17β-HSD1 inhibitor compounds, pharmaceutical composition and use thereof

Abstract

Provided in the present invention are compounds represented by formula (I) and racemates, stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof. The compounds have good 17β-HSD1 inhibition effect, can be used for treating or preventing 17β-HSD1-mediated disorders and diseases, and can be used for preparing drugs for treating or preventing such disorders and diseases.

Description

17β-HSD1 inhibitor compounds, pharmaceutical compositions and applications thereof

[0001] This application claims priority to the following three prior applications: Patent Application No. 202410268503.0, filed with the State Intellectual Property Office of China on March 8, 2024, entitled “17β-HSD1 Inhibitor Compounds, Pharmaceutical Compositions, and Uses Thereof”; Patent Application No. 202411487100.1, filed with the State Intellectual Property Office of China on October 23, 2024, entitled “17β-HSD1 Inhibitor Compounds, Pharmaceutical Compositions, and Uses Thereof”; and Patent Application No. 202510237483.5, filed with the State Intellectual Property Office of China on February 28, 2025, entitled “17β-HSD1 Inhibitor Compounds, Pharmaceutical Compositions, and Uses Thereof”. The entire contents of each of the prior applications are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical compounds, and in particular relates to 17β-HSD1 inhibitor compounds, pharmaceutical compositions and their applications in medicine. Background Art

[0003] The 17β-hydroxysteroid dehydrogenase (17β-HSD) family, comprising at least 15 members, catalyzes the redox reaction between the 17-hydroxyl and 17-keto groups of various estrogens and androgens, making it a key enzyme in sex hormone metabolism. Because the conversion of 17-hydroxyl and 17-keto groups affects the binding activity of sex hormones to receptors, 17β-HSDs are widely involved in regulating sex hormone-related physiological functions by modulating sex hormone activity. Some 17β-HSD family proteins are also considered potential drug targets for some sex hormone-related diseases.

[0004] 17β-HSD1, expressed from the HSD17β1 gene, catalyzes the reduction of the inactive estrogen estrogen (estrone / E1, 17-keto form) to the highly active estradiol (estradiol / E2, 17-hydroxy form), using nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor. E2 binds strongly to both ERα and ERβ, and its estrogen receptor activation potency is 10-fold greater than that of E1. 17β-HSD1 also catalyzes the reduction of dehydroepiandrosterone (DHEA) to androstenediol, but has a higher affinity for E1. In humans, 17β-HSD1 is primarily expressed in tissues such as the ovary, breast, and placenta. In contrast to 17β-HSD1, 17β-HSD2 uses NAD+ as a cofactor to oxidize E2, androstenediol, and testosterone to E1, DHEA, and 4-androstene, respectively. 17β-HSD2 is widely expressed in the uterus, placenta, liver, gastrointestinal tract, and urinary system. 17β-HSD2 may protect solid tissues from the harmful effects of excessive sex hormones.

[0005] Endometriosis refers to the appearance, growth, and infiltration of endometrial tissue (glands and stroma) within the lining of the uterine cavity and outside the uterus, leading to recurrent bleeding and subsequent pain, infertility, and nodules or masses. Endometriosis is a common and frequent disease in women of childbearing age, often characterized by estrogen dependence. Studies have found that E2 expression in endometrial tissue is upregulated by an average of 2.7-fold. In endometrial lesions, all reductases that promote E2 synthesis are upregulated, with 17β-HSD1 being the most significantly upregulated, by an average of 559-fold. However, the oxidase HSD17β2 is downregulated. Inhibiting 17β-HSD1 significantly reduces E2 levels in endometrial lesions, suggesting that an imbalance in the 17β-HSD1 / 2 ratio is the primary cause of E2 upregulation in endometriosis. Furthermore, 17β-HSD1 / 2 imbalances have been found in some E2-dependent cancers, such as breast and endometrial cancers, with, for example, Hsd17b1 gene amplification and Hsd17b2 loss of heterozygosity. Therefore, 17β-HSD1 inhibitors hold promise for the clinical treatment of endometriosis and breast cancer. Summary of the Invention

[0006] To solve the problems existing in the prior art, the present invention provides a compound represented by Formula I or its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt:

[0007] wherein ring A is selected from C 3-14 Carbocyclic ring, 3-14 membered heterocyclic ring, C 6-14 Aromatic ring or 5-14 membered heteroaromatic ring;

[0008] Each R a The same or different, independently selected from H, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -C(=O)-N(R a11 )(R a12 )、-N(R a13 )(R a14 ),-S(=O)2-R a15 、-C(=O)-R a16 、-C(=O)OR a17 、-P(=O)(R a18 )(R a19 ); or, two R attached to different carbon atoms a Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted R a1 Substituted by the following groups: 3-14 membered carbocyclic ring or 3-14 membered heterocyclic ring; each R a1 The same or different, independently selected from OH, CN, halogen, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl or -NH2; R a11 、R a12 、R a13 、R a14 、R a15 、R a16 、R a17 、R a18 、R a19 The same or different, independently selected from H, C 1-12 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group;

[0009] R1 is selected from OH, COOH, unsubstituted or optionally substituted by one, two or more R 1a Substituted with the following groups: C 1-12 Alkyl or C 1-12 Alkoxy; each R 1a the same or different, independently selected from OH or COOH;

[0010] R2 is selected from H, halogen, nitro, cyano, -S(=O)2-C 1-12 Alkyl or -(CH2) p -N(R 21 )(R 22 ), where R 21 、R 22 The same or different, independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(=O)-R 23 、-C(=O)OR 24 ; p is selected from 1, 2, 3, 4, 5 or 6; R 23 、R 24 The same or different, independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group;

[0011] L is absent or selected from -O-, -OC 1-12 Alkylene- or -OC 1-12 Alkylene-O-;

[0012] R3 is selected from H, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R 3a Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, 3-14 membered cyclic hydrocarbon, 3-14 membered heterocyclic group; each R 3a The same or different, independently selected from H, OH, CN, halogen, amino, oxo (=O), C 1-12 Alkyl, halogenated C 1-12 Alkyl, cyano C 1-12 Alkyl, hydroxy-C 1-12 Alkyl, C 1-12 Alkoxy, -C(O)-C 1-12 Alkyl or -S(O)2-C 1-12 alkyl;

[0013] m is selected from 0, 1, 2, 3, 4 or 5.

[0014] According to some embodiments, Ring A is selected from C 6-14 Aromatic ring or 5-14 membered heteroaromatic ring;

[0015] Each R a The same or different, independently selected from H, OH, CN, halogen, C 1-12 Alkyl, halogenated C 1-12 Alkyl, cyano-C 1-12 Alkyl or hydroxy-C 1-12Alkyl; or, two R attached to different carbon atoms a Together with the atoms to which they are attached, they form a 3-14 membered carbocyclic ring;

[0016] R1 is selected from OH, COOH, unsubstituted or optionally substituted by one, two or more R 1a Substituted C 1-12 Alkyl or C 1-12 Alkoxy; each R 1a the same or different, independently selected from OH or COOH;

[0017] R2 is selected from H, CN, nitro or -S(O)2-C 1-12 alkyl;

[0018] L is absent or selected from -O-, -OC 1-12 Alkylene- or -OC 1-12 Alkylene-O-;

[0019] R3 is selected from H, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R 3a Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, 3-14 membered cyclic hydrocarbon, 3-14 membered heterocyclic group; each R 3a The same or different, independently selected from H, OH, CN, halogen, amino, oxo (=O), C 1-12 Alkyl, halogenated C 1-12 Alkyl, cyano C 1-12 Alkyl, hydroxy-C 1-12 Alkyl, C 1-12 Alkoxy, -C(O)-C 1-12 Alkyl or -S(O)2-C 1-12 alkyl;

[0020] m is selected from 0, 1, 2, 3, 4, and 5.

[0021] According to some embodiments, Ring A is selected from C 3-8 Carbocyclic ring, 3-8 membered heterocyclic ring, C 6-10 aromatic ring or 5-10 membered heteroaromatic ring.

[0022] According to some embodiments, Ring A is selected from C 3-8 carbocyclic ring, 5-6 membered heterocyclic ring, benzene ring or 5-6 membered heteroaromatic ring.

[0023] According to some embodiments, ring A is selected from a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a piperidine ring, a piperazine ring, a pyrazole ring, an imidazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a thiadiazole ring, a pyridine ring, a dihydropyridine ring (such as a 1,2-dihydropyridine ring), a pyridazine ring, a pyrimidine ring, and a pyrazine ring.

[0024] According to some embodiments, Ring A is selected from

[0025] According to some embodiments, Ring A is selected from a 5-6 membered heteroaryl ring.

[0026] According to some embodiments, ring A is selected from a thiazole ring and a pyridazine ring.

[0027] According to some embodiments, Ring A is selected from

[0028] According to some embodiments, each R a The same or different, independently selected from H, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -C(=O)-N(R a11 )(R a12 )、-N(R a13 )(R a14 ),-S(=O)2-R a15 、-C(=O)OR a17 ; or, two R attached to different carbon atoms a Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted R a1 Substituted by the following groups: 3-8 membered carbocyclic ring or 3-8 membered heterocyclic ring; each R a1 The same or different, independently selected from OH, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or -NH2; R a11 、R a12 、R a13 、R a14 、R a15 、R a17 The same or different, independently selected from H, C 1-6 alkyl.

[0029] According to some embodiments, each R aThe same or different, independently selected from H, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one or two R a1 Substituted with the following groups: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, -C(=O)-N(R a11 )(R a12 )、-N(R a13 )(R a14 ),-S(=O)2-R a15 、-C(=O)OR a17 ; or, two R attached to different carbon atoms a Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted R a1 Substituted by the following groups: 5-6 membered carbocyclic ring or 5-6 membered heterocyclic ring; each R a1 The same or different, independently selected from OH, CN, halogen, C 1-3 Alkyl, C 1-3 Alkoxy; R a11 、R a12 、R a13 、R a14 、R a15 、R a17 The same or different, independently selected from H, C 1-3 alkyl.

[0030] According to some embodiments, each R a The same or different, independently selected from H, OH, CN, F, Cl, Br, oxo (=O), unsubstituted or optionally substituted by one or two R a1 Substituted from the following groups: methyl, ethyl, isopropyl, cyclopropyl, piperidinyl, morpholinyl, piperazinyl, -C(=O)-N(CH3)2, -S(=O)2-CH3, -C(=O)OCH3; or two R groups attached to different carbon atoms a Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted R a1 substituted 5-6 membered carbocyclic ring; each R a1 are identical or different and are independently selected from OH, CN, halogen, methyl or methoxy.

[0031] According to some embodiments, each R a The same or different, independently selected from H, OH, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano-C 1-6 Alkyl or hydroxy-C 1-6Alkyl; or, two R attached to different carbon atoms a Together with the atoms to which they are attached, they form a 3-8 membered carbon ring;

[0032] According to some embodiments, each R a The same or different, independently selected from H, CN, halogen, C 1-3 Alkyl or halogenated C 1-3 Alkyl; or, two R attached to different carbon atoms a Together with the atoms to which they are attached, they form a 3-6 membered carbon ring.

[0033] According to some embodiments, each R a the same or different, independently selected from H, CN, F, Cl, Br, OH, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxymethyl, oxo (=O), cyclopropyl, mesyl, -CH2OCH3, -COOCH3, Alternatively, two R attached to different carbon atoms a Together with the atoms to which they are attached, they form a cyclopentene ring or a cyclohexene ring.

[0034] According to some embodiments, each R a The same or different, independently selected from H, CN, F, Cl, Br, methyl or trifluoromethyl; or, two R attached to different carbon atoms a Together with the atoms to which they are attached, they form a cyclopentene ring.

[0035] According to some embodiments, Selected from

[0036] According to some embodiments, Selected from

[0037] According to some embodiments, R1 is selected from OH, -COOH, -CH2OH or -CH2COOH.

[0038] According to some embodiments, R2 is selected from H, halogen, nitro, cyano, mesyl or -CH2-N(R 21 )(R 22 ), where R 21 、R 22 The same or different, independently selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl, -C(=O)-R 23 、-C(=O)OR 24; R 23 、R 24 The same or different, independently selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl or 5-6 membered heterocyclic group.

[0039] According to some embodiments, R2 is selected from H, F, Cl, nitro, cyano, methanesulfonyl, -CH2NH2, -CH2NHBoc,

[0040] According to some embodiments, R2 is selected from H, nitro, cyano or methylsulfonyl.

[0041] According to some embodiments, L is absent.

[0042] According to some embodiments, L is selected from -O-, -OC 1-6 Alkylene- or -OC 1-6 Alkylene-O-.

[0043] According to some embodiments, L is selected from -O-, -O-CH2-, -O-CH2CH2-, -O-CH2CH2CH2-, -O-CH2-O-, -O-CH2CH2-O-, or -O-CH2CH2CH2-O-.

[0044] According to some embodiments, R3 is selected from H, OH, CN, halogen, unsubstituted or optionally substituted with one, two or more R 3a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group.

[0045] According to some embodiments, R3 is selected from H, OH, CN, halogen, unsubstituted or optionally substituted with one, two or more R 3a Substituted from the following groups: methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothienyl, tetrahydro-2H-pyranyl or tetrahydro-2H-thiopyranyl.

[0046] According to some embodiments, R3 is selected from H, OH, CN, halogen, unsubstituted or optionally substituted with one, two or more R 3a Substituted from the following groups: methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydro-2H-pyranyl or tetrahydro-2H-thiopyranyl.

[0047] According to some embodiments, R3 is selected from H, OH, CN, F, Cl, Br, unsubstituted or optionally substituted with one, two or more R 3a Substituted groups: methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl,

[0048] According to some embodiments, R3 is selected from H, OH, CN, F, Cl, Br, unsubstituted or optionally substituted with one, two or more R 3a Substituted groups: methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl,

[0049] According to some embodiments, each R 3a The same or different, independently selected from H, OH, CN, halogen, amino, oxo (=O), C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano-C 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl or -S(O)2-C 1-6 alkyl;

[0050] According to some embodiments, each R 3a The same or different, independently selected from H, OH, CN, halogen, amino, oxo (=O), C 1-3 Alkyl, halogenated C 1-3 Alkyl, cyano-C 1-3 Alkyl, hydroxy-C 1-3 Alkyl, C 1-3 Alkoxy, -C(O)-C 1-3 Alkyl or -S(O)2-C 1-3 alkyl.

[0051] According to some embodiments, each R 3a are identical or different and are independently selected from H, OH, CN, F, Cl, Br, amino, oxo (=O), methyl, methoxy, acetyl or methylsulfonyl.

[0052] According to some embodiments, -L-R3 is selected from hydroxy, cyano,

[0053] According to some embodiments, -L-R3 is selected from cyano,

[0054] According to some embodiments, the compound represented by Formula I is selected from the following structures:

[0055] Among them, ring A, R1, R2, R3, R a , L, and m have the definitions described herein.

[0056] According to some embodiments, the compound represented by Formula I is selected from the following structures:

[0057] Among them, each R a The same or different, independently selected from halogen; preferably, R a Selected from Cl;

[0058] m is selected from 1 or 2; preferably, m is 1;

[0059] R1, R2, R3, and L have the definitions described herein.

[0060] According to an embodiment of the present invention, among the compounds represented by Formula I and their racemates, stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts, illustrative, non-limiting specific examples of the compounds of Formula I are as follows:

[0061] According to some embodiments, the compound represented by Formula I is selected from the following structures:

[0062] The present invention further provides a pharmaceutical composition comprising the compound of formula I described in the present invention and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt.

[0063] In some embodiments, the pharmaceutical composition described in the present invention further comprises a therapeutically effective amount of the compound of formula I described in the present invention and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0064] The carrier in the pharmaceutical composition is "acceptable" in that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject being treated. One or more pharmaceutical excipients may be used for delivery of the active compound.

[0065] The present invention further provides the use of the compound of formula I and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt or pharmaceutical composition in the preparation of 17β-HSD1 inhibitors.

[0066] The present invention further provides the use of the compound of formula I and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of a medicament for diagnosing, preventing and / or treating endometriosis.

[0067] The present invention also provides a method for diagnosing, preventing and / or treating endometriosis, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the present invention, alone or, optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

[0068] In some embodiments, the compound is used as a 17β-HSD1 inhibitor, including but not limited to endometriosis.

[0069] The compounds of the present invention may be used in combination with additional therapeutic agents. Beneficial effects

[0070] The compound provided by the present invention has good 17β-HSD1 inhibitory activity; the compound of the present invention not only has good biological activity and good safety, but also improves the pharmacokinetic properties of the compound and increases bioavailability.

[0071] Definitions and Explanations of Terms

[0072] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0073] Unless otherwise indicated, numerical ranges recited in this specification and claims are equivalent to reciting at least each specific integer value therein. For example, the numerical range "1-14" is equivalent to reciting each integer value in the numerical range "1-14", namely, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14.

[0074] The term "optional" (or "optionally", "optionally") in the general formula definitions of this application means the situation of being substituted by zero, one or more substituents, for example, "optionally substituted by one, two or more R" means that it may not be substituted by R (unsubstituted) or may be optionally substituted by one, two or more R.

[0075] "More" means three or more.

[0076] The term "carbocycle" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (for example, a monocyclic ring such as a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, a cyclononane ring, or a bicyclic ring, including a spirocyclic, fused or bridged system (such as a bicyclo[1.1.1]pentane ring, a bicyclo[2.2.1]heptane ring, a bicyclo[3.2.1]octane ring or a bicyclo[5.2.0]nonane ring, a decalin ring, etc.), which may be optionally substituted with one or more (such as one, two or three) suitable substituents. The term "3-6 membered carbocycle" refers to a carbocycle containing 3, 4, 5 or 6 ring-forming carbon atoms.

[0077] The term "C 1-12 "Alkyl" is understood to mean straight-chain and branched alkyl groups having 1 to 12 carbon atoms, "C 1-8 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C 1-6 The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0078] “C 2-12"Alkenyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, more preferably "C 2-8 Alkenyl". "C 2-8 "Alkenyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, e.g. 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C 2-3 It is understood that when the alkenyl group contains more than one double bond, the double bonds may be separated from one another or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl , 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0079] The term "C 2-12 "Alkynyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, for example having 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e., "C 2-8 alkynyl”), having 2, 3, 4, 5, or 6 carbon atoms (i.e., “C 2-6Alkynyl”), having 2 or 3 carbon atoms (“C 2- The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent- In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0080] The term "C 3-12 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as condensed, bridged, spiro) hydrocarbon ring or tricyclic alkane having 3 to 12 carbon atoms, preferably "C 3-10 Cycloalkyl", more preferably "C 3-8 Cycloalkyl". The term "C 3-12 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (eg bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 3-12 The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or a tricyclic hydrocarbon group such as adamantyl.

[0081] The term "C 3-12 "Cycloalkenyl" is understood to mean a monovalent monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring) or tricyclic olefin containing a carbon-carbon double bond, which has 3 to 12 carbon atoms, preferably "C3-10 Cycloalkenyl", more preferably "C 3-8 "cycloalkenyl", which may have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 3-12 The cycloalkenyl group may be a monocyclic hydrocarbon group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, or a bicyclic hydrocarbon group such as spiro[2.5]oct-5-enyl, spiro[3.5]non-6-enyl, spiro[4.5]dec-7-enyl.

[0082] The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which may be a single aromatic ring or polyaromatic rings fused together, preferably "C 6-10 Aryl". The term "C 6- 14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl”), such as anthracenyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution position, and for example, the substitution may be at the ortho, para or meta position.

[0083] The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-10 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in each case, may additionally be benzofused. "Heteroaryl" also refers to a radical in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4- , 5-, 6-, 7- or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aHcarbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-pyridinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-phenanthridinyl, oxazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolinyl, 2-, 3-, 4- or 5-thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]oxazolyl, 2-, 4- or 54H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido[2,3

[0015] In some embodiments, the present invention further comprises carbazolyl, 2-, 3-, 6-, or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-4H-pyrrolo[1,2-b][2]benzazepinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5- to 14-membered heteroaryl group is linked to other groups to form a compound of the present invention, the carbon atoms on the 5- to 14-membered heteroaryl ring may be linked to the other groups, or heteroatoms on the 5- to 14-membered heteroaryl ring may be linked to the other groups. When the 5- to 14-membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, a hydrogen atom connected to a carbon atom on a heteroaryl ring may be substituted, or a hydrogen atom connected to a heteroatom on a heteroaryl ring may be substituted.

[0084] Unless otherwise defined, the term "3-14 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13- or 14-membered tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O)2- states. Preferably, the heterocyclyl may be selected from "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclic group can be connected to the rest of the molecule by any one of the carbon atoms or nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. In particular, the heterocyclic group can include but is not limited to: 4-membered rings, such as azetidinyl, oxetane; 5-membered rings, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings, such as diazepanyl. Optionally, the heterocyclic group can be benzo-fused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. When the 3-14-membered heterocyclic group is linked to other groups to form the compounds of the present invention, the linking may be to a carbon atom of the 3-14-membered heterocyclic group or to a heterocyclic atom on the 3-14-membered heterocyclic group ring. For example, when the 3-14 membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl group may be connected to the other group. Or when the 3-14 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom at the para position thereof may be connected to the other group.

[0085] The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

[0086] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0087] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0088] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0089] "Halo" means substituted with one or more halogens.

[0090] The term "Boc" is the abbreviation of t-Butyloxy carbonyl, which has the structure

[0091] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be Or it contains both configurations. In the chemical structure of the compound disclosed in the present invention, the bond It means that the configuration is not specified, that is, it can be Z configuration or E configuration, or both configurations.

[0092] Wavy lines intersecting chemical bonds Used to indicate the connection position between a group and other atoms in the molecular structure. Indicates the connection with the 2-position of thiazolyl. When the group connection position is not fixed, taking thiazolyl as an example, The above-mentioned embodiment shows that the thiazole group can be connected to any position on the thiazole group. Unless otherwise specified, similar expressions in this application are interpreted in the same way as above.

[0093] In the present invention, the compounds referred to also include isotopically labeled compounds, which are the same as those shown in Formula I, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F, and Cl, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 32 P. 35 S. 18 F and 36 Cl. Compounds of the invention, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or prodrugs containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the invention. Certain isotopically labeled compounds of the invention, for example, those incorporating radioactive isotopes (such as3 H and 14 C) compounds can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon 14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. 2 Substitution with hydrogen (H or D) may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) derived from greater metabolic stability and may therefore be preferred in certain circumstances. The compounds of the present invention as claimed in the claims may be specifically limited to substitution with deuterium or tritium. Furthermore, the absence of separate listing of the term deuterium or tritium for hydrogen present in a substituent does not exclude deuterium or tritium, but rather may also include deuterium or tritium.

[0094] It will be appreciated by those skilled in the art that the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form internal salts.

[0095] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0096] Depending on their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Thus, these compounds may exist in racemic or optically active forms. The compounds of the present invention encompass isomers or mixtures thereof, racemates, in which each chiral carbon is in the R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, appropriate N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids. Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, e.g., hexane / isopropanol / acetonitrile.

[0097] The corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.

[0098] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0099] The term "therapeutically effective amount" refers to that amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) prevents disease, e.g., prevents a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibits disease, e.g., inhibits the disease, disorder, or condition (i.e., prevents further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) alleviates disease, e.g., alleviates the disease, disorder, or condition (i.e., reverses the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. DETAILED DESCRIPTION

[0100] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0101] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0102] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0103] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0104] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. Unless otherwise stated, all reactions of the present invention were carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, with dry solvents, and reaction temperatures are reported in degrees Celsius.

[0105] Example 1

[0106] Synthesis of 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propionamide (Compound Intel001)

[0107] Synthesis of 3-((8R,9S,13S,14S,15R,E)-17-((fluoromethoxy)imino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propionamide (Compound 001)

[0108] Step 1: Synthesis of Compound 001-2

[0109] Estrone 001-1 (10.0 g, 0.037 mol) was dissolved in acetonitrile (5 mL), and potassium carbonate (10.2 g, 0.074 mol) and benzyl bromide (9.4 g, 0.056 mol) were added sequentially. The reaction mixture was stirred at 80°C for 16 hours. After the reaction, the reaction mixture was cooled to room temperature, the solid was filtered, and the mother liquor was concentrated to dryness and then crystallized by adding petroleum ether. Filtration afforded (8R,9S,13S,14S)-3-(benzyloxy)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopentyl[1,2-a]phenanthrene-17-one 001-2 (11.0 g, white solid) in a yield of 82.5%. MS m / z (ESI): 361.1 (M+1).

[0110] Step 2: Synthesis of Compound 001-3

[0111] Compound 001-2 (11.0 g, 0.030 mol) was suspended in ethylene glycol (15 mL) and triethyl orthoformate (25 mL), and p-toluenesulfonic acid (420 mg, 2.44 mmol) was added. The reaction mixture was stirred at 35°C for 3.5 hours. After completion of the reaction, LCMS indicated that the reaction mixture was poured into water, whereupon a white solid precipitated. Filtering afforded (8R,9S,13S,14S)-3-(benzyloxy)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydrospiro[cyclopentyl[1,2-a]phenanthrene-17,2'-[1,3]dioxolane] 001-3 (10.2 g, white solid) in a yield of 82.7%.

[0112] MS m / z (ESI): 405.2 (M+1).

[0113] Step 3: Synthesis of Compound 001-4

[0114] Compound 001-3 (10.0 g, 0.025 mol) was dissolved in ethylene glycol dimethyl ether (50 mL) and ethylene glycol (10 mL). Pyridine tribromide (12.0 g, 0.037 mol) was added portionwise at room temperature. The reaction mixture was stirred at 30°C for 16 hours. After completion, the reaction was quenched with aqueous sodium thiosulfate and extracted with DCM (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain (8R,9S,13S,14S)-3-(benzyloxy)-16-bromo-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydrospiro[cyclopentyl[1,2-a]phenanthrene-17,2'-[1,3]dioxolane] 001-4 (11 g, white solid) in a yield of 92%.

[0115] MS m / z (ESI): 483.0 (M+1).

[0116] Step 4: Preparation of Compound 001-5

[0117] Compound 001-4 (11.0 g, 0.11 mmol) was dissolved in DMSO (100 mL), and potassium tert-butoxide (11.0 g, 0.23 mmol) was added portionwise. The reaction mixture was stirred at 25°C for 3 hours. After completion of the reaction, water (550 mL) was added dropwise. The mixture was extracted with DCM (300 mL x 3). The organic phase was washed with water and sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to dryness, and purified on a silica gel column (petroleum ether:dichloromethane = 5:1) to obtain (8R,9S,13S,14S)-3-(benzyloxy)-13-methyl-6,7,8,9,11,12,13,14-octahydrospiro[cyclopentyl[1,2-a]phenanthrene-17,2'-[1,3]dioxolane] 001-5 (7.33 g, white solid) in an 80% yield.

[0118] MS m / z (ESI): 403.1 (M+1).

[0119] Step 5: Synthesis of Compound 001-6

[0120] Compound 001-5 (7.33 g, 0.11 mmol) was dissolved in acetone (150 mL) and water (20 mL), and p-toluenesulfonic acid (420 mg, 2.442 mmol) was added. The reaction mixture was stirred at 30°C for 3 hours. After the reaction, 500 mL of water was added, and a white solid precipitated. The solid was filtered and dried to obtain (8R,9S,13S,14S)-3-(benzyloxy)-13-methyl-6,7,8,9,11,12,13,14-octahydro-17H-cyclopentyl[1,2-a]phenanthrene-17-one 001-6 (5.33 g, white solid) in a yield of 82%.

[0121] MS m / z (ESI): 359.1 (M+1).

[0122] Step 6: Synthesis of Compound 001-7

[0123] Dissolve cuprous iodide (1.88 g, 9.85 mmol) and anhydrous lithium chloride (0.42 g, 9.84 mmol) in THF (20 mL). Stir the reaction mixture at room temperature for 15 minutes. N2 displacement protection was applied and the mixture was cooled to -78°C. A solution of allylmagnesium chloride in THF (10 mL, 10 mmol) and trimethylsilyl chloride (0.91 mL) were added dropwise. A solution of compound 001-6 (1.0 g, 2.81 mol) in THF (12 mL) was then added dropwise. The reaction mixture was stirred at -78°C for 1 hour, then naturally warmed to room temperature and stirred for 3 hours. Aqueous ammonium chloride was added to quench the mixture, and the mixture was extracted with EA (200 mL x 2). The organic phase was washed with aqueous ammonium chloride until a distinct blue color disappeared. The mixture was then washed with 1 M HCl (100 mL) and saturated aqueous sodium chloride. The organic phase was dried over anhydrous sodium sulfate. The residue was concentrated to dryness and purified by column chromatography (PE:EA=10:1) to give (8R,9S,13S,14S,15R)-15-allyl-3-(benzyloxy)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopentyl[1,2-a]phenanthrene-17-one 001-7 (7.8 g, white solid) in a yield of 70%.

[0124] MS m / z (ESI): 401.2 (M+1).

[0125] Step 7: Synthesis of Compound 001-8

[0126] Dissolve compound 001-7 (600 mg, 1.5 mmol) in THF (5 mL), cool to 0°C, and add a solution of BH3 in THF (6 mL, 6 mmol). Stir the reaction mixture at room temperature for 3 hours. Cool the reaction mixture to 0°C, add 2.5 mL of 3M NaOH solution dropwise, and then add H2O2 (1.0 mL). Stir the reaction mixture at room temperature overnight. The mixture was extracted with EA (100 mL × 3), and the organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by column chromatography (PE:EA=3:1) to give (8R,9S,13S,14S,15R)-3-(benzyloxy)-15-(3-hydroxypropyl)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[1,2-a]phenanthrene-17-ol 001-8 (400 mg, white solid) in a yield of 63%.

[0127] MS m / z (ESI): 421.2 (M+1).

[0128] Step 8: Synthesis of Compound 001-9

[0129] Compound 001-8 (400 mg, 0.9524 mmol) was dissolved in acetone (5 mL). The reaction solution was cooled to 0°C and Jones reagent (1.0 g of chromium trioxide dissolved in 3 mL of concentrated sulfuric acid and 7 mL of water at 0°C) was added dropwise until a green color appeared. LCMS indicated completion of the reaction. The mixture was extracted with EA (10 mL x 3). The organic phase was washed with water and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, concentrated to dryness, and purified by column chromatography (DCM:MeOH = 30:1) to afford 3-((8R,9S,13S,14S,15R)-3-(benzyloxy)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[1,2-a]phenanthren-15-yl)propanoic acid 001-9 (200 mg, white solid) in a 50% yield.

[0130] MS m / z (ESI): 433.3 (M+1).

[0131] Step 9: Synthesis of Compound 001-10

[0132] Compound 001-9 (200 mg, 0.46 mmol) was dissolved in methanol (5 mL) and THF (2 mL), and palladium / carbon (50 mg) was added. The system was hydrogenated at room temperature and 1 atom for 3 hours. LCMS indicated the reaction was complete. The palladium / carbon was removed by filtration. The filtrate was concentrated to dryness to afford 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[1,2-a]phenanthren-15-yl)propanoic acid 001-10 (138 mg, white solid) in a yield of 86%.

[0133] MS m / z (ESI): 343.2 (M+1).

[0134] Step 10: Synthesis of compound Intel001

[0135] Compound 001-10 (34.2 mg, 0.1 mmol) was dissolved in DMF (5 mL), and HATU (57 mg, 0.15 mmol), 5-methylthiazol-2-amine (22.8 mg, 0.2 mmol), and DIPEA (40 mg, 0.3 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, 30 mL of water was added dropwise to precipitate a yellow solid, which was filtered and dried to obtain 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propionamide Intel001 (30 mg, white solid) in a 68% yield.

[0136] MS m / z (ESI): 439.2 (M+1).

[0137] HPLC: 98.72% (214nm), 98.84% (254nm).

[0138] 1 H NMR(400MHz, CDCl3) δ7.14(d,J=8.4Hz,2H),6.70–6.56(m,2H),2.89(d,J=4.4Hz,3H),2.58(s,3H),2 .50–2.21(m,5H),2.20–2.04(m,2H),1.92(d,J=11.7Hz,1H),1.75(m,2H),1.47(m,2H),1.06(s,3H).

[0139] Step 11: Synthesis of Compound 001-12

[0140] 2-Hydroxyisoindole-1,3-dione 001-11 (1 g, 6.1 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (930 mg, 9.2 mmol) and iodomethane (930 mg, 6.13 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column to obtain 2-(fluoromethoxy)isoindoline-1,3-dione 001-12 (0.26 g, white solid) in a yield of 21.6%.

[0141] 1 H NMR (400MHz, CDCl3) δ7.95–7.90(m,2H),7.86–7.79(m,2H),5.75(s,1H),5.62(s,1H).

[0142] Step 11: Synthesis of Compound 001-13

[0143] 2-(Fluoromethoxy)isoindoline-1,3-dione 001-12 (250 mg, 1.28 mmol) was dissolved in ethanol (2 mL), and hydrazine hydrate (77 mg, 1.54 mmol) was added. The reaction mixture was stirred at 45°C for 16 hours. After the reaction, the reaction mixture was filtered directly, and the filtrate was purified to obtain crude O-(fluoromethyl)hydroxylamine 001-13 (80 mg, colorless oil) in a 96% yield. MS m / z (ESI): 66.1 (M+1). + .

[0144] Step 13: Synthesis of Compound 001

[0145] O-(Fluoromethyl)hydroxylamine 001-13 (30 mg, 0.46 mmol) was dissolved in dioxane (2 mL), and Intel001 (40 mg, 0.09 mmol) was added. The mixture was stirred at 80°C for 16 hours. After the reaction, the solvent was evaporated to dryness to obtain the crude product, which was then purified by preparative purification to obtain 3-((8R,9S,13S,14S,15R,E)-17-((fluoromethoxy)imino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide 001 (2.6 mg) in a yield of 5.8%.

[0146] MS m / z(ESI):486.2(M+1) + .

[0147] HPLC: 73.17% (214nm), 93.54% (254nm).

[0148] 1 H NMR (400 MHz, CDCl 3) δ7.18–7.07(m,2H),6.67–6.50(m,2H),5.71(dd,J=21.4,11.6Hz,1H),5.57(dd,J=20.8,11.8Hz,1H),2.99–2.88(m,2H),2.69(m ,1H),2.61(s,2H),2.46–2.41(s,3H),2.34–2.22(m,4H),2.09–1.99(m,4H),1.74–1.63(m,3H),1.54–1.44(m,2H),1.28(s,3H).

[0149] Example 2

[0150] Synthesis of 3-((8R,9S,13S,14S,15R,E)-3-hydroxy-13-methyl-17-((2,2,2-trifluoroethoxy)imino)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propionamide (Compound 002)

[0151] 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide Intel001 (50 mg, 0.11 mmol) was dissolved in ethanol (2 mL). O-(2,2,2-trifluoroethyl)hydroxylamine hydrochloride 002-1 (26 mg, 0.17 mmol) and pyridine (18 mg, 0.23 mmol) were added sequentially. The reaction mixture was stirred at 90°C for 16 hours. After the reaction, the product was concentrated and the residue was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2 x 250 mm 10 μm; mobile phase 1: water (containing 0.1% ammonia); mobile phase 2: acetonitrile; gradient ratio: acetonitrile phase: water 60%-100%, flow rate: 25 mL / min). After purification by reverse phase column, 3-((8R,9S,13S,14S,15R,E)-3-hydroxy-13-methyl-17-((2,2,2-trifluoroethoxy)imino)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propanamide 002 (2.18 mg) was obtained in a yield of 3%.

[0152] MS m / z (ESI): 536.2 (M+1).

[0153] HPLC: 97.72% (214nm), 95.91% (254nm).

[0154] 1 H NMR (400MHz, CDCl3) δ7.14(d,J=8.4Hz,1H),7.09(s,1H),6.63(dd,J=8.4,2.6Hz,1H),6.58(d,J=2.6Hz,1H),4.43–4.3 4(m,2H),2.92–2.85(m,2H),2.66–2.59(m,1H),2.52–2.16(m,9H),2.11–1.98(m,3H),1.73–1.43(m,6H),1.11(s,3H).

[0155] Example 3

[0156] Synthesis of 3-((8R,9S,13S,14S,15R,E)-17-((2,2-difluoroethoxy)imino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propionamide (Compound 003)

[0157] Step 1: Synthesis of Compound 003-2

[0158] 2-Hydroxyisoindole-1,3-dione 003-1 (1 g, 6.1 mmol) was dissolved in tetrahydrofuran (10 mL). 2,2-difluoroethane-1-ol (550 mg, 0.67 mmol), diethyl azodicarboxylate (1.27 g, 73.2 mmol), and triphenylphosphine (1.92 g, 73.2 mmol) were added sequentially and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column to obtain 2-(2,2-difluoroethoxy)isoindole-1,3-dione 003-2 (0.9 g, white solid) in a yield of 59.02%.

[0159] MS m / z(ESI):228.1(M+1) + .

[0160] Step 2: Synthesis of Compound 003-3

[0161] 2-(2,2-difluoroethoxy)isoindole-1,3-dione 003-2 (300 mg, 1.32 mmol) was dissolved in ethanol (5 mL), and hydrazine hydrate (159 mg, 1.58 mmol) was added. The reaction solution was stirred at 45°C for 1 hour. After the reaction, the reaction solution was directly filtered, and the filtrate was filtered without purification to obtain crude O-(2,2-difluoroethyl)hydroxylamine 003-3 (128 mg, colorless oil) in a 100% yield.

[0162] MS m / z(ESI):98.21(M+1) + .

[0163] Step 3: Synthesis of Compound 003

[0164] Compound 003-3 (128 mg, 1.3 mmol) was dissolved in ethanol (2 mL), and 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide Intel001 (50 mg, 0.11 mmol) was added thereto and stirred at 80 degrees Celsius for 16 hours. After the reaction, the solvent was dried to give a crude product, which was purified by preparative method to give the product 3-((8R,9S,13S,14S,15R,E)-17-((2,2-difluoroethoxy)imino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide 003 (6.3 mg) in a yield of 10.67%.

[0165] MS m / z(ESI):518.2(M+1) + .

[0166] HPLC: 95.9% (214nm), 97.43% (254nm).

[0167] 1 H NMR (400MHz, CDCl3) δ7.13(d,J=8.4Hz,1H),7.06(s,1H),6.63(d,J=8.4Hz,1H),6.58(s,1H),5.97(tt,J=56.0,4.0Hz,1H),4.19(t,J= 12.4Hz,2H),2.96–2.80(m,4H),2.71–2.54(m,2H),2.41(s,1H),2.37–2.22(m,1H),2.12–1.95(m,3H),1.74–1.41(m,2H),1.09(s,3H).

[0168] Example 4

[0169] Synthesis of 3-((8R,9S,13S,14S,15R,E)-17-((2-fluoroethoxy)imino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propionamide (Compound 004)

[0170] Step 1: Synthesis of Compound 004-1

[0171] 2-Hydroxyisoindole-1,3-dione 003-1 (1 g, 6.1 mmol) was dissolved in N,N-dimethylformamide (8 mL). 1-Bromo-2-fluoroethane (3.64 g, 28.7 mmol) and triethylamine (1.36 g, 13.42 mmol) were added sequentially, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. Purification on a silica gel column gave 2-(2-fluoroethoxy)isoindole-1,3-dione 004-1 (0.89 g, white solid) in a yield of 69.50%.

[0172] MS m / z(ESI):210.1(M+1) + .

[0173] Step 2: Synthesis of Compound 004-2

[0174] 2-(2-Fluoroethoxy)isoindole-1,3-dione 004-1 (100 mg, 0.48 mmol) was dissolved in ethanol (2 mL), and hydrazine hydrate (58 mg, 0.58 mmol) was added. The reaction mixture was stirred at 45°C for 1 hour. After the reaction, the reaction mixture was directly filtered, and the filtrate was filtered without purification to obtain crude O-(2-fluoroethyl)hydroxylamine 004-2 (37 mg, white colorless oil) in a yield of 97.87%. MS m / z (ESI): 80.1 (M+1). + .

[0175] Step 3: Synthesis of Compound 004

[0176] O-(2-Fluoroethyl)hydroxylamine 004-2 (37 mg, 0.48 mmol) was dissolved in ethanol (2 mL), and 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide Intel001 (30 mg, 0.068 mmol) was added thereto and stirred at 80 °C for 16 hours. After the reaction, the solvent was dried to give a crude product, which was purified by preparative method to give the product 3-((8R,9S,13S,14S,15R,E)-17-((2-fluoroethoxy)imino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide 004 (6.3 mg,) with a yield of 35.81%.

[0177] MS m / z(ESI):500.3(M+1) + .

[0178] HPLC: 96.60% (214nm), 100% (254nm).

[0179] 1 H NMR (400MHz, CDCl3) δ7.14(d,J=8.4Hz,1H),7.07(s,1H),6.66–6.59(m,1H),6.58(d,J=2.4Hz,1H),4.62(dt,J=47.8,4.2Hz,2H),4.37– 4.18(m,2H),2.92–2.77(m,3H),2.64–2.57(m,1H),2.41(s,4H),2.38–2.20(m,4H),2.08–1.98(m,3H),1.69–1.40(m,6H),1.10(s,3H).

[0180] Example 5

[0181] Synthesis of 3-((8R,9S,13S,14S,15R,E)-17-((cyclopropylmethoxy)imino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propionamide (Compound 005)

[0182] 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide Intel001 (50 mg, 0.11 mmol) was dissolved in ethanol (5 mL). O-(cyclopropylmethyl)hydroxylamine hydrochloride (30 mg, 0.34 mmol) and pyridine (18 mg, 0.23 mmol) were added sequentially. The reaction mixture was stirred at 80°C for 1 hour. After the reaction, the mixture was concentrated and purified by reverse phase column to give 3-((8R,9S,13S,14S,15R,E)-17-((cyclopropylmethoxy)imino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide 005 (10.31 mg) in a yield of 17%.

[0183] MS m / z (ESI): 508.2 (M+1).

[0184] HPLC: 98.85% (214nm), 98.97% (254nm).

[0185] 1 H NMR (400MHz, CDCl3) δ7.12(d,J=8.4Hz,1H),7.08(s,1H),6.63(dd,J=8.4,2.8Hz,1H),6.57( d,J=2.4Hz,1H),3.91-3.80(m,2H),3.55(s,1H),3.40(s,1H),2.94-2.78(m,3H),2.67-2.59 (m,1H),2.48-2.36(m,5H),2.34-2.17(m,3H),2.08-1.95(m,3H),1.75-1.65(m,1H),1.63-1 .57(m,2H),1.52-1.36(m,2H),1.15-1.01(m,4H),0.58-0.45(m,2H),0.27(q,J=5.2Hz,2H).

[0186] Example 6

[0187] Synthesis of 3-((8R,9S,13S,14S,15R,E)-17-(cyclobutyloxyamino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propionamide (Compound 006)

[0188] 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide Intel001 (50 mg, 0.11 mmol) was dissolved in ethanol (5 mL). O-cyclobutylhydroxylamine hydrochloride (42 mg, 0.34 mmol) and pyridine (18 mg, 0.23 mmol) were added sequentially. The reaction mixture was stirred at 80°C for 1 hour. After the reaction, the mixture was concentrated and purified by reverse phase column to give 3-((8R,9S,13S,14S,15R,E)-17-(cyclobutyloxyamino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide 006 (7.33 mg) in a yield of 13%.

[0189] MS m / z (ESI): 508.2 (M+1).

[0190] HPLC: 95.89% (214nm), 99.72% (254nm).

[0191] 1 H NMR (400MHz, CDCl3) δ7.13(d,J=8.4Hz,1H),7.10(s,1H),6.63(dd,J=8.4,2.4Hz,1H),6.57(d,J=2.4Hz,1H),4.63(p,J=7.2Hz,1H),3.00-2.75(m, 4H),2.69-2.60(m,1H),2.43(s,3H),2.36-2.13(m,6H),2.10-1.99(m,5H ),1.79-1.67(m,2H),1.67-1.48(m,5H),1.48-1.40(m,1H),1.08(s,3H).

[0192] Example 7

[0193] Synthesis of 3-((8R,9S,13S,14S,15R,E)-17-((ethoxymethoxy)imino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propionamide (Compound 007)

[0194] O-(Fluoromethyl)hydroxylamine 001-13 (30 mg, 0.46 mmol) was dissolved in ethanol (2 mL), and 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide Intel001 (20 mg, 0.046 mmol) was added thereto, and the mixture was stirred at 80°C for 16 hours. After the reaction, the solvent was dried to give a crude product, which was purified by preparative method to give the product 3-((8R,9S,13S,14S,15R,E)-17-((ethoxymethoxy)imino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide 007 (4.88 mg) in a yield of 20.90%.

[0195] MS m / z(ESI):512.2(M+1)+ .

[0196] HPLC: 99.08% (214nm), 100% (254nm).

[0197] 1 H NMR (400MHz, CDCl3) δ7.15 (d, J=8.4Hz, 1H), 7.10 (s, 1H), 6.63 (dd, J=8.4, 2.8Hz, 1H),6.58(d,J=2.4Hz,1H),5.14(d,J=3.2Hz,2H),3.68(d,J=7.2Hz,2H),2.92–2. 86(m,2H),2.65(s,2H),2.44(s,3H),2.36–2.28(m,3H),2.22(s,2H),2.09–2.04( m,3H),1.73–1.65(m,2H),1.62–1.41(m,4H),1.23(t,J=7.2Hz,3H),1.12(s,3H).

[0198] Example 8

[0199] Synthesis of 2-((8R,9S,13S,14S,15R,E)-17-(methoxyimino)-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopropyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-3-ylacetic acid (Compound 008)

[0200] Step 1: Synthesis of Compound 008-1

[0201] Under a nitrogen atmosphere, a three-necked round-bottom flask was charged with 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide Intel001 (400 mg, 0.91 mmol), dichloromethane (15 mL), and triethylamine (369 mg, 3.65 mmol). Trifluoromethanesulfonic anhydride (515 mg, 1.82 mmol) was slowly added dropwise under ice-cooling. The solution was stirred under ice-cooling for 1 hour and then allowed to warm to room temperature and stirred for 16 hours. Water was added and the mixture was extracted with dichloromethane. The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel chromatography to give (8R,9S,13S,14S,15R)-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopropyl)-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-3-yl trifluoromethanesulfonate 008-1 (200 mg, white solid) in a yield of 38%.

[0202] MS m / z (ESI): 571.1 (M+1).

[0203] Step 2: Synthesis of Compound 008-2

[0204] Under a nitrogen atmosphere, potassium acetate (21 mg, 0.21 mmol), compound 008-1 (40 mg, 0.09 mmol), XPhos-Pd-G2 (6 mg, 0.01 mmol), XPhos (7 mg, 0.01 mmol), propylene glycol (32 mg, 0.42 mmol), tetrakis(dimethylamino)diborane (42 mg, 0.21 mmol) and ultra-dry 2-methyltetrahydrofuran (2 mL) were added to the reaction flask in sequence. The reaction mixture was stirred at 80 ° C for 2 hours. Potassium carbonate (19 mg, 0.14 mmol) was then dissolved in water (0.5 mL) and added dropwise to the above reaction mixture. Ethyl 2-chloroacetate (17 mg, 0.14 mmol) was added dropwise and stirring was continued at 80 ° C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite and washed with ethyl acetate. The solvent was removed and the residue was purified by silica gel column chromatography to give ethyl 2-((8R,9S,13S,14S,15R)-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopropyl)-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl)acetate 008-2 (15 mg, yellow oil) in a yield of 34%.

[0205] MS m / z (ESI): 509.3 (M+1).

[0206] Step 3: Synthesis of Compound 008-3

[0207] Compound 008-2 (15 mg, 0.03 mmol) was dissolved in tetrahydrofuran (2 mL), and lithium hydroxide (1 mg, 0.04 mmol) was added. Water (0.2 mL) and ethanol (0.5 mL) were then added dropwise. The reaction mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was removed to obtain 2-((8R,9S,13S,14S,5R)-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopropyl)-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthren-3-yl)acetic acid 008-3 (20 mg, yellow solid).

[0208] MS m / z (ESI): 481.2 (M+1).

[0209] Step 4: Synthesis of Compound 008

[0210] Compound 008-3 (20 mg, 0.27 mmol) was dissolved in ethanol (2 mL), and pyridine (6 mg, 0.08 mmol) and methoxyamine hydrochloride (5 mg, 0.06 mmol) were added. The reaction mixture was stirred at 80°C for 16 hours. After the reaction, the product was concentrated and the residue was purified by HPLC (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150 x 19 mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; gradient ratio: acetonitrile phase: water 57%-67%, flow rate: 20 mL / min) to obtain 2-((8R,9S,13S,14S,15R,E)-17-(methoxyimino)-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopropyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthren-3-ylacetic acid 008 (1.35 mg) in a yield of 6%.

[0211] MS m / z (ESI): 510.2 (M+1).

[0212] HPLC: 99.54% (214nm), 96.41% (254nm).

[0213] 1H NMR (400MHz, CDCl3) δ7.27 (s, 1H), 7.11 (d, J = 8.2Hz, 1H), 7.04 (s, 1H), 7.0 0(s,1H),3.85(s,3H),3.58(d,J=3.6Hz,2H),2.91–2.79(m,3H),2.61–2.55 (m,1H),2.38(s,3H),2.35–2.32(m,1H),2.23–2.14(m,2H),2.06–2.00(m, 3H),1.73–1.64(m,3H),1.61–1.55(m,3H),1.40–1.32(m,2H),1.09(s,3H).

[0214] Example 9

[0215] Synthesis of (8R,9S,13S,14S,15R,E)-17-(methoxyimino)-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopropyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-3-carboxylic acid (Compound 009)

[0216] Step 1: Synthesis of Compound 009-1

[0217] (8R,9S,13S,14S,15R)-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopropyl)-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-3-yl trifluoromethanesulfonate 008-1 (100 mg, 0.175 mmol) was dissolved in dioxane (10 mL). Vinylboronic acid pinacol ester (81 mg, 0.52 mmol), cesium carbonate (114 mg, 0.35 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (14 mg, 0.017 mmol) were added sequentially. The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the product was concentrated and purified by flash silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 3-((8R,9S,13S,14S,15R)-13-methyl-17-oxo-3-vinyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide 009-1 (70 mg, white solid) in a yield of 89%. MS m / z (ESI): 449.2 (M+1).

[0218] Step 2: Synthesis of Compound 009-2

[0219] Compound 009-1 (80 mg, 0.18 mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL), and potassium osmate dihydrate (6.57 mg, 0.018 mmol) and sodium periodate (114 mg, 0.54 mmol) were added sequentially. The reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, the mixture was concentrated and purified by flash silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 3-((8R,9S,13S,14S,15R)-3-formyl-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propanamide 009-2 (60 mg, white solid) in a yield of 74%.

[0220] MS m / z (ESI): 451.2 (M+1).

[0221] Step 3: Synthesis of Compound 009-3

[0222] Compound 009-2 (25 mg, 0.055 mmol) was dissolved in tert-butanol (3 mL), tetrahydrofuran (3 mL), and water (1.5 mL). Sodium dihydrogen phosphate (67 mg, 0.55 mmol), sodium chlorite (10 mg, 0.11 mmol), and 2-methyl-2-butene (12 mg, 0.17 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 1 hour. After the reaction, water (25 mL) was added and the mixture was extracted with dichloromethane (25 mL x 3). The mixture was concentrated to give the crude product (8R, 9S, 13S, 14S, 15R)-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopropyl)-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-3-carboxylic acid 009-3 (20 mg, white solid) with a yield of 77%.

[0223] MS m / z (ESI): 467.1 (M+1).

[0224] Step 4: Synthesis of Compound 009

[0225] Compound 009-3 (25 mg, 0.054 mmol) was dissolved in ethanol (3 mL), and O-cyclobutylhydroxylamine hydrochloride (13 mg, 0.27 mmol) and pyridine (18 mg, 0.23 mmol) were added sequentially. The reaction mixture was stirred at 80°C for 2 hours. After completion of the reaction, the mixture was concentrated and purified on a reverse-phase preparative column to afford (8R,9S,13S,14S,15R,E)-17-(methoxyimino)-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopropyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-3-carboxylic acid 009 (5 mg) in a 19% yield.

[0226] MS m / z (ESI): 496.1 (M+1).

[0227] HPLC: 100% (214nm), 100% (254nm).

[0228] 1 HNMR(400MHz,MeOD)δ7.75(d,J=10.8Hz,2H),7.40(d,J=7.8Hz,1H),7.07(s,1H),3.79(d,J=2.0Hz,3H),2.96- 2.80(m,2H),2.82–2.78(m,1H),2.60–2.50(m,1H),2.48–2.40(m,3H),2.39(d,J=5.2Hz,3H),2.34(s,1H),2.19 -2.15(m,2H),2.05(d,J=11.2Hz,2H),1.79–1.57(m,5H),1.53–1.43(m,1H),1.13(s,3H).

[0229] Example 10

[0230] Synthesis of 3-((8R,9S,13S,14S,15R,E)-3-(hydroxymethyl)-17-(methoxyimino)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propionamide (Compound 010)

[0231] Step 1: Synthesis of Compound 010-1

[0232] 3-((8R,9S,13S,14S,15R)-3-formyl-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide 009-2 (25 mg, 0.055 mmol) was dissolved in N,N-dimethylformamide (1 mL). Pinacol borane (28 mg, 0.22 mmol) and potassium fluoride (3.2 mg, 0.056 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 1 hour. After the reaction, methanol was used for quenching and the product was concentrated to give 3-((8R,9S,13S,14S,15R)-3-(hydroxymethyl)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide 010-1 (12 mg, white solid) with a yield of 48%.

[0233] MS m / z (ESI): 453.1 (M+1).

[0234] Step 2: Synthesis of Compound 010

[0235] Compound 010-1 (12 mg, 0.0265 mmol) was dissolved in ethanol (2 mL), and O-cyclobutylhydroxylamine hydrochloride (6.2 mg, 0.13 mmol) and pyridine (18 mg, 0.23 mmol) were added sequentially. The reaction mixture was stirred at 80°C for 1 hour. After completion of the reaction, the mixture was concentrated and purified on a high-efficiency reverse-phase preparative column to obtain the product, 3-((8R,9S,13S,14S,15R,E)-3-(hydroxymethyl)-17-(methoxyimino)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propanamide 010 (1.9 mg), in a yield of 15%.

[0236] MS m / z (ESI): 482.2 (M+1).

[0237] HPLC: 99.37% (214nm), 97.07% (254nm).

[0238] 1HNMR(400MHz, CDCl3)δ7.31(s,1H),7.18–7.06(m,3H),4.64(s,2H),3.85(s,3H),2.95-2.80(m,2H),2.84 -2.80(m,1H),2.66 -2.58(m,1H),2.53-2.50(m,1H),2.45 -2.40(m,3H),2.37-2.30(m,5H),2.21-2.18(m,2H),2.06 -2.00(m,3H),1.73-1.70(m,2H),1.63 -1.59(m,2H),1.50 -1.48(m,1H),1.12(s,3H).

[0239] Example 11

[0240] Synthesis of 3-((8R,9S,13S,14S,15R,E)-3-hydroxy-13-methyl-17-(((S)-tetrahydrofuran-3-yl)oxy)imino)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propionamide (Compound 011)

[0241] Step 1: Synthesis of Compound 011-1

[0242] 2-Hydroxyisoindole-1,3-dione 003-1 (500 mg, 3.1 mmol) was dissolved in tetrahydrofuran (10 mL). (R)-tetrahydrofuran-3-ol (324 mg, 3.7 mmol), triphenylphosphine (1.21 g, 4.6 mmol), and diethyl azodicarboxylate (1.24 g, 6.1 mmol) were added sequentially and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column to obtain (S)-2-((tetrahydrofuran-3-yl)oxy)isoindoline-1,3-dione 011-1 (0.5 g, white solid) in a yield of 69.95%.

[0243] MS m / z(ESI):234.1(M+1) + .

[0244] Step 2: Synthesis of Compound 011-2

[0245] Compound 011-1 (100 mg, 0.43 mmol) was dissolved in dioxane (2 mL), and hydrazine hydrate (22 mg, 0.43 mmol) was added. The reaction mixture was stirred at 45°C for 3 hours. After the reaction, the reaction mixture was directly filtered, and the filtrate was filtered without purification to obtain crude (S)-O-(tetrahydrofuran-3-yl)hydroxylamine 011-2 (44 mg, colorless oil) in a yield of 99.51%.

[0246] MS m / z(ESI):104.1(M+1) + .

[0247] Step 3: Synthesis of Compound 011

[0248] (S)-O-(tetrahydrofuran-3-yl)hydroxylamine 011-2 (44 mg, 0.46 mmol) was dissolved in dioxane (1 mL), and 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide Intel001 (40 mg, 0.09 mmol) was added thereto and stirred at 80 °C for 16 hours. After the reaction, the solvent was dried to obtain a crude product, which was then purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; gradient ratio: acetonitrile phase 60%-70%, flow rate: 20 mL / min) to obtain the product 3-((8R,9S,13S,14S,15R,E)-3-hydroxy-13-methyl-17-(((S)-tetrahydrofuran-3-yl)oxy)imino)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide 011 (1.38 mg) in a yield of 2.89%.

[0249] MS m / z(ESI):524.3(M+1) + .

[0250] HPLC: 95.59% (214nm), 88.56% (254nm).

[0251] 1H NMR(400MHz, CDCl3)δ7.15(d,J=8.2Hz,2H),6.69–6.54(m,2H),4.82(s,1H),3.99–3.78(m,4H),3.00–2.76(m,3H),2.70(s,1H),2.58(s,1 H),2.48(d,J=10.2Hz,3H),2.38–2.26(m,3H),2.26–2.13(m,3H),2.03(d,J=13.3Hz,5H),1.64(s,3H),1.47(d,J=6.8Hz,1H),1.10(s,3H).

[0252] Example 12

[0253] Synthesis of 3-((8R,9S,13S,14S,15R,E)-3-hydroxy-13-methyl-17-((((R)-tetrahydrofuran-3-yl)oxy)imino)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propionamide (Compound 012)

[0254] Step 1: Synthesis of Compound 012-1

[0255] Under a nitrogen atmosphere, 2-hydroxyisoindole-1,3-dione 003-1 (370 mg, 2.51 mmol) was dissolved in ultra-dry tetrahydrofuran (10 mL). Triphenylphosphine (989 mg, 3.77 mmol) and (S)-tetrahydrofuran-3-ol (266 mg, 3.01 mmol) were added sequentially. Diethyl azodicarboxylate (1 g, 5.03 mmol) was slowly added dropwise under an ice bath. After completion of the addition, the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product, which was then purified on a silica gel column to afford (R)-2-((tetrahydrofuran-3-yl)oxy)isoindoline-1,3-dione 012-1 (400 mg, white solid) in a yield of 68%.

[0256] MS m / z(ESI):234.1(M+1) + .

[0257] Step 2: Synthesis of Compound 012-2

[0258] (R)-2-((tetrahydrofuran-3-yl)oxy)isoindoline-1,3-dione 012-1 (400 mg, 1.72 mmol) was dissolved in ethanol (5 mL), and hydrazine hydrate (87 mg, 1.72 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was filtered and the filtrate was used directly in the next step without purification to obtain crude (R)-O-(tetrahydrofuran-3-yl)hydroxylamine 012-2 (150 mg, colorless oil). The yield was 85%.

[0259] MS m / z(ESI):104.2(M+1) + .

[0260] Step 3: Synthesis of Compound 012

[0261] Compound 012-2 (150 mg, 1.46 mmol) was dissolved in ethanol (3 mL), and 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide Intel001 (80 mg, 0.18 mmol) was added thereto and stirred at 80 degrees Celsius for 3 days. After the reaction, the solvent was dried to obtain a crude product, which was then purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5u C18 150x 30mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; gradient ratio: acetonitrile phase 60%-70%, flow rate: 25 mL / min) to obtain the product 3-((8R,9S,13S,14S,15R,E)-3-hydroxy-13-methyl-17-((((R)-tetrahydrofuran-3-yl)oxy)imino)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide 012 (16.41 mg) in a yield of 17%.

[0262] MS m / z(ESI):524.2(M+1) + .

[0263] HPLC: 95.15% (214nm), 96.85% (254nm).

[0264] 1H NMR (400MHz, CDCl3) δ7.13(d,J=8.4Hz,1H),7.08(s,1H),6.63(dd,J=8.4,2.4Hz,1H),6.57(d,J=2.4Hz,1H),4.88–4.80(m,1H),3.98–3.88(m,2 H),3.86–3.76(m,2H),2.90–2.78(m,3H),2.64–2.58(m,1H),2.42(s,3H ),2.38–2.13(m,6H),2.11–1.99(m,5H),1.67–1.44(m,5H),1.09(s,3H).

[0265] Example 13

[0266] 3-((8R,9S,13S,14S,15R,E)-3-Hydroxy-13-methyl-17-(((tetrahydro-2H-pyran-4-yl)oxy)imino)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propanamide

[0267] Synthesis of 3-((8R,9S,13S,14S,15R,Z)-3-hydroxy-13-methyl-17-(((tetrahydro-2-hydro-pyran-4-yl)oxy)imino)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propionamide

[0268] Step 1: Synthesis of Compound 013-1

[0269] N-hydroxyphthalimide 003-1 (1.6 g, 0.01 mol) was dissolved in DMF (15 mL), and 4-bromotetrahydro-2H-pyran (1.6 g, 0.01 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.0 g, 0.02 mmol) were added sequentially. The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the mixture was concentrated to dryness and purified by column chromatography to afford 2-((tetrahydro-2H-pyran-4-yl)oxy)isoindoline-1,3-dione 013-1 (2.0 g, yellow solid) in an 81% yield.

[0270] MS m / z (ESI): 248.1 (M+1).

[0271] Step 2: Synthesis of Compound 013-2

[0272] 2-((Tetrahydro-2H-pyran-4-yl)oxy)isoindoline-1,3-dione 013-1 (247 mg, 1.0 mmol) was dissolved in ethanol (5 mL), and hydrazine hydrate (100 mg, 1.0 mmol, 50%) was added. The reaction mixture was stirred at 60°C for 2 hours. After LCMS indicated completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness to afford O-(tetrahydro-2H-pyran-4-yl)hydroxylamine 013-2, which was used directly in the next reaction without purification.

[0273] MS m / z (ESI): 118.3 (M+1).

[0274] Step 3: Synthesis of compounds 013A and 013B

[0275] O-(Tetrahydro-2H-pyran-4-yl)hydroxylamine 013-2 (118 mg, 1.0 mmol) was dissolved in ethanol (5 mL), and 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide Intel001 (60 mg, 0.1370 mmol) was added. The reaction mixture was stirred at 80°C for 16 hours. After the reaction, the mixture was concentrated to dryness, and the crude product was purified by high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; gradient ratio: acetonitrile phase 62%-72%, flow rate: 20 mL / min) to obtain 013-A (RT: 6.2 min; 2.11 mg, yield 3%) and 013-B (RT: 6.7 min; 1.39 mg, 2%).

[0276] The characterization results of 013-A (RT: 6.2 min) are as follows:

[0277] MS m / z (ESI): 537.3 (M+1).

[0278] HPLC: 97.11% (214nm), 95.26% (254nm).

[0279] 1H NMR (400MHz, CDCl3) δ7.19–7.06(m,2H),6.63(dd,J=8.4,2.4Hz,1H),6.58(d,J=2.2Hz,1H),4. 25(s,1H),3.91(dd,J=10.7,5.4Hz,2H),3.56–3.47(m,2H),2.87(dd,J=19.3,9.0Hz,3H),2.74– 2.60(m,1H),2.52(dd,J=14.9,7.2Hz,1H),2.44(s,3H),2.39–2.26(m,2H),2.22(s,1H),2.10– 1.93(m,5H),1.77–1.62(m,5H),1.62–1.53(m,2H),1.46(dd,J=18.6,12.0Hz,2H),1.10(s,3H).

[0280] The characterization results of 013-B (RT:RT:6.7min) are as follows:

[0281] MS m / z (ESI): 537.3 (M+1).

[0282] HPLC: 91.27% (214nm), 92.77% (254nm).

[0283] 1 H NMR(400MHz, CDCl3) δ7.13(d,J=8.1Hz,2H),6.63(d,J=8.2Hz,1H),6.59(s,1H),4.16 (s,1H),3.94–3.83(m,2H),3.55(dd,J=13.6,5.4Hz,2H),2.88(s,1H),2.65(dd,J=17 .9,8.6Hz,3H),2.46(s,3H),2.39(d,J=17.8Hz,1H),2.24(dd,J=17.9,10.4Hz,5H),1 .97(d,J=6.2Hz,6H),1.80–1.63(m,1H),1.48(dd,J=25.4,19.2Hz,1H),1.24(s,3H).

[0284] Example 14

[0285] Synthesis of 3-((8R,9S,13S,14S,15R,E)-3-hydroxy-17-(((1R,3S)-3-methoxycyclobutyloxy)imino)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propionamide (Compound 014)

[0286] Step 1: Preparation of Compound 014-1

[0287] 2-Hydroxyisoindole-1,3-dione 003-1 (500 mg, 3.1 mmol) was dissolved in tetrahydrofuran (20 mL), and (1S,3S)-3-methoxycyclobutane-1-ol (376 mg, 3.7 mmol) and triphenylphosphine (1.2 g, 4.6 mmol) were added sequentially. Under nitrogen, diisopropyl azodicarboxylate (1.24 g, 6.13 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product, which was then purified on a silica gel column (petroleum ether / ethyl acetate 3:1) to obtain 2-((1R,3R)-3-methoxycyclobutyloxy)isoindole-1,3-dione 014-1 (350 mg, white solid) in a yield of 46%.

[0288] MS m / z(ESI):248.1(M+1) + .

[0289] Step 2: Preparation of Compound 014-2

[0290] 2-((1R,3R)-3-methoxycyclobutyloxy)isoindole-1,3-dione 014-1 (350 mg, 1.41 mmol) was dissolved in ethanol (5 mL), and hydrazine hydrate (35 mg, 0.7 mmol) was added. The reaction solution was stirred at 25°C for 16 hours. After the reaction, the reaction solution was directly filtered, and the filtrate was obtained without purification to obtain crude O-((1R,3R)-3-methoxycyclobutyl)hydroxylamine 014-2 (37 mg, white colorless oil). This product was used directly in the next step without purification.

[0291] MS m / z(ESI):118.1(M+1) + .

[0292] Step 3: Synthesis of Compound 014

[0293] O-((1R,3R)-3-methoxycyclobutyl)hydroxylamine 014-2 (20 mg, 0.17 mmol) was dissolved in ethanol (2 mL), and 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide Intel001 (22 mg, 0.05 mmol) was added. The mixture was stirred at 80°C for 16 hours. After the reaction, the solvent was dried to obtain a crude product, which was then purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Ultimate AQ-C18 21.2 x 250 mm). 10um; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; gradient ratio: acetonitrile phase 60%-70%, flow rate: 25mL / min) to obtain the product 3-((8R,9S,13S,14S,15R,E)-3-hydroxy-17-(((1r,3S)-3-methoxycyclobutyloxy)imino)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide 014 (4.5 mg), yield: 5.0%.

[0294] MS m / z(ESI):538.3(M+1)+.

[0295] HPLC: 96.3% (214nm), 96.7% (254nm).

[0296] 1 H NMR (400MHz, CDCl3) δ7.16-7.14(m,2H),6.73–6.52(m,2H),4.77(dd,J=7.0,3.2Hz,1H),4.10(t,J=6.2Hz,1H),3.25(s,3H),2.99–2. 70(m,4H),2.66–2.61(m,1H),2.48(s,3H),2.41–2.20(m,8H),2.07-2.04(m,3H),1.74–1.66(m,4H),1.23–1.20(m,2H),1.11(s,3H).

[0297] Example 15

[0298] Synthesis of N-(5-cyanothiazol-2-yl)-3-((8R,9S,13S,14S,15R,E)-17-((2-fluoroethoxy)imino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)propanamide (Compound 022)

[0299] Step 1: Synthesis of Compound 022-1

[0300] To a solution of 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthren-15-yl)propanoic acid 001-10 (80 mg, 0.2 mmol) in N,N-dimethylformamide (2 mL) was added 2-aminothiazole-5-carbonitrile (35 mg, 0.2 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (133 mg, 0.3 mmol), and N,N-diisopropylethylamine (60 mg, 0.4 mmol). The reaction mixture was stirred at 25°C for 1 hour. After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to give N-(5-cyanothiazol-2-yl)-3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)propanamide 022-1 (40 mg, yellow solid) in a yield of 34%.

[0301] MS m / z (ESI): 450.1 (M+1).

[0302] Step 2: Synthesis of Compound 022

[0303] N-(5-cyanothiazol-2-yl)-3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)propanamide 022-1 (40 mg, 0.08 mmol) was dissolved in ethanol (1 mL), and O-(2-fluoroethyl)hydroxylamine 004-2 (14 mg, 0.1 mmol) was added. The reaction mixture was stirred at 80°C for 1 hour. After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate (3 × 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrate was purified by HPLC (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; gradient ratio: acetonitrile phase 55%-65%, flow rate: 20 mL / min) and lyophilized to give N-(5-cyanothiazol-2-yl)-3-((8R,9S,13S,14S,15R,E)-17-((2-fluoroethoxy)imino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthren-15-yl)propanamide 022 (2.04 mg) in a yield of 4.2%. MS m / z (ESI): 511.1 (M+1).

[0304] HPLC: 91.90% (214nm), 93.52% (254nm).

[0305] 1 H NMR (400MHz, CDCl3) δ7.96 (s, 1H), 7.15 (d, J = 8.4Hz, 1H), 6.64 (dd, J = 8.4, 2.7Hz, 1H) ,6.59(d,J=2.4Hz,1H),4.70–4.68(m,1H),4.57(t,J=4.2Hz,1H),4.31-4.28(m,1H), 4.24–4.20(m,1H),3.01–2.77(m,4H),2.69–2.61(m,1H),2.51–2.41(m,2H),2.38–2. 28(m,3H),2.22(d,J=22.4Hz,2H),2.04(t,J=13.0Hz,4H),1.25(s,2H),1.12(s,3H).

[0306] Example 16

[0307] Synthesis of tert-butyl (((8R,9S,13S,14S,15R,E)-17-((2-fluoroethoxy)imino)-3-hydroxy-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopropyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-2-yl)methyl)carbamate (Compound 061)

[0308] The first step is the preparation of compound 061-2

[0309] 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadienyl[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide Intel001 (500 mg, 1.1 mmol) was dissolved in dichloromethane (5 mL) and methanol (5 mL), and tetrabutylammonium tribromide (530 mg, 1.1 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. After the reaction, the reaction solution was concentrated and separated by column chromatography to give a solid product 3-((8R,9S,13S,14S,15R)-2-bromo-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadien[a]phenanthrene-15-yl)-N-(5-methylthiazol-2-yl)propanamide 061-2 (260 mg) in a yield of 45%.

[0310] MS m / z (ESI): 519 (M+1).

[0311] Step 2 Preparation of Compound 061-3

[0312] Compound 061-2 (260 mg, 0.5 mmol) was dissolved in 1,4-dioxane (3 mL), and potassium ((tert-butyloxycarbonyl)amino)methyl)trifluoroborate (474 ​​mg, 2 mmol), potassium phosphate (318 mg, 1.5 mmol) and PdRuphos were added. G3 (41 mg, 0.05 mmol), the reaction solution was stirred at 90 ° C for 16 hours. After the reaction, the reaction solution was concentrated and separated by column chromatography to give a solid product, tert-butyl (((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopropyl)-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-2-yl)methyl)carbamate 061-3 (68 mg), with a yield of 24%.

[0313] MS m / z (ESI): 568 (M+1).

[0314] Step 3 Preparation of Compound 061

[0315] 061-3 (68 mg, 0.1 mmol) was dissolved in ethanol (3 mL), and O-(2-fluoroethyl)hydroxylamine (16 mg, 0.2 mmol) was added. The reaction solution was stirred at 80°C for 2 hours. After the reaction was completed, the residue was purified by high performance liquid chromatography (Waters MS-trigger ed Prep-LC with SQD2 detector, chromatographic column: Xbridge 5μm, C18 150×19mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; gradient ratio: acetonitrile phase 67%-77%, flow rate: 20 mL / min) was purified to obtain tert-butyl (((8R,9S,13S,14S,15R,E)-17-((2-fluoroethoxy)imino)-3-hydroxy-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopropyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-2-yl)methyl)carbamate 061 (2 mg) in a yield of 3%.

[0316] MS m / z (ESI): 629 (M+1).

[0317] HPLC: 93.88% (214nm), 98.32% (254nm).

[0318] 1 H NMR(400MHz, CDCl3)δ7.12(s,1H),6.95(s,1H),6.69(s,1H),5.38–5.34(m,2H),5.19(s,1H),4.71–4.66(m,1H),4.58–4.54(m,1H),4.31–4.28 (m,1H),4.24–4.16(m,3H),2.93–2.86(m,3H),2.56–2.42(m,3H),2.35 –2.21(m,4H),2.11–1.99(m,8H),1.77–1.62(m,9H),1.23–1.09(m,3H).

[0319] Example 17

[0320] Synthesis of 3-((8R,9S,13S,14S,15R,E)-2-(aminomethyl)-17-((2-fluoroethoxy)imino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propionamide (Compound 062)

[0321] Step 1 Preparation of Compound 062

[0322] Compound 061 (60 mg, 0.1 mmol) was dissolved in ethyl acetate hydrochloride (3 mL), and the reaction solution was stirred at room temperature for 1 hour. After the reaction, the residue was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5 μm, C18 150×19 mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; gradient ratio: acetonitrile phase 26%-36%, flow rate: 20 mL / min) was purified to obtain 3-((8R,9S,13S,14S,15R,E)-2-(aminomethyl)-17-((2-fluoroethoxy)imino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-N-(5-methylthiazol-2-yl)propanamide 062 (10 mg), yield: 18%.

[0323] MS m / z (ESI): 529 (M+1).

[0324] HPLC: 99.50% (214nm), 99.60% (254nm).

[0325] 1 H NMR(400MHz,DMSO-d6)δ7.13–7.07(m,2H),6.51(s,1H),4.67–4.63(m,1H),4.5 6–4.51(m,1H),4.31–4.19(m,1H),4.16–4.12(m,1H),3.96–3.76(m,2H),2.81–2 .71(m,3H),2.36–2.28(m,6H),2.26–2.19(m,1H),2.13–2.09(m,1H),2.07–2.0 0(m,1H),1.96–1.87(m,2H),1.61–1.49(m,5H),1.43–1.33(m,2H),1.04(s,3H).

[0326] Example 18

[0327] Synthesis of N-(5-chlorothiazol-2-yl)-3-((8R,9S,13S,14S,15R,E)-17-(cyclopropylmethoxy)imino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthrene-15-yl)propanamide

[0328] Step 1 Preparation of Compound 083-1

[0329] To a solution of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (590 mg, 2.10 mmol) in N,N-dimethylformamide (10 mL) was added N-methylimidazole (432 mg, 5.26 mmol) at room temperature and stirred for 5 minutes. Subsequently, 3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[1,2-a]phenanthrene-15-yl)propanoic acid 001-10 (600 mg, 1.75 mmol) was added and stirred for 5 minutes. Subsequently, 5-chlorothiazol-2-amine hydrochloride (330 mg, 1.92 mmol) was added and the reaction mixture was stirred at 50 ° C for 2 hours. After the reaction, water was added to precipitate a solid, which was filtered and the filter cake collected to give N-(5-chlorothiazol-2-yl)-3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-15-yl)propanamide 083-1 (700 mg, yellow solid) in an 87% yield. MS m / z (ESI): 459.0 (M+1).

[0330] Step 2 Preparation of Compound 083

[0331] N-(5-chlorothiazol-2-yl)-3-((8R,9S,13S,14S,15R)-3-hydroxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadien[a]phenanthrene-15-yl)propanamide 083-1 (700 mg, 1.53 mmol) was dissolved in ethanol (15 mL), and O-(cyclopropylmethyl)hydroxylamine hydrochloride (283 mg, 2.29 mmol) and pyridine (181 mg, 2.29 mmol) were added. The reaction mixture was stirred at 80 degrees for 16 hours. After the reaction, the product was concentrated and the residue was purified by HPLC (Waters MS-triggered Prep-LC with QDA detector, column: Gemini 5u C18 100 x 21.2 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; gradient ratio: acetonitrile phase 73% to 83%, flow rate: 25 mL / min) to obtain N-(5-chlorothiazol-2-yl)-3-((8R,9S,13S,14S,15R,E)-17-(cyclopropylmethoxy)imino)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl[a]phenanthren-15-yl)propanamide 083 (485.35 mg) in a yield of 60%. MS m / z (ESI): 528.2 (M+1).

[0332] HPLC: 95.82% (214nm), 97.50% (254nm).

[0333] 1 H NMR (400MHz, CDCl3) δ7.27(s,1H),7.14(d,J=8.4Hz,1H),6.63(dd,J=8.4,2.6Hz,1H),6.58(d,J=2.6Hz,1H),3.91–3.81(m,2H),2.94–2.82(m,3H),2. 67–2.57(m,1H),2.48–2.26(m,4H),2.24–2.16(m,1H),2.10–1.98(m,3H),1 .74–1.41(m,6H),1.17–1.05(m,4H),0.57–0.49(m,2H),0.30–0.23(m,2H).

[0334] With reference to the similar conditions in the above examples, the compounds listed in Table 1 below were prepared, and their structural characterization data are shown in Table 1.

[0335] Table 1

[0336] Biological evaluation

[0337] Experimental Example 1. E1-induced T47D cell proliferation experiment

[0338] 1.1 Material Information

[0339] 1.1.1 Reagent Information

[0340] 1.1.2 Instrument Information

[0341] 1.2 Test methods

[0342] 1.2.1 Cell culture

[0343] T47D cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum and 0.2 U / mL bovine insulin in an incubator at 37°C and 5% CO2. When cells reached approximately 80% confluence, they were passaged. The medium was discarded, and an appropriate amount of PBS was added and gently shaken to cover adherent cells. The PBS was discarded. An appropriate amount of 0.25% trypsin-EDTA solution was then added and incubated at 37°C for approximately 2 minutes. When cells detached from the bottom of the culture flask, the digestion was terminated by adding an appropriate amount of complete RPMI-1640 medium. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000 rpm for 5 minutes to collect the cells. The supernatant was removed, resuspended, counted, and the appropriate number of cells was transferred to fresh culture medium. When the cell density reached the desired level, the cells were digested and the cell suspension was transferred to a sterile centrifuge tube. The cells were centrifuged at 1000 rpm for 5 minutes to collect the cells, and the supernatant was discarded. Cells were resuspended and counted in RPMI-1640 medium containing 5% charcoal-stripped fetal bovine serum and 10 ng / mL of steroid hormone. Cells were plated evenly at 2,000 cells per well in a 96-well plate in 100 μL of RPMI-1640 medium and incubated for 48 hours to remove excess hormones. The medium was then replaced with fresh RPMI-1640 medium containing 5% charcoal-stripped fetal bovine serum and 10 ng / mL of steroid hormone. Compounds were serially diluted threefold in DMSO and then diluted in medium before being added to the cells to a final working concentration of 3 μM. Three-fold dilutions were performed across nine concentration points in 0.1% DMSO. Estrone was supplemented as a stimulator at a working concentration of 0.02 nM in 0.1% DMSO. The cells were incubated at 37°C in a 5% CO2 incubator for seven days, with the medium replaced and compound treatment added on the third day. The plates were removed from the incubator and allowed to equilibrate to room temperature. 60 μL of cell viability assay reagent (CellCounting-Lite 2.0 Luminescent Cell Viability Assay) was added to each well, and the signal was read using a microplate reader (PHERAstar FSX, BMG) in luminescence mode. Data analysis, curve fitting, and reporting were performed using GraphPad.

[0344] 1.2.2 Data Analysis

[0345] The wells treated with E1 and DMSO served as negative controls (High controls); wells treated with DMSO alone served as positive controls (Low controls). Raw data were converted to inhibition using the formula: Inhibition % = (Ave_H - Sample) / (Ave_H - Ave_L) * 100. Compound IC50 values ​​were calculated using a four-parameter GraphPad analysis.

[0346] Wherein, Ave_H: High control average reading value, only the sample wells with E1 were used as negative control (High control); Ave_L: Low control average reading value, only the wells with DMSO were used as positive control (Low control). Sample: Sample reading value.

[0347] 1.3 Test results

[0348] The test results are shown in Table 2.

[0349] Table 2 IC50 values ​​of the compounds of the present invention in the 17β-HSD1 inhibitory activity test

[0350] Experimental Example 2.17 β-HSD1 enzyme inhibition experiment

[0351] 2.1 Material Information

[0352] 2.1.1 Reagent Information

[0353] 2.1.2 Instrument information

[0354] 2.2 Test methods

[0355] 2.2.1 Experimental steps

[0356] (1) Preparation of experimental buffer: 20 mM K2HPO4 / KH2PO4 aqueous solution containing 1 mM EDTA and 1 mM NADPH;

[0357] (2) Prepare 100× compound, 100× enzyme solution and 100× 13 C-labeled estrone solution;

[0358] (3) Take a 96-well flat-bottom plate and add 194 μL of buffer and 2 μL of 17β-HSD1 to each well; add 2 μL of 100× compound to each well and incubate at room temperature for 30 minutes;

[0359] (4) After the compound incubation, 2 μL of 100× estrone was added to each well;

[0360] (5) Incubate at 37°C for 2 hours;

[0361] (6) After the incubation, all samples were added to acetonitrile and shaken horizontally at 450 rpm for 15 minutes at room temperature;

[0362] (7) Centrifuge at 3900 rpm at 4°C for 20 minutes;

[0363] (8) Take 500 μL of supernatant and freeze at -80°C. LC-MS detection 13 Estradiol and 13 C estrone content

[0364] 2.2.2 Experimental data processing

[0365] (1) Conversion rate % = 13 Estradiol concentration / ( 13 C estrone concentration + 13 C estradiol concentration) × 100;

[0366] (2) Inhibition rate % = (1-sample conversion rate / conversion rate of the well without drug addition) × 100;

[0367] (3)IC 50 The inhibition rate and the corresponding concentration were fitted with four factors using Graphpad (Prism 10) to obtain the IC 50 value.

[0368] 2.2.3 Experimental Results

[0369] The experimental results are shown in Table 3.

[0370] Table 3 IC values ​​of the compounds of the present invention in the 17β-HSD1 inhibitory activity test 50 value

[0371] Test Example 3. Pharmacokinetics of the compounds of the present invention in rats

[0372] 3.1 Experimental Purpose

[0373] The pharmacokinetic behavior of the compound of the present invention in rats was studied to evaluate its pharmacokinetic characteristics.

[0374] 3.2 Experimental plan

[0375] 3.2.1 Experimental drugs

[0376] Example compounds of the present invention.

[0377] 3.2.2 Experimental animals

[0378] Healthy adult female SD rats.

[0379] 3.2.3 Drug preparation

[0380] An appropriate amount of sample was weighed and prepared into a 0.2 mg / mL suspension using a formula of 5% DMSO + 10% Solutol + 85% Saline by ultrasonication.

[0381] 3.2.4 Administration

[0382] Female SD rats were fasted overnight and then given the drug by gavage at a dose of 2 mg / kg.

[0383] 3.3 Operation

[0384] Before administration and at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration, 0.1 mL of blood was collected from heparinized tubes and centrifuged at 3500 rpm for 10 minutes. Plasma was separated and stored at -20°C. Four hours after administration, animals were allowed to resume food and free access to water. The levels of the test compound in rat plasma following oral administration were determined by LC / MS / MS.

[0385] 3.4 Experimental Results

[0386] The experimental results are shown in Table 4.

[0387] Table 4 Pharmacokinetic parameters of the compounds of the present invention

[0388] The above data show that the compounds of the present invention have good pharmacokinetic properties. Through structural optimization, the preferred compounds of the present invention have improved oral bioavailability and better drugability.

[0389] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A compound of formula I or its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt: in, Ring A is selected from C 3-14 Carbocyclic ring, 3-14 membered heterocyclic ring, C 6-14 Aromatic ring or 5-14 membered heteroaromatic ring; Each R a The same or different, independently selected from H, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -C(=O)-N(R a11 )(R a12 )、-N(R a13 )(R a14 ),-S(=O)2-R a15 、-C(=O)-R a16 、-C(=O)OR a17 、-P(=O)(R a18 )(R a19 ); or, two R attached to different carbon atoms a Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted R a1 Substituted by the following groups: 3-14 membered carbocyclic ring or 3-14 membered heterocyclic ring; each R a1 The same or different, independently selected from OH, CN, halogen, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl or -NH2; R a11 、R a12 、R a13 、R a14 、R a15 、R a16 、R a17 、R a18 、R a19 The same or different, independently selected from H, C 1-12 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; R1 is selected from OH, COOH, unsubstituted or optionally substituted by one, two or more R 1a Substituted with the following groups: C 1-12 Alkyl or C 1-12 Alkoxy; each R 1a the same or different, independently selected from OH or COOH; R2 is selected from H, halogen, nitro, cyano, -S(=O)2-C 1-12 Alkyl or -(CH2) p -N(R 21 )(R 22 ), where R 21 、R 22 The same or different, independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(=O)-R 23 、-C(=O)OR 24 ; p is selected from 1, 2, 3, 4, 5 or 6; R 23 、R 24 The same or different, independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; L is absent or selected from -O-, -OC 1-12 Alkylene- or -OC 1-12 Alkylene-O-; R3 is selected from H, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R 3a Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, 3-14 membered cyclic hydrocarbon, 3-14 membered heterocyclic group; each R 3a the same or different, independently selected from H, OH, CN, halogen, amino, oxo (=O), C 1-12 Alkyl, halogenated C 1-12 Alkyl, cyano C 1-12 Alkyl, hydroxy-C 1-12 Alkyl, C 1-12 Alkoxy, -C(O)-C 1-12 Alkyl or -S(O)2-C 1-12 alkyl; m is selected from 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1 or its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt, wherein: Ring A is selected from C 6-14 Aromatic ring or 5-14 membered heteroaromatic ring; Each R a The same or different, independently selected from H, OH, CN, halogen, C 1-12 Alkyl, halogenated C 1-12 Alkyl, cyano-C 1-12 Alkyl or hydroxy-C 1-12 Alkyl; or, two R attached to different carbon atoms a Together with the atoms to which they are attached, they form a 3-14 membered carbocyclic ring; R1 is selected from OH, COOH, unsubstituted or optionally substituted by one, two or more R 1a Substituted C 1-12 Alkyl or C 1-12 Alkoxy; each R 1a the same or different, independently selected from OH or COOH; R2 is selected from H, CN, nitro or -S(O)2-C 1-12 alkyl; L is absent or selected from -O-, -OC 1-12 Alkylene- or -OC 1-12 Alkylene-O-; R3 is selected from H, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R 3a Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, 3-14 membered cyclic hydrocarbon, 3-14 membered heterocyclic group; each R 3a the same or different, independently selected from H, OH, CN, halogen, amino, oxo (=O), C 1-12 Alkyl, halogenated C 1-12 Alkyl, cyano C 1-12 Alkyl, hydroxy-C 1-12 Alkyl, C 1-12 Alkoxy, -C(O)-C 1-12 Alkyl or -S(O)2-C 1-12 alkyl; m is selected from 0, 1, 2, 3, 4, and 5.

3. The compound according to claim 1 or 2, or its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt, wherein: Ring A is selected from C 3- 8-carbon ring, 3-8-membered heterocyclic ring, C 6-10 Aromatic ring or 5-10 membered heteroaromatic ring; Preferably, ring A is selected from C 3-8 Carbocyclic ring, 5-6 membered heterocyclic ring, benzene ring or 5-6 membered heteroaromatic ring; Preferably, ring A is selected from a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a piperidine ring, a piperazine ring, a pyrazole ring, an imidazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a thiadiazole ring, a pyridine ring, a dihydropyridine ring (such as a 1,2-dihydropyridine ring), a pyridazine ring, a pyrimidine ring, and a pyrazine ring; Preferably, ring A is selected from Preferably, ring A is selected from a 5-6 membered heteroaryl ring; Preferably, ring A is selected from a thiazole ring and a pyridazine ring; Preferably, ring A is selected from Preferably, each R a The same or different, independently selected from H, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -C(=O)-N(R a11 )(R a12 )、-N(R a13 )(R a14 ),-S(=O)2-R a15 、-C(=O)OR a17 ; or, two R attached to different carbon atoms a Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted R a1 Substituted by the following groups: 3-8 membered carbocyclic ring or 3-8 membered heterocyclic ring; each R a1 The same or different, independently selected from OH, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or -NH2; R a11 、R a12 、R a13 、R a14 、R a15 、R a17 The same or different, independently selected from H, C 1-6 alkyl; Preferably, each R a The same or different, independently selected from H, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one or two R a1 Substituted with the following groups: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, -C(=O)-N(R a11 )(R a12 )、-N(R a13 )(R a14 ),-S(=O)2-R a15 、-C(=O)OR a17 ; or, two R attached to different carbon atoms a Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted R a1 Substituted by the following groups: 5-6 membered carbocyclic ring or 5-6 membered heterocyclic ring; each R a1 The same or different, independently selected from OH, CN, halogen, C 1-3 Alkyl, C 1-3 Alkoxy; R a11 、R a12 、R a13 、R a14 、R a15 、R a17 The same or different, independently selected from H, C 1-3 alkyl; Preferably, each R a The same or different, independently selected from H, OH, CN, F, Cl, Br, oxo (=O), unsubstituted or optionally substituted by one or two R a1 Substituted from the following groups: methyl, ethyl, isopropyl, cyclopropyl, piperidinyl, morpholinyl, piperazinyl, -C(=O)-N(CH3)2, -S(=O)2-CH3, -C(=O)OCH3; or two R groups attached to different carbon atoms a Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted R a1 substituted 5-6 membered carbocyclic ring; each R a1 are the same or different and are independently selected from OH, CN, halogen, methyl or methoxy; Preferably, each R a The same or different, independently selected from H, OH, CN, halogen, C 1-6 Alkyl, halogenated C 1- 6-alkyl, cyano-C 1-6 Alkyl or hydroxy-C 1-6 Alkyl; or, two R attached to different carbon atoms a Together with the atoms to which they are attached, they form a 3-8 membered carbon ring; Preferably, each R a The same or different, independently selected from H, CN, halogen, C 1-3 Alkyl or halogenated C 1-3 Alkyl; or, two R attached to different carbon atoms a Together with the atoms to which they are attached, they form a 3-6 membered carbon ring; Preferably, each R a the same or different, independently selected from H, CN, F, Cl, Br, OH, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxymethyl, oxo (=O), cyclopropyl, mesyl, -CH2OCH3, -COOCH3, Alternatively, two R attached to different carbon atoms a Together with the atoms to which they are attached, they form a cyclopentene ring or a cyclohexene ring; Preferably, each R a The same or different, independently selected from H, CN, F, Cl, Br, methyl or trifluoromethyl; or, two R attached to different carbon atoms a Together with the atoms to which they are attached, they form a cyclopentene ring; Preferably, Selected from Preferably, Selected from 4. The compound according to any one of claims 1 to 3, or its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt, wherein: R1 is selected from OH, -COOH, -CH2OH or -CH2COOH; Preferably, R2 is selected from H, halogen, nitro, cyano, mesyl or -CH2-N(R 21 )(R 22 ), where R 21 、R 22 The same or different, independently selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl, -C(=O)-R 23 、-C(=O)OR 24 ; R 23 、R 24 The same or different, independently selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl or 5-6 membered heterocyclic group; Preferably, R2 is selected from H, F, Cl, nitro, cyano, mesyl, -CH2NH2, -CH2NHBoc, Preferably, R2 is selected from H, nitro, cyano or methylsulfonyl.

5. The compound according to any one of claims 1 to 4, or its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt, wherein: L is absent, or L is selected from -O-, -OC 1-6 Alkylene- or -OC 1-6 Alkylene-O-; Preferably, L is selected from -O-, -O-CH2-, -O-CH2CH2-, -O-CH2CH2CH2-, -O-CH2-O-, -O-CH2CH2-O- or -O-CH2CH2CH2-O-; Preferably, R3 is selected from H, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R 3a Substituted from the following groups: methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, tetrahydro-2H-pyranyl or tetrahydro-2H-thiopyranyl; Preferably, R3 is selected from H, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R 3a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; Preferably, R3 is selected from H, OH, CN, halogen, unsubstituted or optionally substituted by one, two or more R 3a Substituted from the following groups: methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydro-2H-pyranyl or tetrahydro-2H-thiopyranyl; Preferably, R3 is selected from H, OH, CN, F, Cl, Br, unsubstituted or optionally substituted with one, two or more R 3a Substituted groups: methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, Preferably, R3 is selected from H, OH, CN, F, Cl, Br, unsubstituted or optionally substituted with one, two or more R 3a Substituted groups: methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, Preferably, each R 3a the same or different, independently selected from H, OH, CN, halogen, amino, oxo (=O), C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano-C 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl or -S(O)2-C 1-6 alkyl; Preferably, each R 3a the same or different, independently selected from H, OH, CN, halogen, amino, oxo (=O), C 1-3 Alkyl, halogenated C 1-3 Alkyl, cyano-C 1-3 Alkyl, hydroxy-C 1-3 Alkyl, C 1-3 Alkoxy, -C(O)-C 1-3 Alkyl or -S(O)2-C 1-3 alkyl; Preferably, each R 3a are the same or different and are independently selected from H, OH, CN, F, Cl, Br, amino, oxo (=O), methyl, methoxy, acetyl or methylsulfonyl; Preferably, -L-R3 is selected from hydroxyl, cyano, Preferably, -L-R3 is selected from cyano, 6. The compound according to any one of claims 1 to 5, or its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt, wherein: The compound shown in Formula I has the structure shown below: Among them, ring A, R1, R2, R3, R a , L, and m have the definitions as described in any one of claims 1-5.

7. The compound according to any one of claims 1 to 6, or its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt, wherein: The compound shown in Formula I has the structure shown below: Among them, each R a The same or different, independently selected from halogen; preferably, R a Selected from Cl; m is selected from 1 or 2; preferably, m is 1; R1, R2, R3, and L have the meanings as defined in any one of claims 1 to 6.

8. The compound according to any one of claims 1 to 7, or its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt, wherein: The compound is selected from the following structures:

9. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1 to 8 and at least one of its racemates, stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts.

10. Use of the compound according to any one of claims 1 to 8 and at least one of its racemates, stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 9 in the preparation of a medicament; Preferably, the drug is a 17β-HSD1 inhibitor; Preferably, the medicament is for use in diagnosing, preventing and / or treating a disease or disorder mediated by 17β-HSD1.

11. A method for diagnosing, preventing and / or treating a disease or condition mediated by 17β-HSD1, said method comprising administering to a patient in need of such treatment an effective amount of at least one compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9, alone or, optionally, in combination with at least one other type of therapeutic agent.

12. The use according to claim 10 or the method according to claim 11, characterized in that The 17β-HSD1-mediated disease or condition is selected from endometriosis.

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