Prodrugs of fulvestrant

Abstract

To provide a compound or a salt thereof which is rapidly metabolized to produce fulvestrant in the body.SOLUTION: The compound is a compound of formula (IV), an enantiomer, a diastereomer, a racemate, a pharmaceutically acceptable salt or a solvate thereof: Wherein R7 comprises certain phosphorus-containing esters and R8 represents certain substituents.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to fulvestrant prodrugs and processes for their preparation. The present disclosure also relates to pharmaceutical compositions of fulvestrant prodrugs and methods of treatment using the same. [Background technology]

[0002] Fulvestrant is an estrogen receptor antagonist marketed as Faslodex™ for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women whose disease has progressed after anti-estrogen therapy. Fulvestrant has demonstrated clinical efficacy in patients who have failed tamoxifen. Therefore, among the many drugs used to treat breast cancer, fulvestrant is the only anti-estrogen that can be widely used in clinical treatment after tamoxifen failure, providing a new approach to treating hormone-sensitive breast cancer. Because fulvestrant has poor solubility and oral bioavailability, the drug is currently administered by intramuscular injection of an oil-based fulvestrant formulation. The Faslodex™ product is approved for intramuscular administration on days 1, 15, and 29, and monthly thereafter. This injection contains up to 10% benzyl alcohol, which can act as an anesthetic, and castor oil, which can be painful to inject due to its high viscosity, is used as a release rate modifier. According to the FDA drug approval summary, injection site reactions and hot flashes have been observed.

[0003] Fulvestrant is a highly lipophilic molecule that is poorly soluble in water, which limits its bioavailability. Drugs with low solubility often have low bioavailability and require high doses to achieve therapeutically effective blood drug concentrations.

[0004] Patent Document 1 describes that intramuscular injections of fulvestrant in the form of aqueous suspensions are unsuitable for use: these suspensions lead to severe local tissue irritation at the injection site and an insufficient release profile due to the presence of fulvestrant in solid particle form.

[0005] The use of prodrugs allows those skilled in the art to alter one or more properties of a biologically active compound. Prodrugs include chemical derivatives of a biologically active parent compound that, when administered, ultimately liberate the active parent compound in vivo. The release rate of the active drug is affected by several factors, including the hydrolysis rate of the linker that connects the biologically active parent compound to the prodrug carrier.

[0006] Patent Document 2 discloses a boron-based fulvestrant prodrug for the treatment of breast cancer. This application also discloses the need to improve the bioavailability of fulvestrant to make it a more effective treatment regimen for tamoxifen-resistant breast cancer. Despite the clinical effectiveness of fulvestrant, its usefulness is limited by the amount of drug that can be administered in a single injection and by reduced bioavailability.

[0007] Non-Patent Document 1 discloses that fulvestrant undergoes rapid and extensive O-glucuronidation and O-sulfation to form inactive, water-soluble, polar phase II metabolites.

[0008] Therefore, an object of the present invention is to provide a compound or a salt thereof that can overcome the above problems and is rapidly metabolized to produce fulvestrant in the body. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] US Patent No. 6,774,122 B2 [Patent Document 2] International Publication No. 2016 / 004166 A1 [Non-patent literature]

[0010] [Non-Patent Document 1] J. Med. Chem., 2016, 59 (17), pp. 8134-8140 Summary of the Invention [Problem to be solved by the invention]

[0011] In one embodiment, the present invention provides a compound of formula I: [ka] (In the formula, R1 is: [ka] wherein R17 is selected from NH2, NHR18, or NR19R20; R18 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, which may be optionally substituted; R19 and R20 are independently selected from the group consisting of alkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, which may be optionally substituted; or R19 and R20 together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle, optionally containing one or more substituted aryls at substitutable positions. and optionally substituted with R groups, wherein the one or more R groups are each independently selected from the group consisting of alkyl, alkylcarbonyl, formyl, halo, haloalkyl, alkylphosphate, phosphate, oxo, cyano, nitro, amino, alkoxy, alkoxycarbonyl, carboxyalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylthio, cycloalkyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, and alkoxyalkyl, each of which is optionally substituted; R2 independently represents one of the following i) to iv): [ka] wherein R21 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; or -CR22R23; wherein R22 and R23 together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and which is optionally substituted at substitutable positions with one or more R24 groups, each independently selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl, formyl, halo, alkylphosphate, phosphate, cyano, nitro, alkoxy, amino, alkoxycarbonyl, alkenyl, alkynyl, alkylthio, and arylcarbonyl; [ka] (wherein each R25 is independently selected from hydrogen; optionally substituted alkyl, aryl, or heteroaryl); [ka] wherein each R26 is independently selected from hydrogen; optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; iv) an amino acid attached via an ester bond at the attachment point; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0012] In another embodiment, the present invention provides a compound of formula IV: [ka] (In the formula, R7 is as follows: [ka] or [ka] wherein R25 and R26 are each independently selected from hydrogen; optionally substituted alkyl, aryl, or heteroaryl; R8 independently represents one of the following i) to v): [ka] wherein R21 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; or -CR22R23; wherein R22 and R23 together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and which is optionally substituted at substitutable positions with one or more R24 groups, each independently selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl, formyl, halo, alkylphosphate, phosphate, cyano, nitro, alkoxy, amino, alkoxycarbonyl, alkenyl, alkynyl, alkylthio, and arylcarbonyl; [ka] wherein R17 is selected from NH2, NHR18, or NR19R20; R18 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, which may be optionally substituted; R19 and R20 are independently selected from the group consisting of alkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, which may be optionally substituted; or R19 and R20 together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle, optionally substituted with one or more R21 groups at substitutable positions. wherein the one or more R groups are independently selected from the group consisting of optionally substituted alkyl, alkylcarbonyl, formyl, halo, haloalkyl, alkylphosphate, phosphate, oxo, cyano, nitro, amino, alkoxy, alkoxycarbonyl, -C(O)-amino acid, carboxyl, carboxyalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylthio, cycloalkyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, and alkoxyalkyl; [ka] wherein R27 is selected from the group including optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; [ka] wherein R28 is selected from the group including optionally substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and one or more substitutions are selected from formyl, halo, phosphate, cyano, nitro, or amino. v) an amino acid attached via an ester bond at the attachment point; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0013] In another embodiment, the present invention provides a compound of formula VI: [ka] (Wherein R10 is the following: [ka] wherein R28 is selected from the group including optionally substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and one or more substitutions are selected from formyl, halo, phosphate, cyano, nitro, amino, hydroxy, heterocycloalkyl, or alkoxy; R11 is hydrogen or: [ka] wherein R21 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl; or -CR22R23; wherein R22 and R23 together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and optionally substituted at substitutable positions with one or more R24 groups, each independently selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl, formyl, halo, alkylphosphate, phosphate, cyano, nitro, alkoxy, amino, alkoxycarbonyl, alkenyl, alkynyl, alkylthio, and arylcarbonyl; provided that when R11 is hydrogen, R10 is not methyl or ethyl. and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0014] In another embodiment, the present invention provides a compound of formula VIII: [ka] wherein R13 is selected from hydrogen, alkyl; R14 is selected from the group consisting of optionally substituted alkyl, heterocycloalkyl, or aryl; one or more substitutions are selected from alkyl, alkoxy, halo, heteroaryl, heterocycloalkyl, cycloalkyl, amino, or hydroxy; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0015] In another embodiment, the present invention provides a prodrug of fulvestrant of formula IX: [ka] wherein S is selected from O, C, or N; T is optionally substituted aryl, heteroaryl, heterocycloalkyl, cycloalkyl, amino, [ka] or [ka] wherein one or more substitutions are selected from alkyl, alkoxy; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0016] In another embodiment, the present invention provides a prodrug of fulvestrant of formula X: [ka] wherein Q is selected from C or N; When Q is C, P1 is independently optionally substituted alkyl, optionally substituted: [ka] Selected from the following: [ka] is alkyl; P2 and P3 are independently selected from hydrogen or alkyl; When Q is N, P2 is independently optionally substituted alkyl, optionally substituted: [ka] Selected from the following: [ka] is alkyl; P1 is hydrogen and P3 is optionally substituted alkyl; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0017] In another embodiment, the present invention provides a compound of formula XI: [ka] wherein R15 and R16 together form a cyclic structure; the cyclic structure is selected from optionally substituted cycloalkyl or heterocycloalkyl; one or more substitutions are selected from alkyl, alkoxy, halo, amino, or hydroxy; and m and n can independently be 1 to 3. and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0018] In a preferred embodiment, the invention relates to compounds of formula XI, wherein m and n are both 1 or 2.

[0019] In another embodiment, the present invention relates to a pharmaceutical composition comprising a fulvestrant prodrug, as well as its enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates, and a pharmaceutically acceptable excipient.

[0020] The pharmaceutical compositions of the present disclosure can be in any form known to those of skill in the art. They can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, using a buccal tablet, or via an implanted reservoir, and are preferably administered orally or by injection.

[0021] In another embodiment, the present invention provides the use of a compound of the invention in the preparation of a pharmaceutical formulation as described above for the treatment of benign or malignant diseases of the breast or reproductive organs, preferably for the treatment of breast cancer.

[0022] In another embodiment, the present invention provides compounds for the treatment of benign or malignant diseases of the breast or reproductive organs, preferably for the treatment of breast cancer. DETAILED DESCRIPTION OF THE INVENTION

[0023] As used herein, the term "prodrug" refers to a precursor compound that, after administration, releases a biologically active compound in vivo through a chemical or physiological process. The prodrug itself may lack or possess the desired biological activity.

[0024] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item.

[0025] As used herein, the term "about," when referring to a measurable value, is meant to include a variation of ±10%, preferably ±5%, more preferably ±1%, and even more preferably ±0.1% from the particular value.

[0026] The term "cancer" refers to conditions including solid tumors, lymphomas, and leukemias. Examples of various types of cancer include, but are not limited to, breast cancer, lung cancer, ovarian cancer, prostate cancer, colorectal cancer, liver cancer, kidney cancer, bladder cancer, thyroid cancer, pleural cancer, pancreatic cancer, uterine cancer, cervical cancer, testicular cancer, anal cancer, bile duct cancer, gastrointestinal carcinoid tumors, esophageal cancer, gallbladder cancer, appendix cancer, small intestine cancer, stomach cancer, cancer of the central nervous system, skin cancer, choriocarcinoma, head and neck cancer, blood cancer, osteogenic sarcoma, fibrosarcoma, neuroblastoma, glioma, melanoma, B-cell lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, small cell lymphoma, large cell lymphoma, monocytic leukemia, myeloid leukemia, acute lymphocytic leukemia, acute myeloid leukemia, and multiple myeloma.

[0027] As used herein, the term "alkyl" refers to a straight-chain or branched saturated aliphatic group having 1 to about 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, and the like.

[0028] The term "alkenyl" refers to a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one carbon-carbon double bond. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5, or more. Preferred alkenyl groups include ethenyl (-CH=CH), 2-propenyl (allyl, -CH-CH=CH), and the like.

[0029] The term "alkynyl" refers to alkynyl groups having 2 to 10 carbon atoms and at least 1 or 2 sites of alkynyl unsaturation; preferred alkynyl groups include ethynyl (-C≡CH), propargyl (-CH2-C≡CH), 1-butenyl, 2-butenyl, isobutenyl, butadienyl, and the like.

[0030] The term "cycloalkyl" refers to a saturated carbocyclic group having 3 to 10 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl). Preferred cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0031] The term "heterocycle" refers to an organic compound containing a ring structure that includes atoms such as sulfur, oxygen, or nitrogen as part of the ring in addition to carbon. There can be multiple heteroatom substitutions selected from sulfur, oxygen, or nitrogen in the ring structure. The ring can be a saturated, partially saturated, or unsaturated ring structure, including "heterocycloalkyl" and "heteroaryl."

[0032] The term "heterocycloalkyl" refers to a C3-C10 cycloalkyl group according to the above definition, wherein up to four of the carbon atoms are replaced by heteroatoms selected from the group consisting of O, S, or N. Preferred heterocycloalkyls include pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, tetrahydrothiophenyl, and the like.

[0033] The term "aryl" means a cyclic aromatic hydrocarbon group consisting of one or more fused rings containing from 6 to 14 carbon atoms, wherein at least one ring is aromatic in nature, e.g., phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, indanyl, and the like.

[0034] The term "heteroaryl" refers to a cyclic aromatic hydrocarbon group consisting of one or more fused rings containing 5 to 14 ring atoms, preferably 5 to 10 ring atoms, wherein at least one ring is aromatic in nature and contains a heteroatom selected from N, O, or S, such as pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, benzoquinolyl, and the like.

[0035] The term "halogen" means chlorine, iodine, fluorine, and bromine.

[0036] The term "leaving group" or "L" or "L1" as used herein can be defined as a portion of a substrate that is cleaved by the action of a nucleophile. Examples of leaving groups include, but are not limited to, halogens (F, Cl, Br, and I), tosylate, mesylate, triflate, acetate, hydroxyl, camphorsulfonate, aryloxide, aryloxide, etc.

[0037] The term "alkoxy" refers to the group: --O-alkyl.

[0038] The term "alkoxyalkyloxy" refers to the group alkyl-O-alkyl-O-.

[0039] The term "alkoxycarbonyloxy" refers to the group alkyl-O-CO-O-.

[0040] The term "phosphate" means -O-PO(OH)2.

[0041] The term "phosphonyl" means -PO3H2.

[0042] The term "alkylphosphonate" means (-alkyl-O-PO(OH)2).

[0043] As used herein, the term "amino acid" refers to two stereoisomers, designated "D" and "L." D and L amino acids have identical physical properties and chemical reactivity. However, they rotate the plane of plane-polarized light in similar but opposite directions and react at different rates with asymmetric reagents. All amino acids naturally occurring in proteins are in the L form. Amino acids include lysine, valine, tryptophan, phenylalanine, methionine, leucine, threonine, isoleucine, arginine, histidine, tyrosine, carnitine, serine, glutamine, aspartic acid, proline, glycine, cysteine, alanine, and glutamic acid. Amino acids can exist as either the "D" or "L" enantiomer.

[0044] The term "-C(O)-amino acid" means an amino acid bonded to a carbonyl group via an amide or ester bond, more preferably an amide bond.

[0045] The term "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur.

[0046] The term "pharmaceutically acceptable carrier" means a non-toxic carrier that can be administered to a patient, together with a compound of the invention, and which does not destroy the pharmacological activity thereof.

[0047] As used herein, the term "pharmaceutically acceptable excipient" includes vehicles, adjuvants, or diluents, or other auxiliary substances such as those conventional in the art and readily available to the public. For example, pharmaceutically acceptable excipients include pH adjusting and buffering agents, osmotic pressure adjusting agents, stabilizers, wetting agents, etc.

[0048] The term "salt" as used herein refers to an acid or base salt of a compound of the present invention. Salts of basic compounds are salts formed with mineral acids, organic carboxylic acids, organic sulfonic acids, etc. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Salts of acidic compounds are formed with bases, i.e., cationic species such as alkali and alkaline earth metal cations (e.g., sodium, lithium, potassium, calcium, magnesium ions, and ammonium cations (e.g., ammonium, trimethylammonium, and diethylammonium)). Salts of acidic compounds are formed with organic bases, i.e., tromethamine and meglumine.

[0049] The compounds of the present invention contain one or more asymmetric carbon atoms and therefore exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each asymmetric carbon center can be in the R or S configuration.

[0050] The term "deprotecting agent" as used herein includes, but is not limited to, hydrogen and palladium on carbon (H, Pd / C), ammonium formate and palladium on carbon (HCOONH, Pd / C), hydrogen and palladium hydroxide on carbon (H, Pd(OH) / C), combinations of Pd / C and Pd(OH) / C, and acids such as hydrochloric acid and hydrobromic acid.

[0051] For purposes of the present invention, the term "substituted" shall be understood to include the addition of one or more different atoms to one or more atoms contained in a functional group or compound, or the replacement of one or more atoms contained in a functional group or compound with one or more different atoms.

[0052] Unless otherwise constrained by the definition of each substituent, the aforementioned groups, such as "alkyl," "alkenyl," "alkynyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl," may be optionally substituted with one or more substituents selected from the group consisting of "C1-C8-alkyl," "C2-C8-alkenyl," "C2-C8-alkynyl," "cycloalkyl," "heterocycloalkyl," "aryl," "heteroaryl," "amino," "alkylamino," "acyl," "acyloxy," "acylamino," "aminocarbonyl," "alkoxycarbonyl," "alkoxyalkyloxy," "alkoxycarbonyloxy," "carbamate," "sulfinyl," "sulfonyl," "alkoxy," "sulfanyl," "halogen," "carboxy," "trihalomethyl," "cyano," "hydroxy," "mercapto," "nitro," "phosphate," "alkylphosphate," etc. The number of the one or more substituents is preferably selected from 1 to 10, more preferably 1 to 5.

[0053] The term "coupling reagent" as used herein includes O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate (HBTU), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), acid halides, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-aza-1H-benzotriazole (HOAt), diisopropylcarbodiimide (DIC), ), dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), 2-(6-chloro-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylaminium hexafluorophosphate (HCTU), 1-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethyl-aminomorpholino]-uronium hexafluorophosphate (COMU), and the like.

[0054] The base used in the present invention can be an inorganic base or an organic base. Examples of organic bases include, but are not limited to, amines such as diisopropylethylamine, triethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, N,N-dimethylaniline, N,N-dimethylaminopyridine (DMAP), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or mixtures thereof. Examples of inorganic bases include, but are not limited to, alkali or alkaline earth metal carbonates, bicarbonates, hydroxides, or phosphates such as potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, and sodium phosphate; hydrides such as sodium hydride, lithium hydride, or potassium hydride; alkoxides such as sodium or potassium methoxide or ethoxide, tert-butoxide, or mixtures thereof.

[0055] The term "solvent" as used herein means solvents including, but not limited to, nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, etc.; ethers such as dioxane, diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, etc.; hydrocarbons such as toluene, xylene, hexane, heptane, cyclohexane, etc.; chlorinated hydrocarbons such as methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform, chlorobenzene, etc.; polar aprotic solvents such as N,N-dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO), etc., or mixtures thereof.

[0056] The novel compounds of the present invention can be used in conventional solid or liquid pharmaceutical forms, such as uncoated or film-coated tablets, capsules, powders, granules, solutions, or sprays. For this purpose, the active substance can be treated with conventional pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, sustained-release agents, antioxidants, and / or propellant gases.

[0057] The prodrugs of the present invention are characterized by unexpectedly high water solubility. This solubility allows for the administration of higher doses of the prodrug, resulting in a larger amount of drug per unit dose. The prodrugs of the present invention are also characterized by easy hydrolytic cleavage, which releases the active fulvestrant in vivo. The high water solubility and easy in vivo metabolism increase the bioavailability of the drug.

[0058] When a prodrug of the present invention is co-administered in combination therapy with other agents, they can be administered sequentially or simultaneously to a patient. Alternatively, a pharmaceutical composition of the present invention can be comprised of a combination of a prodrug of the present invention with another therapeutic agent.

[0059] In one embodiment, the present invention provides a compound of formula I: [ka] (In the formula, R1 is: [ka] wherein R17 is selected from NH2, NHR18, or NR19R20; R18 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, which may be optionally substituted; R19 and R20 are independently selected from the group consisting of alkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, which may be optionally substituted; or R19 and R20 together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle, optionally containing one or more substituted aryls at substitutable positions. and optionally substituted with R groups, wherein the one or more R groups are each independently selected from the group consisting of alkyl, alkylcarbonyl, formyl, halo, haloalkyl, alkylphosphate, phosphate, oxo, cyano, nitro, amino, alkoxy, alkoxycarbonyl, carboxyalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylthio, cycloalkyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, and alkoxyalkyl, each of which is optionally substituted; R2 independently represents one of the following i) to iv): [ka] wherein R21 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; or -CR22R23; wherein R22 and R23 together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and which is optionally substituted at substitutable positions with one or more R24 groups, each independently selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl, formyl, halo, alkylphosphate, phosphate, cyano, nitro, alkoxy, amino, alkoxycarbonyl, alkenyl, alkynyl, alkylthio, and arylcarbonyl; [ka] (wherein each R25 is independently selected from hydrogen; optionally substituted alkyl, aryl, or heteroaryl); [ka] wherein each R26 is independently selected from hydrogen; optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; iv) an amino acid attached via an ester bond at the attachment point; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0060] In one embodiment, the present invention provides a compound of formula I: [ka] (In the formula, R1 is: [ka] wherein R17 is selected from NH2, NHR18, or NR19R20; R18 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, which may be optionally substituted; R19 and R20 are independently selected from the group consisting of alkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, which may be optionally substituted; or R19 and R20 together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle, which may be optionally substituted with one or more R21 groups at substitutable positions; The one or more R groups are each independently selected from the group consisting of optionally substituted alkyl, alkylcarbonyl, formyl, halo, haloalkyl, alkylphosphate, phosphate, oxo, cyano, nitro, amino, alkoxy, alkoxycarbonyl, carboxyalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylthio, cycloalkyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, and alkoxyalkyl; R2 is: [ka] wherein R21 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; or -CR22R23; wherein R22 and R23 together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and which is optionally substituted at substitutable positions with one or more R24 groups, each independently selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl, formyl, halo, alkylphosphate, phosphate, cyano, nitro, alkoxy, amino, alkoxycarbonyl, alkenyl, alkynyl, alkylthio, and arylcarbonyl); and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0061] In one embodiment, the present invention provides a compound of formula I: [ka] (In the formula, R1 is: [ka] wherein R17 is selected from NH2, NHR18, or NR19R20; R18 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, which may be optionally substituted; R19 and R20 are independently selected from the group consisting of alkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, which may be optionally substituted; or R19 and R20 together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle, which may be optionally substituted with one or more R21 groups at substitutable positions; The one or more R groups are each independently selected from the group consisting of optionally substituted alkyl, alkylcarbonyl, formyl, halo, haloalkyl, alkylphosphate, phosphate, oxo, cyano, nitro, amino, alkoxy, alkoxycarbonyl, carboxyalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylthio, cycloalkyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, and alkoxyalkyl; R2 is: [ka] wherein each R25 is independently selected from hydrogen; optionally substituted alkyl, aryl, or heteroaryl; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0062] In one embodiment, the present invention provides a compound of formula I: [ka] (In the formula, R1 is: [ka] wherein R17 is selected from NH2, NHR18, or NR19R20; R18 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, which may be optionally substituted; R19 and R20 are independently selected from the group consisting of alkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, which may be optionally substituted; or R19 and R20 together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle, which may be optionally substituted with one or more R21 groups at substitutable positions; The one or more R groups are each independently selected from the group consisting of optionally substituted alkyl, alkylcarbonyl, formyl, halo, haloalkyl, alkylphosphate, phosphate, oxo, cyano, nitro, amino, alkoxy, alkoxycarbonyl, carboxyalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylthio, cycloalkyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, and alkoxyalkyl; R2 is: [ka] wherein each R26 is independently selected from hydrogen; optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0063] In one embodiment, the present invention provides a compound of formula I: [ka] (In the formula, R1 is: [ka] wherein R17 is selected from NH2, NHR18, or NR19R20; R18 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, which may be optionally substituted; R19 and R20 are independently selected from the group consisting of alkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, which may be optionally substituted; or R19 and R20 together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle, which may be optionally substituted with one or more R21 groups at substitutable positions; The one or more R groups are each independently selected from the group consisting of optionally substituted alkyl, alkylcarbonyl, formyl, halo, haloalkyl, alkylphosphate, phosphate, oxo, cyano, nitro, amino, alkoxy, alkoxycarbonyl, carboxyalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylthio, cycloalkyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, and alkoxyalkyl; R2 is an amino acid attached via an ester bond at the attachment point. and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0064] In another embodiment, the present invention provides a compound of formula II: [ka] wherein X is selected from O, C, and N; Y is selected from optionally substituted aryl, heteroaryl, heterocycloalkyl, or cycloalkyl; R3 independently represents one of the following i) to iv): [ka] wherein R21 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; or -CR22R23; wherein R22 and R23 together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and which is optionally substituted at substitutable positions with one or more R24 groups, each independently selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl, formyl, halo, alkylphosphate, phosphate, cyano, nitro, alkoxy, alkoxycarbonyl, alkenyl, alkynyl, alkylthio, and arylcarbonyl; [ka] (wherein each R25 is independently selected from hydrogen; optionally substituted alkyl, aryl, or heteroaryl); [ka] wherein each R26 is independently selected from hydrogen; optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; iv) an amino acid attached via an ester bond at the attachment point; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0065] In a preferred embodiment, the present invention provides a compound of formula II: [ka] wherein X is selected from O, C, and N; Y is selected from optionally substituted aryl, heteroaryl, heterocycloalkyl, or cycloalkyl; said one or more substitutions are selected from alkyl or alkoxy; R3 independently represents one of the following i) to iv): [ka] wherein R21 is an optionally substituted alkyl; one or more substitutions are selected from amino, phosphate, alkylphosphate, or hydroxy; [ka] (wherein each R25 is independently selected from hydrogen; optionally substituted alkyl); [ka] (wherein each R26 is independently selected from hydrogen; optionally substituted alkyl); iv) an amino acid attached via an ester bond at the attachment point; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0066] In another embodiment, the present invention provides a compound of formula III: [ka] wherein R5 is selected from hydrogen, alkyl; R6 is selected from optionally substituted alkyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl; R4 independently represents one of the following i) to iv): [ka] wherein R21 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; or -CR22R23; wherein R22 and R23 together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and which is optionally substituted at substitutable positions with one or more R24 groups, each independently selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkylcarbonyl, formyl, halo, alkylphosphate, phosphate, cyano, nitro, alkoxy, amino, alkoxycarbonyl, alkenyl, alkynyl, alkylthio, and arylcarbonyl; [ka] (wherein each R25 is independently selected from hydrogen; optionally substituted alkyl, aryl, or heteroaryl); [ka] wherein each R26 is independently selected from hydrogen; optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; iv) an amino acid attached via an ester bond at the attachment point; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0067] In another embodiment, the present invention provides a compound of formula III: [ka] wherein R5 is selected from hydrogen, alkyl; R6 is selected from the group including optionally substituted alkyl or aryl, wherein one or more substitutions are selected from alkyl, alkoxy, halo, heteroaryl, heterocycloalkyl, cycloalkyl, amino, or hydroxy; R4 independently represents one of the following i) to iv): [ka] wherein R21 is an optionally substituted alkyl; one or more substitutions are selected from amino, phosphate, alkylphosphate, or hydroxy; [ka] (wherein each R25 is independently selected from hydrogen or optionally substituted alkyl); [ka] (wherein each R26 is independently selected from hydrogen or optionally substituted alkyl); iv) an amino acid attached via an ester bond at the attachment point; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0068] In another embodiment, the present invention provides a compound selected from the group consisting of: [ka] and pharmaceutically acceptable salts or solvates thereof.

[0069] In another embodiment, the present invention provides a compound of formula IV: [ka] (Wherein R7 is the following: [ka] or [ka] wherein R25 and R26 are each independently selected from hydrogen; optionally substituted alkyl, aryl, or heteroaryl; R8 independently represents one of the following i) to v): [ka] wherein R21 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; or -CR22R23; wherein R22 and R23 together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and which is optionally substituted at substitutable positions with one or more R24 groups, each independently selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl, formyl, halo, alkylphosphate, phosphate, cyano, nitro, alkoxy, amino, alkoxycarbonyl, alkenyl, alkynyl, alkylthio, and arylcarbonyl; [ka] wherein R17 is selected from NH2, NHR18, or NR19R20; R18 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, which may be optionally substituted; R19 and R20 are independently selected from the group consisting of alkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, which may be optionally substituted; or R19 and R20 together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle, optionally substituted with one or more R21 groups at substitutable positions. wherein the one or more R groups are independently selected from the group consisting of optionally substituted alkyl, alkylcarbonyl, formyl, halo, haloalkyl, alkylphosphate, phosphate, oxo, cyano, nitro, amino, alkoxy, alkoxycarbonyl, -C(O)-amino acid, carboxyl, carboxyalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylthio, cycloalkyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, and alkoxyalkyl; [ka] wherein R27 is selected from the group including optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; [ka] wherein R28 is selected from the group including optionally substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and one or more substitutions are selected from formyl, halo, phosphate, cyano, nitro, or amino. v) an amino acid attached via an ester bond at the attachment point; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0070] In another embodiment, the present invention provides a compound of formula IV: [ka] (Wherein R7 is the following: [ka] or [ka] wherein R25 and R26 are each independently selected from hydrogen; optionally substituted alkyl, aryl, or heteroaryl; R8 is: [ka] wherein R21 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; or -CR22R23; wherein R22 and R23 together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and which is optionally substituted at substitutable positions with one or more R24 groups, each independently selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl, formyl, halo, alkylphosphate, phosphate, cyano, nitro, alkoxy, amino, alkoxycarbonyl, alkenyl, alkynyl, alkylthio, and arylcarbonyl); and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0071] In another embodiment, the present invention provides a compound of formula IV: [ka] (Wherein R7 is the following: [ka] or [ka] wherein R25 and R26 are each independently selected from hydrogen; optionally substituted alkyl, aryl, or heteroaryl; R8 is: [ka] wherein R17 is selected from NH2, NHR18, or NR19R20; R18 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, which may be optionally substituted; R19 and R20 are independently selected from the group consisting of alkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, which may be optionally substituted; or R19 and R20 together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle, optionally substituted with one or more R21 groups at substitutable positions. wherein the one or more R groups are independently selected from the group consisting of alkyl, alkylcarbonyl, formyl, halo, haloalkyl, alkylphosphate, phosphate, oxo, cyano, nitro, amino, alkoxy, alkoxycarbonyl, -C(O)-amino acid, carboxyl, carboxyalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylthio, cycloalkyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, and alkoxyalkyl, each of which may be optionally substituted; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0072] In another embodiment, the present invention provides a compound of formula IV: [ka] (Wherein R7 is the following: [ka] or [ka] wherein R25 and R26 are each independently selected from hydrogen; optionally substituted alkyl, aryl, or heteroaryl; R8 is: [ka] wherein R27 is selected from the group including optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0073] In another embodiment, the present invention provides a compound of formula IV: [ka] (Wherein R7 is the following: [ka] or [ka] wherein R25 and R26 are each independently selected from hydrogen; optionally substituted alkyl, aryl, or heteroaryl; R8 is: [ka] wherein R28 is selected from the group including optionally substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and one or more substitutions are selected from formyl, halo, phosphate, cyano, nitro, or amino. and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0074] In another embodiment, the present invention provides a compound of formula IV: [ka] (Wherein R7 is the following: [ka] or [ka] wherein R25 and R26 are each independently selected from hydrogen; optionally substituted alkyl, aryl, or heteroaryl; R8 is an amino acid attached via an ester bond at the attachment point; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0075] In another embodiment, the present invention provides a compound of formula V: [ka] wherein W is selected from the group consisting of hydrogen or optionally substituted alkyl; R9 independently represents one of the following i) to v): [ka] wherein R21 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; or -CR22R23; wherein R22 and R23 together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and which is optionally substituted at substitutable positions with one or more R24 groups, and each of the one or more R24 groups is independently selected from the group consisting of optionally substituted alkyl, cycloalkyl, aryl, and heteroaryl; [ka] wherein R17 is selected from NHR18 or NR19R20; R18 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R19 and R20 together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle, optionally substituted at substitutable positions with one or more R21 groups, each independently selected from the group consisting of optionally substituted alkyl, carboxyl, alkylcarbonyl, amino, -C(O)-amino acid, cycloalkyl, aryl, aralkyl, and heterocycloalkyl; [ka] wherein R27 is selected from the group including optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; the substitution can be amino; [ka] wherein R28 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and the substitution is amino; v) an amino acid attached via an ester bond at the attachment point; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0076] In another embodiment, the present invention provides a compound of formula VA: [ka] wherein W is selected from the group consisting of hydrogen or optionally substituted alkyl; R9 independently represents one of the following i) to v): [ka] wherein R21 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; or -CR22R23; wherein R22 and R23 together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and which is optionally substituted at substitutable positions with one or more R24 groups, and each of the one or more R24 groups is independently selected from the group consisting of optionally substituted alkyl, cycloalkyl, aryl, and heteroaryl; [ka] wherein R17 is selected from NHR18 or NR19R20; R18 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R19 and R20 together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle, optionally substituted at substitutable positions with one or more R21 groups, each independently selected from the group consisting of optionally substituted alkyl, carboxyl, alkylcarbonyl, amino, -C(O)-amino acid, cycloalkyl, aryl, aralkyl, and heterocycloalkyl; [ka] wherein R27 is selected from the group including optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; the substitution can be amino; [ka] wherein R28 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and the substitution is amino; v) an amino acid attached via an ester bond at the attachment point; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0077] In another embodiment, the present invention provides a compound selected from the group consisting of: [ka] and pharmaceutically acceptable salts or solvates thereof.

[0078] In another embodiment, the present invention provides the following compound: [ka] and pharmaceutically acceptable salts or solvates thereof.

[0079] In another embodiment, the present invention provides a compound selected from the group consisting of: [ka] [ka] and pharmaceutically acceptable salts or solvates thereof.

[0080] In another embodiment, the present invention provides the following compound: [ka] and pharmaceutically acceptable salts or solvates thereof.

[0081] In another embodiment, the present invention provides a compound of formula VI: [ka] (Wherein R10 is the following: [ka] wherein R28 is selected from the group including optionally substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and one or more substitutions are selected from formyl, halo, phosphate, cyano, nitro, amino, hydroxy, heterocycloalkyl, or alkoxy; R11 is hydrogen or: [ka] wherein R21 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; or -CR22R23; wherein R22 and R23 together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and optionally substituted at substitutable positions with one or more R24 groups, wherein the one or more R24 groups are each independently selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl, formyl, halo, alkylphosphate, phosphate, cyano, nitro, alkoxy, amino, alkoxycarbonyl, alkenyl, alkynyl, alkylthio, and arylcarbonyl; provided that when R11 is hydrogen, R10 is not methyl or ethyl. and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0082] In another embodiment, the present invention provides a compound of formula VII: [ka] wherein Z1 and Z2 are each independently selected from optionally substituted hydroxy, phosphate, or heterocycloalkyl; R12 is hydrogen or: [ka] wherein R21 is selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; or -CR22R23; wherein R22 and R23 together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and which is optionally substituted at substitutable positions with one or more R24 groups, each independently selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl, formyl, halo, alkylphosphate, phosphate, cyano, nitro, alkoxy, alkoxycarbonyl, alkenyl, alkynyl, alkylthio, and arylcarbonyl); and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0083] In another embodiment, the present invention provides a compound of formula VII: [ka] wherein Z1 and Z2 are each independently selected from optionally substituted hydroxy, phosphate, or heterocycloalkyl; R12 is hydrogen or: [ka] wherein R21 is selected from the group including optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl; one or more substitutions are selected from alkyl, amino, or cycloalkyl); and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0084] In another embodiment, the present invention provides a compound selected from the group consisting of: [ka] and pharmaceutically acceptable salts or solvates thereof.

[0085] In another embodiment, the present invention provides a compound of formula VIII: [ka] wherein R13 is H; optionally substituted alkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl; R14 is optionally substituted alkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl; or R13 and R14 together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle, optionally substituted at substitutable positions with one or more R21 groups, each independently selected from the group consisting of optionally substituted alkyl, alkylcarbonyl, formyl, halo, haloalkyl, alkylphosphate, phosphate, phosphonyl, oxo, cyano, nitro, amino, alkoxy, alkoxycarbonyl, carboxyalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylthio, cycloalkyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, and alkoxyalkyl; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0086] In another embodiment, the present invention provides a compound of formula VIII: [ka] wherein R13 and R14 together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle, optionally substituted at substitutable positions with one or more R21 groups, each independently selected from the group consisting of alkyl, alkylcarbonyl, formyl, halo, haloalkyl, alkylphosphate, phosphate, phosphonyl, oxo, cyano, nitro, amino, alkoxy, alkoxycarbonyl, carboxyalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylthio, cycloalkyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, and alkoxyalkyl; and enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, or solvates thereof. In one embodiment, one or more substitutions on the R21 group are selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, alkylamino, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, alkoxyalkyloxy, alkoxycarbonyloxy, carbamate, sulfinyl, sulfonyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, nitro, phosphate, alkylphosphate. In another embodiment, the present invention provides a compound of formula VIII: [ka] wherein R13 and R14 together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle, substituted at available positions with one or more R21 groups, each independently selected from the group consisting of alkyl, alkylcarbonyl, formyl, halo, haloalkyl, alkylphosphate, phosphate, phosphonyl, oxo, cyano, nitro, amino, alkoxy, alkoxycarbonyl, carboxyalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylthio, cycloalkyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, and alkoxyalkyl; and enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, or solvates thereof. In one embodiment, the one or more substitutions on the R21 group are selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, alkylamino, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, alkoxyalkyloxy, alkoxycarbonyloxy, carbamate, sulfinyl, sulfonyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, nitro, phosphate, alkylphosphate.

[0087] In another embodiment, the present invention provides a compound of formula VIII: [ka] wherein R13 is selected from hydrogen, alkyl; R14 is selected from the group consisting of optionally substituted alkyl, heterocycloalkyl, or aryl; one or more substitutions are selected from alkyl, alkoxy, halo, heteroaryl, heterocycloalkyl, cycloalkyl, amino, or hydroxy; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0088] In another embodiment, the present invention provides a compound selected from the group consisting of: [ka] and pharmaceutically acceptable salts or solvates thereof.

[0089] In another embodiment, the present invention provides a prodrug of fulvestrant of formula IX: [ka] wherein S is selected from O, C, or N; T is optionally substituted aryl, heteroaryl, heterocycloalkyl, cycloalkyl, amino, [ka] or [ka] and wherein one or more substitutions are selected from alkyl, alkoxy; and enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates thereof.

[0090] In another embodiment, the present invention provides a compound selected from the group consisting of: [ka] and pharmaceutically acceptable salts or solvates thereof.

[0091] In another embodiment, the present invention provides a prodrug of fulvestrant of formula X: [ka] wherein Q is selected from C or N; When Q is C, P1 is independently optionally substituted alkyl, optionally substituted: [ka] Selected from the following: [ka] is alkyl; P2 and P3 are independently selected from hydrogen or alkyl; When Q is N, P2 is independently optionally substituted alkyl, optionally substituted: [ka] Selected from the following: [ka] is alkyl; P1 is hydrogen and P3 is optionally substituted alkyl; and their enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates.

[0092] In another embodiment, the present invention provides a compound selected from the group consisting of: [ka] and pharmaceutically acceptable salts or solvates thereof.

[0093] In another embodiment, the present invention provides a compound of formula XI: [ka] wherein R15 and R16 together form a cyclic structure; said cyclic structure is selected from optionally substituted cycloalkyl or heterocycloalkyl; one or more substitutions are selected from alkyl, alkoxy, halo, amino, or hydroxy; and m and n can independently be 1 to 3; and enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, or solvates thereof.

[0094] In a preferred embodiment, the invention relates to compounds of formula XI, wherein m and n are both 1 or 2.

[0095] In another embodiment, the present invention provides a compound selected from the group consisting of: [ka] and pharmaceutically acceptable salts and solvates thereof.

[0096] In another embodiment, the present invention provides a compound selected from the group consisting of: [ka] and pharmaceutically acceptable salts or solvates thereof.

[0097] In another embodiment, the present invention relates to the meglumine salt of the following compound: [ka]

[0098] In another embodiment, the present invention relates to the dimeglumine salt of the following compound: [ka]

[0099] In another embodiment, the present invention relates to the following compounds: [ka]

[0100] In another embodiment, the compounds of the present invention can also be delivered in the form of a pharmaceutical composition comprising a compound of the present invention, and its enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates, and a pharmaceutically acceptable excipient.

[0101] In another embodiment, the present invention relates to a pharmaceutical composition comprising a fulvestrant prodrug, and its enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates, and a pharmaceutically acceptable excipient.

[0102] The fulvestrant prodrug of the pharmaceutical composition is selected from compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI; and enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, and solvates thereof.

[0103] The pharmaceutical compositions of the present disclosure can be in any form known to those of skill in the art. The pharmaceutical compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccal tablet, or via an implanted reservoir, preferably orally or by injection.

[0104] For example, in some embodiments, the pharmaceutical composition comprising the desired product is formulated for oral delivery, hi one embodiment, the pharmaceutical composition comprising the desired product is selected from the group consisting of a concentrate, a dry powder, a liquid, a capsule, a pellet, and a pill.

[0105] For example, in some embodiments, the pharmaceutical composition comprising the desired product is for parenteral administration, hi one embodiment, the pharmaceutical composition comprising the desired product is selected from the group consisting of intravenous injection, intramuscular injection, subcutaneous injection, powder for injectable solution, powder for injectable suspension, liposomes, oily injection, and sustained release particles.

[0106] The pharmaceutical compositions disclosed herein may also further comprise carriers, binders, diluents, and excipients.

[0107] In one embodiment, the present disclosure provides a pharmaceutical composition in the form of a fulvestrant prodrug for the treatment of a disease and / or condition that the parent drug molecule is intended to treat, wherein the composition may contain an amount of the fulvestrant prodrug that is as therapeutically effective as the parent drug, or a more therapeutically effective amount.

[0108] In another embodiment, the present invention provides the use of a compound of the invention in the preparation of a pharmaceutical formulation as described above for the treatment of benign or malignant diseases of the breast or reproductive organs, preferably for the treatment of breast cancer.

[0109] In another embodiment, the present invention provides compounds for the treatment of benign or malignant diseases of the breast or reproductive organs, preferably for the treatment of breast cancer.

[0110] In another embodiment, the present invention provides fulvestrant prodrugs useful in the treatment of estrogen-dependent indications such as breast cancer, and gynecological disorders such as endometriosis.

[0111] The fulvestrant prodrug for said treatment of benign or malignant diseases of the breast or reproductive organs is selected from the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VA, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI.

[0112] In another embodiment, the present invention provides a method of treating a benign or malignant disease of the breast or reproductive organs, preferably treating breast cancer, comprising the administration of a compound selected from Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI; and enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, and solvates thereof.

[0113] In another embodiment, the present invention provides a method of treating a benign or malignant disease of the breast or reproductive organs, preferably treating breast cancer, comprising the administration of a compound selected from Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VA, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI; and enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof.

[0114] In yet another embodiment, the present disclosure relates to the new fulvestrant prodrugs and any stereochemically isomeric forms, hydrates, solvates, or pharmaceutically acceptable salts thereof, by themselves or in combination with at least one additional therapeutic agent, in the treatment of diseases and / or conditions that the original drug is intended to treat. The combination with the additional therapeutic agent can take the form of combining the new fulvestrant prodrug compounds with any known therapeutic agent.

[0115] The following examples are given for the purpose of illustrating the present invention and should not be construed as limiting the scope of the present invention.

[0116] Example 01: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-(piperidin-1-yl)phenyl)carbamate [ka] To a stirred solution of fulvestrant (0.5 g) in dichloromethane (7 mL), diisopropylethylamine (0.21 mL) and triphosgene (0.122 g) were added at 0° C., and the reaction mixture was stirred at the same temperature for 10 minutes. After 10 minutes, 4-(piperidin-1-yl)aniline (0.218 g) was added to the reaction mixture at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (3×40 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain a crude material. The crude material was purified by preparative HPLC and the product fractions were lyophilized to afford 0.060 g of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-(piperidin-1-yl)phenyl)carbamate as a white solid. LCMS: 99.69% (m / z: 809.59, [M+1]+, 214nm). 1H NMR (400 MHz, DMSO-d6): δ 9.85 (s, 1H), 7.30 (m, 3H), 6.89 (m, 4H), 4.49 (s, 1H), 3.54 (m, 1H), 3.03 (t, J = 5.2 Hz, 4H), 2.87-2.80 (m, 2H), 2.75-2.70 (m, 3H), 2.68-2.66 (m, 1H), 2.50-2.49 (m, 2H), 2.38-2.29 (m, 2H), 1.92 - 1.88 (m, 3H), 1.82 (d, J = 12.4 Hz, 1H), 1.75 (m, 1H), 1.63-1.58 (m, 7H), 1.52-1.49 (m, 3H), 1.38-1.20 (m, 18H) 0.9 (m, 1H), 0.68 (s, 3H).

[0117] Example 02: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl-4-(phosphonooxy)piperidine-1-carboxylate [ka] Step 1: Preparation of tert-butyl 4-((bis(benzyloxy)phosphoryl)oxy)piperidine-1-carboxylate A stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g) in tetrahydrofuran (20 mL) was cooled to -10 °C, and then a 1 M solution of sodium bis(trimethylsilyl)amide (NaHMDS) in tetrahydrofuran (9.9 mL) was added, and the reaction mixture was stirred at the same temperature for 30 minutes. Tetrabenzyl diphosphate (5.34 g) was then added, and the reaction mixture was again stirred at room temperature for 16 hours. After completion of the reaction by TLC, the mixture was diluted with water, extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude material (2.1 g, crude LCMS purity 70%) as a pale yellow solid. The crude material was used in the next step without further purification. LCMS purity: 70.00% Step 2: Preparation of dibenzylpiperidin-4-yl phosphate (trifluoroacetate salt) [ka] To a stirred solution of tert-butyl 4-((bis(benzyloxy)phosphoryl)oxy)piperidine-1-carboxylate (1 g of the crude material) in dichloromethane (40 mL) was added trifluoroacetic acid (6 mL) at 0° C. and stirred at the same temperature for 2 hours. After completion of the reaction by TLC, the mixture was concentrated under reduced pressure to give the crude material (1.0 g, crude LCMS purity 63.6%) as a sticky yellow solid. The crude material was used in the next step without further purification. LCMS purity: 63.60% Step 3: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl-4-((bis(benzyloxy)phosphoryl)oxy)piperidine-1-carboxylate [ka] To a stirred solution of (7R,8R,9S,13S,14S,17S)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol (1 g) in dichloromethane (20 mL) was added diisopropylethylamine (0.55 mL) and triphosgene (0.245 mL) at 0°C, and the mixture was stirred at the same temperature for 10 minutes. Then, dibenzylpiperidin-4-yl phosphate (trifluoroacetate salt) (0.9 g) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with dichloromethane (2×50 mL), and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude material (1.1 g, crude LCMS purity 27%) as a colorless thick oil, which was used in the next step without further purification. LCMS purity: 27.00% Step 4: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl-4-(phosphonooxy)piperidine-1-carboxylate [ka] To a stirred solution of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl-4-((bis(benzyloxy)phosphoryl)oxy)piperidine-1-carboxylate (0.68 g of the crude material) in methanol (40 mL) was added 10% palladium on charcoal:10% palladium hydroxide (1:1, 540 mg), and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction by TLC, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to provide the crude material (0.6 g, crude LCMS purity 44%). The crude material was purified by preparative HPLC and the product fractions were lyophilized to give 0.047 g of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl-4-(phosphonooxy)piperidine-1-carboxylate as a white solid. LCMS: 97.8% (m / z: 812.22, [M+1]+,214nm). 1H NMR (400 MHz, DMSO-d6): δ 7.22 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 2 Hz, 1H), 4.24 (bd, J = 3.6 Hz,1H), 3.74 (bs, 1H), 3.67 (bs, 1H), 3.51 (t, J = 8.4 Hz, 1H), 3.36 (bs, 1H), 3.22 (bs, 1H), 2.83-2.75 (m, 2H), 2.74-2.61 (m, 4H), 2.24- 2.21 (m, 4H), 1.92- 1.77 (m, 6H), 1.71- 1.62 (m, 1H), 1.62-1.42 (m, 6H), 1.41-1.01 (m, 19H), 0.81 (bs, 1H), 0.64 (s, 3H).

[0118] Example 03: Preparation of (7R,8R,9S,13S,14S,17S)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-3-(phosphonooxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl 3-(dimethylamino)propanoate [ka] Step 1: Preparation of (7R,8R,9S,13S,14S,17S)-3-((bis(benzyloxy)phosphoryl)oxy)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl 3-(dimethylamino)propanoate To a stirred solution of dibenzyl ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)phosphate (1 g) in dimethylformamide (10 mL) was added dicyclohexylcarbodiimide (0.712 g) and 4-dimethylaminopyridine (0.07 g) at 0° C. After 20 minutes, 3-(dimethylamino)propanoic acid hydrogen chloride (0.529 g) was added, and the resulting mixture was stirred at room temperature for 4 hours. After completion of the reaction by LCMS, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude material (0.75 g, crude LCMS purity 38%) as a yellow sticky solid, which was used in the next step without further purification. LCMS purity: 38.00% Step 2: Preparation of (7R,8R,9S,13S,14S,17S)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-3-(phosphonooxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl 3-(dimethylamino)propanoate [ka] To a stirred solution of (7R,8R,9S,13S,14S,17S)-3-((bis(benzyloxy)phosphoryl)oxy)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl 3-(dimethylamino)propanoate (0.75 g of the crude material above) in methanol (50 mL) was added 10% palladium on carbon:10% palladium hydroxide (1:1, 0.6 g), and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction by TLC, the reaction mixture was filtered through a bed of Celite, and the filtrate was concentrated under reduced pressure to give the crude material (0.510 g, LCMS purity 69%). The crude material was purified by preparative HPLC and the product fractions were lyophilized to give 0.13 g of (7R,8R,9S,13S,14S,17S)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-3-(phosphonooxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl-3-(dimethylamino)propanoate as a white solid. LCMS: 90.2% (m / z: 786.32 [M+1]+, 214nm). 1H NMR (400 MHz, DMSO-d6): δ 7.07 (d, J = 8 Hz, 1H), 6.83 (s, 1H), 6.82 (d, J = 7.8 Hz, 1H), 4.65 (t, J = 8.4 Hz, 1H), 2.86-2.81 (m, 3H), 2.76-2.61 (m, 4H), 2.63-2.61 (m, 2H), 2.43-2.33 (m, 10H), 2.28-2.20 (m, 2H), 2.10 (bs, 1H), 1.92-1.88 (m, 2H), 1.65-1.56 (m, 5H), 1.51-1.42 (m, 3H), 1.38-1.17 (m, 17H), 0.91 (bs, 1H), 0.64 (s, 3H).

[0119] Example 04: Preparation of (7R,8R,9S,13S,14S,17S)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-3-(phosphonooxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl[1,4'-bipiperidine]-1'-carboxylate Step 1: Preparation of (7R,8R,9S,13S,14S,17S)-3-((bis(benzyloxy)phosphoryl)oxy)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl[1,4'-bipiperidine]-1'-carboxylate [ka] To a solution of dibenzyl ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)phosphate (0.300 g) in tetrahydrofuran (5 mL) was added sodium bis(trimethylsilyl)amide (0.7 mL) at 0° C. The resulting mixture was stirred at the same temperature for 30 minutes. Then, [1,4′-bipiperidine]-1′-carbonyl chloride (0.160 g) was added at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by LCMS, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude material (320 mg, LCMS purity 35%) as a brown sticky solid, which was used in the next step without further purification. LCMS purity: 35.00% Step 2: Preparation of (7R,8R,9S,13S,14S,17S)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-3-(phosphonooxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl[1,4'-bipiperidine]-1'-carboxylate [ka] A solution of (7R,8R,9S,13S,14S,17S)-3-((bis(benzyloxy)phosphoryl)oxy)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl[1,4'-bipiperidine]-1'-carboxylate (0.250 mg of crude material from Step 1) in trifluoroacetic acid (6 mL) was stirred at 70°C for 2 hours. After completion by LCMS, the reaction was cooled to room temperature and concentrated under reduced pressure to give the crude material (200 mg, LCMS purity 19%). The crude material was purified by preparative HPLC and the product fractions were lyophilized to give 0.02 g of (7R,8R,9S,13S,14S,17S)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-3-(phosphonooxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl[1,4′-bipiperidine]-1′-carboxylate as a white solid. LCMS: 96.7% (m / z: 881.52, [M+1]+,214nm). 1H NMR (400 MHz, DMSO-d6): δ 7.16 (bs, 1H), 6.75 (bs, 2H), 4.08-4.06 (m, 3H), 2.99-2.50 (m, 10H), 2.39-2.32 (m, 5H), 2.03-1.86 (m, 7H), 1.79-1.50 (m, 14H), 1.33-1.21 (m, 20H), 0.92 (m, 1H), 0.66 (s, 3H).

[0120] Example 05: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl-methyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)carbamate Step 1: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate [ka] To a stirred solution of fulvestrant (2.0 g) in acetonitrile (20 mL) was added cesium carbonate (3.24 g) and 4-nitrophenyl chloroformate (0.99 g) at room temperature, and the reaction mixture was stirred at the same temperature for 15 minutes. After completion of the reaction by TLC, the reaction was diluted with water (15 mL) and extracted with ethyl acetate (2×30 mL), the combined organic layers were dried over anhydrous sodium sulfate, and the organics were concentrated under reduced pressure to afford (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate (2.3 g crude material, LCMS 60%), which was used in the next step without further purification. LCMS purity: 60.00% Step 2: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl-methyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)carbamate [ka] To a stirred solution of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate (0.5 g) in dimethylformamide (3 mL) was added (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol (0.370 g) at room temperature, and the reaction mixture was stirred at the same temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layers were combined and dried over sodium sulfate, and the organic layer was concentrated under reduced pressure to give 0.510 g of crude material, which was purified by preparative HPLC and the product fractions were lyophilized to give 0.072 g of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-ylmethyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)carbamate as a white solid. LCMS: 99.41% (m / z: 828.34, [M+1]+, 214nm). 1H NMR (400 MHz, DMSO-d6): δ 7.25 (d, J = 8.4 Hz, 1H), 6.82-6.81 (d, J = 8.4 Hz, 1H), 6.76 ( bs, 1H), 4.89-4.81 (m, 1H), 4.52 (s, 1H), 4.50 (d, J = 4.8 Hz, 1H), 4.30-445 (m, 3H), 3.89-3.82 (m, 1H), 3.58-3.52 (m, 3H), 3.46-3.37 (m, 4H), 3.32-3.29 (m, 1H), 3.05-2.92 (m, 3H), 2.87-2.60 (m, 6 H), 2.42-2.37 (m, 2H), 2.33-2.24 (m, 2H), 1.94-1.85 (m, 3H), 1.80 (d, J = 12 Hz, 1H), 1.71-1.68 (bs, 1H), 1.63-1.47 (m, 4H), 1.38-1.18 (m, 18H), 0.90 (bs, 1H), 0.67 (s, 3H).

[0121] Example 06: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)carbamate Step 1: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate [ka] To a stirred solution of fulvestrant (2.0 g) in acetonitrile (20 mL) was added cesium carbonate (3.24 g) and 4-nitrophenyl chloroformate (0.99 g) at room temperature, and the reaction mixture was stirred at the same temperature for 15 minutes. After completion of the reaction by TLC, the reaction was diluted with water (15 mL) and extracted with ethyl acetate (2×30 mL), the combined organic layers were dried over anhydrous sodium sulfate, and the organics were concentrated under reduced pressure to afford (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate (2.3 g crude material, LCMS 60%), which was used in the next step without further purification. LCMS purity: 60.00% Step 2: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)carbamate [ka] To a stirred solution of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate (0.5 g) in dimethylformamide (3 mL) was added 2-amino-2-(hydroxymethyl)propane-1,3-diol (0.156 g) at room temperature, and the reaction mixture was stirred at the same temperature for 2 hours. After completion of the reaction by TLC, the reaction mixture was diluted with ice water (15 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and the organics were concentrated under reduced pressure to give 0.510 g of crude material, which was purified by preparative HPLC and the product fractions were lyophilized to give 0.140 g of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)carbamate as a white solid. LCMS: 99.18% (m / z: 754.35, [M+1]+, 214nm). 1H NMR (400 MHz, DMSO-d6): δ 7.25 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 2, 8.4 Hz, 1H), 6.77 (d, J = 2 Hz, 1H), 6.68 (s, 1H), 4.53-4.49 (m, 4H), 3.57-3.54 (m, 7H), 2.87-2.80 (m, 2H), 2.76-2.71 (m, 2H), 2.67-2.62 (m, 1H), 2.43-2.37 (m, 2H), 2.32-2.23. (m, 2H), 1.94-1.86 (m, 3H), 1.80 (d, J = 12 Hz, 1H), 1.71-1.68 (m, 1H), 1.63-1.56 (m, 4H), 1.38-1.18 (m, 19 H), 0.90-0.88 (m, 1H), 0.67 (s, 3H)

[0122] Example 07: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 4-(azepan-1-yl)piperidine-1-carboxylate Step 1: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate [ka] To a stirred solution of fulvestrant (2.0 g) in acetonitrile (20 mL) was added cesium carbonate (3.24 g) and 4-nitrophenyl chloroformate (0.99 g) at room temperature, and the reaction mixture was stirred at the same temperature for 15 minutes. After completion of the reaction by TLC, the reaction was diluted with water (15 mL) and extracted with ethyl acetate (2×30 mL), the combined organic layers were dried over anhydrous sodium sulfate, and the organics were concentrated under reduced pressure to afford (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate (2.3 g crude material, LCMS 60%), which was used in the next step without further purification. LCMS purity: 60.00% Step 2: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 4-(azepan-1-yl)piperidine-1-carboxylate [ka] To a stirred solution of 1-(piperidin-4-yl)azepane hydrochloride (0.212 g) in acetonitrile (5 mL) was added potassium carbonate (0.88 g) and stirred at room temperature for 2 hours. Then, (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate (0.500 g) was added and the reaction was stirred at room temperature for 30 minutes. After completion of the reaction by TLC, the reaction was diluted with ice water (15 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.580 g of crude material. The crude material was purified by preparative HPLC, and the product fraction was lyophilized to give 0.082 g of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl-4-(azepan-1-yl)piperidine-1-carboxylate as a white solid. LCMS: 99.07% (m / z: 815.48, [M+1]+, 214nm). 1H NMR (400 MHz, DMSO-d6): δ 7.25 (d, J = 8.4 Hz, 1H), 6.82-6.80 (m, 1H), 6.77 (s, 1H), 4.50 (bs, 1H), 3.95-4.15 (m, 2H), 3.54 (t, J = 8 Hz, 1H), 2.95-2.92 (m, 1H), 2.87-2.76 (m, 4H), 2.74-2.65 (m, 2H), 2.62-2.61 (m, 5H), 2.43-2.36 (m, 2H), 2.32-2.24 (m, 2H), 1.94-1.86 (m, 3H), 1.65-1.85 (m, 6H), 1.63-1.52 (m, 12H), 1.38-1.15 (m, 20H), 0.90-0.87 (m, 1H), 0.67 (s, 3H).

[0123] Example 08: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(1'-methyl-[1,4'-bipiperidin]-4-yl)carbamate Step 1: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate [ka] To a stirred solution of fulvestrant (2.0 g) in acetonitrile (20 mL) was added cesium carbonate (3.24 g) and 4-nitrophenyl chloroformate (0.99 g) at room temperature, and the reaction mixture was stirred at the same temperature for 15 minutes. After completion of the reaction by TLC, the reaction was diluted with water (15 mL) and extracted with ethyl acetate (2×30 mL), the combined organic layers were dried over anhydrous sodium sulfate, and the organics were concentrated under reduced pressure to afford (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate (2.3 g crude material, LCMS 60%), which was used in the next step without further purification. LCMS purity: 60.00% Step 2: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(1'-methyl-[1,4'-bipiperidin]-4-yl)carbamate [ka] To a stirred solution of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate (0.5 g) in ACN (7 mL) was added potassium carbonate (0.223 mg), followed by 1'-methyl-[1,4'-bipiperidine]-4-amine (0.191 mg), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was monitored by TLC (mobile phase: 70% ethyl acetate in hexane). After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate (3 x 120 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude material.The crude material was purified by preparative HPLC, and the product fraction was lyophilized to obtain 0.197 g of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(1'-methyl-[1,4'-bipiperidin]-4-yl)carbamate as a white solid. LCMS: 99.23% (m / z: 830.58, [M+1]+, 214nm). 1H NMR (400 MHz, DMSO-d6): δ 7.65 (d, J = 8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.79 (dd, J = 2, 8 Hz, 1H), 6.75 (s, 1H), 4.49 (bs, 1H), 3.54 (t, J = 8 Hz, 1H), 3.24 (m, 1H), 2.83-2.67 (m, 10H), 2.50-2.29 (m, 4H), 2.15- 2.10 (m, 6H), 1.92- 1.77 (m, 10 H), 1.75-1.56 (m, 7H), 1.56- 1.23 (m, 22H), 1.17 (m, 1H), 0.67 (s, 3H)

[0124] Example 09: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 4-(pyrrolidin-1-yl)piperidine-1-carboxylate [ka] To a stirred solution of fulvestrant (0.250 g) in dichloromethane (4 mL), diisopropylethylamine (0.11 mL) and triphosgene (0.062 g) were added at 0°C, and the reaction mixture was stirred at the same temperature for 10 minutes. (10) After that, 4-(pyrrolidin-1-yl)piperidine (0.099 g) was added to the reaction mixture at 0°C, and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water (4 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.8 g of crude material, which was purified by flash chromatography using 8-9% methanol in dichloromethane. The desired fractions were concentrated under reduced pressure to give the pure compound. LCMS purity: 99.25% (m / z: 787.51, [M+1]+, 214nm). 1H NMR (400 MHz, DMSO-d6): δ 7.27 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.78 (s, 1H), 4.50 (d, J = 4.4 Hz, 1H), 4.02-3.88 (m, 2H), 3.57-3.52 (m, 1H), 3.10 (bs, 1H), 2.96 (bs, 1H), 2.88-2.62 (m, 7H), 2.48-2.27 (m, 7H), 1.94-1.79 (m, 6H), 1.69-1.48 (m, 9H), 1.38- 1.16 (m, 21H), 0.90-0.85 (m, 1H), 0.67 (s, 3H)

[0125] Example 10 Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl-9-methyl-3,9-diazaspiro[5.5]undecane-3-carboxylate [ka] To a stirred solution of fulvestrant (0.5 g) in dichloromethane (7 mL), diisopropylethylamine (0.21 mL) and triphosgene (0.122 g) were added at 0° C., and the reaction mixture was stirred at the same temperature for 10 minutes. After 10 minutes, 3-methyl-3,9-diazaspiro[5.5]undecane (0.207 g) was added to the reaction mixture at 0° C., and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (3×40 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude material. The crude material was purified by preparative HPLC and the product fractions were lyophilized to give 0.060 g of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl-9-methyl-3,9-diazaspiro[5.5]undecane-3-carboxylate as a white solid. LCMS: 98.96% (m / z: 801.46, [M+1]+, 214nm). 1H NMR (400 MHz, DMSO-d6): δ 7.24 (d, J = 8.4 Hz, 1H), 6.81 (dd, J = 2, 8.8 Hz, 1H), 6.76 (d, J = 2 Hz, 1H), 4.49 (d, J = 4.8 Hz, 1H), 3.53 (m, 3H), 3.39 (bs, 2H), 2.84-2.50 (m, 6H), 2.49-2.26 (m, 9H), 1.90-1.79 (m, 4H), 1.67-1.56 (m, 5H), 1.60-1.18 (m, 28H), 1.17 (m, 1H), 0.67 (s, 3H).

[0126] Example 11 Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 6-methyl-2,6-diazaspiro[3.3]heptane-2-carboxylate Step 1: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate [ka] To a stirred solution of fulvestrant (2.0 g) in acetonitrile (20 mL) was added cesium carbonate (3.24 g) and 4-nitrophenyl chloroformate (0.99 g) at room temperature, and the reaction mixture was stirred at the same temperature for 15 minutes. After completion of the reaction by TLC, the reaction was diluted with water (15 mL) and extracted with ethyl acetate (2×30 mL), the combined organic layers were dried over anhydrous sodium sulfate, and the organics were concentrated under reduced pressure to afford (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate (2.3 g crude material, LCMS 60%), which was used in the next step without further purification. LCMS purity: 60.00% Step 2: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 6-methyl-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] To a stirred solution of 2-methyl-2,6-diazaspiro[3.3]heptane hydrochloride (0.109 g) in acetonitrile (5 mL) was added potassium carbonate (0.93 g) and stirred at room temperature for 2 hours. Then, (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate (0.500 g) was added and the reaction was stirred at room temperature for 30 minutes. After completion of the reaction by TLC, the reaction was diluted with ice water (15 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and the organics were then concentrated under reduced pressure to give 0.450 g of crude material, which was purified by preparative HPLC and the product fractions were lyophilized to give 0.150 g of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 6-methyl-2,6-diazaspiro[3.3]heptane-2-carboxylate as a white solid. LCMS: 99.24% (m / z: 745.37, [M+1]+, 214nm). 1H NMR (400 MHz, DMSO-d6): δ 7.24 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 2.4, 8.8 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 4.50 (bs, 1H), 4.16 (s, 2H), 3.99 (s, 2H), 3.54 (t, J = 8.8 Hz, 1H), 3.23 (s, 4H), 2.84-2.80 (m, 2H), 2.76-2.70 (m, 2H), 2.66-2.64 (m, 1H), 2.39-2.37 (m, 2H), 2.32-2.28 (m, 2H), 2.15 (s, 3H), 1.92-1.86 (m, 3H), 1.78 (m, 1H), 1.68 (m, 1H), 1.64 (m, 1H), 1.61-1.55 (m, 4H), 1.37-1.15 (m, 18H), 0.90-0.87 (m, 1H), 0.66 (s, 3H).

[0127] Example 12: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(2-(dimethylamino)ethyl)(methyl)carbamate [ka] To a solution of fulvestrant (0.5 g) in dichloromethane (5 mL) was added diisopropylethylamine (0.23 mL), followed by triphosgene (0.12 g) at 0° C., and the reaction was stirred for 10 minutes. N1,N1,N2-trimethylethane-1,2-diamine (0.29 g) was then added, and the reaction mixture was stirred again at the same temperature for 15 minutes, then at room temperature for 18 hours. The progress of the reaction was monitored by TLC (mobile phase: 50% ethyl acetate in heptane). After completion of the reaction by LCMS, the reaction mixture was diluted with water (5 mL), extracted with dichloromethane (2×25 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The organic layers were evaporated under reduced pressure to give the crude material. The crude material was purified by preparative HPLC to give (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(2-(dimethylamino)ethyl)(methyl)carbamate (0.04 g) as a white solid. LCMS: 98.0% (m / z: 735.45, [M+1]+, 214nm). 1H NMR (400 MHz, DMSO-d6): δ 7.27 (d, J = 8.4 Hz, 1H), 6.81-6.77 (m, 2H), 4.49 (d, J = 4.8 Hz, 1H), 3.57-3.54 (m, 1H), 3.44-3.32 (m, 2H), 3.01-2.89 (m, 3H), 2.86-2.64 (m, 5H) 2.39-2.24 (m, 5H), 2.19-2.17 (m, 6H), 1.94-1.49 (m, 9H), 1.35-1.24 (m, 20H), 0.90 (bs, 1H), 0.67 (s, 3H).

[0128] Example 13 Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 4-(pyridin-4-yl)piperidine-1-carboxylate Step 1: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate [ka] To a stirred solution of fulvestrant (2.0 g) in acetonitrile (20 mL) was added cesium carbonate (3.24 g) and 4-nitrophenyl chloroformate (0.99 g) at room temperature, and the reaction mixture was stirred at the same temperature for 15 minutes. After completion of the reaction by TLC, the reaction was diluted with water (15 mL) and extracted with ethyl acetate (2×30 mL), the combined organic layers were dried over anhydrous sodium sulfate, and the organics were concentrated under reduced pressure to afford (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate (2.3 g crude material, LCMS 60%), which was used in the next step without further purification. LCMS purity: 60.00% Step 2: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl-4-(pyridin-4-yl)piperidine-1-carboxylate [ka] To a solution of 4-(piperidin-4-yl)pyridine (0.094 g) in acetonitrile (5 mL) was added potassium carbonate (0.134 g), followed by (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-nitrophenyl)carbonate (0.3 g). The reaction was then stirred at room temperature for 45 minutes. The progress of the reaction was monitored by TLC (mobile phase: 70% ethyl acetate in hexane). After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude material. The crude material was purified by preparative HPLC to afford (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl-4-(pyridin-4-yl)piperidine-1-carboxylate (0.07 g, 99%) as a white solid. LCMS: 99.14% (m / z: 795.49, [M+1]+, 214nm). 1H NMR (400 MHz, DMSO-d6): δ 8.49 (d, J = 5.2 Hz, 2H), 7.32 (d, J = 5.2 Hz, 2H), 7.27 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.81 (s, 1H), 4.50 (d, J = 4.4 Hz, 1H), 4.24-4.16 (m, 2H), 3.56-3.55 (m, 1H), 3.10-2.95 (m, 2H), 2.88-2.64 (m, 7H), 2.37-2.28 (m, 3H), 1.94-1.80 (m, 6H), 1.69-1.50 (m, 8H), 1.48-1.23 (m, 18H) 0.91 (bs, 1H), 0.68 (s, 3H).

[0129] Example 14: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 4-(dimethylamino)piperidine-1-carboxylate [ka] Potassium carbonate (0.341 g) was added to a solution of N,N-dimethylpiperidin-4-amine hydrochloride (0.081 g) in dichloromethane (2 mL), and the resulting reaction mixture-1 was stirred at room temperature for 1 hour. In a separate vessel, fulvestrant (0.2 g) was taken up in dichloromethane (2 mL), and diisopropylethylamine (0.086 mL) was added, followed by triphosgene (0.049 g) at 0° C. under a nitrogen atmosphere. The mixture was left at the same temperature for 15 minutes, and then reaction mixture-1 was added, followed by stirring at room temperature for 18 hours. The progress of the reaction was monitored by TLC (mobile phase: 70% ethyl acetate in heptane). After completion of the reaction, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the organic layer was evaporated under reduced pressure to obtain a crude material. The crude compound was purified by flash column chromatography to give (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 4-(dimethylamino)piperidine-1-carboxylate (0.04 g) as a white solid. LCMS: 99.04% (m / z: 761.77, [M+1]+, 214nm). 1H NMR (400 MHz, DMSO-d6): δ 7.26 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.78 (s, 1H), 4.50 (d, J = 4.4 Hz, 1H), 4.13-4.02 (m, 2H), 3.57-3.52 (m, 1H), 3.00 (bs, 1H), 2.94-2.81 (m, 3H), 2.76-2.61 (m, 4H), 2.40-2.30 (m, 9H), 1.94-1.79 (m, 6H), 1.69 (bs, 1H), 1.62-1.54 (m, 3H), 1.49-1.18 (m, 23H), 0.98-0.85 (m, 1H), 0.67 (s, 3H).

[0130] Example 15: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 4-(1,4-oxazepan-4-yl)piperidine-1-carboxylate [ka] To a solution of 4-(piperidin-4-yl)-1,4-oxazepane (0.250 g) in dichloromethane (2 mL), triethylamine (0.341 g) was added, and the resulting reaction mixture-1 was stirred at room temperature for 2 hours. In a separate container, fulvestrant (0.27 g) was taken up in dichloromethane (5 mL), and diisopropylethylamine (0.12 mL) and then triphosgene (0.067 g) were added at 0° C. The reaction mixture was stirred at the same temperature for 15 minutes. To this mixture, reaction mixture-1 was added, and the mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC (mobile phase: 5% methanol in dichloromethane). After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the reaction mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the organic layer was evaporated under reduced pressure to obtain a crude material. The crude compound was purified by preparative HPLC to give (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl-4-(1,4-oxazepan-4-yl)piperidine-1-carboxylate (0.065 g) as a white solid. LCMS: 99.64% (m / z: 817.56, [M+1]+, 214nm). 1H NMR (400 MHz, DMSO-d6), TFA salt: δ 7.28 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 2.4, 8.4 Hz, 1H), 6.79 (s, J = 2.4 Hz, 1H), 4.49 (bs, 1H), 4.15-4.16 (m, 2H), 3.86-3.77 (m, 3H), 3.71-3.53 (m, 3H), 3.35-3.25 (m, 3H), 3.02-2.81 (m, 4H), 2.76-2.61 (m, 5H), 2.44-2.25 (m, 4H), 2.06-2.03 (m, 4H), 1,94-1.85 (m, 3H), 1.83-1.80 (m, 1H), 1.72-1.54 (m, 6H), 1.50-1.16 (m, 19H), 0.92-0.87 (m, 1H), 0.67 (s, 3H).

[0131] Example 16: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 3-oxa-9-azaspiro[5.5]undecane-9-carboxylate [ka] To a stirred solution of fulvestrant (0.300 g) in dichloromethane (10 mL), diisopropylethylamine (0.12 mL) and triphosgene (0.07 g) were added at 0° C., and the reaction mixture was stirred at the same temperature for 10 minutes. After 10 minutes, 3-oxa-9-azaspiro[5.5]undecane (0.15 g) was added to the reaction mixture at 0° C., and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water (25 mL) and extracted with dichloromethane (2×25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.5 g of crude material (crude LCMS purity 60%). The crude material was purified by preparative HPLC to give 0.100 g of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 3-oxa-9-azaspiro[5.5]undecane-9-carboxylate as a white solid (yield: 100 mg, 32.6%). LCMS: 94.37% (m / z: 788.68, [M+1]+,, 214nm). 1H NMR (400 MHz, DMSO-d6) δ 7.26 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.77 (s, 1H), 4.50 (bs, 1H), 3.58-3.55 (m, 7H), 3.40 (bs, 2H), 2.88-2.81 (m, 2H), 2.76-2.60 (m, 4H), 2.45-2.24 (m, 4H), 1.94-1.87 (m, 3H), 1.82-1.80 (m, 1H), 1.71-1.69 (m, 1H), 1.64-1.45 (m, 11H), 1.38-1.18 (m, 19H), 0.90-0.85 (m, 1H), 0.67 (s, 3H).

[0132] Example 17: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-(1-methylpiperidin-4-yl)phenyl)carbamate [ka] To a solution of fulvestrant (0.5 g) in DCM (8 mL), DIPEA (0.21 mL) and triphosgene (0.122 g) were added at 0° C., and the reaction mixture was stirred at the same temperature for 10 minutes. After 10 minutes, 4-(1-methylpiperidin-4-yl)aniline (0.235 g) was added to the reaction mixture at 0° C., and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water (5 mL) and extracted with DCM (2×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.7 g of crude material, which was further purified by reverse phase chromatography to give (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-(1-methylpiperidin-4-yl)phenyl)carbamate as a light brown solid. LCMS purity: 88%

[0133] Example 18: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-morpholinophenyl)carbamate [ka] To a solution of fulvestrant (0.5 g) in DCM (8 mL), DIPEA (0.21 mL) and triphosgene (0.122 g) were added at 0° C., and the reaction mixture was stirred at the same temperature for 10 minutes. After 10 minutes, 4-morpholinoaniline (0.220 g) was added to the reaction mixture at 0° C., and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water (5 mL) and extracted with DCM (2×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.7 g of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(4-morpholinophenyl)carbamate as a pale yellow gum. LCMS purity: 66%

[0134] Example 19: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(2-(dimethylamino)ethyl)carbamate [ka] To a solution of fulvestrant (0.5 g) in DCM (8 mL), DIPEA (0.21 mL) and triphosgene (0.122 g) were added at 0° C., and the reaction mixture was stirred at the same temperature for 10 minutes. After 10 minutes, N,N-dimethylethane-1,2-diamine (0.108 g) was added to the reaction mixture at 0° C., and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water (5 mL) and extracted with DCM (2×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.5 g of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl(2-(dimethylamino)ethyl)carbamate as a light brown solid. LCMS purity: 22%

[0135] Example 20: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 4-morpholinopiperidine-1-carboxylate [ka] To a solution of fulvestrant (0.5 g) in DCM (8 mL), DIPEA (0.21 mL) and triphosgene (0.122 g) were added at 0° C., and the reaction mixture was stirred at the same temperature for 10 minutes. After 10 minutes, 4-(piperidin-4-yl)morpholine (0.209 g) was added to the reaction mixture at 0° C., and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water (5 mL) and extracted with DCM (2×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.56 g of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 4-morpholinopiperidine-1-carboxylate as a light brown solid. LCMS purity: 48%

[0136] Example 21: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate [ka] To a solution of fulvestrant (0.5 g) in DCM (8 mL), DIPEA (0.21 mL) and triphosgene (0.122 g) were added at 0° C., and the reaction mixture was stirred at the same temperature for 10 minutes. After 10 minutes, 1-methyl-4-(piperidin-4-yl)piperazine (0.225 g) was added to the reaction mixture at 0° C., and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water (5 mL) and extracted with DCM (2×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.1 g of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate as a light brown solid. LCMS purity: 65%

[0137] Example 22: Preparation of (7R,8R,9S,13S,14S,17S)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-17-(phosphonooxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl[1,4'-bipiperidine]-1'-carboxylate [ka] Step 1: To a solution of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl[1,4'-bipiperidine]-1'-carboxylate (0.500 g) in THF (5 mL) was added NaHMDS (1.25 mL) at 0°C. The resulting reaction mixture was stirred at the same temperature for 30 minutes. Tetrabenzyl pyrophosphate (0.671 g) was then added at room temperature. The reaction mixture was then stirred at room temperature for 16 hours. After completion of the reaction by LCMS, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (7R,8R,9S,13S,14S,17S)-17-((bis(benzyloxy)phosphoryl)oxy)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl[1,4′-bipiperidine]-1′-carboxylate (550 mg, LCMS purity 21%), which was used in the next step without further purification. Step 2: A solution of (7R,8R,9S,13S,14S,17S)-17-((bis(benzyloxy)phosphoryl)oxy)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl[1,4'-bipiperidine]-1'-carboxylate (0.550 g of the product from Step 1) in TFA (6 mL) was stirred at 80°C for 3 hours. After completion of the reaction by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude material (450 mg, LCMS purity 21%), which was purified by preparative HPLC to give 23 mg of (7R,8R,9S,13S,14S,17S)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-17-(phosphonooxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl[1,4'-bipiperidine]-1'-carboxylate. LCMS purity: 97%

[0138] Example 23 Preparation of (7R,8R,9S,13S,14S,17S)-17-((D-valyl)oxy)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl[1,4'-bipiperidine]-1'-carboxylate [ka] Step 1: To a stirred solution of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl[1,4'-bipiperidine]-1'-carboxylate (0.5 g) in DMF (10 mL) was added DCC (0.386 g) and DMAP (0.045 g) at room temperature. After 20 minutes, (tert-butoxycarbonyl)-D-valine (0.244 g) was added, and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction by LCMS, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (7R,8R,9S,13S,14S,17S)-17-(((tert-butoxycarbonyl)-D-valyl)oxy)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl[1,4′-bipiperidine]-1′-carboxylate (0.8 g, LCMS purity 47%), which was used in the next step without further purification. Step 2: To a solution of (7R,8R,9S,13S,14S,17S)-17-(((tert-butoxycarbonyl)-D-valyl)oxy)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl[1,4'-bipiperidine]-1'-carboxylate (0.8 g of the product from Step 1) in DCM (50 mL) was added TFA (10 mL) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure at 25-28° C. to give 0.7 g of (7R,8R,9S,13S,14S,17S)-17-((D-valyl)oxy)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl[1,4′-bipiperidine]-1′-carboxylate as a brown sticky oil. LCMS purity: 49% (0.7g, LCMS purity 49%)

[0139] Example 24 Preparation of 3-(((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)oxy)propane-1,2-diol [ka] To a solution of fulvestrant (0.150 g) in ethanol (3 mL) was added a NaOH solution (0.014 g in 0.8 mL of water), and the resulting solution was stirred at 80° C. for 30 minutes. 3-Chloropropane-1,2-diol (0.040 g) was then added to the reaction mixture, and the resulting suspension was stirred at 80° C. for 16 hours. After completion of the reaction by TLC, the reaction was cooled to room temperature and diluted with water (10 mL). The reaction was extracted with DCM (2×25 mL) and the organic layer was washed with brine (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude material which was further purified by preparative HPLC to give 0.083 g of 3-(((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)oxy)propane-1,2-diol as a white semi-solid (LCMS purity 98.5%). 1H-NMR (DMSO): δ 7.159 (d, 1H), 6.662 (dd, 1H), 6.590 (d, 1H), 4.888 (d, 1H), 4.626 (t, 1H), 4.494 (d, 1H), 3.919-3.884 (m, 1H), 3.815-3.724 (m, 2H), 3.564-3.512 (m, 1H), 3.415 (t, 2H), 2.859-2.688 (m, 5H), 2.641-2.624 (m, 1H), 2.390-2.327 (m, 2H), 2.306-2.212 (m, 2H), 1.942-1.865 (m, 3H), 1.807-1.777 (m, 1H), 1.670-1.472 (m, 5H), 1.367-1.166 (m, 18H), 0.937-0.904 (m, 1H), 0.663 (s, 3H)

[0140] Example 25 Preparation of 2-hydroxy-4-(((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)oxy)-4-oxobutanoic acid [ka] Step 1: To a stirred solution of fulvestrant (0.7 g) and 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (0.201 g) in DCM, DIPEA (1 mL), EDC.HCl (0.661 g), and HOBt (0.265 g) were added, followed by DMAP (0.028 g), and the resulting reaction mixture was stirred vigorously at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (0.7 g, LCMS purity 49%) as a viscous oil, which was used in the next step without further purification. Step 2: To a stirred solution of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (obtained in Step 1, 0.7 g) in THF (7 mL) was added 2N HCl (7 mL) at 0° C., and then the reaction mixture was stirred at 70° C. for 6 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with ethyl acetate (2×25 mL), the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC to give 0.031 g of 2-hydroxy-4-(((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)oxy)-4-oxobutanoic acid as a white solid. 1H-NMR (DMSO): δ 12.112 (br s, 1H), 7.044 (d, 1H), 6.495 (dd, 1H), 6.412 (d, 1H), 4.556-4.141 (m, 3H), 3.557-3.505 (m, 1H), 2.903-2.808 (m, 2H), 2.783-2.710 (m, 3H), 2.695-2.576 (m, 3H), 2.439-2.371 (m, 2H), 2.310-2.317 (m, 2H), 1.944-1.866 (m, 3H), 1.826-1.767 (m, 1H), 1.723-1.438 (m, 5H), 1.382-1.152 (m, 18H), 0.921-0.905 (m, 1H), 0.674-0.659 (m, 3H)

[0141] Example 26: Preparation of tetraethyl ((7R,8R,9S,13S,14S,17S)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyl)bis(phosphate) [ka] To a solution of fulvestrant (0.250 g) in DCM (3 mL) was added TEA (0.3 mL), titanium tert-butoxide (0.068 g), and diethyl phosphorochloridate (0.354 g), and the resulting solution was stirred at room temperature for 16 hours. After completion of the reaction by TLC, the reaction mixture was diluted with water (10 mL) and extracted with DCM (2×25 mL), and the organic layer was washed with brine (2×10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC to give 0.092 g of tetraethyl ((7R,8R,9S,13S,14S,17S)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diyl)bis(phosphate) as a brown viscous liquid (LCMS purity 95.6%). 1H-NMR (DMSO): δ 7.299 (d, 1H), 6.941-6.919 (m, 1H), 6.878 (s, 1H), 4.262-4.203 (m, 1H), 4.166-4.091 (m, 4H), 4.045-3.958 (m, 4H), 2.861-2.809 (m, 2H), 2.747-2.611 (m, 4H), 2.421-2.300 (m, 3H), 2.114-2.082 (m, 1H), 1.942-1.884 (m, 2H), 1.855-1.832 (m, 1H), 1.720-1.693 (m, 1H), 1.621-1.566 (m, 5H), 1.491-1.334 (m, 9H), 1.271-1.228 (m, 20H), 1.169 (br s, 1H), 0.873 (br s, 1H), 0.771 (s, 3H)

[0142] Example 27: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl dihydrogen phosphate, di(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-N-methylhexane-1-aminium salt (dimeglumine salt) [ka] An aqueous solution of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl dihydrogen phosphate (0.06 g) and (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol (0.034 g) was stirred at room temperature for 12 hours. The reaction mixture was lyophilized to give (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl dihydrogen phosphate, di(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-N-methylhexane-1-aminium salt as a white solid (yield: 0.095 g, LCMS purity 96.12%). 1H-NMR (DMSO): δ 7.064 (d, 1H), 6.818-6.796 (m, 2H), 4.891 (br s, 12H), 4.490 (br s, 1H), 3.710 (q, 2H), 3.645-3.632 (m, 2H), 3.604-3.568 (m, 2H), 3.537-3.517 (m, 1H), 3.498-3.454 (m, 3H), 3.413-3.325 (m, 6H), 2.868-2.815 (m, 2H), 2.767-2.696 (m, 3H), 2.642-2.599 (m, 4H), 2.393-2.371 (m, 2H), 2.323 (s, 6H), 2.291-2.184 (m, 2H), 1.941-1.883 (m, 3H), 1.865-1.809 (m, 1H), 1.658-1.486 (m, 5H), 1.370-1.167 (m, 18H), 0.924-0.890 (m, 1H), 0.665 (s, 3H)

[0143] Example 28: Preparation of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl dihydrogen phosphate di(2-amino-2-(hydroxymethyl)propane-1,3-diol) [ka] An aqueous solution of (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl dihydrogen phosphate (0.06 g) and 2-amino-2-(hydroxymethyl)propane-1,3-diol (0.021 g) was stirred at room temperature for 12 hours. The reaction mixture was lyophilized to give (7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl dihydrogen phosphate di(2-amino-2-(hydroxymethyl)propane-1,3-diol) as a white solid (yield: 0.077 g, LCMS purity 96.67%). 1H-NMR (DMSO): δ 7.059 (d, 1H), 6.822-6.790 (m, 2H), 4.483 (br s, 9H), 3.538 (t, 2H), 3.281 (s, 12H), 2.868-2.598 (m, 7H), 2.391-2.182 (m, 5H), 1.943-1.866 (m, 3H), 1.809-1.777 (m, 1H), 1.682-1.660 (m, 1H), 1.619-1.486 (m, 4H), 1.369-1.168 (m, 19H), 0.936-0.918 (m, 1H), 0.665 (s, 3H).

Claims

1. Compounds of formula IV below, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates thereof. 【Chemistry 23】 (In the formula, R ７ Below: 【Chemistry 24】 or 【Chemistry 25】 wherein R ２５ and R ２６ are each independently selected from hydrogen; optionally substituted alkyl, aryl, or heteroaryl; R ８ are independently selected from the following i) to v): 【Chemistry 26】 (In the formula, R ２１ is selected from the group comprising alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, optionally substituted; or -CR ２２ R ２３ wherein R ２２ and R ２３ together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and optionally one or more R ２４ group, and one or more of the R ２４ groups are independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl, formyl, halo, alkylphosphate, phosphate, cyano, nitro, alkoxy, amino, alkoxycarbonyl, alkenyl, alkynyl, alkylthio, and arylcarbonyl, each of which may be optionally substituted; 【Chemistry 27】 (In the formula, R １７ is NH ２ , N.H.R. １８ , or NR １９ R ２０ is selected from: R １８ is selected from the group comprising optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １９ and R ２０ is independently selected from the group consisting of alkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, which may be optionally substituted; or R １９ and R ２０ together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocyclic ring, optionally containing one or more R ２１ group, and one or more of the R ２１ The groups are independently selected from the group consisting of alkyl, alkylcarbonyl, formyl, halo, haloalkyl, alkylphosphate, phosphate, oxo, cyano, nitro, amino, alkoxy, alkoxycarbonyl, -C(O)-amino acid, carboxyl, carboxyalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylthio, cycloalkyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, alkoxyalkyl, which may be optionally substituted; 【Chemistry 28】 (In the formula, R ２７ is selected from the group comprising optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; 【Chemistry 29】 (In the formula, R ２８ is selected from the group comprising optionally substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ２８ is substituted, the R ２８ one or more substitutions on are selected from formyl, halo, phosphate, cyano, nitro, or amino; v) an amino acid attached via an ester bond at the point of attachment.

2. In the compound of formula IV, R ２１ is selected from optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl; R ２１ is substituted, the R ２１ 2. The compound of claim 1, wherein one or more substitutions on is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, alkylamino, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, alkoxyalkyloxy, alkoxycarbonyloxy, carbamate, sulfinyl, sulfonyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, nitro, phosphate, alkylphosphate.

3. 10. The compound of claim 1, which is a compound of formula V, an enantiomer, a diastereomer, a racemate, a pharmaceutically acceptable salt or a solvate thereof: 【Transformation 30】 wherein W is selected from the group consisting of hydrogen or optionally substituted alkyl; R ９ are independently selected from the following i) to v): 【Chemistry 31】 (In the formula, R ２１ is selected from the group comprising alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, optionally substituted; or -CR ２２ R ２３ wherein R ２２ and R ２３ together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and optionally one or more R ２４ group, and one or more of the R ２４ groups are independently selected from the group consisting of optionally substituted alkyl, cycloalkyl, aryl, and heteroaryl; 【Chemistry 32】 (In the formula, R １７ is NHR １８ or NR １９ R ２０ is selected from: R １８ is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R １９ and R ２０ together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocyclic ring, optionally containing one or more R ２１ may be substituted with a group, and the R ２１ The groups are independently selected from the group consisting of alkyl, carboxyl, alkylcarbonyl, amino, —C(O)-amino acid, cycloalkyl, aryl, aralkyl, heterocycloalkyl, which may be optionally substituted; 【Transformation 33】 (In the formula, R ２７ is selected from the group comprising optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ２７ is substituted, the R ２７ The substitution for may be amino; 【Transformation 34】 (In the formula, R ２８ is selected from the group comprising optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ２８ is substituted, the R ２８ The substitution for is amino; v) an amino acid attached via an ester bond at the point of attachment.

4. 2. The compound of claim 1, which is a compound of the following formula VA, an enantiomer, a diastereomer, a racemate, a pharmaceutically acceptable salt or a solvate thereof: 【Chemistry 35】 wherein W is selected from the group consisting of hydrogen or optionally substituted alkyl; R ９ are independently selected from the following i) to v): 【Transformation 36】 (In the formula, R ２１ is selected from the group comprising alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, optionally substituted; or -CR ２２ R ２３ wherein R ２２ and R ２３ together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and optionally one or more R ２４ group, and one or more of the R ２４ groups are independently selected from the group consisting of optionally substituted alkyl, cycloalkyl, aryl, and heteroaryl; 【Chemistry 37】 (In the formula, R １７ is NHR １８ or NR １９ R ２０ is selected from: R １８ is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R １９ and R ２０ together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocyclic ring, optionally containing one or more R ２１ may be substituted with a group, and the R ２１ The groups are independently selected from the group consisting of alkyl, carboxyl, alkylcarbonyl, amino, —C(O)-amino acid, cycloalkyl, aryl, aralkyl, heterocycloalkyl, which may be optionally substituted; 【Transformation 38】 (In the formula, R ２７ is selected from the group comprising optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ２７ is substituted, the R ２７ The substitution for may be amino; 【Chemistry 39】 (In the formula, R ２８ is selected from the group comprising optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ２８ is substituted, the R ２８ The substitution for is amino; v) an amino acid attached via an ester bond at the point of attachment.

5. 2. The compound of claim 1, which is a compound selected from the group consisting of the following chemical formulas: a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 40】 【change】

6. Compounds of formula VI below, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates thereof. 【Chemistry 41】 (In the formula, R １０ Below: 【Chemistry 42】 (In the formula, R ２８ is selected from the group comprising optionally substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ２８ is substituted, the R ２８ wherein one or more substitutions on are selected from formyl, halo, phosphate, cyano, nitro, amino, hydroxy, heterocycloalkyl, or alkoxy; R １１ is hydrogen, or: 【Chemistry 43】 (In the formula, R ２１ is selected from the group comprising alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, optionally substituted; or -CR ２２ R ２３ wherein R ２２ and R ２３ together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and optionally one or more R ２４ group, and one or more of the R ２４ groups are independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl, formyl, halo, alkylphosphate, phosphate, cyano, nitro, alkoxy, amino, alkoxycarbonyl, alkenyl, alkynyl, alkylthio, and arylcarbonyl, each of which may be optionally substituted; However, R １１ is hydrogen, R １０ is neither methyl nor ethyl.

7. In the compound of formula VI, R ２１ is selected from optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl; R ２１ is substituted, the R ２１ 7. The compound of claim 6, wherein one or more substitutions on is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, alkylamino, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, alkoxyalkyloxy, alkoxycarbonyloxy, carbamate, sulfinyl, sulfonyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, nitro, phosphate, alkylphosphate.

8. 7. The compound of claim 6, which is a compound of the following formula VII, an enantiomer, a diastereomer, a racemate, a pharmaceutically acceptable salt or a solvate thereof: 【Chemistry 44】 (In the formula, Z １ and Z ２ are each independently selected from optionally substituted hydroxy, phosphate, or heterocycloalkyl; R １２ is hydrogen, or: 【Chemistry 45】 (In the formula, R ２１ is selected from the group comprising alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, optionally substituted; or -CR ２２ R ２３ wherein R ２２ and R ２３ together with the carbon to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocycle in which up to four carbon atoms are replaced with heteroatoms selected from the group consisting of O, S, or N, and optionally one or more R ２４ group, and one or more of the R ２４ groups are independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl, formyl, halo, alkylphosphate, phosphate, cyano, nitro, alkoxy, alkoxycarbonyl, alkenyl, alkynyl, alkylthio, and arylcarbonyl, each of which may be optionally substituted;

9. 7. The compound of claim 6, which is a compound of the following formula VII, an enantiomer, a diastereomer, a racemate, a pharmaceutically acceptable salt or a solvate thereof: 【Chemistry 46】 (In the formula, Z １ and Z ２ are each independently selected from optionally substituted hydroxy, phosphate, or heterocycloalkyl; R １２ is hydrogen, or: 【Chemistry 47】 (In the formula, R ２１ is selected from the group comprising optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl; R ２１ is substituted, the R ２１ One or more substitutions on are selected from alkyl, amino, or cycloalkyl.

10. 7. The compound of claim 6, which is a compound selected from the group consisting of the following chemical formulas: a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 48】

11. Compounds of formula VIII below, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates thereof. 【Chemistry 49】 (In the formula, R １３ is selected from the group consisting of H; optionally substituted alkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl; R １４ is selected from the group comprising alkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, optionally substituted; or R １３ and R １４ together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocyclic ring, optionally containing one or more R ２１ group, and one or more of the R ２１ The groups are each independently selected from the group consisting of alkyl, alkylcarbonyl, formyl, halo, haloalkyl, alkylphosphate, phosphate, phosphonyl, oxo, cyano, nitro, amino, alkoxy, alkoxycarbonyl, carboxyalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylthio, cycloalkyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, and alkoxyalkyl, each of which may be optionally substituted.

12. 12. The compound of claim 11, which is a compound of the following formula VIII, an enantiomer, a diastereomer, a racemate, a pharmaceutically acceptable salt or a solvate thereof: [Transformation 50] (In the formula, R １３ and R １４ together with the nitrogen to which they are attached form a 3- to 7-membered saturated, partially unsaturated, or unsaturated heterocyclic ring, optionally containing one or more R ２１ group, and one or more of the R ２１ groups are each independently selected from the group consisting of substituted alkyl, alkylcarbonyl, formyl, halo, haloalkyl, alkylphosphate, phosphate, phosphonyl, oxo, cyano, nitro, amino, alkoxy, alkoxycarbonyl, carboxyalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylthio, cycloalkyl, aryl, heteroaryl, aralkyl, heterocycloalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, and alkoxyalkyl; ２１ The one or more substitutions on the group selected as are selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, alkylamino, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, alkoxyalkyloxy, alkoxycarbonyloxy, carbamate, sulfinyl, sulfonyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, nitro, phosphate, alkylphosphate.

13. 12. The compound of claim 11, which is a compound of the following formula VIII, an enantiomer, a diastereomer, a racemate, a pharmaceutically acceptable salt or a solvate thereof: 【Chemistry 51】 (In the formula, R １３ is selected from hydrogen, alkyl; R １４ is selected from the group consisting of optionally substituted alkyl, heterocycloalkyl, or aryl; R １４ is substituted, the R １４ The one or more substitutions on are selected from alkyl, alkoxy, halo, heteroaryl, heterocycloalkyl, cycloalkyl, amino, or hydroxy.

14. 14. The compound of claim 13, which is a compound selected from the group consisting of the following chemical formulas: a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 52】

15. 12. The compound of claim 11, which is a compound of the following formula IX, an enantiomer, a diastereomer, a racemate, a pharmaceutically acceptable salt or a solvate thereof: 【Chemistry 53】 wherein S is selected from O, C, or N; T is an optionally substituted aryl, heteroaryl, heterocycloalkyl, cycloalkyl, amino, 【Chemistry 54】 or 【Transformation 55】 and when T is substituted, one or more substitutions on said T are selected from alkyl, alkoxy.

16. 16. The compound of claim 15, which is a compound selected from the group consisting of the following chemical formulas: a pharmaceutically acceptable salt or solvate thereof: 【Transformation 56】

17. Compounds of formula X, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates thereof. 【Chemistry 57】 wherein Q is selected from C or N; When Q is C, P １ are independently optionally substituted alkyl, optionally substituted: 【Chemistry 58】 Selected from: below: 【Chemistry 59】 The substitution on P is alkyl; ２ and P ３ is independently selected from hydrogen or alkyl; When Q is N, P ２ are independently optionally substituted alkyl, optionally substituted: 【Transformation 60】 Selected from: below: 【Chemistry 61】 The substitution on P is alkyl; １ is hydrogen, and P ３ is optionally substituted alkyl.

18. 18. The compound of claim 17, which is a compound selected from the group consisting of the following chemical formulas: a pharmaceutically acceptable salt or solvate thereof: 【Transformation 62】

19. Compounds of formula XI below, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates thereof. 【Transformation 63】 (In the formula, R １５ and R １６ together form a cyclic structure; said cyclic structure is selected from optionally substituted cycloalkyl or heterocycloalkyl; if said cyclic structure is substituted, one or more substitutions on said cyclic structure are selected from alkyl, alkoxy, halo, amino, or hydroxy; and m and n can independently be 1 to 3.

20. 20. The compound of claim 19, which is a compound selected from the group consisting of the following chemical formulas: a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 64】

21. A compound selected from the group consisting of the following chemical formulas, a pharmaceutically acceptable salt or solvate thereof: 【Transformation 65】

22. A compound of the formula: 【Chemical Formula 66】

23. The meglumine salt of the compound of the formula: 【Transformation 67】

24. 23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22; and a pharmaceutically acceptable excipient.

25. A pharmaceutical composition for treating breast cancer, comprising a compound according to any one of claims 1 to 22.

26. A breast cancer therapeutic agent comprising a compound according to any one of claims 1 to 22.

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