Compounds for targeted therapy of castration-resistant prostate cancer

Abstract

Provided is a tetracyclic compound useful for the treatment of cancer, particularly castration-resistant prostate cancer. The present invention relates to a compound having the following formula: TIFF2026041733000130.tif52170 During the ceremony, TIFF2026041733000131.tif9170 is a single bond or a double bond, and when it is a single bond, X is alkyloxy, and when it is a double bond, X is O, S, NH, etc. R2: H or methyl. R5: H, alkyl, alkenyl, etc. R1: H and R6: H, alkyl, hydroxyethyl, or R1: methyl and R6: H, ethyl, hydroxyethyl.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application is a continuation of U.S. Provisional Application No. 62 / 811,747, filed February 28, 2019. No. 60 / 699,493, filed on Dec. 1, 2003, the contents of which are incorporated herein by reference in their entirety into this disclosure. It can be enjoyed.

[0002] The present invention relates generally to novel compounds for therapeutic use. In particular, the present disclosure relates to compounds for the treatment of cancer The present invention relates to novel tetracyclic compounds useful in the treatment of castration-resistant prostate cancer. and pharmaceutical compositions containing therapeutically effective amounts of such compounds alone, together with other therapeutic agents, and Also described herein are methods for treating cancer patients by administering the compound in a pharmaceutical composition. It is written in the book. [Background technology]

[0003] This section introduces aspects that may help facilitate a better understanding of the present disclosure. Accordingly, these statements should be read in this light, but It should not be understood as an admission about what is or is not.

[0004] Prostate cancer is the most common malignancy in older men and accounts for 100% of the total number of men in the United States. The majority of prostate cancers are caused by a condition known as prostate cancer. androgens (e.g., testosterone) for patients with advanced prostate cancer However, early treatment is dependent on androgen deprivation therapy (ADT), which is the mainstay of treatment. Despite this, prostate cancer almost always develops resistance to androgen deprivation. This is called castration-resistant prostate cancer (CRPC). There is an unmet medical need for more effective treatments. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention relates generally to novel compounds for therapeutic use. In particular, the present disclosure relates to compounds for the treatment of cancer , and relates to novel tetracyclic compounds useful in the treatment of castration-resistant prostate cancer.

[0006] Pharmaceutical compositions of such compounds, and therapeutically effective amounts of such compounds alone or in combination with other therapeutic agents Methods for treating cancer patients by administering are also described herein. [Means for solving the problem]

[0007] In some exemplary embodiments, the present invention provides a compound having formula (I) or a pharmaceutical Regarding physiologically acceptable salts: [ka] During the ceremony, [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen, C1-C6 alkyl, alkenyl or alkyl. Nil, R3 is hydrogen, hydroxyl, thiol, halo, azido, nitro, cyano, alkyl, Alkenyl, alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, Aminoalkyl, thiolalkyl, mercaptoalkyl, heteroalkyl, heteroalkenyl alkynyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cyclo cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, aryl arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally replaced with the selection, R4 is hydrogen, hydroxyl, halo, azido, nitro, cyano, alkyl, alkenyl , alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, aminoalkynyl alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cyclo Alkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl , aryl, heteroaryl, arylalkyl, arylalkenyl, or aryl alkynyl, each of which is optionally substituted.

[0008] In some exemplary embodiments, the present invention provides a compound having formula (II) or a pharmaceutical Regarding physiologically acceptable salts: [ka] During the ceremony, [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen, C1-C6 alkyl, alkenyl or alkyl. Nil, R3 is hydrogen, hydroxyl, thiol, halo, azido, nitro, cyano, alkyl, Alkenyl, alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, Aminoalkyl, thiolalkyl, mercaptoalkyl, heteroalkyl, heteroalkenyl alkynyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cyclo cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, aryl arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally replaced with the selection, R6 is hydrogen, alkyl, alkenyl, alkynyl, alkylalkynyl, alkylo hydroxyalkyl, aminoalkyl, heteroalkyl, heteroalkenyl, hete alkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkynyl, alkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl , arylalkenyl, or arylalkynyl, each of which is optionally substituted. can be.

[0009] In some exemplary embodiments, the present invention provides a compound having formula (III) or Regarding pharmaceutically acceptable salts: [ka] During the ceremony, [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen, C1-C6 alkyl, alkenyl or alkyl. Nil, R5 is hydrogen, alkyl, alkenyl, alkynyl, alkylalkynyl, hydroxy Alkyl, aminoalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, Heterocycyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cyclohexene Alkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkene aryl, or arylalkynyl, each of which is optionally substituted; R6 is hydrogen, alkyl, alkenyl, alkynyl, alkylalkynyl, alkylo hydroxyalkyl, aminoalkyl, heteroalkyl, heteroalkenyl, hete alkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkynyl, alkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl , arylalkenyl, or arylalkynyl, each of which is optionally substituted. can be.

[0010] In some exemplary embodiments, the present invention provides a compound of formula (III) as disclosed herein. ) [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen or methyl; R5 is hydrogen, alkyl, alkenyl, alkynyl, alkylalkynyl, hydroxy Alkyl, aminoalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, Heterocycyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cyclohexene Alkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkene aryl, or arylalkynyl, each of which is optionally substituted; R6 is hydrogen or C1-C6 alkyl.

[0011] In some exemplary embodiments, the present invention provides a compound of formula (III) as disclosed herein. ) [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen or methyl; R5 and R6 are hydrogen.

[0012] In some exemplary embodiments, the present invention relates to a compound having the formula (III): The compounds are compounds 1 to 6 in FIG.

[0013] In some exemplary embodiments, the present invention relates to a compound having the formula (III): The compounds are compounds 15 to 22 in FIG.

[0014] In some exemplary embodiments, the present invention relates to a compound having the formula (III): The compounds are compounds 23 to 40 in FIG.

[0015] In some exemplary embodiments, the present invention provides a compound of formula (III) as disclosed herein. ) [ka] represents a double bond, and X is O, S, NH, N-OH, N-NH2, or NR7. , R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen or methyl; R5 and R6 are hydrogen.

[0016] In some exemplary embodiments, the present invention provides a compound of formula (III) as disclosed herein. ) [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen or methyl; R5 is [ka] and R6 is hydrogen.

[0017] In some exemplary embodiments, the present invention provides a compound having formula (IV) or a pharmaceutical Regarding physiologically acceptable salts: [ka] During the ceremony, [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen, C1-C6 alkyl, alkenyl or alkyl. Nil, R3 is hydrogen, hydroxyl, thiol, halo, azido, nitro, cyano, alkyl, Alkenyl, alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, Aminoalkyl, thiolalkyl, mercaptoalkyl, heteroalkyl, heteroalkenyl alkynyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cyclo cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, aryl arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally replaced with the selection, R4 is hydrogen, hydroxyl, halo, azido, nitro, cyano, alkyl, alkenyl , alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, aminoalkynyl alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cyclo Alkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl , aryl, heteroaryl, arylalkyl, arylalkenyl, or aryl alkynyl, each of which is optionally substituted.

[0018] In some exemplary embodiments, the present invention provides a compound having formula (V) or a pharmaceutical Regarding physiologically acceptable salts: [ka] During the ceremony, [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen, C1-C6 alkyl, alkenyl or alkyl. Nil, R3 is hydrogen, hydroxyl, thiol, halo, azido, nitro, cyano, alkyl, Alkenyl, alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, Aminoalkyl, thiolalkyl, mercaptoalkyl, heteroalkyl, heteroalkenyl alkynyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cyclo cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, aryl arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally replaced with the selection, R4 is hydrogen, hydroxyl, halo, azido, nitro, cyano, alkyl, alkenyl , alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, aminoalkynyl alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cyclo Alkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl , aryl, heteroaryl, arylalkyl, arylalkenyl, or aryl alkynyl, each of which is optionally substituted.

[0019] In some exemplary embodiments, the present invention provides a compound having formula (V) as disclosed herein: Regarding the compound having the formula (I), the compound is selected from compounds 7 to 14 in FIG. 2, or [ka] This includes compounds of the formula:

[0020] In some exemplary embodiments, the present invention provides a pharmaceutical composition comprising a pharmaceutical composition comprising one or more diluents, excipients, or carriers. together with one or more compounds as disclosed herein, or pharmaceutically acceptable salts thereof. The present invention relates to pharmaceutical compositions comprising salts thereof.

[0021] In some exemplary embodiments, the present invention provides one or more of the methods disclosed herein. With respect to the compound, the compound is for the treatment of cancer.

[0022] In some exemplary embodiments, the present invention provides one or more of the methods disclosed herein. With respect to the compound, the compound is for the treatment of cancer.

[0023] In some exemplary embodiments, the present invention provides one or more of the methods disclosed herein. With regard to the compounds, the compounds are for the treatment of castration-resistant prostate cancer.

[0024] In some exemplary embodiments, the present invention provides a method for treating a cancer patient, comprising: a therapeutically effective amount of one or more compounds as disclosed herein, and one or more carriers; administering the diluent or excipient to a patient in need of relief from said cancer. , relating to a method.

[0025] In some exemplary embodiments, the present invention provides a method for treating a cancer patient, comprising: a therapeutically effective amount of one or more compounds as disclosed herein, and one or more carriers; and administering the diluent or vehicle to a patient in need of relief from said castration-resistant prostate cancer. The present invention relates to a method comprising the steps of:

[0026] In some exemplary embodiments, the present invention provides a method for treating a cancer patient, comprising: and a therapeutically effective amount of one or more compounds as disclosed herein, with the same or different effects. in combination with one or more other compounds of the mechanism and one or more carriers, diluents, or excipients. and administering to a patient in need of relief from said cancer.

[0027] In some exemplary embodiments, the present invention provides a method for treating a cancer patient, comprising: and a therapeutically effective amount of one or more compounds as disclosed herein, with the same or different effects. in combination with one or more other compounds of the mechanism and one or more carriers, diluents, or excipients. and administering to a patient in need of relief from said castration-resistant prostate cancer. Regarding the method.

[0028] In some exemplary embodiments, the present invention provides a method for the treatment of cancer, comprising administering to a subject a cancer-related disease ... and , together with one or more diluents, excipients or carriers, one or more of the compounds as disclosed herein or a pharmaceutically acceptable salt thereof.

[0029] In some exemplary embodiments, the present invention provides a method for treating a cancer patient, comprising: a therapeutically effective amount of one or more compounds, together with one or more carriers, diluents, or excipients; administering to a patient in need of relief from said cancer, a compound comprising: It has the following formula or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen, C1-C6 alkyl, alkenyl or alkyl. Nil, R3 is hydrogen, hydroxyl, thiol, halo, azido, nitro, cyano, alkyl, Alkenyl, alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, Aminoalkyl, thiolalkyl, mercaptoalkyl, heteroalkyl, heteroalkenyl alkynyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cyclo cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, aryl arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally replaced with the selection, R4 is hydrogen, hydroxyl, halo, azido, nitro, cyano, alkyl, alkenyl , alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, aminoalkynyl alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cyclo Alkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl , aryl, heteroaryl, arylalkyl, arylalkenyl, or aryl alkynyl, each of which is optionally substituted.

[0030] In some exemplary embodiments, the present invention provides a method for treating a cancer patient, comprising: and a therapeutically effective amount of one or more compounds as disclosed herein, with the same or different effects. in combination with one or more other compounds of the mechanism and one or more carriers, diluents, or excipients. and administering to a patient in need of relief from said cancer, Resistant prostate cancer.

[0031] In some exemplary embodiments, the present invention relates to a drug conjugate, The conjugates comprise one or more compounds disclosed herein, and the conjugates can be used in any cell type. or tissue-type targeting, or the conjugate is a compound disclosed herein. Targeting alternative pathways that cooperate with the action of

[0032] In some exemplary embodiments, the present invention provides a pharmaceutical composition comprising a pharmaceutical composition comprising one or more diluents, excipients, or carriers. and a pharmaceutical composition comprising nanoparticles of one or more compounds disclosed herein. do.

[0033] These and other features, aspects, and advantages of the present invention are set forth in the following figures, description, and claims. It will be better understood by reference to: [Brief explanation of the drawings]

[0034] These and other objects, features, and advantages of the present invention will be discussed in conjunction with the following description and drawings. This will become clearer when the results are released. [Figure 1A-F]Figure 1 shows parent lead compounds and their anticancer activity. Figure 1A shows cell viability IC50 plots for the parent leads tibolone (TIB), norethisterone (NOR), and levonorgestrel (LEV) in LNCaP and C4-2 cells. Figure 1B shows the IC50 graph for the parent lead in the normal human prostate epithelial RWPE-1 cell line. Figure 1C shows the effect of the initial lead on the degradation of AR expression in LNCaP and C4-2 cells by Western blot. Figure 1D shows AR expression in both LNCaP and C4-2 cells quantified from Western blot. Figure 1E shows immunofluorescence staining of LNCaP and C4-2 cells for AR expression after 24 hours of treatment with 1 μM of the indicated compound. Figure 1F shows nuclear AR expression in both LNCaP and C4-2 cells quantified from the image in Figure 1E. Tibolone, norethisterone, and levonorgestrel have been identified as active, non-toxic parent leads for CRPC. [Figure 2A] The structures of the parent leads tibolone (TIB), norethisterone (NOR), and levonorgestrel (LEV) and the general parent scaffold are shown; [Figure 2B] The structures of new small molecules (1-40) are shown. [Figure 3A-F] The anticancer activity of synthetic molecules is shown. (Figure 3A) IC50 plots for synthetic molecules 1-40 and abiraterone (ABI) in the CRPC C4-2 cancer cell line. (Figure 3B) IC50 plots for active compounds and ABI in the RWPE-1 normal cell line. (Figure 3C) Western blot analysis of AR and β-actin (loading control) in C4-2 cells treated with vehicle and 1 μM active compounds for 24 h. (Figure 3D) and (Figure 3E) show the migration rate and wound closure rate, respectively, in both LNCaP and C4-2 cells in the presence of active and non-toxic compounds. Figure 3F shows the metabolic stability of the active lead after 60 min of incubation with human and mouse liver microsomes, respectively. Warfarin (WAR) is the negative control, and verapamil (VER) is the positive control in the mouse liver microsome assay. [Figure 4A-B] Immunofluorescence staining of C4-2 cells for the known target AR (Figure 4A) and expression of the identified proteomic targets RORG, SHBG, and CYP17A1 after 24 h treatment with 1 μM of the indicated compounds (Figure 4B). [Figure 5A-B] Immunofluorescence staining of C4-2 cells for known targets AR and CYP17A1 (Figure 5A) and expression of identified proteomic targets RORG and PR after 24 h treatment with 1 μM of the indicated compounds (Figure 5B). [Figure 6A-B] Immunofluorescence staining of C4-2 cells for the known target AR (Fig. 6A) and expression of the identified proteomic targets RORG and PR after 24 h treatment with 1 μM of the indicated compounds (Fig. 6B). [Figure 7A-C] LuCaP35 CRPC study for potent, non-toxic lead compound 1. (FIG. 7A) Schematic representation of the LUCaP35 CRPC mouse model study. (FIG. 7B) Mean tumor size plot for various treatments on LuCaP35 CRPC mice. (FIG. 7C) Mean percent weight change for all types of treated mice. Synthetic lead 1 was more potent than the known drug abiraterone in the LuCaP35 CRPC model. DETAILED DESCRIPTION OF THE INVENTION

[0035] For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to the embodiments illustrated in the drawings. Certain terms will be used to describe them. It will nevertheless be understood that no limitation of the scope of the disclosure is thereby intended.

[0036] As used herein, the following terms and phrases shall have the meanings set forth below: Unless otherwise defined, all technical and scientific terms used herein has the same meaning as commonly understood by one of ordinary skill in the art.

[0037] In this disclosure, the term "about" refers to the degree of variation in a value or range, e.g., the published Expect to be within 10%, 5%, or 1% of the published limits of the stated value or range. In this disclosure, the term "substantially" refers to the degree of variation in a value or range. For example, within 90%, 95%, or or within 99%.

[0038] In this document, the terms "a," "an," or "the" are used interchangeably unless the context clearly dictates otherwise. The term "or" is used to include one or more unless otherwise indicated. It is used to refer to an exclusive "or." In addition, as used herein and unless otherwise defined, The phraseology and terminology used herein is for descriptive purposes only and not for limiting purposes. , understood. The optional use of section headings is intended to aid in the reading of the document. Furthermore, the information related to the section headings Information may occur within or outside that particular section. All publications, patents, and patent documents are hereby incorporated by reference as if individually incorporated by reference. This document and those incorporated by reference are incorporated herein by reference in their entirety. In the event of inconsistent usage between the document and the It is considered a supplement to that of this document and in the event of any incompatible differences, the terms of this document shall be used in their entirety. Usage takes precedence.

[0039] "Halogen" means F, Cl, Br or I. "Halogen substituted" or "halo" "Substituted" means replacement of one or more halogen atoms with F, Cl, Br or I.

[0040] As used herein, the term "alkyl" refers to a carbon-containing alkyl group, which may be optionally branched. For embodiments containing alkyl, exemplary variables for those embodiments are: Examples of forms are lower alkyl groups such as C1-C6 alkyl, methyl, ethyl, propyl, and 3-methylpentyl. It is understood that this includes dialkyl.

[0041] As used herein, the term "alkenyl" refers to a group that is optionally branched. It refers to an unsaturated monovalent chain of carbon atoms containing at least one double bond. In these embodiments, exemplary variations include C2-C6, C2-C4 alkenyl, etc. It is understood to include lower alkenyl.

[0042] As used herein, the term "alkynyl" refers to a group that is optionally branched. It refers to an unsaturated monovalent chain of carbon atoms containing at least one triple bond. In some embodiments, exemplary variations of these embodiments include C2-C6, C2-C4 alkynyl, etc. It is understood that the term "alkynyl" includes lower alkynyl of the formula:

[0043] As used herein, the term "cycloalkyl" refers to a monovalent chain of carbon atoms, In embodiments containing cycloalkyl, a portion of the group forms a ring. Suitable variations include C3-C8 cycloalkyl, cyclopropyl, cyclohexyl, 3-ethyl It is understood to include lower cycloalkyl such as cyclopentyl.

[0044] As used herein, the term "cycloalkenyl" refers to an unsaturated monovalent chain of carbon atoms. In embodiments containing cycloalkenyl, those embodiments are Exemplary variations of this embodiment include lower cycloalkenyls such as C3-C8 and C3-C6 cycloalkenyls. It is understood that alkynyl is included.

[0045] As used herein, the term "alkylene" refers to a carbonyl group that may be optionally branched. In embodiments containing alkylene, an exemplary alkylene group is Suitable variations include C2-C4 alkylene, methylene, ethylene, propylene, 3-methylpentene, It is understood to include lower alkylenes such as ethylene.

[0046] Alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkylene, and polyalkylenes Each of the rings may be selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboalkyl, carboxylic acids and their derivatives, including esters, amides, and nitrites; Alkoxy, acyloxy, amino, alky and dialkylamino, acyl Optionally, independently selected groups such as amino, thio, and the like, as well as combinations thereof. It is understood that alternatives can be substituted.

[0047] As used herein, the term "heterocyclic" or "heterocycle" refers to a carbon and heterocycle. refers to a monovalent chain of atoms, heteroatoms are selected from nitrogen, oxygen, and sulfur, some of which are At least one heteroatom forms a ring. The term "heterocycle" includes "aromatic heterocycle" and Heterocycles include both "aromatic heterocycles" and "non-aromatic heterocycles." Heterocycles include imidazolyl, thiazolyl, oxazolyl, Zolyl, oxazinyl, thiazinyl, dithianil, dioxanyl, isoxazolyl, iso Thiazolyl, triazolyl, furanyl, tetrahydrofuranyl, dihydrofuranyl, pyrazolyl nyl, tetrazolyl, pyrazolyl, pyrazinyl, pyridazinyl, imidazolyl, pyridinyl pyrrolyl, dihydropyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrimidinyl thiophenyl, azetidinyl, oxazolidinyl, morpholinyl, tetrahydrothiophenyl, thiophenyl, azetidinyl, oxazolidinyl 4- to 7-membered monocyclic rings and 8- to 9-membered monocyclic rings such as cetyl, thiiranyl, oxiranyl, and aziridinyl 12 Bicyclic rings. A "heterocycle" is a ring in which any one or more positions can have a hydrogen atom. The .alpha.-substituted ...

[0048] As used herein, the term "aryl" refers to monocyclic and polycyclic aromatic carbocyclic rings. groups, each of which may be optionally substituted. The term "optionally substituted aryl" is halo, hydroxyl, amino, alkyl, or alkoxy, alkylsulfonyl (a alkylsulfony), cyano, nitro, or one or more independently selected substituents. aromatic monocyclic or cyclic rings of carbon atoms, such as phenyl, naphthyl, which may be more optionally substituted; refers to a polycyclic ring.

[0049] The term "heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic monocyclic ring. The ring structure preferably contains a 5- to 7-membered ring, more preferably a 5- or 6-membered ring, and the ring structure contains at least Each of the heteroatoms has one heteroatom, preferably one to four heteroatoms, more preferably one or two The term "heteroaryl" also refers to a ring having one or two heteroatoms. The system may include a ring system in which at least one of the rings is heteroaromatic, e.g., the other cyclic ring is , cycloalkyl, cycloalkenyl, cycloalkynyl, aromatic carbocycle, heteroaryl Heteroaryl groups can be, without limitation, pyridyl, N- Oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, chiral Noryl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyryl, o oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl Zolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, iridazolyl Sothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, India In some embodiments, heteroaryl groups include 1 to about 20 carbon atoms, and the like. In further embodiments, the alkyl group has from about 3 to about 20 carbon atoms. In certain embodiments, the heteroaryl group has 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or or 1 to 2 hetero atoms.

[0050] In some embodiments, a "heterocycloalkyl" can have one or more of the ring-forming atoms. is a heteroatom such as an O, N, or S atom. The alkyl group may be monocyclic or polycyclic (e.g., 2, 3, or 4 rings), as well as spirocyclic. Exemplary heterocycloalkyl groups include morphoalkyl groups, morphoalkyl groups, and morphoalkyl groups. thionyl, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-Dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxol San, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazo Heterozygous groups include azolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Also included in the definition of chloroalkyl are non-aromatic heterocyclic rings, such as phthalimidazole. benzo derivatives of heterocyclic rings fused to one or more aromatic rings A heterocycloalkyl group having one or more fused aromatic rings is a moiety having an aromatic ring. Either aromatic or non-aromatic moieties may be attached.

[0051] The terms "optionally substituted" or "optional substituents" as used herein If present, it may be unsubstituted or substituted with one or more of the specified substituents. When the group in question is substituted with two or more substituents, the substituents may be the same or Furthermore, the terms "independently" and "independently" "Independently are" and "Independently selected from" "Pendently selected from" means that the groups in question are the same or Some of the terms defined herein may be different. , occur more than once in a structure, and on such occurrence, each word is defined independently of the other. It should be.

[0052] The term "patient" refers to any animal, including humans, companion animals (such as dogs and cats), and livestock animals. This includes non-human animals. Livestock animals are animals raised for food production. or mammals, particularly humans.

[0053] The term "pharmaceutically acceptable carrier" is art-recognized and refers to any compound of interest. A liquid or solid filler involved in carrying or transporting an object or its components , pharmaceutically acceptable materials, compositions, such as diluents, excipients, solvents or encapsulating materials Each carrier is defined as being compatible with the subject composition and its components. Pharmaceutically acceptable substances must be "acceptable" in the intended use and not harmful to the patient. Some examples of materials that can serve as carriers are: (1) lactose, glucose, and sucrose. (2) sugars such as corn starch and potato starch; (3) Cellulose, as well as sodium carboxymethylcellulose, ethylcellulose (4) powdered tragacanth; (5) malt; (6) gelatin, (7) talc, (8) excipients such as cocoa butter and suppository wax, ( 9) Peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and Oils such as soybean oil, (10) glycols such as propylene glycol, (11) glycerin polyols such as ethanol, sorbitol, mannitol and polyethylene glycol; 2) esters such as ethyl oleate and ethyl laurate, (13) agar, (14) buffering agents such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (1 6) Pyrogen-free water, (17) Isotonic saline, (18) Ringer's solution, (19) Ethyl Alcohol, (20) phosphate buffer solution, (21) other non-toxic compatible substances used in pharmaceutical preparations Contains substances.

[0054] As used herein, the term "administering" includes oral (po), intravenous (iv), , intramuscular (im), subcutaneous (sc), transdermal, inhalation, oral, ocular, sublingual, vaginal, rectal, etc. introducing the compounds and compositions described herein into a patient, including, but not limited to, The compounds and compositions described herein can be administered by conventional non-toxic pharmaceutical and / or may be administered in a formulation.

[0055] Solid pharmaceutical forms include calcium carbonate, calcium phosphate, sodium phosphate, lactate Starch, Mannitol, Alginate, Gelatin, Guar Gum, Stearic Acid Maize Magnesium, aluminum stearate, methylcellulose, talc, highly dispersed silicic acid, silica Corn oil, high molecular weight fatty acids (such as stearic acid), gelatin, agar or vegetable or are animal fats or oils, or solid high molecular weight polymers (such as polyethylene glycol) ) and carrier materials, and is suitable for oral administration. The product may contain additional flavorings and / or sweeteners, if desired.

[0056] Liquid pharmaceutical forms may be sterilized and / or contain, where appropriate, preservatives, stabilizers, wetting agents, etc. , osmotic agents, emulsifiers, diffusing agents, solubilizers, salts, for adjusting osmotic pressure or buffering The composition may contain auxiliary substances such as sugars or sugar alcohols for the preparation of the emulsion, and / or viscosity adjusting agents. Examples of such additives are tartaric acid and citrate buffers, ethanol and sequestering agents (ethyl acetate). Liquid polyethylene oxide, microcrystalline Cellulose, carboxymethylcellulose, polyvinylpyrrolidone, dextran or High molecular weight polymers such as gelatin are suitable for adjusting viscosity. Examples of solid carrier materials Starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acid, High molecular weight fatty acids (stearic acid, etc.), gelatin, agar, calcium phosphate, stearin Solids such as magnesium hydroxide, animal and vegetable fats, and polyethylene glycol It is a high molecular weight polymer.

[0057] Oil suspensions for parenteral or topical application are in each case prepared from fatty acids with 8 to 22 carbon atoms in the fatty acid chain. Vegetable synthetic or semi-synthetic oils such as liquid fatty acid esters containing hydrogen atoms, e.g., palmitoyl Acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, arachidic acid, Stearic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brassidic acid (br acid), erucic acid, or oleic acid, which can be , ethanol, propanol, butanol, pentanol or their isomers, glycol Monovalent to trivalent alcohols with 1 to 6 carbon atoms, such as ethanol or glycerol Examples of such fatty acid esters are, inter alia, the commercially available Miglyol (miglyol), isopropyl myristate, isopropyl palmitate, isopropyl Pyrstearate, PEG-6-caprate, saturated fatty alcohol caprylic / capric acid Esters, Polyoxyethylene Glycerol Trioleate, Ethyl Oleate, Artificial Da Artificial ducktail gland fat Waxy fatty acid esters, coconut fatty acid isopropyl esters, oleyl oleate ester, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl acrylate Dipartite, polyol fatty acid ester. Silicone oil of different viscosity, or isotonic acid. decyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or Fatty alcohols such as oleyl alcohol or fatty acids such as oleic acid are also suitable. In addition, castor oil, almond oil, olive oil, sesame oil, cottonseed oil, and peanut oil It is possible to use vegetable oils such as soybean oil.

[0058] The preferred solvents, gelatinizing agents and solubilizing agents are water or water-miscible solvents. Examples of solvents are alcohols such as ethanol or isopropyl alcohol, benzyl alcohol, ethanol, 2-octyldodecanol, polyethylene glycol, phthalate, adipate, Propylene glycol, glycerol, di- or tri-propylene glycol, wax, Methyl cellosolve, cellosolve, ester, morpholine, dioxane, dimethyl sulfoxide These include cyclohexanone, dimethylformamide, tetrahydrofuran, and cyclohexanone.

[0059] Mixtures of gelatinizing agents and film-forming agents are also entirely possible. In this case, in particular , sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and the like These salts, sodium amylopectin semiglycolate (sodium salt) um amylopectin semiglycolate), alginate or pro Pyrene glycol alginate, gum arabic, xanthan gum, guar gum or carrot The use of geenan is made. The following may be used as additional formulation adjuvants: glycerol paraffin of different viscosities, triethanolamine, collagen, allantoin, Novantisolic acid. Surfactant, emulsifier or humectant. Lubricants, such as sodium lauryl sulfate, fatty alcohol ether sulfate, disodium -N-Lauryl-iminodipropionate, polyethoxylated castor oil or sorbitan Monooleate, sorbitan monostearate, polysorbates (e.g., Tween) , cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene Tealate, alkylphenol polyglycol ether, cetyl chloride trimethylammonium Sodium or mono- / dialkyl polyglycol ether orthophosphate monoethanolamine Antioxidants, such as amine salts, may also be required in the formulation to stabilize emulsions or to provide antioxidants, e.g. For example, active substances such as tocopherol or butylated hydroxyanisole, or p-hydroxyanisole Montmorillonite or cobalt to prevent decomposition of preservatives such as hydroxybenzoates Stabilizers such as silicic acid may likewise be used to prepare the desired formulation.

[0060] Preparations for parenteral administration are presented in discrete dosage units such as ampoules or vials. Preferably, solutions of the active compound are obtained, preferably aqueous solutions, and in particular isotonic solutions, and These injection forms are available as ready-to-use preparations. or immediately before use, containing the active compound, e.g., other solid carrier materials, if desired. The resulting lyophilisate is mixed with the desired solvent or suspending agent. It can only be prepared by

[0061] Intranasal preparations may be administered as aqueous or oily solutions or as aqueous or oily suspensions. They may also be prepared using a suitable solvent or suspending agent before use. It may exist as a lyophilizate.

[0062] The inhalable preparation may be present as a powder, a solution or a suspension. The preparation may be in powder form, for example, as a mixture of the active ingredient with a suitable formulation such as lactose. It is in this state.

[0063] The preparation is produced, portioned and sealed under customary high microbial and aseptic conditions.

[0064] As noted above, the compounds of the present invention may be used in combination with additional active agents, such as those for treating cancer, e.g., prostate COMBINATION THERAPY USING THERAPEUTIC ACTIVE COMPOUNDS USEFUL IN THE TREATMENT OF CARCINOMA, OVXANIA, LUNG, OR BREAST CANCER - Patent application For combination therapy, the active ingredients may be administered in several doses in a single dosage form. as a composition containing the active ingredient and / or as individual active ingredients in separate dosage forms. The active ingredients used in the combination therapy may be formulated as a kit containing: They may be administered simultaneously or separately.

[0065] The total daily dosage of the compounds and compositions described herein is determined within the scope of sound medical judgment. The particular therapeutically effective dose level for any particular patient can be determined by the attending physician within the The disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition of the drug; the patient's age, weight, general health, sex, and diet; the time of administration and use The excretion rate of the specific compound used, the duration of treatment, and the specific compound and combination used drugs used in conjunction with or in combination with other drugs; researchers, veterinarians, physicians, or other clinical professionals in the field The amount of time that the dose will vary will depend on similar factors well known to medical practitioners.

[0066] Depending on the route of administration, doses ranging from about 1 μg / kg to about 1 g / kg are included. A wide range of acceptable dosages is contemplated. Doses may be single or divided, qd ., bid, tid, or even every other day, once a week, once a month, etc. It may be administered according to a variety of dosing protocols. The therapeutically effective amount corresponds to an example of administration, or alternatively, corresponds to a total daily, weekly, or monthly dose. do.

[0067] As used herein, a "therapeutically effective amount" refers to a therapeutically effective amount that can be administered to a researcher, veterinarian, physician, or other clinician. a tissue system, including alleviation of symptoms of the disease or disorder being treated, An active compound or pharmaceutical agent that elicits a biological or medical response in animals or humans In one aspect, a therapeutically effective amount refers to that amount of an agent. It can treat or alleviate a disease or a symptom of a disease with a benefit / risk ratio .

[0068] As used herein, the term "therapeutically effective amount" refers to the amount administered to a patient, This may be based on the area, patient weight, and / or patient condition. The correlation of the dosages determined in the study with those determined for animals, including test animals. That a relationship exists (based illustratively on milligrams per square meter of body surface): Understood, Freireich, EJ, et al., Cancer Chemot Her. Rep. 1966, 50(4), 219, the disclosure of which is incorporated herein by reference. Body surface area can be approximately determined from the patient's height and weight. (e.g., Scientific Tables, Geigy Pharmaceut icals, Ardley, New York, pages 537-538 (1970 )). A therapeutically effective amount of the compounds described herein can be used to treat malignant cells or cancer a population of cells found in a patient in need of relief from such cancer or malignancy. It can be defined as any amount useful for inhibiting the growth (or death) of a population, such as Typically, such an effective amount is about 5 mg / kg to about 500 mg / kg of patient body weight. g, about 5 mg / kg to about 250 mg / kg, and / or about 5 mg / kg to about 150 mg The effective amount is in the range of 1000 mg / kg of compound. The effective amount also depends on the route of administration, the optional excipients used, and treatment with other conventional and non-conventional therapies, including other anti-tumor agents, radiation therapy, etc. The dosage may vary depending on the possibility of simultaneous use of the compounds.

[0069] The present invention relates generally to novel compounds for therapeutic use. In particular, the present disclosure relates to compounds for the treatment of cancer , and relates to novel tetracyclic compounds useful in the treatment of castration-resistant prostate cancer.

[0070] Pharmaceutical compositions of such compounds, and therapeutically effective amounts of such compounds alone or in combination with other therapeutic agents Methods for treating cancer patients by administering are also described herein.

[0071] In some exemplary embodiments, the present invention provides a compound having formula (I) or a pharmaceutical Regarding physiologically acceptable salts: [ka] During the ceremony, [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen, C1-C6 alkyl, alkenyl or alkyl. Nil, R3 is hydrogen, hydroxyl, thiol, halo, azido, nitro, cyano, alkyl, Alkenyl, alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, Aminoalkyl, thiolalkyl, mercaptoalkyl, heteroalkyl, heteroalkenyl alkynyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cyclo cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, aryl arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally replaced with the selection, R4 is hydrogen, hydroxyl, halo, azido, nitro, cyano, alkyl, alkenyl , alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, aminoalkynyl alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cyclo Alkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl , aryl, heteroaryl, arylalkyl, arylalkenyl, or aryl alkynyl, each of which is optionally substituted.

[0072] In some exemplary embodiments, the present invention provides a compound having formula (II) or a pharmaceutical Regarding physiologically acceptable salts: [ka] During the ceremony, [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen, C1-C6 alkyl, alkenyl or alkyl. Nil, R3 is hydrogen, hydroxyl, thiol, halo, azido, nitro, cyano, alkyl, Alkenyl, alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, Aminoalkyl, thiolalkyl, mercaptoalkyl, heteroalkyl, heteroalkenyl alkynyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cyclo cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, aryl arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally replaced with the selection, R6 is hydrogen, alkyl, alkenyl, alkynyl, alkylalkynyl, alkylo hydroxyalkyl, aminoalkyl, heteroalkyl, heteroalkenyl, hete alkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkynyl, alkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl , arylalkenyl, or arylalkynyl, each of which is optionally substituted. can be.

[0073] In some exemplary embodiments, the present invention provides a compound having formula (III) or Regarding pharmaceutically acceptable salts: [ka] During the ceremony, [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen, C1-C6 alkyl, alkenyl or alkyl. Nil, R5 is hydrogen, alkyl, alkenyl, alkynyl, alkylalkynyl, hydroxy Alkyl, aminoalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, Heterocycyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cyclohexene Alkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkene aryl, or arylalkynyl, each of which is optionally substituted; R6 is hydrogen, alkyl, alkenyl, alkynyl, alkylalkynyl, alkylo hydroxyalkyl, aminoalkyl, heteroalkyl, heteroalkenyl, hete alkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkynyl, alkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl , arylalkenyl, or arylalkynyl, each of which is optionally substituted. can be.

[0074] In some exemplary embodiments, the present invention provides a compound of formula (III) as disclosed herein. ) [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen or methyl; R5 is hydrogen, alkyl, alkenyl, alkynyl, alkylalkynyl, hydroxy Alkyl, aminoalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, Heterocycyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cyclohexene Alkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkene aryl, or arylalkynyl, each of which is optionally substituted; R6 is hydrogen or C1-C6 alkyl.

[0075] In some exemplary embodiments, the present invention provides a compound of formula (III) as disclosed herein. ) [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen or methyl; R5 and R6 are hydrogen.

[0076] In some exemplary embodiments, the present invention relates to a compound having the formula (III): The compounds are compounds 1 to 6 in FIG.

[0077] In some exemplary embodiments, the present invention relates to a compound having the formula (III): The compounds are compounds 15 to 22 in FIG.

[0078] In some exemplary embodiments, the present invention relates to a compound having the formula (III): The compounds are compounds 23 to 40 in FIG.

[0079] In some exemplary embodiments, the present invention provides a compound of formula (III) as disclosed herein. ) [ka] represents a double bond, and X is O, S, NH, N-OH, N-NH2, or NR7. , R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen or methyl; R5 and R6 are hydrogen.

[0080] In some exemplary embodiments, the present invention provides a compound of formula (III) as disclosed herein. ) [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen or methyl; R5 is [ka] and R6 is hydrogen.

[0081] In some exemplary embodiments, the present invention provides a compound having formula (IV) or a pharmaceutical Regarding physiologically acceptable salts: [ka] During the ceremony, [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen, C1-C6 alkyl, alkenyl or alkyl. Nil, R3 is hydrogen, hydroxyl, thiol, halo, azido, nitro, cyano, alkyl, Alkenyl, alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, Aminoalkyl, thiolalkyl, mercaptoalkyl, heteroalkyl, heteroalkenyl alkynyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cyclo cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, aryl arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally replaced with the selection, R4 is hydrogen, hydroxyl, halo, azido, nitro, cyano, alkyl, alkenyl , alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, aminoalkynyl alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cyclo Alkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl , aryl, heteroaryl, arylalkyl, arylalkenyl, or aryl alkynyl, each of which is optionally substituted.

[0082] In some exemplary embodiments, the present invention provides a compound having formula (V) or a pharmaceutical Regarding physiologically acceptable salts: [ka] During the ceremony, [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen, C1-C6 alkyl, alkenyl or alkyl. Nil, R3 is hydrogen, hydroxyl, thiol, halo, azido, nitro, cyano, alkyl, Alkenyl, alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, Aminoalkyl, thiolalkyl, mercaptoalkyl, heteroalkyl, heteroalkenyl alkynyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cyclo cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, aryl arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally replaced with the selection, R4 is hydrogen, hydroxyl, halo, azido, nitro, cyano, alkyl, alkenyl , alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, aminoalkynyl alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cyclo Alkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl , aryl, heteroaryl, arylalkyl, arylalkenyl, or aryl alkynyl, each of which is optionally substituted.

[0083] In some exemplary embodiments, the present invention provides a compound having formula (V) as disclosed herein: Regarding the compound having the formula (I), the compound is selected from compounds 7 to 14 in FIG. 2, or [ka] This includes compounds of the formula:

[0084] In some exemplary embodiments, the present invention provides a compound having formula (I) as disclosed herein: For compounds having [ka] TIFF2026041733000071.tif168170 TIFF2026041733000072.tif170170 TIFF2026041733000073.tif140170 TIFF2026041733000074.tif170170 TIFF2026041733000075.tif161170 TIFF2026041733000076.tif183170 TIFF2026041733000077.tif178170 TIFF2026041733000078.tif161170 TIFF2026041733000079.tif174170 is.

[0085] In some exemplary embodiments, the present invention provides a pharmaceutical composition comprising a pharmaceutical composition in combination with one or more diluents, excipients, or carriers. together with one or more compounds as disclosed herein, or pharmaceutically acceptable salts thereof. The present invention relates to pharmaceutical compositions comprising the salts.

[0086] In some exemplary embodiments, the present invention provides a method for treating a cancer cell comprising administering to a patient a cancer treatment agent comprising one or more chemical compounds as disclosed herein. With respect to the compound, the compound is for the treatment of cancer.

[0087] In some exemplary embodiments, the present invention provides a method for treating a cancer cell comprising administering to a patient a cancer treatment agent comprising one or more chemical compounds as disclosed herein. With respect to the compound, the compound is for the treatment of cancer.

[0088] In some exemplary embodiments, the present invention provides a method for treating a cancer cell comprising administering to a patient a cancer treatment agent comprising one or more chemical compounds as disclosed herein. With respect to the compound, the compound is for the treatment of castration-resistant prostate cancer.

[0089] In some exemplary embodiments, the present invention provides a method for treating a cancer patient, comprising: a therapeutically effective amount of one or more compounds as disclosed herein, and one or more carriers, diluents administering the agent, or excipient, to a patient in need of relief from said cancer. Regarding the law.

[0090] In some exemplary embodiments, the present invention provides a method for treating a cancer patient, comprising: a therapeutically effective amount of one or more compounds as disclosed herein, and one or more carriers, and administering the compound, or a vehicle, to a patient in need of relief from said castration-resistant prostate cancer. The present invention relates to a method comprising the steps of:

[0091] In some exemplary embodiments, the present invention provides a method for treating a cancer patient, comprising: a therapeutically effective amount of one or more compounds as disclosed herein, having the same or different mechanisms of action, in combination with one or more other compounds of the preceding paragraph and one or more carriers, diluents, or excipients. to a patient in need of relief from said cancer.

[0092] In some exemplary embodiments, the present invention provides a method for treating a cancer patient, comprising: a therapeutically effective amount of one or more compounds as disclosed herein, having the same or different mechanisms of action, in combination with one or more other compounds of the preceding paragraph and one or more carriers, diluents, or excipients. to a patient in need of relief from said castration-resistant prostate cancer. Regarding.

[0093] In some exemplary embodiments, the present invention provides a method for the treatment of cancer, comprising administering to a subject a cancer-related disease ... and , together with one or more diluents, excipients or carriers, one or more of the compounds as disclosed herein The present invention relates to a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof.

[0094] In some exemplary embodiments, the present invention provides a method for treating a cancer patient, comprising: a therapeutically effective amount of one or more compounds, together with one or more carriers, diluents, or excipients, 20. The method of claim 19, comprising administering to a patient in need of relief from cancer, the compound comprising: It has the following formula: [ka] During the ceremony, [ka] represents a single or double bond, [ka] represents a single bond, X is hydroxyl or alkyloxy, or [ka] represents a double bond, X is O, S, NH, N-OH, N-NH2, or NR7 and R7 is C1-C6 alkyl; R1 and R2 are independently hydrogen, C1-C6 alkyl, alkenyl or alkyl. Nil, R3 is hydrogen, hydroxyl, thiol, halo, azido, nitro, cyano, alkyl, Alkenyl, alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, Aminoalkyl, thiolalkyl, mercaptoalkyl, heteroalkyl, heteroalkenyl alkynyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cyclo cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, aryl arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally replaced with the selection, R4 is hydrogen, hydroxyl, halo, azido, nitro, cyano, alkyl, alkenyl , alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, aminoalkynyl alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cyclo Alkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl , aryl, heteroaryl, arylalkyl, arylalkenyl, or aryl alkynyl, each of which is optionally substituted.

[0095] In some exemplary embodiments, the present invention provides a method for treating a cancer patient, comprising: a therapeutically effective amount of one or more compounds as disclosed herein, having the same or different mechanisms of action, in combination with one or more other compounds of the preceding paragraph and one or more carriers, diluents, or excipients, administering to a patient in need of relief from said cancer, It's prostate cancer.

[0096] Use the CANDO calculator to determine whether your risk of castration-resistant prostate cancer (CRPC) is high or low. or interact with a subset of targets known to be overexpressed therein, Ten human-approved drugs, namely azaperone (AZA), buspirone (BUS), Cinnarizine (CIN), talampicillin (TAL), pipamperon (PIP), setraki Cetart (CET), didanosine (DID), tibolone (TIB), norethisterone (N A set of OR (OR) and levonorgestrel (LEV) was developed to identify initial leads. To achieve this, we first performed in vitro studies in human prostate cancer LNCaP and CRPC C4-2 cells. All 10 drugs were tested in vitro to confirm their growth inhibitory effects. Among the drugs tested, TIB, NOR, and LEV were the most effective in inhibiting the growth of LNCaP and C4-2 cells. Both showed promising growth inhibition, 24.86 and 32%, respectively, in LNCaP cells. .52 and 181.0 nM in C4-2 cells and 3.12, 7.04 and 41. The IC50 was 78 nM, whereas for the other drugs, the IC50 value was 5.0 The effects of these three drugs on CRPC C4-2 cell proliferation were >μM (Fig. 1a). Encouraged by the significant inhibition of growth of normal human prostate epithelial RWPE-1 cells, The cytotoxicity IC50 of TIB, NOR and LEV was were found to be 23.29, 86.30, and 59.70 μM, respectively (Fig. 1b ) Due to the known implication of the androgen receptor (AR) in CRPC, this These initial leads can induce degradation of AR itself in LNCaP and C4-2 cells. We investigated whether this was the case.

[0097] LNCa after treatment with the indicated drugs / compounds to confirm whole-cell expression of AR Western blot analysis of P and C4-2 cell lysates was performed (Figures 1C-1D). Western blot results showed that all of these reads were 2.5 times higher than those treated with vehicle. It was shown that C degrades AR in LNCaP cells by 5-45%. In 4-2 cells, this degradation was 15-25% compared to vehicle treatment. Next, we aimed to determine how these leads induce degradation of nuclear AR expression. To understand this, we investigated fixation and cleavage in Triton X-100. Anti-AR immunofluorescence staining of LNCaP and C4-2 cells after permeabilization was performed, followed by Probing was performed with both monoclonal and polyclonal antibodies against AR ( Figure 1 E-1F). Except for TIB, both NOR and LEV treatments were significantly different from LNCaP and LEV, respectively. A 60% and 30% reduction in nuclear AR levels in C4-2 and C4-3 cells was observed in their Western blot analysis. Our findings suggest that the hormone-induced T, a drug commonly used for contraception, hormonal contraception, and birth control treatments BI, NOR, and LEV have significant inhibitory effects on the proliferation of CRPC cells revealed that:

[0098] Using both the scaffold and functionalization of the parent leads TIB, NOR, and LEV (shown in Figure 2A) We designed and synthesized a library of novel small molecules (1–40, Figure 2B). Design a library of C3-keto, C17 hydroxyl, and C17 ethynyl derivatives of the parent lead. These were created through variation of substituents on or in groups. Well-established oxidation, reduction, alkylation These selected molecules were synthesized using reactions such as C—C bond coupling. A head-to-head coupling reaction was used to introduce aryl functionality through a C—C bond, and these molecules Some of the alkylations can be carried out in the presence of bases such as triethylamine and sodium hydride. This was achieved by reacting alkyl halides in the presence of HCl.

[0099] Toxicity of the synthetic molecule in prostate cancer cells as well as the active molecule in normal human cell lines The anti-cancer activity of the compounds was evaluated. All of the compounds synthesized, 1 to 40, were tested in C4-2 cells. The anti-cancer activity of these compounds was confirmed. The results showed that the compounds inhibited the proliferation of C4-2 cells with IC50 values ​​of 1, 2, and 3, respectively. 13 and 15, IC50 0.72, 11.01, 3.5 and 4.1nM) On the other hand, in C4-2 cells, compounds 3, 4, 8, 9, 11, 12, 14 and 16 ~22 had IC50s below 100 nM, the rest of the compounds were inactive and above 5.0 μM The IC50 was 0.01 (Fig. 3A).

[0100] Additionally, current steroidal CRPC drugs, namely abiraterone (ABI), a potent CYP2 inhibitor, We were interested in confirming the efficacy of our most potent compound 1 against rhesus malabsorption (P17A1 inhibitor). The proliferation IC50 of 1 was much lower in C4-2 cells than that of ABI. The cytotoxicity IC50 of these active molecules was found to be 1, 2, 13, and 16, respectively. and 15 in RWPE-1 cells were 54.6, 18.3, 17.8, and 13.5 The cytotoxicity IC50 of 1 was found to be A in RWPE-1 cells. These were found to be much higher than those of BI (7.20 μM) (Fig. 3b). To determine whether active and non-toxic synthetic compounds can induce degradation of AR, Perform Western blot analysis of C4-2 cell lysates after treatment with indicated drugs / compounds Western blot results showed that synthetic compound 1 inhibited the activity of the vehicle and known C Compared with other treatments, including the RPC drug ABI, It was found to be efficiently decomposed.

[0101] The effect of active leads on cancer cell migration was evaluated, but in most cases, prostate cancer cells The cells metastasize to bone and cause aggressive prostate cancer. A titer assay was performed to assess the activity of LNCaP and IFN-γ in the presence of treatment with all of these active synthetic compounds. The migration rate of both C4-2 and C4-3 cells was calculated based on the distance traveled per hour. Untreated LNCaP cells migrated at a speed of 4.8 μm / h, whereas 1, 2, 3, and 4 Treatment with induced a slower rate of migration (2.2, 3.5, 2.6 and 3.7 μm / s, respectively). h), which was almost half the migration rate compared to that of untreated cells. C4-2 cells migrated at a speed of 6.5 μm / h, whereas those treated with 1, 2, 3, and 4 , resulting in slower rates of migration (2.4, 3.3, 3.9, and 2.5 μm / h, respectively). Migration is the first step to invasion, and cancer cells 1, 2, 3 and Lead 1 is expressed in both cells, as lead 1 and lead 4 may also interfere with the metastatic process. It was found to be the most efficient of these based on running speed rate.

[0102] The metabolic stability of the active compounds was evaluated in the presence of both mouse liver microsomes and cerebrospinal fluids. In each case, the lead compound was incubated with each microsome at 37°C. The incubated mixture was then analyzed by LC-MS / MS to determine the amount of remaining parent molecules. The data are shown in Figure 3F. d) outperformed current CRPC drug ABI in mouse liver microsome assays It was stable.

[0103] We then investigate how these active leads mediate the degradation of known and identified proteomic targets. I was interested to see if fixation with Triton X-100 and Anti-AR immunofluorescence staining of C4-2 cells after permeabilization was performed, followed by immunofluorescence staining of the protein target. The results are shown in Figure 4( for lead compounds 1-4), Figure 5 (for lead compounds 7 and 9), and Figure 6 (for lead compounds 13, 14, 18 and 22).

[0104] To determine whether the most potent and non-toxic synthetic lead 1 contributes to tumor growth, Chopr a et al. conducted a study on the LuCaP35CR patient-derived xenograft (PDX) mouse model. A study was performed (Figure 7A). Castrated mice bearing LuCaP35CR xenografts were Treatment with Lead 1 and abiraterone, a known CRPC drug. 10 mg of Lead 1 Treatment with the 1 / kg dose rapidly suppressed tumor growth compared to that of untreated vehicle mice. Abiraterone treatment had no effect on tumor growth, even at doses as high as 175 mg / kg. Our results show that Lead 1 has no significant effect on LuCaP35. Better efficacy compared to that of the current drug, abiraterone, in CRPC models Furthermore, treatment with Lead 1 demonstrated in vivo efficacy over a 16-day period. The mean body weight did not change over time for both vehicle and abiraterone-treated mice. (Figure 7C). [Example]

[0105] Experimental Method Reagents and solvents were purchased from commercial suppliers and used without further purification. The spectra were analyzed using a 500 MHz spectrometer (Bruker Ultrasheild Plus- The NMR peak separation patterns were recorded at room temperature. m" and "singlet, doublet, triplet, quartet, and multiplet" respectively. Chemical shifts (δ) are shown relative to MeOD (δ = 3.30 ppm) or C as internal standard. LC-MS spectra were obtained from Agilent. ent Technologies 6460 Triple Quad LC / MS Recorded.

[0106] cell culture LNCaP, C4-2, and RWPE-1 cell lines were kindly provided by Timothy Ratlif Professor f (Purdue University Center for Cancer All of these cells were provided by the American According to the American Type Culture Collection (ATCC) protocol Maintained at 37°C with 5% CO2 in a humidified incubator. LNCaP cells The medium was then diluted with 10% FBS (Atlanta Biologics), 20 mM HEPES, and RPMI supplemented with 1% penicillin / streptomycin (Invitrogen) C4-2 cells were grown in 10% FBS (Atl anta Biologics), 1% penicillin / streptomycin (Invitrogen) ogen), 3mg / mL sodium bicarbonate, 5μg / mL insulin, 1.36n g / mL triiodothyronine, 5 μg / mL transferrin, 0.25 μg / mL 4:1 DMEM / F12-K supplemented with 0.01% biotin and 25 μg / mL adenine For normal growth, RWPE-1 cells were grown in 0.05% ethanol medium (Gibco). 0.05 mg / mL bovine pituitary extract (BPE) and 5 ng / mL epidermal growth factor (E Keratinocyte serum-free medium (K-SFM) (Invitrogen) supplemented with GF All compounds were maintained in a high concentration (20 mM) of dimethyl sulfoxide (DMS 0), followed by filtration through a 0.22 μm syringe filter. The compound was diluted with culture medium to prepare an effective treatment concentration of the compound. For experiments, cells were used at passages 3 to 12 after thawing.

[0107] Cell proliferation assay Cell proliferation experiments were performed using the "Cell Titer-Blue Cell Viability In this assay, approximately 5,000 cells / well were Plated in 100 μL of growth medium in a poly-L-lysine coated 96-well plate The next day, the cells were incubated in a humidified incubator at 37°C and 5% CO2 for 6 days. During this time, an additional 100 μL of test compound at various concentrations or DMSO as an untreated control was added. The cells were treated with 10 μL of "Cell Titer-Blue Reagent" After 6 days, the cells were added directly to each well and the plate was incubated at 37°C for 3 hours. Resazurin can be converted to resorufin, and the fluorescent signal is then detected by multiplate EL ISA reader (Bio-Tek Synergy HT plate reader, Bio-Tek) The results were measured at 590 nm using a fluorometric analyzer (Kelek, Winooski, VT). The percentage of surviving cells was calculated relative to the absorbance of the DMSO growth medium treated sample, taken as 100%. Data were analyzed and IC50 values ​​were calculated using GraphPad Pro. Calculations were performed using sm Software. All experimental points were performed in triplicate, and the experiment was performed three times. repeated.

[0108] Cell viability assay Cell viability assays were performed using the standard methylthiazolyldiphenyltetrazolium bromide ( The assay was performed using a MTT (Method of Transferring Tissue to Cells) assay. In this assay, approximately 5,000 cells / well were used. Cells were plated in 100 μL of growth medium in poly-L-lysine coated 96-well plates. One day after transplantation, the cells were placed in a humidified incubator at 37°C and 5% CO2 atmosphere. An additional 100 μL of various concentrations of test compound or untreated control was added to the cultures for 3 days in a centrifuge. After 3 days, the culture medium was replaced with 100 μL of MT per well. Replace with T solution (using a 1 mg / ml stock solution in growth medium) and incubate at 37°C for 3-4 hours. The mitochondrial reductase from living cells formed in each well. To dissolve the formazan plasma, 100 μL of DMSO was added to each well. The wells were shaken at room temperature for 30 minutes using an orbital shaker. The assay was performed using a multi-plate ELISA reader (Bio-Tek Synergy HT Plate). Measurements were taken at 570 nm using a chromatograph (Bio-Tek, Winooski, VT). The percentage of viable cells in compound-treated samples was compared to that in DMSO growth medium-treated samples. The absorbance was calculated by considering the absorbance of 100%. All experimental points were performed in triplicate. The experiment was repeated three times.

[0109] Liver microsome assay All test compounds were assayed at 3 μM using mouse and human liver microsomes at 37°C. The reaction mixture was incubated in 100 mM potassium phosphate buffer at pH 7.4. Microsomal enzymes were included in the buffer. Warfarin and verapamil were added to this assay. were used as negative and positive controls after 0 and 60 minutes of incubation. An aliquot was removed from each experimental and control reaction and an equal volume of ice-cold stop solution (acetonitrile) was added. The samples were centrifuged to remove precipitated proteins and then mixed with 0.3% acetic acid in ethanol. The supernatant was analyzed by LC-MS / MS to quantify the remaining parent molecule. The residual percentages are expressed as % relative to the time zero concentration.

[0110] Western blot First, 0.5 × 106 cells / well were plated on 6 wells coated with 0.01% poly-L-lysine. The next day, cells were treated with 1 μM concentration of drug / compound or vehicle control. The treatment was carried out in 0.01% DMSO growth medium as a control, and the treatment was maintained at 37°C and 5% CO2 atmosphere. The treatment was continued for 24 hours in a humidified incubator. After the treatment, the cells were washed with cold PBS and TBSN buffer (20 mM) supplemented with 1x protease inhibitor cocktail tablet l / L Tris, pH 8.0, 150 mmol / L NaCl, 1.5 mmol / L E DTA, 5 mmol / L EGTA, 0.5% Nonidet P-40, and 0.5 mmol The cell lysate was obtained by dissolving the cells in 1000kJ / L Na3VO4. The degree of cleavage was measured using the Pierce BCA Protein Assay (Thermo Scientific) Lysates were analyzed by SDS-PAGE gel (per lane). 40 μg of protein) and β-actin (clone 8H10D10, Cell Signaling Technology) was used as a loading control. The protein was transferred to a PVDF membrane, and nonspecific binding was determined by 5% milk in PBS-T (PBS buffer). The membrane was then blocked with 0.05% Tween-20 for 1 hour. Anti-AR clone D6F11, Cell Signaling Technology) The cells were incubated overnight at 4°C with PBS-T solution, washed for 1 hour, and then washed with horseradish permeate. peroxidase-conjugated goat anti-rabbit (for AR) and goat anti-mouse (β This was followed by a 1.5 hour incubation with an IgG secondary antibody (for actin). The mixture was washed with PBS-T for 1 hour, and the protein bands were visualized by chemiluminescence reagent (Thermo Sc ientific) and visualized in the FluorChem® system. Protein expression was normalized to β-actin and analyzed using ImageJ software. The concentration measurements were calculated.

[0111] Immunofluorescence staining Cells (0.25 × 106) were plated onto 24-well plates coated with 0.01% poly-L-lysine. The next day, cells were treated with 0.01% DMSO control as a vehicle and various After 24 hours, the cells were treated with various compounds (1 μM). Fix for 5 minutes, wash with 0.1% Triton-X in PBS, and permeabilize with methanol for 2 minutes. Upon washing with 0.1% Triton-X PBS buffer, the cells were treated with PBS. Blocked with prepared 3% bovine serum albumin for 60 minutes and incubated with primary antibody (anti-AR clone D6 F11, Cell Signaling Technology; anti-PR clone D8 Q2J,Cell Signalling Technology;Anti-SHBG,R & D Systems) at 4°C for 12 hours, followed by a 1-hour secondary Antibodies (Alexafluor 594 goat anti-rabbit IgG for AR and PR; SHBG This was followed by incubation with Alexafluor 488 donkey anti-goat (Alexafluor 488 for ELISA). The sections were stained with 4,6-diamidino-2-phenylindole (DAPI) for 10 minutes and then resuspended in PB. The cells were washed three times with 500 μL of PBS and images were taken at 40°C using a Nikon A1R-MP confocal laser scanning microscope. Recordings were made using a 2x objective.

[0112] Synthesis of Compound 1: Tibolone (62.4 mg, 0.2 mmol) was dissolved in 10 ml of a 9:1 THF / water mixture. Next, the solution was placed in RB containing p-toluenesulfonic acid (38.0 mg, 0.2 mmol). l) was added thereto and the mixture was refluxed for 48 hours, and the progress of the reaction was monitored by TLC. The reaction mixture was then evaporated to dryness to give the crude product. The product was purified using a 20% ethyl acetate in petroleum ether solvent mixture as the eluent. Purification by column chromatography gave pure white compound 1 (yield =70%). 1 H-NMR (500MHz, CD3OD, 25℃): δ=5.80(s, 1H),2.88(s,1H),2.57-2.54(m,1H),2.38-2.29 (m,4H),2.27-2.22(m,1H),2.21-2.15(m,1H),2 .00-1.93(m,3H),1.76-1.71(m,2H),1.69-1.61 (m,3H),1.58-1.50(m,1H),1.40-1.22(m,3H),1 .17-1.12(m,1H),1.10-0.90(m,3H),0.79-0.78 (m,3H) ppm. 13 C-NMR(500MHz,CD3OD,25℃):δ=2 01.08,167.85,125.31,87.27,78.82,73.43,47 .26,47.09,46.66,45.81,43.03,42.75,42.17, 38.27, 36.01, 32.24, 30.65, 26.41, 21.70, 11.7 6. LC-MS m / z(100%): [(C 21 H 28 O2)][M+H] + Against Calculated value: 313.45; Found value: 313.60. HP-LC: Retention time: 9.874 min .

[0113] Synthesis of Compound 2: Compound 2 was commercially available as ethisterone. LC-MS m / z(100%): Calculated for [(C21H28O2)][M+H]+ 313.44 ;Measured value: 313.20.

[0114] Synthesis of compound 3: A vigorously stirred suspension of hydroxylammonium hydrochloride (13.90 mg, 0.2 10 mM) with sodium acetate (24.60 mg, 0.3 mM) and 70% aqueous acetic acid (10 mL); Compound 2 (62.48 mg, 0.2 mM) was added and stirring was continued for 72 h. The reaction mixture was poured into 100 mL of cold water. The precipitated product was filtered off and washed with water, 5% Wash thoroughly with aqueous ammonium hydroxide and water until neutral, then dry at less than 50°C. The resulting crude product was purified by flash chromatography to give the title compound. Product 3 was obtained (E, Z) (yield = 55%). 1 H-NMR (500 MHz, CDCl3, 2 5℃):δ=6.56(s,1H),5.85(s,1H),5.81(s,1H),5 .35(s,1H),3.12(s,1H),3.10(s,1H),2.58-2.5 7(m,2H),2.43-2.40(m,8H),2.32-2.29(m,2H), 2.28-2.21(m,2H),2.18-2.16(m,6H),2.04-2.0 (m,6H),1.98-1.91(m,6H),1.89-1.69(m,2H),1 .67-1.62(m,6H),1.60-1.18(m,6H),0.91-0.87 (m,6H), 0.78-.076(m,6H) ppm. 13 C-NMR (500MH z,CDCl3):δ=165.09,150.46,149.08,126.52,1 19.46, 87.40, 79.77, 74.13, 46.95, 46.03, 4.94 ,43.71,43.45,43.35,43.07,42.98,42.04,41. 77,38.73,32.33,30.70,30.29,29.70,26.84,2 6.72, 26.64, 25.84, 22.23, 12.84, 12.79, 12.62 LC-MS m / z(100%): [(C 21 H 29 NO2)][M+H] + Against Calculated value: 328.46; Found value: 328.30. HP-LC: E / Z isomers retention times of 9.913 and 10.121 min.

[0115] Synthesis of compound 4: A vigorously stirred suspension of hydroxylammonium hydrochloride (13.90 mg, 0.2 10 mM) with sodium acetate (24.60 mg, 0.3 mM) and 70% aqueous acetic acid (10 norethisterone (59.70 mg, 0.2 mM) was added and the mixture was stirred for 72 hours. The reaction mixture was poured into 100 mL of cold water. The precipitated product was removed by filtration. Wash well with water, 5% aqueous ammonium hydroxide, and water until neutral, then add 50°C The resulting crude product was purified by flash chromatography to give The title compound 4 was obtained (E, Z) (yield=52%). 1 H-NMR (500 MHz, CDC l3,25℃):δ=6.62(s,1H),5.87(s,1H),5.82(s,1 H),5.30(s,1H),3.16(s,1H),3.13(s,1H),2.58 -2.57(m,2H),2.43-2.40(m,8H),2.32-2.29(m, 2H),2.28-2.21(m,2H),2.18-2.16(m,6H),2.04 -2.0(m,6H),1.98-1.91(m,6H),1.89-1.69(m,2 H),1.67-1.62(m,6H),1.60-1.20(m,6H),0.89- 0.85(m,6H)ppm. 13 C-NMR (500 MHz, CDCl): δ = 1 66.71, 157.31, 155.62, 151.45, 117.81, 111.30 ,87.46,79.74,74.06,49.37,49.26,49.18,49. 10, 46.88, 43.11, 42.54, 41.96, 41.23, 41.15, 4 1.01, 38.81, 36.48, 35.71, 35.47, 35.09, 32.46 ,30.99,30.80,3065,29.60,27.19,27.07,2655 ,26.29,26.20,26.11,25.75,22.99,2099,12.6 9. LC-MS m / z(100%): [(C 20 H 27 NO2)][M+H] + to Calculated value: 314.44; Found value: 314.30. HP-LC: For E / Z isomers Retention times of 9.530 and 9.775 min.

[0116] Synthesis of compound 5: A solution of 2 (31.2 mg, 0.1 mM) in tBuOH (10 mL) was added with excess chloraniline. The reaction mixture was refluxed for 24 hours. Finally, the solvent was evaporated to dryness. The crude product was obtained and purified by flash chromatography to give the title compound. (Yield = 40%). LC-MS m / z: [(C21H27O2)][M+H]+ The calculated value was 311.20; the measured value was 311.20.

[0117] Synthesis of compound 6: t To a solution of norethisterone (29.8 mg, 0.1 mM) in BuOH (10 mL) Excess chloranil was added and the reaction mixture was refluxed for 24 hours. The solvent was evaporated to give the crude product. The product was purified by flash chromatography to give the title compound (yield: rate=45%). LC-MS m / z(100%): [(C20H25O2)][M+H Calculated value for ]+, 297.19; observed value, 297.20.

[0118] Synthesis of compound 7: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by ethanol in toluene (2 mL). Tetrahydrofuran (0.2 mmol) was added and the mixture was stirred for another 10 min at room temperature, after which This was followed by the addition of 3-bromo-pyridine (0.2 mmol). The reaction mixture was stirred for 70-80 minutes. The mixture was stirred for 12 hours at a temperature of ° C. The reaction was quenched with 10% aqueous citric acid (20 mL) and The combined extracts were washed with 10% aqueous NaOH (20 mL), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation. The crude products were purified using flash chromatography to obtain the respective pure compounds. I got something.

[0119] Synthesis of compound 8: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by norethoxylated toluene (2 mL). Tisterone (0.2 mmol) was added and the mixture was stirred for a further 10 min at room temperature. This was followed by the addition of 2-chloropyridine (0.2 mmol). The mixture was stirred for 12 hours at a temperature of 80° C. The reaction was quenched with 10% aqueous citric acid (20 mL). The combined extracts were washed with 10% aqueous NaOH ( 20 mL), washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation. The crude product was purified using flash chromatography to give the respective pure The compound was obtained.

[0120] Synthesis of compound 9: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to Al. The mixture was added under a nitrogen atmosphere, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by ethyl acetate in toluene (2 mL). Ron (0.2 mmol) was added and the mixture was stirred for a further 10 min at room temperature, after which This was followed by the addition of 2-chloro-pyridine (0.2 mmol). The reaction mixture was heated to 70-80°C. The reaction was stirred for 12 hours at a temperature of 0.05°C. The reaction was quenched with 10% aqueous citric acid (20 mL) and The combined extracts were washed with 10% aqueous NaOH (20 ml). L), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation. The crude product was purified using flash chromatography to give the respective pure compounds obtained.

[0121] Synthesis of compound 10: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by norethoxylated toluene (2 mL). Tisterone (0.2 mmol) was added and the mixture was stirred for a further 10 min at room temperature. This was followed by the addition of 3-bromo-pyridine (0.2 mmol). The mixture was stirred for 12 hours at a temperature of 80° C. The reaction was quenched with 10% aqueous citric acid (20 mL). The combined extracts were washed with 10% aqueous NaOH ( 20 mL), washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation. The crude product was purified using flash chromatography to give the respective pure The compound was obtained.

[0122] Synthesis of compound 11: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by toluene (2 mL) of compound (III). 1 (0.2 mmol) was added and the mixture was stirred for another 10 min at room temperature, after which 3 This was followed by the addition of 1,2-dibromo-pyridine (0.2 mmol). The reaction mixture was heated to 70-80°C. The reaction was stirred at room temperature for 12 hours. The reaction was quenched with 10% aqueous citric acid (20 mL) and DC The combined extracts were extracted with 10% aqueous NaOH (20 mL). ), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation, and the crude The products were purified using flash chromatography to obtain the respective pure compounds. Got it.

[0123] Synthesis of compound 12: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by toluene (2 mL) of compound (III). 1 (0.2 mmol) was added and the mixture was stirred for another 10 min at room temperature, after which 2 This was followed by the addition of 1,2-chloro-pyridine (0.2 mmol). The reaction mixture was heated to 70-80°C. The reaction was stirred at room temperature for 12 hours. The reaction was quenched with 10% aqueous citric acid (20 mL) and DC The combined extracts were extracted with 10% aqueous NaOH (20 mL). ), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation, and the crude The products were purified using flash chromatography to obtain the respective pure compounds. Got it.

[0124] Synthesis of compound 13: Tibolone (0.2 mmol) was placed in RB containing 10 ml of THF. -toluenesulfonic acid (0.2 mmol) was added thereto, and the mixture was refluxed for 48 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then evaporated to dryness to give crude HCl. The product was obtained and purified by elution with 10% ethyl acetate in petroleum ether solvent mixture as eluent. The mixture was purified by column chromatography using HPLC to give the title compound.

[0125] Synthesis of compound 14: Norethisterone (0.2 mmol) was placed in RB containing 10 ml of THF. Then, p-toluenesulfonic acid (0.2 mmol) was added thereto, and the mixture was refluxed for 48 hours. The reaction mixture was then evaporated to dryness. The crude product was obtained, which was purified by elution with 10% ethyl acetate in petroleum ether solvent mixture as eluent. Purification by column chromatography using ethyl acetate gave the title compound. Ta.

[0126] Synthesis of compound 15: Compound 1 (0.2 mM) and sodium hydride (0.3 mM) were dissolved in 10 ml of dry TH F and the mixture was stirred for 60 minutes at room temperature, followed by the addition of excess methyl iodide. The reaction was continued for 48 hours at room temperature. After the reaction was complete, excess sodium hydride was added. The product formed was removed from the reaction mixture by partial evaporation of the solvent. The crude product was separated from the mixture, followed by extraction. Purification by HPLC gave the title compound.

[0127] Synthesis of compound 16: Norethisterone (0.2 mM) and sodium hydride (0.3 mM) were added to 10 ml of The mixture was stirred at room temperature for 60 minutes, and then excess methyl iodide was added. The addition continued. The reaction was continued for 48 hours at room temperature. After the reaction was complete, the excess sodium hydride was removed. The sodium was decomposed by adding water dropwise. The formed product was separated by partial evaporation of the solvent. The crude product was separated from the reaction mixture by flash chromatography followed by extraction. Purification by chromatography gave the title compound.

[0128] Synthesis of compound 17: Compound 1 (0.2 mM) and sodium hydride (0.3 mM) were dissolved in 10 ml of dry TH F and the mixture was stirred for 60 minutes, followed by the addition of excess ethyl iodide. The reaction was continued for 48 hours at room temperature. After the reaction was complete, excess sodium hydride was added to the reaction mixture in a solution of water. The formed product was removed from the reaction mixture by partial evaporation of the solvent. The crude product was purified by flash chromatography. Purification thereto afforded the title compound.

[0129] Synthesis of compound 18: Norethisterone (0.2 mM) and sodium hydride (0.3 mM) were added to 10 ml of The mixture was stirred at room temperature for 60 minutes, and then excess ethyl iodide was added. The addition continued. The reaction was continued for 48 hours at room temperature. After the reaction was complete, the excess sodium hydride was removed. The sodium was decomposed by adding water dropwise. The formed product was separated by partial evaporation of the solvent. The crude product was separated from the reaction mixture by flash chromatography followed by extraction. Purification by chromatography gave the title compound.

[0130] Synthesis of compound 19: A vigorously stirred suspension of methylamine (0.2 mM) was added to sodium acetate (0.3 mM M), 70% aqueous acetic acid (10 mL) and compound 1 (0.2 mM) were added and the stirring was continued for 72 The reaction mixture was then poured into 100 mL of cold water. The precipitated product was filtered off. Filter and remove, then wash thoroughly with water, 5% ammonium hydroxide solution, and water until neutral, then The crude product was purified by flash chromatography. and purified to give the title compound.

[0131] Synthesis of compound 20: A vigorously stirred suspension of methylamine (0.2 mM) was added to sodium acetate (0.3 mM Add 70% aqueous acetic acid (10 mL) and norethisterone (0.2 mM) and stir. Stirring was continued for 72 hours at room temperature. The reaction mixture was poured into 100 mL of cold water. The precipitated product The residue was removed by filtration and thoroughly washed with water, 5% ammonium hydroxide solution, and water until neutral. The crude product was purified by flash chromatography. The title compound was obtained by purification by HPLC.

[0132] Synthesis of compound 21: A vigorously stirred suspension of hydrazine hydrochloride (0.2 mM) was added to sodium acetate (0. 3 mM), 70% aqueous acetic acid (10 mL) and compound 1 (0.2 mM) were added and stirred. The mixture was allowed to stand at room temperature for 72 hours. The reaction mixture was poured into 100 mL of cold water. The precipitated product was , filtered off, and washed thoroughly with water, 5% ammonium hydroxide solution, and water until neutral. The crude product was purified by flash chromatography. Purification thereto afforded the title compound.

[0133] Synthesis of compound 22: A vigorously stirred suspension of hydrazine hydrochloride (0.2 mM) was added to sodium acetate (0. 3 mM), 70% aqueous acetic acid (10 mL) and norethisterone (0.2 mM) were added. Stirring was continued for 72 hours at room temperature. The reaction mixture was poured into 100 mL of cold water. The product was filtered off and washed with water, 5% aqueous ammonium hydroxide, and water until neutral. The crude product was purified by flash chromatography. Purification by filtration gave the title compound.

[0134] Synthesis of compound 23: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by toluene (2 mL) of compound (III). 1 (0.2 mmol) was added and the mixture was stirred for another 10 min at room temperature, after which 2 This was followed by the addition of 1,2-chloro-pyridine (0.2 mmol). The reaction mixture was heated to 70-80°C. The reaction was stirred at room temperature for 12 hours. The reaction was quenched with 10% aqueous citric acid (20 mL) and DC The combined extracts were extracted with 10% aqueous NaOH (20 mL). ), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation and The crude product was purified using rush chromatography to obtain the respective pure compounds. Got it.

[0135] Synthesis of compound 24: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by norethoxylated toluene (2 mL). Tisterone (0.2 mmol) was added and the mixture was stirred for a further 10 min at room temperature. This was followed by the addition of 2-chloropyridine (0.2 mmol). The mixture was stirred for 12 hours at a temperature of 80° C. The reaction was quenched with 10% aqueous citric acid (20 mL). The combined extracts were washed with 10% aqueous NaOH ( 20 mL), washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation. The crude product was purified using flash chromatography to give the respective pure The compound was obtained.

[0136] Synthesis of compound 25: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by toluene (2 mL) of compound (III). 1 (0.2 mmol) was added and the mixture was stirred for another 10 min at room temperature, after which 3 This was followed by the addition of 1,2-dibromo-pyridine (0.2 mmol). The reaction mixture was heated to 70-80°C. The reaction was stirred at room temperature for 12 hours. The reaction was quenched with 10% aqueous citric acid (20 mL) and DC The combined extracts were extracted with 10% aqueous NaOH (20 mL). ), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation and The crude product was purified using rush chromatography to obtain the respective pure compounds. Got it.

[0137] Synthesis of compound 26: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by norethoxylated toluene (2 mL). Tisterone (0.2 mmol) was added and the mixture was stirred for a further 10 min at room temperature. This was followed by the addition of 3-bromo-pyridine (0.2 mmol). The mixture was stirred for 12 hours at a temperature of 80° C. The reaction was quenched with 10% aqueous citric acid (20 mL). The combined extracts were washed with 10% aqueous NaOH ( 20 mL), washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation. The crude product was purified using flash chromatography to give the respective pure The compound was obtained.

[0138] Synthesis of compound 27: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by toluene (2 mL) of compound (III). 1 (0.2 mmol) was added and the mixture was stirred for another 10 min at room temperature, after which 2 This was followed by the addition of iodophenol (0.2 mmol). The reaction mixture was heated to 70-80°C. The reaction was stirred for 12 hours at a temperature of 0.05°C. The reaction was quenched with 10% aqueous citric acid (20 mL) and The combined extracts were washed with 10% aqueous NaOH (20 ml). L), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation. The crude product was purified using flash chromatography to give the respective pure compounds obtained.

[0139] Synthesis of compound 28: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by norethoxylated toluene (2 mL). Tisterone (0.2 mmol) was added and the mixture was stirred for a further 10 min at room temperature. This was followed by the addition of 2-iodophenol (0.2 mmol). The reaction was stirred for 12 hours at a temperature of ∼80° C. The reaction was quenched with 10% aqueous citric acid (20 mL). The combined extracts were washed with 10% aqueous NaOH. (20 mL), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation. The crude product was purified using flash chromatography to obtain the respective pure A suitable compound was obtained.

[0140] Synthesis of compound 29: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by toluene (2 mL) of compound (III). 1 (0.2 mmol) was added and the mixture was stirred for another 10 min at room temperature, after which 2 This was followed by the addition of 1,2-dibromo-aniline (0.2 mmol). The reaction mixture was heated to 70-80°C. The reaction was stirred at room temperature for 12 hours. The reaction was quenched with 10% aqueous citric acid (20 mL) and DC The combined extracts were extracted with 10% aqueous NaOH (20 mL). ), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation and The crude product was purified using rush chromatography to obtain the respective pure compounds. Got it.

[0141] Synthesis of compound 30: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by norethoxylated toluene (2 mL). Tisterone (0.2 mmol) was added and the mixture was stirred for a further 10 min at room temperature. This was followed by the addition of 2-bromoaniline (0.2 mmol). The mixture was stirred for 12 hours at a temperature of 80° C. The reaction was quenched with 10% aqueous citric acid (20 mL). The combined extracts were washed with 10% aqueous NaOH ( 20 mL), washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation. The crude product was purified using flash chromatography to give the respective pure The compound was obtained.

[0142] Synthesis of compound 31: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by toluene (2 mL) of compound (III). 1 (0.2 mmol) was added and the mixture was stirred for another 10 min at room temperature, after which 2 This was followed by the addition of iodophenol (0.2 mmol). The reaction mixture was heated to 70-80°C. The reaction was stirred for 12 hours at a temperature of 0.05°C. The reaction was quenched with 10% aqueous citric acid (20 mL) and The combined extracts were washed with 10% aqueous NaOH (20 ml). L), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation. The crude product was purified using flash chromatography to give the respective pure compounds obtained.

[0143] Synthesis of compound 32: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by norethoxylated toluene (2 mL). Tisterone (0.2 mmol) was added and the mixture was stirred for a further 10 min at room temperature. This was followed by the addition of 2-iodophenol (0.2 mmol). The reaction was stirred for 12 hours at a temperature of ∼80° C. The reaction was quenched with 10% aqueous citric acid (20 mL). The combined extracts were washed with 10% aqueous NaOH. (20 mL), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation. The crude product was purified using flash chromatography to obtain the respective pure A suitable compound was obtained.

[0144] Synthesis of compound 33: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by toluene (2 mL) of compound (III). 1 (0.2 mmol) was added and the mixture was stirred for another 10 min at room temperature, after which 2 This was followed by the addition of 1,2-dibromo-aniline (0.2 mmol). The reaction mixture was heated to 70-80°C. The reaction was stirred at room temperature for 12 hours. The reaction was quenched with 10% aqueous citric acid (20 mL) and DC The combined extracts were extracted with 10% aqueous NaOH (20 mL). ), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation and The crude product was purified using rush chromatography to obtain the respective pure compounds. Got it.

[0145] Synthesis of compound 34: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by norethoxylated toluene (2 mL). Tisterone (0.2 mmol) was added and the mixture was stirred for a further 10 min at room temperature. This was followed by the addition of 2-bromoaniline (0.2 mmol). The mixture was stirred for 12 hours at a temperature of 80° C. The reaction was quenched with 10% aqueous citric acid (20 mL). The combined extracts were washed with 10% aqueous NaOH ( 20 mL), washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation. The crude product was purified using flash chromatography to give the respective pure The compound was obtained.

[0146] Synthesis of compound 35: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by toluene (2 mL) of compound (III). 1 (0.2 mmol) was added and the mixture was stirred for another 10 min at room temperature, after which 4 This was followed by the addition of 1,2-dichlorobenzyl alcohol (0.2 mmol). The mixture was stirred for 12 hours at a temperature of 80° C. The reaction was quenched with 10% aqueous citric acid (20 mL). The combined extracts were washed with 10% aqueous NaOH ( 20 mL), washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation. The crude product was purified using flash chromatography to give the respective pure The compound was obtained.

[0147] Synthesis of compound 36: In a two-necked RB flask equipped with a magnetic stir bar and reflux condenser, add Pd(PPh3)2Cl 2 (0.04 mmol), CuI (0.04 mmol), and PPh3 (catalytic amount) were added to the The mixture was then added under an atmosphere of argon, followed by dry, degassed toluene (5 mL) and triethylamine. The mixture was stirred for 10 min, followed by norethoxylated toluene (2 mL). Tisterone (0.2 mmol) was added and the mixture was stirred for a further 10 min at room temperature. This was followed by the addition of 4-chlorobenzyl alcohol (0.2 mmol). The mixture was stirred for 12 hours at a temperature of 70-80° C. The reaction was diluted with 10% aqueous citric acid (20 mL). The mixture was quenched and extracted with DCM (3 x 30 mL). The combined extracts were washed with 10% aqueous N The solution was washed with HCl (20 mL), water, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation. The crude product was purified using flash chromatography to give The pure compound was obtained.

[0148] Synthesis of compound 37: Palladium on carbon (Pd / C) in an amount of 10% by weight of the substrate was dissolved in MeOH (10 ml) The reaction mixture was heated at room temperature for 6 hours under slight pressure. The resulting mixture was then filtered and concentrated in vacuo to give the corresponding The reduced product was obtained.

[0149] Synthesis of compound 38: Palladium on carbon (Pd / C) in an amount of 10% by weight of the substrate was dissolved in MeOH (10 ml). The reaction mixture was stirred at room temperature for 6 hours with a slight The resulting mixture was then filtered and concentrated in vacuo to give a 100% aqueous solution of 1,000 sulphuric acid. , to give the corresponding reduced product.

[0150] Synthesis of compound 39: In this reaction, the first compound 1 (0.2 mM) was dissolved in 20 ml of ice-cold methanol. Then, the reducing agent sodium borohydride (0.2 mM) was added, and the mixture was stirred under ice-cooling conditions for 1 The reaction was continued for 2 hours. After the reaction was complete, excess sodium borohydride was removed using aqueous HCl. The reaction mixture was acidified (slowly and with stirring) using The formed product was separated from the reaction mixture by partial evaporation of the solvent, followed by Extraction followed. The resulting crude product was purified by flash chromatography to give the following: The title compounds (α, β) were obtained.

[0151] Synthesis of compound 40: In this reaction, first norethisterone (0.2 mM) was dissolved in 20 ml of ice-cold methanol. After dissolution, the reducing agent sodium borohydride (0.2 mM) was added and the mixture was stirred in an ice-cold bath. The reaction was continued under these conditions for 12 hours. After the reaction was complete, excess sodium borohydride was added to the reaction mixture in aqueous H Acidify the reaction mixture (slowly and with stirring) using Cl The formed product was separated from the reaction mixture by partial evaporation of the solvent. This was followed by extraction. The crude product obtained was purified by flash chromatography. As a result, the title compounds (α, β) were obtained.

[0152] Those skilled in the art will appreciate that many modifications can be made to the specific implementations described above. Implementations should not be limited to the specific limitations described. Other implementations are possible. It could be.

[0153] While the present invention has been illustrated and described in detail in the drawings and foregoing description, the same may be The invention is to be considered illustrative and not limiting in nature, and only certain embodiments are shown. All changes and modifications that are within the scope of what is described and the spirit of the invention are reserved. It is understood that the scope of the present method and apparatus is set forth in the following claims. However, the present disclosure is intended to be defined by the spirit and scope of the present disclosure. It is understood that the invention may be practiced otherwise than as specifically explained and illustrated without departing from the spirit and scope of the invention. must be understood.

Claims

1. A compound having the following formula: or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, 【Chemistry 2】 represents a single or double bond, 【Transformation 3】 represents a single bond, X is hydroxyl or alkyloxy, or 【Chemistry 4】 represents a double bond, X is O, S, NH, N—OH, N—NH ２ , or NR ７ in Yes, R ７ is C1-C6 alkyl, R １ and R ２ are independently hydrogen, C1-C6 alkyl, alkenyl or alkynyl It is R ３ is hydrogen, hydroxyl, thiol, halo, azido, nitro, cyano, alkyl, Alkenyl, alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, Aminoalkyl, thiolalkyl, mercaptoalkyl, heteroalkyl, heteroalkenyl alkynyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cyclo cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, aryl arylalkyl, arylalkenyl, or arylalkynyl, each of which is is optionally replaced, R ４ is hydrogen, hydroxyl, halo, azido, nitro, cyano, alkyl, alkenyl , alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, aminoalkynyl alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cyclo Alkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl , aryl, heteroaryl, arylalkyl, arylalkenyl, or aryl and alkynyl, each of which is optionally substituted.

2. 2. The compound of claim 1, wherein the compound has the formula: Salt: 【Transformation 5】 During the ceremony, 【Transformation 6】 represents a single or double bond, 【Transformation 7】 represents a single bond, X is hydroxyl or alkyloxy, or 【Transformation 8】 represents a double bond, X is O, S, NH, N—OH, N—NH ２ , or NR ７ in Yes, R ７ is C1-C6 alkyl, R １ and R ２ are independently hydrogen, C1-C6 alkyl, alkenyl or alkynyl It is R ３ is hydrogen, hydroxyl, thiol, halo, azido, nitro, cyano, alkyl, Alkenyl, alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, Aminoalkyl, thiolalkyl, mercaptoalkyl, heteroalkyl, heteroalkenyl alkynyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cyclo cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, aryl arylalkyl, arylalkenyl, or arylalkynyl, each of which is is optionally replaced, R ６ is hydrogen, alkyl, alkenyl, alkynyl, alkylalkynyl, alkylo hydroxyalkyl, aminoalkyl, heteroalkyl, heteroalkenyl, hete alkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkynyl, alkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl , arylalkenyl, or arylalkynyl, each of which is optionally substituted. It will be exchanged.

3. 2. The compound of claim 1, wherein the compound has the formula: Salt: 【Chemistry 9】 During the ceremony, 【Chemistry 10】 represents a single or double bond, 【Chemistry 11】 represents a single bond, X is hydroxyl or alkyloxy, or 【Chemistry 12】 represents a double bond, X is O, S, NH, N—OH, N—NH ２ , or NR ７ in Yes, R ７ is C1-C6 alkyl, R １ and R ２ are independently hydrogen, C1-C6 alkyl, alkenyl or alkynyl It is R ５ is hydrogen, alkyl, alkenyl, alkynyl, alkylalkynyl, hydroxy Alkyl, aminoalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, Heterocycyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cyclohexene Alkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkene aryl, or arylalkynyl, each of which is optionally substituted; R ６ is hydrogen, alkyl, alkenyl, alkynyl, alkylalkynyl, alkylo hydroxyalkyl, aminoalkyl, heteroalkyl, heteroalkenyl, hete alkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkynyl, alkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl , arylalkenyl, or arylalkynyl, each of which is optionally substituted. It will be exchanged. 【Request Item 4】 【Chemistry 13】 represents a single or double bond, 【Chemistry 14】 represents a single bond, X is hydroxyl or alkyloxy, or 【Chemistry 15】 represents a double bond, X is O, S, NH, N—OH, N—NH ２ , or NR ７ in Yes, R ７ is C1-C6 alkyl, R １ and R ２ are independently hydrogen or methyl; R ５ is hydrogen, alkyl, alkenyl, alkynyl, alkylalkynyl, hydroxy Alkyl, aminoalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, Heterocycyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cyclohexene Alkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkene aryl, or arylalkynyl, each of which is optionally substituted; R ６ The compound of claim 3, wherein is hydrogen or C1-C6 alkyl. 【Request Item 5】 【Chemistry 16】 represents a single or double bond, 【Chemistry 17】 represents a single bond, X is hydroxyl or alkyloxy, or [Chemistry 18] represents a double bond, X is O, S, NH, N—OH, N—NH ２ , or NR ７ in Yes, R ７ is C1-C6 alkyl, R １ and R ２ are independently hydrogen or methyl; R ５ and R ６ The compound of claim 4, wherein is hydrogen.

6. The compound according to claim 4, wherein the compound is a compound 1 to 6 in FIG.

7. The compound according to claim 4, wherein the compound is a compound of compounds 15 to 22 in FIG.

8. The compound according to claim 4, wherein the compound is a compound of compounds 23 to 40 in FIG. 【Request Item 9】 【Chemistry 19】 represents a double bond, and X represents O, S, NH, N—OH, or N—NH ２ , or NR ７ and R ７ is C1-C6 alkyl, R １ and R ２ are independently hydrogen or methyl; R ５ and R ６ The compound of claim 3 wherein is hydrogen. 【Request Item 10】 【Chemistry 20】 represents a single or double bond, 【Chemistry 21】 represents a single bond, X is hydroxyl or alkyloxy, or 【Chemistry 22】 represents a double bond, X is O, S, NH, N—OH, N—NH ２ , or NR ７ in Yes, R ７ is C1-C6 alkyl, R １ and R ２ are independently hydrogen or methyl; R ５ but, 【Chemistry 23】 and R ６ The compound of claim 3 wherein is hydrogen.

11. A compound having the following formula: or a pharmaceutically acceptable salt thereof: 【Chemistry 24】 During the ceremony, 【Chemistry 25】 represents a single or double bond, 【Chemistry 26】 represents a single bond, X is hydroxyl or alkyloxy, or 【Chemistry 27】 represents a double bond, X is O, S, NH, N—OH, N—NH ２ , or NR ７ in Yes, R ７ is C1-C6 alkyl, R １ and R ２ are independently hydrogen, C1-C6 alkyl, alkenyl or alkynyl It is R ３ is hydrogen, hydroxyl, thiol, halo, azido, nitro, cyano, alkyl, Alkenyl, alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, Aminoalkyl, thiolalkyl, mercaptoalkyl, heteroalkyl, heteroalkenyl alkynyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cyclo cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, aryl arylalkyl, arylalkenyl, or arylalkynyl, each of which is is optionally replaced, R ４ is hydrogen, hydroxyl, halo, azido, nitro, cyano, alkyl, alkenyl , alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, aminoalkynyl alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cyclo Alkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl , aryl, heteroaryl, arylalkyl, arylalkenyl, or aryl and alkynyl, each of which is optionally substituted.

12. A compound having the following formula: or a pharmaceutically acceptable salt thereof: 【Chemistry 28】 During the ceremony, 【Chemistry 29】 represents a single or double bond, 【Transformation 30】 represents a single bond, X is hydroxyl or alkyloxy, or 【Chemistry 31】 represents a double bond, X is O, S, NH, N—OH, N—NH ２ , or NR ７ in Yes, R ７ is C1-C6 alkyl, R １ and R ２ are independently hydrogen, C1-C6 alkyl, alkenyl or alkynyl It is R ３ is hydrogen, hydroxyl, thiol, halo, azido, nitro, cyano, alkyl, Alkenyl, alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, Aminoalkyl, thiolalkyl, mercaptoalkyl, heteroalkyl, heteroalkenyl alkynyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cyclo cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, aryl arylalkyl, arylalkenyl, or arylalkynyl, each of which is is optionally replaced, R4 is hydrogen, hydroxyl, halo, azido, nitro, cyano, alkyl, alkenyl , alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, aminoalkynyl alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cyclo Alkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl , aryl, heteroaryl, arylalkyl, arylalkenyl, or aryl and alkynyl, each of which is optionally substituted.

13. The compound is selected from the group consisting of compounds 7 to 14 in FIG. 【Chemistry 32】 13. The compound of claim 12, comprising a compound of formula:

14. The compound is 【Transformation 33】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 2. The compound of claim 1, wherein:

15. One or more compounds according to claims 1 to 14 together with one or more diluents, excipients or carriers. or a pharmaceutically acceptable salt thereof.

16. The compound according to any one of claims 1 to 14, wherein the compound is for the treatment of cancer. Compound.

17. 15. Any of claims 1 to 14, wherein the compound is for the treatment of castration-resistant prostate cancer. The compound according to any one of claims 1 to 4.

18. A method for treating cancer patients, comprising administering a therapeutically effective amount of one or more of the compounds according to claims 1 to 14. and one or more carriers, diluents, or excipients to a subject in need of relief from said cancer. Administering the compound to a patient.

19. 19. The method of claim 18, wherein the cancer is castration-resistant prostate cancer.

20. A method for treating cancer patients comprising administering a therapeutically effective amount of a compound according to claims 1 to 14. The compound may be administered in the presence of one or more other compounds of the same or different mechanism of action, and one or more carriers, diluents, or or in combination with an excipient, and administering to a patient in need of relief from said cancer. Including, a method.

21. 20. The method of claim 19, wherein the cancer is castration-resistant prostate cancer.

22. together with one or more diluents, excipients or carriers for use as a medicament against cancer. , one or more compounds according to any one of claims 1 to 14, or pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising a salt thereof.

23. A drug conjugate comprising one or more compounds according to claims 1 to 14, wherein said conjugate The conjugate confers cell type or tissue type targeting or the conjugate is A drug conjugate that targets a different pathway that cooperates with the action of the compound of claims 1 to 14. to.

24. 1. A method for treating cancer patients, comprising administering to a subject a composition comprising a compound selected from the group consisting of acetaminophen, ... and administering a therapeutically effective amount of one or more compounds to a patient in need of relief from said cancer. wherein the compound has the following formula: ： 【Transformation 34】 During the ceremony, 【Chemistry 35】 represents a single or double bond, 【Transformation 36】 represents a single bond, X is hydroxyl or alkyloxy, or 【Chemistry 37】 represents a double bond, X is O, S, NH, N—OH, N—NH ２ , or NR ７ in Yes, R ７ is C1-C6 alkyl, R １ and R ２ are independently hydrogen, C1-C6 alkyl, alkenyl or alkyl Nil, R ３ is hydrogen, hydroxyl, thiol, halo, azido, nitro, cyano, alkyl, Alkenyl, alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, Aminoalkyl, thiolalkyl, mercaptoalkyl, heteroalkyl, heteroalkenyl alkynyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cyclo cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, aryl arylalkyl, arylalkenyl, or arylalkynyl, each of which is is optionally replaced, R ４ is hydrogen, hydroxyl, halo, azido, nitro, cyano, alkyl, alkenyl , alkynyl, alkylalkynyl, alkyloxy, hydroxyalkyl, aminoalkynyl alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cyclo Alkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl , aryl, heteroaryl, arylalkyl, arylalkenyl, or aryl and alkynyl, each of which is optionally substituted.

25. 25. The method of claim 24, wherein the cancer is castration-resistant prostate cancer.

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