-cold water (100 mL), and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine solution (200 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (silica gel, 100-200 mesh) eluting with 0-5% MeOH in DCM. Pure fractions were combined and concentrated under reduced pressure to afford (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexanoyl)piperazine-1-carboxylate (605 mg, 31%) as an off-white solid.

[0316] 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.47 - 8.54 (m, 1H), 8.40 (d, J = 8.38 Hz, 1H), 8.29 (s, 1H), 8.04 - 8.16 (m, 2H), 7.76 (t, J = 7.63 Hz, 1H), 7.66 (d, J = 8.63 Hz, 1H), 7.43 (d, J = 10.76 Hz, 1H), 7.30 - 7.38 (m, 2H), 6.51 (s, 1H), 5.40 - 5.46 (m, 2H), 5.28 - 5.35 (m, 2H), 3.41 - 3.85 (m, 10H), 2.35 - 2.44 (m, 2H), 2.20 (s, 6H), 1.80 - 1.95 (m, 2H), 1.50 - 1.64 (m, 10H), 1.33 - 1.44 (m, 2H), 1.20 - 1.30 (m, 2H), 0.89 (t, J = 6.69 Hz, 3H).LCMS:1080.30 [M+H] + . HPLC purity 96.1%.

[0317] (Example S10) Preparation of (S)-10-((4-(1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carbonyl)piperazin-1-yl)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-methylpiperazine-1-carboxylate (Compound No. 10) [ka]

[0318] Step-1: Preparation of (S)-10-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-methylpiperazine-1-carboxylate (Intermediate-A5)

[0319] To a stirred solution of tert-butyl (S)-4-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)piperazine-1-carboxylate (Intermediate-3, 300 mg, 0.53 mmol, 1.0 equiv.) in DCM (15 mL) was added DIPEA (0.3 mL, 1.60 mmol, 3 equiv.) and DMAP (20 mg, 0.16 mmol, 0.25 equiv.) at room temperature, followed by 4-methylpiperazine-1-carbonyl chloride (Starting Material-1, 129 mg, 0.80 mmol, 1.5 equiv.) in DCM (5 mL) and stirring for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was washed with water (100 mL) and extracted with DCM (2 x 200 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column eluted with 6% methanol in DCM to give Intermediate-A5 (260 mg, 70%) as an off-white solid.

[0320] 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.12 (d, J = 9.29 Hz, 1H), 7.63 (d, J = 8.80 Hz, 1H), 7.34 (s, 1H), 6.51 (s, 1H), 5.43 (s, 2H), 5.30 (s, 2H), 3.87 (s, 2H), 3.68-3.70 (m, 2H), 3.48-3.50 (m, 2H), 3.20-3.25 (m, 2H), 2.38-2.42 (m, 8H), 2.25 (s, 3H), 1.84-1.91 (m, 2H), 1.39 (s, 9H), 1.25 (br dd, J = 11.98, 6.11 Hz, 2H), 0.89 (br t, J = 7.09 Hz, 3H).LCMS:689.4 [M+H] + .

[0321] Step-2: Preparation of (S)-4-ethyl-4-hydroxy-3,14-dioxo-10-(piperazin-1-ylmethyl)-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-methylpiperazine-1-carboxylate trifluoroacetate (Intermediate-A6)

[0322] To a stirred solution of (S)-10-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-methylpiperazine-1-carboxylate (Intermediate-A6, 250 mg, 0.36 mmol, 1.0 equiv.) in DCM (10 mL) was added TFA (0.3 mL, 3.5 mmol, 10 equiv.) at 0°C under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, washed with diethyl ether (20 mL), and dried under vacuum to give Intermediate-A6 (210 mg, 98%) as an off-white solid.

[0323] 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.66 (br s, 2H), 8.18 (d, J = 9.29 Hz, 1H), 7.69 (d, J = 9.29 Hz, 1H), 7.35 (s, 1H), 6.55 (br s, 1H), 5.44 (s, 2H), 5.31 (s, 2H), 4.40 (br s, 1H), 4.16 (br s, 1H), 3.96-3.99 (m, 3H), 3.49.3.54 (m, 3H), 3.20-3.22 (m, 2H), 3.01-3.05 (m, 4H), 2.90 (s, 3H), 2.62-2.68 (m, 4H), 1.82 - 1.93 (m, 2H), 0.89 (br t, J = 7.09 Hz, 3H).LCMS:589.2 [M+H] + .

[0324] Step-3: Preparation of (S)-10-((4-(1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carbonyl)piperazin-1-yl)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-methylpiperazine-1-carboxylate

[0325] (S)-4-Ethyl-4-hydroxy-3,14-dioxo-10-(piperazin-1-ylmethyl)-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-methylpiperazine-1-carboxylate TFA salt (Intermediate-A6, 200 mg, 0.34 mmol, 1.0 equiv.) and 1-(6-(((1r,4r)- To a stirred solution of 4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carboxylic acid (Intermediate-13, 185 mg, 0.37 mmol, 1.1 equiv.) in DMF (5 mL) was added HATU (243 mg, 0.68 mmol, 2 equiv.) and DIPEA (0.177 mL, 1.02 mmol, 3 equiv.) at room temperature and stirred for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was washed with water (60 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The resulting crude was purified by combiflash® column eluted with 5% methanol in DCM to afford the title compound (86 mg, 24%) as an off-white solid.

[0326] 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.57 (br d, J = 8.25 Hz, 1H), 8.14 (d, J = 9.26 Hz, 1H), 7.83 (dd, J = 15.76, 9.13 Hz, 2H), 7.65 (d, J = 9.26 Hz, 1H), 7.30 - 7.45 (m, 3H), 7.13 (dd, J = 8.82, 2.44 Hz, 1H), 6.52 (s, 1H), 5.44 (s, 2H), 5.32 (s, 2H), 4.40 - 4.58 (m, 3H), 3.84 - 3.94 (m, 3H), 3.69-3.71 (m, 2H), 3.37 - 3.56 (m, 6H), 3.11 (br t, J = 11.94 Hz, 3H), 2.38-2.42 (m, 6H), 2.26 (s, 3H), 2.05 - 2.14 (m, 2H), 1.84 - 1.95 (m, 4H), 1.46 - 1.76 (m, 10H), 0.89 (t, J = 7.32 Hz, 3H).LCMS:1055.65 [M+H] + . HPLC purity 96.0%.

[0327] (Example S11) Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(1-(6-(((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)-cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carbonyl)piperazine-1-carboxylate (Compound No. 11) [ka]

[0328] Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-A) [ka]

[0329] Step-A1: Preparation of tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate (Intermediate-A1)

[0330] To a stirred solution of tert-butyl piperazine-1-carboxylate (starting material-1, 5 g, 26.8 mmol, 1.0 equiv.) in DCM (100 mL) was added pyridine (2.97 g, 37.6 mmol, 1.4 equiv.) and triphosgene (3.19 g, 10.7 mmol, 0.4 equiv.) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was washed with water (100 mL) and extracted with DCM (2 × 100 mL). The combined organic extracts were washed again with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give Intermediate-A1 (6.0 g, 90%) as a crude oil.

[0331] 1 H NMR (400 MHz, DMSO-d6) δ 3.64 (d, J = 4.40 Hz, 2H), 3.52 (br s, 2H), 3.27 - 3.47 (m, 3H), 2.93 - 3.21 (m, 1H), 1.41 (s, 9H).

[0332] Step-A2: 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]indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-A2)

[0333] To a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione HCl salt (starting material-2, 10 g, 23.7 mmol, 1.0 equiv.) in DCM (250 mL) was added DIPEA (15.3 g, 118 mmol, 5 equiv.) and DMAP (724 mg, 5.9 mmol, 0.25 equiv.) at 0 °C, followed by the dropwise addition of tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate (Intermediate-A1, 5.89 g, 23.7 mmol, 1 equiv.) in DCM (100 mL) over 10 min. The resulting reaction mixture was warmed to room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was washed with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic extracts were washed again with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column using 7% methanol in DCM to give Intermediate-A2 (10 g, 66%) as an off-white solid.

[0334] 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.11 (d, J = 9.29 Hz, 1H), 7.65 (d, J = 9.29 Hz, 1H), 7.34 (s, 1H), 6.53 (s, 1H), 5.43 (s, 2H), 5.31 (s, 2H), 3.67 - 3.79 (m, 4H), 3.41 - 3.55 (m, 6H), 2.20 (s, 6H), 1.80 - 1.93 (m, 2H), 1.44 (s, 9H), 0.89 (t, J = 7.34 Hz, 3H).LCMS:634.2 [M+H] + .

[0335] 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]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-A)

[0336] Under a nitrogen atmosphere, to a stirred solution 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]indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-A2, 1 g, 15 mmol, 1.0 equiv.) in DCM (20 mL) was added TFA (3 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure, saturated NaHCO3 solution (50 mL) was added, and the aqueous solution was extracted with EtOAc (2 × 100 mL). The solvent was evaporated under reduced pressure to give Intermediate-A (1.02 g, crude) as an off-white solid.

[0337] 1H NMR (400 MHz, DMSO-d6) δ 10.12 (br s, 1H), 9.03 - 9.27 (m, 2H), 8.35 (d, J = 9.29 Hz, 1H), 7.86 (d, J = 9.29 Hz, 1H), 7.37 (s, 1H), 6.57 (br s, 1H), 5.45 (br s, 2H), 5.33 (br s, 2H), 4.86 (br s, 2H), 3.90-3.95 (m, 2H), 3.68-3.71 (m, 2H), 3.30 (d, J = 12.23 Hz, 2H), 2.89 (s, 6H), 1.80 - 1.95 (m, 3H), 1.08 (t, J = 7.09 Hz, 1H), 0.89 (br t, J = 6.85 Hz, 3H).LCMS:534.2 [M+H] + .

[0338] Step-1: Preparation of tert-butyl ((1r,4r)-4-((3-chloro-4-cyanophenyl)amino)cyclohexyl)carbamate (Intermediate-1)

[0339] To a stirred solution of 2-chloro-4-fluorobenzonitrile (starting material-1, 4 g, 25 mmol, 1.0 equiv.) in DMSO (40 mL) at room temperature was added tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (starting material-2, 5.5 g, 25 mmol, 1.0 equiv.) and K2CO3 (7.1 g, 51 mmol, 2 equiv.). The reaction mixture was heated to 90 °C for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water (200 mL) and extracted with ethyl acetate (2 × 400 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The resulting crude material was purified by combiflash® column eluted with 64% ethyl acetate in heptane to give Intermediate-1 (7.1 g, 78%) as an off-white solid.

[0340] 1 H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J = 8.80 Hz, 1H), 6.86 (d, J = 6.85 Hz, 1H), 6.80 (d, J = 6.85 Hz, 1H), 6.75 (br s, 1H), 6.59 (d, J = 8.80 Hz, 1H), 3.20-3.23 (m, 2H), 1.91 (d, J = 11.25 Hz, 2H), 1.79 (d, J = 10.76 Hz, 2H), 1.38 (s, 9H), 1.13 - 1.33 (m, 4H).

[0341] Step-2: Preparation of tert-butyl ((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)carbamate (Intermediate-2)

[0342] Under a nitrogen atmosphere, to a stirred solution of tert-butyl ((1r,4r)-4-((3-chloro-4-cyanophenyl)amino)cyclohexyl)carbamate (Intermediate-1, 5.5 g, 15 mmol, 1.0 equiv.) in DMF (25 mL) was added NaH (63%, 500 mg, 21 mmol, 1.3 equiv.) in small portions at 0° C. The reaction mixture was warmed to room temperature and stirred for 30 minutes, and then methyl iodide (1.1 mL, 21 mmol, 1.3 equiv.) was added dropwise at 0° C. The reaction mixture was warmed to room temperature and stirred for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, water (150 mL) was added and the mixture was extracted with ethyl acetate (2×200 mL). The solvent was evaporated under reduced pressure to give the crude product, which was purified by combiflash® column eluted with 15% ethyl acetate in heptane to give intermediate-2 (3.2 g, 55%) as an off-white solid.

[0343] LCMS: 364.2 [M+H] + .

[0344] Step-3: Preparation of 4-(((1r,4r)-4-aminocyclohexyl)(methyl)amino)-2-chlorobenzonitrile trifluoroacetate (Intermediate-3)

[0345] Under a nitrogen atmosphere, to a stirred solution of tert-butyl ((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)-carbamate intermediate-2 (1.1 g, 3 mmol, 1.0 equiv) in DCM (10 mL) was added TFA (10 mL, 10 vol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure, washed with diethyl ether (20 mL), and dried under vacuum to give intermediate-3 (852 mg, 74%) as an off-white solid.

[0346] LCMS: 264.1 [M+H] + .

[0347] Step-4: Preparation of 6-chloro-N-((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)pyridazine-3-carboxamide (Intermediate-4)

[0348] To a stirred solution of 4-(((1r,4r)-4-aminocyclohexyl)(methyl)amino)-2-chlorobenzonitrile trifluoroacetate (Intermediate-3, 800 mg, 8 mmol, 1.0 equiv.) and 6-chloropyridazine-3-carboxylic acid (Starting Material-3, 336 mg, 8 mmol, 1.0 equiv.) in DMF (3 mL) was added HATU (1.21 g, 12 mmol, 1.5 equiv.) and DIPEA (0.74 mL, 16 mmol, 2 equiv.) at room temperature, and the resulting reaction mixture was stirred for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, water (50 mL) was added and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product, which was purified by combiflash® column eluted with 4% methanol in DCM to give intermediate-4 (700 mg, 81%) as an off-white solid.

[0349] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 9.25 Hz, 1H), 8.21 (d, J = 9.25 Hz, 1H), 7.95 (s, 1H), 7.68 (dd, J = 8.32, 4.62 Hz, 1H), 7.58 (d, J = 9.25 Hz, 1H), 6.80 (dd, J = 9.25, 2.31 Hz, 1H), 3.79 - 3.89 (m, 1H), 3.70-3.73 (m, 1H), 2.69 (s, 3H), 1.84-1.87 (m, 2H), 1.51 - 1.77 (m, 6H).LCMS:404.1 [M+H] + .

[0350] Step-5: Preparation of ethyl 1-(6-(((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)carbamoyl)-pyridazin-3-yl)piperidine-4-carboxylate (Intermediate-5)

[0351] To a stirred solution of 6-chloro-N-((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)-pyridazine-3-carboxamide (Intermediate-4, 250 mg, 0.6 mmol, 1.0 equiv.) and ethyl piperidine-4-carboxylate (Starting Material-4, 0.1 mL, 0.6 mmol, 1.0 equiv.) in DMF (2 mL) was added KCO (129 mg, 0.9 mmol, 1.5 equiv.) at room temperature. The reaction mixture was heated to 80° C. for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, water (50 mL) was added, and the aqueous mixture was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product, which was purified by combiflash® column eluted with 62% ethyl acetate in heptane to give Intermediate-5 (198 mg, 60%) as a pale yellow solid.

[0352] 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.82 (d, J = 9.78 Hz, 1H), 7.60 (d, J = 9.29 Hz, 1H), 7.36 (d, J = 9.29 Hz, 1H), 6.94 (d, J = 2.45 Hz, 1H), 6.83 (dd, J = 9.29, 2.45 Hz, 1H), 4.35-4.37 (m, 2H), 4.08 (q, J = 7.34 Hz, 2H), 3.76 - 3.88 (m, 2H), 3.12 - 3.22 (m, 2H), 2.85 (s, 3H), 2.69 - 2.76 (m, 4H), 1.89 - 1.95 (m, 3H), 1.64 - 1.76 (m, 4H), 1.54 - 1.60 (m, 2H), 1.19 (t, J = 7.09 Hz, 3H).LCMS:525.2 [M+H] + .

[0353] Step-6: Preparation of 1-(6-(((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)carbamoyl)-pyridazin-3-yl)piperidine-4-carboxylic acid (Intermediate-6)

[0354] To a stirred solution of ethyl 1-(6-(((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)-carbamoyl)pyridazin-3-yl)piperidine-4-carboxylate (Intermediate-5, 190 mg, 0.36 mmol, 1.0 equiv) in THF (2 mL) and water (1 mL) was added LiOH (27 mg, 1.1 mmol, 3 equiv) at room temperature and stirring was continued for 5 h. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure, water (10 mL) was added, and the reaction mixture was acidified to pH 6 with 1 M HCl (6 mL). The precipitate was filtered and dried under vacuum to give Intermediate-6 (158 mg, 87%) as a pale yellow solid.

[0355] 1 H NMR (400 MHz, DMSO-d6) δ 12.26 (br s, 1H), 8.50 (d, J = 8.31 Hz, 1H), 7.82 (d, J = 9.29 Hz, 1H), 7.60 (d, J = 8.80 Hz, 1H), 7.36 (d, J = 9.78 Hz, 1H), 6.94 (br s, 1H), 6.83 (d, J = 8.80 Hz, 1H), 4.34-4.36 (m, 2H), 3.73 - 3.93 (m, 1H), 3.16 (t, J = 11.74 Hz, 2H), 2.85 (s, 3H), 2.61 (t, J = 10.27 Hz, 1H), 1.92 (d, J = 10.76 Hz, 4H), 1.48 - 1.80 (m, 8H), 1.14 - 1.28 (m, 1H).LCMS:497.2 [M+H] + .

[0356] Step-7: Preparation of 6(S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(1-(6-(((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)-amino)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carbonyl)piperazine-1-carboxylate

[0357] 1-(6-(((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)-carbamoyl)pyridazin-3-yl)piperidine-4-carboxylic acid (Intermediate-6, 110 mg, 0.22 mmol, 1.0 equiv.) and (S)-10-((dimethyl-amino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro- To a stirred solution of 4-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-A, 118 mg, 0.22 mmol, 1.0 equiv.) in DMF (3 mL) was added HATU (126 mg, 0.33 mmol, 1.5 equiv.) and DIPEA (0.12 mL, 0.66 mmol, 3 equiv.) at room temperature, and stirring was continued for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, water (25 mL) was added, and the aqueous mixture was extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product, which was purified by combiflash® column chromatography eluting with 10% methanol in DCM to give the title compound (65 mg, 19%) as an off-white solid.

[0358] 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.48 (d, J = 7.82 Hz, 1H), 8.13 (d, J = 9.29 Hz, 1H), 7.84 (d, J = 9.78 Hz, 1H), 7.67 (d, J = 8.80 Hz, 1H), 7.60 (d, J = 9.29 Hz, 1H), 7.38 (d, J = 9.29 Hz, 1H), 7.34 (s, 1H), 6.93 - 6.96 (m, 1H), 6.80 - 6.86 (m, 1H), 6.51 (s, 1H), 5.43 (s, 2H), 5.32 (s, 2H), 4.47 - 4.57 (m, 2H), 3.82 - 3.90 (m, 1H), 3.78 (s, 3H), 3.43 - 3.72 (m, 6H), 3.04 - 3.21 (m, 4H), 2.85 (s, 3H), 2.22 (s, 6H), 1.85 - 1.97 (m, 5H), 1.72 - 1.84 (m, 3H), 1.54 - 1.71 (m, 7H), 0.89 (t, J = 7.09 Hz, 3H).LCMS:1010.60 [MH] - . HPLC purity 95.8%.

[0359] (Example S12) Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-(heptanoyloxy)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylate (Compound No. 12) [ka]

[0360] Step-1-1: Preparation of tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate

[0361] To a stirred solution of tert-butyl piperazine-1-carboxylate (starting material-2, 5 g, 26.8 mmol, 1.0 equiv.) in DCM (100 mL) was added pyridine (2.97 g, 37.6 mmol, 1.4 equiv.) and triphosgene (3.19 g, 10.7 mmol, 0.4 equiv.) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction progress was monitored by TLC. After completion of the starting material, the reaction mixture was washed with water (100 mL) and extracted with DCM (2 × 100 mL). The combined organic extracts were washed again with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate (6.0 g, 90%) as a crude oil.

[0362] 1 H NMR (400 MHz, DMSO-d6) δ 3.64 (br d, J = 4.40 Hz, 2H), 3.52 (br s, 2H), 3.27 - 3.47 (m, 3H), 2.93 - 3.21 (m, 1H), 1.41 (s, 9H).

[0363] Step-1-2: 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]indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-1)

[0364] To a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione hydrochloride (starting material-1, 10 g, 23.7 mmol, 1.0 equiv.) in DCM (100 mL, 10 vol.) was added DIPEA (15.3 g, 118 mmol, 5 equiv.) and DMAP (724 mg, 5.9 mmol, 0.25 equiv.) at 0° C., followed by the dropwise addition of tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate (5.89 g, 23.7 mmol, 1 equiv.) in DCM (100 mL, 10 vol.) over 10 min. The resulting reaction mixture was allowed to warm to room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was washed with water (500 mL) and extracted with DCM (3 x 100 mL). The combined organic extracts were washed again with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by combiflash column eluted with 7% methanol in DCM to give Intermediate-1 (10 g, 66%) as an off-white solid.

[0365] 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.11 (d, J = 9.29 Hz, 1H), 7.65 (d, J = 9.29 Hz, 1H), 7.34 (s, 1H), 6.53 (s, 1H), 5.43 (s, 2H), 5.31 (s, 2H), 3.67 - 3.79 (m, 4H), 3.41 - 3.55 (m, 6H), 2.20 (s, 6H), 1.80 - 1.93 (m, 2H), 1.44 (s, 9H), 0.89 (br t, J = 7.34 Hz, 3H).LCMS:634.2 [M+H] + .

[0366] Step-2: Preparation of (S)-1-(tert-butyl) 4-(10-((dimethylamino)methyl)-4-ethyl-4-(heptanoyloxy)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-2)

[0367] To a stirred solution 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]indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-2, 7.0 g, 11.05 mmol, 1.0 equiv.) in DCM (70 mL, 10.0 vol.) was added heptanoic acid (Starting Material-3, 2.15 g, 16.57 mmol, 1.5 equiv.), EDC.HCl (3.168 g, 16.57 mmol, 1.5 equiv.), and DMAP (606 mg, 4.97 mmol, 0.45 equiv.) under an argon atmosphere at 0°C. The reaction mixture was stirred at room temperature until TLC showed complete consumption of the starting material. The reaction mixture was then diluted with ice-cold water (250 mL) and extracted with DCM (2 × 250 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography, and the pure fractions were concentrated under reduced pressure to give (S)-1-(tert-butyl)4-(10-((dimethylamino)methyl)-4-ethyl-4-(heptanoyloxy)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-2, 6 g, 73%) as an off-white solid.

[0368] 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.07 (d, J = 8.80 Hz, 1H), 7.65 (d, J = 9.29 Hz, 1H), 7.01 - 7.04 (m, 1H), 5.46 - 5.50 (m, 2H), 5.30 - 5.34 (m, 2H), 3.68 - 3.78 (m, 4H), 3.44 - 3.53 (m, 6H), 3.24 - 3.30 (m, 1H), 3.07 - 3.15 (m, 1H), 2.45 - 2.49 (m, 1H), 2.20 (s, 7H), 1.53 - 1.61 (m, 2H), 1.42 - 1.48 (m, 11H), 1.20 - 1.32 (m, 4H), 0.92 (t, J = 7.09 Hz, 3, 0.74 - 0.79 (m, 3H).LCMS:746.5 [M+H] + .

[0369] Step-3: Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-(heptanoyloxy)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-3)

[0370] To a stirred solution of (S)-1-(tert-butyl) 4-(10-((dimethylamino)methyl)-4-ethyl-4-(heptanoyloxy)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-3, 5 g, 6.71 mmol, 1.0 equiv.) in DCM (50 mL, 10 vol.) was added TFA (5.1 mL, 67.1 mmol, 10.0 equiv.) at ambient temperature. The reaction mixture was stirred at room temperature until TLC showed complete consumption of the starting material. The reaction mixture was then evaporated under reduced pressure, diluted with DCM (500 mL), washed with saturated bicarbonate solution (2×250 mL), brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-10-((dimethylamino)methyl)-4-ethyl-4-(heptanoyloxy)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-3, 3 g, 69%) as a brown solid.

[0371] 1 H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.04 - 8.10 (m, 1H), 7.61 - 7.67 (m, 1H), 7.00 - 7.06 (m, 1H), 5.45 - 5.51 (m, 2H), 5.28 - 5.35 (m, 2H), 3.56 - 3.81 (m, 4H), 3.36 - 3.46 (m, 2H), 2.73 - 2.89 (m, 4H), 2.52 - 2.57 (m, 1H), 2.44 - 2.48 (m, 1H), 2.14 - 2.21 (m, 8H), 1.51 - 1.61 (m, 2H), 1.17 - 1.34 (m, 7H), 0.89 - 0.95 (m, 3H), 0.74 - 0.79 (m, 3H).LCMS:646.5 [M+H] + .

[0372] Step-4: Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-(heptanoyloxy)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylate

[0373] To a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4-(heptanoyloxy)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-3, 3.0 g, 4.65 mmol, 1.0 equiv.) in MeOH (30 mL, 10 vol) under an argon atmosphere was added At 0° C., (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-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-C, 2.59 g, 4.65 mmol) and acetic acid (1 mL, catalytic amount) were added. The reaction mixture was stirred at room temperature under an argon atmosphere for 1 hour, and then NaCNBH (586 mg, 9.3 mmol) was added at 0° C. The resulting reaction mixture was stirred at room temperature until TLC showed complete consumption of the starting material. The reaction mixture was then quenched with saturated sodium bicarbonate solution (250 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Spherical-C18, 40 μM, 100A; mobile phase A: 0.1% FA in water; mobile phase B: acetonitrile; flow rate: 25 mL / min, diluent: THF + DMSO).Pure fractions were combined and lyophilized under reduced pressure to give (S)-10-((dimethylamino)methyl)-4-ethyl-4-(heptanoyloxy)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylate (1.51 g, 27%) as an off-white solid.

[0374] 1 H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.07 (d, J = 9.26 Hz, 1H), 7.63 (d, J = 9.26 Hz, 1H), 6.96 - 7.04 (m, 3H), 6.56 - 6.62 (m, 2H), 5.67 (s, 1H), 5.48 (d, J = 1.25 Hz, 2H), 5.32 (d, J = 3.00 Hz, 2H), 4.40 (d, J = 6.88 Hz, 1H), 3.67 - 3.79 (m, 4H), 3.44 - 3.49 (m, 2H), 3.25 (d, J = 7.25 Hz, 3H), 2.64 - 2.83 (m, 6H), 2.53 - 2.60 (m, 3H), 2.31 - 2.48 (m, 6H), 2.08 - 2.22 (m, 15H), 1.86 - 2.01 (m, 5H), 1.65 - 1.74 (m, 2H), 1.41 - 1.62 (m, 7H), 1.18 - 1.36 (m, 12H), 0.92 (t, J = 7.44 Hz, 3H), 0.74 - 0.79 (m, 3H), 0.24 (s, 3H).LCMS:1189.1 [M+H] + .

[0375] (Example S13) Preparation of (S)-10-((4-(1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carbonyl)piperazin-1-yl)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl[1,4'-bipiperidine]-1'-carboxylate (Compound No. 13) [ka]

[0376] Step-1: Preparation of (S)-10-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl[1,4'-bipiperidine]-1'-carboxylate (Intermediate-2)

[0377] To a stirred solution of starting material-1 (60 mg, 0.35 mmol, 1.0 equiv.) in DCM (10 mL) at 0 °C, triethylamine (0.14 mL, 1.06 mmol, 3 equiv.) and triphosgene (105 mg, 0.35 mmol, 1 equiv.) were added. The reaction mixture was warmed to room temperature and stirred for 1 h. After 1 h, intermediate-1 (200 mg, 0.35 mmol, 1 equiv.), KCO (49 mg, 0.35 mmol, 1 equiv.), and catalytic amount of DMAP (20 mg) were added to the reaction mixture, and stirring was continued for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with water (100 mL) and extracted with DCM (2 × 200 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by combiflash column using 4% methanol in DCM to give Intermediate-2 (200 mg, 74%) as an off-white solid.

[0378] 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.11 (br d, J = 9.29 Hz, 1H), 7.63 (br d, J = 9.29 Hz, 1H), 7.34 (s, 1H), 6.51 (br s, 1H), 5.43 (br s, 2H), 5.30 (br s, 2H), 4.26-4.28 (m, 1H), 4.06-4.08 (m, 3H), 3.86 (br s, 2H), 3.25-3.28 (m, 6H), 3.16-3.18 (m, 4H), 2.85 - 2.99 (m, 1H), 2.39-2.43 (m, 4H), 1.80-1.89 (m, 6H), 1.35 - 1.46 (m, 4H), 1.32(s, 9H), 0.89 (br t, J = 7.34 Hz, 3H).LCMS:757.4 [M+H] + .

[0379] Step-2: Preparation of (S)-4-ethyl-4-hydroxy-3,14-dioxo-10-(piperazin-1-ylmethyl)-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl[1,4'-bipiperidine]-1'-carboxylate (Intermediate-3)

[0380] To a stirred solution of intermediate-2 (200 mg, 0.26 mmol, 1.0 equiv) in DCM (10 mL) under nitrogen atmosphere was added TFA (0.2 mL, 2.64 mmol, 10 equiv) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure, washed with diethyl ether (25 mL) and pentane (20 mL), and dried under vacuum to give intermediate-3 (170 mg, 98%) as an off-white solid.

[0381] 1H NMR (400 MHz, DMSO-d6) δ 9.73 (br d, J = 8.80 Hz, 1H), 9.03 (s, 1H), 8.82 (br s, 2H), 8.16 (br d, J = 9.29 Hz, 1H), 7.66 (br d, J = 9.29 Hz, 1H), 7.34 (s, 1H), 5.44 (s, 2H), 5.31 (s, 2H), 4.39-4.42 (m, 1H), 4.13 - 4.28 (m, 1H), 3.96 (br s, 2H), 3.47 (br d, J = 10.76 Hz, 2H), 2.84 - 3.27 (m, 8H), 2.67-2.71 (m, 4H), 2.14-2.18 (m, 2H), 1.61 - 2.08 (m, 10H), 1.44 (br d, J = 12.72 Hz, 1H), 0.89 (t, J = 7.34 Hz, 3H).LCMS:657.20 [M+H] + .

[0382] Step-3: Preparation of (S)-10-((4-(1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carbonyl)piperazin-1-yl)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl[1,4'-bipiperidine]-1'-carboxylate

[0383] To a stirred solution of Intermediate-3 (170 mg, 0.25 mmol, 1.0 equiv.) and Intermediate-13 (125 mg, 0.25 mmol, 1.0 equiv.) in DMF (5 mL) was added HATU (185 mg, 0.51 mmol, 2.0 equiv.) and DIPEA (0.13 mL, 0.77 mmol, 3 equiv.) at room temperature, and the reaction mixture was stirred for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product. The crude material was purified by combiflash® column eluted with 13% methanol in DCM to give the title compound (108 mg, 37%) as an off-white solid.

[0384] 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.57 (br d, J = 8.13 Hz, 1H), 8.43 (s, 1H), 8.13 (d, J = 9.13 Hz, 1H), 7.81 - 7.89 (m, 1H), 7.64 (d, J = 9.13 Hz, 1H), 7.30 - 7.40 (m, 3H), 7.13 (dd, J = 8.82, 2.31 Hz, 1H), 6.55 (s, 1H), 5.43 (s, 2H), 5.31 (s, 2H), 4.42 - 4.59 (m, 3H), 4.24 - 4.36 (m, 1H), 4.02 - 4.13 (m, 1H), 3.81 - 3.93 (m, 3H), 3.50-3.52 (m, 2H), 3.10-3.13 (m, 3H), 2.87 - 3.05 (m, 3H), 2.54 - 2.57 (m, 3H), 2.46-2.50 (m, 4H), 2.40-2.42 (m, 3H), 2.08-2.11 (m, 2H), 1.80 - 1.93 (m, 6H), 1.42 - 1.74 (m, 14H), 1.34-1.37 (m, 2H), 0.89 (br t, J = 7.32 Hz, 3H).LCMS: 1122.4 [M+H] + . HPLC purity 92.4%.

[0385] (Example S14) Preparation of (S)-10-((dimethylamino)methyl)-4-((dimethylglycyl)oxy)-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylate (Compound No. 14) [ka]

[0386] Step-1-1: Preparation of tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate

[0387] To a stirred solution of tert-butyl piperazine-1-carboxylate (starting material-2, 5 g, 26.8 mmol, 1.0 equiv.) in DCM (100 mL) was added pyridine (2.97 g, 37.6 mmol, 1.4 equiv.) and triphosgene (3.19 g, 10.7 mmol, 0.4 equiv.) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction progress was monitored by TLC. After completion of the starting material, the reaction mixture was washed with water (100 mL) and extracted with DCM (2 × 100 mL). The combined organic extracts were washed again with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate (6.0 g, 90%) as a crude oil.

[0388] 1 H NMR (400 MHz, DMSO-d6) δ 3.64 (br d, J = 4.40 Hz, 2H), 3.52 (br s, 2H), 3.27 - 3.47 (m, 3H), 2.93 - 3.21 (m, 1H), 1.41 (s, 9H).

[0389] Step-1-2: 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]indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-1)

[0390] To a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione hydrochloride (starting material-1, 10 g, 23.7 mmol, 1.0 equiv.) in DCM (100 mL, 10 vol.) was added DIPEA (15.3 g, 118 mmol, 5 equiv.) and DMAP (724 mg, 5.9 mmol, 0.25 equiv.) at 0° C., followed by the dropwise addition of tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate (5.89 g, 23.7 mmol, 1 equiv.) in DCM (100 mL, 10 vol.) over 10 min. The resulting reaction mixture was allowed to warm to room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was washed with water (500 mL) and extracted with DCM (3 x 100 mL). The combined organic extracts were washed again with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by combiflash column eluted with 7% methanol in DCM to give Intermediate-1 (10 g, 66%) as an off-white solid.

[0391] 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.11 (d, J = 9.29 Hz, 1H), 7.65 (d, J = 9.29 Hz, 1H), 7.34 (s, 1H), 6.53 (s, 1H), 5.43 (s, 2H), 5.31 (s, 2H), 3.67 - 3.79 (m, 4H), 3.41 - 3.55 (m, 6H), 2.20 (s, 6H), 1.80 - 1.93 (m, 2H), 1.44 (s, 9H), 0.89 (br t, J = 7.34 Hz, 3H).LCMS:634.2 [M+H] + .

[0392] Step-2: Preparation of (S)-1-(tert-butyl) 4-(10-((dimethylamino)methyl)-4-((dimethylglycyl)oxy)-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-2)

[0393] To a stirred solution 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]indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-1, 7.0 g, 11.05 mmol, 1.0 equiv.) in DCM (70 mL, 10.0 vol.) was added dimethylglycine (Starting Material-3, 1.7 g, 16.57 mmol, 1.5 equiv.), DCC (3.41 g, 16.57 mmol, 1.5 equiv.), and DMAP (134 mg, 1.105 mmol, 0.1 equiv.) under an argon atmosphere at 0°C. The reaction mixture was stirred at ambient temperature until TLC showed complete consumption of the starting material. The reaction mixture was then diluted with ice-cold water (250 mL) and extracted with DCM (2 × 250 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography, and the combined pure fractions were concentrated under reduced pressure to give (S)-1-(tert-butyl)4-(10-((dimethylamino)methyl)-4-((dimethylglycyl)oxy)-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-2, 6 g, 75%) as an off-white solid.

[0394] 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.09 (d, J = 8.31 Hz, 1H), 7.65 (d, J = 9.29 Hz, 1H), 7.06 (s, 1H), 5.41 - 5.59 (m, 2H), 5.26 - 5.39 (m, 2H), 3.76 (s, 2H), 3.65 - 3.73 (m, 2H), 3.40 - 3.56 (m, 5H), 3.23 - 3.31 (m, 1H), 3.07 - 3.15 (m, 1H), 2.94 (s, 2H), 2.24 - 2.28 (m, 4H), 2.19 - 2.22 (m, 4H), 2.11 - 2.18 (m, 1H), 1.55 - 1.76 (m, 1H), 1.44 (s, 9H), 1.40 (s, 3H), 0.93 (t, J = 7.09 Hz, 3H).LCMS:719.5 [M+H] + .

[0395] Step-3: Preparation of (S)-10-((dimethylamino)methyl)-4-((dimethylglycyl)oxy)-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-3)

[0396] To a stirred solution of (S)-1-(tert-butyl) 4-(10-((dimethylamino)methyl)-4-((dimethylglycyl)oxy)-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-2, 5 g, 6.96 mmol, 1.0 equiv.) in DCM (50 mL, 10 vol.) was added TFA (5.32 mL, 69.6 mmol, 10.0 equiv.) at ambient temperature. The reaction mixture was stirred at room temperature until TLC showed complete consumption of the starting material. The reaction mixture was then concentrated under reduced pressure, diluted with DCM (500 mL), washed with saturated bicarbonate solution (2×250 mL), brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-10-((dimethylamino)-methyl)-4-((dimethylglycyl)oxy)-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-3, 2.2 g, 51%) as a pale yellow solid.

[0397] 1 H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.08 (d, J = 9.26 Hz, 1H), 7.63 (d, J = 9.26 Hz, 1H), 7.06 (s, 1H), 5.50 (s, 2H), 5.32 (s, 2H), 3.76 (s, 2H), 3.63 (s, 2H), 3.37 - 3.47 (m, 4H), 2.72 - 2.87 (m, 5H), 2.55 - 2.64 (m, 1H), 2.26 (s, 5H), 2.20 (s, 6H), 2.16 (dd, J = 7.44, 2.19 Hz, 2H), 0.93 (t, J = 7.38 Hz, 3H).LCMS:619.3 [M+H] + .

[0398] Step-4: Preparation of (S)-10-((dimethylamino)methyl)-4-((dimethylglycyl)oxy)-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylate

[0399] To a stirred solution of (S)-10-((dimethylamino)methyl)-4-((dimethylglycyl)oxy)-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-3, 2.5 g, 4.04 mmol, 1.0 equiv) in MeOH (25 mL, 10 vol) was added under an argon atmosphere. (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-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-C, 2.26 g, 4.04 mmol) and acetic acid (1 mL, catalytic amount) were added at 0° C. under an argon atmosphere. The reaction mixture was stirred at room temperature for 1 hour, and then NaCNBH (509 mg, 8.08 mmol) was added at 0° C. The reaction mixture was stirred at room temperature until complete consumption of the starting material was indicated by TLC. The reaction mixture was quenched with saturated sodium bicarbonate solution (250 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: spherical-C18, 40 μM, 100 A; mobile phase A: 0.1% FA in water; mobile phase B: acetonitrile; flow rate: 25 mL / min, diluent: THF+DMSO).Pure fractions were combined and lyophilized under reduced pressure to give (S)-10-((dimethylamino)methyl)-4-((dimethylglycyl)oxy)-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylate (663 mg, 14%) as an off-white solid.

[0400] 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.09 (d, J = 9.29 Hz, 1H), 7.63 (d, J = 9.29 Hz, 1H), 7.06 (s, 1H), 6.99 (d, J = 8.31 Hz, 2H), 6.59 (d, J = 8.31 Hz, 2H), 5.67 (s, 1H), 5.50 (s, 2H), 5.30 - 5.35 (m, 2H), 4.38 - 4.43 (m, 1H), 3.67 - 3.77 (m, 4H), 3.37 - 3.47 (m, 6H), 3.22 - 3.27 (m, 4H), 2.82 (s, 3H), 2.61 - 2.82 (m, 3H), 2.53 - 2.58 (m, 2H), 2.41 (s, 2H), 2.30 - 2.37 (m, 3H), 2.26 (s, 5H), 2.16 - 2.21 (m, 10H), 2.10 (s, 4H), 2.00 (s, 4H), 1.86 - 1.98 (m, 2H), 1.62 - 1.77 (m, 1H), 1.39 - 1.52 (m, 5H), 1.26 - 1.36 (m, 5H), 0.90 - 0.95 (m, 3H), 0.24 (s, 3H).LCMS:1162.1 [M+H] + .

[0401] (Example S15) Preparation of N-((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)-6-(4-(4-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)-piperazine-1-carbonyl)piperidin-1-yl)pyridazine-3-carboxamide (Compound No. 15) [ka]

[0402] Preparation of (S)-4-ethyl-4,9-dihydroxy-10-(piperazin-1-ylmethyl)-1,12-dihydro-14H-pyrano[3',4':6,7]-indolizino[1,2-b]quinoline-3,14(4H)-dione trifluoroacetate (Intermediate-B) Step-B1: Preparation of tert-butyl (S)-4-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)piperazine-1-carboxylate (Intermediate-B1)

[0403] Under an inert atmosphere, to a stirred solution of (S)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione HCl salt (starting material-1, 2.5 g, 6.86 mmol, 1.0 equiv.) and tert-butyl piperazine-1-carboxylate (starting material-2, 1.85 g, 10.3 mmol, 1.5 equiv.) in acetic acid (10 mL) was added 37% formaldehyde solution (0.29 mL, 8.24 mmol, 1.2 equiv.) at room temperature. The reaction mixture was heated to 80 °C in a sealed tube for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure to give the crude product, which was basified to pH 9 with aqueous ammonia. The resulting solid was filtered, washed with water (10 mL) and dried under vacuum to give Intermediate-B1 (1.9 g, 50%) as a yellow solid.

[0404] LCMS: 463.46 [M-100] + (Cleavage of the Boc group was observed in LCMS).

[0405] Step-B2: Preparation of (S)-4-ethyl-4,9-dihydroxy-10-(piperazin-1-ylmethyl)-1,12-dihydro-14H-pyrano-[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione trifluoroacetate (Intermediate-B)

[0406] To a stirred solution of tert-butyl (S)-4-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)piperazine-1-carboxylate (Intermediate-B1, 2 g, 3.5 mmol, 1.0 equiv.) in DCM (20 mL) was added TFA (2.7 mL, 35 mmol, 10 equiv.) at 0° C. under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was washed with diethyl ether (10 mL) and dried under vacuum to give Intermediate-B (1.4 g, 83%) as a yellow solid.

[0407] 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (br s, 2H), 8.10 (d, J = 9.25 Hz, 1H), 7.58 (d, J = 9.25 Hz, 1H), 7.21 - 7.32 (m, 2H), 6.97 - 7.15 (m, 1H), 6.34 - 6.64 (m, 1H), 5.42 (s, 2H), 5.26 (s, 2H), 4.40 (s, 2H), 3.10-3.30 (m, 8H), 1.85 - 1.89 (m, 2H), 0.88 (t, J = 7.17 Hz, 3H).

[0408] Preparation of N-((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)-6-(4-(4-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)-piperazine-1-carbonyl)piperidin-1-yl)pyridazine-3-carboxamide

[0409] 1-(6-(((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)carbamoyl)-pyridazin-3-yl)piperidine-4-carboxylic acid (Intermediate-6 of Example S11, 300 mg, 0.60 mmol, 1.0 equiv.) and (S)-4-ethyl-4,9-dihydroxy-10-(piperazin-1-ylmethyl)-1,12-dihydro-14H-pyrano[3',4':6,7 To a stirred solution of ]indolizino[1,2-b]quinoline-3,14(4H)-dione trifluoroacetate (Intermediate-B, 278 mg, 0.60 mmol, 1.0 equiv.) in DCM (10 mL) was added HOBt (138 mg, 0.90 mmol, 1.5 equiv.), EDCI.HCl (173 mg, 0.90 mmol, 1.5 equiv.), and DIPEA (155.7 mg, 1.20 mmol, 2 equiv.) at room temperature and stirred for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, water (50 mL) was added, and the aqueous solution was extracted with DCM (2 × 100 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product, which was purified by preparative HPLC using ammonium bicarbonate in water and acetonitrile as the mobile phase to give the title compound (60 mg, 10%) as an off-white solid.

[0410] 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.48 (d, J = 8.26 Hz, 1H), 7.99 (d, J = 9.26 Hz, 1H), 7.82 (d, J = 9.51 Hz, 1H), 7.60 (d, J = 9.01 Hz, 1H), 7.47 (d, J = 9.13 Hz, 1H), 7.35 (d, J = 9.76 Hz, 1H), 7.26 (s, 1H), 6.94 (d, J = 2.38 Hz, 1H), 6.83 (dd, J = 9.07, 2.44 Hz, 1H), 6.48 (s, 1H), 5.42 (s, 2H), 5.26 (s, 2H), 4.48 (br d, J = 13.01 Hz, 2H), 4.03 (s, 2H), 3.75 - 3.88 (m, 2H), 3.41 - 3.62 (m, 3H), 2.96 - 3.16 (m, 3H), 2.85 (s, 3H), 2.51-2.54 (m, 2H), 1.83 - 1.97 (m, 5H), 1.51 - 1.79 (m, 12H), 0.88 (t, J = 7.32 Hz, 3H). (1H exchangeable hydrogen not observed in the spectrum). LCMS: 941.4 [M+H] + . HPLC: 94.2%.

[0411] (Example S16) Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-((((S)-10-((dimethylamino)-methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyridazine-3-carboxamide (Compound No. 16) [ka]

[0412] Step-1: Preparation of tert-butyl (S)-4-(((10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)piperidine-1-carboxylate (Intermediate-1)

[0413] To a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione HCl salt (starting material-1, 2 g, 4.75 mmol, 1.0 equiv.) in DMF (10 mL) was added KCO (1.31 g, 9.5 mmol, 2.0 equiv.) and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (starting material-2, 1.71 g, 6.17 mmol, 1.3 equiv.) at room temperature under a nitrogen atmosphere. The reaction mixture was heated to 50°C for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give Intermediate-1 (1.0 g, crude) as a yellow solid, which was used in the next step without further purification.

[0414] LCMS:617.2 [MH] - .

[0415] Step-2: Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-9-(piperidin-4-ylmethoxy)-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione trifluoroacetate (Intermediate-2)

[0416] To a stirred solution of intermediate-1 (1.0 g, 1.41 mmol, 1.0 equiv) in DCM (50 mL) was added TFA (10 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure to give the crude product, which was triturated with diethyl ether:pentane (80:20) three times (25 mL each) and dried under vacuum to give intermediate-2 (800 mg, crude) as a pale yellow solid, which was used in the next step without further purification.

[0417] LCMS: 519.26 [M+H] + .

[0418] Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-((((S)-10-((dimethylamino)-methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)piperidine-1-carbonyl)piperidin-1-yl)pyridazine-3-carboxamide

[0419] To a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-9-(piperidin-4-ylmethoxy)-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Intermediate-2, 370 mg, 0.772 mmol, 1.0 equiv.) in DMF (3 mL) was added DIPEA (0.27 mL, 1.54 mmol, 2.0 equiv.) and HATU (440 mg, 1.15 mmol, 1.5 equiv.). After 5–10 min at room temperature, Intermediate-13 (400 mg, 0.772 mmol, 1.0 equiv.) was added, and stirring was continued for an additional 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was evaporated and the resulting residue was triturated with diethyl ether (20 mL), filtered, dried and purified by preparative HPLC eluted with mobile phase A: 0.1% TFA in water and mobile phase B: acetonitrile to afford the title compound (50 mg, 6%) as a white solid.

[0420] 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.58 (d, J = 8.13 Hz, 1H), 8.31 (s, 2H), 8.07 - 8.16 (m, 1H), 7.69 - 7.90 (m, 2H), 7.29 - 7.41 (m, 2H), 7.07 - 7.22 (m, 1H), 6.40 - 6.54 (m, 1H), 5.37 - 5.45 (m, 2H), 5.21 - 5.31 (m, 2H), 4.43 - 4.58 (m, 4H), 4.05 - 4.23 (m, 3H), 3.86 (br s, 3H), 3.06 - 3.20 (m, 5H), 2.62 (br s, 1H), 2.21 (s, 6H), 2.07 - 2.14 (m, 2H), 1.79 - 1.99 (m, 6H), 1.70 - 1.79 (m, 2H), 1.47 - 1.70 (m, 6H), 1.39 (d, J = 10.88 Hz, 1H), 1.21 - 1.30 (m, 1H), 0.82 - 0.95 (m, 3 H).LCMS:984.3 [M+H]+ . HPLC purity 96.3%.

[0421] (Example S17) Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl(2R,5S)-4-(1-(6-(((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)-amino)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carbonyl)-2,5-dimethylpiperazine-1-carboxylate (Compound No. 17) [ka]

[0422] Step-1: Preparation of tert-butyl (2S,5R)-4-(chlorocarbonyl)-2,5-dimethylpiperazine-1-carboxylate (Intermediate-1)

[0423] To a stirred solution of tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate (starting material-1, 3.0 g, 13.99 mmol, 1.0 equiv.) in DCM (25 mL) at 0 °C, a solution of triphosgene (1.24 g, 41.99 mmol, 0.3 equiv.) in pyridine (1.7 mL, 20.99 mmol, 1.5 equiv.) and DCM (5 mL) was added dropwise over 10 min. The reaction mixture was warmed to room temperature and stirred for 30 min. The reaction progress was monitored by TLC (a nonpolar spot was observed). After completion of the reaction, the reaction mixture was poured into ice-cold water (50 mL) and extracted with DCM (2 × 30 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give Intermediate-1 (3.7 g, crude) as a light brown gum, which was used in the next step without further purification.

[0424] 1H NMR (400 MHz, DMSO-d6) δ 4.09 - 4.55 (m, 2H), 3.46 - 3.69 (m, 2H), 3.13 - 3.41 (m, 2H), 1.40 (s, 9H), 0.98 - 1.28 (m, 6H).

[0425] Step-2: Preparation of 1-(tert-butyl) 4-((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)(2S,5R)-2,5-dimethylpiperazine-1,4-dicarboxylate (Intermediate-2)

[0426] To a solution of tert-butyl (2S,5R)-4-(chlorocarbonyl)-2,5-dimethylpiperazine-1-carboxylate (Intermediate-1, 3.6 g, 13.05 mmol, 2 equiv.) and (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano-[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione hydrochloride (Starting Material-2, 3.1 g, 6.52 mmol, 1 equiv.) in THF (30 mL) and DMF (30 mL) was added DIPEA (5.67 mL, 32.6 mmol, 5 equiv.) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column chromatography eluted with 10% methanol in DCM to give Intermediate-2 (2.5 g, 58%) as a pale yellow foam.

[0427] 1H NMR (400 MHz, DMSO-d6) δ 8.95 (br s, 1H), 8.11 (d, J = 9.29 Hz, 1H), 7.54 - 7.76 (m, 1H), 7.34 (s, 1H), 6.53 (s, 1H), 5.43 (s, 2H), 5.31 (s, 2H), 4.19 - 4.41 (m, 2H), 3.61 - 3.81 (m, 2H), 3.17 (d, J = 12.91 Hz, 1H), 2.20 (d, J = 6.36 Hz, 6H), 1.80 - 1.95 (m, 3H), 1.26 - 1.41 (m, 14H), 1.18 (d, J = 6.36 Hz, 3H), 0.89 (t, J = 6.36 Hz, 3H).LCMS:662.4 [M+H] + .

[0428] 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]indolizino[1,2-b]quinolin-9-yl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (Intermediate-3)

[0429] To a stirred solution of 1-(tert-butyl) 4-((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)(2S,5R)-2,5-dimethylpiperazine-1,4-dicarboxylate (Intermediate-2, 1.5 g, 2.26 mmol, 1.0 equiv) in DCM (20 mL) was added TFA (3 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 5 h / 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure, saturated NaHCO3 (60 mL) was added, and the aqueous solution was extracted with ethyl acetate (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give Intermediate-3 (1.20 g, 78%) as a pale yellow solid.

[0430] 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (br s, 1H), 9.08 (br s, 3H), 8.32 (d, J = 9.00 Hz, 1H), 7.80 (d, J = 9.39 Hz, 1H), 7.34 (s, 1H), 6.53 (br s, 1H), 5.41 (s, 2H), 5.30 (s, 2H), 4.79 (br s, 2H), 3.91 (br s, 2H), 3.69 (br s, 2H), 3.11 (d, J = 12.91 Hz, 1H), 2.84 (br s, 6H), 1.86-1.92 (m, 2H), 1.38 (br s, 6H), 1.21 (d, J = 6.65 Hz, 1H), 0.85 (t, J = 7.24 Hz, 3H).LCMS:562.5 [M+H] + .

[0431] 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]indolizino[1,2-b]quinolin-9-yl(2R,5S)-4-(1-(6-(((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)-amino)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carbonyl)-2,5-dimethylpiperazine-1-carboxylate

[0432] (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl(2R,5S)-2,5-dimethylpiperazine-1-carboxylate (Intermediate-3, 380 mg, 0.67 mmol, 1.2 equiv.) and 1-(6-(((1r,4r)-4-((3 To a stirred solution of (4-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)-carbamoyl)pyridazin-3-yl)piperidine-4-carboxylic acid (Intermediate-6, 280 mg, 0.56 mmol, 1.0 equiv.) in DMF (3 mL) was added HATU (323 mg, 0.85 mmol, 1.5 equiv.) and DIPEA (0.20 mL, 1.5 mmol, 2 equiv.) at room temperature, and stirring was continued for an additional 16 h. The reaction progress was monitored by TLC. After completion of the reaction, water (50 mL) was added, and the aqueous solution was extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product, which was purified by preparative HPLC using ammonium bicarbonate in water and acetonitrile as the mobile phase to give the title compound (108 mg, 37%) as an off-white solid.

[0433] 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.49 (br d, J = 8.25 Hz, 1H), 8.13 (br d, J = 9.01 Hz, 1H), 7.84 (d, J = 9.63 Hz, 1H), 7.55 - 7.73 (m, 2H), 7.29 - 7.46 (m, 2H), 6.95 (d, J = 2.38 Hz, 1H), 6.83 (dd, J = 9.07, 2.31 Hz, 1H), 6.52 (s, 1H), 5.43 (s, 2H), 5.32 (s, 2H), 4.70 - 4.79 (m, 1H), 4.42 - 4.64 (m, 3H), 4.16 - 4.38 (m, 1H), 3.57 - 4.03 (m, 6H), 3.10-3.14 (m, 3H), 2.85 (s, 3H), 2.21 (d, J = 6.82 Hz, 6H), 1.82 - 1.99 (m, 5H), 1.60 - 1.81 (m, 9H), 1.42 (br dd, J = 10.51, 6.75 Hz, 2H), 1.32 (br d, J = 6.75 Hz, 1H), 1.21 - 1.29 (m, 3H), 1.12 (br dd, J = 10.38, 6.88 Hz, 1H), 0.89 (t, J = 7.32 Hz, 3H).LCMS:1041.7 [M+H] + . HPLC: 99.42%.

[0434] (Example S18) Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-((1-(6-(((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)-amino)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (Compound No. 18) [ka]

[0435] To a stirred solution of N-((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)-6-(4-formylpiperidin-1-yl)pyridazine-3-carboxamide (Intermediate-6, 280 mg, 0.58 mmol, 1.0 equiv.) in methanol (5 mL), (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate (Intermediate-A, 312 mg, 0.58 mmol, 1.0 equiv.) and acetic acid (0.1 mL) were added at room temperature, and the mixture was stirred for 2 hours. To this reaction mixture was added NaCNBH3 (58 mg, 0.9 mmol, 1.5 equiv) in small portions at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, cold water (50 mL) was added and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by combiflash® column eluted with 8% methanol in DCM to give the title compound (125 mg, 23%) as an off-white solid.

[0436] 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.51 (br d, J = 8.31 Hz, 1H), 8.12 (d, J = 8.80 Hz, 1H), 7.82 (d, J = 9.29 Hz, 1H), 7.59 - 7.66 (m, 2H), 7.31 - 7.38 (m, 2H), 6.95 (br s, 1H), 6.83 (br d, J = 9.29 Hz, 1H), 6.54 (s, 1H), 5.44 (s, 2H), 5.32 (br s, 2H), 4.48-4.52 (m, 2H), 3.70 - 3.81 (m, 5H), 3.47-3.50 (m, 2H), 2.99 - 3.08 (m, 3H), 2.85 (s, 3H), 2.48-2.51 (m, 4H) 2.20-2.22 (m, 2H), 2.19 (s, 6H) 1.82 - 1.96 (m, 6H), 1.62 - 1.79 (m, 5H), 1.11 - 1.23 (m, 4H), 0.88 (br t, J = 6.85 Hz, 3H).LCMS:998.2 [M+H] + . HPLC purity: 96.8%.

[0437] (Example S19) Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((2-(4-((((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-piperidin-1-yl)-2-oxoethyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodeca-hydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Compound No. 19) [ka]

[0438] Step-1: Preparation 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-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-1)

[0439] To a stirred solution of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-(dimethylamino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (starting material-1, 10 g, 21 mmol, 1.0 equiv.) in methanol (150 mL) and THF (150 mL) was added potassium acetate (20.6 g, 210 mmol, 10 equiv.) and iodine (13.1 g, 105 mmol, 5 equiv.) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with sodium thiosulfate (NaSO) solution (50 g in 30 mL of water) and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give Intermediate-1 (8.0 g, 82%) as an off-white solid, which was used in the next step without further purification.

[0440] 1H NMR (400 MHz, DMSO-d6) δ 11.91 (br s, 1H), 6.91 (d, J = 8.31 Hz, 2H), 6.44 (d, J = 8.31 Hz, 2H), 5.67 (s, 1H), 4.37 (m, 1H), 2.75 (s, 2H), 2.61 (d, J = 4.40 Hz, 3H), 2.30 - 2.40 (m, 1H), 2.07 - 2.16 (s, 5H), 1.99 (s, 6H), 1.63 - 1.77 (m, 2H), 1.21 - 1.45 (m, 5H), 0.86 (t, J = 6.60 Hz, 1H), 0.16 - 0.28 (m, 3H).LCMS:462.28 [M+H] + .

[0441] Step-2: Preparation of tert-butyl N-(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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylglycinate (Intermediate-2)

[0442] To a stirred solution 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-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-1, 1 g, 2.17 mmol, 1 equiv.) in EtOH:HO (20 mL, 1:1) was added starting material-2 (0.32 mL, 2.17 mmol, 1 equiv.) and NaHCO (911 mg, 10.85 mmol, 5 equiv.) at room temperature. The reaction mixture was heated to 80 °C and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with cold water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was triturated with n-heptane (2 x 30 mL), filtered, and dried under vacuum to give Intermediate-2 (900 mg, 72%) as a pale yellow solid.

[0443] 1 H NMR (400 MHz, DMSO-d6) δ 7.00 (d, J = 8.31 Hz, 2H), 6.56 (d, J = 8.31 Hz, 2H), 5.67 (s, 1H), 5.67 (s, 1H), 4.41 (d, J = 6.85 Hz, 1H), 4.00 (s, 2H), 2.91 (s, 3H), 2.58 - 2.82 (m, 3H), 2.54 - 2.57 (m, 1H), 2.29 - 2.38 (m, 1H), 2.06 - 2.23 (m, 6H), 1.84 - 2.03 (m, 5H), 1.61 - 1.79 (m, 2H), 1.34 - 1.46 (m, 3H), 1.30 (s, 9H), 0.22 (s, 3H).LCMS:576.2 [M+H] + .

[0444] Step-3: Preparation of N-(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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylglycine (Intermediate-3)

[0445] To a stirred solution of tert-butyl N-(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-dodecahydro-1H-cyclopenta[a]phenanthrene-11-yl)phenyl)-N-methylglycinate (Intermediate-2, 300 mg, 0.521 mmol, 1 equiv) in trifluoroethanol (5 mL) at 0° C. was added chlorotrimethylsilane (1.31 mL, 10.43 mmol, 20 equiv) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was evaporated and the resulting residue was washed with pentane (2×20 mL) and dried under vacuum to give Intermediate-3 (250 mg, 92%) as a pale yellow solid.

[0446] 1H NMR (400 MHz, DMSO-d6) δ 6.99 (d, J = 8.50 Hz, 2H), 6.55 (d, J = 8.76 Hz, 2H), 5.67 (s, 1H), 4.40 (d, J = 6.63 Hz, 1H), 4.01 (s, 2H), 2.92 (s, 2H), 2.59 - 2.79 (m, 3H), 2.55 (br s, 2H), 2.32 - 2.39 (m, 1H), 2.02 - 2.22 (m, 1H), 2.13 - 2.18 (m, 2H), 2.09 (s, 3H), 1.99 (s, 4H), 1.87 - 1.97 (m, 2H), 1.65 - 1.75 (m, 2H), 1.33 - 1.40 (m, 2H), 1.24 - 1.32 (m, 3H), 0.84 - 0.87 (m, 2H).LCMS:520.2 [M+H] + .

[0447] Step 4: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((2-(4-((((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-piperidin-1-yl)-2-oxoethyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodeca-hydro-1H-cyclopenta[a]phenanthren-17-yl acetate

[0448] (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-9-(piperidin-4-ylmethoxy)-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione TFA salt (Intermediate-C, 350 mg, 0.675 mmol, 1.0 equiv.) and N-(4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-oxo-1-methyl-2 ... To a stirred solution of (iso-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-11-yl)phenyl)-N-methylglycine (Intermediate-3, 350 mg, 0.675 mmol, 1.0 equiv.) in DMF (4 mL) was added DIPEA (0.35 mL, 2.02 mmol, 3.0 equiv.) and HATU (384 mg, 1.01 mmol, 1.5 equiv.) at room temperature, and stirring was continued for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with cold water (30 mL), and the resulting solid was filtered and purified by preparative HPLC purification eluted with mobile phase A: 0.1% FA in water and mobile phase B: acetonitrile to give the title compound (24 mg, 3%) as an off-white solid.

[0449] 1H NMR (400 MHz, DMSO-d6) δ 9.34 (br s, 1H), 8.94 (s, 1H), 8.33 (d, J = 9.29 Hz, 1H), 7.91 (d, J = 9.29 Hz, 1H), 7.30 (s, 1H), 6.93 (d, J = 7.83 Hz, 2H), 6.51 (d, J = 8.80 Hz, 3H), 5.64 (s, 1H), 5.41 (s, 2H), 5.25 (s, 2H), 4.75 (br s, 2H), 4.36 (br s, 2H), 4.10 - 4.24 (m, 4H), 3.86 - 3.97 (m, 2H), 2.88 (br s, 9H), 2.51 - 2.55 (m, 3H), 2.18 - 2.59 (m, 2H), 2.07 (s, 8H), 1.96 (s, 9H), 1.60 - 1.73 (m, 3H), 1.24 - 1.41 (m, 5H), 0.86 (t, J = 6.85 Hz, 3H), 0.20 (s, 2H).LCMS:1020.5 [M+H] + . HPLC purity 94.3%.

[0450] (Example S20) Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl(2R,5S)-4-((1-(6-(((1r,4r)-4-((3-chloro-4-cyanophenyl)-(methyl)amino)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)-2,5-dimethylpiperazine-1-carboxylate (Compound No. 20) [ka]

[0451] Step-D1: Preparation of tert-butyl (2S,5R)-4-(chlorocarbonyl)-2,5-dimethylpiperazine-1-carboxylate (Intermediate-D1)

[0452] To a stirred solution of tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate (starting material-1, 3.0 g, 13.99 mmol, 1.0 equiv.) in DCM (25 mL) at 0 °C, a solution of triphosgene (1.24 g, 41.99 mmol, 0.3 equiv.) in pyridine (1.7 mL, 20.99 mmol, 1.5 equiv.) and DCM (5 mL) was added dropwise over 10 min. The reaction mixture was warmed to room temperature and stirred for 30 min. The reaction progress was monitored by TLC (a nonpolar spot was observed). After completion of the reaction, the reaction mixture was poured into ice-cold water (50 mL) and extracted with DCM (2 × 30 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford Intermediate-D1 (3.7 g, crude) as a light brown gum, which was used in the next step without further purification.

[0453] 1 H NMR (400 MHz, DMSO-d6) δ 4.09 - 4.55 (m, 2H), 3.46 - 3.69 (m, 2H), 3.13 - 3.41 (m, 2H), 1.40 (s, 9H), 0.98 - 1.28 (m, 6H).

[0454] Step-D2: Preparation of 1-(tert-butyl) 4-((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)(2S,5R)-2,5-dimethylpiperazine-1,4-dicarboxylate (Intermediate-D2)

[0455] To a solution of tert-butyl (2S,5R)-4-(chlorocarbonyl)-2,5-dimethylpiperazine-1-carboxylate (Intermediate-D1, 3.6 g, 13.05 mmol, 2 equiv.) and (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione hydrochloride (Starting Material-2, 3.1 g, 6.52 mmol, 1 equiv.) in THF (30 mL) and DMF (30 mL) was added DIPEA (5.67 mL, 32.6 mmol, 5 equiv.) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column chromatography eluted with 10% methanol in DCM to give Intermediate-D2 (2.5 g, 58%) as a pale yellow foam.

[0456] 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (br s, 1H), 8.11 (d, J = 9.29 Hz, 1H), 7.54 - 7.76 (m, 1H), 7.34 (s, 1H), 6.53 (s, 1H), 5.43 (s, 2H), 5.31 (s, 2H), 4.19 - 4.41 (m, 2H), 3.61 - 3.81 (m, 2H), 3.17 (d, J = 12.91 Hz, 1H), 2.20 (d, J = 6.36 Hz, 6H), 1.80 - 1.95 (m, 3H), 1.26 - 1.41 (m, 14H), 1.18 (d, J = 6.36 Hz, 3H), 0.89 (t, J = 6.36 Hz, 3H).LCMS:662.4 [M+H] + .

[0457] Step-D3: Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (Intermediate-D)

[0458] To a stirred solution of 1-(tert-butyl) 4-((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)(2S,5R)-2,5-dimethylpiperazine-1,4-dicarboxylate (Intermediate-D2, 1.5 g, 2.26 mmol, 1.0 equiv) in DCM (20 mL) was added TFA (3 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure, saturated NaHCO3 solution (50 mL) was added, and the aqueous solution was extracted with EtOAc (2 x 60 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give Intermediate-D (1.20 g, 78%) as a pale yellow solid.

[0459] 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (br s, 1H), 9.08 (br s, 3H), 8.32 (d, J = 9.00 Hz, 1H), 7.80 (d, J = 9.39 Hz, 1H), 7.34 (s, 1H), 6.53 (br s, 1H), 5.41 (s, 2H), 5.30 (s, 2H), 4.79 (br s, 2H), 3.91 (br s, 2H), 3.69 (br s, 2H), 3.11 (d, J = 12.91 Hz, 1H), 2.84 (br s, 6H), 1.86-1.92 (m, 2H), 1.38 (br s, 6H), 1.21 (d, J = 6.65 Hz, 1H), 0.85 (t, J = 7.24 Hz, 3H).LCMS:562.5 [M+H]+ .

[0460] Step-1: Preparation of N-((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (Intermediate-5)

[0461] To a stirred solution of Intermediate-4 (2.0 g, 5 mmol, 1.0 equiv.) in DMF (10 mL) was added piperidin-4-ylmethanol (Starting Material-3, 0.690 g, 6 mmol, 1.2 equiv.) and K2CO3 (1.1 g, 8 mmol, 1.6 equiv.) at room temperature. The reaction mixture was heated to 90 °C for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, cold water (50 mL) was added to the reaction mixture and extracted with ethyl acetate (2 x 150 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by combiflash® column eluted with 100% ethyl acetate to give Intermediate-5 (1.3 g, 54%) as an off-white solid.

[0462] 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (br d, J = 8.31 Hz, 1H), 7.80 (d, J = 9.78 Hz, 1H), 7.61 (d, J = 8.80 Hz, 1H), 7.33 (d, J = 9.78 Hz, 1H), 6.94 (d, J = 1.96 Hz, 1H), 6.78 - 6.86 (m, 1H), 4.42 - 4.55 (m, 3H), 3.72 - 3.92 (m, 2H), 3.20-3.27 (m, 3H), 2.98 (br t, J = 12.47 Hz, 2H), 2.85 (s, 3H), 1.91 (br d, J = 9.29 Hz, 2H), 1.64 - 1.78 (m, 8H), 1.08 - 1.21 (m, 2H).LCMS:483.2 [M+H]+ .

[0463] Step-2: Preparation of N-((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)-6-(4-formylpiperidin-1-yl)pyridazine-3-carboxamide (Intermediate-6)

[0464] To a stirred solution of N-((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (Intermediate-5, 350 mg, 0.72 mmol, 1.0 equiv) in DCM (6 mL) under a nitrogen atmosphere at 0° C., Dess-Martin periodinane (400 mg, 0.92 mmol, 1.3 equiv) was added in small portions. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, water (50 mL) was added and the aqueous reaction mixture was extracted with DCM (2×50 mL). The combined organic extracts were washed with saturated NaHCO3 (50 mL) and saturated sodium thiosulfate (50 mL) solutions, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product Intermediate-6 (320 mg, 91%) as an off-white solid, which was used in the next step without purification.

[0465] 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.51 (br d, J = 8.31 Hz, 1H), 7.82 (d, J = 9.78 Hz, 1H), 7.61 (d, J = 8.80 Hz, 1H), 7.29 - 7.41 (m, 1H), 6.94 (s, 1H), 6.82 (br d, J = 7.83 Hz, 1H), 4.31 (br d, J = 13.21 Hz, 1H), 3.98 - 4.08 (m, 1H), 3.72 - 3.91 (m, 1H), 3.21 - 3.31 (m, 2H), 2.85 (s, 3H), 2.65-2.68(m, 1H), 1.86 - 2.03 (m, 4H), 1.60 - 1.82 (m, 5H), 1.45 - 1.60 (m, 2H), 1.17 (t, J = 7.09 Hz, 2H).LCMS:481.2 [M+H] + .

[0466] 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]indolizino[1,2-b]quinolin-9-yl(2R,5S)-4-((1-(6-(((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)-amino)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)-2,5-dimethylpiperazine-1-carboxylate

[0467] To a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl(2R,5S)-2,5-dimethylpiperazine-1-carboxylate (Intermediate-6, 320 mg, 0.66 mmol, 1.0 equiv.) in methanol (5 mL) was added Intermediate-D (486 mg, 0.86 mmol, 1.3 equiv.) and acetic acid (0.1 mL) at room temperature, and the reaction mixture was stirred for an additional 2 hours. To the reaction mixture was added NaCNBH3 (64 mg, 1 mmol, 1.5 equiv.) in small portions at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, cold water (50 mL) was added and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column eluted with 6% methanol in DCM to give the title compound (369 mg, 54%) as an off-white solid.

[0468] 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.48 (br d, J = 8.38 Hz, 1H), 8.11 (d, J = 9.13 Hz, 1H), 7.81 (d, J = 9.51 Hz, 1H), 7.57 - 7.65 (m, 2H), 7.31 - 7.38 (m, 2H), 6.95 (d, J = 2.38 Hz, 1H), 6.83 (dd, J = 9.13, 2.50 Hz, 1H), 6.51 (s, 1H), 5.28 - 5.46 (m, 4H), 4.43 - 4.57 (m, 2H), 3.71 - 3.89 (m, 5H), 2.96-3.11 (m, 4H), 2.85 (s, 3H), 2.80-2.82 (m, 2H), 2.41 (br d, J = 11.63 Hz, 1H), 2.20 - 2.35 (m, 3H), 2.14 (s, 6H), 1.58 - 2.03 (m, 14H), 1.30 - 1.45 (m, 2H), 1.10 - 1.22 (m, 1H), 0.96 - 1.12 (m, 3H), 0.89 (t, J = 7.32 Hz, 3H).LCMS:1026.4 [M+H] + . HPLC purity: 94.5%.

[0469] (Example S21) Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl(2R,5S)-4-(1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carbonyl)-2,5-dimethylpiperazine-1-carboxylate formate (Compound No. 21) [ka]

[0470] Step-E1: Preparation of tert-butyl ((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)carbamate (Intermediate-E1)

[0471] To a stirred solution of tert-butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate (starting material-2, 10 g, 46.5 mmol, 1.0 equiv.) in DMF (100 mL) was added NaH (4.08 g, 102 mmol, 2.2 equiv.) under a nitrogen atmosphere at 0 °C, warmed to room temperature, and stirred for 30 min. 2-Chloro-4-fluoro-3-methylbenzonitrile (starting material-1, 7.86 g, 46.51 mmol, 1.0 equiv.) was added portionwise over 10 min at room temperature, and the resulting reaction mixture was stirred for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, ice-cold water (100 mL) was added, and the precipitated solid formed. It was filtered and dried to give Intermediate-E1 (15 g, 88%) as an off-white solid.

[0472] 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 8.31 Hz, 1H), 7.22 (d, J = 8.80 Hz, 1H), 6.82 (s, 1H), 4.37 - 4.55 (m, 2H), 2.21 (s, 3H), 1.98 - 2.11 (m, 2H), 1.76 - 1.88 (m, 2H), 1.42 - 1.51 (m, 4H), 1.38 (s, 9H).LCMS:309 [M-56+H] + .

[0473] Step-E2: Preparation of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chloro-3-methylbenzonitrile hydrochloride (Intermediate-E2)

[0474] To a solution of Intermediate-E1 (15 g, 41.1 mmol) in DCM (25 mL) was added 4 M HCl in 1,4-dioxane (75 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 16 h. After completion of the reaction, the volatiles were evaporated under reduced pressure and the resulting residue was washed with diethyl ether (2×80 mL) to afford Intermediate-E2 (15 g, crude) as an off-white solid, which was used directly in the next step.

[0475] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (br s, 3H), 7.75 (d, J = 8.80 Hz, 1H), 7.28 (d, J = 8.80 Hz, 1H), 4.44 - 4.55 (m, 1H), 3.00 - 3.15 (m, 1H), 2.21 (s, 3H), 2.07 - 2.15 (m, 2H), 1.97 - 2.06 (m, 2H), 1.41 - 1.63 (m, 4H).LCMS:264.75 [M+H] + .

[0476] Step-E3: Preparation of 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)pyridazine-3-carboxamide (Intermediate-E3)

[0477] To a mixture of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chloro-3-methylbenzonitrile hydrochloride (Intermediate-E2, 15 g, 56.9 mmol, 1.0 equiv.) and 6-chloropyridazine-3-carboxylic acid (Starting Material-3, 9 g, 56.9 mmol, 1.0 equiv.) in DMF (100 mL) was added HATU (32.4 g, 85.44 mmol, 1.5 equiv.) and DIPEA (49 mL, 284 mmol, 5.0 equiv.) at 0° C. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the volatiles were evaporated under reduced pressure, diluted with water (500 mL), and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with water (400 mL), brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by column chromatography eluting with 60-80% ethyl acetate in hexanes to give Intermediate-E3 (6 g, 27%) as an off-white solid.

[0478] 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J = 8.31 Hz, 1H), 8.22 (d, J = 8.80 Hz, 1H), 8.10 (d, J = 8.80 Hz, 1H), 7.77 (d, J = 8.80 Hz, 1H), 7.27 (d, J = 8.80 Hz, 1H), 4.43 - 4.57 (m, 1H), 3.85 - 4.01 (m, 1H), 2.23 (s, 3H), 2.08 - 2.17 (m, 2H), 1.86 - 1.96 (m, 2H), 1.64 - 1.77 (m, 2H), 1.49 - 1.62 (m, 2H).LCMS: 404.9 [M+H] + .

[0479] Step-E4: Preparation of ethyl 1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)carbamoyl)-pyridazin-3-yl)piperidine-4-carboxylate (Intermediate-E4)

[0480] To a stirred solution of 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-pyridazine-3-carboxamide (Intermediate-E3, 7 g, 17 mmol, 1.0 equiv.) and ethyl piperidine-4-carboxylate (Starting Material-4, 4 g, 25 mmol, 1.5 equiv.) in DMF (70 mL) at room temperature was added potassium carbonate (5.86 g, 42 mmol, 2.5 equiv.). The reaction mixture was heated to 80° C. for 12 hours. The progress of the reaction was monitored by TLC. After completion of the starting material, the reaction mixture was diluted with ice-cold water (300 mL), stirred for 10 minutes, and the precipitated solid was filtered and dried to give Intermediate-E4 (6 g, 66%) as an off-white solid.

[0481] 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 7.82 Hz, 1H), 7.80 (d, J = 9.29 Hz, 1H), 7.75 (d, J = 8.80 Hz, 1H), 7.35 (d, J = 9.78 Hz, 1H), 7.24 (d, J = 8.80 Hz, 1H), 4.44 - 4.55 (m, 1H), 4.30 - 4.41 (m, 2H), 4.00 - 4.11 (m, 2H), 3.80 - 3.92 (m, 1H), 3.08 - 3.23 (m, 2H), 2.64 - 2.76 (m, 1H), 2.22 (s, 3H), 2.05 - 2.15 (m, 2H), 1.85 - 1.97 (m, 4H), 1.44 - 1.71 (m, 6H), 1.17 (t, J = 7.34 Hz, 3H).LCMS:526.2 [M+H] + .

[0482] Step-E5: Preparation of 1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carboxylic acid (Intermediate-E)

[0483] To a solution of ethyl 1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)carbamoyl)-pyridazin-3-yl)piperidine-4-carboxylate (Intermediate-E4, 6.0 g, 11.5 mmol, 1.0 equiv) in THF (20 mL) and water (5 mL) was added LiOH.HO (2.49 g, 57.9 mmol, 5.0 equiv) at 0° C., and the reaction mixture was stirred for 5 hours. The reaction progress was monitored by TLC. After completion of the reaction, the volatiles were removed under reduced pressure, diluted with water (80 mL), acidified to pH 3 with 1 N aqueous HCl, and extracted with ethyl acetate (3×80 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give Intermediate-E (5.4 g, 94%) as an off-white solid.

[0484] LCMS: 498.37 [M+H] + .

[0485] Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl(2R,5S)-4-(1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine-4-carbonyl)-2,5-dimethylpiperazine-1-carboxylate formate

[0486] (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl(2S,5R)-2,5-dimethylpiperazine-1-carboxylate (Intermediate-D, 1.19 g, 2.012 mmol, 1.0 equiv.) and 1-(6-(((1r,4r)-4-(3-chloro- To a stirred solution of (4-cyano-2-methylphenoxy)cyclohexyl)carbamoyl)-pyridazin-3-yl)piperidine-4-carboxylic acid (Intermediate-E, 1 g, 2.012 mmol, 1.0 equiv.) in DMF (10 mL) was added HATU (1.14 g, 3.018 mmol, 1.5 equiv.) and DIPEA (1.75 mL, 10.06 mmol, 5.0 equiv.) at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (60 mL) and extracted with 10% methanol in DCM (2 × 60 mL). The combined organic extracts were washed with water (80 mL), brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC with the formic acid method (0.5% aqueous formic acid in CHCN) to give the title compound (600 mg, 28%) as an off-white solid.

[0487] 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.59 (d, J = 8.13 Hz, 1H), 8.14 (dd, J = 8.94, 2.56 Hz, 1H), 7.81 - 7.85 (m, 1H), 7.77 (d, J = 8.76 Hz, 1H), 7.60 - 7.72 (m, 1H), 7.38 (dd, J = 9.51, 3.38 Hz, 1H), 7.35 (s, 1H), 7.26 (d, J = 8.88 Hz, 1H), 6.52 (s, 1H), 5.41 - 5.46 (m, 2H), 5.28 - 5.35 (m, 2H), 4.40 - 4.65 (m, 4H), 3.72 - 4.04 (m, 6H), 2.98 - 3.22 (m, 4H), 2.07 - 2.36 (m, 12H), 1.81 - 1.98 (m, 3H), 1.38 - 1.78 (m, 10H), 1.22 - 1.34 (m, 4H), 1.08 - 1.16 (m, 2H), 0.89 (t, J = 7.25 Hz, 3H).LCMS:1041.4 [M+H] + . HPLC purity 98.6%.

[0488] (Example S22) Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(6-((1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)-cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)(methyl)amino)hexyl)piperazine-1-carboxylate formate (Compound No. 22) [ka]

[0489] Step-F1: Preparation of tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate (Intermediate-F1)

[0490] To a stirred solution of tert-butyl piperazine-1-carboxylate (starting material-1, 5 g, 26.8 mmol, 1.0 equiv.) in DCM (100 mL) was added pyridine (2.97 g, 37.6 mmol, 1.4 equiv.) and triphosgene (3.19 g, 10.7 mmol, 0.4 equiv.) at 0 °C, warmed to room temperature, and stirred for 2 h. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was diluted with water (100 mL) and extracted with DCM (2 × 100 mL). The combined organic extracts were washed again with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give Intermediate-F1 (6.0 g, 90%) as an oil.

[0491] 1 H NMR (400 MHz, DMSO-d6) δ 3.64 (d, J = 4.40 Hz, 2H), 3.52 (br s, 2H), 3.27 - 3.47 (m, 3H), 2.93 - 3.21 (m, 1H), 1.41 (s, 9H).

[0492] Step-F2: 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]indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-F2)

[0493] To a stirred solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione hydrochloride (Starting Material-2, 10 g, 23.7 mmol, 1.0 equiv.) in DCM (250 mL) was added DIPEA (15.3 g, 118 mmol, 5 equiv.) and DMAP (724 mg, 5.9 mmol, 0.25 equiv.) at 0 °C. Then, tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate (Intermediate-F1, 5.89 g, 23.7 mmol, 1 equiv.) in DCM (20 mL) was added dropwise over 10 min and stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was diluted with water (100 mL) and extracted with DCM (3×100 mL). The combined organic extracts were washed again with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by combi flash column using 7% methanol in DCM to give Intermediate-F2 (10 g, 66%) as an off-white solid.

[0494] 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.11 (d, J = 9.29 Hz, 1H), 7.65 (d, J = 9.29 Hz, 1H), 7.34 (s, 1H), 6.53 (s, 1H), 5.43 (s, 2H), 5.31 (s, 2H), 3.67 - 3.79 (m, 4H), 3.41 - 3.55 (m, 6H), 2.20 (s, 6H), 1.80 - 1.93 (m, 2H), 1.44 (s, 9H), 0.89 (t, J = 7.34 Hz, 3H).LCMS:634.2 [M+H] + .

[0495] Step-F3: Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate hydrochloride (Intermediate-F)

[0496] Under a nitrogen atmosphere, (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]indolizino[1,2-b]quinolin-9-yl)piperazine-1,4-dicarboxylate (Intermediate-F2, 5 g, 7.89 mmol, 1.0 equiv.) was added with 4 M HCl in 1,4-dioxane (50 mL) at 0 °C, warmed to room temperature, and stirred for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the volatiles were evaporated under reduced pressure, and the residue was triturated with diethyl ether (3 × 100 mL) to give Intermediate-F (5 g, crude) as an off-white solid.

[0497] LCMS: 534.2 [M+H] + .

[0498] Step-1: Preparation of tert-butyl (1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)carbamoyl)-pyridazin-3-yl)piperidin-4-yl)(methyl)carbamate (Intermediate-1)

[0499] To a stirred solution of 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-pyridazine-3-carboxamide (Intermediate-E3, 6 g, 14.85 mmol, 1.0 equiv.) and tert-butylmethyl(piperidin-4-yl)carbamate (Starting Material-1, 4.76 g, 22.27 mmol, 1.5 equiv.) in DMF (60 mL) was added potassium carbonate (4.10 g, 29.7 mmol, 2.0 equiv.) at room temperature. The reaction mixture was then heated to 80° C. and stirred for 4 hours. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was diluted with ice-cold water (300 mL), stirred for 10 minutes, and the precipitated solid was filtered and dried to give Intermediate-1 (6 g, 27%) as an off-white solid.

[0500] 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 8.25 Hz, 1H), 7.82 (d, J = 9.63 Hz, 1H), 7.77 (d, J = 8.76 Hz, 1H), 7.38 (d, J = 9.63 Hz, 1H), 7.26 (d, J = 8.88 Hz, 1H), 4.56 - 4.64 (m, 2H), 4.46 - 4.55 (m, 1H), 3.97 - 4.23 (m, 1H), 3.81 - 3.94 (m, 1H), 2.95 - 3.07 (m, 2H), 2.64 (s, 3H), 2.24 (s, 3H), 2.08 - 2.15 (m, 2H), 1.86 - 1.95 (m, 2H), 1.49 - 1.71 (m, 8H), 1.39 (s, 9H).LCMS:583.1 [M+H] + .

[0501] Step-2: Preparation of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6-(4-(methylamino)-piperidin-1-yl)pyridazine-3-carboxamide hydrochloride (Intermediate-2)

[0502] To a solution of tert-butyl (1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)carbamoyl)-pyridazin-3-yl)piperidin-4-yl)(methyl)carbamate (Intermediate-1, 7.0 g, 12.02 mmol, 1.0 equiv) was added 4 M HCl in 1,4-dioxane (70 mL) at 0° C., and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the volatiles were evaporated under reduced pressure and the resulting residue was washed with diethyl ether (2×80 mL) to afford Intermediate-2 (7 g, crude) as an off-white solid, which was used without further purification.

[0503] 1H NMR (400 MHz, DMSO-d6) δ 9.13 (br s, 2H), 8.61 (d, J = 8.31 Hz, 1H), 7.88 (d, J = 9.78 Hz, 1H), 7.77 (d, J = 8.31 Hz, 1H), 7.47 (d, J = 9.78 Hz, 1H), 7.26 (d, J = 8.80 Hz, 1H), 4.45 - 4.56 (m, 2H), 3.83 - 3.96 (m, 1H), 3.57 (s, 3H), 3.08 (t, J = 12.23 Hz, 2H), 2.54 (t, J = 5.14 Hz, 2H), 2.24 (s, 3H), 2.06 - 2.18 (m, 4H), 1.86 - 1.96 (m, 2H), 1.48 - 1.72 (m, 6H).LCMS:483.41 [M+H] + .

[0504] Step-3: Preparation of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6-(4-((6-hydroxyhexyl)-(methyl)amino)piperidin-1-yl)pyridazine-3-carboxamide (Intermediate-3)

[0505] To a solution of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6-(4-(methylamino)-piperidin-1-yl)pyridazine-3-carboxamide hydrochloride (Intermediate-2, 3.5 g, 7.26 mmol, 1.0 equiv.) and 6-bromohexan-1-ol (Starting Material-2, 4.7 mL, 36.3 mmol, 5 equiv.) in ethanol (70 mL) and water (70 mL) was added NaHCO3 (6.1 g, 72.61 mmol, 10 equiv.) at room temperature. The reaction mixture was heated to 100°C and stirred for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was filtered through a pad of Celite and washed with ethyl acetate (40 mL). The filtrate was concentrated under reduced pressure, diluted with water (120 mL), and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by combi flash chromatography eluting with 2-5% methanol in DCM to give Intermediate-3 (4 g, 47%) as an off-white solid.

[0506] 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 8.31 Hz, 1H), 7.82 (d, J = 9.29 Hz, 1H), 7.77 (d, J = 8.80 Hz, 1H), 7.37 (d, J = 9.29 Hz, 1H), 7.26 (d, J = 8.80 Hz, 1H), 4.46 - 4.62 (m, 3H), 4.29 - 4.35 (m, 1H), 3.83 - 3.94 (m, 1H), 3.34 - 3.41 (m, 3H), 3.00 (t, J = 12.23 Hz, 2H), 2.23 - 2.25 (m, 4H), 2.07 - 2.16 (m, 3H), 1.74 - 1.96 (m, 4H), 1.52 - 1.71 (m, 5H), 1.35 - 1.51 (m, 6H), 1.20 - 1.33 (m, 6H).LCMS:583.17 [M+H] + .

[0507] Step-4: Preparation of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6-(4-(methyl(6-oxohexyl)amino)piperidin-1-yl)pyridazine-3-carboxamide (Intermediate-4)

[0508] To a stirred solution of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6-(4-((6-hydroxyhexyl)(methyl)amino)piperidin-1-yl)pyridazine-3-carboxamide (Intermediate-3, 4.0 g, 6.87 mmol, 1 equiv.) in dichloromethane (50 mL) at 0° C., pyridinium chlorochromate (PCC, 2.21 g, 10.30 mmol, 1.5 equiv.) was added portionwise, and the reaction mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under vacuum to give Intermediate-4 (4.2 g, crude) as a brown solid, which was used directly in the next step.

[0509] LCMS: 582.2 [M+H] + .

[0510] Step-5: Preparation of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(6-((1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)-cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)(methyl)amino)hexyl)piperazine-1-carboxylate formate

[0511] To a solution of (S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-ylpiperazine-1-carboxylate hydrochloride (Intermediate-F, 3.67 g mg, 6.89 mmol, 1 equiv.) in methanol and dichloromethane (40, 160 mL) was added EtN (0.9 mL, 6.89 mmol, 1.0 equiv.) and the resulting solution was stirred for 30 min. To this solution was added N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6-(4-(methyl(6-oxohexyl)amino)piperidin-1-yl)pyridazine-3-carboxamide (Intermediate-4, 4 g, 6.89 mmol, 1 equiv.) and glacial acetic acid (0.1 mL) at room temperature and stirred for 2 hours. To this reaction mixture was added NaBH(OAc)3 (5.81 mg, 27.58 mmol, 4 equiv.) at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the volatiles were evaporated under reduced pressure, quenched with ice-cold water (100 mL), and extracted with 10% methanol in DCM (2 x 80 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC purification method eluted with mobile phase A: 0.1% HCOOH in water and mobile phase B: acetonitrile to give the title compound (260 mg) as an off-white solid.

[0512] 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.57 (d, J = 7.83 Hz, 1H), 8.08 - 8.19 (m, 3H), 7.81 (d, J = 9.29 Hz, 1H), 7.76 (d, J = 8.31 Hz, 1H), 7.63 (d, J = 8.80 Hz, 1H), 7.32 - 7.40 (m, 2H), 7.21 - 7.28 (m, 1H), 6.51 (brs, 1H), 5.39 - 5.45 (m, 2H), 5.27 - 5.35 (m, 2H), 4.45 - 4.60 (m, 3H), 3.81 - 3.94 (m, 2H), 3.61 - 3.80 (m, 4H), 3.44 - 3.58 (m, 4H), 2.92 - 3.06 (m, 3H), 2.72 - 2.84 (m, 1H), 2.29 - 2.47 (m, 6H), 2.17 - 2.26 (m, 10H), 2.06 - 2.15 (m, 2H), 1.76 - 1.96 (m, 6H), 1.38 - 1.69 (m, 10H), 1.23 - 1.35 (m, 5H), 0.89 (t, J = 6.11 Hz, 3H).LCMS:1098.0 [M+H] + . HPLC purity 95.6%.

[0513] (Example S23) Preparation of (S)-4-ethyl-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl 4-((1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (Compound No. 23) [ka]

[0514] Step-1: Preparation of N-((1r,4r)-4-(3-chloro(Cchloro)-4-cyano-2-methylphenoxy)cyclohexyl)-6-(4-(hydroxylmethyl)-piperidin-1-yl)pyridazine-3-carboxamide (Intermediate-1)

[0515] A flask was charged with 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-pyridazine-3-carboxamide (Intermediate-E3, 1 g, 2.46 mmol, 1.0 equiv), piperidin-4-ylmethanol (Starting Material-1, 425 mg, 3.70 mmol, 1.5 equiv), KCO (1 g, 7.40 mmol, 3.0 equiv), and DMF (10 mL, 10 volumes). The reaction mixture was stirred at ambient temperature under a nitrogen atmosphere until TLC indicated complete consumption of the starting material. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×200 mL), and the combined organic layers were washed with brine solution (100 mL) and dried over sodium sulfate. The organic layer was filtered, concentrated under reduced pressure, and purified by flash column (silica, 50-60% ethyl acetate / hexanes). Pure fractions were combined and concentrated under reduced pressure to give N-((1r,4r)-4-(3-chloro-4-cyano-2-methyl-phenoxy)cyclohexyl)-6-(4-(hydroxylmethyl)piperidin-1-yl)pyridazine-3-carboxamide (Intermediate-1, 1 g, 84%) as an off-white solid.

[0516] 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 8.31 Hz, 1H), 7.95 (s, 1H), 7.78 (t, J = 9.05 Hz, 2H), 7.33 (d, J = 9.78 Hz, 1H), 7.26 (d, J = 8.80 Hz, 1H), 4.42 - 4.55 (m, 5H), 3.81 - 3.94 (m, 1H), 3.27 (t, J = 5.14 Hz, 2H), 2.23 (s, 3H), 2.11 (d, J = 10.76 Hz, 2H), 1.90 (d, J = 10.27Hz, 2H), 1.46 - 1.81 (m, 7H), 1.06 - 1.22 (m, 2H).LCMS:484.4 [M+H] + .

[0517] Step-2: Preparation of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)pyridazine-3-carboxamide (Intermediate-2)

[0518] A flask was charged with N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6-(4-(hydroxyl-methyl)piperidin-1-yl)pyridazine-3-carboxamide (Intermediate-1, 800 mg, 1.65 mmol, 1.0 equiv), Dess-Martin periodinane (1 g, 2.47 mmol, 1.5 equiv), and DCM (10 mL, 10 vol). The reaction mixture was stirred at ambient temperature under a nitrogen atmosphere until TLC indicated complete consumption of the starting material. The reaction mixture was quenched with saturated bicarbonate solution (100 mL), and the desired compound was extracted with DCM (2×200 mL). The combined organic layers were washed with brine solution (100 mL) and dried over sodium sulfate. The organic solvent was filtered and concentrated under reduced pressure to give N-((1r,4r)-4-(3-chloro-4-cyano-2-methyl-phenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)pyridazine-3-carboxamide (Intermediate-2, 750 mg, 94%) as an off-white solid, which was used without further purification.

[0519] 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.60 (d, J = 7.83 Hz, 1H), 7.8 (d, J = 8.40 Hz, 1H), 7.37 (d, J = 9.78 Hz, 1H), 7.26 (d, J = 8.80 Hz, 1H), 4.48 - 4.50 (m, 1H), 4.31 (d, J = 13.21 Hz, 2H), 3.86 -3.89 (m, 1H), 3.26 (t, J = 11.98 Hz, 2H), 2.61 - 2.76 (m, 1H), 2.20 - 2.30 (m, 4H), 2.10 - 2.12 (m, 2H), 1.81 - 2.00 (m, 4H), 1.46 - 1.70 (m, 6H).LCMS:482.4 [M+H] + .

[0520] Step-3: Preparation of tert-butyl 4-((1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (Intermediate-3)

[0521] To a stirred solution of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)pyridazine-3-carboxamide (Intermediate-2, 1.8 g, 3.74 mmol, 1 equiv.) and tert-butyl piperazine-1-carboxylate (Starting Material-2, 1.38 g, 7.46 mmol, 2 equiv.) in methanol (18 mL) was added a catalytic amount of glacial acetic acid (0.4 mL) at room temperature and stirred for 3 hours. To this reaction mixture was added NaBH3CN (462 mg, 7.46 mmol, 2 equiv.) at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the solvent was evaporated under reduced pressure, quenched with ice-cold water (50 mL), and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by combiflash column chromatography eluted with 80% EtOAc in heptane to give Intermediate-3 (1.0 g, 41%) as an off-white solid.

[0522] 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 7.34 Hz, 1H), 7.78 (t, J = 7.83 Hz, 2H), 7.32 (d, J = 8.31 Hz, 1H), 7.26 (d, J = 8.31 Hz, 1H), 4.42 - 4.57 (m, 3H), 3.81 - 3.94 (m, 1H), 3.27 - 3.31 (m, 4H), 2.99 (t, J = 12.23 Hz, 2H), 2.26 - 2.32 (m, 4H), 2.24 (s, 3H), 2.07 - 2.18 (m, 4H), 1.75 - 1.96 (m, 5H), 1.48 - 1.72 (m, 4H), 1.39 (s, 9H), 1.02 - 1.19 (m, 2H).LCMS:652.64 [M+H] + .

[0523] Step-4: Preparation of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6-(4-(piperazin-1-ylmethyl)piperidin-1-yl)pyridazine-3-carboxamide trifluoroacetate (Intermediate-4)

[0524] Under a nitrogen atmosphere, to a stirred solution of tert-butyl 4-((1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (Intermediate-3, 500 mg, 0.77 mmol, 1.0 equiv) in DCM (10 mL) was added TFA (1.17 mL) at 0° C., and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure to give the crude product. The resulting crude was triturated twice with n-pentane (2×30 mL) to give N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)-cyclohexyl)-6-(4-(piperazin-1-ylmethyl)piperidin-1-yl)pyridazine-3-carboxamide trifluoroacetate (Intermediate-4, 348 mg, 82%) as an off-white solid.

[0525] LCMS: 552.68 [M+H] + .

[0526] Step 5: Preparation of (S)-4-ethyl-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino-[1,2-b]quinolin-4-yl 4-((1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0527] To a solution of (S)-4-ethyl-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino-[1,2-b]quinolin-4-yl 4-nitrobenzoate (Intermediate-4, 600 mg, 1.1 mmol, 1 equiv.) and N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6-(4-(piperazin-1-ylmethyl)piperidin-1-yl)pyridazine-3-carboxamide trifluoroacetate (Intermediate-5, 730 mg, 1.32 mmol, 1.2 equiv.) in acetonitrile (10 mL) was added KCO (457 mg, 3.31 mmol, 3 equiv.). The resulting reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by LCMS / TLC. After completion of the reaction, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude was purified by preparative HPLC eluted with mobile phase A: 0.1% FA in water and mobile phase B: acetonitrile to give the title compound (95 mg, 8%) as an off-white solid.

[0528] 1H NMR (400 MHz, DMSO-d6) δ 8.55 - 8.59 (m, 2H), 8.06 (d, J = 9.01 Hz, 1H), 7.80 (d, J = 9.63 Hz, 1H), 7.77 (d, J = 8.88 Hz, 1H), 7.49 - 7.55 (m, 2H), 7.33 (d, J = 9.76 Hz, 1H), 7.26 (d, J = 8.88 Hz, 1H), 7.00 (s, 1H), 5.44 (d, J = 3.88 Hz, 2H), 5.29 (s, 2H), 4.42 - 4.57 (m, 3H), 3.95 (s, 3H), 3.83 - 3.93 (m, 1H), 3.67 - 3.78 (m, 1H), 3.55 - 3.65 (m, 1H), 3.18 - 3.26 (m, 2H), 2.94 - 3.06 (m, 2H), 2.53 - 2.58 (m, 1H), 2.29 - 2.37 (m, 1H), 2.24 (s, 3H), 2.07 - 2.22 (m, 8H), 1.86 - 1.96 (m, 3H), 1.75 - 1.85 (m, 2H), 1.48 - 1.71 (m, 4H), 1.05 - 1.19 (m, 2H), 0.91 (t, J = 7.44 Hz, 3H).LCMS: 956.2 [M+H] + . HPLC purity 95.7%.

[0529] (Example S24) Preparation of (S)-4-ethyl-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylate formate (Compound No. 24) [ka]

[0530] Step-1: Preparation of (S)-4-ethyl-4-hydroxy-9-methoxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Intermediate-1)

[0531] To a stirred solution of 10-hydroxycamptothecin (starting material-1, 1 g, 2.75 mmol, 1 equiv.) in DMF (10 mL) was added KCO (752 mg, 5.49 mmol, 2 equiv.) at 0° C., followed by methyl iodide (0.25 mL, 4.12 mmol, 1.5 equiv.). The reaction mixture was stirred at 80° C. for 3 hours. The progress of the reaction was monitored by TLC / LCMS. After completion of the reaction, the mixture was poured into ice-cold water (30 mL) and the resulting solid was filtered, washed with cold water and dried to give (S)-4-ethyl-4-hydroxy-9-methoxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Intermediate-1, 0.93 g, 90%) as an off-white solid.

[0532] 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.06 (d, J = 9.78 Hz, 1H), 7.47 - 7.53 (m, 2H), 7.28 (s, 1H), 6.49 (s, 1H), 5.41 (s, 2H), 5.25 (s, 2H), 3.94 (s, 3H), 1.78 - 1.95 (m, 2H), 0.88 (t, J = 7.34 Hz, 3H).LCMS:379.36 [M+H] + .

[0533] Step-2: Preparation of (S)-4-ethyl-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino-[1,2-b]quinolin-4-yl(4-nitrophenyl)carbonate (Intermediate-2)

[0534] To a stirred solution of (S)-4-ethyl-4-hydroxy-9-methoxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino-[1,2-b]quinoline-3,14(4H)-dione (Intermediate-1, 1.5 g, 3.96 mmol, 1 equiv.) in DCM (15 mL) was added 4-nitrophenyl chloroformate (1.19 g, 5.9 mmol, 1.5 equiv.), DMAP (98 mg, 0.79 mmol, 0.2 equiv.), and triethylamine (1.10 mL, 7.9 mmol, 2 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the mixture was quenched with ice-cold water (20 mL) and extracted with 10% MeOH in DCM (2 × 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was triturated twice with diethyl ether (2 × 20 mL) to give (S)-4-ethyl-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-4-yl(4-nitrophenyl)carbonate (Intermediate-2, 2.0 g, crude) as a light yellow solid.

[0535] 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 6.85 Hz, 1H), 8.27 (t, J = 8.80 Hz, 1H), 8.08 (d, J = 8.80 Hz, 2H), 8.01 - 8.04 (m, 1H), 7.44 - 7.50 (m, 2H), 6.86 (d, J = 8.80 Hz, 2H), 5.38 - 5.51 (m, 2H), 5.18 - 5.26 (m, 2H), 3.92 (s, 3H), 2.10 - 2.32 (m, 2H), 0.85 - 0.95 (m, 3H).

[0536] Step-3: Preparation of (S)-1-(tert-butyl) 4-(4-ethyl-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)piperazine-1,4-dicarboxylate (Intermediate-3)

[0537] To a stirred solution of (S)-4-ethyl-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-4-yl(4-nitrophenyl)carbonate (Intermediate-2, 200 mg, 0.36 mmol, 1 equiv.) in acetonitrile (5 mL) was added tert-butyl piperazine-1-carboxylate (82 mg, 0.44 mmol, 1.2 equiv.) and K2CO3 (149 mg, 1.08 mmol, 3 equiv.). The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with water (20 mL) and extracted with 5% MeOH in DCM (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by combiflash® column chromatography eluting with 100% ethyl acetate to afford (S)-1-(tert-butyl) 4-(4-ethyl-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl)piperazine-1,4-dicarboxylate (Intermediate-3, 110 mg, 50%) as an off-white solid.

[0538] 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.05 (d, J = 9.29 Hz, 1H), 7.46 - 7.56 (m, 2H), 7.01 (s, 1H), 5.42 - 5.47 (m, 2H), 5.28 (s, 2H), 3.94 (s, 3H), 3.58 - 3.74 (m, 2H), 3.37 - 3.55 (m, 2H), 3.21 - 3.28 (m, 4H), 2.10 - 2.20 (m, 2H), 1.41 (s, 9H), 0.91 (t, J = 7.34 Hz, 3H).LCMS:591.58 [M+H] + .

[0539] Step-4: Preparation of (S)-4-ethyl-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino-[1,2-b]quinolin-4-ylpiperazine-1-carboxylate (Intermediate-4)

[0540] To a stirred solution of (S)-1-(tert-butyl) 4-(4-ethyl-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)piperazine-1,4-dicarboxylate (Intermediate-3, 480 mg, 0.81 mmol, 1.0 equiv.) in DCM (5 mL) was added TFA (1.6 mL) at 0 °C under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure, saturated NaHCO solution (20 mL) was added, and the aqueous mixture was extracted with DCM (2 × 30 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude material was triturated twice with n-pentane (2 × 30 mL) to afford (S)-4-ethyl-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-ylpiperazine-1-carboxylate (Intermediate-4, 380 mg, 95%) as an off-white solid.

[0541] 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.06 (d, J = 8.80 Hz, 1H), 7.46 - 7.54 (m, 2H), 6.97 (s, 1H), 5.36 - 5.48 (m, 2H), 5.26 (s, 2H), 3.93 (s, 3H), 3.50 - 3.63 (m, 2H), 3.09 - 3.22 (m, 2H), 2.70 - 2.89 (m, 2H), 2.53 - 2.66 (m, 2H), 2.07 - 2.16 (m, 2H), 0.88 (t, J = 7.09 Hz, 3H). (No exchangeable protons observed). LCMS: 491.49 [M+H] + .

[0542] Step-5: Preparation of (S)-4-ethyl-9-methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino-[1,2-b]quinolin-4-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-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexyl)piperazine-1-carboxylate formate

[0543] (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-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (Intermediate-C, 855 mg, 1.53 mmol, 1.5 equiv.) and (S)-4-ethyl-9- To a stirred solution of methoxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-4-ylpiperazine-1-carboxylate (Intermediate-4, 500 mg, 1.02 mmol, 1 equiv.) in methanol (10 mL) was added triethylamine (0.14 mL) and glacial acetic acid (0.06 mL) at room temperature, and the mixture was stirred for 2 hours. To the reaction mixture was added NaCNBH3 (126 mg, 2.04 mmol, 2 equiv.) at 0 °C, warmed to room temperature, and stirred for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure, quenched with ice-cold water (20 mL), and extracted with 10% methanol in DCM (2 × 20 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by preparative HPLC purification eluted with mobile phase A: 0.1% FA in water and mobile phase B: acetonitrile to afford the title compound (90 mg, 8%) as an off-white solid.

[0544] 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.04 (d, J = 9.13 Hz, 1H), 7.44 - 7.56 (m, 2H), 6.93 - 7.02 (m, 3H), 6.58 (d, J = 8.76 Hz, 2H), 5.66 (s, 1H), 5.37 - 5.49 (m, 2H), 5.28 (s, 2H), 4.39 (d, J = 6.75 Hz, 1H), 3.94 (s, 3H), 3.49 - 3.81 (m, 2H), 3.16 - 3.25 (m, 4H), 2.81 (s, 3H), 2.64 - 2.76 (m, 2H), 2.52 - 2.61 (m, 4H), 2.42 - 2.47 (m, 2H), 2.21 - 2.38 (m, 5H), 2.11 - 2.19 (m, 5H), 2.09 (s, 3H), 1.99 (s, 2H), 1.85 - 1.95 (m, 2H), 1.61 - 1.77 (m, 3H), 1.18 - 1.53 (m, 12H), 0.91 (t, J = 7.32 Hz, 3H), 0.23 (s, 3H).LCMS:1034.4 [M+H] + . HPLC purity 93.8%.

[0545] (Example S25) Preparation of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6-(4-(4-(((S)-4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)piperazine-1-carbonyl)piperidin-1-yl)pyridazine-3-carboxamide (Compound No. 25) [ka]

[0546] To a stirred solution of 1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)carbamoyl)-pyridazin-3-yl)piperidine-4-carboxylic acid (Intermediate-E, 4 g, 8.26 mmol, 1 equiv) in DMF (40 mL) was added EDC.HCl (2.37 g, 12.39 mmol, 1.5 equiv), HOBT (1.89 g, 12.39 mmol, 1.5 equiv) and DIPEA (3.19 g, 24.78 mmol, 3.0 equiv). (S)-4-Ethyl-4,9-dihydroxy-10-(piperazin-1-ylmethyl)-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione trifluoroacetate (Intermediate-B, 5.7 g, 9.91 mmol, 1.2 equiv.) was added at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water (120 mL), and the formed solid was filtered and dried to give 7.6 g of crude product as a pale yellow solid. A portion (2 g) of the crude product was purified by preparative HPLC eluting with mobile phase A: 0.1% FA in water and mobile phase B: acetonitrile to give the title compound (508 mg) as a pale yellow solid.

[0547] 1H NMR (400 MHz, DMSO-d6) δ...

Claims

1. A compound of Formula I, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof: A １ -L １ -B １ I [In the formula, B １ is a nuclear receptor targeting epitope, L １ is a covalent bond or linking moiety, A １ is represented by formula IA: 【171】 It is of During the ceremony, R １ , R ２ , R ３ , R ４ and R ５ are each independently hydrogen, halo, cyano, nitro, -OR １５ , -SR １５ , -NR １５ R １６ , C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ Aryl, 5- to 12-membered heteroaryl, —C(═O)R １５ , -C(=O)OR １５ , —OC(═O)R １５ , -OC(=O)NR １５ R １６ , —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) １～２ NR １５ R １６ , -NR １５ S (= O) １～２ R １６ , -Si(R １５ ) ３ or -C=NOR １５ and each of them, as valence permits, may contain one or more R １０ or independently and optionally replaced by or R １ and R ２ together with the atoms to which they are attached, ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ aryl or 5- to 12-membered heteroaryl, each of which, valence permitting, may be joined by one or more R １０ or independently and optionally replaced by or R ２ and R ３ together with the atoms to which they are attached, ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ aryl or 5- to 12-membered heteroaryl, each of which, valence permitting, may be joined by one or more R １０ or independently and optionally replaced by or R ３ and R ４ together with the atoms to which they are attached, ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ aryl or 5- to 12-membered heteroaryl, each of which, valence permitting, may be joined by one or more R １０ and independently and optionally substituted by Each R １０ are independently halo, cyano, nitro, -OR １７ , -SR １７ , -SF ５ , -NR １７ R １８ , C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ Aryl, 5- to 12-membered 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 and each of them, as far as valence permits, is selected from halo, cyano, nitro, hydroxyl, amino, C １～１２ Alkoxy, C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ is optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R １５ and R １６ are independently hydrogen, C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ aryl or 5- to 12-membered heteroaryl, each of which, as valence permits, is selected from halo, cyano, nitro, hydroxyl, amino, C １～１２ Alkoxyl, C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; or R １５ and R １６ together with the atom to which they are attached, valence permitting, halo, cyano, nitro, hydroxyl, amino, C １～１２ Alkoxyl, C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ forming a 5- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R １７ and R １８ are independently hydrogen, C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ aryl or 5- to 12-membered heteroaryl, each of which, as valence permits, is selected from halo, cyano, nitro, hydroxyl, amino, C １～１２ Alkoxyl, C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; or R １７ and R １８ together with the atom to which they are attached, valence permitting, halo, cyano, nitro, hydroxyl, amino, C １～１２ Alkoxyl, C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ forming a 5- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; One or more atoms of formula IA (e.g., hydrogen, methyl, or hydroxyl) may be selected from L １ is replaced by a direct covalent bond to

2. 10. The compound of claim 1, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, wherein the compound is not a compound selected from the group of compounds in Table 1X, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.

3. R １ 3. The compound of claim 1 or 2, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein is hydrogen.

4. R １ is one or more R １０ C optionally substituted with １～１２ 3. The compound of claim 1 or 2, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein R is alkyl.

5. R １ is one or more R １０ optionally substituted with —Si(R １５ ) ３ 3. The compound of claim 1 or 2, wherein:

6. R １ is one or more R １０ optionally substituted with —C═NOR １５ 3. The compound of claim 1 or 2, wherein:

7. R １ 3. The compound of claim 1 or 2, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein is ethyl.

8. R １ but 【172】 3. The compound of claim 1 or 2, wherein:

9. R １ but, 【Chemistry 173】 3. The compound of claim 1 or 2, wherein:

10. R １ but 【Chemical 174】 3. The compound of claim 1 or 2, wherein:

11. R １ but 【Chemistry 175】 3. The compound of claim 1 or 2, wherein:

12. R ２ 12. The compound of any one of claims 1 to 11, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein is hydrogen.

13. R ２ is one or more R １０ C optionally substituted with １～１２ 12. The compound of any one of claims 1 to 11, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein:

14. R ２ but, 【176】 12. The compound of any one of claims 1 to 11, wherein:

15. R ２ is nitro, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof.

16. R ２ but, 【177】 12. The compound of any one of claims 1 to 11, wherein:

17. R １ and R ２ together with the atoms to which they are attached to form one or more R １０ C optionally substituted with ３～１２ 3. A compound according to claim 1 or 2, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which forms a cycloalkyl.

18. R １ and R ２ together with the atoms to which they are bonded, 【178】 3. The compound of claim 1 or 2, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which forms:

19. R ３ is one or more R １０ -OR optionally substituted with １５ 19. The compound of any one of claims 1 to 18, wherein:

20. R ３ is one or more R １０ C optionally substituted with １～１２ 19. The compound of any one of claims 1 to 18, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein:

21. R ３ is one or more R １０ -OC(=O)NR optionally substituted with １５ R １６ 19. The compound of any one of claims 1 to 18, wherein:

22. R ３ is -OH, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof.

23. R ３ 19. The compound of any one of claims 1 to 18, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein is methyl.

24. R ３ but, 【179】 19. The compound of any one of claims 1 to 18, wherein:

25. R ３ but, 【Chemistry 180】 19. The compound of any one of claims 1 to 18, wherein:

26. R ３ but, 【Chemistry 181】 19. The compound of any one of claims 1 to 18, wherein:

27. R ３ but, 【Chemistry 182】 19. The compound of any one of claims 1 to 18, wherein:

28. R ３ but, 【Chemistry 183】 19. The compound of any one of claims 1 to 18, wherein:

29. R ３ is methoxy, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof.

30. R ３ is hydrogen, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof.

31. R ４ 31. The compound of any one of claims 1 to 30, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein is hydrogen.

32. R ４ is halo, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof.

33. R ３ and R ４ together with the atoms to which they are attached to form one or more R １０ 19. The compound of any one of claims 1 to 18, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which forms a 5- to 12-membered heterocyclyl optionally substituted by

34. R ３ and R ４ together with the atoms to which they are bonded, 【Chemistry 184】 19. The compound of any one of claims 1 to 18, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which forms:

35. R ５ is hydrogen, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof.

36. R ５ is one or more R １０ -C(=O)R optionally substituted with １５ 35. The compound of any one of claims 1 to 34, wherein:

37. R ５ but, 【Chemistry 185】 35. The compound of any one of claims 1 to 34, wherein:

38. A １ but, 【Chemistry 186】 【187】 3. The compound of claim 1 or 2, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, derived from:

39. A １ but, 【Chemistry 188】 【Chemistry 189】 3. The compound of claim 1 or 2, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, derived from:

40. The hydrogen atom of formula IA is L １ 40. The compound of any one of claims 1 to 39, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein:

41. The methyl of formula IA is L １ 40. The compound of any one of claims 1 to 39, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein:

42. The hydroxyl of formula IA is L １ 40. The compound of any one of claims 1 to 39, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein:

43. L １ A １ or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein

44. L １ A １ or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein

45. A １ but, 【190】 【Chemistry 191】 3. The compound of claim 1 or 2, wherein:

46. A １ but, 【Chemistry 192】 【193】 3. The compound of claim 1 or 2, wherein:

47. B １ 47. The compound of any one of claims 1 to 46, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein

48. B １ 48. The compound of any one of claims 1 to 47, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein

49. B １ 49. The compound of any one of claims 1 to 48, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein

50. B １ 50. The compound of any one of claims 1 to 49, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein

51. B １ is of formula IIA: 【Chemistry 194】 [In the formula, The wavy line bond is L １ represents a connection point to R ３０ is hydrogen, C １～１２ Alkyl, C １～１２ Haloalkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl or C ３～１２ is cycloalkyl, and C １～１２ Alkyl, C １～１２ Haloalkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl or C ３～１２ Each cycloalkyl may be optionally substituted with one or more R １００ and optionally independently substituted by R ４０ is hydrogen, C １～１２ Alkyl, C １～１２ Haloalkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl or C ３～１２ is cycloalkyl, and C １～１２ Alkyl, C １～１２ Haloalkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl or C ３～１２ Each cycloalkyl may be optionally substituted with one or more R １００ and optionally independently substituted by Each R ５０ and R ５１ are independently halo, cyano, nitro, -OR １７０ , -SR １７０ , -NR １７０ R １８０ , C １～１２ Alkyl, C １～１２ Haloalkyl, C ２～１２ alkenyl or C ２～１２ alkynyl, C １～１２ Alkyl, C １～１２ Haloalkyl, C ２～１２ alkenyl or C ２～１２ each alkynyl is independently optionally substituted with one or more halo, hydroxyl, or amino, as valence allows; Each R １００ are independently oxo, halo, cyano, nitro, -OR １７０ , -SR １７０ , -SF ５ , -NR １７０ R １８０ , C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ Aryl, 5- to 12-membered 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 , or -NR １７０ C(=O)OR １８０ and each of them, as far as valence permits, is selected from halo, cyano, nitro, hydroxyl, amino, C １～１２ Alkoxy, C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ is optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R １７０ and R １８０ are independently hydrogen or, where valence allows, C optionally substituted with oxo, halo, hydroxyl, or amino. １～１２ Is it alkyl? or R １７０ and R １８０ together with the atom to which they are attached, represent C optionally substituted by halo, or by oxo, halo, hydroxyl or amino. １～１２ forming a heterocyclyl optionally substituted by alkyl.

47. The compound of any one of claims 1 to 46, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which is

52. B １ but, 【Chemistry 195】 47. The compound of any one of claims 1 to 46, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein:

53. B １ is of formula IIB': 【Chemistry 196】 [In the formula, The wavy line bond is L １ represents a connection point to R Ｎ is H or C １～１２ is alkyl, R ６０ is hydrogen, -OR １０１ , -NR １０１ R １０２ , C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ Aryl, 5- to 12-membered heteroaryl, —C(═O)R １０１ , -C(=O)OR １０１ , —OC(═O)R １０１ , -OC(=O)NR １０１ R １０２ , —C(═O)NR １０１ R １０２ , -NR １０１ C(=O)R １０２ , -NR １０１ C(=O)OR １０２ and each of them, as valence permits, may contain one or more R １００ and optionally independently substituted by R ８０ is hydrogen, -OR １０１ , -NR １０１ R １０２ , C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ Aryl, 5- to 12-membered heteroaryl, —C(═O)R １０１ , -C(=O)OR １０１ , -OC(=O)R １０１ , -OC(=O)NR １０１ R １０２ , —C(═O)NR １０１ R １０２ , -NR １０１ C(=O)R １０２ , -NR １０１ C(=O)OR １０２ and each of them, as valence permits, may contain one or more R １００ and optionally independently substituted by R ８１ is hydrogen, -OR １０１ , -NR １０１ R １０２ , C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ Aryl, 5- to 12-membered heteroaryl, —C(═O)R １０１ , -C(=O)OR １０１ , -OC(=O)R １０１ , -OC(=O)NR １０１ R １０２ , —C(═O)NR １０１ R １０２ , -NR １０１ C(=O)R １０２ , -NR １０１ C(=O)OR １０２ and each of them, as valence permits, may contain one or more R １００ or independently substituted as needed by or R ８０ and R ８１ together with the atom to which they are attached, represent C optionally substituted by halo, or by oxo, halo, hydroxyl or amino. １～１２ forming a heterocyclyl optionally substituted by alkyl, R ８２ is hydrogen, -OR １０１ , -NR １０１ R １０２ , C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ Aryl, 5- to 12-membered heteroaryl, —C(═O)R １０１ , -C(=O)OR １０１ , —OC(═O)R １０１ , -OC(=O)NR １０１ R １０２ , —C(═O)NR １０１ R １０２ , -NR １０１ C(=O)R １０２ , -NR １０１ C(=O)OR １０２ and each of them, as valence permits, may contain one or more R １００ and optionally independently substituted by Each R １０１ and R １０２ are independently hydrogen, C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ aryl or 5- to 12-membered heteroaryl, each of which, as valence permits, is selected from halo, cyano, nitro, hydroxyl, amino, C １～１２ Alkoxyl, C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ is optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R １００ are independently oxo, halo, cyano, nitro, -OR １７０ , -SR １７０ , -SF ５ , -NR １７０ R １８０ , C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ Aryl, 5- to 12-membered 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 , or -NR １７０ C(=O)OR １８０ and each of them, as far as valence permits, is selected from halo, cyano, nitro, hydroxyl, amino, C １～１２ Alkoxy, C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ is optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R １７０ and R １８０ are independently hydrogen or, where valence allows, C optionally substituted with oxo, halo, hydroxyl, or amino. １～１２ Is it alkyl? or R １７０ and R １８０ together with the atom to which they are attached, represent C optionally substituted by halo, or by oxo, halo, hydroxyl or amino. １～１２ forming a heterocyclyl optionally substituted by alkyl.

47. The compound of any one of claims 1 to 46, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which is

54. R Ｎ 54. The compound of claim 53, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein is methyl.

55. B １ but, 【Chemistry 197】 47. The compound of any one of claims 1 to 46, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein:

56. B １ but, 【Chemistry 198】 47. The compound of any one of claims 1 to 46, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein:

57. B １ but, 【Chemistry 199】 47. The compound of any one of claims 1 to 46, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein:

58. B １ but, 【Chemistry 200】 47. The compound of any one of claims 1 to 46, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein:

59. B １ is of formula IIC': 【Chemistry 201】 [In the formula, The wavy line bond is L １ represents a connection point to A" and A'" are each independently O or S; R ａ and R ｂ are each independently CH ３ or CH ２ CH ３ or R ａ and R ｂ together with the atoms to which they are attached, ３～６ forming a cycloalkyl, oxirane, oxetane or tetrahydrofuran, B, B １０ , B ２ , B ３ , B', B １’ , B ２’ and B ３’ are each independently CR ｃ or N, Each R ｃ are independently hydrogen, fluoro, CN or methyl; D is absent, NH, O, S, CH ２ , —NH(C═O)—, —(C═O)NH—, or C═O; X" is CN, halo or NO ２ and Y" is CH ３ , C.H. ２ R ｄ , CHF ２ or CF ３ and R ｄ is a halo, Z" is H, C １～２ Alkyl, C ２ Alkenyl or NO ２ or X" and Y" come together, 【Chemistry 202】 and the dashed line indicates a bond to the ring, or or Y" and Z" together, 【Chemistry 203】 Form each 【Chemistry 204】 is a single or double bond, the dashed line indicates the bond to the ring, Z' is CH or N.

47. The compound of any one of claims 1 to 46, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which is

60. D is NH, O, S, CH ２ 60. The compound of claim 59, wherein the compound is —NH(C═O)—, —(C═O)NH—, or C═O, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof.

61. B １ but, 【Chemistry 205】 47. The compound of any one of claims 1 to 46, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein:

62. B １ but, 【Chemistry 206】 47. The compound of any one of claims 1 to 46, wherein:

63. B １ is of formula IID': 【Chemistry 207】 [In the formula, W is O, S or NH; each 【Chemistry 208】 are independently a double bond or a single bond; Each R ６１ and R ６２ are independently hydrogen, C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl or C ３～１２ is cycloalkyl, and C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl or C ３～１２ Each cycloalkyl may be optionally substituted with one or more R １００ and optionally independently substituted by Each R １００ are independently oxo, halo, cyano, nitro, -OR １７０ , -SR １７０ , -SF ５ , -NR １７０ R １８０ , C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ Aryl, 5- to 12-membered 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 , or -NR １７０ C(=O)OR １８０ and each of them, as far as valence permits, is selected from halo, cyano, nitro, hydroxyl, amino, C １～１２ Alkoxy, C １～１２ Alkyl, C ２～１２ Alkenyl, C ２～１２ Alkynyl, C ３～１２ cycloalkyl, 5- to 12-membered heterocyclyl, C ６～１２ is optionally substituted independently with one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Each R １７０ and R １８０ are independently hydrogen or, where valence allows, C optionally substituted with oxo, halo, hydroxyl, or amino. １～１２ Is it alkyl? or R １７０ and R １８０ together with the atom to which they are attached, represent C optionally substituted by halo, or by oxo, halo, hydroxyl or amino. １～１２ forming a heterocyclyl optionally substituted by alkyl.

47. The compound of any one of claims 1 to 46, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which is

64. B １ is of formula IID: 【Chemistry 209】 64. The compound of claim 63, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which is:

65. B １ but, 【Chemistry 210】 47. The compound of any one of claims 1 to 46, wherein:

66. B １ but, 【Chemistry 211】 47. The compound of any one of claims 1 to 46, wherein:

67. B １ is of formula IIE: 【Chemistry 212】 [In the formula, The wavy bond indicates the point of attachment to L; Q is, 【Chemistry 213】 wherein bond a is bonded to ring a and bond b is bonded to ring b; R ａ and R ｂ are each independently —CH ３ or -CH ２ CH ３ or R ａ and R ｂ together with the atoms to which they are attached, ３～５ forming a cycloalkyl, oxiranyl, oxetanyl or tetrahydrofuranyl, A and A' are each independently O or S; E, E １ , E ２ and E ３ are each independently CR ｃ or N, and each R ｃ are independently hydrogen, halo, CN or methyl; E ４ is CF, CH or N, Q １ is a bond, CH ２ , C═O or (C═O)NH; Q ２ are NH, O, S, CH ２ , NH(C═O), C(═O)NH or C═O; R ４４ , R ４５ and R ４６ are each independently hydrogen, CN or C １～２ is alkyl, t is 0, 1, 2, 3, or 4; Each R ｅ and R ｆ are independently halo, cyano, C １～４ Alkyl or C １～４ is haloalkyl, R ４１ is halo, CN or NO ２ and R ４２ Ha, Halo, CH ３ , C.H. ２ F, CHF ２ Or CF ３ or R ４１ and R ４２ Let's get together and 【Chemical 214】 where the dashed line indicates the bond to ring a, R ４３ is hydrogen, halo, C １～２ Alkyl, C ２ Alkenyl, NO ２ , C.F. ３ or R ４２ and R ４３ Let's get together and 【Chemistry 215】 Form each 【Chemistry 216】 is a single or double bond, and the dashed line indicates the bond to ring a.

47. The compound of any one of claims 1 to 46, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which is

68. B １ but, 【Chemistry 217】 47. The compound of any one of claims 1 to 46, wherein:

69. B １ but, 【Chemical 218】 47. The compound of any one of claims 1 to 46, wherein:

70. B １ but, 【Chemical 219】 47. The compound of any one of claims 1 to 46, wherein:

71. B １ but, 【Chemistry 220】 47. The compound of any one of claims 1 to 46, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein:

72. B １ However, progesterone, enobosarm, bicalutamide, apalutamide, testosterone, dihydrotestosterone, testosterone, 19-nortestosterone, progesterone, andarine, cortisol, prednisone, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, megestrol acetate, estramustine, abiraterone, L 47. The compound of any one of claims 1 to 46, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, derived from GD-2941, BMS-564929, ostarine, ulipristal acetate, asoprisnil (J867), mifepristone, telapristone (CDB-4124, Proellex, Progenta) or an analogue thereof.

73. L １ But the formula: -(L ａ ) ｑ - [In the formula, Each L ａ are independently W, -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) ２ NR １１０ -, -NR １１０ S (O) ２ NR １１０ -, -CR １２０ = N-NR １１０ -, -NR １１０ -N=CR １２０ -, -C(O)-, -OC(O)-, -OC(O)O-, -C(O)O-, C １～１２ Alkylene, C ２～１２ Alkenylene, C ２～１２ Alkynylene, C ６～１２ Arylene, C ３～１２ cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12-membered heteroarylene, each of which is represented by —OH, —NH ２ , -CN, oxo, halo, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ is independently optionally substituted with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl; Each W is independently 【Chemical 221】 and R ｎ are independently expressed as H, C for each occurrence. １～４ Alkyl or C １～４ haloalkyl, and R ｗ are independently expressed as H, C for each occurrence. ３～１２ Cycloalkyl, C ６～１２ aryl (optionally substituted with one or more of halo or OH) or C １～４ alkyl (one or more independently selected halo, OH, —SH, —S(C １～４ alkyl), -CONH ２ , -COOH, -NHC(=NH)NH ２ , -NH ２ , -NHCOCH ３ , -NHCHO, -NHCONH ２ , C ６～１２ optionally substituted by aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl; Each R １１０ are independently hydrogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ cycloalkyl or 5- to 12-membered heterocyclyl; Each R １２０ are independently hydrogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ cycloalkyl or 5- to 12-membered heterocyclyl; and q is an integer from 0 to 40.

73. The compound of any one of claims 1 to 72, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which is

74. L １ But the formula: -(L ａ ) ｑ - [In the formula, Each L ａ are independently -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) ２ NR １１０ -, -NR １１０ S (O) ２ NR １１０ -, -CR １２０ = N-NR １１０ -, -NR １１０ -N=CR １２０ -, -C(O)-, -OC(O)-, -OC(O)O-, -C(O)O-, C １～１２ Alkylene, C ２～１２ Alkenylene, C ２～１２ Alkynylene, C ６～１２ Arylene, C ３～１２ cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12-membered heteroarylene, each of which is selected from oxo, halo, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ is independently optionally substituted with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl; Each R １１０ are independently hydrogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ cycloalkyl or 5- to 12-membered heterocyclyl; Each R １２０ are independently hydrogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ cycloalkyl or 5- to 12-membered heterocyclyl; and q is an integer from 0 to 20.

73. The compound of any one of claims 1 to 72, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which is

75. L １ But the formula: -Y １０ -(CHR １３０ ) ｎ’ -Y ２０ -(CHR １４０ ) ｎ” -Y ３０ -(CHR １５０ ) ｍ” -Y ４０ -(CHR １６０ ) ｐ -Y ５０ -(CHR １７０ ) ｐ’ -Y ６０ - [In the formula, Each Y １０ , Y ２０ , Y ３０ , Y ４０ , Y ５０ and Y ６０ are independently -(W) ｓ -, 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) ２ NR １１０ -, -NR １１０ S (O) ２ NR １１０ -, -CR １２０ = N-NR １１０ -, -NR １１０ -N=CR １２０ -, -C(O)-, -OC(O)-, -OC(O)O-, -(CH ２ CH ２ O) １～５ -, -C(O)O-,C １～１２ Alkylene, C ２～１２ Alkenylene, C ２～１２ Alkynylene, C ６～１２ Arylene, C ３～１２ cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12-membered heteroarylene, each of which is represented by —OH, —NH ２ , -CN, oxo, halo, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ is independently optionally substituted with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl; Each W is independently 【Chemical 222】 and R ｎ are independently expressed as H, C for each occurrence. １～４ Alkyl or C １～４ haloalkyl, and R ｗ are independently expressed as H, C for each occurrence. ３～１２ Cycloalkyl, C ６～１２ aryl (optionally substituted with one or more of halo or OH) or C １～４ alkyl (one or more independently selected halo, OH, —SH, —S(C １～４ alkyl), -CONH ２ , -COOH, -NHC(=NH)NH ２ , -NH ２ , -NHCOCH ３ , -NHCHO, -NHCONH ２ , C ６～１２ optionally substituted by aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl; Each R １１０ , R １２０ , R １３０ , R １４０ , R １５０ , R １６０ and R １７０ are independently hydrogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ cycloalkyl or 5- to 12-membered heterocyclyl, each of which is —OH, —NH ２ , -CN, oxo, halo, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ is independently optionally substituted with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl; n', n", m", s, p and p' are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.

73. The compound of any one of claims 1 to 72, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which is

76. L １ But the formula: -Y １０ -(CHR １３０ ) ｎ’ -Y ２０ -(CHR １４０ ) ｎ” -Y ３０ -(CHR １５０ ) ｍ” -Y ４０ - [In the formula, Each Y １０ , Y ２０ , Y ３０ and Y ４０ are independently a 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) ２ NR １１０ -, -NR １１０ S (O) ２ NR １１０ -, -CR １２０ = N-NR １１０ -, -NR １１０ -N=CR １２０ -, -C(O)-, -OC(O)-, -OC(O)O-, -(CH ２ CH ２ O) １～５ -, -C(O)O-,C １～１２ Alkylene, C ２～１２ Alkenylene, C ２～１２ Alkynylene, C ６～１２ Arylene, C ３～１２ cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12-membered heteroarylene, each of which is selected from oxo, halo, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy or C １～４ and independently optionally substituted with one or more substituents independently selected from haloalkoxy; Each R １１０ are independently hydrogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ cycloalkyl or 5- to 12-membered heterocyclyl; Each R １２０ are independently hydrogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ cycloalkyl or 5- to 12-membered heterocyclyl; Each R １３０ are independently hydrogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ cycloalkyl or 5- to 12-membered heterocyclyl; Each R １４０ are independently hydrogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ cycloalkyl or 5- to 12-membered heterocyclyl; Each R １５０ are independently hydrogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ cycloalkyl or 5- to 12-membered heterocyclyl; n', n" and m" are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.

73. The compound of any one of claims 1 to 72, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which is

77. L １ But the formula: -L ２ -L ３ -[y1-L ４ -[y2-L ５ -L ６ - [In the formula, Each L ２ , L ３ , L ４ L ５ and L ６ are independently a bond, C １～１２ alkylene, —O—, —NHC(═O)—, —C(═O)NH—, —C(═O)—O—, —O—C(═O)— or C═O, １～１２ one or more carbon atoms in the alkylene are optionally replaced by oxygen; Cy1 and Cy2 each independently represent a bond, C ６～１２ Arylene, C ３～１２ cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12-membered heteroarylene, each of which is represented by —OH, —NH ２ , -CN, oxo, halo, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ and optionally substituted independently with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl.

73. The compound of any one of claims 1 to 72, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which is

78. Cy1 is —OH, —NH ２ , -CN, oxo, halo, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ 78. The compound of claim 77, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, which is a 5- to 12-membered heterocyclylene optionally substituted with one or more substituents independently selected from cycloalkyl and 5- to 12-membered heterocyclyl.

79. 78. The compound of claim 77, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein Cy1 is a bond.

80. Cy2 is —OH, —NH ２ , -CN, oxo, halo, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ 80. The compound of any one of claims 77-79, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which is a 5-12 membered heterocyclylene optionally substituted with one or more substituents independently selected from cycloalkyl and 5-12 membered heterocyclyl.

81. 80. The compound of any one of claims 77-79, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, wherein Cy2 is a bond.

82. L １ But the formula: 【Chemical 223】 [In the formula, Each L ２ , L ３ and L ４ are independently a bond, C １～１２ alkylene, —NHC(═O)—, —C(═O)NH—, —C(═O)—O—, —O—C(═O)— or C═O; Each R ２００ and R ２０１ are independently halo, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ６～１２ aryl, 5- to 12-membered heteroaryl, C ３～１２ cycloalkyl and 5- to 12-membered heterocyclyl; s and s' are each independently 0, 1, 2, 3, or 4.

73. The compound of any one of claims 1 to 72, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, which is

83. The linking moiety has the formula: 【Chemical 224】 【Chemical 225】 【Chemical 226】 【Chemical 227】 【Chemical 228】 【Chemical 229】 【Chemistry 230】 【Chemistry 231】 It is of " ＊ " and a wavy or dashed line represents a covalent bond; 73. A compound according to any one of claims 1 to 72, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof.

84. The linking moiety has the formula: 【Chemical 232】 【Chemical 233】 【Chemical 234】 【Chemistry 235】 【Chemical 236】 【Chemical 237】 It is of " ＊ " and a wavy or dashed line represents a covalent bond; 83. A compound according to any one of claims 1 to 72 or 82, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof.

85. A compound selected from the compounds of Table 1, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof.

86. 86. A pharmaceutical composition comprising a compound of any one of claims 1 to 85, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analogue or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

87. 87. A method for treating cancer, comprising administering an effective amount of a compound according to claims 1 to 85, or a pharmaceutical composition according to claim 86, to an individual in need thereof.

88. The cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft tissue sarcoma, chronic lymphocytic leukemia, Wandenstrom's macroglobulinemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small cell lung carcinoma, gastric carcinoma, colon carcinoma.

88. The method of claim 87, wherein the cancer is selected from the group consisting of malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosis fungoides, head and neck carcinoma, osteosarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenocortical carcinoma, skin cancer, trophoblastic neoplasm, and prostate carcinoma.

Images